56

Predictors and Consequences of Severe Hypoglycemia 

in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

APPENDIX A. SEARCH STRATEGY

Database: Ovid MEDLINE(R)

Search Strategy:

--------------------------------------------------------------------------------

1 exp Hypoglycemia/ or hypoglycemia.mp. 

2 exp Diabetes Mellitus, Type 2/ or type 2 diabetes.mp. 

3 1 and 2 

4 limit 3 to (english language and humans) 

5 limit 4 to (addresses or bibliography or biography or dictionary or directory or duplicate 

publication or editorial or interview or introductory journal article or lectures or legal cases 

or legislation or letter or news or newspaper article or patient education handout or portraits 

or comment or historical article or interview or case reports) 

6 4 not 5 

7 limit 6 to “all child (0 to 18 years)” 

8 limit 6 to “all adult (19 plus years)” 

9 7 not 8 

10 6 not 9 

NOTE: an additional search was performed using the British spelling (hypoglycaemia) as a 

title/abstract word
57

Predictors and Consequences of Severe Hypoglycemia 

in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

APPENDIX B. Criteria Used in Quality Assessment of

Non-Randomized Studies

We evaluated each non-randomized trial based on the five elements below. To be considered 

low risk of bias for any element, a “yes” response was required for each of the questions (a, b, 

c) pertaining to the element, if applicable. Plots were developed to show the percent of the nonrandomized trials in each area (human resources practices, organizational culture, and physical 

environment) that were assigned a yes (met criteria) or no (failed to meet criteria) for each 

element.

1) Population

a. Is the sample representative of the population of interest?

b. Did researchers apply inclusion/exclusion criteria uniformly to all comparison groups 

and is the selection of the comparison group appropriate?

c. Is the sampling method appropriate (i.e., appropriate database or sample for research 

question, adequate response rate for survey studies, etc.)?

2) Outcomes

a. Are important outcomes assessed and reported (i.e., not just intermediate or surrogate 

outcomes)?

b. Was the length of follow-up appropriate for the research questions (consider benefits 

and harms)?

c. Is the impact of loss to follow-up (or differential loss to follow-up) considered in the 

analysis?

3) Measurement

a. Are outcome, predictor and covariates assessed in the same way for everyone? 

b. Is this blinded such that, for example, a person’s exposure status would not be known 

at the time outcome status was assessed? This is where recall bias and other types of 

differential assessment come into play. 

c. Are the tools used to assess exposures and outcomes accurate and reliable (i.e., are 

standard measures used)?

4) Confounding

a. Are the statistical methods and study design adequate for minimizing confounding?

b. Aside from the exposure of interest, are groups balanced in terms of factors that might 

bias the exposure and outcome association?

c. Are the appropriate confounding factors included in the analysis?

5) Intervention (if applicable)

a. Is the intervention clearly described and transferrable (i.e., could someone else repeat 

this study with different staff and patients and get similar results)?
58

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

R REVIEW COMMENTS/AUTHOR RESPONSES

RESPONSE

nd methods for this review clearly described? 

ethods are clearly articulated and relatively easy to follow. A couple minor 

 in the methods:

eate how each study defined severe hypoglycemia, I did not see the review 

ning “severe hypoglycemia” for the purposes of study selection – I got the 

ery inclusive and left the definitions up to each study, but this would be worth 

lso inferred from results that study had to essentially report incidence of 

, worth stating in methods. Also, what if the study did not explicitly define 

st presented incidences of glucose < 40 or < 60 or < 70? I assume these 

e there was no mention of symptoms/need for assistance? 

ing studies of duration < 6 mos? Severe hypoglycemia is not really a 

gh the consequences of it may be). In any case, this is probably a moot 

h, but may be worth more clearly defining rationale here. Also, the KQ1 

methods, but then is presented in flow diagram – this may be confusing for 

xtension” rationale and methods in the Methods section. 

c summ background paragraph states intensive control only associated with 

 the introduction in body of paper more properly states the broader impact of 

nclude UKPDS) on other microvascular outcomes. 

that seems to be missing from this is patient behaviors – certainly things 

edication mishandling etc would contribute to risk. I doubt these things are 

dies, but the lack of such evidence may still be important to know about. 

We moved the definition of severe hypoglycemia to the Methods section. We chose to exclude studies with fewer than 500 subjects and less than 26 weeks’ duration for feasibility; as it is we abstracted 60 studies for KQ1. As suggested, we included the rationale and methods for KQ1-extension in the Methods Section. We revised the executive summary background and the analytic framework as recommended.

tion requires a yes/no answer, neither is really correct. The review fails to 

oper context. There is considerable variation in the definitions applied in 

tion and controversy surrounding it is important background. In addition, 

 severe hypoglycemia was chosen, there is a serious limitation as far as 

hat is the incidence of clinically significant hypoglycemia? Their definition of 

“an episode with typical symptoms (e.g., sweating, dizziness, tremor, visual 

atment (oral carbohydrate, intramuscular glucagon, or intravenous glucose) 

here is clinically significant hypoglycemia that does not meet this definition. 

issue of hypoglycemia unawareness which can result in unrecognized and 

 of glucose <40 mg/dl. (Compare reported rates to those reported on CGMS)

We agree that there is clinically significant hypoglycemia that does not meet our definition and that asymptomatic low blood sugar (e.g., hypoglycemia unawareness) is not accounted for in this definition; however this is the definition that we chose based on its common use in the literature and that was approved by our TEP. We have acknowledged this point in our discussion.

s in our synthesis of the evidence? 

n of studies, from my perspective the report does not sufficiently emphasize 

d possible morbidity/mortality for patients who are treated in the control arms of 

data. For example, rates of potentially serious hypoglycemia in insulin treated 

arge HMO (Sarkar, 2010, Question 1). The association of serious hypoglycemia 

dard arms of ACCORD/VADT/ADVANCE. Although observation data is not of as 

of high rates and potential harms in the selected VA populations which are not 

d data. These issues are commented upon in section 4.

Although it was included in KQ3, we realized that Sarkar et al. 2010 should have been included in KQ1 ext and added it. Thank you.
59

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

RESPONSE

e needed to detect outcomes (i.e. severe hypoglycemia) that occur relatively 

many trials with 400-499 patients with T2DM that reported the incidence of 

se trials were part of the drug development program for the agent. What was 

500 patient cut-off? I am concerned that omitting these trials could introduce 

See previous page, first response.

stion requires a yes/no answer, neither is really correct. My concern the 

he use of the word “low” as in the following: “Overall incidence of severe 

majority of the 60 reviewed studies, particularly those of metformin (0-1.5%), 

ogs (< 1%), dipeptidyl-peptidase-4 (DPP-4) inhibitors (<1%), insulin detemir 

nides (0%) and thiazolidinediones (TZDs) (<1%). Annual rates of severe 

% for sulfonylureas and the following insulin preparations: neutral protamine 

nd glulisine.”

When up to 18% of patients on insulin report an episode of hypoglycemia 

 year, that doesn’t sound low. 

ation of additional studies “to gain a broader population-based perspective on 

emia.”

We agree that use of the term “low” to describe the frequency of severe hypoglycemia is a value judgment and we have either removed or modified that term in the final report.

published studies that we may have overlooked?

CL, Miller DR, Pogach LM. Risk of hypoglycemia in older veterans with 

 implications for practice and policy. J Am Geriatr Soc. 2011 Dec; 59(12):2263-

d hypoglycemia in Veterans with cognitive impairment or dementia 

Feinglos M, Goff DC Jr, Peterson K, Senior P; for the ACCORD Investigators. 

gnized Hypoglycemia on Mortality in the ACCORD Study. Diabetes Care.

Wang S, Getahun D, Zhang Q. Contribution of hypoglycemia to medical care 

ity in employees with diabetes. J Occup Environ Med. 2005 May; 47(5):447-

):409-414. Epub 2011 Dec 16.

We thank the reviewers for bringing these articles to our attention. Of these, 3 were published after November 2011 which is when our last literature search was performed (Bonds, Feil, Seaquist); 2 had been excluded due to the fact that severe hypoglycemia was not defined (Raz, Swinnen); one we had already included (Rhoads), one was a duplicate publication of a study already included (Miser); one was a study of a newer agent approved by the FDA after our study was initiated (Owens); two meet our criteria, were not previously reviewed and have been added to our final report in KQ1 (Nauck, Russell Jones).
60

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

RESPONSE

ugs (lispro, detemir, linagliptin, and liraglutide) and searched PubMed to see 

 I came across the following articles that were >500 patients, ≥ 6 months, 

oglycemia. It is not clear to me why these studies were excluded.

us fasting glycemia on cardiovascular outcomes in type 2 diabetes: the 

09 Mar;32(3):381-6. 

-label, parallel-group evaluations of basal-bolus therapy versus insulin lispro 

ype 2 diabetes mellitus failing to achieve control with starter insulin treatment 

mic drugs: a noninferiority intensification substudy of the DURABLE trial. Clin 

domized, treat-to-target trial comparing initiation of insulin glargine once-daily 

atients with type 2 diabetes inadequately controlled on oral glucose-lowering 

(6):1176-8.

ty of linagliptin in persons with type 2 diabetes inadequately controlled by a 

honylurea: a 24-week randomized study. Diabet Med. 2011 Nov;28(11):1352-

Effect and Action in Diabetes 5 (LEAD-5) met+SUStudy Group. Liraglutide vs 

bination with metformin and sulfonylurea therapy in type 2 diabetes mellitus 

ontrolled trial. Diabetologia. 2009 Oct;52(10):2046-55.

comparison of liraglutide, glimepiride, and placebo, all in combination with 

etes Care 2009; 32: 84-90.

See comment above.

hether or not long-term consequences of inpatient hypoglycemia are 

t, but there is a study looking at long-term outcomes in patients who had had 

AM, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper

cause mortality risk in diabetic patients with acute coronary events. Eur Heart 

This article was not included because it focused on inpatients.

RD should be included, notably the ACCORD-EYE study and the ACCORD

on of retinopathy and reduction of brain shrinkage with intensive control of 

4T study: Holman RR et al. NEJM 2009;361:1736-47

gas on associations of hypoglycemia with mortality risk, consider: Kosiborod 

d Boucai L et al. Am J Med 2011;124: 1028-35

We have reviewed all the articles mentioned, none of which met our criteria for inclusion (Kosiborod, ACCORD-EYE and ACCORD-MIND) or had already been included (4T Holman). Some of these, however, have been included in the discussion.
61

f Severe Hypoglycemia 

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RESPONSE

mments

 supports the following logic sequence that is relevant to VHA patient safety 

 thru in recommendations of the report.

 medications, most of which are industry funded and of shorter duration, 

n, even in insulin treated patients. 

VANCE studies were consistent in that while serious hypoglycemia was 

 the health impact was greater in the standard arm for cardiovascular 

NEJM 2010, Bonds DE BMJ 2010, Davis SJ (abstract, 2009), as well as with 

er et al BMJ 2010). The adjusted strength of association in the standard 

4.76); ADVANCE death from a cardiovascular cause (hazard ratio, 2.68; 95% 

shed, but the OR for recurrent severe hypoglycemia and mortality was 3.7. 

s et al (2012) found that prior episodes of serious hypoglycemia attenuated 

mia and mortality, it did not do so in the control arm. While it is not likely that 

resolved, the reviewer concludes that hypoglycemia is a strong risk factor 

 who are not “intensively treated”

glycemia are varied and differ across the studies, but include other medical 

athy, cognitive impairment, limited health literacy. Although causality of 

mes cannot be proven, the results from the 3 major trials would clearly 

or serious hypoglycemia can be identified.

sk of severe hypoglycemia in general practice, particularly for insulin 

 an HMO (Sarkar 2010) noted that 59% of patients on insulin reported 

year. The Budnitz 2010 study, which will be included after review, will 

urea remain high risk medications in the elderly. As noted, the Veteran 

e and cognitive impairment are two highly prevalent conditions associated 

tors, such as decreased health literacy, are also likely to be common in the 

 an article documenting an association with biochemical hypoglycemia 

dditionally, other studies (see section 2) indicate high rates of coded 

ed hypoglycemia on insulin, and in an insured population on insulin. The 

lusion of Key Question 1 may thus underestimate the rates in high risk 

th insured and Veteran populations.

Most of these excellent points have been included in our revised discussion.

written as insulin aspartame. Insulin aspartame is incorrect and should be 

part.

sing vildagliptin were included (p. 95, 130-131); however, this product is not 

apy) studies, 4/5 allowed the patient’s prior oral diabetes medications to be 

id not allow concomitant oral agents). Therefore, these 4 trials were not truly 

ted under A. Regular Insulin and Lispro Studies; Fast-short Acting. The 

/25 mix, which is an intermediate and fasting acting mixture so it should be 

ermediate and fast-acting mixture.

As suggested, we changed “aspartame” to “aspart”. Although vildagliptin is not FDA approved, it does appear in some of our tables because it was included in some of the studies that also used FDA approved agents.The Buse study is now listed under “C” on Table 3B, as suggested.
62

f Severe Hypoglycemia 

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RESPONSE

the statement “Overall incidence of severe hypoglycemia was low in the vast 

...”. Though this is true, it is somewhat misleading because the subsequent 

nto the issue of glucose targets enough. If the achieved HbA1c in 58/60 

rvention group, the low incidence of hypoglycemia in the vast majority of 

ch and it may suggest to readers that the bulk of evidence suggests that 

 I think the intensity of control really matters here and should be more clearly 

from results and tables how the glucose target and/or glucose achieved 

Consider also saying more about the intensive vs less intensive evidence 

xec summary. Also, it might be useful to include the glucose targets for each 

alysis results are interesting. Many clinicians consider using glargine to help 

PH. I know this is not the focus of this paper, but the finding that the two 

ycemia has potential clinical importance and you could consider highlighting 

d CI – I’m not sure I would say “risk is slightly higher” but not statistically 

y no significant difference. 

As suggested, we included an additional column in Table 1 (formerly Table 3) specifying the A1C targets and commented more extensively on the issue of intensive control in the executive summary, the summary statement, and the discussion. We amended the statement regarding NPH vs glargine to indicate that the risk was not different, as recommended.

lycemia from the Evidence Based Synthesis Program ESP of the V.A. The 

 evidence synthesis on clinical practice topics and develop clinical policies 

plementation of effective services to improve patient outcomes and set the 

at detail the data available on hypoglycemia in adults with type 2 diabetes. 

s a complete, well documented compilation of current information on severe 

esource for investigators in the area. It will also be of use in clinical care of 

sed in the study are appropriate and comprehensive. The study will be a 

hypoglycemia for future clinical studies and will be of use in defining future 

n its use by non-investigators in that the limitations of the various studies are 

accessible manner for the non-expert. 

oned throughout the document, but it would be much more useful to the 

ons defined and a summary to help to better evaluate the data. As a simple 

mining hypoglycemia in randomized control trials (RCTs) are obtained from 

ose is to establish non-inferiority of their agent against other agents in a 

s is mentioned in the document, but again that could be lost for someone 

e document. Another example is the use of superficially similar excellent 

pulations and for different reasons to come to a single conclusion. One of 

CCORD and ADVANCE trials, two of the best studies done on treatment of rected at different populations for different purposes. The ADVANCE study 

s with very few of the patients on insulin and low A1cs and ACCORD with a 

almost half of the patients on insulin and much higher A1cs at the initiation 

d higher hypoglycemic numbers and consequences of treatment that may 

 which were quite detrimental. (continued)

Thank you.We have summarized the limitations of the data in the executive summary and the discussion.
63

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

RESPONSE

r the reader could be addressed in an additional summary of the limitations udies. Another limitation of the current presentation is the difficulty in 

e. While mentioned in the study, the clinical results in terms of outcomes of 

es may not justify the risk of very intensive control and perhaps standards of 

e risk of complications of treatment more clearly in the guideline.

ents used for treatment of patients with type 2 diabetes, rarely if ever cause 

ual agents in patients without severe complications. The report clearly 

tformin, DPP-4 inhibitors, glinides, etc. Some of the insulins have not been 

r example detemir data are mostly derived from pharmaceutical studies 

f hypoglycemia. Other agents such NPH or glargine have much real world 

 For true risk of hypoglycemia with agents that do not typically cause 

include studies that use these agents in combination with the hypoglycemic 

give a better view of the risk in the usual use of these agents. 

ent in the manuscript, the most glaring of which is on page 4 under 

ce is somewhat confusing.

carefully done, and valuable document for dissemination to professionals in 

l be planning future studies. I highly endorse this document and believe that 

d outside the V.A. for other practitioners and scientists.
64

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

RESPONSE

mplications other than albuminuria have indeed been shown: see the 

M

re: glycated Hb is usually abbreviated as HbA1c, not HgbA1c.

ere insulin aspart is incorrectly referred to as ‘aspartame.’ Aspartame is 

nsulin analogue. If the computer search was done with ‘aspartame’ it is 

mia was found. It cannot be concluded that aspart does not cause severe 

other rapid acting insulin analogues in this way. An excellent report including 

art is: Holman RR et al. NEJM 2009;361:1736-47. Furthermore, the main 

RD trial was aspart, and in the intensive arm of this trial the incidence of 

e was greater than 3% yearly.

here, ‘data’ is a plural noun.

gliclazide excluded from analyses? The ADVANCE trial is one of the best 

m hypoglycemic risks, and it used gliclazlide. This drug is widely used 

oint is glossed over here. Studies were included if they reported severe 

ariations between studies in both definitions of severe events and (just as 

vents. This is the main limitation of this analysis.

orrectly spelled ‘Ramadam.’

ary statement reports annual incidence of severe events greater than 1% 

and sulfonylureas. Notably missing are aspart (a leading cause of severe 

lin (a leading cause of events in 4T and possibly the main cause of severe 

ular insulin (certainly a leading cause of events when used in sliding scales 

ical trials and therefore missing from this analysis). Somewhere the probably 

be discussed. 

 reads: “It is also possible that the robust recent findings that intense 

han two-fold increase in risk of severe hypoglycemia without any clear 

appropriate relaxation in HgbA1c goal levels by both clinicians and guideline 

 be amended in several ways. First, some guidelines are currently available 

he A1c goals is appropriate for some patients, but not others. These 

r balance to this speculation. Also, the statement that there are no “clear 

E and VADT, microalbuminuria was reduced. In ACCORD, microalbuminuria, 

ere all reduced. In the long-term followup of UKPDS, all-cause mortality was 

scular events.

1) We have re-worded the executive summary to reflect the benefits of tight control on a variety of microvascular complications2) All HgbA1C have been changed to HbA1C4) The verbs accompanying the noun “data” are now in the plural form5) As per our pre-determined methodology, gliclazide was not included since it is not an FDA approved medication6) Our discussion points out that definitions and ascertainment of hypoglycemic events varied between studies and ascertainment may have been incomplete7) We have corrected the spelling for Ramadan

ance measures, programs, quality improvement measures, patient care 

l be directly affected by this report? If so, please provide detail. 

 medication within VHA in the high alert medication group, with a final report 

e has been renewed discussion in OSC, PBM, and some VISNs about the 

gher risk for hypoglycemia in order to decrease potential over treatment and 

elehealth, post hospital discharge) for those with identified events.ervices (PBM) along with the Medical Advisory Panel and VISN Pharmacist 

rmining formulary status and guidance for use for pharmaceutical agents in 

 made aware of any policies that would result from this report.

nature of diabetes performance measurement.

ght be the design of prospective and structured collection of data to address 

ed by this review of heterogenous data.

We have included this point in our discussion.
65

f Severe Hypoglycemia 

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RESPONSE

dations on how this report can be revised to more directly address or 

er recommends that the report give greater prominence to concerns that 

ed risk factor for morbidity in and morality in “non-intensively treated subjects” 

DT with mean achieved A1cs of 7.5%-8.4%; rates based upon survey and 

ce of potential serious hypoglycemia up to 59%; and that risk factors for mong the Veteran population. 

efully done and generally confirm the findings of earlier efforts, including 

data. However, the important limitations of the methods necessarily used 

dpoint in question (hypoglycemia) is rarely the primary endpoint of 

it is not a secondary endpoint either, just an occasionally reported safety 

 meta-analytic methods cannot overcome this limitation of the data provided. 

me of the therapeutic agents commonly used have been included in the 

his analysis. Hence, data are not available for drugs of interest. Regular 

use of hypoglycemia but its relative importance cannot be assessed using 

nificant risk of severe hypoglycemia also cannot be addressed by 

sons: the sulfonylurea glyburide, and all forms of premixed insulin. 

evidence available, few firm conclusions are possible. Rather, most of the 

ating. Hence, a leading conclusion from this report should be that collection 

VA data-handling system, would be very helpful.

We have included most of these points and limitations in our discussion. 
66

Predictors and Consequences of Severe Hypoglycemia 

in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

APPENDIX D. Study Quality Tables

Table 1. Individual Study Quality for KQ1, Randomized Studies

Study Allocation

concealment Blinding Intention-totreat analyses

Withdrawals 

adequately 

described

Quality

Abraira (VA-CSDM)

199530 Unclear

Outcomes/

endpoints No Yes Fair

ACCORD 2008, 

20113, 7 Adequate

Outcomes/

endpoints Yes Yes Good

ADVANCE 20084 Adequate

Outcomes/

endpoints Yes Yes Good

Anderson 199747 Unclear No Yes No Fair

Arechaveleta 201152 Unclear Yes (double) Yes Yes Fair

Aschner 2006136 Unclear Yes (double) Yes Yes Fair

Aschner 201060 Unclear Yes (double)* No Yes Fair

BARI 2D58 Unclear

Outcomes/

endpoints Yes Yes Fair

Barnett 2008171 Adequate No Yes Yes Fair

Bolli 2008 and 

2009172, 173 Unclear Yes (double) Yes Yes Fair

Buse 2009, 201136, 110 Adequate

Outcomes/

endpoints Yes Yes Good

Chou 200855 Unclear Yes (double) No Yes Fair

Dailey 200446 Unclear No Yes Yes Fair

Davies 200538 Unclear No No Yes Fair

Dormandy 

(PROactive) 2005174 Adequate Yes (double)* Yes Yes Good

Drouin 200432 Unclear Yes (double) No Yes Fair

Duckworth (VA-DT)

20095 Adequate

Outcomes/

endpoints* Yes Yes Good

Fritsche 200344 Adequate No

No (2 

excluded) Yes Fair

Garber 201151 Adequate Yes (double)

No (1 

excluded) Yes Good

Haak 200533 Adequate No Yes Yes Fair

Heine 200542 Adequate No No Yes Fair

Holman 2009, 

200743, 111 Adequate

Outcomes/

endpoints

No (1 

excluded) Yes Good

Kendall 200556 Unclear Yes (double)

No (1 

excluded) Yes Fair

Kennedy 200637 Adequate No No Yes Fair

Liebl 2009 PREFER48 Unclear No No Yes Fair

Marre 2009175 Unclear Yes (double)

No (1 

excluded) Yes Fair

Matthews 201049 Unclear Yes (double) No Yes Fair

Meneghini 

PREDICTIVE 2007176 Unclear No No Yes Fair

Nauck 2009177 Adequate Yes (double)

No (2 

excluded) Yes Good

Olansky 2011178 Unclear Yes (double) No Yes Fair

Pratley 2010179 Adequate

Outcomes/

endpoints

No (7 

excluded) Yes Good

Raskin 200931 Unclear No Yes Yes Fair

Ratner 200234 Unclear Yes (double) No Yes Fair

Rayman 200745 Unclear No No Yes Fair
67

Predictors and Consequences of Severe Hypoglycemia 

in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

Study Allocation

concealment Blinding Intention-totreat analyses

Withdrawals 

adequately 

described

Quality

Riddle 2003, Dailey 

200941, 132 Adequate

Outcomes/

endpoints No Yes Fair

Rosenstock 200139 Unclear No Yes Yes Fair

Rosenstock 200840 Adequate No, open-label No Yes Fair

Rosenstock 200935 Unclear No No Yes Fair

Russell-Jones 200954 Adequate

Double*(insulin arm 

open-label) No Yes Good

Saloranta 200259 Unclear Yes (double) Unclear No Fair

Schernthaner 200457 Unclear Yes (double) No Yes Fair

Seck, 2010, Nauck 

200750, 177 Unclear Yes (double) No Yes Fair

Standl 2006180 Unclear No No Yes Fair

UKPDS 3321 Adequate Unclear Yes No Good

Williams-Herman 

2009, Goldstein 

2007113, 181 Unclear Yes (double)* No Partially Fair

Zinman 2009182 Adequate Yes (double)

No (3 

excluded) Yes Good

*plus end points adjudicated by blinded committee

Table 2. Individual Study Quality for KQ1, Non-Randomized Studies

Study Design Population of 

interest

Outcomes

assessed and 

reported

Measurement

same for all

subjects

Confounding

controlled

Asche 200823 Retrospective cohort Yes Yes Yes Yes

Berntorp 201115 Prospective cohort Yes Yes Yes No

Bodmer 200824

Retrospective cohort 

with nested case/

control

Yes Yes Yes Yes

Davis 201016 Prospective cohort Partially* No Yes Yes

Holstein 200117 Prospective cohort Yes Yes Yes Yes

Leese 200325 Retrospective cohort Yes Yes Yes No

Marre 2009 

(PREDICTIVE)18 Prospective cohort Partially* Yes Yes No

Murata 200519 Prospective cohort Yes Yes Yes No

Nichols 201026 Retrospective cohort Yes Yes Yes No

Pencek 200920 Prospective cohort Yes Yes Yes No

Quilliam 2011183 Retrospective cohort Yes Yes Yes Yes

Stahl 199928 Retrospective case 

series No Yes Yes Yes

UK Hypoglycaemia 

Study Group21 Prospective cohort Yes Yes No No

Valensi 2009

IMPROVE22 Prospective cohort Yes Yes Yes Yes

*Included diabetes type 1
68

Predictors and Consequences of Severe Hypoglycemia 

in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

Table 3. Individual Study Quality for KQ2, Randomized and Non-Randomized Studies

RANDOMIZED CONTROLLED TRIALS

Study Allocation

concealment Blinding Intention-totreat analyses

Withdrawals 

adequately 

described

Quality

ACCORD Miller 

201089 Adequate

Outcomes/

endpoints Yes Yes Good

ADVANCE 

Zoungas 201090 Adequate

Outcomes/

endpoints Yes Yes Good

NON-RANDOMIZED TRIALS

Study Design Population of 

interest

Outcomes

assessed and 

reported

Measurement

same for all

subjects

Confounding

controlled

Akram 200684

Cross-sectional 

survey No Yes No Yes

Bruce 200992

Prospective 

cohort No No No No

Davis 201016

Prospective 

cohort Partially* No Yes Yes

Davis 201193

Prospective 

cohort Partially* Yes No Yes

Duran-Nah 2008104 Case-control No Yes Yes Yes

Holstein 2009102 Case-control No Yes Yes Yes

Holstein 2011103 Case-control No Yes Yes Yes

Miller 2001100 Cross-sectional Yes Yes Yes Yes

Quilliam 201127

Nested Casecontrol Yes No Yes Yes

Sarkar 201078 Cross-sectional Yes Yes No Yes

Shen 2008101 Cross-sectional Yes Yes Yes Yes

Shorr 199797

Retrospective 

cohort Yes Yes Yes Yes

*Included diabetes type 1
69

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

vidence Tables

luded Studies

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Men ages 40-69, with non-insulin dependent diabetes who were being treated with insulin or judged clinically to require insulin because of failure of other therapyExclusion criteria:Serious illness or predicted poor compliance, diagnosed >15 years prior

N=153Age: 60.2 years% male: 100Race/ethnicity: White=49.5Black=24Other=3BMI: 31.0Duration of diabetes: 7.8 yearsHistory of MI: 13.7%History of CHF: 2.0%History of CVA: 6.5%Current smoker: 15%

Intensive group: stepped regimen of insulin goal of HbA1c =5.1+/-1%Standard group: one or two injections of insulin/dayGoal was to avoid diabetic symptoms, excessive glycosuria, or overt hypoglycemia

Impaired consciousness requiring the help of another person, or coma, or seizure; confirmed low blood glucose concentration or rapid response to treatments expected to raise the level of blood glucose also required

Allocation Concealment: YesBlinding: YesIntention-to-Treat Analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:type 2 diabetes and HbA1c ≥7.5%; either 40-79 years old with CV disease or 55-79 years old with significant atherosclerosis, albuminuria, LVH, or at least 2 additional risk factors for CV diseaseExclusion criteria:Frequent or recent serious hypoglycemic events, unwillingness to do home glucose monitoring or inject insulin, BMI > 45, Cr > 1.5 mg/dL or other serious illness

N=10,251Age: 62.2 years% male: 61.5Race/Ethnicity (%):White=64.5Black=19.0Hispanic=7.2BMI: 32.2Duration of Diabetes: 10 yearsHbA1c: 8.3% (median)

Intensive group:Targeted an HbA1c below 6.0%Standard group: Targeted an HbA1c from 7.0% to 7.9%

Requiring medical assistanceRequiring any assistance

Allocation Concealment: YesBlinding: Outcomes assessment (endpoints)Intention-to-Treat Analysis (ITT): Yes Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Diagnosis of type 2 diabetes at 30 years or older, an age of at least 55 years at the time of study entry, and a history of major macrovascular or microvascular disease or at least one other risk factor for vascular disease Exclusion criteria:Definite indication for, or contraindication to, any of the study treatments or a definite indication for long-term insulin therapy at the time of study entry

N=11,140 Age: 66 years % male: 57.5 Weight (lbs): 171.6BMI: 28Type 2 (%): 100Duration of diabetes: 8.0 yearsHbA1c: 7.5%Aspirin: 44%

Intensive glucose control:defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycosylated Hgb value of 6.5% or less. Standard glucose control:(with target glycosylated Hgb level defined on the basis of local guidelines

Blood glucose < 2.8 mmol/L or the presence of typical symptoms and signs of hypoglycemia without other apparent cause.Severe: transient dysfunction of the CNS unable to treat themselves (i.e. requiring assistance from another person)

Allocation Concealment: Yes Blinding: Outcomes assessment (endpoints)Intention to Treat Analysis (ITT): Yes Withdrawals/dropouts adequately described: Yes 
70

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes treated for at least one year with diet or oral glucose-lowering agents before commencement of insulin therapy. Exclusion criteria:Patients treated with sulfonylureas, ESRD, malignant disease, pregnancy, inability to complete questionnaire

N=401Age: 66 years% male: 58BMI: 29 Duration of diabetes: 15 yearsInsulin duration: 7 yearsHbA1c: 8.3% Impaired hypoglycemic awareness: 46%

N/A Need for 3rd party 

assistance

Population: NoOutcomes: YesMeasurement: NoConfounding: YesIntervention: N/A

Inclusion criteria:Type 2 diabetes, age > 30 whose physicians added a SU or a TZD to metformin monotherapy between Jan 2001 and Jan 2006 and who had at least one HbA1c measure in the 12-month period before the visit dateExclusion criteria:Type 1 diabetes; pregnant women, including those with gestational diabetes; patients with diabetes secondary to other factors and patients who could not complete the questionnaire or were participating in another clinical study

N=1709Age: 62.9 years% male: 54.9BMI: 31.7Duration of diabetes: 7.8 yearsHbA1c: 7.1%Microvascular complications: 2.2Macrovascular complications: 26.4

N/ATarget HbA1c ≤ 6.5%

Needing the assistance of others to manage symptoms or needing medical attention

Population: NoOutcomes: NoMeasurement: YesConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes, age > 30; physician added a SU or a TZD to metformin monotherapy Jan 2001 to Jan 2006 and who had at least one HbA1c measure in the 12-month period before the visit dateExclusion criteria:Type 1 diabetes; pregnant women, including those with gestational diabetes; patients with diabetes secondary to other factors and patients who could not complete the questionnaire or were participating in another clinical study

N=1709Age: 63 years% male: 55BMI: 31.7Duration of diabetes: 7.84Microvascular events: 2.2%Cardiovascular events: 26.4%HbA1c: 7.1%

N/ATarget HbA1c ≤ 6.5%

Needing the assistance of others to manage symptoms or needing medical attention

Population: NoOutcomes: NoMeasurement: YesConfounding: NoIntervention: N/A
71

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes, ages 35-85, on insulin for at least 2 months Exclusion criteria:Other severe disease, use of beta blockers or glucocorticoids, use of insulin infusion device, severe hypoglycemia unawareness, insulin dose > 2.0U/kg or BMI > 35

N=722Age: 59 years% male: 54BMI: 28Duration of Diabetes: 12.4 yearsDuration of insulin: 6.0 yearsHbA1c: 8.9%

Intervention: Insulin lisproControl: regular insulin 

Episode requiring glucagon or IV glucose

Allocation Concealment: UnclearBlinding: NoIntention-to-Treat Analysis (ITT): YesWithdrawals/dropouts adequately described: No

Inclusion criteria:Patients ≥18 years of age, with type 2 diabetes and with inadequate glycemic control (defined as HbA1c ≥ 6.5% and ≤9.0%) while on metformin as well as diet and exercise for at least 12 weeks prior to the screening visit Exclusion criteria:History of type 1 diabetes, used any OHA besides metformin within 12 weeks of the screening visit, had renal function impairment prohibiting the use of metformin or had a fasting finger stick glucose of <6.1 or >13.3 mmol/l at randomization

N=1035Age: 54.9 years% male: 54.4Race/Ethnicity (%):White=57.5Asian=21.3Multiracial=14.9Other=5.2Black or AA=1.2Weight (lbs): 178.9BMI: 30Duration of diabetes: 6.8HbA1c: 7.5%

Sitagliptin + metformin (n=516)Glimepiride + metformin (n=519)

Requiring non-medical assistance of others, and those requiring medical intervention or exhibiting markedly depressed level of consciousness or seizure

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Patients with type 2 diabetes age >65 treated with metformin, SUs or TZDs (never having been on any of these meds before)

N=5438 SU: 58/2223 (2.6%)

SU without insulin: 55/2117 (2.6%)SU with insulin: 3/106 (2.8%)metformin: 0TZD: 20/889 (2.2%):TZD w/o insulin: 12/702 (1.7%)TZD w/ insulin: 8/187 (4.3%)

Drug-related AE defined as being coded in the database (i.e., a visit to a provider) for hypoglycemia in people who had NOT had a similar drug-related AE PRIOR to the initiation of the metformin, SU or TZD

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A
72

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:18-75 years old; compliant during run-inExclusion criteria:Unstable cardiac disease, significant renal impairment, elevated AST, ALT, or CK

N=741Duration of diabetes: 4.4 years HbA1c: 8%

Sitagliptin monotherapy:100 mg qdSitagliptin monotherapy: 200 mg qdPlacebo: qd

Loss of consciousness or requirement for medical assistance

Allocation concealment: unclearBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria: Type 2 diabetes, 18-78 years old had not been on any antihyperglycemic medications for at least 16 weeks with HbA1c between 6.5% and 9.0%

N=894Age: 56 years% males: 46BMI: 30.8Duration of Diabetes: 2.4 yearsHbA1c: 7.2%

Sitagliptin 100mg qd (528)Metformin 1000 mg bid (522)

Required medical assistance

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Cases 19 patients with hypoglycemia (fatal or otherwise serious, unexpected, or remarkable) in patients treated with glipizide 1980-87Controls patients on glipizide from local health care centers, matched on gender and birth date

N=19 casesAge: 75 years% male: 42 Duration of diabetes (before event): 3 years (median)

N/A Fatal or otherwise 

serious, unexpected, or remarkable

Population: NoOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes and CAD, candidates for elective PCI or CABG.Exclusion criteria:Required immediate re-vascularization, had left main disease, Cr > 2, HbA1c > 13%, class 3 or 4 CHF, hepatic dysfunction, PCI or CABG within 12 months

N=2368 Age: 62.4 years% male: 70BMI: 32Type 2 (%): 100Diabetes duration: 10.4 yearsCurrently on insulin: 28% Baseline HbA1c: 7.7%Smoking in previous year: 22%ACE inhibitor: 77% Antithrombotic agent: 88% Beta blocker: 73%

Revascularization vs. medical therapy for CAD and insulin sensitive therapy vs. insulin therapy

Target HbA1c < 7.0%

Requiring assistancewith treatment and either a blood glucose level of <50 mg per deciliter or confusion, irrational or uncontrollable behavior, convulsions, or coma reversed by treatment that raises blood glucose levels

Allocation concealment: UnclearBlinding: Outcomes assessment (endpoints)Intention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes 
73

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Patients with type 2 diabetes, age 40-80 years old, on OHAs with HbA1c between 7% and 10%

N=610Age: 56 years% male: 50Weight: 251.7 lbsBMI: 30.4Duration of diabetes: 2.8 years

Self-monitored blood glucose(SMBG) No SMBG 

Required 3d party assistance (grade 3) or required medical assistance (grade 4)

Allocation concealment: AdequateBlinding: NoIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Adult; nonalcoholic; nonepileptic; age 17 and older, type 2 or type 1 diabetes

N=102Age (median): 72 years% male: 40Type 2: 92%Duration of diabetes (median): 10 years

N/A All patients had druginduced hypoglycemic 

coma

Population: NoOutcomes: YesMeasurement: NoConfounding: N/AIntervention: N/A

Inclusion criteria:Patients with at least one prescription for a SU, biguanide, TZD, acarbose, or prandial glucose regulator; with or without insulin use; ages 30-79

N=1154Age: 65 years% male: 60BMI: 29.4Duration of Diabetes: 8.1 yearsHbA1c: 8.8%

N/A Event w/ severe CNS 

symptoms consistent with hypoglycemia in which subject was unable to treat himself/herself and either plasma glucose <3.1 mmol/L or reversal of symptoms upon glucagon/glucose administration 

Population: YesOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:At least one prescription for a SU, biguanide, TZD, acarbose, or prandial glucose regulator; with or without insulin use; ages 30-79Exclusion criteria:Type 1 diabetes, pts with <3years data in the database before prescreen of first diabetes drug, pts with h/o ETOH, cancer, and gestational diabetes 

N=50,048Age: 60.7 years% male: 45Case subjects: 2025 w/ recorded hypoglycemia; 73 “severe”

N/A Mild/moderate: treated 

by the GPSevere: hospitalized or died

Population: YesOutcomes: YesMeasurement: NoConfounding: YesIntervention: N/A
74

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria: Type 2 diabetes with HbA1c of 7.5% to 11.0% on a stable dose of metformin >1500 mg/day. Age 18-77, BMI 22-45, FPG < 15mmolExclusion criteria:History of type 1 or secondary forms of diabetes; acute metabolic diabetic complications; myocardial infarction, unstable angina or coronary artery bypass surgery within the previous 6 months; CHF or liver disease

N=576 Age: 57 years% male: 63 Race/ Ethnicity (%):White=82Hispanic=9Asian=4Black=3Other=2Weight (lbs): 200.2BMI: 32Type 2 (%): 100Duration of diabetes: 6.4 yearsBaseline HbA1c: 8.4%

Vildagliptin 50 mg bidPioglitazone 30 mg qdIn patients on a stable metformin dose

Any episode requiring the assistance of another party

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes 

Inclusion criteria:302 of the 587 survivors age > 70 agreed to cognitive assessment in 2001; of the 246/302 who were NOT demented in 2001, 205 agreed to second assessment 18 months later

N=205Age: 76 yearsType 2 (%): 99 On insulin: 28% On SU: 45%Severe hypoglycemia: 7.2% HbA1c<7: 46%

N/A Episodes requiring 

second party assistance

Population: NoOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Insulin naïve, 30-80 years old, HbA1c>7% on at least 2 OHAs for 90 daysExclusion criteria:History of scheduled long term insulin use; recent use of other OHAs, BMI>45, recent history of severe hypoglycemia; significant hematology, oncology, renal, cardiac, hepatic, or GI disease; steroid use, pregnant or nursing

N=2091Age: 57 years% male: 53 Race/Ethnicity (%)White=63Asian=15 Hispanic=12 Black=6Other=3Weight (lbs): 195.8BMI: 32Type 2 (%):100Duration of diabetes: 9.5 yearsHbA1c: 9.1%

Lispro mix (75/25) Glargine Added to patient’s current OHA therapy which had to be maintained at current dosesTarget HbA1c<6.5%

Requiring assistance from another person for treatment with oral carbohydrate, intravenous glucose, or glucagon

Allocation concealment: YesBlinding: NoIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes Withdrawals (by group): Yes
75

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Men and women, ages 18 to 75, type 2 diabetes, HbA1c of 7.5-12.0%, fasting C-peptide ≥ 0.8 ng/ml, FPG ≥126 mg/dl, treated with diet and/or exercise alone or who had not taken oral anti-diabetic medication or insulin for >15 days in preceding 4 monthsExclusion criteria: History of severe hypoglycemia, severe edema or prior history of severe edema, prior history of hepatocellular reaction, clinically significant hepatic or renal disease, unstable or severe angina or CHF requiring pharmacological treatment, anemia, uncontrolled HTN (systolic >170 mmHg or diastolic >100 mmHg on therapy)

N=901Age: 54.0 years% male: 58.8Race/Ethnicity (%):White=77.3Hispanic/Latino=9.4Asian=7.8Black=4.8Other=0.7Weight (lbs): 199.1BMI: 31.6Type 2 (%): 100Duration of diabetes (median): 1.5 yearsBaseline HbA1c: 9.1%

1) Glimepiride (GLIM) monotherapy (1 mg OD titrated to max of 4 mg OD); n=2252) Rosiglitazone (RSG) monotherapy (4 mg OD titrated to max of 8 mg OD); n=2323) RSG/GLIM regimen A (4 mg/1 mg titrated to max of 4 mg/4 mg OD); n=2254) RSG/GLIM regimen B (4 mg/1 mg titrated to max of 8 mg/4 mg); n=219Target HbA1c: documented ≤6.5% and <7.0%

Not defined; reported results for patients with hypoglycemia receiving external assistance

Allocation concealment: UnclearBlinding: Yes Intention to treat analysis (ITT): No (1 dose required)Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Age 18 or older, multiple diagnostic claims for type 2 diabetes, converted to BIAsp 70/30 pen for the first time; previously treated with insulin administered by syringe; data for 6 months before conversion and at least 2 years after

N=496Age: 45.1 years% male: 56.4 

N/A Requiring emergency 

department visits or hospitalizations

Population: Yes Outcomes: YesMeasurement: YesConfounding: YesIntervention: Yes
76

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Established type 2 diabetes, age ≥ 18 years who had been on insulin therapy for ≥ 6 months before study with HbA1c 6-11%. Exclusion criteria:Clinically significant hepatic disease, renal impairment, a history of lactic acidosis, unstable or severe angina, known congestive heart failure (CHF, New York Heart Association class I, II, III, or IV), or uncontrolled hypertension

Age: 58.3 years% male: 52.9Race/Ethnicity (%): Caucasian=85.4Black=11.3Asian=1.9Multiracial=1.4Hispanic Origin=6.8%BMI: 34.6Type 2 (%):100Duration of diabetes: 14.0 yearsHbA1c: 7.6%

Intervention:Glulisine subcutaneous injections 0-15 before breakfast and dinner (n=435)Comparator:RHI/NPH subcutaneous injections 30-45 before breakfast and dinner (n=441)

Severe hypoglycemia: symptomatic requiring assistance from another person and BG < 36 mg/dl or associated with prompt recovery following oral carbohydrate, IV glucose or glucagon

Allocation Concealment: Unclear Blinding: No (openlabel)Intention to Treat Analysis (ITT): YesWithdrawals/Dropouts adequately described: Yes

Inclusion criteria:Type 2 diabetes sub-optimally controlled; age ≥ 18; on any OHA or insulin for > 6 months, requiring in the opinion of local MD basal long acting insulin, HbA1c > 7% and < 12%; BMI < 40Exclusion criteria:Impaired renal function, acute or chronic metabolic acidosis; active liver disease or elevated ALT or AST; h/o hypoglycemic unawareness; diabetic retinopathy w/ recent surgery or planned surgery within 3 months; pregnancy

N=4961Age: 58% male: 49BMI: 29Type 2 (%): 100Duration of diabetes: 12.3 yearsDuration of insulin use: 5.1 years

Algorithm 1: titration at every visit; managed by MD. Glargine 10 IU qhs (N=2529)Algorithm 2: titration every 3 days managed by patient (N=2504)in insulin naïve ptsGlargine at a dose = to highest value of FBG in MMol over previous 7 days 

Requiring assistance from another person and BG < 50 mg/dl

Allocation concealment: UnclearBlinding: No Intention to treat analysis (ITT): PartiallyWithdrawals/dropouts adequately described: Yes 

Inclusion criteria: Patients with known type 1 or type 2 diabetes N=3200

Response rate: 861/3200 (27%)% male: 55Type 2 (%): 69

N/A Help from other person 

required 

Population: NoOutcomes: NoMeasurement: NoConfounding: YesIntervention: N/A
77

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:All patients with type 2 diabetes

N=616Age: 67 years% male: 52.3 BMI: 28Type 2 (%): 100Duration of Diabetes: 7.7 years (median)HbA1c (%): Median=7.2%

Target HbA1c: N/A Requiring ambulance 

attendance,emergency department services, and/or hospitalization

Population: NoOutcomes: NoMeasurement: YesConfounding: NoIntervention: N/A

Inclusion criteria:All patients with type 2 diabetes in the Fremantle Hospital primary catchment 

N=602Age: 67.1 years% male: 52Duration of diabetes: 7.7 years (median)HbA1c: 7.2%

N/A Patient with a 

subnormal blood/plasma/serum glucose required documented health service use (ambulance, emergency department, or hospitalization)

Population: NoOutcomes: YesMeasurement: NoConfounding: YesIntervention: N/A
78

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Adults (aged 35–75 yr, inclusive); type 2 diabetes; history of macrovascular disease; current use of pioglitazone or other thiazolidinediones and insulin Exclusion criteria: Monotherapy for 2 wk or longer at any time in the previous 3 months 

N=5238Age: 61.7 years % male: 66.1 Race/Ethnicity (%): White=98.6BMI: 30.9Type 2 (%): 100Duration of diabetes: 9.5 yearsBaseline HbA1c: 8.1%Smoking:Current: 13.8%Past: 45%

Pioglitazone titrated from 15-45 Placebo Charbonel SGA an analysis of those in each randomized group who were receiving insulin at baseline*with insulin at baselinePioglitazone (n=864) 45 U/dayPlacebo (n=896)*w/o insulin at baselinePioglitazone 45 U/dayPlacebo 

Resulting in hospital admission

Allocation concealment: YesBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Type 2 diabetes for at least 6 months, > 35 years old, BMI 22-35 treated for at least 3 months with diet with or without an OHA agent; HbA1c of 7.8% to 13.9% after washout from any previous OHA

N=507Age: 61.5 years% male: 54BMI: 28.5Duration of diabetes: 6.5 yearsHbA1c: 8.14%

Diamicron (gliclazide) n=399Diamicron MR (gliclazide modified release) n=401

Grade 3: required external assistanceGrade 4: required medical assistance

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes
79

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Male and female veterans; ≥ 41 years old; nonresponsive to a maximum dose of at least one oral agent and/or daily insulin injections (centrally measured HbA1c level > 4 SD above normal mean (i.e., ≥ 7.5%) or else local HbA1c ≥ 8.3%)

N=1791Age: 60.4 years% male: 97Race/Ethnicity (%):White=62 Hispanic white=16.2Black=16.7Other=5Weight (lbs): 214BMI: 31.3Type 2 (%): 100Duration of diabetes: 11.5 yearsHbA1c: 9.4%Insulin: 52%Current smoker: 16%

IntensiveGoal of absolute reduction of 1.5% in the HbA1c compared to standard Rx (N=892)Standard regimenOne-half the max dose of intensive regimen (N=899)

Life threatening, death, hospitalization, disability or incapacity or other event requiring medical intervention/treatment

Allocation Concealment: YesBlinding: NoIntention-to-Treat Analysis (ITT): YesWithdrawals/dropouts adequately described: Yes 

Inclusion criteria:Cases: consecutive patients with type 2 diabetes ≥ 30 years old, presenting to ER and hospitalized for symptomatic hypoglycemia, had to be on a diabetes medication.Controls: type 2 diabetes patients admitted for other problems

N=282% male: 38Age: 59 yearsDuration of diabetes: 13.7 years

N/A ≤ 72 mg/dL glucose 

concentration, with a neurological clinical picture consistent with a severely confused mental state or worse, non-arousable

Population: NoOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A

Inclusion criteria:Patients type 2 diabetes presenting to ER with one of the relevant ICD9 codesExclusion criteria:Patients with type 1 diabetes, secondary diabetes, other potential cause of coma

N=192(126 cases included)Age: 77 years % male: 44

N/A Led to hospitalization Population: No

Outcomes: YesMeasurement: YesConfounding: NoIntervention: N/A
80

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes, <75 years old, BMI <35, previous oral therapy with any sulfonylurea or combination, FBG≥120 mg/dl, HbA1c 7.5-10.5% Exclusion criteria: Pregnancy, breast feeding, insulin or other investigational drugs in previous 3 months, clinically relevant somatic or mental diseases

N=468Age: 61 years% male: 53.7Duration of diabetes: 8.8 yearsWeight (lbs): 178.9BMI: 28.7HbA1c: 9.1%

Bedtime NPH, Bedtime glargine, Morning glargineAll groups on 3 mg gllmepiride throughout studyBaseline insulin doses based on FBG; titrated at every visitTarget HbA1c ≤7.5%

Symptoms consistent with hypoglycemia that require assistance of another person, associated with blood glucose <50 mg/dL, and followed by prompt recovery with carbohydrate, IV glucose, or glucagon

Allocation concealment: YesBlinding: NoIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Type 2 diabetes, age 18-80, BMI<45, had received diet or OHA therapy (up to half of the highest dose) for at least 2 months, HbA1c between 7% and 11% (diet) or between 7% and 10% if on OHAExclusion criteria:Insulin treatment during previous 3 months, treatment with systemic corticosteriods, hypoglycemia unawareness or recurrent severe hypoglycemia, and impaired liver function

N=746Age: 53 years% male: 49.7Race/Ethnicity (%):White=78.2Black=12.6Asian=3.5Other=5.1Weight: 204.4BMI: 33.1Duration of diabetes: 5.4 yearsHbA1c: 8.3%

Liraglutide 1.2 mg SC qd (251; 149 ext)Liraglutide 1.8 mg SC qd (246;154 ext)Glimepiride 8mg qd (248; 137 ext)

Major: Plasma glucose < 3.1 and required 3rd party assistance

Allocation concealment: YesBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Patients with isolated hypoglycemia, no co-existing acute medical issue requiring a hospital stay of > 24 hours. Neurological signs and symptoms with which patients first presented must have been completely resolved with the reversal of hypoglycemia 

N=203% male: 36.9Race/Ethnicity (%):Chinese=67.5Malay=18.2Indian=12.3Other=2.0%Type 2 diabetes: 94.6Previous symptomatic hypoglycemia: 21.2%

N/A Admission to the ER Population: No

Outcomes: NoMeasurement: NoConfounding: NoIntervention: N/A
81

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Ages 18 to 78, type 2 diabetes, on or not on an oral anti-hyperglycemic agent at screeningExclusion criteria: Type 1 diabetes, unstable cardiac disease, significant renal impairment, elevated liver enzymes

N=1091Age: 53.5 years% male: 49.4Race/Ethnicity (%):White: 51.7Black: 6.9Hispanic: 27.2Asian: 5.7Other: 8.5BMI: 32.1Type 2 (%): 100Duration of diabetes: 4.5 yearsHbA1c: 8.8%

1) Sitagliptin 100 mg OD2) Metformin 500 mg BID3) Metformin 1,000 mg BID4) Sitagliptin 50 mg + Metformin 500 mg BID5) Sitagliptin 50 mg + Metformin 1,000 mg BID6) PlaceboAll patients received counseling on diet and exercise throughout the study

Loss of consciousness or requirement for medical assistance

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Partially

Inclusion criteria:Patients admitted to the hospital with severe hypoglycemia between January 1, 2001 and December 31, 2008 

N=99/5377 medical admissions due to diabetes attributed to severe hypoglycemiaAge (median): 84.7% male: 36.4BMI: 27.8Duration of diabetes:15.7 years

N/A Symptomatic episode 

requiring assistance of another person and treatment with intravenous glucose or glucagon injection. Confirmed by blood glucose of 50mg/dl 

Population: YesOutcomes: YesMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Attended outpatient clinic weekly or biweekly for 1 year; taking conventional insulin therapy (1-2 injections), no oral medications

N=165 (baseline data reported for 114 with type 2 diabetes)Age: 58.9 years% male: 44.7 BMI: 29.8Duration of diabetes: 12.9 years

N/A Patient unable to take 

yes action themselvesOR Coma requiring parenteral glucose administered in hospital setting 

Population: NoOutcomes: NoMeasurement: YesConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes for ≥12 months, age >35, HbA1c in past 12 months, on insulin for ≥ 2 monthsExclusion criteria:Received OHAs within 2 months of the trial; pregnant or breast feeding; proliferative retinopathy; uncontrolled hypertension; recurrent major hypoglycemia; impaired renal or hepatic function; cardiac problems; total daily basal insulin dose >100 IU/day

N=505Age: 60.4 years% male: 51.1Race/Ethnicity (%):White=99Asian-Pacific Islander=1Weight (lbs): 191.1BMI: 30.4Duration of diabetes: 13.2 yearsHbA1c: 7.9%

Detemir (341)NPH (164)

Patient unable to treat him/herself

Allocation concealment: NoBlinding: NoIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes
82

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Patients with diabetes (Type 1, Type 2, or unclassified); driving at least 1000 km annually, driver’s license for at least 1 year, treated with potentially hypoglycemia-inducing medication for at least 1 year

Oral Antidiabetic (OA) group(116/122 type 2)Age: 64.2 yearsDuration of diabetes: 8.6 yearsRecent HbA1c: 7.9%Impaired visual function related to diabetes: 8.2%Antihypertensive treatment: 52.5%CNS-relevant medication: 5.7%Conventional Insulin Therapy (CT) group (108/151 type 2): Age: 58.8 yearsDuration of diabetes: 11.7 yearsRecent HbA1c: 7.9%Impaired visual function related to diabetes: 20.5%Antihypertensive treatment: 38.4%CNS-relevant medication: 5.3%

N/A Patients instructed to 

report hypoglycemia during driving and hypoglycemiainduced accidents with hypoglycemia as a range of events from impaired psycho-physiological performance, requiring immediate selftreatment to interruption of driving events requiring external assistance 

Population: NoOutcomes: YesMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Inadequate glycemic control on max dose SU and metformin, age 30-75, HbA1c 7-10%, BMI 25-45, stable body weightExclusion criteria: Participated in a study 30 days prior, experienced > 3 severe hypoglycemic episodes in the past 6 months, undergoing therapy for malignant disease other than basal or squamous cell skin cancer, class III or IV cardiac disease, serum creatinine > 1.5 mg/dL (men) or 1.2 mg/dL (women), symptoms of liver disease, on long term glucocorticoid therapy, prior use of weight loss drugs, treated for > 2 consecutive weeks with insulin within 3 months prior to screening 

N=549Age: 59 years% male: 56 Race/Ethnicity (%):White=80Black=1Asian=1Hispanic=16Other=2BMI: 31Duration of diabetes: 10 yearsHbA1c: 8.3%

Intervention: exenatide 5 ug bid for 4 wks then 10Ug bid till end of studyControl: glargine 10U/hs then adjusted by algorithm to achieve FBS < 100Metformin and SU maintained at pre-study doses

Patient required assistance of another person and had a BS< 50mg/dl

Allocation Concealment: YesBlinding: No Intention to Treat Analysis (ITT): NoWithdrawals/dropouts adequately described: Unclear
83

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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Aged 67-84 with valid driver’s license in Quebec; resident for at least 2 years before June 1 1990; followed until death, end of study (May 31 1993), date of event, age 85 years, or emigration from provinceExclusion criteria:Residence in a long-term care setting during the study period; previous hosp within past 60 days; hosp of 30 or more days any time in previous year

Cases: Had an injurious MVA (N=5579) Age: 74 years % male: 80Controls: Random sample of 6% of the subjects from the cohort (N=13,300) Age 73 years% male: 73

N/A N/A Population: Yes 

Outcomes: No Measurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes; 2 or more injections of insulin daily for at least 1 year 

N=215Age: 68 years (median)

N/A Required external 

assistance to effect recovery

Population: YesOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:type 2 diabetes, treated with dietary modification and oral agents for at least 2 years before start of insulin therapy; treated with insulin for at least 1 year

N=104 Age: 63 years% male: 50BMI: 27Duration of diabetes: 12 yearsDuration of insulin therapy: 4 yearsHbA1c: 10.5%

N/A Patient unable to take 

appropriate restorative action and required assistance of another person for treatment (home or hospital) to administer either oral or parenteral glucose or glucagon by injection

Population: YesOutcomes: YesMeasurement: No Confounding: YesIntervention: N/A

Inclusion criteria: Referred for inpatient treatment (mostly for treatment of late complications or difficulty achieving glycemic control); age 18-75 yrs

N=388 (51 had severe hypoglycemia)Age: 35% 18-48 yrs, 35% 49-62 yrs, 30% >62 yrs% male: 62Type 2: 63%Duration of diabetes: 31% <6 yrs, 37% 7-16 yrs; 32% >16 yrsHbA1c: 31% <7.5%, 34% 7.5-8.3%, 36% >8.3

N/A Requiring assistance Population: Yes

Outcomes: YesMeasurement: NoConfounding: YesIntervention: N/A
84

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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:18 years and older, 12 mo or longer history of diabetes, not on insulin; HbA1c7-10% on maximal doses of metformin and SU for at least 4 months; BMI<40; Exclusion criteria:History of TZD therapy or triple OHA therapy

N=708Age: 61.7 yearsDuration of diabetes (median): 9 years

Biphasic insulin aspart bid before meals; (n=235)Prandial insulin aspart tid before meals; (n=239)Basal insulin detemir qhs (n=234)

Third party assistance required

Allocation concealment: YesBlinding: Outcomes assessment (endpoints)Intention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria:All emergency room patients from only hospital in area (n=30,768); this publication focuses only on SUassociated hypoglycemia

N=45 Age: 83.5 years% male: 36.3Duration of diabetes: 7.2 yearsBMI: 23.6HbA1c: 5.2%Note: non-diabetic range 3.4-4.9%

N/A Symptomatic event 

requiring treatment with IV glucose or glucagon and confirmed by blood glucose measurement of <2.8 mmol/L

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: Yes

Responses received from 24/400 MDs (6%)

N=93 episodesAge: 77.7 years% male: 41 BMI: 24.7Duration of diabetes: 9.1 yearsHbA1c: 5.3% Note: non-diabetic range 3.4-4.9%

N/A Symptomatic event 

requiring administration of IV glucose or glucagon and confirmed by blood glucose < 2.8 mmol/l

Population: No Outcomes: YesMeasurement: No Confounding: No Intervention: N/A
85

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Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:All episodes of severe hypoglycemia in all patients presenting in the emergency department of one hospital, 1997-2000

N=148 (56%) cases of severe hypoglycemia in 121 patients with type 2 diabetesAge: 76 years% male: 36BMI: 25.7Duration of diabetes: 17 yearsRenal failure (CrCl<60 ml/min): 54%HbA1c: 6.2% Note: non-diabetic range 3.4-4.9%

N/A Symptomatic event 

requiring administration of IV glucose or glucagon injection that relieved symptoms and confirmed by blood glucose measurement

Population: Yes Outcomes: YesMeasurement: YesConfounding: No Intervention: N/A

Inclusion criteria:Type 2 diabetes, on sulfonylureasExclusion criteria:On insulin

Cases:43 (mean glucose level at time of event: 32)Controls:54

N/A Symptomatic event 

requiring therapy with IV glucose confirmed by blood glucose < 50 mg/dl

Population: No Outcomes: YesMeasurement: YesConfounding: YesIntervention: N/A

Inclusion criteria:Patients attending the ED of LippeDetmold Clinic and taking sulfonylurea

N=203Age: 78.4 years% male: 52.7BMI: 26.9Duration of diabetes:11.3 yearsHbA1c: 6.9%

Patients on sulfonylurea:Patients experiencing severe hypoglycemia (n=102) Patients with no severe hypoglycemia (n=101)

Symptomatic event requiring treatment with intravenously administered glucose and confirmed by blood glucose measurement of <50 mg/dl 

Population: NoOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A
86

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Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

N/A N=1065 patients with type 2 

diabetesAge: 65.4 years

N/A Required the help 

of another person to recover from a hypoglycemic episode. 

Population: NoOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Non-insulin dependent diabetesExclusion criteria:Required strict blood pressure control or beta blockade; severe vascular disease, severe concurrent illness; pregnant women

N=758Age: 57 years% male: 53 Race/ethnicity (%):Caucasian=87%Asian=5%Afro-Carribean=8%BMI: 29Duration of diabetes: 3.2 yearsHbA1c: 6.8%Smoking: 22% current

Tight blood pressure control (<150/85 mmHg) (N=497)Less tight control (<180/105 mmHg) (N=261)Part of UKPDS

Requiring medical assistance or admission to hospital

Allocation concealment: UnclearBlinding: UnclearIntention to treat analysis (ITT): Not for hypoglycemic reactionsWithdrawals/dropouts adequately described: No 

Inclusion criteria:Age 22-77: taking metformin and SU; FPG <13.3, BMI 27-45, HbA1c: 7.5 to 11%; metformin at least 1500 mg/d and SU at maximally effect dose for 3 months; weight stable for 3 months; no abnormal labs; women postmenopausal , surgically sterile or on OCs for 3 monthsExclusion criteria:Other significant medical conditions or use of other oral glucose lowering drugs or weight loss drugs within 3 months; on steroids, drugs affect GI motility, transplantation or invest drugs 

N=733 Age: 56 years% male: 58Race/Ethnicity (%):White=68Black=11Weight (lbs):215.6BMI: 34Type 2 (%):100Diabetes duration: 8.9 yearsHbA1c: 8.5%ACE inhibitor: 50%

Exenatid 5ug bid N=245Exenatide 10ug bid N=241Placebo N=247

Required the assistance of a third party

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes
87

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Men and women, ≥18 years of age, diagnosis of type 2 diabetes for ≥1 year, inadequate glycemic control (A1c >7.0%) despite diet, exercise, OHAs; candidate for insulin; stable doses of current medications for ≥2 months before randomizationExclusion criteria:Severe heart failure; significant renal or hepatic disease; pregnancy or lactation; malignancy in last 5 years (except treated basal cell carcinoma); dementia; hypersensitivity to insulin glargine; any other condition that could interfere with study completion; treated with metformin with impaired renal function (modified after 498 randomized to allow continuation in study if metformin was discontinued)

N=5,721Age: 57 years% male: 49Race/Ethnicity (%):White=71Black=16Hispanic=10Other=3BMI: 34.3Type 2 (%): 100Duration of diabetes: 8.5 yearsHbA1c: 8.9%

1) Insulin glargine usual titration and laboratory HbA1c testing; n=1,9782) Insulin glargine usual titration and point-of-care (POC) HbA1c testing; n=1,9753) Insulin glargine active titration and laboratory HbA1c testing; n=1,9674) Insulin glargine active titration and POC HbA1c testing; n=1,973

Patient required assistance and 1) there was prompt response to treatment (e.g., glucose or glucagon) or 2) SMBG level <36 mg/dl

Allocation concealment: YesBlinding: NoIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Individuals between 60 and 74 years old with a confirmed diagnosis of type 2 diabetesExclusion criteria:Non-type 2 diabetes, non-English speakers, or unable to read large print. 

N=1066Age: 67.9 years% male: 51.3Race/Ethnicity (%):White=95.3Other=4.7Duration of diabetes: 9.1 yearsHbA1c: 7.4%History of severe hypoglycemia: 10.8%MI: 14.1%Angina: 28%Cerebrovascular disease: 8.7%

N/A Needing assistance by 

another person

Population: YesOutcomes: NoMeasurement: YesConfounding: YesIntervention: N/A
88

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Age >18 years; multiple claims indicating a diagnosis of type 2 diabetes and use of insulin therapy; initiated treatment with insulin analogue pen device July 1, 2001 to December 31, 2002; data for at least 6 months before index date and at least 2 years of continuous enrollment after 

N=1156 Age: 45.4 years% male: 53.8 Metabolic disease: 8.2%Neuropathy: 8.2%nephropathy: 7.6%retinopathy: 7.2% CVD: 6.7%

Conversion to insulin pen therapyTarget HbA1c: N/A

No clear definition ED visits, hospitalizations, MD visits related to hypoglycemia

Population: YesOutcomes: NoMeasurement: YesConfounding: YesIntervention: Yes

Inclusion criteria:Type 1 or 2 diabetes in the registry who were alive in 1997 and who were either still alive in 1998 or had died but had not emigrated from the area during the one year study period 

N=977 w/ type 1 and 7678 w/ type 2Type 2:Age: 65 years% male: 52Duration of diabetes: 8 years

N/A Required emergency 

treatment from primary care, ambulance, or other emergency services; severedefined as blood sugar < 3.5 mmol/L requiring treatment with glucagon, IV dextrose or paramedic confirmation of low blood sugar with rapid recovery following treatment

Population: YesOutcomes: YesMeasurement: YesConfounding: NoIntervention: N/A

Inclusion criteria:Male or female; ages 18 years and older; type 1 or 2 diabetes; treated with insulin alone or with OHAs for at least 1 yr

N=335 (97% of patients screened)N=133 with type 2Age: 60 yearsBMI: 32HbA1c: 7.5%

N/A Required external 

assistance and plasma glucose <2.8 mmol/L

Population: NoOutcomes: YesMeasurement: YesConfounding: N/AIntervention: N/A
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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Adults; BMI<40; on 1 or 2 OHAs with or without insulin; HbA1c > 7.0% and < 12%Exclusion criteria:Cardiac disease, impaired hepatic or renal failure, proliferative retinopathy, recent treatment with 3 or more OHAs or use of short-acting or pre-mixed insulin in past 6 months

N=719Age: 60 years% male: 57 BMI: 31Type 2 (%): 100HbA1c: 8.5%

Basal-bolus with insulin detemir and insulin aspart (N=541) Premixed analogue insulin with biphasic insulin aspart (n=178)target HbA1c not specified

Patient unable to treat themselves

Allocation concealment: UnclearBlinding: NoIntention to treat analysis (ITT): No (1 dose)Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Age> 35; type 2 diabetes, treatment with OHA and/or insulin

N=309115 w/ hypoglycemia; 194 withoutAge: 65 yearsMicrovascular complication: 39%Macrovascular complication: 28%

NA Required assistance of 

a third party to rectify the situation

Population: NoOutcomes: NoMeasurement: NoConfounding: YesIntervention: N/A

Inclusion criteria:Treated with OHAs for > 3 months; 18-80 years old; HbA1c 7—10%; BMI < 45; Exclusion criteria:Insulin use within 3 months; impaired liver or renal function; uncontrolled HTN; cancer or any drugs apart from OHAs likely to affect glucose concentrations

N=1041Age: 56 years% male: 50Weight (lbs): 180.4 BMI: 30Type 2 (%): 100Duration of diabetes: 6.5 yearsHbA1c: 8.5%

Glimepiride, 2-4mg/day PLUS: a) Liraglutide 0.6 SC and rosiglitazone b) Liraglutide 1.2 SC and 

rosiglitazone

c) Liraglutide 1.8 SC and rosiglitazoned) Liraglutide and rosiglitazone 4mg/dayHbA1c<7%

Self-measured blood glucose = 3.0 mmol/l

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): No (1 dose)Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Patients prescribed insulin detemir by physician, including those who switched from treatment with other basal insulin and insulin-naïve patients Exclusion criteria:Patients unlikely or unable to comply with the study protocol; patients not classified as diabetes type 1 or 2 

N=1772Type 1 diabetes (n=643)Type 2 diabetes (n=1129)Age: 57 years% male: 50 Weight (lb): 172.6BMI: 28.2Type 2 (%): 63.7Duration of diabetes: 15.5 yearsMajor hypoglycemia: 6.7%HbA1c: 8.6%

N/A Severe CNS symptoms 

consistent with hypoglycemia; subject unable to treat himself/herself and third-party intervention is needed; has one of the following:a) Blood glucose <2.8 mmol/l (50 mg/dl)b) Reversal of symptoms after food intake, glucagon or intravenous glucose

Population: No Outcomes: YesMeasurement: YesConfounding: No Intervention: Yes
90

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Those who reported being treated with one or more OHAAs any time during the previous 6 monthsExclusion criteria:Patients who reported insulin use within the same previous 6 months

N=1984Age: 58.1% male: 56.7BMI: 34.5Duration of diabetes: 7.3 yearsMicrovascular: 22.5%Heart attack: 8%Angina: 8.5%Stroke: 4.3%Peripheral Vascular Disease: 0.96%CHF: 4.3%

N/A Required the assistance 

of others to manage symptoms or requiring medical assistance

Population: YesOutcomes: YesMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Men, non-fertile women and women of child-bearing potential using medically approved birth control; aged 18–73 years; Type 2 diabetes inadequately controlled (HbA1c 6.5–8.5%) by metformin monotherapy

N=3118 Age: 57.5 years% male: 53.5Race/Ethnicity (%):White=86.8Black=1.2Asian=2.9Hispanic=8.4Other=0.7Weight (lbs): 196.2BMI: 31.8Duration of diabetes: 5.7HbA1c: 7.3%Current Smokers: 16.6%

Vidagliptin 50 bid Glimepiride starting at 2 mgGroups added to metformin therapy

Any episode requiring assistance of another party

Allocation concealment: NoBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: No
91

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes; >18 years old; HbA1c <12%; BMI <45; likely to benefit from initiation of detemir, addition of detemir to other therapy, change to detemir, or continuation of detemirExclusion criteria:Any glucose lowering medication not indicated in combination with detemir; anticipate starting on another medication known to interfere with glucose metabolism (e.g., steroids); proliferative retinopathy or maculopathy; history of hypoglycemia unawareness or recurrent major hypoglycemia; pregnant; nursing; had serious illness

N=4937 Age: 59 years% male: 52Race/Ethnicity (%):White=77Black=17Asian=2Other=5BMI: 33.8Type 2 (%): 100Duration of diabetes: 11.4 yearsHbA1c: 8.5%

Randomization by study site (n=1083) to:a) Intervention: selfadjustment of insulin according to algorithm b) Control: adjustment by investigator according to standard of careEveryone was on detemir qhs as basal insulin; other medications as neededNo target HbA1c

Symptoms of low blood sugar that resolved with oral carbohydrates, glucagon or IV glucose AND blood sugar < 56 AND patient was unable to treat himself

Allocation concealment: UnclearBlinding: NoIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Type 2 diabetes with follow-up data > 2 months

N=1055Age: 60.9 years% male: 28.2Race/Ethnicity (%):White=3.6Black=93.8Other=2.6BMI: 33.0Duration of diabetes: 10.8 yearsHbA1c: 7.6%

N/A Loss of consciousness 

or other major alteration of mental status caused by hypoglycemia that required the assistance of another person to treat the condition

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A

Inclusion criteria:At least one acute care hospitalization between Oct 1, 2004 – Sept 30, 2005 and at least one outpatient measure of serum creatinine between week 1 and 1 year before hospitalization

N=243,222 N/A Severity denoted by 

categorical glucose measures:≥60 and <70 mg/dl; ≥50 and <60 mg/dl; <50 mg/dl

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A
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f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 taking at least 1 dose of long acting insulin daily; did not self-titrate insulin; stable for 2 months.Exclusion criteria:History of ETOH or SUD, chronic liver disease, pancreas insufficiency, chronic infectious disease, endocrinopathy, creatinine > 3, on corticosteroids or immunosuppressant drugs, insulin pump, life expectancy < 1 yr

N=344Age: 66 years % male: 96 BMI: 32Diabetes duration: 15 yearsInsulin treatment: 8 yearsAlso on OHA: 48%HbA1c: 8.0%

N/A Blood sugar< 60 with 

symptoms of affected mental function or requiring assistance of others

Population: YesOutcomes: No Measurement: No Confounding: No Intervention: N/A

Inclusion criteria:Age 18-78; Type 2 diabetes; not currently on an OHA or on an OHA other than metformin monotherapy at a dose ≥1500 mg/day or on metformin in combination with another OHA; HbA1c >6.5% and < 10% 

N=1172Age: 56.7 years% male: 59.2Race/Ethnicity (%):White=73.9Black=6.5Hispanic=7.6Asian=8.4Other=3.6Weight(lbs): 197.2BMI: 31.3Duration of diabetes: 6.4 yearsHbA1c: 7.7%

Sitagliptin 100mg qd Glipizide starting at 5 mg qd Groups added to metformin therapy

Required nonmedical assistanceRequired medical assistance

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Type 2 diabetes; age 18-80 yrs; HbA1c 7-11% (if prestudy OHA monotherapy ≥3 months) or 7-10% (if prestudy combination OHA therapy ≥3 months); BMI ≤ 40Exclusion criteria:Insulin use during previous 3 months

N=1087 Age: 57 years% male: 58Race/Ethnicity (%):White=87Black=3Asian/Pacific Islander=9Other=1BMI: 31Duration of diabetes: 7.6 yearsHbA1c: 8.4%

Liraglutide (once-daily)1) 0.6 mg (n=242)2) 1.2 mg (n=240)3) 1.8 mg (n=242)Glimepiride (once-daily): 4 mg (n=242)Placebo (n=121)

Required third-party assistance

Allocation concealment: NoBlinding: Yes (reported to be double-blind)Intention to treat analysis (ITT): No (excluded 4 who did not receive a treatment dose)Withdrawals/dropouts adequately described: Yes
93

f Severe Hypoglycemia 

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Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes, 18 or older with no prior insulin use who then were started on insulin between 1999-2004Exclusion criteria:No HbA1c in the 6 months prior to insulin initiation or only had 1 insulin prescription filled

N=3332Age: 60 years % male: 49 Duration of diabetes: 6.8 years BMI: 34HbA1c: 9.3%Hypertension: 61%Current smokers: 12%CVD: 25% Nephropathy: 10%Retinopathy: 17%

N/A Defined as ICD-9 251.0 

and 251.2 during an outpatient visit

Population: YesOutcomes: YesMeasurement: YesConfounding: No Intervention: Yes

Inclusion criteria: Type 2 diabetes; age 18-78; HbA1c >7.5% on diet; on no OHA for previous 4 months

N=815Age: 49.7 years% male: 56.5BMI: 33.4Duration of diabetes: 3.4 yearsHbA1c: 9.9%

Sitagliptin 50/metformin 500 bid titrated up to 50/1000 bid (n=625)Metformin 500 bid titrated up to 1000 bid (N=621)

Required nonmedical or medical assistance

Allocation concealment: NoBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Duration of type 2 diabetes ≥ 5 years and being treated with insulinExclusion criteria:Known renal failure or increased serum creatinine levels >1.5 mg/dl; cardiac abnormality-history of symptomatic angina, cardiac insufficiency or history of myocardial infarction or abnormal ECG; SGOT/SGPT more than two times upper limit of normal; more than 60 ml alcohol/day 

N=124Age: 57.1 years% male: 47 Weight (lb): 149.7Type 2 (%): 100HbA1c: 11.5%

Triple drug combination of: pioglitazone 15 mg/d glibenclamide 5 mg metformin 500mg three times a day Each in addition to insulin

“Significant hypoglycemia” Not defined in paper

Population: YesOutcomes: YesMeasurement: No Confounding: No Intervention: Yes
94

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Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:MDs selected patients they thought would benefit from pramlinitide 

N=1297Age: 48.7 years% male: 38.6Race/Ethnicity (%):White=84.7Black=9.6Hispanic=3.8Other=1.2Weight (lbs): 214.6BMI: 34.1Duration of diabetes: 18.5HbA1c: 8%

N/A Patient reported as selftreatable or requiring 

assistance (either of another person (PASH) or of a medical (MASH))

Population: NoOutcomes: YesMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes; age≥35; metformin and SU for at least 6 monthsExclusion criteria:Type 1 diabetes; HIV or hepatitis; gestational diabetes; any treatment with insulin; any treatment with akarbos, repaglinid during last 6 months

N=430Age: 69 years% male: 61BMI: 28.7Microvascular events: 20%Macrovascular events: 33%Major medical events: 23%

N/A Severe: Needed the 

assistance of others to manage symptomsVery Severe: Needed medical attention

Population: YesOutcomes: NoMeasurement: YesConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes; age 18-80; HbA1c 7.5 - 10.0%; BMI < 45; metformin for at least 3 monthsExclusion criteria:Treatment with any OHA except metformin within 3 months of trial; recurrent major hypoglycemia or hypoglycemic unawareness; present use of any drug except metformin that could affect glucose; impaired renal or hepatic function; clinically significant cardiovascular disease; or cancer 

N=675Age: 55.3 years% male: 52.9Race/Ethnicity (%):White=86.6Hispanic=16.2Black=7.2Asian Pacific Islander=2.0Other=4.2Weight (lbs): 206.4BMI: 32.8Duration of diabetes: 6.2 yearsHbA1c: 8.4%

Lirgulitide 1.2 mg qd (225)Lirgulitide 1.8 mg qd (221)Sitagliptin 100 mg qd (219)

Required third party assistance

Allocation concealment: YesBlinding: NoIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes
95

f Severe Hypoglycemia 

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Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Adults; 18+ years of age with at least 2 outpatient or inpatient claims for diabetes during 2004 to 2008 taking at least 1 OHAExclusion criteria:At least 12 months of continuous eligibility within a non-capitated health plan after the initial fill date of an OHA, and those with 1 medical claim (inpatient or outpatient) for type 1 or gestational diabetes during the study period

N=14,729Age: 54.8 years% male: 53.5

Cases: patients with hypoglycemic events (n=1339)Controls: patients without hypoglycemic events but with similar exposure status (n=13,390)

Requiring inpatient medical intervention 

Population: YesOutcomes: NoMeasurement: YesConfounding: YesIntervention: N/A

Inclusion criteria:Type 2 diabetes; age 18+; at least 2 claims for diabetes during study period; taking at least 1 OHAExclusion criteria:At least 12 months continuous eligibility; 1 claim for type 1 or gestational diabetes

N=536,581Age:18-34 (3.3%)35-49 (25.7%)50-64 (70.8%65+ (0.1%)% male: 54%Insulin Use: 6.0%Macrovascular complications: 7.0%Microvascular complications: 4.3%

N/A Required medical 

intervention

Population: YesOutcomes: NoMeasurement: YesConfounding: YesIntervention: N/A
96

f Severe Hypoglycemia 

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Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Adults with type 2; currently on OHA medication monotherapy (at least 2 months) or dual therapy; HbA1c between 7.5 and 11% inclusive (monotherapy) or between 7.0 and 10% inclusive (dual therapy)Exclusion criteria:Pregnant or nursing women; significant disease history; any investigational drug within 4 weeks of screening; treatment with TZD or systemic corticosteroids within 2 months of screening; history of hypoglycemic unawareness or recurrent severe hyperglycemia

N=561 Repaglinide/metformin 

BIDRepaglinide/metformin TIDRosiglitazone /metformin BID

Required the assistance of others

Allocation concealment: UnclearBlinding: No (openlabel)Intention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Men and women ≥18 years; BMI ≤40 kg/m2 ; HbA1c <12.0%; history of type 2 

diabetes ≥1 yearExclusion criteria:Significant medical disorder; hypoglycemic unawareness or recurrent major hypoglycemia; pregnant or breastfeeding women; allergy to insulin

N=395Age: 58.2 years% male: 42.1 Race/Ethnicity (%):Caucasian=99.7Non-Caucasian=0.3Weight (lbs): 177.7BMI: 29.2Type 2 (%): 100Duration of diabetes: 14.1 yearsHbA1c: 8.1%

Insulin detemir (IDet) (100U/mL) in combo with insulin aspart (IAsp)(n=195)NPH insulin (NPH) (100IU/mL) in combo with regular human insulin (HIS) (n=199)

Individual unable to treat him/herself

Allocation Concealment: NoBlinding: YesIntention to Treat Analysis (ITT): NoWithdrawals/ Dropouts: Yes

Inclusion criteria:Age 26-76; type 2 diabetes; on insulin for at least 6 months; HbA1c 7.5-13%, body weight +/-60% of desirable according to Met Life tables Exclusion criteria:IHD; uncontrolled HTN; GI or renal disease (CR > 2); unstable diabetic retinopathy; treatment with drugs known to affect gastric motility or glucose metabolism

N=538Age: 56 years% male: 60Race/Ethnicity (%):White=58Black=9 Hispanic=7Other=1 Unknown=25BMI: 31Duration of diabetes: 12 yearsHbA1c: 9.2% 

Mealtime (tid) injections of placebo, or 30, 75, or 150 ug of pramlintideTarget HbA1c < 8%

Events requiring assistance of another individual, or administration of glucagon, or IV glucose.Were then rated mild, moderate, severe by PI

Allocation Concealment: UnclearBlinding: Yes Intention to Treat Analysis (ITT): No (1 dose)Withdrawals/Dropouts adequately described: Yes
97

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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Age > 18; Type 2 DM; > 6 months continuous insulin therapy; HbA1c 6.0 - 11.0%

N=890Age: 60 years% male: 49.7BMI: 31.3Duration of diabetes: 13.5 yearsHbA1c: 7.5%

Insulin glulisine and NPH (N=448)RHI + NPH (N=442)

Requiring assistance of another person and confirmed by blood sugar <36 mg/dl or associated with prompt recovery with oral carbohydrate, IV glucose, or glucagon

Allocation concealment: UnclearBlinding: No (openlabel)Intention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Licensed drivers in Ontario 1/1/05-1/1/07 with commercial license annual review, report after crash, or diabetic patients reviewed for other reasonExclusion criteria:No HbA1c available

N=795Age: 52 yr% male: 80Duration of diabetes: approx 20 yrsHbA1c: ranged from 4.4-14.7%

N/A Required outside 

assistance

Population: YesOutcomes: YesMeasurement: NoConfounding: YesIntervention: N/A

Inclusion criteria:Employees eligible in incur absence and/or short term disability with pharm. benefits; at least 12 mos continuous enrollment; at least 2 drug claims for same class of DM-related medications

N=442 with hypoglycemiaAge: 44 years% male: 71

N/A ICD-9-CM 250.8, 251.1, 

251.2

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A
98

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Men and women; ages 30-70 years; diabetes for ≥ 2 years, treated with stable dose of 1 or 2 OHAs (sulfonylurea, metformin, pioglitazone, rosiglitazone) for ≥ 3 mos; BMI 26-40 kg/m2; HbA1c 7.5-

10%; FPG ≥ 140 mg/dl at screeningExclusion criteria:Prior use of insulin except for gestational diabetes or for <1 wk; current use of α-glucosidase inhibitor or rapid-acting insulin secretagogue; use of other agents effecting glycemic control, history of ketoacidosis or self-reported inability to recognize hypoglycemia; serum alanine aminotransferase or aspratate aminotransferase > 2 times upper limit of normal

N=756Age: 67 years% male: 56Race/Ethnicity (%):White=84 Black=12Asian=3Multiracial=1Hispanic=8BMI: 32.4Duration of diabetes: 8.7 yearsHbA1c: 8.6%

Glargine starting dose 10 IU at bedtime, titrated weekly NPH sameHbA1c ≤7.0% was study outcome

Symptoms consistent with hypoglycemia during which the subject required the assistance of another person and was associated with either a glucose level <56mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon

Allocation concealment: YesBlinding: NoIntention-to-Treat Analysis (ITT): No (1 dose)Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Insulin naïve pts with type 2 diabetes; age ≥18; diabetes for at least 1 year; BMI < 40; HbA1c 7.5 – 10%; on one or two OHA for at least 4 months at least 1⁄2 the maximal recommended dose

N=582Age: 58.9 years% male: 57.9Race/Ethnicity (%):White=88.1Black=5.8Asian Pacific Islander=2.4Other=3.6Weight (lbs): 192.3BMI: 30.5Duration of diabetes: 9.1 yearsHbA1c: 8.6%

Detemir (291)Glargine (291) qhs titrated to target FPG <6.0

Required assistance from a third party

Allocation concealment: NoBlinding: NoIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes
99

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes, age 40-80, on insulin for > 3 months HbA1c 7-12%, BMI < 40Exclusion criteria:Significant hepatic or renal dysfunction, had received treatment with an OHA within prior 3 months

N=518Age: 59 years% male: 60 Race/Ethnicity (%): White=80Black=40Hispanic=22BMI: 30.6Type 2 (%): 100Duration of diabetes(years): 13.7Duration of insulin use (years): 8.4 yearsSymptomatic hypoglycemia during screening:27%HbA1c: 8.6%

Glargine: qdNPH: qd or bidTarget HbA1c: <6.7%

Event with symptoms consistent with hypoglycemia in which the subject required assistance of another person and was either accompanied by a blood glucose of < 2.0 mmol/L or had prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration 

Allocation concealment: UnclearBlinding: NoIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Age 30-70; Type 2 for > 1 yr; stable dose for > 3months on OHAs or insulin alone or in combination; HbA1c 6-12%Exclusion criteria: Proliferative or severe non-proliferative retinopathy; history of laser vitrectomy or photocoagulation; use of insulin within 3 months; SBP >150 or DBP > 90; history of hypoglycemia unawareness

N=1024 Age: 55 years% male: 54 Weight (lbs): 217.8BMI: 34Type 2 (%): 100Diabetes duration: 11 yearsDuration of insulin use (years): 5 yearsRenal insufficiency: 10%HbA1c: 8.4%

Insulin glargine (N=513) qdNPH insulin (N=504)bid

Symptomatic hypoglycemia requiring assistance and either with blood glucose levels of ≤3.1 mmol/l or treated withoral or injectable carbohydrate or glucagon injection

Allocation concealment: UnclearBlinding: NoIntention to treat analysis (ITT): No (1 dose)Withdrawals/dropouts adequately described: Yes
100

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes; age 18-80; treated with OHAs for ≥3 months before screening; HbA1c 7.5-10% if on oral monotherapy or 7-10% if on combination therapy; BMI ≤45Exclusion criteria:Insulin use within 3 months prior to trial; impaired hepatic or renal function; clinically significant CV disease; proliferative retinopathy or maculopathy; hypertension (≥180/100 mmHg) or cancer; pregnant; recurrent hypoglycemia or hypoglycemia unawareness; seropositive for hepatitis B antigen or hepatitis C antibody; using any other medications that could affect blood glucose levels

N=576Age: 57.5 years% male: 56.6Race/Ethnicity: NRWeight (kg): 85.3BMI: 30.5Duration of diabetes: 9.4 yearsHbA1c: 8.3%

Randomized if received glimepiride (4 mg) and metformin (2 g) for at least 3 weeks and had fasting glucose of 7.5 to 12.8 mmol/l after 6 week run-inLiraglutide once-daily (1.8 mg) (blinded) (n=230)Liraglutide placebo once-daily (blinded) (n=114)Insulin glargine oncedaily (open label) (n=232)All in combination with metformain and glimepiride (open label)

Requiring third-party assistance

Allocation concealment: YesBlinding: Partial, participants, investigators, study monitors for liraglutide and placebo groups (see interventions)Intention to treat analysis (ITT): No (excluded 5 who did not receive a treatment dose) Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Men and women, age 30 or older; type 2 diabetes for ≥6 weeks; maintained on diet alone for ≥6 weeks before screening; FPG 7.0-8.3 mmol/LExclusion criteria:Type 1 diabetes; pancreatic injury; acute metabolic or significant diabetic complications

N=675Age: 60.2 years% male: 62.5Race/Ethnicity (%): Caucasian=95.6 Black=1Asian=1.3Other=2.1BMI: 28.9Duration of diabetes: 3.6 yearsHbA1c: 6.5%

Nateglinide 30, 60, or 120 mg(maintain diet and exercise during study)Goal HbA1c <6.0%

Requiring outside assistance

Allocation concealment: UnclearBlinding: Yes - double Intention to treat analysis (ITT): UnclearWithdrawals/dropouts adequately described: No

Inclusion criteria:Type 2 diabetes on medications; age 30-75

N=14,357Age: 58 years % male: 51Race/Ethnicity (%):White=22Black=17Latino=23Asian=20Other/mixed=20 Duration of diabetes: 10 yearsHbA1c: 7.6%

N/A Participant report of 

having a “severe low blood sugar reaction, such as passing out or needing help to treat the reaction”

Population: YesOutcomes: YesMeasurement: NoConfounding: YesIntervention: N/A
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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Type 2 diabetes treated with sulfonylureaExclusion criteria:Patients with factitious hypoglycemia owing to the mistaken use of medicine or attempted suicide, severe acute infection, heart failure, acute coronary syndrome, hepatic dysfunction, endocrine disorders, or renal failure

N=157Age: 66 years% male: 59.9BMI: 24Duration of diabetes: 8.9 yearsHbA1c: 7.8%

Case: Admission to hospital with severe hypoglycemia(n=32)Control: Outpatients without severe hypoglycemia (n=125)

Characteristic symptoms and a plasma glucose level of less than 50 mg/dl which required intravenous glucose administration

Population: NoOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A

Inclusion criteria:Type 2 diabetes, >35 years old, treated for at least 3 months with diet alone or in combination with metformin or an α-glucosidase inhibitor HbA1c 6·9-11·5%, able to perform home blood glucose monitoringExclusion criteria:Contraindication to study drugs, no effective contraception in women with child-bearing potential, elevated transaminases more than threefold the upper normal range 

N=845Age: 60.5 years% male: 51.5Weight (lbs): 183.6BMI: 30.6Duration of diabetes: 5.7 yearsHbA1c: 8.3%Macrovascular: 21.4%Microvascular: 10.5%

Gliclazide modified release (MR)Glimepiride Both arms either as monotherapy or with pts current therapy maintained at a stable dose

Symptomatic episodes requiring external assistance owing to severe impairment in consciousness or behavior, with BGL < 3 mmol/L

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): No (1 dose)Withdrawals/dropouts adequately described: Yes

Inclusion criteria:Discharge diagnosis of diabetesExclusion criteria:Age < 18, pregnancy, skin diagnoses, transfers to other hospitals, discharges with “missing values”

N=787,836 Age: 66 years% male: 46

N/A “Acute hypoglycemic 

condition” as a discharge diagnosis

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A

Inclusion criteria:All Tennessee Medicaid enrollees aged 65 years and older who used insulin or oral hypoglycemic drugs from 1985 through 1989 and experienced severe hypoglycemia; 1 full year of Medicaid enrollment was required

N=586Age: 78 years% male: 18Race/Ethnicity (%): White=48Non-white=52

N/A Neuroglycopenic or 

autonomic symptoms, with a concomitant blood glucose determination of <50 mg/dL)

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A
102

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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Patients admitted due to severe hypoglycemia

N=207Age: 62 years% male: 41Duration of diabetes: 7.4 yearsHbA1c: 6.8%

N/A Comatose or precomatose on arrival at 

ED; glucose < 50, and needing IV glucose

Population: YesOutcomes: YesMeasurement: No Confounding: YesIntervention: N/A

Inclusion criteria:Type 2 diabetes treated with long versus short-acting sulfonylurea Exclusion criteria:Insulin treatment

N=28Age: 71.8 years% male: 46.4Duration of diabetes:10.2 years

Long- acting sulfonylurea (n=16)Short-acting sulfonylurea (n=12)

Episodes of hypoglycemia leading to hospital admission

Population: NoOutcomes: YesMeasurement: NoConfounding: YesIntervention: Yes

Inclusion criteria:men or women, age 18-80 years, type 2 diabetes diagnosed at least 3 years prior to study entry, on oral anti-diabetics for at least 6 months with poor control (HbA1c ≥7.5% and ≤10.5%, FBG ≥120 mg/dl), BMI ≤35 kg/m2

N=624Age: 61.8 years% male: 54.5BMI: 28.5Type 2 (%): 100Duration of diabetes: 9.9 yearsHbA1c: 8.8%

AM Glargine titrated to target FBG ≤ 100 mg/dl and AM glimepiride (6 to 9 am) PM Glargine n=312; titrated to target FBG ≤ 100 mg/dl and AM glimepiride (6 to 9 am)

Symptoms consistent with hypoglycemia during which the person required the assistance of another person and was associated with a blood glucose level <50 mg/dl or with prompt recovery after oral carbohydrate, IV glucose or glucagon administration

Allocation concealment: UnclearBlinding: NoIntention to treat analysis (ITT): NoWithdrawals/dropout adequately described: No

Inclusion criteria:Diabetic patients admitted for serious hypoglycemia

N=137 Age: 66.4 years Type 2: 73.7% Treated with insulin: 26.3%

N/A Requiring immediate 

aid in a health care institution

Population: YesOutcomes: YesMeasurement: No Confounding: YesIntervention: N/A
103

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Adults ages 20 to 65 with a diabetes duration of 2 years, absence of cardiovascular disease or neuropathy, visual acuity > 16/20 in both eyes, drivers licenseExclusion criteria:Medication use that would influence hypoglycemia counter-regulation. 

N=20 (Type 2 diabetes)Age: 51.6 years% male: 80Weight (lbs): 196.7 BMI: 28.3Duration of diabetes: 8.7 yearsHbA1c: 7.9%

Type 1 diabetes with impaired hypoglycemic awarenessType 1 diabetes with normal hypoglycemic awarenessType 2 diabetes with normal awareness 

N/A Population: No

Outcomes: YesMeasurement: NoConfounding: NoIntervention: Yes

Exclusion criteria:Children, intentional drug overdose, nondiabetic 

113 diabetic patients with 130 admissions (126 admissions among 109 patients who had been prescribed hypoglycemic agents)Race/ethnicity: Native American (100%)Duration of diabetes: 11.9 years (based on data from 108 patients)

N/A Definition not given - 

all patients had been admitted to a hospital

Population: YesOutcomes: YesMeasurement: YesConfounding: No Intervention: N/A

Inclusion criteria:Type 2 diabetes; patients with type 1 diabetes for < 5 years or > 15 years.Exclusion criteria:HbA1c >9%, measured centrally by an HPLC; severe diabetic complications, e.g., binocular visual acuity <6/12, major amputation, severe peripheral sensory neuropathy; treatment with metformin or acarbose alone; seizures unrelated to hypoglycemia; concurrent malignant disease; severe systemic diseases unrelated to diabetes; pregnancyInsulin users had to be taking two or more injections daily

N=274 Age: 57.2 years% male: 68.2BMI: 29.8Type 2 (%): 43HbA1c: 7.5%

Subjects were given hypoglycemia reporting forms, on which they were asked to document the time, duration, symptoms, glucose level (if checked) and treatment required during any episode of hypoglycemia 

Requiring help forrecovery 

Population: YesOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A
104

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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:Newly diagnosed with diabetes (confirmed with FPG > 6mmol/l); age 25 to 65 years Exclusion criteria:Ketouria > 3 mmol/l; myocardial infarction in the previous year; current angina or HF; >1 major vascular episode;, serum creatinine > 175 umol/l; retinopathy requiring photocoagulation; malignant hypertension; uncorrected endocrine abnormality; occupation precluding insulin therapy; severe concurrent illness; inadequate comprehension 

N=3867Age: 59 years% male: 59Race/Ethnicity (%): Caucasian=78Afro-Caribbean=12Asian=10Weight (lbs): 178.2BMI: 29.1Type 2 (%): 100HbA1c: 7.3%

FPG goal of 6 mmol/L. (n=2729); these patients received dietary advice; sulfonylureas used were: chlorpropamide 100-500mg; glibenclamide 2.5-20mg; glipizide 2.5-40mg.FPG goal of15 mmol/L. (n=1138)

Requiring thirdparty assistance or hospitalization 

Allocation Concealment: Yes Blinding: UnclearIntention to Treat Analysis (ITT): YesWithdrawals/dropouts adequately described: Unclear

Inclusion criteria:Newly diagnosed with diabetes (confirmed with FPG > 6mmol/l); age 25 to 65 years Exclusion criteria:Ketouria > 3 mmol/l; myocardial infarction in the previous year; current angina or HF; >1 major vascular episode; serum creatinine > 175 umol/l; retinopathy requiring photocoagulation; malignant hypertension; uncorrected endocrine abnormality; occupation precluding insulin therapy; severe concurrent illness; inadequate comprehension

N=743Age: 59 years% male: 59Race/Ethnicity (%): White=78Afro-Caribbean=12Asian=10Weight (lbs): 178.2BMI: 29.1Type 2 (%): 100HbA1c: 7.3%

Of 1704 overweight pts 743 were randomized:Diet (N=411)

Intense glucose control 

(w/ metformin) (N=342)

Required third party help or medical intervention

Allocation Concealment: Yes Blinding: UnclearIntention to Treat Analysis (ITT): YesWithdrawals/dropouts adequately described: Unclear

Inclusion criteria:Type 2 dm newly started on BIASP30/70

N=52,419Age: 55 years % male: 57Weight (%): 156.2BMI: 26Duration of diabetes: 7 yearsHbA1c: 9.3%

N/A Severe CNS symptoms; 

patient unable to selftreat; accompanied by blood sugar < 50 or symptoms reversed after carbohydrate intake, glucagon or IV glucose

Population: YesOutcomes: NoMeasurement: NoConfounding: NoIntervention: N/A
105

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:> 35 years old, type 2, on SU and metformin for at least 6 monthsExclusion criteria: Using insulin, type 1, being treated for hepatitis or HIV, h/o gestational diabetes

N=400Age: 62 years % male: 53 Weight (lbs): 178.2Duration of diabetes > 7 years: 46%Current smoking: 14%HbA1c: 7.2%

Severe-needing third party assistanceVery severe-needing medical attention

Population: NoOutcomes: NoMeasurement: NoConfounding: YesIntervention: N/A

Inclusion criteria:Outpatients 66 years and older; diabetes mellitus; prescriptions for glyburide, insulin or metformin 

N=2650 Normal renal function:

Case (N=204)Control (N=802)Impaired renal function:Case (N=354)Control (N=1290)

Presenting to the hospital or emergency room with an admission diagnosis of hypoglycemia

Population: NoOutcomes: NoMeasurement: YesConfounding: NoIntervention: N/A

Inclusion criteria:Enrollees in KP as of January 2003; no prior diagnosis of dementia, MCI, or memory loss; history of type 2 diabetes;age > 55 years old

N=16,667Age: 65 years% male: 55Race/Ethnicity (%):White=63Black=11 Hispanic=11Asian=12 Duration of diabetes: 9.6 yearsAt least 1 episode of hypoglycemia: 8.8%HbA1c: 8.1%

NA Hospitalization and ED 

codes for hypoglycemia before 2003

Population: YesOutcomes: YesMeasurement: YesConfounding: YesIntervention: N/A
106

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matic Review of the Evidence Evidence-based Synthesis Program

Inclusion/Exclusion Criteria Patient Characteristics

Intervention/

Control

Target HbA1c

Definition of Severe 

Hypoglycemia Study Quality

Inclusion criteria:18-78years old; not on an OHA; HbA1c >7.5% to < 11% after a run-in period w/ no meds; good compliance during second placebo run in period

N=1091 Age: 53.5% male: 57BMI: 32Duration of diabetes: 4 yearsHbA1c: 8.5%

a) Metformin 1000 mg bid (n=78)b) Sitagliptin 100 mg qd (n=106)c) Metfromin 500 mg bid (n=122)d) Metformin 1000 mg bid (n=137)e) Sitagliptin 50 bid + metformin 500 bid (n=148)f) Sitagliptin 50 bid +metformin 100mg bid (n=157)Target HbA1c< 7%

Requiring medical intervention or exhibiting markedly depressed level of consciousness, including loss of consciousness, or seizure

Allocation concealment: UnclearBlinding: YesIntention to treat analysis (ITT): NoWithdrawals/dropouts adequately described: Yes

Inclusion criteria:Death certificate mentioning diabetes as underlying or contributory factor

N=741Age: 58.8 years

N/A Hypoglycemia noted 

as a cause of, or contributing cause of death

Population: NoOutcomes: YesMeasurement: NoConfounding: YesIntervention: N/A

Inclusion criteria:18-80 years old; HbA1c 7-11% on prestudy OHA for > 3 months; BMI < 45

Exclusion criteria:Use of insulin during previous 3 months

N=533 Age: 55 years% male: 57Race/Ethnicity (%):White=82Black=12Asian=2Hispanic=15 Other=3BMI: 33Type 2 (%):100Duration of diabetes: 9 yearsHbA1c: 8.5%

Group 1 (n= 178) 1.2 mg ligragulatide qd sc Group 2 (178) 1.8 mg lig qd scGroup 3 (n=177 ) placebo PLUS metformin and rosiglitazone in all 3 groups

Requiring third party assistance or medical intervention 

Allocation concealment: YesBlinding: YesIntention to treat analysis (ITT): YesWithdrawals/dropouts adequately described: Yes 

ass Index; CABG = Coronary Artery Bypass Grafting; CHF = Congestive Heart Failure; CK = Creatinine Kinase; CNS = Central Nervous System; 

ovascular Accident; d/c = Discontinued; ER = Emergency Room; ESRD = End-stage Renal Disease; ETOH = Alcohol; GI = Gastrointestinal; GP 

moglobin A1c; HTN = Hypertension; LVH = Left Ventricular Hypertrophy; MI = Myocardial Infarction; N/A = Not Applicable; NR = Not Reported; 

CT = Randomized Controlled Trial; SMBG = Self-monitored Blood Glucose; SU = Sulfonylurea; SUD = Substance Use Disorder; TZD = 

a
107

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matic Review of the Evidence Evidence-based Synthesis Program

udies Included in Extended Analysis for Key Question #1

dy Design

a sources

 of Follow-up

Population Definition of Hypoglycemia Results Study Quality

ctional 

naire 

N=1709Type 2, age > 30, who had had a SU or TZD added to metformin in the previous 5 years

Self-report of episodes in past year, rated: 1. no interruption in activities2. interrupt in activities but no help required3. needed assistance of others4. needed medical attention

38% reported one or more episodes of any severity; 26.8% reported level 3 and 5.1% reported level 4

Population: YesOutcomes: NoMeasurement: NoConfounding: Yes Intervention: N/A

ctional 

naire

N=401 of 671 asked to participateType 2, exclusions: on SUs, on dialysis, concomitant malignancy, pregnancy, inability to complete questionnaire

Severe: required assistance of another person

66/401 (16.5%) had at least one severe event in the past year

Population: NoOutcomes: YesMeasurement: NoConfounding: Yes Intervention: N/A

ctional 

naire

N=2257Type 2, older than 30, on OHA for at least 6 months 

Self-report of episodes in past 6 months, rated: 1. no interruption in activities2. interrupt in activities but no help required3. needed assistance of others4. needed medical attention

66 + 94 (160) of 2257 reported one or more severe or very severe events (7%)

Population: NoOutcomes: YesMeasurement: NoConfounding: No Intervention: N/A

ve cohort 267 Type 1 and 2 (N=173) Required 3d party assistance, self report 

by diary 

5 type 2 patients had one or more severe events over 1 month(5/173=2.8%)

Population: NoOutcomes: NoMeasurement: YesConfounding: Yes Intervention: N/A

ctional 

naire

N=215 type 2 diabetics treated with insulin at one clinic

Required external assistance; approx estimates of number of episodes in past year 

32 (15%) people reported one or more severe episodes in past year 

Population: NoOutcomes: YesMeasurement: NoConfounding: No Intervention: N/A

ctional

naire, EMRs, 

ce records

N=680 Patients over age 18 with Type 1 or Type 2 DM (n=480) all on insulin living in two communities 

Needs the help of another person to recover

53/480 T2DM patients (12.3%) had one or more severe (self reported) episodes over 1 year; 10/53 required ambulance or emergency care

Population: NoOutcomes: YesMeasurement: NoConfounding: No Intervention: N/A
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dy Design

a sources

 of Follow-up

Population Definition of Hypoglycemia Results Study Quality

ctional 

naire

N=219 Age 40-65 with type 2 attending a single clinic who were treated with OHAs

Symptoms associated with a blood sugar reading of < 3 mmol and precipitated by reduced carbohydrate intake or increased exertion; relieved by carbohydrates; occurred after the institution of OHA therapy; and no other explanation for the hypoglycemic episode

In past 6 months: 41/203 (20%) patients on SU; 0/16 patients on metformin

Population: NoOutcomes: YesMeasurement: NoConfounding: No Intervention: N/A

ctional

ata and survey 

s and providers

Random sample of 10,000 adults (36% responded)Treated for diabetes and living in France sent a questionnaire 

Required the help of another person 26.5 % of 635 T2D on 

insulin and 6.3% of 2689 T2DM on OHA reported one or more severe episode in 2001

Population: NoOutcomes: YesMeasurement: NoConfounding: No Intervention: N/A

ctive cohort

rative claims 

400 on NPH and 1698 on glargineT2DM patients < 65 years old, NOT pregnant, and were in the database for 6 months pre and 6 months post index date; index date was first prescribed for glargine or NPH 

ICD 9 codes 251.0x, 251.1x, 251.2x, 250.3x. A hypoglycemic-related hospitalization event was defined by at least one claim with the codes above during a hospitalization

NONE in either group Population: Yes

Outcomes: NoMeasurement: YesConfounding: Yes Intervention: N/A

n based survey N=1984 

Type 2 diabetes treated with one or more OHA in past 6 months but NOT on insulin

Severe—needed assistance of othersVery severe—needed medical assistance 

In past 6 months , 13% reported severe and 4% reported very severe episodes 

Population: YesOutcomes: YesMeasurement: NoConfounding: Yes Intervention: N/A

ctive cohort N=243,222

VHA database of patients with CKD who had a t least one hospitalization in 2004-2005 and at least one outpatient measurement of CR between 1week and 1 year before they were hospitalized 

Among 92,003 CKD patients with diabetes, 9264 had at least one glucose < 50 in the database

Population: YesOutcomes: YesMeasurement: YesConfounding: Yes Intervention: N/A

urvey N=11,529 

Type 2 diabetics on SU but not insulin 

Required assistance of another person 5965 responses to this 

question 538/5965 (9%) identified the episode as severe

Population: YesOutcomes: YesMeasurement: NoConfounding: Yes Intervention: Yes
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f Severe Hypoglycemia 

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dy Design

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 of Follow-up

Population Definition of Hypoglycemia Results Study Quality

ctional 

urvey 

N=430 Patients with type 2 dm, age 35 or older, on metformin and SU for past 6 months

1. Mild: no interruption in activities2. Moderate: interrupt in activities but no help required3.Severe: needed assistance of others4. Very severe: needed medical attention. 

17% reported level 2; 1% reported level 3 and 1% reported level 4 hypoglycemic episode within past 6 months 

Population: NoOutcomes: YesMeasurement: NoConfounding: No Intervention: N/A

ctional patient 

nked with 

ecords

N=14,357 Adults with type 2 diabetes treated with OHAs past year

Survey question: In the past year, how many times have you had SEVERE low blood sugar reaction such as passing out or needing help to the treat the reaction? 

1579 (11%) reported at least one episode; Insulin: 59%Mixed OHAs 23%Secretagogues alone: 13%Metformin alone: 5%129/1579 (8%) had evidence of a documented ER visit or hospitalization for hypoglycemia in the prior year

Population: YesOutcomes: YesMeasurement: NoConfounding: Yes Intervention: N/A 

urvey N=392 

Type 2, 35 years old or older, treated in prior 6 months with either a combination of metformin and a glitazone or met and a SU 

1. No interruption in activities2. interrupt in activities but no help required3. needed assistance of others4. needed medical attention. 

w/in previous 6 months 9/392 reported severe (#3) and 6/392 reported very severe (#4)

Population: NoOutcomes: NoMeasurement: NoConfounding: No Intervention: N/A

ctional 

urvey

N=10374 Patients with T2DM currently on one or more OHAs but not insulin invited...of whom 2074 completed the survey

If you answered yes to: In the prior 2 weeksdid you have either “symptoms of low blood sugar” or “low blood sugar in the middle of the night” some most or all of the time

286/2074 (14%) Population: Yes

Outcomes: YesMeasurement: NoConfounding: Yes Intervention: N/A

Rs = Electronic Medical Records; ER = Emergency Room; HbA1c = Hemoglobin A1c; N/A = Not Applicable; NR = Not Reported; OHA = Oral 

mized Controlled Trial; SU = Sulfonylurea; T2DM = Type 2 diabetes mellitus; TZD = Thiazolidinedione; SU = Sulfonylurea
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Table 3. Incidence of Severe Hypoglycemia by Treatment Arms 

Table 3a. Intensive versus Standard Glycemic Control Studies

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence % (n/N)

Risk ratio

[95% CI]

Duckworth (VADT) 

20095 RCT 5.6 yrs Intensive control 8.5 (76/892) 2.74 [1.79 to 4.18] Standard control 3.1 (28/899)

ACCORD 20083 RCT 3.5 yrs Intensive control 16.6 (849/5128) 3.10 [2.72 to 3.53] Standard control 5.3 (274/5123) 

ADVANCE 20084 RCT 5 yrs Intensive control 2.7 (150/5571) 1.88 [1.44 to 2.46] Standard control 1.5 (81/5669)

UKPDS 33 1998*21 RCT 10 yrs Intensive control 1.1 (33/3071) 1.53 [0.71 to 3.30] Standard control 0.7 (8/1138)

Abraira (VACSDM) 199530 RCT 2.3 yrs Intensive control 6.7 (5/75) 2.60 [0.52 to 12.99] Standard control 2.6 (2/78)

Totals Intensive control 7.6 (1113/14737) 2.40 [1.76 to 3.27] Standard control 3.0 (393/12907)

*Data obtained from Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal T, Hemmingsen C,Wetterslev J. Targeting intensive 

glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic 

Reviews 2011, Issue 6. Art. No.: CD008143. DOI: 10.1002/14651858.CD008143.pub2.

Table 3b. Insulin Studies

Study and year Study type Study

duration

Intervention(s)

Control

Hypoglycemia

Incidence % 

(n/N)

A. Regular insulin and Lispro studies: fast-short acting

Anderson, 199747

(crossover study) RCT 26 wks Regular human insulin phase 0.6 (4/722)

Insulin lispro phase 0.1 (1/722)

B. Insulin aspart studies: rapid-acting

Holman, 200943

(4T study) RCT 3 yrs

Prandial insulin aspart 2.1 (5/239)

Biphasic insulin aspart 2.6 (6/235)

Insulin detemir (basal) 0.9 (2/234)

C. Biphasic insulin: intermediate- and fast-acting mixture

Berntorp, 201115 Prospective cohort 26 wks Biphasic insulin aspart 0.2 (2/1154)

Buse, 201136 RCT 2.5 yrs Insulin lispro 75/25 mix 4.2 (20/473)

Insulin glargine (long-acting) 2.9 (12/419)

Holman 200943 

(4T study) RCT 3 yrs

Biphasic insulin aspart 2.6 (6/235)

Prandial insulin aspart 2.1 (5/239)

Insulin detemir (basal) 0.9 (2/234)

Liebl, 200948 RCT Biphasic insulin aspart 0/178

Insulin detemir and insulin aspart 0.9 (5/537)

Valensi 

(IMPROVE) 200922 Prospective cohort 26 wks Biphasic insulin aspart

0.13 (69/52,419)

0.008 events

per patient-year

D. Mixed fast and long-acting insulins studies

Liebl, 200948 RCT 26 wks Insulin detemir and insulin aspart 0.9 (5/537)

Biphasic insulin aspart 0/178

Rayman, 200645 RCT 26 wks Regular human insulin + NPH 1.6 (7/442)

Insulin glulisine + NPH 0.5 (2/448)

Dailey, 200446 RCT 26 wks Regular human insulin + NPH 1.2 (5/441)

Insulin glulisine + NPH 1.4 (6/435)

E. NPH insulin studies: intermediate acting
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Study and year Study type Study

duration

Intervention(s)

Control

Hypoglycemia

Incidence % 

(n/N)

Rosenstock, 

200935 RCT 5 yrs NPH insulin 11.1 (55/504)

Insulin glargine 7.6 (38/513)

Rayman, 200745 RCT 26 wks NPH (basal therapy) + regular human insulin 1.6 (7/442)

NPH (basal therapy) + insulin glulisine 0.5 (2/448)

Haak, 200533 RCT 26 wks

Insulin detemir <2% both arms

(numbers not 

given) NPH insulin

Dailey, 200446 RCT 26 wks

NPH (basal therapy) + regular human 

insulin 1.2 (5/441)

NPH (basal therapy) + insulin glulisine 1.4 (6/435)

Fritsche, 200344 RCT 24 wks

NPH insulin + glimepiride (G) 3 mg 2.6 (6/232)

Bedtime Insulin glargine + G 1.8 (4/227)

Morning Insulin glargine + G 2.1 (5/236)

Riddle, 200341 RCT 24 wks

Adjunct NPH insulin to 1-2 oral 

antiglycemic agents (sulfonylurea, 

metformin, or glitazone)

1.8 (7/389)

Adjunct Insulin glargine to 1-2 oral 

antiglycemic agents (sulfonylurea, 

metformin, or glitazone)

2.5 (9/367)

Rosenstock, 

200139 RCT 28 wks NPH insulin 2.3 (6/259)

Insulin glargine 0.4 (1/259)

F. Insulin detemir studies: long-acting

Holman, 2009 

(4T study)43 RCT 3 yrs

Insulin detemir (basal) 0.9 (2/234)

Insulin aspart (prandial) 2.1 (5/239)

Biphasic insulin aspart 2.6 (6/235)

Liebl, 200948 RCT 26 wks Insulin detemir and insulin aspart 0.9 (5/537)

Biphasic insulin aspart 0/178

Rosenstock,

200840 RCT 52 wks Insulin detemir 1.7 (5/291)

Insulin glargine 2.7 (8/291)

Meneghini 

(PREDICTIVE) 

2007176

RCT 26 wks

Insulin detemir - Algorithm care 0.26 events per 

patient years

Insulin detemir - Standard care 0.20 events per 

patient years

Haak, 200533 RCT 26 wks

Insulin detemir <2% in both 

arms

(numbers NR) NPH insulin

Marre 

(PREDICTIVE) 

200918

Prospective cohort 52 wks Insulin detemir 0.3 (4/1129)

G. Insulin glargine studies: long-acting

Buse, 201136 RCT 2.5 yrs 

follow-up

Insulin glargine (long-acting) 2.9 (12/419)

Insulin lispro 75/25 mix 4.2 (20/473)

Rosenstock, 200935 RCT 5 yrs Insulin glargine (long-acting) 7.6 (38/513)

NPH insulin (intermediate acting) 11.1 (55/504)

Russell-Jones, 

200954 RCT 26 wks

Insulin glargine (long-acting) added to 

metformin and sulfonylurea) 0/232

Liraglutide added to metformin and 

sulfonylurea) 2.2 (5/230)

Placebo added to metformin and 

sulfonylurea) 0/114
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Predictors and Consequences of Severe Hypoglycemia 

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Study and year Study type Study

duration

Intervention(s)

Control

Hypoglycemia

Incidence % 

(n/N)

Rosenstock,

200840 RCT 52 wks Insulin glargine 2.7 (8/291)

Insulin detemir 1.7 (5/291)

Kennedy, 200637 RCT 24 wks

Insulin glargine, usual and active titration 3 (228/7607)

Insulin glargine, usual titration 0.09 events per

patient-year

Insulin glargine, active titration 0.14 events per

patient-year

Standl, 2006180 RCT 24 wks

Insulin glargine, morning administration + 

Glimepiride (G) 2-4 mg 1.3 (4/299)

Insulin glargine, bedtime administration + 

G 2-4 mg 0.7 (2/281)

Davies, 200538 RCT 24 wks

Insulin glargine algorithm 1 (investigator 

led) 0.9 (21/2315)

Insulin glargine algorithm 2 (performed by 

study subjects) 1.1 (25/2273)

Heine, 200542 RCT 26 wks

Adjunct Insulin glargine (long-acting) 

added to oral therapy (metformin and 

sulfonylurea

1.5 (4/267)

Adjunct Exenatide added to oral therapy 

(metformin and sulfonylurea) 1.4 (4/282)

Fritsche, 200344 RCT 24 wks

Bedtime Insulin glargine + G 1.8 (4/227)

Morning Insulin glargine + G 2.1 (5/236)

NPH insulin (intermediate acting) +G 2.6 (6/232)

Riddle, 200341 RCT 24 wks Insulin glargine (long-acting) 2.5 (9/367)

NPH insulin (intermediate acting) 1.8 (7/389)

Rosenstock, 

200139 RCT 28 wks Insulin glargine (long-acting) 0.4 (1/259)

NPH insulin (intermediate acting) 2.3 (6/259)

H. Non-specific Insulin studies

UK Hypoglycemia 

Group 2007190 Prospective cohort 9-12 mos

Treated with insulin for <2 years ~7.0* (6/89)

Treated with insulin for >5 years ~25.0* (19/77)

Sulfonylurea 7.0 (8/108)

Murata, 200519 Prospective cohort 41 wks Long-acting insulin 5.5 (19/344)

Nichols, 201026 Retrospective cohort 49 mos

All types (regular, quick-acting, NPH, mixed, etc.)

Hypoglycemia requiring a medical contact occurred in 

1.9% of patients in the first year of insulin use, but by the 

fifth year the rate had fallen to 0,4%. No cases of required 

hospitalization.

Asche, 200823 Retrospective cohort 395 days 

of followup

Insulin with sulfonylurea 2.8 (3/106)

Insulin with thiazolidinedione 4.3 (8/187)

Sulfonylurea monotherapy 2.6 (55/2117)

Thiazolidinedione monotherapy 1.7 (12/702)

Metformin 0/2326

Leese, 200325 Retrospective cohort NR Insulin

7.3 (66/901)

11.8/100 patient 

yrs [95% CI 9.5 

to 14.1]

*extracted from graph
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Table 3c. Sulfonylurea Studies

Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Arechavaleta, 

201152 RCT 30 wks

Adjunct Glimepiride 1-6 mg added to 

metformin 1.5 (8/519)

Adjunct Sitagliptin 100 mg added to metformin 0.2 (1/516)

Garber, 201151 RCT 52 wks

Glimepiride 8 mg 0/248

Liragultide 1.2 mg 0/251

Liragultide 1.8 mg 0/247

Matthews, 

201049 RCT 2 yrs

Adjunct Glimepiride 2-6 mg added to 

metformin 1.8 (15/1546)

Adjunct Vildagliptin 100 mg added to 

metformin 0/1553

Seck, 2010;50

Nauck, 2007177 RCT 2 yrs

Adjunct Glipizde 5 mg added to metformin

Non-med. Assist.

1.5 (9/584)

Med. Assist.

1.5 (9/584)

Adjunct Sitagliptin 100 mg added to metformin

Non-med. Assist.

0.2 (1/588)

Med. Assist.

0.2 (1/588)

Marre, 2009175 RCT 52 wks

Glimepiride 2-4 mg + liragultide 0.6 mg 0/233

Glimepiride 2-4 mg + liragultide 1.2 mg 0/228

Glimepiride 2-4 mg + liragultide 1.8 mg 1.7 (4/234)

Glimepiride 2-4 mg 0/114

Rosiglitazone 8 mg + Glimepiride 2-4 mg 0/232

Nauck, 200953

LEAD-2 RCT 26 wks

Glimepiride 4 mg plus Metformin 0/242

Liragultide 0.6 mg plus Metformin 0/242

Liragultide 1.2 mg plus Metformin 0/241

Liragultide 1.8 mg plus Metformin 0/242

Placebo plus Metformin 0/121

Russell-Jones, 

200954 LEAD-5 RCT 26 wks

Insulin glargine (long-acting) added to 

metformin and sulfonylurea) 0/232

Liraglutide added to metformin and 

sulfonylurea) 2.2 (5/230)

Placebo added to metformin and sulfonylurea) 0/114

Chou, 200855 RCT 28 wks

Glimepiride (G) 1–4 mg 0/225

Rosiglitazone (R) 4-8 mg 0/232

R to 4 mg + G to 4 mg (Regimen A) 0.4 (1/225)

R to 8 mg + G to 4 mg (Regimen B) 0.9 (2/219)

Standl, 2006180 RCT 24 wks

Glimepiride 2-4 mg + Insulin glargine, morning 

administration + .3 (4/299)

Glimepiride 2-4 mg + Insulin glargine, bedtime 

administration 0.7 (2/281)

Heine, 200542 RCT 26 wks

Adjunct Exenatide 20 μg added to oral therapy 

(metformin and sulfonylurea) 1.4 (4/282)

Adjunct Insulin glargine added to oral therapy 

(metformin and sulfonylurea) 1.5 (4/267)
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Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Kendall, 200556 RCT 30 wks

Adjunct Exenatide 20 μg to oral therapy 

(metformin and sulfonylurea) 0/241

Adjunct Exenatide 10 μg to oral therapy 

(metformin and sulfonylurea) 0.4 (1/245)

Adjunct Placebo to oral therapy (metformin 

and sulfonylurea) 0/247

Drouin, 200432 RCT 10 mos Gliclazide modified release 30–120 mg 0/401

Gliclazide 80–120 mg 0.3 (1/399)

Schernthaner, 

200457 RCT 27 wks Glimepiride 1–6 mg 0/440

Gliclazide 30–120 mg 0/405

Fritsche, 200344 RCT 24 wks

Glimepiride 3 mg + NPH insulin 2.6 (6/232)

Glimepiride 3 mg + Bedtime Insulin glargine 1.8 (4/227)

Glimepiride 3 mg + Morning Insulin glargine 2.1 (5/236)

UK 

Hypoglycemia 

Group190

Prospective 

cohort 9-12 mos

Sulfonylurea 7.0 (8/108)

Treated with insulin for <2 years ~7.0* (6/89)

Treated with insulin for >5 years ~25.0* (19/77)

Holstein, 200117

Prospective 

populationbased cohort4 yrs

Overall 5.6/100,000 

inhabitants/yr

Glimepiride 2 mg

0.3 (6/1768)

0.86/1000 person 

yrs

Gilbenclamide 7 mg 2.2 (38/1721)

5.6/1000 person yrs

Asche, 200823 Retrospective 

cohort

395 days 

of followup

Sulfonylurea monotherapy 2.6 (55/2117)

Sulfonylurea with Insulin 2.8 (3/106)

Thiazolidinedione with insulin 4.3 (8/187)

Thiazolidinedione monotherapy 1.7 (12/702)

Metformin 0/2326

Bodmer, 200824

N=50,048 

of which 73 

had severe 

hypoglycemia

Retrospective 

cohort with 

nested case 

control

NR/NA Sulfonylurea

110/100,000

person yrs

(22 patients on 

monotherapy

[16 gliclazide,

5 glibenclamide,

1 glimepiride],

11 combined with 

metformin)

Leese, 200325 Retrospective 

cohort NR/NA Sulfonylurea

0.8 (23/2823)

0.09/100 patient yrs 

[95%CI 0.6 to 1.3]

Stahl, 199928 Retrospective 

case series 12 yrs

Long-acting Sulfonylureas 

2.7 (16/594)

(15 glibenclamide, 

1 chlorpropamide)

Short-acting Sulfonylureas 0.9 (12/1334)

Glibornuride 0.9 (10/1138)

Gliclazide 1.0 (2/196)

Any Sulfonylurea 1.5 (28/1928)

* Not reported, estimated from figure
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Table 3d. Metformin (Biguanides) Studies

Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Arechavaleta, 

201152 RCT 30 wks Metformin with adjunct glimepiride 1-6 mg 1.5 (8/519)

Metformin with adjunct sitagliptin 100 mg 0.2 (1/516)

Matthews, 201049 RCT 2 yrs Metformin with adjunct glimepiride 2-6 mg 1.8 (15/1546)

Metformin with adjunct vildagliptin 100 mg 0/1553

Olansky, 2011178 RCT 44 wks Metformin up to 2000 mg 0/625

Metformin and sitagliptin up to 100 mg 0/621

Aschner, 201060 RCT 24 wks Metformin 2000 mg 0/522

Sitagliptin 100 mg 0.4 (2/528)

Pratley, 2010179 RCT 26 wks

Metformin with adjunct sitagliptin 100 mg 0/219

Metformin with adjunct liragultide 1.2 mg 0.4 (1/225)

Metformin with adjunct liragultide 1.8 mg 0/221

Seck, 2010;50

Nauck, 2007177 RCT 2 yrs

Metformin with adjunct Sitagliptin 100 mg 

Non-med. Assist.

0.2 (1/588)

Med. Assist.

0.2 (1/588)

Metformin with adjunct Glipizde 5 mg 

Non-med. Assist.

1.5 (9/584)

Med. Assist.

1.5 (9/584)

Nauck, 200953

LEAD-2 RCT 26 wks

Liragultide 0.6 mg plus Metformin 0/242

Liragultide 1.2 mg plus Metformin 0/241

Liragultide 1.8 mg plus Metformin 0/242

Glimepiride 4 mg plus Metformin 0/242

Placebo plus Metformin 0/121

Raskin, 200931 RCT 26 wks

Metformin 2000 mg and repaglinide bid 

(maximum dose 4 mg) 0/177

Metformin tid (doses 1000,500,1000 mg) 

and repaglinide tid (maximum doses 4,2, 

and 4 mg)

0/178

Metformin 2000 mg and rosiglitazone bid 

(maximum dose 4 mg) 0/206

Russell-Jones, 

200954

LEAD-5

RCT 26 wks

Insulin glargine (long-acting) added to 

metformin and sulfonylurea) 0/232

Liraglutide added to metformin and 

sulfonylurea) 2.2 (5/230)

Placebo added to metformin and 

sulfonylurea) 0/114

WilliamsHerman, 2009;113

Goldstein, 

2007181

Patients could be 

on oral meds

RCT 54 wks

Metformin (M) 500 mg 1.1 (2/182)

Metformin 1000 mg 0/182

Sitagliptin 100 mg 0/179

Sitagliptin 50 mg +

Metformin 500 mg 0/190

Placebo/ Metformin 1000 mg 0/176

Zinman, 2009 RCT 26 wks

Metformin (M) 2 g + rosiglitazone (R) 8 mg 

and liraglutide 1.2 mg 0/178

M+R and liraglutide 1.8 mg 0/178

M+R and placebo 0/177
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Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Bolli, 2008172 RCT 24 wks

Adjunct Pioglitazone 30 mg + metformin ≥ 

1500 mg 0/281

Adjunct Vildagliptin 100 mg + metformin ≥ 

1500 mg 0/295

Heine, 200542 RCT 26 wks

Adjunct Exenatide 20 μg added to oral 

therapy (metformin and sulfonylurea) 1.4 (4/282)

Adjunct Insulin glargine added to oral 

therapy (metformin and sulfonylurea) 1.5 (4/267)

Kendall, 200556 RCT 30 wks

Adjunct Exenatide 20 μg to oral therapy 

(metformin and sulfonylurea) 0/241

Adjunct Exenatide 10 μg to oral therapy 

(metformin and sulfonylurea) 0.4 (1/245)

Adjunct Placebo to oral therapy (metformin 

and sulfonylurea) 0/247

UKPDS 28 

1998191 RCT 3 yrs Adjunct metformin to 2250 mg + sulfonylurea 0.3 (1/291)

Sulfonylurea 0/300

Bodmer, 200824

N=50,048 

of which 73 

had severe 

hypoglycemia

Retrospective 

cohort with 

nested casecontrol

NR/NA Metformin

60/100,000

person yrs

(3 patients on 

monotherapy,

11 combined with 

sulfonylurea)

Asche, 200823 Retrospective 

cohort

395 days of 

followup

Metformin 0/2326

Sulfonylurea monotherapy 2.6 (55/2117)

Sulfonylurea with Insulin 2.8 (3/106)

Thiazolidinedione monotherapy 1.7 (12/702)

Thiazolidinedione with insulin 4.3 (8/187)

Leese, 200325 Retrospective 

cohort NR/NA Metformin or diet

0.05/100 patient 

yrs [95% CI 0.01 

to 0.2]

Table 3e. Dipeptidyl-Peptidase-4 Inhibitors (DPP-4) Studies

Study and year Study type Study 

duration

Intervention (daily dose) 

Control

Hypoglycemia 

Incidence % (n/N)

Arechavaleta, 

201152 RCT 30 wks

Adjunct Sitagliptin 100 mg added to 

metformin 0.2 (1/516)

Adjunct Glimepiride 1-6 mg added to 

metformin 1.5 (8/519)

Matthews, 201049 RCT 2 yrs

Adjunct Vildagliptin 100 mg added to 

metformin 0/1553

Adjunct Glimepiride 2-6 mg added to 

metformin 1.8 (15/1546)

Olansky, 2011178 RCT 44 wks

Sitagliptin up to 100 mg and metformin up to 

2000 mg 0/625

Metformin up to 2000 mg 0/621

Aschner, 201060 RCT 24 wks Sitagliptin 100 mg 0.4 (2/528)

Metformin 2000 mg 0/522
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in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

Study and year Study type Study 

duration

Intervention (daily dose) 

Control

Hypoglycemia 

Incidence % (n/N)

Pratley, 2010179 RCT 26 wks

Adjunct Sitagliptin 100 mg added to 

metformin 0/219

Adjunct Liragultide 1.2 mg added to 

metformin 0.4 (1/225)

Adjunct Liragultide 1.8 mg added to 

metformin 0/221

Seck 2010;50

Nauck, 2007177 RCT 2 yrs

Adjunct Sitagliptin 100 mg added to 

metformin

Non-med. Assist.

0.2 (1/588)

Med. Assist.

0.2 (1/588)

Adjunct Glipizde 5 mg added to metformin

Non-med. Assist.

1.5 (9/584)

Med. Assist.

1.5 (9/584)

Williams-Herman, 

2009;113 Goldstein, 

2007181

Patients could be 

on oral meds

RCT 54 wks

Sitagliptin 100 mg 0/179

Sitagliptin 50 mg + Metformin 500 mg 0/190

Sitagliptin 50 mg + Metformin 1000 mg 0/182

Metformin 500 mg 1.1 (2/182)

Metformin 1000 mg 0/182

Placebo/ Metformin 1000 mg 0/176

Bolli 

2008/2009172, 173 RCT 24 wks

Adjunct Vildagliptin 100 mg + 

metformin ≥ 1500 mg 0/295

Adjunct Pioglitazone 30 mg + 

metformin ≥ 1500 mg 0/281

Aschner, 2006136

Patients could be 

on oral meds

RCT 24 wks

Sitagliptin 100 mg 0/238

Sitagliptin 200 mg 0/250

Placebo 0/253

Table 3f. Glucagon-like Peptide-1 (GLP-1) Analogs Studies

Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Garber, 201151 RCT 52 wks

Liragultide 1.2 mg 0/251

Liragultide 1.8 mg 0/247

Glimepiride 8 mg 0/248

Pratley, 2010179 RCT 26 wks

Adjunct Liragultide 1.2 mg added to metformin 0.4 (1/225)

Adjunct Liragultide 1.8 mg added to metformin 0/221

Adjunct Sitagliptin 100 mg added to metformin 0/219

Marre, 2009175 RCT 52 wks

Liragultide 0.6 mg + glimepiride 2-4 mg 0/233

Liragultide 1.2 mg + glimepiride 2-4 mg 0/228

Liragultide 1.8 mg + glimepiride 2-4 mg 1.7 (4/234)

Glimepiride 2-4 mg 0/114

Rosiglitazone 8 mg + Glimepiride 2-4 mg 0/232

Nauck, 200953

LEAD-2 RCT 26 wks

Liragultide 0.6 mg plus Metformin 0/242

Liragultide 1.2 mg plus Metformin 0/241

Liragultide 1.8 mg plus Metformin 0/242

Glimepiride 4 mg plus Metformin 0/242

Placebo plus Metformin 0/121
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Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Russell-Jones, 

200954

LEAD-5

RCT 26 wks

Liraglutide added to metformin and 

sulfonylurea) 2.2 (5/230) 

Insulin glargine (long-acting) added to 

metformin and sulfonylurea) 0/232

Placebo added to metformin and sulfonylurea) 0/114

Zinman, 2009182 RCT 26 wks

Liragultide 1.2 mg plus Metformin (M) 2 g + 

rosiglitazone (R) 8 mg 0/178

Liragultide 1.8 mg and M + R 0/178

Placebo and M + R 0/177

Heine, 200542 RCT 26 wks

Adjunct Exenatide 20 μg added to oral therapy 

(metformin and sulfonylurea) 1.4 (4/282)

Adjunct Insulin glargine added to oral therapy 

(metformin and sulfonylurea) 1.5 (4/267)

Kendall, 200556 RCT 30 wks

Adjunct Exenatide 20 μg to oral therapy 

(metformin and sulfonylurea) 0/241

Adjunct Exenatide 10 μg to oral therapy 

(metformin and sulfonylurea) 0.4 (1/245)

Adjunct Placebo to oral therapy (metformin 

and sulfonylurea) 0/247

* One event in the liraglutide1.8 mg group occurred after regular insulin was infused during the extension period (post 52 weeks)

Table 3g. Bari 2D, Insulin Sensitization versus Insulin Provision

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence % (n/N)

BARI 2D*58 RCT 5.3 yrs

Insulin sensitization therapy 5.9 (68/1153)

Insulin-provision therapy 9.2 (106/1154)

P=0.003

* Medication use among all patients was as follows: metformin 54%; sulfonylurea 53%; insulin 28%; any thiazolidinedione 19%; 

rosiglitazone 10%.

Table 3h. Amylin Analog Studies

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence % (n/N)

Ratner, 200234 RCT 52 wks

Adjunct Pramlintide 30 μg tid to insulin 

therapy (some patients were also on oral 

agents)

1.6 (2/122)

Adjunct Pramlintide 75 μg tid to insulin 

therapy (some patients were also on oral 

agents)

0.7 (1/136)

Adjunct Pramlintide 150 μg tid to insulin 

therapy (some patients were also on oral 

agents)

1.4 (2/144)

Adjunct Placebo to insulin therapy (some 

patients were also on oral agents) 1.5 (2/136)
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in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence % (n/N)

Pencek, 201020 Prospective 

cohort 6 mos Adjunct Pramlintide to insulin therapy (some patients were also on oral agents)

Patient-ascertained

severe 

hypoglycemia

1) adjustment 

period (0–3 

months)

2.8% (n=531);

2) maintenance 

period (>3–6 

months)

0.4% (n=387)

Medicallyassisted severe 

hypoglycemia

1) adjustment 

period

(0–3 months)

0.4% (n=531);

2) maintenance 

period (>3–6 

months)

0.3% (n=387)

Table 3i. Glinide Studies

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence* % (n/N)

Raskin, 200931 RCT 26 wks

Repaglinide bid (maximum dose 4 mg) /

metformin 2000 mg 0/177

Repaglinide tid (maximum doses 4,2, and 4 

mg)/metformin tid (doses of 1000,500,1000 

mg) 

0/178

Rosiglitazone bid (maximum doses 4 mg)/

metformin 2000 mg 0/206

Saloranta, 200259

Serious events 

rare (Not reported)

Diet alone 

subjects

RCT 24 wks

Nateglinide 30 mg tid 0/166

Nateglinide 60 mg tid 0/175

Nateglinide 1200 mg tid 0/171

Placebo tid 0/163

* Requiring assistance from an outside party

Table 3j. Thiazolidinedione Studies

Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Marre, 2009175 RCT 26 wks

Rosiglitazone 8 mg + Glimepiride 2-4 mg 0/232

Glimepiride 2-4 mg + liragultide 0.6 mg 0/233

Glimepiride 2-4 mg + liragultide 1.2 mg 0/228

Glimepiride 2-4 mg + liragultide 1.8 mg 1.7 (4/234)

Glimepiride 2-4 mg 0/114
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Predictors and Consequences of Severe Hypoglycemia 

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Study and year Study type Study

duration

Intervention (daily dose)

Control

Hypoglycemia

Incidence % (n/N)

Raskin, 200931 RCT 26 wks

Rosiglitazone bid (maximum dose 4 mg) /

metformin 2000 mg 0/206

Repaglinide bid (maximum dose 4 mg) /

metformin 2000 mg 0/177

Repaglinide tid (maximum doses 4,2, and 4 

mg)/metformin tid (doses 1000-500-1000 mg) 0/178

Zinman, 2009182 RCT 26 wks

Rosiglitazone (R) 8 mg + Metformin (M) 2 g 

and liraglutide 1.2 mg 0/178

R + M and liraglutide 1.8 mg 0/178

R + M and placebo 0/177

Bolli, 2008172 RCT 24 wks

Adjunct Pioglitazone 30 mg + metformin ≥ 

1500 mg 0/281

Adjunct Vildagliptin 100 mg + metformin ≥ 

1500 mg 0/295

Chou, 200855

Drug-naive 

subjects

RCT 28 wks

Glimepiride (G) 1–4 mg 0/232

Rosiglitazone (R) 4-8 mg 0/225

R to 4 mg + G to 4 mg (Regimen A) 0.4 (1/225)

R to 8 mg + G to 4 mg (Regimen B) 0.9 (2/219)

Dormandy, 

2005174

(PROactive)

RCT 34.5 mos

Adjunct Pioglitazone 15-45 mg + other 

glucose lowering drugs 0.73 (19/2605)

Adjunct Placebo + other glucose lowering 

drugs 0.42 (11/2633)

Asche, 200823 Retrospective 

cohort

395 days of 

followup

Thiazolidinedione monotherapy 1.7 (12/702)

Thiazolidinedione with insulin 4.3 (8/187)

Sulfonylurea monotherapy 2.6 (55/2117)

Sulfonylurea with Insulin 2.8 (3/106)

Metformin 0

Table 3k. Studies in Which Patients are on a Variety of Medications

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence % (n/N)

Davis, 201016

Prospective 

communitybased cohort6.4 yrs Several, not described

8.4 (52/616)

1.7 per 100

patient-years

Quilliam, 2011183

Retrospective 

cohort of 

working-age 

patients

Patients 

who were 

represented 

for at least 

one year in a 

database

The most common classes of OHAs were 

metformin (75.7%), sulfonylureas (42.3%), 

and thiazolidinediones (33.3%). Insulin 

use in addition to OHA use was relatively 

infrequent, (6.0%) 

3.5 (653/18,657)

1.5 per 100

patient-years

Table 3l. Management (Self vs. GP or Nurse Management) Studies

Study and year Study type Study

duration

Intervention

Control

Hypoglycemia

Incidence % (n/N)

Barnett, 2008171 RCT 27 wks

Gliclazide - self-monitoring of blood

glucose (SMBG) 0/311

Gliclazide – Non-SMBG 0/299

Meneghini 

(PREDICTIVE) 

2007176

RCT 26 wks

Insulin detemir - Algorithm care 0.26 events per 

patient years

Insulin detemir - Standard care 0.20 events per 

patient years
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urvey 

istance from 

o treat the 

receding year

pleted, 66 at least 

otal episodes, 

 of severe 

44 episodes/

Univariate analysis (RAE – risk of any event, RRE – risk of repeated events) 

RAE OR 95% CI p value RRE RR 95% CI p value

Age 1.01 0.99–1.04 0.366 0.98 0.97–1.00 0.030

Diabetes duration 1.02 0.98–1.06 0.400 0.96 0.94–0.98 < 0.001

Diabetes duration prior to insulin start 0.98 0.93–1.02 0.403 0.93 0.91–0.96 < 0.001

Duration of insulin therapy 1.07 1.01–1.13 0.018 0.99 0.96–1.02 0.370

Impaired awareness 2.66 1.55–4.56 < 0.001 1.18 0.87–1.59 0.229

Insulin regimens:Twice daily 2.89 0.67–12.6 0.157 0.45 0.25–0.87 0.017

Three times daily 2.07 0.27–16.1 0.489 0.18 0.04–0.82 0.027

Four times daily 4.81 1.05–22.1 0.043 0.54 0.28–1.03 0.059

Retinopathy (untreated) 0.99 0.56–1.78 0.979 0.63 0.45–0.86 0.004

Peripheral neuropathy (asymptomatic) 1.64 0.80–3.39 0.181 2.00 1.33–2.99 0.001

Peripheral neuropathy (symptomatic) 1.69 0.92–3.11 0.089 1.42 0.97–2.07 0.071

Hypertension 0.57 0.33–0.97 0.039 1.40 1.03–1.90 0.033

Hypertension therapy:RAS blocking 0.89 0.31–2.54 0.826 0.65 0.39–1.08 0.096

Non-RAS blocking drugs 1.55 0.65–3.71 0.323 0.38 0.24–0.59 < 0.001

Combination of both 0.63 0.27–1.43 0.266 0.65 0.44–0.95 0.027

Macrovascular complication (stroke, MI) 1.14 0.57–2.27 0.719 1.78 1.28–2.48 0.001

Metformin 0.51 0.25–1.01 0.052 1.05 0.72–1.55 0.789

Marital status (married) 2.57 1.32–5.01 0.006 1.19 0.80–1.79 0.393

Exercise (strenuous) 0.49 0.19–1.31 0.154 2.06 1.33–3.18 0.001

Smoking 0.74 0.38–1.46 0.389 1.43 1.02–2.02 0.041

Use of tranquilizers 1.66 0.93–2.98 0.087 1.57 1.17–2.12 0.003

Multivariate analysis - Risk of any eventImpaired awareness 3 fold increased risk of any eventLong duration of DM (per 10 years) 2 fold increased risk of any eventBeing married 2 fold increased risk of any eventRate of severe hypoglycemia (risk of repeated events)Peripheral neuropathy 3x increased rateLong duration of DM (per 10 years) prior to insulin therapy 3x decreased rateTx with RAS blocking drugs 1⁄2 rate of severe hypoglycemia
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atients

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oss-sectional, 

r to question 

elt symptoms of 

w blood sugar) in 

ed assistance of 

e symptoms

al attention, 

aw doctor or nurse

Patient reported outcomes and HbA1c goal statusCharacteristic patients at goal patients not at goal p value

Hypoglycemic symptoms who felt the need for assistance, including medical attention, to manage symptoms 

5.8 (11/190) 4.8 (22/462) 0.0152* 

*This p value was combined with other hypoglycemia symptom severities 

gender and age

mmol/l

tose,3 reduced 

ve fully alert 

mptoms of 

d sought medical 

lipizide, - 19 with 

emia 844 controls

Cases Controls P value

Duration of diabetes (months) 36 (14-48) 75 (52-108) 0.004Duration of sulfonylurea treatment (months) 14 (6-43) 51 (34-75) 0.004Duration of glipizide treatment (months) 12 (3-26) 41.5 (26-59) <0.001Glipizide dose (mg day) 10 (5-15) 10 (5-15) NSNumber of concomitant drugs (excluding glipizide) 5 (3.5-5) 2 (1-1) <0.001Cardiac Disorders, Renal Disorders, Liver Disorders, Cerebral Disorders all more common in hypoglycemia groupOnly significant in renal disease: OR 4.0 95% CI 1.2-13.1Circulatory disease 14/19 (74%)Hepatic failure (moderate) 2/19 (11%)Other meds taken by cases:Diuretic 13/19 (68%);Cardiac clycosides 6/19; Benzodiazepines 5/19; NSAIDS 4/19; beta-blocker 4/19; salicylates 4/19Significant drug ORs (cases vs. controls):Any diuretic OR=8.5 (CI 1.7-29.3)Benzodiazepines OR=10.0 (CI 1.4-71.8)
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trol within 

ort

evere 

djusted for generic 

ading to an 

talization or death

cts, 7,278 

ad severe 

“Numbers too small for a meaningful model.” – formal risk analysis not performedOf 73 case subjects35 were on insulin (26 were on insulin only and 9 used insulin in combination with an oral antidiabetes drug)22 used sulfonylureas only3 metformin only11 a combination of sulfonylureas and metformin2 were past users of antidiabetes drugs. Among 22 users of sulfonlyureas only, 16 used gliclazide, 5 glibenclamide, and 1 glimepiride, and 17 used a high dose and 5 a low dose.

ort 

ultivariate

hazards;

al regression 

emia

ave you ever 

spital because 

c attack?” or 

ad a serious 

ack that made you 

”

se for 

SH)(used as 

emia during 

g ambulance y department 

or hospitalization 

 as the primary 

 during followup

At study entry:No significant independent associations between dementia and any measure of hypoglycemia, however:Cognitive impairment without dementia: 

Self reported severe hypoglycemia (OR 2.96 (1.05-8.33))Doctor verified neuroglycopenia (OR 5.10 (1.46-17.87))

HSH (OR 9.65 (1.65-56.60))

Significant Risk FactorsTime to first HSH

HR 95% CI p value 

Dementia 3.02 (1.07-8.53) 0.037

Insulin therapy 2.77 (1.18-6.46) 0.019

Low BMI 5.94 (1.85-19.06) 0.003

Inability to self manage medications 4.19 (1.43-12.25) 0.009

History of self reported severe hypoglycemia 3.51 (1.15-10.76) 0.028

Frequency of HSH

RR 95% CI p value

Dementia 20.26 (6.00-68.44) <0.001Insulin therapy 14.60 (3.49-61.12) <0.001Renal Impairment 4.70 (1.02-21.70) 0.048
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atients

Risk Factors for Severe Hypoglycemia OR Patient Characteristics If No Formal Risk Factor Analysis 

rt 

ultivariate

ich a patient with 

d/plasma/serum 

 health service use 

a was the primary 

es of severe 

Univariate associates HR (95% CI) p valueAge 65 yr or older 1.15 (0.65-2.02) 0.63Male sex 0.97 (0.56-1.67) 0.90BMI <29.0 kg/m^2 0.97 (0.56-1.68) 0.92Education attainment higher than primary level 1.65 (0.78-3.51) 0.19English ability (not fluent) 0.53 (0.19-1.48) 0.23Any exercise in past 2 wks 0.60 (0.34-1.04) 0.07Daily alcohol consumption of three or more standard drinks 1.38 (0.55-3.46) 0.50GAD ab positive 4.41 (1.75-11.10) 0.002Diabetes duration > or equal to 8 yr 2.92 (1.60-5.32) <0.001FSG >or equal to 8.0 mmol/liter 1.32 (0.73-2.38) 0.35AbA1c > or equal to 7.0% 2.11 (1.13-3.95) 0.020Sulfonylurea treatment (vs. lifestyle/other oral agents) 2.50 (1.16-5.38) 0.019Insulin treatment (+/- oral agents) 4.29 (2.44-7.55) <0.001Time on insulin (increase of 1 yr) 1.42 (1.24-1.63) <0.001Blood glucose self monitoring 1.01 (0.48-2.15) 0.98History of severe hypoglycemia 6.59 (2.62-16.60) <0.001eGFR <60 ml.min per 1.73 m^2 2.90 (1.68-5.00) <0.001Peripheral neuropathy 2.89 (1.60-5.21) <0.001Orthostatic hypotension 1.74 (0.99-1.15) 0.34QTc interval (increase of 10 msec^0.5) 1.05 (0.95-1.15) 0.34Five or more prescribed medications 1.84 (1.07-3.17) 0.028Anticoagulant therapy 2.93 (1.06-8.13) 0.039Regular aspirin use (> or equal to 75 mg/d) 1.31 (0.74-2.31) 0.36NSAID treatment 1.29 (0.61-2.74) 0.51Allopurinol treatment 1.62 (0.65-4.08) 0.30Fibrate treatment 1.86 (0.74-4.67) 0.19Beta-blocker treatment 1.26 (0.63-2.51) 0.51Hospitalized in 1998 1.77 (1.03-3.05) 0.039Independent associates HR (95% CI) p valueTime on insulin (increase of 1 yr) 1.33 (1.15-1.53) <0.001History of severe hypoglycemia 5.66 (2.21-14.50) <0.001eGFR <60 ml/min per 1.73 m^2 2.39 (1.37-4.15) 0.002Peripheral neuropathy 2.44 (1.33-4.47) 0.004Education attainment higher than primary level 2.34 (1.09-5.04) 0.029
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mantle

rt patients 

ented health 

E genotyped, 49 

 63 episodes of 

Independent baseline predictors of time to first severe hypoglycemic event and frequency of severe hypoglycemia during follow-upTime to first event Hazard ratio (95% CI) p valueTime on insulin (increase of 1 yr) 1.33 (1.15–1.53) 0.001History of severe hypoglycemia 5.48 (2.05–14.64) 0.001eGFR _ 60 ml/min per 1.73m2 2.63 (1.46–4.73) 0.001Peripheral neuropathy 2.57 (1.36–4.84) 0.004Educational attainment beyond primary level 2.82 (1.25– 6.38) 0.013ACE DD genotype 2.35 (1.13–1.53) 0.006ACE-I use 1.77 (0.99 –3.13) 0.052Frequency Incidence rate ratio (95% CI) p valueLogit modelTime on insulin (increase of 1 yr) 0.34 (0.18–0.66) 0.001eGFR _ 60 ml/min per 1.73m2 0.18 (0.06–0.50) 0.001Peripheral neuropathy 0.18 (0.06–0.49) 0.001Educational attainment beyond primary school level 0.17 (0.04–0.87) 0.033Count modelHbA1c (increase of 1%) 1.36 (1.08 –1.71) 0.009FSG (increase of 1 mmol/liter) 0.83 (0.73– 0.94) 0.004ACE DD genotype 1.80 (1.00 –3.24) 0.050

or equal to 72 in 

ological clinical 

t with a severely 

state or worse, 

hould respond to 

ts with 

d 188 without 

Variable OR (95% CI) p valueAge (years) 0.95 (0.88-0.09) 0.008Diabetes duration (years) 1.110 (1.05-1.2) 0.001Illiteracy-primary 3.7 (1.4-10.0) 0.009Attending physician (FP) 2.8 (1.02-7.9) 0.04Chronic renal failure (yes) 3.0 (1.2-7.7) 0.01Missed meals (yes) 19.8 (9.1-43.1) <0.001Previous hypoglycemia (yes) 2.9 (1.3-6.5) 0.01Combined therapy (yes) 5.2 (2.3-11.8) <0.01Polypharmacy use (yes) 4.9 (0.7-35.1) 0.11
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hort

at led to 

ulin)

nts: low carb 

ange in therapy 

dministration of 

ith other typical 

 as education)

mes:

yndrome

0% Insulin, p=0.85

0 days Insulin, 

p

4% Insulin p=0.02

Characteristic OHAs Insulin p valueAge, years 79.7 (11.4) 74.7 (10.1) 0.009Male sex (%) 46.0 41.3 0.66Institutionalized (%) 7.9 4.8 0.73First blood glucose (mg/dl) 38.2 (11.2) 39.7 (11.5) 0.33Coma (%) 54.0 30.2 0.002Fall (%) 25.4 17.5 0.27Duration of hypoglycemia (h) 8.1 (8.9) 3.9 (4.3) 0.001HbA1c (%) 6.75 (1.0) 8.1 (2.1) <0.001Serum creatinine (mmol/l) 106.6 (45.4) 120.6 (115.9) 0.64eGFR >60 ml/min/1.73 m2 37 43 0.63eGFR 30–59 ml/min/m2 21 16 0.32eGFR 15–29 ml/min/m2 5 1 0.09eGFR <ml/min/m2 0 3 0.080–4 years from diagnosis(%) 39.7 26.9 0.135–9 years from diagnosis (%) 17.5 9.5 0.1910–19 years from diagnosis (%) 17.4 19.1 0.8220+ years from diagnosis (%) 25.4 44.5 0.03Obesity (%) 30.2 23.8 0.27Dyslipidemia (%) 19.0 12.7 0.74Hypertension (%) 79.4 79.4 0.78Coronary artery disease (%) 39.7 31.7 0.53Peripheral artery disease (%) 47.6 38.1 0.27Retinopathy (%) 9.5 27.0 0.007Known neuropathy (%) 6.3 17.5 0.023Liver disease (%) 3.2 25.4 0.001Cancer (%) 12.7 22.2 0.25COPD (%) 22.2 11.1 0.19Rheumatoid arthritis (%) 0.0 3.2 0.25Dementia (%) 3.2 4.8 0.44Beta-blockers (%) (selective (%)) 19.0 (19.0) 15.9 (12.7) 0.56ACE inhibitors (%) 58.7 61.9 0.52Aspirin (%) 57.1 41.3 0.46NSAIDs (%) 1.6 3.2 0.41Cimetidine (%) 0.0 1.6 0.25CNS depressants (%) 15.9 17.5 0.49
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l assistance, 

stive of 

at had resolved 

nt with oral 

had required 

renteral glucose 

2 people

r patient per year

Frequency of severe hypoglycemia increased with:Age (p<0.05 r=0.2)Duration of diabetes (p<0.05, r=0.2)Duration of insulin therapy (p<0.05, r=0.2)Impaired awareness (9 fold higher rate) – not associated with age duration of DM, or duration of tx with DMNormal awareness: 0.22 episodes/patient/yearImpaired awareness 2.15 episodes/patient/yearNo association with:Lower HbA1cHigher insulin dose

hich the patient was 

propriate restorative 

d the assistance 

for treatment 

in the hospital) to 

oral or parenteral 

on by injection

atients

r=0.39 (p<0.001) - # episodes and duration of insulinAll patients with partial awareness (n=6) and 3 of 80 (4%) with normal awareness had severe hypoglycemia in past yearCharacteristic No Severe Hypoglycemia (n=62) Severe hypoglycemia (n=25)Age (years) 62 ± 8 64 ± 11Body mass index 28 ± 5 26 ± 4Duration of diabetes (yrs) 11 13Duration of insulin therapy (yrs) 2 6Daily insulin dose (U/kg) 0.6 0.7Glycated hemoglobin (%) 10.4 10.7

ance needed

Hypoglycemic events (no/patient/year) Biphasic Prandial Basal

All patients Grade 3 0 0 0

Patients with an HbA1c of less than or equal to 6.5% Grade 3 0 0 0 
128

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vent requiring 

 glucose and 

BG of <50 mg/dl 

e hypoglycemia All 

nd no insulin

Characteristic Control (n=54) Severe Hypoglycemia (n=43) p valueSex (male / female) 28 / 26 20 / 23 0.60 *Age (years) 80.1 ± 8.8 75.2 ± 10.4 0.01BMI (kg / m 2 ) 26.80 ± 4.73 26.72 ± 4.67 0.94Creatinine (mg/ dl) 1.83 ± 1.23 1.53 ± 0.93 0.18Creatinine clearence (ml / min) 38.89 ± 18.85 48.91 ± 23.65 0.02HbA 1c ( % ) 7.15 ± 0.96 6.73 ± 1.28 0.07Age at onset of diabetes (years) 69.1 ± 12.3 66.1 ± 14.3 0.30Diabetes duration (years) 10.8 ± 8.1 8.6 ± 11.3 0.30Co-medication (number of all drugs) 7 ± 2 6 ± 3 0.08Metformin treatment (number of patients) 22 13 0.28 *Variable Univariate analysis OR and p value Multivariate analysis and p value

Gender 0.81 (0.36 – 1.80) 0.60 0.79 (0.30 – 2.07) 0.63

Age (years) 0.95 (0.91 – 0.99) 0.02 0.92 (0.88 – 0.98) 0.005Diabetes duration (years) 0.97 (0.93 – 1.03) 0.31 0.96 (0.91 – 1.01) 0.11Sulfonylurea daily dose (mg) 1.16 (0.99 – 1.36) 0.07 1.25 (1.03 – 1.52) 0.02

HbA 1c ( % ) 0.69 (0.45 – 1.04) 0.08 0.67 (0.42 – 1.05) 0.08

KCNJ11 (E23K) 0.54 (0.30 – 0.98) 0.04 0.68 (0.34 – 1.35) 0.27

vent requiring 

IV glucose or 

on glimepiride, 56 

Glimepiride (n=37) Glibenclamide (n=56) Treatment Differences (95% CI) p value

Age (years) 77.1±11.2 (43–93) 78.1±9.6 (43–97) -1.0 (-6.0; 4.0) 0.721

Female sex (%) 57% (21/37) 61% (34/56) -4.0% (-24.4; 16.5) 0.830

Body mass index 24.6±4.5 (16.9–38.4) 24.8±4.5 (17.8–36.9) -0.2 (-2.6; 2.2) 0.942

Duration of diabetes (years) 7.0±7.0 (0–32) 10.5±8.7 (0–33) -3.5 (-7.4; 0.4) 0.095

HbA1c (HPLC; non-diabetic range 3.4–4.9%)

5.4±0.7 (4.6–7.7) 5.2±0.9 (3.7–7.5) 0.2 (-0.2; 0.6) 0.345

Initial blood glucose (mmol/l) 1.9±0.66 (0.78–2.9) 1.8±0.89 (0–3.7) 0.1 (-0.24; 0.6) 0.443

Co-medication (number of drugs)

6.2±3.0 (0–15) 3.6±3.0 (0–16) 2.60 (1.2; 4.0) <0.001

Creatinine-clearance (ml/min) 38±23 (10–87) 54±32 (8–180) -16.0 (-30.1; -1.9) 0.016

Possible causes identified for 75 of 93 (81%): missed meals (59%), alcohol (15%), increased activity (5%), incorrect dosing (1%)
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vent requiring an 

cagon injection 

ptoms and 

y blood glucose 

n ED,

s per 100 patients 

DM2

 100 for overall 

Characteristic in type 2 DM (n=148) with SHAge (year) 76 +/- 12 (44-95)Percent female 64% (95/148)BMI 25.7 +/- 4.8 (15.8-39.7)Initial blood glucose (mg/dl) 34 +/- 16 (0-61)Diabetes duration 17 +/- 11 (0-40)HbA1c% 6.2 +/- 1.8 (3.9-15.5)Renal failure (cr clearance less than 60 ml/min) 54% (80/148)Comorbidity (number of concomitant diseases 3.6 +/- 2.6 (0-7)Comedication (number of drugs) 3.3 +/- 3.0 (0-18)Patients with recurrent hypoglycemia in the study period 12% (14/121)Characteristic CT (n=78) SU (n=45) CT+SU (n=25) pvalue pvalue pvalue

CT vs SU CT vs CT+SU SU vs CT+SU

Age (year) 76 +/- 11) 79 +/- 13 72 +/- 10 0.176 0.109 0.023Percent female 63% 62% 44% 1.000 0.109 0.209BMI 25.0 +/- 5.1 24.4 +/- 5.0 24.4 +/- 3.3 

Diabetes duration (years)

19+/-10 12+/-10 16+/-10 <0.001 0.195 0.113

Initial blood glucose 38+/-19 31+/16 34+/-16 0.040 0.345 0.455HbA1c % 6.7+/-2.0 5.4+/-0.9 6.6+/-1.8 <0.001 0.824 <0.001Insulin dose 37+/-18 27+/-20 0.017 Frequency and dose of glibenclamide

n=38, 6.1+/- 3.1 n=18, 7.2+/-1.1

Frequency and dose of glimepiride 

n=6, 2.5+/-0.8 n=7 2.1+/-0.6 

Comedication (number of drugs) 

3.7 +/- 2.5 3.8 +/- 2.8 5.2 +/- 3.6 0.838 0.022 0.075

Renal failure (cr cl < 60 ml/min) 

53% (41/78) 58% (26/45) 52% (13/25) 0.707 1.000 0.802

Attributed causes for 68/148 (46%) episodes in type 2 patients: missed meals (59%), incorrect dosing (19%), alcohol (13%), increased activity (9%)
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nt requiring 

 glucose and was 

 <50 mg/dl

 101 controls

Basic characteristics of type 2 diabetic patients with sulfonylurea-induced hypoglycemia versus control groupVariable Severe hypoglycemia (n = 102) Control (n = 101) p value

Sex (female/male) 45/57 51/50 0.36

Age (years) 77.4 ± 9.2 79.3±9.2 0.13

Body mass index (kg/m2) 26.7±5.5 27.0±4.4 0.76

Serum creatinine (mg/dl) 1.55±0,87 1.72±1.03 0.19

Creatinine clearance (ml/min) 45.8±22. 6 38.0±18.1 0.02

HbA1c (%) 6.5±1.2 7.2±1.3 0.0004

Co-medication (number of drugs) 7.0±2. 8 7.4±2.8 0.28

Duration of diabetes (years) 11.0±9.9 11.5±8.3 0.71

Patients with glimepiride mean daily dose 76 (74.5%) 2.8±1.6 mg 81 (80.2%) 2.3±1.3 mg 0.33 (chi2) 0.04 (t-test)Patients with glibenclamide mean daily dose 25 (24.5%) 6.1±3.7 mg 1 8 (17.8%) 5.0±3.6 mg 0.2 (chi2) 0.3 (t-test)Patients with gliquidone mean daily dose 1 (1.0%) 30 mg 2 (2%) 60 mg 0.62 Additional treatment with metformin mean daily dose 37 (36%) 1731±602 mg 43 (43%) 1715±494 mg 0.36 (chi2) 0.90 (t-test)Additional treatment with insulin mean daily dose 29 (28%) 36.4±22 I.E. 20 (20%) 36.8±21.5 I.E. 0.15 (chi2) 0.96 (t-test)Co-medication with other CYP2C9 main substrates 24 (24%) 33 (49%) 0.001 (chi2)Co-medication with other drugs being at least one CYP2C9 substrate 39 (39%) 32 (47%) 0.30 (chi2)Risk factors for severe hypoglycemia in 102 sulfonylurea-treated type 2 diabetic patients with severe hypoglycemia versus control group (n=101)Variable Relative risk (95% CI) p value

HbA1c (%) 1.56 (1.20–2.04) 0.001Dose of sulfonylurea 1.00 (0.96–1.04) 0.95CYP2C9-genotypes *2/*2, *2/*3, and *3/*3 0.58 (0.14–2.50) 0.47Co-medication with other CYP2C9-main substrates 0.34 (0.17–0.65) 0.001Co-medication with other drugs being at least one CYP2C9-substrate 0.72 (0.39–1.34) 0.30Co-medication with insulin 1.61 (0.84–3.09) 0.15Co-medication with angiotensin-converting enzyme inhibitor 1.35 (0.77–2.34) 0.29Co-medication with analgetics 1.21 (0.59–2.50) 0.60Co-medication with gyrase inhibitors 0.99 (0.20–5.03) 0.99Presence of coronary heart disease 2.38 (1.35–4.18) 0.003Presence of heart failure 1.46 (0.84–2.55) 0.18Presence of dementia 1.97 (0.94–4.15) 0.09Previous participation at structured diabetes education 1.09 (0.59–2.00) 0.79Kind of accommodation (home vs. nursing home) 1.29 (0.87–1.92) 0.21
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rt 

vent requiring an 

cagon injection 

ptoms and 

y blood glucose 

n ED,

s per 100 patients 

DM2

 100 for overall 

Basic characteristics of the diabetic patients presenting with sulfonylurea-induced hypoglycemiaCharacteristic Glibenclamide Glibenclamide Glimepiride Treatment difference

+glimepiride (n=1) (n=38) (n=6) and 95% CI glibenclamide

vs glimepiride

Age (years) 84 83.5 83.5 0 (-17.1; 9.1)Sex (% female) 0% 63.2% 66.7% -3.5 (-44.1; 37.3)Diabetes duration (years) 4 6.0 16.0 -10 (-19.0; 0.8)BMI (kg/m2) 24.8 22.9 28.2 -5.3 (-10.7; 1.1)

Sulfonylurea dose (mg) 3.5 and 2 4.4 3.0 1.4 (0.6; 6.6)

Initial venous blood glucose (mmol/l) 

2.24 1.7 1.8 -0.1 (-0.97; 0.95)

HbA1c (HPLC; non-diabetic range 3.4–4.9%) 

5.6 5.25 4.7 0.55 (-0.3; 1.9)

Patients with impaired renal function 

1/1 (100%) 23/38 (60.5%) 4/6 (66.7%) -6.1% (-46.9; 34.7)

Co-medication (number of drugs) 

7 3.0 3.5 -0.5 (-3.7; 3.1)

Participation in diabetes education programs (%) 

0% 3% (1/38) 0% Not done

mic events: 

 assistance or 

No difference between allocations in the proportion of patients having hypoglycemic episodesAnnual rates of major hypoglycemic episodes over 5 yearsTime post randomization Captopril Atenolol Less tight control

n 247 223 228

1st year 2.5% 0.5% 0.8%

2nd year 0.9% 1.0% 0.4%

3rd year 0 1.0% 0.8%

4th year 1.0% 3.1% 0.9%

5th year 0.5% 1.6% 1.8%

Ever over 5 years 4.0% 4.9% 3.1%

hort 

uiring external help

 DM

Number HbA1c % Age (years) Duration of DM (years) BMI Sex (% male)

On insulin, no hypo 835 8.23 63.2 11.8 30.1 47.7

On insulin, hypo 66 7.87 66.6 13.5 26.7 47.0

P value 0.097 0.038 0.137 <0.001 0.914

On sulfonylurea, no hypo 2,800 7.16 65.4 6.3 29.6 52.2

On sulfonylurea, hypo 23 8.00 65.0 7.2 28.1 47.8

P value 0.064 0.884 0.517 0.122 0.687
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sted

glycemia requiring 

or be admitted to 

glycemia requiring 

ce (HMA), or 

se” requiring any 

cal or non medical 

 2003: plasma 

han 2.8 mmol/l (50 

ms that promptly 

bohydrate also a 

HR (95% CI) p value

HMA (both intensive and standard arms)Female (v male) 1.21 (1.02 to 1.43) 0.0300

Race <0.0001

 Non Hispanic white 1.0 African-American 1.43 (1.20 to 1.71) <0.0001

 Hispanic 0.93 (0.68 to 1.27) 0.6500

 Other 0.64 (0.47 to 0.88) 0.0100

History of CV disease (yes v no) 1.10 (0.94 to 1.28) 0.2200

History of peripheral neuropathy (yes v no) 1.19 (1.02 to 1.38) 0.0300

Time since diagnosis of diabetes (years) 0.7394 < or equal to 5 1.06-10 0.98 (0.77 to 1.24) 0.8500

11-15 1.06 (0.83 to 1.37) 0.6200

16+ 1.37 (1.09 to 1.73) 0.0100

BMI 0.0023

 <25 1.0 >or equal to 25 to< 30 0.78 (0.60 to 1.02) 0.0700

 30+ 0.65 (0.50 to 0.85) <0.0001

Albumin to creatinine ratio <0.0001

 <30 1.0 30-300 1.20 (1.02 to 1.43) 0.0300

 >300 1.74 (1.37 to 2.21) <0.0001

Serum creatinine (micromol/l) 0.0010

 <88.4 1.0 88.4-114.9 1.21 (1.02 to 1.43) 0.0300

 >114.9 1.66 (1.25 to 2.19) <0.0001

Age (per 1 year increase) 1.03 (1.02 to 1.05) <0.0001

sness or other 

of mental status 

lycemia that 

stance of another 

e condition

No significant predictors of severe hypoglycemiaAge, sex, race, diabetes duration, BMI, follow-up fasting plasma glucose level, follow-up HbA1c level, type of diabetes therapy, hypoglycemia at baseline visit, and whether diabetes medication therapy was increased at the baseline visit Patient Sex/Age, y BMI Diabetes HbA1c, % Therapy Type Insulin 

Number Duration, y Dosage, U/kg per day1 F/73.7 48.1 18.7 6.3 Insulin 0.322 F/53.2 29.6 6.4 5.6 Insulin and metformin 0.633 M/68.1 34.9 18.4 8.3 Insulin 0.514 F/74.2 26.6 23.3 8.3 Insulin 0.445 M/61.5 N/A 16.4 12.1 Insulin 0.32All black race
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trol 

quiring 

sed ICD9 codes

90 controls

Independent predictors of inpatient hypoglycemia admissions.Variable

Cases, % Controls, % Crude OR (95% CI) Adjusted OR*(95% CI)

(n 1339) (n 13,390)

GenderFemale 49.2 46.3 1.00 (N/A) 1.00 (N/A)

Male 50.8 53.7 0.89 (0.80–0.99) 0.84 (0.73–0.96)

Age, y18–34 1.3 2.1 1.00 (N/A) 1.00 (N/A)

35–49 13.3 21.1 0.99 (0.60–1.63) 1.01 (0.58–1.79)

50–64 82.6 74.5 1.75 (1.08–2.84) 1.14 (0.66–1.97)

_65 2.8 2.4 1.88 (1.04–3.39) 0.91 (0.46–1.81)

Oral diabetes medications†,‡Sulfonylureas: Continuous availability§ 41.1 30.0 2.36 (2.06–2.70) 2.25 (1.93–2.63)

Sulfonylureas: Intermittent availability 25.1 14.6 2.88 (2.48–3.35) 2.28 (1.90–2.74)

Metformin: Continuous availability§ 34.1 47.9 0.48 (0.42–0.55) 0.62 (0.53–0.73)Metformin: Intermittent availability 23.8 23.3 0.70 (0.60-0.81) 0.76 (0.64-0.92)

Thiazolidinediones:  Continuous availability§ 22.9 23.8 1.00 (0.87–1.15) 1.06 (0.90–1.24)Thiazolidinediones:  Intermittent availability 16.9 13.8 1.27 (1.09–1.49) 1.22 (1.01–1.47)

Other OHA: Continuous availability§ 4.5 3.9 1.15 (0.88–1.52) 1.11 (0.80–1.55)

Other OHA: Intermittent availability 3.7 3.2 1.17 (0.86–1.59) 1.09 (0.75–1.59)
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Cases, % Controls, % Crude OR (95% CI) Adjusted OR*(95% CI)

(n 1339) (n 13,390)

Other medications#Allopurinol 5.5 2.6 2.15 (1.66–2.78) 1.54 (1.13–2.12)Benzodiazepine 14.6 6.2 2.57 (2.17–3.03) 1.90 (1.55–2.33)Beta-blocker 35.1 21.3 2.01 (1.78–2.26) 1.20 (1.03–1.40)Blood glucose monitoring supplies 30.9 30.6 1.02 (0.90–1.15) 0.83 (0.71–0.96)Fluoroquinolone 10.7 2.5 4.69 (3.82–5.77) 2.59 (1.99–3.39)Insulin 16.8 6.7 2.84 (2.42–3.33) 2.23 (1.83–2.72)NSAID 13.8 10.4 1.38 (1.17–1.63) 1.27 (1.05–1.54)Trimethoprim 3.3 0.9 3.81 (2.68–5.41) 1.97 (1.26–3.08)Comorbid conditionsPrevious outpatient visit  for hypoglycemia 12.5 0.9 16.17 (12.60–20.76) 7.88 (5.68–10.93)Previous ED visit for hypoglycemia 6.2 0.1 48.53 (28.80–81.78) 9.48 (4.95–18.15)Macrovascular complicationsArrhythmia 6.8 1.4 5.25 (4.05–6.81) 1.69 (1.17–2.44)Coronary artery disease 21.0 7.8 3.12 (2.69–3.61) 1.48 (1.21–1.81)Heart failure 14.0 1.5 10.99 (8.86–13.64) 2.33 (1.72–3.15)Stroke 3.4 0.4 9.62 (6.37–14.52) 2.78 (1.62–4.77)Microvascular complicationsAcute renal failure 8.3 0.6 15.43 (11.43–20.83) 3.10 (2.05–4.67)Chronic renal pathophysiology 8.4 1.1 8.37 (6.49–10.81) 2.22 (1.56–3.15)Ulcer 6.4 1.4 4.98 (3.82–6.49) 1.71 (1.20–2.44)Charlson comorbidity (per 1 U change) 1.72 (1.66–1.79) 1.37 (1.32-1.44)*Adjusted for all factors listed in the table.†As identified in pharmacy claims in the 6 months before the index date.‡Nonavailability of the medication/class of medication is the referent group.§Participants with continuous availability had medication coverage in each of all six 30-day periods preceding the index date._Participants with intermittent availability had medication coverage in at least 1 of the preceding 6 intervals.¶Includes persons taking glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors, or meglitinides.#Defined as medication availability in the previous 30 days.
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e question “”In the 

any times have 

RE low blood 

uch as passing 

elp to treat the 

ncluded, 1,579 

nt hypoglycemia

Self reported Health literacy 

unadjusted OR (95% CI) adjusted OR (95% CI)

Problems learning 1.5 (1.3-1.8) 1.4 (1.1-1.7)Need help reading 1.5 (1.3-1.8) 1.3 (1.1-1.6)Not confident with forms 1.5 (1.3-1.8) 1.3 (1.1-1.6)p value for all <0.0001

dy 

 sex, HbA1c, 

tes, and 

mptoms and a 

evel of than 50 

uired IV glucose

ntrols

Clinical characteristics of patients with or without severe hypoglycemia. Variable Severe hypoglycemic Diabetic control p-value 

group (n = 32) group (n = 125)

Age 74.8 ± 8.5 63.7 ± 11.3 <0.001† Sex (M/F) 12 (37%)/20 (63%) 82 (66%)/43 (34%) <0.001† BMI (kg/m2) 23.2 ± 4.4 24.2 ± 4.0 0.26 HbA1c‡ (%) 6.54 ± 1.1 8.11 ± 1.5 <0.001† Creatinine (mg/dl) 0.88 ± 0.55 0.78 ± 0.28 0.69 eGFR§ (ml/min/1.73 m2) 71.0 ± 33.5 77.6 ± 23.0 0.29 Duration of diabetes (year) 14.9 ± 10.2 7.3 ± 5.8 <0.001† Number of total drugs 6.0 ± 2.6 4.3 ± 2.6 0.001† Dosage of sulfonylurea Glimepiride (mg/day) 2.7 ± 1.7 1.2 ± 0.93 <0.001† Glibenclamide (mg/day) 4.25 ± 2.5 4.27 ± 2.3 0.88 Comedication Metformin 9 (28%) 45 (36%) 0.4 Pioglitazone 7 (22%) 16 (13%) 0.16 a-glucosidase inhibitor 16 (50%) 27 (22%) 0.001† Insulin 6 (17%) 18 (14%) 0.36 Data are expressed as mean ± standard deviation or %. †Significant difference (p < 0.05). ‡At the time of the event of severe hypoglycemia in the hypoglycemic group. §eGFR calculated according to the Modification of Diet in Renal Disease Study equation. eGFR: Estimated glomerular filtration rate; F: Female; HbA1c: Hemoglobin A1c; M: Male.
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or hypoglycemia, 

e admitted to 

es

Acute hypoglycemic condition 

Odds ratio (95% CI)

African American 1.62 (1.55-1.69)Hispanic 1.24 (1.18-1.30)Asian 1.15 (1.03-1.75)

hort 

mergency 

ssion, or death 

ypoglycemic 

blood glucose of ol/l (50 mg/dl)

 severe 

t of 33048 person 

Covariate Person Years No. of events Rate Relative Risk (95% CI)

Drug Sulfonylurea 20714 255 1.23 reference value 

 Insulin 11978 331 2.76 2.1 (1.8-2.5)

 Insulin and sulfonylurea 355 12 3.38 2.9 (1.6-9.2)

Age, y 65-69 10627 156 1.46 reference value

 70-74 8281 130 1.57 1.1 (0.9-1.4)

 75-79 7159 142 1.98 1.5 (1.2-1.9)

 >80 6980 170 2.43 1.8 (1.4-2.3)

Sex M 5304 107 2.01 reference value

 F 27743 491 1.77 0.8 (0.7-1.0)

Race W 21207 313 1.47 reference value

 B 8974 239 2.66 2.0 (1.7-2.4)

County of residence Rural (non-SMSA) 9121 198 2.17 reference value

 Rural (SMSA) 7169 137 1.91 1.1 (0.8-1.3)

 Urban 16758 263 1.57 0.9 (0.7-1.1)

Days since hospital discharge >366 21491 272 1.27 reference value

 31-365 10096 231 2.29 1.7 (1.4-2.0)

 1-30 1460 95 6.50 4.5 (3.5-5.7)

Nursing home resident No 26233 444 1.69 reference value

 Yes 6815 154 2.26 1.0 (0.8-1.3)

No. of concomitant medications 0-4 24440 395 1.61 reference value

 >5 8608 203 2.35 1.3 (1.1-1.5)

New hypoglycemic drug therapy No 31808 559 1.75 reference value

 Yes 1240 39 3.15 1.4 (1.0-1.9)
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roup or risk factor 

-comatose 

 to the Glasgow rrival at the 

 serum glucose 

l, and necessity 

ministration for 

mitted, 207 had 

emia (7.2%)

Out of 207 patients with severe hypoglycemiaCharacterisitic Mean (SD) RangeAge (years) 62.1 (8.7) 45–88Duration of diabetes (years) 7.4 (2.8) 1–14HbA1c level (%) 6.8 (1.3)Characteristic No. %Sex

Male 85 41.1

 Female 122 58.9Presentation Coma 146 70.5 Semi-coma 61 29.5Usual treatment Insulin 72 34.8 Sulfonylureas 132 63.8 Insulin and sulfonylureas 3 1.4Follow-up in diabetes clinic Yes 59 28.5 No 148 71.5Educational status Illiterate 28 13.5 Elementary 117 56.5 Middle 47 22.7 Higher 15 7.3Diabetes knowledge Poor 175 85.4 Good 30 14.6Causes of hypoglycaemia Missed meal 76 30.8 Chronic renal failure 54 21.9 Exercise 28 11.4 Alcohol 20 8.2 Dosage error 16 6.5 Unknown 34 13.9
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hort

iate aid in a health 

ns

 with insulin

with orals

ary DM)

Serum creatinine >2 mg/dL prior to hypoglycemia: (20) 20.2% of insulin treated, (1) 2.7% of oral med groupIschemic heart disease: (56) 55.5% of insulin group, (28) 80% of oral med groupLeg vessel disease: (29) 28.7% of insulin group, (17) 48.6% of oral med groupPolyneuropathy: (17) 16.8% of insulin group, (3) 8% of oral med groupRetinopathy: (16) 15.8% of insulin group, (3) 8% or oral med groupCauses (allowing for multiple causes)Physical effort: (13) 12.9% insulin, (6) 17.1% oral medsDietary Non-compliance: (60) 59.4% insulin, (14) 40% oral medsDosage error: (7) 7% insulin, (4) 11.4% oral medsAlcohol: (7) 7% insulin, (2) 5.7% oral medsUnknown: (12)11.9% insulin, (7) 20% oral meds

hort 

ion to the hospital 

 for NIDDM

a associated 

son years

46.8% of admissions were males9.5% had change in prescribe dose of hypoglycemic agent within 30 days prior to admissionRR=2.79 (95%CI 1.6-4.9) (risk of hospitalization if prescribed glyburide vs. chlorpropamide)
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ort

nd ED diagnoses 

using codes 

d 251.2

ycemia

No. (%)Hypoglycemia (n=1465) Nonhypoglycemia (n=15,202) p value

Age at survey, mean(SD), y 66.32 (7.54) 64.78 (7) <0.001

Educationd 0.09

 Elementary or grade school 108 (7.4) 1004 (6.6)

 High/trade/business school 607 (41.4) 5997 (39.3)

 College/higher degree 750 (51.2) 8222 (54.1)

Men 804 (54.9) 8289 (54.5) 0.79

Race/ethnicity <0.001

 White 877 (59.8) 9588 (63.1)

 African American 261 (17.8) 1626 (10.7)

 Hispanic 159 (10.8) 1667 (10.9)

 Asian 125 (8.5) 1917 (12.6)

 Native American 39 (2.6) 341 (2.2)

 Other 4 (0.3) 63 (0.4)

Duration of diabetes from self report in  1994, mean (SD), y 13.72 (9.2) 9.15 (7.9)

Duration of Kaiser Permanente membership,  mean (SD), y 22.66 (5.32) 22.98 (5.34) 0.03

Medical utilization rate 2003-2004,  mean (SD), y 20.12 (16.60) 15.2 (12.71) <0.001

Time since first diabetes diagnosis in  Kaiser Permanente system, mean (SD), y 15.24 (3.59) 14.52 (2.89) <0.001

Comorbidity Heart disease 1224 (83.5) 9368 (61.6) <0.001

 Hyperlipidemia 1298 (88.6) 13,488 (88.7) 0.89

 Hypertension 1429 (97.5) 14,557 (95.8) 0.001

 Stroke 645 (43.0) 4389 (28.9) <0.001

 End-stage renal disease 167 (11.4) 416 (2.74) <0.001

HbA1c 1995-2002, mean (SD),% 8.22 (1.29) 8.08 (1.30) <0.001
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No. (%)Hypoglycemia (n=1465) Nonhypoglycemia (n=15,202) p value

Diabetes treatment type 2002-2003 <0.001

Insulin only 533 (37.75) 2157 (14.19)Oral only 446 (30.44) 8615 (56.67)Insulin and oral agents 352 (24.03) 2794 (18.38)Nonpharmacological-controlled 114 (7.70) 1636 (10.70)Years of insulin use from 1994 to  censored date, mean number 7.23 (2.6) 6.52 (2.94) <0.001Frequency of hypoglycemic episodes by dementia status

No. (%) Dementia Nondementia Age-adjusted incidence Excess(n=1822) (n=14,845) rates per 10,000 attributable risk 

person-years per year,(95% CI) % (95% CI)

Any hypoglycemia No 1572 (10.34) 13,630 (89.66) 327.60 (311.02-343.18) Yes 250 (16.95) 1215 (83.05)b 566.82 (496.52-637.48) 2.39 (1.72-3.01)

No. of hypoglycemic episodes 0 1572 (10.34) 13,630 (89.66) 327.60 (311.02-343.18) 1 150 (14.84) 852 (85.16) 491.73 (412.60-570.80) 1.64 (0.91-2.36)

 2 57 (22.26) 201 (77.74) 761.75 (561.24-962.27) 4.34 (2.36-6.32) 3 or more 43 (20.40) 162 (79.60)b 755.46 (526.46-984.46) 4.28 (2.10-6.44)

bp value less than 0.001
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ultivariate 

portional 

s

8 mmol/l (50 

esence of 

 symptoms 

 transient 

e CNS who 

eat themselves 

om another 

Unadjusted AdjustedHR ( 95% CI ) p value HR ( 95% CI) p value

Age (per year) 1.06 (1.04 - 1.08) <0.0001 1.05 (1.03 - 1.07) <0.0001Gender (female vs. male) 1.08 (0.83 - 1.40) 0.56Diabetes duration (per year) 1.05 (1.03 - 1.07) <0.0001 1.02 (1.00 - 1.04) 0.03History of Macrovascular disease (yes vs. no) 1.25 (0.96 - 1.64) 0.10 1.17 (0.89 - 1.54) 0.27History of Microvascular disease (yes vs. no) 2.62 (1.92 - 3.57) <0.0001 2.14 (1.47 - 3.11) <0.0001Glycated hemoglobin (per 1%) 1.08 (1.00 - 1.17) 0.05 1.04 (0.96 - 1.13) 0.35Creatinine level (per μmol/L ) 1.01 (1.00 - 1.01) <0.0001 1.01 (1.00 - 1.01) <0.0001Albumin to Creatinine ratio (per μg/ml) 1.001 (1.00 1.002) <0.01 1.00 (1.00 - 1.00) 0.58Body Mass Index (per kg/m2) 0.95 (0.93 - 0.98) <0.01 0.95 (0.93 - 0.98) <0.01Ever smoker (yes vs. no) 1.32 (1.02 - 1.71) 0.03 1.43 (1.09 - 1.88) 0.01Age at completion of formal education (per year) 0.97 (0.95 - 0.99) <0.01 0.98 (0.96 - 1.00) 0.05Mini Mental State Examination score (per 1/30) 0.89 (0.84 - 0.93) <0.0001 0.93 (0.87 - 0.99) 0.01Sulfonylurea alone (yes vs. no) 1.09 (0.81 - 1.46) 0.58Metformin alone (yes vs. no) 0.43 (0.27 - 0.69) <0.001 0.63 (0.36 - 1.09) 0.10Two or more oral glucose lowering  agents (yes vs. no) 1.79 (1.37 - 2.34) <0.001 1.50 (1.10 - 2.03) <0.01Any blood pressure lowering agent  (yes vs. no) 0.89 (0.67 - 1.18) 0.42Treatment allocation (intensive vs. 

 standard glucose control) 1.86 (1.42 - 2.44) <0.0001 1.88 (1.42 - 2.48) <0.001
142

f Severe Hypoglycemia 

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re Hypoglycemia Reported in the Individual Studies

Gender

Diabetes 

Duration

A1c

Previous 

Hypoglycemia

Polypharmacy

Education Level

BMI

Renal Disease

Impaired 

Awareness

Microvascular 

Complications

Macrovascular 

complications

Dementia or 

psych 

Time on insulin

Marital status

Smoking

Intense vs 

Standard contro

Metformin 

Sulfonlyurea 

Other agents

Insulin or insulin 

dose

Alcohol

Race

Other

√ √ √ √ √ √ √ √ √ √ √ √ √ √

√

√ √ √ √ √

√ √ √ √ √ √ √ √ √ √ √ √ √√ √ √ √ √ √ √ √ √ √ √ √ √ √

√ √ √ √ √ √ √

√ √ √ √ √ √ √

√ √ √ √ √ √ √ √ √ √

√ √ √ √ √√ √ √ √ √ √

√ √ √ √

√

√ √ √ √ √ √ √ √√ √ √ √ √ √ √√ √ √ √ √ √ √ √ √ √√ √ √ √ √ √ √ √√ √ √ √ √ √ √ √ √ √ √ √√ √ √ √ √√ √ √ √ √√ √ √ √ √ √ √ √ √ √√ √ √ √ √ √ √ √ √ √

√

√ √ √ √ √ √ √ √ √

√

√ √ √ √ √ √√ √ √ √ √ √ √

√ √ √ √

√

√ √ √ √ √ √ √ √ √ √ √ √√ √ √ √ √ √ √ √ √ √ √ √
143

f Severe Hypoglycemia 

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n Multivariate Studies

Other risk factors and multivariate controls

 Factors

etes duration prior to insulin therapy (per 10 yrs) , Treatment with ACE-I or ARB 

variate Controls

ertension, HTN therapy: RAS blocking, Non-RAS blocking, combination of both, Exercise, Use of tranquilizers

 Factors

lity to self manage medications 

variate Controls

ically plausible variables”

 Factors

er FSG (less than or equal to 8.0 mmol/liter) 

variate Controls

sh ability, Exercise in past 2 weeks, GAD antibody positive, Blood glucose self monitoring, Orthostatic hypotension, QTc interval 

ease), Anticoagulant therapy, Regular ASA use, NSAID treatment, Allopurinol treatment, Fibrate therapy, Beta Blocker treatment, 

pitalized in 1998

 Factors

-I use X, ACE DD genotype 

variate Controls

sh ability, Exercise in past 2 weeks, GAD antibody positive, sulfonlyurea treatment, Blood glucose self monitoring, Anticoagulant 

apy, Regular ASA use, NSAID treatment, Allopurinol treatment, Fibrate therapy, Beta Blocker treatment, Hospitalized in 1998 for 

glycemia, Any hospitalization in past 12 months

 Factors

nding physician (FP) , Missed Meals , Combined antihyperglycemic therapy 

 Factors

J11 (E23K) gene X

 Factors

medication with other CYP2C9-main substrates , CYP2C9-genotypes *2/*2, *2/*3, and *3/*3 X, Co-medication with other 

s being at least one CYP2C9-substrate X, Co-medication with angiotensin-converting enzyme inhibitor X, co-medication with 

gesics X, Co-medication with gyrase inhibitors X, Presence of heart failure X, Previous participation at structured diabetes 

ation X, Kind of accommodation (home vs nursing home) X

variate Controls

pecified

 Factors

w-up fasting glucose X, Diabetes therapy increased at baseline visit X

 Factors

level (> or equal to 2.59 mmol/l) 

variate Controls

g arrangement (alone or with others), Systolic blood pressure, Use of beta blockers, Thiazolidinediones

 Factors

s: TZDs Continuous X, Intermittent ; Other OAD Continuous X, Intermittent X; Other medications: Allopurinol , 

zodiazepine , Beta-Blocker , Blood glucose monitoring supplies , Flouroquinolone , NSAID , Trimethoprim ; Charlson 

orbidity (per 1 U change) 
144

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

variate Controls

English language, Household Income, Self monitoring of blood glucose, Medication adherence

variate Controls

gestive heart failure, Depression, Hypertension, Health insurance status, Median income level

 Factors

nty of residence (rural vs. urban) X, Nursing home residence X, New hypoglycemia drug therapy , Days since hospital 

harge 

variate Controls

tion of hypoglycemic drug use

 Factors

or more oral glucose lowering agents (yes vs. no) 
145

f Severe Hypoglycemia 

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Patients with Severe Hypoglycemia

All-Cause Mortality n/N (%) MI, nonfatal n/N (%) Stroke, non-fatal n/N (%) Other Neurological Events (coma, seizures) n/N (%)

x (Int)

NR Int: 0%

Std: 0%

NR Loss of consciousness

Int: 0/0 (0%)Std: 2/2 (100%) or 2/78 (2.6%) overall 

t)

Definite role of hypoglycemiaInt: 1/816 (0.1%)Std: 0/256 (0%)Probable role of hypoglycemiaInt: 1/816 (0.1%)Std: 2/256 (0.8%)Possible role of hypoglycemiaInt: 25/816 (3.1%)Std: 13/256 (5.1%)

NR NR NR

t)

Int: 0/150 (0%)Std: 1/81 (1.2%)Median follow-up of 5 years≥1 episode of severe hypoglycemia: 45/231 (19.5%)No severe hypoglycemia: 986/10,090 (9.0%)Adj HR=3.27 (95%CI 2.3-4.7)

NR NR NR

min)

Glimipiride: 0%Sitagliptin: 0%

NR NR Glimepiride: 6 episodes in 3 patients 

required medical assistance or were accompanied by neurological symptoms Sitagliptin: 1 episode in 1 patient

NR Lispro mix 75/25: 1/22 (4.5%)

Glargine: 0/12 (0%)

NR NR

Glulisine: 0%Regular Human Insulin: 0%

NR NR NR

t)

age 60.4 

NR NR NR Impaired consciousness 

Int 9/100 pt yearStd 3/100 pt year (p<0.001)Complete loss of consciousness Int 3/100 pt year Std 1/100 pt year; p<0.001

ical 

rom 

Exanatide: 0%Insulin glargine: 0%*

NR NR NR
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f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

All-Cause Mortality n/N (%) MI, nonfatal n/N (%) Stroke, non-fatal n/N (%) Other Neurological Events (coma, seizures) n/N (%)

sulin 

), 64% 

No deaths related to hypoglycemia at 1 year follow-up (Holman, 2007)

NR NR Loss of consciousness at 3-year 

follow-up (Holman, 2009)Biphasic aspart: 1/235 (0.4%)Prandial asprt: 0/239 (0%)Basal detemir: 3/234 (1.3%) 

PH + 

Insulin detemir + aspart: 0%NPH+ HIS: 0% 

NR NR Coma 

Insulin detemir + aspart: 0%NPH+ HIS: 1/199 (0.5%) 

NR NR NR Glargine: 0%

NPH: 0%

rgine

rs

NR NR NR Coma: 0%

Seizures: 0%

t)

Int: 1/8 (12.5%)Std: 0/33 (0%)

NR NR NR

No deaths related to hypoglycemia None None NR

e; 

0% (based on 66 episodes in 52 patients)

NR NR NR

001-

In-hospital: 2/126 (1.6%) due to irreversible hypoglycemia (treatment group not reported)Total deaths (at median follow-up of 23.2 months; cause of death not reported)On oral agent: 31.7%On insulin: 52.4%

NR NR Coma 

On oral agent: 54%On insulin: 30.2%(NOTE: the 2 deaths were due to irreversible hypoglycemia with seizures and shock)

quently 

No deaths among patients treated in a hospital setting

NR NR NR

ere 

a only 

0/45 (0%) at time of event16/45 (35.6%) deaths during follow-up (mean of 22.8 months after event)

NR NR Coma: 23/45 (51%)

Disorientation: 8/45 (18%)Somnolence: 5/45 (11%)Paralysis: 4/45 (9%)Cerebral seizures: 3/45 (7%)Psychological disturbances: 2/45 (5%)
147

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All-Cause Mortality n/N (%) MI, nonfatal n/N (%) Stroke, non-fatal n/N (%) Other Neurological Events (coma, seizures) n/N (%)

n) with 

uring 1 

ucose 

udy 

Outpatient risk of death within one day of a hypoglycemic event (glucose <50 mg/dl)OR=13.28 (9.30-19.18) for patients without chronic kidney disease (CKD)OR=6.84 (4.41-10.62) for patients with CKD (with glucose ≥ 70 mg/dl and no CKD as reference group)

NR NR NR

rious 

cy room 

2/586 (0.3%) 3/586 (0.5%) 7/586 (1.2%) Loss of consciousness: 49% of 598 

episodesSeizures: 5% of 598 episodesIrrational behavior: 6% of 598 episodesTIA: 4/586 (0.7%)

ge 66 

ia

Insulin: 7/101 (6.9%)Oral meds: 3/36 (8.3%) 

NR NR NR

mean 

ons 

ajo 

abetes

4/109 (3.7%) (only one death was attributed to hypoglycemia)

NR NR NR

ll taking 

Drug 

87

2/19 (11%) within 6 days of eventAdditional 1/19 (5.3%) within 23 days of event

NR 1/19 (5%) had stroke prior 

to hypoglycemic event with further functional impairment after event

During eventComatose: 11/19 (58%) Reduced conscious level: 3/19 (16%) After eventSevere confusion: 2/19 (11%)

al 

 

5/102 (5%) Transient asymptomatic 

myocardial ischemia: 2/102 (2%)

NR Seizure: 8/102 (8%)

Transient right hemiplegia: 1/102 (1%)

s 

0/99 (0%) NR NR Coma: 19/99 (19%)

Somnolence: 51/99 (51%)Reported cerebral seizures and/or psychological disturbances in remaining patients

vere 

NR NR NR Convulsions: 3/86 (4%)
148

f Severe Hypoglycemia 

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All-Cause Mortality n/N (%) MI, nonfatal n/N (%) Stroke, non-fatal n/N (%) Other Neurological Events (coma, seizures) n/N (%)

e 78 yrs

es 

ey 

ans 

Glimepiride: 0/37 (0%)Glibenclaminde: 0/56 (0%)

NR NR Severe brain damage

Glimepiride: 1/37 (2.7%)Glibenclaminde: (0%)Presented withComa: 45%Disorientation: 18%Somnolence: 14%Cerebral seizure: 10%Local neuromuscular deficits: 8%Abnormal or inappropriate behavior: 5%

 by 

0/148 (0%) in type 2 diabetic patients (1 death in non-diabetic patient with protracted spontaneous hypoglycemia)

NR NR NR

0/207 (0%) NR 2/207 (1.0%) TIA: 2/207 (1.0%)

Presented withComa: 146/207 (71%)Semi-coma: 61/207 (29%)Convulsions: 3/207 (1.4%)

mitted 

ycemia 

No hypoglycemia-related deaths (e.g., within 72 hrs of admission)

NR NR Coma or stupor at admission: 6/28 

(21%)

re 

o 

eath 

Hypoglycemia was a cause of death in 22/693 (3.2%) 

NR NR NR

ndard Treatment; Tx = Treatment; NR = Not Reported; MI = Myocardial Infarction; TIA = Transient Ischemic Attack; CKD = Chronic Kidney 
149

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atients with Severe Hypoglycemia

pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

vention: 0%

rol: 0%

NR NR NR NR NANR NR NR Permanent disability 

Int: 1/150 (0.7%)Std: 1/81 (1.2%)

NA

NR NR NR Glimepiride: 6 episodes in 

3 patients required medical assistance (location not specified) or were accompanied by neurological symptoms Sitagliptin: 1 episode in 1 patient

NA

atide: 0%

n Glargine: 

Exanatide: 0%Insulin Glargine: 0%

NR NR NR NA

n detemir 

part: 1/195 

%) 

 + HSI: 2/199 

%)

NR NR NR NR NA

gine: 0%

: 0%

Glargine: 0%NPH: 2/13 events in 9 patients (15.4%)

NR NR Withdrawal from study due to 

severe hypoglycemiaGlargine: 1/9 (12%)NPH: 3/9 (33%)

NA
150

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR NR NR Medical Assistance

Liraglutide: 1/5 (20%)(no serious events in placebo or glargine groups)

NA

e None None None None NA

NR NR NR Cognitive decline: 33/205 

(16%) (no difference in prior hypoglycemia episode between those with decline and those without) Severe hypoglycemia: more likely in patients with cognitive impairment (11.6%) or dementia (20.8%) than normal (3.0%) (p<0.01)

NA

pen: 8/44 

glycemic ts (18%) 

-pen: 21/64 

ts (33%) 

Pre-pen: 10/44 events (23%) Post-pen: 13/64 events (20%) 

NR NR Physician visits

Pre-pen: 15/44 events (34%) Post-pen: 21/64 events (33%) Outpatient visitsPre-pen: 4/44 events (9%) Post-pen: 6/64 events (9%) 

NR

atients were 

italized (study 

gn)

Not applicable Falls

Oral meds: 25.4%Insulin: 17.5%

NR Acute coronary syndrome

Oral meds: 17.5%Insulin: 19.0%Duration of hospital stayOral meds: 9.8 daysInsulin: 8.0 days

NA

03 (16%) 

ferred to 

ient team for 

er period of 

ment

All patients were seen in emergency department (study design)

NR NR 151 patients were contacted at 7 

and 28 days after discharge; 6/151 had recurrent hypoglycemia (2 were admitted)

NA
151

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

episode/

nt/year

NR NR NR NR NA

atients were 

italized (study 

gn)

14/45 (31%) initial treatment in emergency department

Soft tissue injuries or fractures: 6/45 (13%) 

NR NR NA

pen: 13/77 

glycemic ts (17%)

-pen: 41/139 

ts (30%)

0.88 (0.47-

Pre-pen: 12/77 events (16%)Post-pen: 19/139 events (14%)OR=0.44 (0.21-0.92)

NR NR Physician visits

Pre-pen: 29/77 events (38%)Post-pen: 39/139 events (30%)OR=0.39 (0.24-0.64)Outpatient visitsPre-pen: 6/77 events (8%) Post-pen: 17/139 events (12%)OR=0.79 (0.31-2.01)

1

44 episodes 

)

19/244 episodes (8%) emergency or primary care visit 134/244 episodes (55%) ambulance + emergency or primary care visit

NR NR 89/244 episodes (36%) ambulance 

service only

severe 

odes in 19 

nts 

NR NR NR NR NA

italizations in 

 patient-years servation

NR NR NR 1.9% required medical contact for 

hypoglycemia in 1st year of insulin 

use; 0.4% by 5th year

NA
152

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

(7.1%) NR NR NR NR NA

issions per 

oglycemia 

ng: 0.97

ypoglycemia 

ng: 0.48 

01)

Visits per yearHypoglycemia coding: 0.85No hypoglycemia coding: 0.40 (p<0.01)

NR NR Short Term Disability Use

Hypoglycemia coding: 47% for mean of 19.5 days per P-YNo hypoglycemia coding: 32% for mean of 11.0 days per P-Y (both p<0.01)

NA

nts identified 

spital or 

rgency 

rtment

Patients identified in hospital or emergency department

Injury 10/586 (1.7%)

NR NR NA

NR Bone injuries 

Insulin: 10/101 (9.9%) Oral med: 0/36 (0%)

NR NR

er 1000 

on-years

NR NR NR NR NA
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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR NR NR In patients who developed 

dementia:History of at least one episode of severe hypoglycemia in prior 22 years: 17.0%No history of severe hypoglycemia: 10.3%

3 Positive graded association between severe hypoglycemia and risk of dementia;2.39% increase in absolute risk of dementia per year in patients with h/o hypoglycemia compared to those without; adjusted Hazard Ratio for dementia : 1.44 (95% CI 1.25-1.66) for ≥ 1 episode vs. none

NR NR EQ-5D VAS by severity of 

hypoglycemic symptomsNone: 73.5Mild: 71.0Moderate: 65.8Severe: 54.3(p<0.0001)Adjusted model Severe symptoms associated with EQ-5D VAS (p<0.0001)

NR 3 age, gender, activity, 

weight, HbA1c, microvascular or cardiovascular history

NR NR SF-36: scores lower for 

patients with self-reported severe (vs. mild/moderate) hypoglycemia for all domains except vitalityEQ-5D: lower scores for patients with severe (vs. mild/moderate)

Productivity: more days lost for severe (8.6) than mild/moderate (2.7); severity was predictor of productivity (p<0.05)Resource use: more contacts with health service for severe (13.2) than mild/moderate (11.5)

Adjusted for age, gender, diabetes complications, BMI, and type of diabetes
154

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR Accidents per 

year driven on latest therapeutic regimenOA group: 2.05X10-3

CT group: 7.17X10-3All type 2: 3.09X10-3

Hypoglycemiainduced accidents per year drivenOA: 2/122 (1.6%)CT: 3/151 (2.0%)Symptomatic hypoglycemias per year driven (all Type 2): 0.04

NR Breaks in driving caused by 

hypoglycemiaOA group: 0.1 CT group: 0.2

NA

NR NR Severe hypoglycemia in past 

12 months associated with increased risk for clinical (OR=4.4 [1.3-14.4]) and subclinical (OR=2.7 [1.1-6.9]) affective disorder but not anxiety disorder

NR NA

NR NR NR Lifetime history of severe 

hypoglycemia (at least 1 episode) associated with symptoms of anxiety (ß=0.293, p<0.001) but not depression

Adjusted for gender, depression score, marital status, treatment for depression, diabetes treatment 
155

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

Emergency 

artment Visits

5.5% emergency or hospital visit 

NR Lifestyle changes sometimes 

or always made after severe hypoglycemic episode (of n=19 reporting severe hypoglycemia in past 12 months)Modified insulin dose: 58%Tested blood glucose more often: 84%Greater fear of future episode: 84%Additional concerns about driving: 16%Asked someone to check on them: 58%Went home from work, school, other activity: 32%Stayed home next day: 26%

Additional physician visits: 2.5%Additional consultations: 0.4%(unclear if denominator is 19 or 34 patients)

NA

NR NR EQ-5D by severity 

(p<0.0001)Mild: 0.83Moderate: 0.77Severe/very severe: 0.67HFS II worry by severity (p<0.0001)Mild: 12.3Moderate: 20.1Severe/very severe: 27.5Adjusted models:Severe/very severe positively associated with HFS II worry and negatively associated with EQ-5D (both p<0.001) EQ-5D decreased and HFS II worry increased as frequency of episodes increased 

NR 3 age, gender, BMI, 

education, duration of diabetes, HbA1c, diabetes complications
156

f Severe Hypoglycemia 

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR NR EQ-5D VAS score by 

severityNone: 0.76Mild: 0.73Moderate: 0.71Severe: 0.68Very severe: 0.66(p=0.01 none/mild vs. moderate or worse)EQ-5D dimensions with significant differences (none/mild vs. moderate or worse)Pain/discomfort: p=0.01Anxiety/depression: 0=0.02HFS-II worry score by severityNone: 4Mild: 7Moderate: 8Severe: 19Very severe: 26(p=0.06 none/mild vs. moderate or worse)

1579 (8%) 

ital or ER

19.0 (13.0-

 compared 

6% of 

cipants 

out significant 

glycemia

see hospitalization

NR NR NR
157

f Severe Hypoglycemia 

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR NR EQ-5D summary score by 

symptom severity (p=0.04)None: 0.80Mild: 0.73Moderate: 0.70Severe/very severe: 0.54Worry score by symptom severity (p=0.02)None: 10.2Mild: 16.5Moderate: 22.2Severe/very severe: 25.3Severe hypoglycemia significantly associated with HFS-II worry and EQ-5D summary scores (p<0.0001)

NR 3 Adjusted for age, 

gender, marital status, education, activity, duration of DM, history of microvascular events, major medical events, adequate glycemic control

NR NR NR Prolonged hypoglycemia (23-60 

hours): 5/19 (26%)

atients were 

italized (study 

gn)

Not applicable 7/102 (7%) NR Protracted hypoglycemia (12-72 

hours): 40/102 (39%)

an 

italization 

ays (cohort 

ed by italization)

NR NR NR Protracted hypoglycemia (12-72 

hrs): 61/99 (61%)
158

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR Injurious motor 

vehicle crashAny insulin: RR*=1.3 (95% CI 1.0-1.8)Insulin only: RR=1.4 (95% CI 1.0-2.0)Combined oral^:RR=1.3 (95% CI 1.0-1.7) with dose response 

NR NR Adjusted for age, 

gender, previous motor vehicle crashes, place of residence

NR Injury (not 

defined): 4/86 (5%)

NR NR

NR NR NR Prolonged severe hypoglycemia 

(>12 hr)Glimepiride: 8/37 (22%)Glibenclamide: 5/56 (9%)

0%) 3 visits among 

6 pts requiring healthcare for hypoglycemia in past month

NR NR 8 nurse visits, 3 physician visits, 

1 telephone contact with medical care among 6 patients requiring healthcare for hypoglycemia in past month
159

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pitalizations n/N (%)

Emergency 

Department 

Visits

n/N (%)

Accidents/

Trauma

n/N (%)

Quality of Life Other Outcomes

Type of Analysis 

1=unadjusted; 

2=minimal adjustment; 

3=multivariate

NR Severe 

hypoglycemia in past 2 years34/57 (60%) who had crash 200/738 (27%) without crashOR=4.07 (2.35-7.04)

NR NR 1

atients were 

italized (study 

gn)

NR NR NR Prolonged hypoglycemia: 1/28 

(3.6%)

1

NR NR NR 11/20 (55%) felt hypoglycemic:

5/11 (45%) would measure glucose6/11 (55%) would not drive9/20 (45%) “maybe” felt hypoglycemic: 3/9 (33%) would drive2/9 (22%) “maybe” drive2/9 (22%) would measure glucose2/9 (22%) would not drive 

able
160

Predictors and Consequences of Severe Hypoglycemia 

in Adults with Diabetes – Systematic Review of the Evidence Evidence-based Synthesis Program

APPENDIX F. FOREST PLOTS FOR KEY QUESTION #1

Appendix F, Figure 1.

Severe hypoglycemia event rates for insulin glargine studies*

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper 

Rate Limit Limit Total

long-term Rosenstock 2009 0.074 0.054 0.100 38 / 513

long-term Buse 2011 0.029 0.016 0.050 12 / 419

long-term Rosenstock 2008 0.027 0.014 0.054 8 / 291

long-term 0.041 0.019 0.084 58 / 1223

short-term Kennedy 2006 0.030 0.026 0.034 228 / 7607

short-term Riddle 2003 0.025 0.013 0.046 9 / 367

short-term Heine 2005 0.015 0.006 0.039 4 / 267

short-term Davies 2005 0.010 0.008 0.013 45 / 4588

short-term Rosenstock 2001 0.004 0.001 0.027 1 / 259

short-term 0.016 0.008 0.032 288 / 13088

Overall 0.025 0.015 0.041 346 / 14311

*Alone or added to OHAs

Appendix F, Figure 2.

Severe hypoglycemia event rates for insulin detemir studies

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper 

Rate Limit Limit Total

long-term Holman 4T 2009 0.009 0.002 0.034 2 / 234

long-term Rosenstock 2008 0.017 0.007 0.041 5 / 291

long-term 0.014 0.007 0.029 7 / 525

moderate-term Marre 2009 0.004 0.001 0.009 4 / 1129

moderate-term 0.004 0.001 0.009 4 / 1129

Overall 0.009 0.005 0.015 11 / 1154

Appendix F, Figure 3.

Severe hypoglycemia event rates for NPH insulin studies

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper 

Rate Limit Limit Total

long-term Rosenstock 2009 0.109 0.085 0.139 55 / 504

long-term 0.109 0.085 0.139 55 / 504

short-term Rosenstock 2001 0.023 0.010 0.051 6 / 259

short-term 0.023 0.010 0.051 6 / 259

Overall 0.093 0.073 0.118 61 / 763

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25
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Appendix F, Figure 4.

Severe hypoglycemia event rates for NPH insulin studies*

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper 

Rate Limit Limit Total

long-term Rosenstock 2009 0.109 0.085 0.139 55 / 504

long-term 0.109 0.085 0.139 55 / 504

short-term Frische 2003 0.026 0.012 0.056 6 / 232

short-term Rosenstock 2001 0.023 0.010 0.051 6 / 259

short-term Riddle 2003 0.018 0.009 0.037 7 / 389

short-term Rayman (glulisine) 2007 0.004 0.001 0.018 2 / 448

short-term Dailey (glulisine) 2004 0.014 0.006 0.030 6 / 435

short-term Rayman (RHI) 2007 0.016 0.008 0.033 7 / 442

short-term Dailey (RHI) 2004 0.011 0.005 0.027 5 / 441

short-term 0.016 0.012 0.022 39 / 2646

Overall 0.050 0.041 0.061 94 / 3150

*NPH insulin as either primary therapy or in combination (Frische, sulfonylurea; Riddle oral OHAs; Rayman and Dailey, glulisine or 

regular insulin) 

Appendix F, Figure 5.

Severe hypoglycemia events, NPH insulin versus insulin glargine studies*

Study Name Events / Total Risk ratio and 95% Cl

Risk Lower Upper NPH Insuline

Ratio limit limit insulin glargine

Rosenstock 2009 1.473 0.993 2.186 55 / 504 38 / 513

Riddle 2003 0.734 0.276 1.950 7 / 389 9 / 367

Rosenstock 2001 6.000 0.727 49.489 6 / 259 1 / 259

1.367 0.666 2.806 68 / 1152 48 / 1139

Appendix F, Figure 6.

Severe hypoglycemia event rates for insulin lispro studies

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper

Rate Limit Limit Total

long-term Buse 2011 0.042 0.027 0.064 20 / 476

long-term 0.042 0.027 0.064 20 / 476

short-term Anderson 1997 0.001 0.000 0.010 1 / 722

short-term 0.001 0.000 0.010 1 / 722

Overall 0.036 0.023 0.054 21 / 1198

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

0.01 0.1 1 10 100
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Appendix F, Figure 7.

Severe hypoglycemia event rates for insulin aspart studies

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper 

Rate Limit Limit Total

long-term Holman 4T 2009 (Prandial) 0.021 0.009 0.049 5 / 239

long-term Holman 4T 2009 (Biphasic) 0.026 0.012 0.056 6 / 235

long-term 0.023 0.013 0.042 11 / 474

short-term Bentrop 2011 (Biphasic) 0.002 0.000 0.007 2 / 1154

short-term Liebl 2009 (Biphasic) 0.003 0.000 0.043 0 / 178

short-term Valensi IMPROVE 2009 (Biphasic) 0.001 0.001 0.002 69 / 52419

short-term 0.001 0.002 0.002 71 / 53751

Overall 0.002 0.002 0.002 82 / 54225

*Subjects may also have received OHAs in addition to insulin aspart.

Appendix F, Figure 8.

Severe hypoglycemia event rates for insulin glulisine (+NPH insulin) 

short-term (26 wks) studies

Study Name Statistics for each study Event rate and 95% Cl

Event Lower Upper

Rate limit limit Total

Rayman 2006 0.004 0.001 0.018 2 / 448

Daily 2004 0.014 0.006 0.030 6 / 435

0.009 0.003 0.026 8 / 883

Appendix F, Figure 9.

Severe hypoglycemia rates for sulfonylurea studies*

Group By Study Name Statistics for Each Study Event rate and 95% CI

Duration

Event Lower Upper 

Rate Limit Limit Total

long-term Holstein 2001 0.013 0.009 0.017 44 / 3489

long-term 0.013 0.009 0.017 44 / 3489

moderate-term Matthews 2011 0.010 0.006 0.016 15 / 1546

moderate-term Seck 2010 0.015 0.008 0.029 9 / 584

moderate-term Garber 2011 0.002 0.000 0.031 0 / 248

moderate-term Marre 2009 0.004 0.000 0.066 0 / 114

moderate-term 0.011 0.007 0.017 24 / 2492

short-term UK Hypoglycemia Group 0.074 0.037 0.141 8 / 108

short-term Arechavaleta 2011 0.015 0.008 0.031 8 / 519

short-term Nauck 2009 0.002 0.000 0.032 0 / 242

short-term Russell-Jones 2009 0.004 0.000 0.066 0 / 114

short-term Chou 2008 0.002 0.000 0.034 0 / 225

short-term Kendall 2005 0.002 0.000 0.031 0 / 247

short-term Drouin 2004 0.001 0.000 0.009 1 / 800

short-term Schernthaner 2004 0.001 0.000 0.009 0 / 845

short-term 0.005 0.001 0.019 17 / 3100

Overall 0.012 0.009 0.015 85 / 9081

*Sulfonylurea monotherapy and combined sulfonylurea and metformin studies

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25

-0.25 -0.13 0.00 0.13 0.25
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Appendix F, Figure 10.

Severe hypoglycemia events for BARI 2D study, insulin sensitization versus 

insulin provision

Study name Events/Total Risk ratio and 95% CI

Risk Lower Upper

ratio limit limit Sensitization Provision

BARI 2D 2009 0.642 0.479 0.861 68 / 1153 106 / 1154

0.642 0.479 0.861 68 / 1153 106 / 1154

Favors Sens. Favors Prov.

Appendix F, Figure 11.

Severe hypoglycemia events for intensive glycemic control versus usual care 

studies

Study name Events/Total Risk ratio and 95% Cl

Risk Lower Upper Intensive Usual

ratio limit limit control care

VADT 2009 2.736 1.792 4.177 76 / 892 28 / 899

ACCORD 2008 3.096 2.717 3.527 849 / 5128 274 / 5123

ADVANCE 2008 1.884 1.442 2.463 150 / 5571 81 / 5669

UKPDS-33 1998 1.529 0.708 3.299 33 / 3071 8 / 1138

VA-CSDM 1995 2.600 0.520 12.993 5 / 75 2 / 78

2.396 1.757 3.268 1113 / 14737 393 / 12907

Favors Intensive Favors Usual

0.1 0.2 0.5 1 2 5 10

0.1 0.2 0.5 1 2 5 10

0.1 0.2 0.5 1 2 5 10

0.1 0.2 0.5 1 2 5 10