Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service

April 2012

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Minneapolis VA Medical Center

Minneapolis, MN

Timothy J. Wilt, M.D., M.P.H., Director

Predictors and Consequences

of Severe Hypoglycemia

in Adults with Diabetes –

A Systematic Review of the Evidence

Investigators:

Principal Investigator: 

Hanna E. Bloomfield, M.D., M.P.H.

Co-Investigators: 

Nancy Greer, Ph.D.

David Newman, M.D.

Research Associates:

Roderick MacDonald, M.S.

Maureen Carlyle, M.P.H.

Patrick Fitzgerald, M.P.H.

Indulis Rutks, B.S.
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Predictors and Consequences of Severe Hypoglycemia 

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

PREFACE

Quality Enhancement Research Initiative’s (QUERI) Evidence-based Synthesis Program 

(ESP) was established to provide timely and accurate syntheses of targeted healthcare topics 

of particular importance to Veterans Affairs (VA) managers and policymakers, as they work to 

improve the health and healthcare of Veterans. The ESP disseminates these reports throughout 

VA.

QUERI provides funding for four ESP Centers and each Center has an active VA affiliation. The ESP 

Centers generate evidence syntheses on important clinical practice topics, and these reports help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient 

outcomes and to support VA clinical practice guidelines and 

performance measures, and 

• set the direction for future research to address gaps in clinical 

knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of QUERI Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of QUERI field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Bloomfield HE, Greer N, Newman D, MacDonald R, Carlyle M, 

Fitzgerald P, Rutks I, and Wilt, TJ. Predictors and Consequences of Severe Hypoglycemia in 

Adults with Diabetes – A Systematic Review of the Evidence. VA-ESP Project #09-009; 2012.

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Minneapolis VA Medical Center, Minneapolis, MN funded 

by the Department of Veterans Affairs, Veterans Health Administration, Office of 

Research and Development, Quality Enhancement Research Initiative. The findings 

and conclusions in this document are those of the author(s) who are responsible for 

its contents; the findings and conclusions do not necessarily represent the views of 

the Department of Veterans Affairs or the United States government. Therefore, no 

statement in this article should be construed as an official position of the Department 

of Veterans Affairs. No investigators have any affiliations or financial involvement (e.g., 

employment, consultancies, honoraria, stock ownership or options, expert testimony, 

grants or patents received or pending, or royalties) that conflict with material presented 

in the report.
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Predictors and Consequences of Severe Hypoglycemia 

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

TABLE OF CONTENTS

EXECUTIVE SUMMARY

Background.................................................................................................................................................... 1

Methods......................................................................................................................................................... 1

Data Synthesis............................................................................................................................................... 2

Peer Review................................................................................................................................................... 2

Results ........................................................................................................................................................... 2

Future Research Recommendations.............................................................................................................. 4

INTRODUCTION............................................................................................................................................... 5

METHODS

Topic Development........................................................................................................................................ 6

Search Strategy.............................................................................................................................................. 6

Study Selection.............................................................................................................................................. 7

Data Abstraction ............................................................................................................................................ 8

Quality Assessment ....................................................................................................................................... 8

Data Synthesis............................................................................................................................................... 8

Peer Review................................................................................................................................................... 9

RESULTS

Literature Flow ............................................................................................................................................ 10

Key Question #1: What is the incidence of severe hypoglycemia in adults with type 2 diabetes on 

one or more hypoglycemic agents?. ............................................................................................................ 11

Key Question #2: What are the risk factors for severe hypoglycemia in adults with type 2 diabetes 

on one or more hypoglycemic agents (e.g., demographics, co-morbidities, diabetes treatment 

regimen, other medication use, goal and achieved HbA1c)? ...................................................................... 16

Key Question #3: What is the effect of severe hypoglycemia on other outcomes in adults with type 2 

diabetes on one or more hypoglycemic agents (e.g., quality of life, mortality, morbidity, utilization)?..... 21

SUMMARY AND DISCUSSION

Summary of Evidence by Key Question ..................................................................................................... 30

Recommendations for Future Research....................................................................................................... 38

REFERENCES ................................................................................................................................................... 40

TABLES

Table 1. Incidence of Severe Hypoglycemia – Trials of Intensive vs. Conventional Glycemic 

Control...................................................................................................................................... 13

Table 2. Frequency of Severe Hypoglycemia in Prior Reviews ............................................................ 14

Table 3. Significant Risk Factors for Severe Hypoglycemia ................................................................. 18
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Predictors and Consequences of Severe Hypoglycemia 

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

FIGURES

Figure 1. Analytic Framework................................................................................................................... 7

Figure 2. Literature Flow Diagram.......................................................................................................... 10

APPENDIX A. Search Strategies............................................................................................................ 56

APPENDIX B. Criteria used in Quality Assessment of 

Non-Randomized Studies............................................................................................... 57

APPENDIX C. Peer Review Comments/Author responses............................................................ 58

APPENDIX D. Study Quality Tables

Table 1. Individual Study Quality for KQ1, Randomized Studies......................................................... 66

Table 2. Individual Study Quality for KQ1, Non-Randomized Studies................................................. 67

Table 3. Individual Study Quality for KQ2, Randomized and Non-Randomized Studies..................... 68

APPENDIX E. Evidence Tables

Table 1. Characteristics of Included Studies.......................................................................................... 69

Table 2. Characteristics of Studies Included in Extended Analysis for Key Question #1 ................... 107

Table 3. Incidence of Severe Hypoglycemia by Treatment Arms........................................................ 110

Table 4. Risk Factor Data Table for Key Question #2 ......................................................................... 121

Table 5. Risk Factors for Severe Hypoglycemia Reported in the Individual Studies.......................... 142

Table 6. Other Risk Factors in Multivariate Studies............................................................................ 143

Table 7. Clinical Outcomes in Patients with Severe Hypoglycemia.................................................... 145

Table 8. Other Outcomes in Patients with Severe Hypoglycemia ....................................................... 149

APPENDIX F. Forest Plots for Key Question #1

Figure 1. Severe hypoglycemia event rates for the insulin glargine studies......................................... 160

Figure 2. Severe hypoglycemia event rates for insulin detemir studies................................................ 160

Figure 3. Severe hypoglycemia event rates for NPH insulin studies..................................................... 160

Figure 4. Severe hypoglycemia event rates for NPH insulin studies..................................................... 161

Figure 5. Severe hypoglycemia events, NPH insulin versus insulin glargine studies........................... 161

Figure 6. Severe hypoglycemia event rates for insulin lispro studies ................................................... 161

Figure 7. Severe hypoglycemia event rates for insulin aspart studies................................................... 162

Figure 8. Severe hypoglycemia event rates for insulin glulisine (+NPH insulin) short-term 

(26 wks) studies...................................................................................................................... 162

Figure 9. Severe hypoglycemia event rates for sulfonylurea studies .................................................... 162

Figure 10. Severe hypoglycemia events for Bari 2D, insulin sensitization versus insulin provision...... 163

Figure 11. Severe hypoglycemia events for intensive glycemic control versus usual glycemic 

control studies ........................................................................................................................ 163
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Predictors and Consequences of Severe Hypoglycemia 

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

EVIDENCE REPORT

INTRODUCTION

Prevalence of type 2 diabetes is increasing at an alarming pace, fueled by the rising rates of 

overweight and obesity in many populations. A recent study estimated that the number of people 

with diabetes increased worldwide from 153 million in 1980 to 347 million in 2008.1

 This study 

estimated that from 1980 to 2008, the age standardized prevalence of diabetes in the United 

States increased from 6% to 12% in men and from 5% to 9% in women. In the VA, prevalence of 

diabetes is higher than in the general population and increasing over time. Miller et al. reported 

estimated rates of diabetes in VA of 17% in fiscal year (FY) 1998, 19% in FY99 and 20% in 

FY00.2

 More recently, it was estimated that nearly 25% of veterans receiving care in the VA have 

diabetes (http://www.va.gov/health/NewsFeatures/20110321a.asp, accessed April 3, 2012).

Although people with diabetes have a substantially increased risk of cardiovascular disease 

(CVD), three large well designed recent clinical trials testing intensive versus conventional 

glucose control strategies (ACCORD3

, ADVANCE4 and VA-DT5), have found that intensive 

glucose control does not reduce the risk of CVD death or all-cause mortality although it reduces 

the risk of microvascular complications (nephropathy, retinopathy and neuropathy)6

 and 

possibly non-fatal myocardial infarction.7 Intensive glucose control also increases the risk of 

hypoglycemic episodes. Several recent meta-analyses that included these large “intensive versus 

conventional control” trials have concluded that intensive control is associated with a 2-2.5 fold 

increased risk of severe hypoglycemia.8-11 However, these reviews included only randomized 

controlled trials; we are unaware of a comprehensive systematic review examining incidence of 

and risk factors for severe hypoglycemia in adults with type 2 diabetes in both real-world and 

clinical trial settings. 

Despite the increased risk of hypoglycemia with intensive glycemic control, influential national 

guidelines support an aggressive approach for patients with type 2 diabetes, recommending a 

target hemoglobin A1c level (HbA1c) of less than 7.12 This recommendation implies that the 

benefits of tight control outweigh the risks even though the balance between these benefits and 

harms is not actually known. In particular, the effects of hypoglycemia on outcomes besides 

CVD events and all-cause mortality have not, to our knowledge, been rigorously evaluated. The 

VA/DoD guidelines recommend a more nuanced approach: target HbA1c levels are based on life 

expectancy and severity of microvascular complications. A level of < 7% is recommended only 

for those with no microvascular complications and a life expectancy of >10 years (http://www.

healthquality.va.gov/diabetes_mellitus.asp, accessed January 27, 2012).

We conducted the current review to provide broader insight into the incidence of, the risk factors 

for, and the clinical impact of severe hypoglycemia in adults with type 2 diabetes treated with 

glucose lowering medications.
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Predictors and Consequences of Severe Hypoglycemia 

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

METHODS

TOPIC DEVELOPMENT

This project was nominated by Leonard Pogach, MD, National Program Director for Diabetes. 

The scope of the report and key questions were refined with input from a technical expert panel.

The key questions, as shown in the analytic framework in Figure 1, were as follows:

Key Question #1: What is the incidence of severe hypoglycemia in adults with type 2 diabetes 

on one or more hypoglycemic agents? 

Key Question #2: What are the risk factors for severe hypoglycemia in adults with type 2 

diabetes on one or more hypoglycemic agents (e.g., demographics, co-morbidities, diabetes 

treatment regimen, other medication use, goal and achieved HbA1c)?

Key Question #3: What is the effect of severe hypoglycemia on other outcomes in adults with type 2 

diabetes on one or more hypoglycemic agents (e.g., quality of life, mortality, morbidity, utilization)?

Extension of Key Question #1: In order to gain a more population-based perspective on hypoglycemia 

incidence (as recommended by our technical expert panel November 1, 2011) we re-reviewed all the 

abstracts identified through the initial search strategy (through November, 2011) to find articles that 

might contain data from more representative groups that had not met the initial inclusion criteria. 

SEARCH STRATEGY

We searched MEDLINE (OVID) for clinical trials and systematic reviews from 1950 to 

December 2010 using standard search terms. The search was updated in November 2011. We 

limited the search to articles involving adult, human subjects and published in the English 

language. Search terms included: hypoglycemia, hypoglycaemia, and diabetes mellitus, type 2. 

The full MEDLINE search strategy is presented in Appendix A.

We obtained additional articles from a search of the Cochrane Library, other systematic reviews, 

reference lists of pertinent studies, reviews, editorials, and by consulting experts. We also searched the 

following Web sites: Centers for Disease Control, ClinicalTrials.gov, Department of Transportation, 

Framingham Heart Study, National Health and Nutrition Examination Survey, National Institute of 

Diabetes and Digestive and Kidney Diseases, and Occupational Safety and Health Administration.
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Predictors and Consequences of Severe Hypoglycemia 

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

Figure 1. Analytic Framework

POPULATION

Adults with Type 2 Diabetes 

on > 1 Hypoglycemic Agents

KQ3

OUTCOMES

KQ1 - Incidence

KQ2

Severe Hypoglycemia

Risk Factors

Patient characteristics: 

Demographics, Comorbidities, 

Behaviors

Medications: Hypoglycemic, Other

A1C: Goal, Achieved

Outcomes Morbidity, Mortality, 

Quality of Life, Utilization

STUDY SELECTION

Investigators and research assistants trained in the critical analysis of literature assessed for 

relevance the abstracts of citations identified from literature searches. Full-text articles of 

potentially relevant abstracts were retrieved for further review. 

Specific exclusion criteria for Key Questions #1 and #2 were as follows:

1. Population: exclude if animal study, age less than 18 years, inpatients, type 1 diabetes, patient 

on dialysis, gestational diabetes, or fasting populations.

2. Publication type: exclude case reports, narrative reviews, case series, letters, editorials, 

commentaries, book chapters, dissertations, other summaries, duplicate publications.

3. Outcomes: exclude if no outcomes of interest. Outcomes of interest are incidence of severe 

hypoglycemia and risk factors for severe hypoglycemia. Exclude if severe hypoglycemia not 

reported or defined.

4. Study duration: exclude if study is less than 6 months in duration.

5. Sample size: exclude if study enrolled fewer than 500 patients.

6. Intervention: exclude if study only includes patients on one or more non-FDA approved 

hypoglycemic agent (vildagliptin, algogliptin, taspoglutide, giclazide, troglitazone, exubera, 

any inhaled insulin) or on continuous insulin infusion.

For Key Question #1 – Extension, we employed the same exclusion criteria with the following 

modifications: we included population or clinic-based studies that may have enrolled fewer 

than 500 patients or had fewer than 6 months of follow-up; in which the definition of 

severe hypoglycemia may not have been rigorously defined but included some definition of 

symptomatic hypoglycemia; and in which there may not have been true incidence data (e.g., 
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Predictors and Consequences of Severe Hypoglycemia 

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

cross-sectional patient surveys). From this search we identified 16 articles (see Figure 2, shaded 

boxes).

For Key Question #3, we placed no restriction on sample size or study duration. The study had 

to report an association between severe hypoglycemia and outcomes of interest. Outcomes 

of interest included all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, 

neurological events (other than stroke), hospitalizations, emergency department visits, accidents/

trauma, quality of life, cognitive function, productivity, and other health resource utilization. 

DATA ABSTRACTION

We abstracted the following data for each included study (as appropriate based on study design): 

study design, definition of severe hypoglycemia, length of follow-up, population characteristics, 

subject inclusion and exclusion criteria, intervention(s), comparison(s), length of follow-up, and 

outcome(s).

QUALITY ASSESSMENT

We assessed study quality for randomized controlled trials using the criteria recommended by 

the Cochrane Collaboration to assess the risk of bias of studies included in a systematic review:13

1) adequate allocation concealment, based on the approach by Schulz and Grimes;14 2) blinding 

methods (participant, investigator, or outcome assessor); 3) how incomplete data were addressed 

(did the study analyze the data based on the intention-to-treat principle, i.e., were all subjects 

who were randomized included in the outcomes analyses), 4) reasons for dropouts/attrition 

reported. Studies were rated good, fair or of poor quality. A rating of good generally indicated 

that the trial reported adequate allocation concealment, blinding, analysis by intent-to-treat, and 

reasons for dropouts/attrition were reported. Studies were generally rated poor if the method of 

allocation concealment was inadequate, blinding was not defined, analysis by intent-to-treat was 

not utilized and reasons for dropouts/attrition were not reported and/or there was a high rate of 

attrition.

Quality assessment for non-randomized studies was based on: 1) population, 2) outcomes, 

3) measurement, 4) confounding, and 5) intervention (if applicable). We assessed whether the 

study fulfilled the descriptive characteristics for each element (see Appendix B). Studies were 

considered to be of higher quality and more applicable if they were prospective, explicitly 

defined severe hypoglycemia, used multivariate analysis and included patients representative of 

typical patients with type 2 diabetes.

DATA SYNTHESIS

We constructed evidence tables showing the study characteristics for all included studies. 

Outcomes tables were organized by key question. We critically analyzed studies to compare their 

characteristics, methods, and findings. We compiled a summary of findings for each key question 

and drew conclusions based on qualitative synthesis of the findings or pooled results, where 

appropriate.
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Predictors and Consequences of Severe Hypoglycemia 

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

For Key Question #1, data were pooled and analyzed in Comprehensive Meta-Analysis 

software© (Biostat, Inc., Englewood, NJ). Risk ratios (RR) were calculated using a randomeffects model if substantial heterogeneity was present. Statistical heterogeneity between trials 

was assessed using the I2

 test with a score of 50% or greater suggesting moderate to substantial 

heterogeneity among studies. 

PEER REVIEW

A draft version of this report was reviewed by technical experts as well as clinical leadership. 

Their comments and our responses are shown in Appendix C.
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Predictors and Consequences of Severe Hypoglycemia 

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

RESULTS

LITERATURE FLOW

We reviewed 2353 titles and abstracts from the electronic search. After applying inclusion/

exclusion criteria at the abstract level, 1914 references were excluded. We retrieved 439 full-text 

articles for further review and another 320 references were excluded. We identified 8 references 

by hand searching reference lists of relevant publications resulting in a total of 127 references 

for inclusion in the current review. We grouped the studies by key question. We re-reviewed 

excluded studies to identify studies that might address a more population-based perspective on 

hypoglycemia incidence (Key Question #1-Extension). Sixteen articles were included in this 

extended view of incidence. Figure 1 details the exclusion criteria and the number of references 

related to each of the key questions.

Figure 2. Literature Flow Diagram 

Excluded Articles (n=320)

Population = 4

Publication type = 46

Outcomes of Interest = 131

Study < 6 months or < 500 pts = 135

Non FDA meds = 2

KQ3 Specific Excludes:

No association between severe 

hypoglycemia and outcomes of interest = 2

Excluded Abstracts 

(n=1914)

MEDLINE Search 

(n=2353 abstracts)

Full Text Review 

(n=439 articles)

Re-reviewed for 

KQ1 Extension 

(n=320)

KQ1 Extension 

Included Articles

(n=16)

KQ1 Included 

Articles (n=72)

Included Articles 

(n=119)

Total Include Articles 

(n=127)

KQ2 Included 

Articles (n=31)

Hand Search (n=8)

KQ3 Included 

Articles (n=59)

*A number of articles provided data for more than one KQ. Therefore, the total number of included articles does not 

equal the sum of the articles for each key question. 
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Predictors and Consequences of Severe Hypoglycemia 

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

KEY QUESTION #1. What is the incidence of severe hypoglycemia in 

adults with type 2 diabetes on one or more hypoglycemic agents?

We identified 72 articles on 60 studies that provided data to address Key Question #1. We 

also identified 21 systematic reviews that were not funded by industry and provided severe 

hypoglycemia data. Four of the reviews included only the “intensive versus conventional” 

studies while 17 reviewed specific drugs or drug combinations. 

Overview of Included Studies (Appendix E, Table 1) 

The 60 studies included 46 RCTs (N>75,000), eight prospective observational studies,15-22 and six retrospective studies.23-28 Five of the RCTs randomized participants to an intensive versus a conventional 

treatment strategy, and not to specific drug regimens.3-5, 21, 29, 30 Thirty were multinational, eighteen 

were conducted in the US and/or Canada, six in the United Kingdom, five elsewhere, and in one it 

was unclear.31 Forty-seven were funded exclusively by pharmaceutical companies, ten by government research institutes with or without supplementary pharmaceutical support, and funding for three 

studies was not reported.28, 32, 33 All studies enrolled both men and women except one VA study which 

enrolled only men.30 Among the RCTs, most enrolled a broad age range of patients from age 18 to no 

upper age limit; only three had a lower age limit of 40.3, 5, 30 As shown in Appendix E, Table 1 there 

was a wide spectrum of hypoglycemic treatment regimens and of other inclusion criteria. 

Definition of Severe Hypoglycemia 

All 60 studies met our pre-specified minimal definition of severe hypoglycemia: an episode with 

typical symptoms (e.g., sweating, dizziness, tremor, visual disturbance) that resolves after treatment 

(oral carbohydrate, intramuscular glucagon, or intravenous glucose) administered by another 

person. Adopting the language used in ACCORD,3 we refer to this type of episode as HA—

Hypoglycemia needing any Assistance. Thirty-seven studies used this definition exclusively. Six 

studies required that the episode be treated by medical personnel to qualify as “severe”—referred 

to as HMA (Hypoglycemia requiring Medical Assistance); ten studies used other definitions (see 

Appendix E, Table 1); and seven studies categorized events by more than one definition. 

Study Quality

As shown in Appendix D, Table 1, only 26% (n=12) of the 46 unique randomized studies 

were rated as a good quality study or having a low risk of bias based on adequate allocation 

concealment, blinding, analysis by intent-to-treat, and adequate study withdrawal reporting. 

The remaining studies were assessed as fair quality with an unclear risk of bias. Adequate 

methods used to conceal allocation was reported in 41% (n=19) of the studies, and any blinding 

(participants, personnel, and/or outcome assessors) was reported in 63% (n=29) of studies. Most 

studies analyzed data based on randomized subjects who had taken at least one dose of study 

medication (modified intent-to-treat). Reasons for dropouts/attrition were generally reported. 

Nearly all studies reported funding from pharmaceutical industries. 

Among the 14 unique non-randomized studies for Key Question #1, eight were prospective 

cohort studies, five were retrospective cohort studies and one was a case series (Appendix D, 

Table 2). Although our intent was to exclude case series, this study was originally misclassified 
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Predictors and Consequences of Severe Hypoglycemia 

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

and was retained in our analysis. Most studies used a study sample that pertained to the 

population of interest, included inclusion/ exclusion criteria, and used appropriate sampling 

methods. Outcomes reporting and measurement assessment were considered appropriate in 

nearly all studies. Methods for minimizing confounding were reported in seven of the studies.

Results 

We tabulated frequency of severe hypoglycemia by treatment regimen (Appendix E, Table 

3). Overall incidence of severe hypoglycemia was low in most studies, particularly studies of 

metformin monotherapy(<1%), GLP-1 analogs (< 1%), DPP-4 inhibitors (<1%), glinides (0%), 

detemir (<1%) and TZDs (<1%). In the single study evaluating pramlintide, the incidence of 

severe hypoglycemia was less than 2%, the same as the placebo incidence.34 We pooled incidence 

data for specific treatment regimens as detailed below.

Long-acting Insulins 

There were eight studies of insulin glargine,

35-42 three long term (pooled incidence 4.1%, 95% CI 

1.9 to 8.4%, N=1223) and five short-term (pooled incidence 1.6%, 95% CI 0.8 to 3.2%, N=13,088) 

(Appendix F, Figure 1). There were three insulin detemir studies18, 40, 43 (Appendix F, Figure 2), two 

long-term (incidence 1.4%, 95% CI 0.7 to 2.9%, N=525) and one moderate term (incidence 0.4%, 

95% CI 0.1 to 0.9%, N=1129). NPH insulin monotherapy was studied in two trials35, 39 (Appendix 

F, Figure 3), with a pooled incidence of 9.3% (95% CI 7.3 to 11.8%, N=763) over a weighted 

average follow-up time of 3.5 years. Six studies with eight treatment arms evaluated NPH insulin 

in combination with other glucose lowering medications35, 39, 41, 44-46 (Appendix F, Figure 4). Five of 

the six studies were short-term and one was long-term. Pooled incidence was 5.0% (95% CI 4.1 to 

6.1%, N=3150) over a weighted average follow-up time of 1.2 years. We also pooled relative risks 

for NPH versus glargine (Appendix F, Figure 5). For this comparison there were three trials,35, 39, 41

one long term and two short-term. There was no difference in risk over a weighted average followup time of 2.5 years, (RR 1.37, 95% CI 0.66 to 2.81, N=2291)

Fast-acting Insulin Analogues 

In the two lispro studies,36, 47 the pooled incidence of severe hypoglycemia was 3.6% (95% CI 2.3 

to 5.4%, N=1198, Appendix F, Figure 6) over a weighted average follow-up time of 1.3 years. In 

the four studies of aspart,15, 22, 43, 48 the pooled incidence of severe hypoglycemia was 0.2% (95% 

CI 0.2% to 0.2%, N=54,225, Appendix F, Figure 7) over a weighted average follow-up time of 

0.5 years. In the 2 studies of glulisine (combined with NPH insulin),45, 46 the incidence of severe 

hypoglycemia was 1.0% (95% CI 0.5 % to 2.1%, N=883, Appendix F, Figure 8) over a weighted 

average follow-up time of 0.5 years.

In the 13 sulfonylurea studies (Appendix F, Figure 9), the pooled incidence of severe 

hypoglycemia was 1.2% (95% CI 0.9 to 1.5%, N=9081) over a weighted average follow-up time 

of 2.3 years.17, 18, 21, 32, 49-57

Insulin Provision versus Insulin Sensitization

One multinational factorial trial enrolled 2307 patients with type 2 diabetes and coronary heart disease 

and randomized them to either a percutaneous or surgical revascularization procedure and to either 
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Predictors and Consequences of Severe Hypoglycemia 

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an insulin sensitization (metformin and TZDs most commonly used) or an insulin provision strategy 

(insulin and sulfonylureas most commonly used). The target HbA1c in both groups was less than 7%. 

The average length of follow-up was 5.3 years. The incidence of severe hypoglycemia was 5.9% in 

the insulin sensitization group and 9.2% in the insulin provision group58 (Appendix F, Figure 10). 

Placebo

Two short-term (24 weeks) studies had a placebo only arm59, 60 and one long-term (10 years) 

study had a diet-only arm21, 29 with a total of 1312 subjects followed for a weighted average time 

of 7 years. The incidence of severe hypoglycemia was 0.6% (95% CI 0.3 to 1.2%). The two 

studies with placebo arms had rates of 0%. 

Trials of Intensive versus Conventional Glycemic Control 

Five trials randomized participants to intensive glycemic control versus conventional control3-5, 21, 

29, 30 (Table 1, below). Length of follow-up ranged from 2.3 to 10 years, with a weighted average 

follow-up time of 5.2 years. The pooled incidence of severe hypoglycemia in these 5 trials was 

7.6% in the intensive group and 3.1% in the conventional group (RR 2.4, 95% CI 1.8 to 3.1, N= 

27,644, Appendix F, Figure 11).

The largest of these trials was ACCORD3 which enrolled over 10,000 patients in the US and 

Canada and randomized them to receive intensive (target HbA1c <6%) or conventional (target 

HbA1c 7-7.9%) treatment. This trial was stopped early due to an increase in all-cause mortality in 

the intensively treated group. Although this group had a higher incidence of serious hypoglycemia 

requiring medical assistance (which might have explained the increased mortality), subsequent 

analyses did not confirm an association between hypoglycemia and increased mortality.61 The 

other four trials did not find increased all-cause mortality in the intensively treated arms. This 

discrepancy may be explained by the fact that ACCORD3

 was the largest of these trials and enrolled 

a higher risk population. For example, in ADVANCE,4

 the next largest trial, fewer than 2% of 

subjects were on insulin at baseline compared to 35% of subjects in ACCORD. Similarly, average 

duration of diabetes and baseline level of HbA1c were higher in ACCORD than ADVANCE. 

Table 1. Incidence of Severe Hypoglycemia – Trials of Intensive vs. Conventional Glycemic Control

Study Standard Intensive Average 

Follow-up 

(Years)

Definition Glycemic Targets 

(conventional /intense)

ACCORD3 261/5123 (5.1%) 830/5128 (16.2%) 3.5 HA HbA1c 7.0 – 7.9/

HbA1c < 6.0

ADVANCE4 81/5569 (1.5%) 150/5571 (2.7%) 5.0 HA Local standards/HbA1c 

≤ 6.5

VA-DT5 28/899 (3.1%) 76/892 (8.5%) 5.6 ** HbA1c < 9/HbA1c < 6

VA-CSDM30 2/78 (2.6%) 5/75 (6.6%) 2.3 HA HbA1c < 13/HbA1c 

4.0 – 6.1

UKPDS#21, 29 8/1138 (0.7%) 33/3071 (1.1%) 10.0 HA FPG 6.1 – 15.0 mmol/l/

FPG < 6.0 mmol/l

** life threatening or resulted in death, hospitalization, disability or incapacity

#

 data for the 2 UKPDS studies are combined as per Hemmingsen 20119

HA—episode of hypoglycemia requiring assistance of another person
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Predictors and Consequences of Severe Hypoglycemia 

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Other Meta-Analyses 

We identified four high quality meta-analyses comparing intensive versus conventional control 

strategies.8-11 These reviews reported a 2- to 2.5- fold increased risk of severe hypoglycemia 

in intensively treated patients, with 5 year incidence rates of 2-3% with conventional control 

and 5-7% with intensive control. In addition, several high quality reviews have pooled data on 

specific diabetes treatments including exenatide,62, 63 sitagliptin,64 long-acting insulin analogs,65, 

66 fast acting insulin analogs,67, 68 liragultide,63 insulin with or without oral hypoglycemic agents 

(OHAs),69 insulin with pioglitzone70 and glinides.71 As shown in Table 2, the frequency of severe 

hypoglycemia was less than1% in all these reviews. 

Table 2. Frequency of Severe Hypoglycemia in Prior Reviews

Treatment Reference # of 

Studies* Frequency of Severe Hypoglycemia

Exenatide Waugh62 7 Rare episodes, mostly when combined with 

sulfonylureas

Shyangdan63 3 1 episode

Sitagliptin Richter64 11 0 episodes

Glargine, Detemir

(long acting insulin 

analogs)

Swinnen65 4 No difference between determir and glargine

Horvath66 4 No difference between analogs and NPH

Lispro, Glulisine, Aspart 

(fast acting insulin 

analogs)

Siebenhofer67 14 Incidence ranged from 0 to 30.3 (median 0.3) 

episodes per 100 pt-yrs compared to 0-50.4 (median 

1.4) per 100 pt-yrs for people on regular insulin

Tran68 2 No difference between Lispro 2/811 (0.1%) and 

Human Insulin 5/811 (0.6%) 

Liragultide Shyangdan63 3 (1.2 mg)

4 (1.8 mg)

1.2 mg dose: 0 episodes; 1.8 mg dose: 6 episodes 

Insulin with or without 

OHA

Goudsward69 14 1 episode 

Insulin with Pioglitazone Clar70 6 “severe hypoglycemia rarely seen”

Glinides Black71 5 4 studies had 0 episodes; 1 study (repaglinide) had 3 

episodes (1%)

* reporting severe hypoglycemia

Extension of Key Question #1

In order to gain a more population-based perspective on hypoglycemia incidence, we rereviewed all the abstracts identified through the initial search strategy (through November 2011) 

to find articles that might contain data from more representative groups that had not met the 

initial inclusion criteria (see Methods). From this search we identified 16 additional studies.

Overview of Included Studies

The 16 studies included 13 cross-sectional patient surveys, retrospective analyses of 

administrative data, and 1 prospective cohort study.72 Six of the studies were from the US, nine 

from Europe, and one from Asia.73 Ten were funded in whole or in part by industry, two by the 

VA,74, 75 three by foundations or other government agencies,76-78 and funding was not reported for 

one study.79 For more details on these studies see Appendix E, Table 2. 
15

Predictors and Consequences of Severe Hypoglycemia 

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

Patient Surveys (n=13) 

Six reported events from the previous 6 months,73, 74, 78, 80-83 five from the previous year,76-79, 84

one from the previous 5 years85 and one from the previous 2 weeks.86 Seven studies included 

patients on any OHA, three on insulin only, two on a SU with or without metformin, and one on 

any combination of medications.79 Eleven studies categorized hypoglycemic events as requiring 

assistance from another person (six further categorized events as requiring medical (HMA) or 

non-medical assistance (HA)) and two had other definitions.80, 86 Sample sizes ranged from 215 to 

5965. 

All the survey studies which had 6 months of follow-up and reported severe hypoglycemia 

included patients on OHA only.73, 74, 82, 83, 87 In these five studies rates of HA were 1%, 2%, 4%, 

9%, and 13% and of HMA were 2%,83 1%,82 4%,87 and 3%.73 In the three of the four studies 

with 1 year of follow-up,76, 77, 84 all of which included patients on insulin only, rates of HA were 

12, 15 and 17 % and of HMA 2% (Honkasalo et al.77 only study to report). The four remaining 

survey studies included one in which 14% of 2074 patients on OHA only reported one or 

more symptomatic episodes (not necessarily severe) in past 2 weeks;86 one in which 27% of 

1709 patients on OHA reported HA and 5% reported HMA over past 5 years;85 one in which 

symptomatic hypoglycemia (not necessarily severe) occurred in the previous 6 months in 20% of 

203 patients;80 and one in which 27% of 635 people on insulin and 6% of 2689 people on OHA 

only reported HA in one year.79

Results from Other Studies (n=3)

• In a community based study in Scotland, a random sample of 173 adults with type 

2 diabetes prospectively recorded hypoglycemic episodes over 1 month. Five (3%) 

experienced one or more severe episodes (required the assistance of another person).72

• In a US study using claims data from a privately insured population of adults age less 

than 65 with type 2 diabetes on either glargine (N=400) or NPH (N=400), 0.75% in each 

group had one or more hypoglycemia related outpatient claims during 1 year.88

• In a retrospective cohort analysis of 243,222 VA patients, diabetic patients with chronic 

kidney disease (CKD) had an average of 2.99 hypoglycemic events (glucose < 50) per 

100 patient-months compared to 1.45 events in those without chronic kidney disease.75

Summary of Key Question #1

Overall incidence of severe hypoglycemia was less than 1% in the majority of the 60 reviewed 

studies, particularly those of metformin monotherapy (<1%), GLP-1 analogs (<1%), DPP-4 inhibitors 

(<1%), insulin detemir (<1%), insulin aspart (<1%), glinides (0%) and TZDs (<1%). The data 

suggest annual rates of severe hypoglycemia greater than 1% for NPH, glargine, lispro, glulisine 

and sulfonylureas. Some of the highest rates of severe hypoglycemia were observed in the intensive 

control arms of large trials comparing this treatment to conventional control (e.g., ACCORD). 

Of the additional 16 studies reviewed to gain a broader population-based perspective on incidence of 

symptomatic hypoglycemia, 13 were survey studies reporting patient-recalled rates. Eleven of these 

13 asked patients to report on events in the past 6 months (N=6) to one year (N=5). In these 11 studies 

patient reported incidences of hypoglycemia varied widely from 1% to 17%. 
16

Predictors and Consequences of Severe Hypoglycemia 

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KEY QUESTION #2. What are the risk factors for severe hypoglycemia 

in adults with type 2 diabetes on one or more hypoglycemic agents 

(e.g., demographics, co-morbidities, diabetes treatment regimen, 

other medication use, goal and achieved HbA1c)?

We identified 31 articles on 28 studies that provided information about risk factors for severe 

hypoglycemia. 

Overview of Included Studies (Appendix E, Table 1)

An overview of the 31 included articles is shown in Appendix E, Table 1. These 31 articles 

represent 28 unique studies, including four randomized controlled trials,43, 89-91 three prospective 

cohort studies (in five articles),16, 17, 92-94 five retrospective cohort studies, 25, 95-98 seven cross 

sectional studies,76, 78, 84, 85, 99-101seven case control studies,24, 27, 102-106 and three case series,107, 108

one of which was related to a prospective cohort study.17 Although we excluded case series, 

two studies were originally misclassified and retained in our analyses. Four studies were 

multinational,3, 4, 85, 107 seven were performed in the United States, three in Germany, three in 

Scotland, three in the UK, and eight in other countries (Australia, Denmark, Mexico, Sweden, 

Italy, Japan, Greece, Poland). All of the studies enrolled both men and women. Average age 

ranged from the mid 50s to the low 80s, with 14 of the studies having an average age in the 60s. 

Six studies17, 24, 25, 27, 43, 85, 109 were entirely funded by a pharmaceutical company. Funding for nine 

studies was supplied by government agencies with or without supplementary pharmaceutical 

company support. Funding for 13 studies was not reported.

Although all 28 studies are included in Appendix E, Tables 4 and 5, in the text below we 

summarize 14 articles on 12 unique study populations. Sixteen articles were not included in this 

summary because they did not report multivariate analyses of risk factors. One additional article 

was excluded since the multivariate analysis evaluated any (not severe) hypoglycemia.24 The 12 

studies included two RCTs, one prospective and one retrospective cohort, four cross sectional, 

and four case control studies.

Definition of Severe Hypoglycemia

All 28 studies met our pre-specified minimal definition of severe hypoglycemia as defined in 

Key Question #1. Of the 12 multivariate adjusted studies, four used HA (Hypoglycemia needing 

any Assistance), three used HMA (Hypoglycemia requiring Medical Assistance), three used 

administration of IV glucose, and two studies categorized events by more than one definition.3, 92

Quality

The quality of both RCTs was good. Of the non-randomized studies, 9 of 12 met criteria for three 

or more of the quality metrics (Appendix D, Table 3).

Results (See Table 3 and Appendix E, Table 6)

Since the studies varied considerably with respect to risk factors evaluated (and their definitions), 

populations studied, and lengths of follow-up, the data were considered unsuitable for pooling. 

We present, instead, a narrative summary. Although impaired hypoglycemia awareness was 
17

Predictors and Consequences of Severe Hypoglycemia 

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

evaluated in only one study, it is frequently listed as a well-established risk factor so we include 

it here as well. The single study that met our criteria was a cross sectional survey of 401 subjects, 

in which impaired awareness was associated with an increased risk of hypoglycemia (OR 2.66, 

95% CI 1.55 to 4.56).84 The risk factor intensive glycemic control is discussed above under Key 

Question #1. 

Gender was evaluated as a risk factor in seven studies,16, 27, 89, 90, 97, 100, 102 with mixed findings. Most 

studies, including the large ADVANCE trial, showed no association between gender and risk 

for severe hypoglycemia.16, 90, 102 One large retrospective cohort study showed that men were at 

higher risk than women, but the 95% confidence interval extended to 1.0.97 In ACCORD, women 

were more likely than men to experience a hypoglycemic event requiring medical assistance (HR 

1.21, 95% CI 1.02 to 1.43). Similarly, in a nested case-control study using a claims database, 

men on at least one OHA had a 16% lower risk of hypoglycemia-associated hospitalization than 

women (OR 0.84, 95% CI 0.73 to 0.96).27
18

f Severe Hypoglycemia 

matic Review of the Evidence Evidence-based Synthesis Program

rs for Severe Hypoglycemia

Male Gender

Nonwhite Race

Married

Advanced Education

Impaired Awareness

Alcohol

Smoking

Lower BMI

Longer 

Diabetes Duration

Higher HbA1c

Previous 

Hypoglycemia

Polypharmacy

Renal Disease

Microvascular Complications

Macrovascular complications

Dementia or cogniftive 

impairment 

Intense control

Insulin or insulin dose

Time on insulin

Metformin 

Sulfonlyurea or dose 

Other

  x   x x x 

x  x   x x   

 x x x       x  x x x x  x   x  x 

   x  

x x x x x x 

  x x x 

x x x x x x x x x

 *****  x  *    x   x x 

        

x  x x x x x x x x x x

 x x

      

    x   x   x 

 hypoglycemia in multivariate analysis

f hypoglycemia in multivariate analysis

variate model AND non significant risk factors

nuria, diabetic eye disease, peripheral neuropathy

sient ischemic attack, myocardial infarction, angina, coronary or peripheral revascularization, leg amputation

tes not significant, but 16+ years 

dy

te models

eated events

Other”

and combined

 as independent variable
19

Predictors and Consequences of Severe Hypoglycemia 

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Race was evaluated in four studies, three of which found that blacks are at higher risk for 

severe hypoglycemia than whites. These studies included one large RCT,89 two retrospective 

cohort studies,97, 100 and one cross-sectional study.101 ACCORD reported that, compared to nonHispanic whites, blacks had a 43% increased risk of HMA (HR 1.43, 95% CI 1.2 to 1.7) and 

that people in racial groups other than Hispanic or black had a lower risk of HMA than whites 

(HR 0.64, 95% CI 0.47 to 0.88).89 An increased risk for African Americans was also seen in a 

large population-based retrospective cohort study of 20,000 Medicaid enrollees over age 65 in 

Tennessee. Specifically, blacks on OHAs had a two-fold increased risk of hypoglycemia-related 

hospitalization, ED visit or death compared to whites (RR 2.0, 95% CI 1.7 to 2.4).97 A crosssectional analysis of hospitalizations among people with type 2 diabetes in US community 

hospitals indicated that blacks were more likely than whites to have a diagnosis of acute 

hypoglycemic condition (OR 1.62, 95% CI 1.55 to 1.69).101

Body mass index was evaluated in five studies, including two large RCTS,89, 90 both of 

which found that a higher BMI was associated with a lower risk of severe hypoglycemia. In 

ACCORD,89 a BMI of 30 or higher was associated with a 35% lower incidence of HMA than a 

BMI of less than 25 (HR 0.65, 95% CI 0.5 to 0.85). Similarly, in ADVANCE90 for each unit (kg/

m2) increase in BMI there was a 5% decrease in risk of HA (HR 0.95, 95% CI 0.93 to 0.98). BMI 

was not found to be associated with risk in three smaller studies.16, 100, 102

Age was evaluated as a risk factor for severe hypoglycemia in nine studies (two RCTs, one 

prospective and one retrospective cohort, one cross sectional, and four case control). The two 

largest trials (ACCORD89 and ADVANCE90) both reported significant associations between 

older age and risk of severe hypoglycemia. In ACCORD,89 the risk of HMA increased by 3% 

for each additional year of age (HR 1.03, 95% CI 1.02 to 1.05). ADVANCE90 reported almost 

identical results (HR 1.05, 95% CI 1.03 to 1.07). Confirming these findings, a population-based 

retrospective cohort study of 20,000 Medicaid enrollees over age 65 in Tennessee, found that 

compared to enrollees age 65-69, older age groups had significantly increased risk (age 70-74: 

RR 1.1, 95% CI 0.9 to 1.4; age 75-79: RR 1.5, 95% CI 1.2 to 1.9; age > 80: RR 1.8, 95% CI 1.4 

to 2.3).97 Six smaller studies showed either no significant association between age and risk of 

severe hypoglycemia16, 27, 84, 100 or a significant inverse association.102, 104

Diabetes duration was evaluated as a risk factor in seven studies (two RCTs, one prospective 

and one retrospective cohort, two case control, one cross sectional). In ACCORD, compared to 

people with diabetes duration of 5 years or less, the risk for those with diabetes duration of 11-15 

years increased by a non-significant 6% (HR 1.06, 95% CI 0.83 to 1.37) and by 37% for those 

with diabetes of 16 or more years (HR 1.37, 95% CI 1.09 to 1.73).89 In ADVANCE each year of 

diabetes was associated with a 2% increase in risk of severe hypoglycemia (HR 1.02, 95% CI 

1.00 to 1.04).90 Similar results were reported by the cross sectional84 and one of the case control 

studies.104 The other three studies did not find statistically significant associations between 

duration of diabetes and incidence of severe hypoglycemia.16, 100, 102

Previous hypoglycemia was evaluated as a risk factor in four studies, two case control,27, 104

one prospective,16 and one retrospective cohort.100 Three studies found that a history of past 

hypoglycemia was a strong predictor of future episodes, and one did not.100 In a large case 

control study based on administrative data, a prior emergency room (ER) visit for hypoglycemia 
20

Predictors and Consequences of Severe Hypoglycemia 

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increased the odds of a subsequent inpatient admission for hypoglycemia by more than nine-fold 

(OR 9.5, 95% CI 5 to 18).27 In the other case control study a reported history of hypoglycemia, 

not further defined, in the previous year was associated with a three-fold increase risk of 

hypoglycemia associated hospitalization or ER visit (OR 2.9, 95% CI 1.3 to 6.5).104 History of 

previous episode requiring health services use was associated with a six-fold increase for another 

episode over the next 8 years (HR 5.7, 95% CI 2.2 to 15) in the prospective cohort study.16

Education was evaluated as a risk factor in five studies, two RCTS,89, 90one cross sectional,78 one 

case control104 and one prospective cohort study.16 Four of the five studies found significant but 

modest associations between level of education and risk for severe hypoglycemia. ADVANCE 

found a marginally significant inverse association between the age at completion of formal 

education and risk of severe hypoglycemia (HR 0.98 95% CI 0.96 to 1.0).90 Similarly, in 

ACCORD, subjects with less than a high school education were at an increased risk for severe 

hypoglycemia (conventional control: HR 1.74, 95% CI 1.02 to 2.95; intensive control: HR 

1.38, 95% CI 1.06 to 1.81) compared to those with more education.89 In the case control study, 

illiteracy was associated with an increased risk (OR 3.7, 95% CI 1.4 to 10).104 In a cross sectional 

study in a community population, Sarkar et al. found that subjects who indicated that they had 

“problems learning,” “needed help reading,” or “lacked confidence with forms” were about 30-

40% more likely to have reported an HA in the previous year.78 Finally, in the prospective cohort 

study, “education level higher than primary level” was associated with an increased risk of severe 

hypoglycemia (HR 2.3, 95% CI 1.09 to 5.04, N=616).16

Renal disease was evaluated as a risk factor in seven studies, two RCTs,89, 90 one prospective,16

one retrospective cohort100 study, and three case control studies.27, 102, 104 Five of these 

studies found that renal insufficiency (defined as elevated serum creatinine level or elevated 

estimated glomerular filtration rate) was significantly associated with increased risk of severe 

hypoglycemia. The only studies that did not find a significant association were a very small 

study,102 and the retrospective cohort study that was conducted in a single institution with a 

predominantly African American population.100 In ACCORD, a urine albumin:creatinine ratio 

greater than 300 or a serum creatinine greater than 115 umol/L were each associated with a 

significantly increased risk of about 70%. In ADVANCE, for each umol/L increase in serum 

creatinine, the risk of a severe hypoglycemic event increased by 1%.90

Other (non-renal) microvascular disease was assessed in five studies.16, 27, 84, 89, 90 In four of the 

five there were significant positive associations; in one relatively small study (N=415), which 

evaluated untreated retinopathy and symptomatic or asymptomatic peripheral neuropathy, 

there were no statistically significant associations for any event, but peripheral neuropathy was 

found in increase the risk of repeated events of severe hypoglycemia.84 In ACCORD a history 

of peripheral neuropathy conferred a modest but significant increased risk (HR 1.2, 95% CI 

1.1 to 1.4).89 In ADVANCE a “history of microvascular disease” conferred a twofold increased 

risk of severe hypoglycemia (HR 2.1, 95% CI 1.5 to 3.).90 In a nested case-control database 

study, peripheral ulceration was found to be positively associated with risk of inpatient hospital 

admission for hypoglycemia (OR 1.71, 95% CI 1.2 to 2.44).27 Finally a population based but 

relatively small study (N=616) found that a history of peripheral neuropathy was significantly 

associated with severe hypoglycemia (HR 2.4, 95% CI 1.3 to 4.5).16
21

Predictors and Consequences of Severe Hypoglycemia 

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

Dementia was evaluated as a risk factor for severe hypoglycemia in three studies.90, 92, 103 In 

ADVANCE, higher cognitive function as measured by the Mini Mental Status Examination was 

significantly associated with a modest decreased risk of severe hypoglycemia (HR 0.93, 95% CI 

0.87 to 0.99).90 In the second study, which was population based and prospectively followed 302 

patients age 70 years and older, patients with dementia at baseline had a significantly higher risk 

for hypoglycemia requiring medical attention than those who did not have dementia (HR 3.0, 

95% CI 1.1 to 8.5).92 In a small case control study, dementia was not found to be a significant 

risk factor.103

Other risk factors evaluated in the 12 studies included genetic markers, marital status, 

smoking, alcohol consumption, polypharmacy, recent discharge from the hospital, and use of 

ACE inhibitors. All were found, in one or more studies, to be associated with increased risk of 

hypoglycemia (See Appendix D, Table 6). However, these findings were generally sparse, often 

conflicting, and ultimately inconclusive.

Summary of Key Question #2 

Factors most consistently and independently associated with risk for severe hypoglycemia in 

adult patients with type 2 diabetes on hypoglycemic medication include: intensive glycemic 

control (discussed above under Key Question #1), history of hypoglycemia, renal insufficiency, 

history of microvascular complications, longer diabetes duration, lower education level, African 

American race and history of dementia. History of hypoglycemia unawareness was evaluated in 

only one study. Gender, age and lower BMI were not consistently associated with risk, although 

higher age and lower BMI were associated with higher risk in the two largest studies.

KEY QUESTION #3. What is the effect of severe hypoglycemia 

on other outcomes in adults with type 2 diabetes on one or more 

hypoglycemic agents (e.g., quality of life, mortality, morbidity, 

utilization)?

We identified 59 articles on 53 studies that provided information about outcomes in patients who 

experienced severe hypoglycemia. 

Overview of Included Studies (Appendix E, Table 1)

An overview of the 59 included articles is provided in Appendix E, Table 1. Among the 53 

studies were 14 randomized controlled trials,3-5, 21, 30, 41, 42, 46, 52, 54, 110-113 16 cohort studies,17, 19, 25, 26, 

75, 92, 94-97, 114-118 12 cross sectional studies,78, 81, 82, 99, 119-126 and 11 case control or case series studies.9, 

28, 105, 107-109, 127-131 Twelve studies were multinational; additionally, twelve were performed in the 

United States, four in Germany, three in the UK, three in Scotland, three in Sweden, and the 

remainder in other countries (Canada, Australia, Singapore, India, Israel, Netherlands, Turkey, 

Switzerland, France, Italy, Greece, and Poland). All but one of the studies30 enrolled both men 

and women. Average age ranged from 30 to 85 years with most studies reporting a mean age in 

the 50 or 60 year range. Twenty one studies were entirely funded by a pharmaceutical company 

while eight studies were funded by government agencies, three by private foundations, and five 

by multiple funding sources. No source of funding was listed for 16 studies.
22

Predictors and Consequences of Severe Hypoglycemia 

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All-Cause Mortality

All-cause mortality associated with severe hypoglycemia was reported in three large randomized 

trials that compared intensive control to conventional control.3, 4, 21, 61, 90 Mortality ranged from 

zero to 12.5 percent in intensively treated people who became hypoglycemic; in two of these 

three studies mortality in this group was 0.1% or less and in the third there was one death in 

eight study subjects (12.5%). In all three randomized trials, mortality in the conventional control 

groups ranged from 0% to 1.2%.

Six additional randomized trials (typically fewer than 1,000 patients enrolled with follow-up less 

than 30 weeks) compared different treatment regimens, including oral medications and different 

forms of insulin.42, 43, 46, 52, 111-113 No deaths related to severe hypoglycemia were reported in these 

studies.

Eight cohort studies reported mortality outcomes, typically in patients seen in an ER or 

hospitalized for severe hypoglycemia. There were no deaths in three studies.16, 17, 116 In four other 

studies, between 0.3% and 8.3% of the patients died following severe hypoglycemic events.95-97,98

One study of veterans with and without CKD did not report number of deaths but reported odds 

ratios for outpatient risk of death within one day of a hypoglycemic event (defined as glucose 

<50 mg/dl) compared to individuals with glucose of ≥70 mg/dl.75 For patients without CKD, the 

odds ratio was 13.28 (95% CI 9.30 to 19.18). For patients with CKD, the odds ratio was 6.84 

(95% CI 4.41 to 10.62).

Mortality was also assessed in six case series. As with the cohort studies, these studies also 

enrolled patients seen in an emergency room or admitted to a hospital as a result of severe 

hypoglycemia. Four studies reported no deaths.28, 108, 109, 128 Three other studies reported that 

between 3.2% and 11% of the enrolled patients died after severe hypoglycemia.105, 127, 131

Three studies reported long-term follow-up mortality data. Participants in the ADVANCE 

trial were followed for a median of 5 years.90 The mortality rate was 19.5% in those who 

had experienced at least one episode of severe hypoglycemia and 9.0% in those who had 

not (adjusted HR 3.27, 95% CI 2.29 to 4.65). The median time to death was 1.05 years. In a 

prospective cohort study, there were no deaths at the time of the event but 16 of the 45 patients 

(35.6%) died during the mean follow-up period of 22.8 months.17 The third study, a retrospective 

cohort study that observed in-hospital mortality of 1.6% (2 of 126 patients), reported long-term 

mortality of 42.1% (53 of 126 patients) during a median follow-up of 23.2 months. Of the 53 

total deaths, 20 were in the group of patients treated with oral medications and 33 were in the 

group treated with insulin (univariate analysis, p=0.02).95 The authors reported that median 

annual mortality in the study population was 22% and compared that to 5.2% in the general 

population (patients with and without diabetes, age 80 years). 

Non-fatal Myocardial Infarction

Three randomized trials, one cohort study, and one case series provided information about 

non-fatal myocardial infarctions among patients with severe hypoglycemia. Two randomized 

trials reported no events.30, 113 The third reported that one patient (4.5%) experienced severe 

hypoglycemia with cardiac arrest.110 The authors did not say how much time elapsed between 

the hypoglycemic episodes and the cardiac arrests. A cohort study that enrolled individuals 
23

Predictors and Consequences of Severe Hypoglycemia 

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who experienced severe hypoglycemia reported three cases (0.5%) with myocardial infarction 

as a complication of the hypoglycemia.97 A case series reported two cases (2%) of transient 

asymptomatic myocardial ischemia associated with severe hypoglycemia.127

Non-fatal Stroke

Non-fatal stroke outcomes were reported in four studies. A randomized trial of several 

hypoglycemic therapies reported no stroke events.113 A cohort study with 586 patients reported 

seven patients (1.2%) experiencing stroke as a complication of severe hypoglycemia.97 A case 

series of 207 patients admitted to a hospital with severe hypoglycemia during a three year 

period, included two patients (0.97%) who experienced cerebrovascular ischemic stroke.108 In a 

case series of 19 patients with severe hypoglycemia associated with glipizide use (over a 7 year 

period), one patient (5.3%) who had a stroke prior to the hypoglycemic event experienced further 

functional impairment. The patient died 23 days after the event.105

Other Neurologic Events

Two randomized trials with veterans assigned to either intensive or conventional control reported 

data on other neurologic events associated with severe hypoglycemia. In one trial, loss of 

consciousness was reported for both of the conventional control group patients who experienced 

severe hypoglycemia (2.6% of the conventional control group) and none of the five intensive 

control patients who experienced severe hypoglycemia (0% of the intensive control group).30

In the second trial, severe hypoglycemia with impaired consciousness was reported in three 

episodes/100 patient-years in the conventional control group compared to nine episodes/100 

patient-years in the intensive control group. In addition, complete loss of consciousness was 

reported in one episode/100 patient-years and three episodes/100 patient-years, respectively. 

Both differences were significant (p<0.001). The median follow-up in the trial was 5.6 years.5

Five randomized trials of different treatment regimens also reported neurologic outcomes. Two 

trials reported zero events.41, 54 In another trial, at the three year follow-up, loss of consciousness 

associated with severe hypoglycemia was reported by four patients – one in the biphasic aspart 

group (0.4%) and three in the basal detemir group (1.3%).43 One trial reported one patient with a 

coma (0.5%) among 199 treated with NPH plus regular human insulin.112 In the last trial, seven 

episodes in four patients either required medical assistance or were accompanied by neurological 

symptoms.52

Three cohort studies provided data on neurologic outcomes. One study reported that, at 

presentation to a hospital, 51% were in a coma, 18% were disoriented, 11% experienced 

somnolence, 9% experienced paralysis, 7% had cerebral seizures and 5% had psychological 

disturbances.17 In another study, among 126 patients admitted for severe hypoglycemia, 54% 

of oral hypoglycemic agent users experienced coma compared to 30.2% of insulin users.95 A 

third study reported transient ischemic attack as a complication of severe hypoglycemia in four 

patients (0.7%).97 At presentation, a loss of consciousness was observed in 49% of episodes, 

seizures in 5% of episodes and irrational behavior in 6% of episodes.97

Seven other studies reported on this outcome. A cross-sectional study reported that 4% of 

patients experienced convulsions associated with episodes of severe hypoglycemia in the 

past year.99 In five case series, coma was reported in 19% to 71% of individuals with severe 
24

Predictors and Consequences of Severe Hypoglycemia 

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hypoglycemia.105, 107, 108, 128 “Semi-coma” (30%),108 coma or stupor (21%),28 somnolence 

(51%),128 decreased consciousness (16%),105 seizures (8-10%),107, 127 disorientation (81%),107 and 

transient right hemiplegia (1%)127 were also reported. One study documented seizures and/or 

psychological disturbances in 30% of patients with severe hypoglycemia.128

Hospitalization

Five randomized trials reported hospitalization data. One trial of intensive versus conventional 

control among veterans reported no hypoglycemia-associated hospitalizations.30 Four trials of 

different treatment regimens found between 0%41, 42, 113, 132 and 0.8%112 were hospitalized for 

hypoglycemia. 

Hospitalizations were also reported in nine cohort studies (10 papers). Among patients starting 

insulin, there were no hospitalizations in 9970 patient years of observation.26 A study of 344 

veterans followed for one year identified 55 severe hypoglycemic episodes in 19 subjects; two of 

these (3.6%) required hospitalization.19 A mean hospitalization rate of 0.15 episode/patient/year 

was reported for type 2 patients based on data from 21 patients with 29 severe hypoglycemic 

episodes.116 A hospitalization rate of 47 per 1000 person-years was reported based on data from 

all discharges from Navajo Area Indian Health Service hospitals during a 5 year period with 

an estimated 26,125 person-years of observation.96 A study that included both type 1 and type 

2 patients reported that over a mean follow-up of 2.5 years, insulin-treated individuals with 

diabetes who had hypoglycemic episodes had more overall hospital admissions (0.97 per year 

vs. 0.48 per year in insulin-treated individuals without hypoglycemic episodes, p<0.01). Forty 

percent of the excess hospital admissions were due to hypoglycemia.118

Three other cohort studies (four papers) reported hospitalization associated with 17% to 33% of 

hypoglycemic events25, 114, 133 or 7.1% of patients experiencing hypoglycemia.117 Another study 

reported that 16% of patients seen in the emergency department were subsequently admitted to 

the hospital.115

In a cross-sectional study of patients with type 2 diabetes from a large diabetes registry, 8% of 

the patients with a self-reported significant hypoglycemia episode had a documented emergency 

room visit or hospitalization. The odds of an emergency room visit or hospitalization were 

significantly higher in patients who reported having at least one significant hypoglycemia 

episode (OR 19.0, 95% CI 13.0 to 26.0) compared to those without a significant hypoglycemia 

episode.78 One other cross-sectional study reported no hospitalizations125 while a second reported 

that 5.5% of patients were treated in an emergency department or hospitalized following severe 

hypoglycemia.124

Length of hospital stay, reported in two case series, ranged from a median of 5.5 days128 to means 

of 9.8 days for patients on oral medications and 8.0 days for patients taking insulin.95

Emergency Department Visits

Two randomized trials reported that no patients with severe hypoglycemia required an 

emergency department visit.42, 113 A third randomized trial reported that either 0% (insulin 

glargine group) or 15.4% (NPH group) of those with severe hypoglycemia were seen in the 

emergency department.41, 132
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Four cohort studies reported emergency department use. One study reported that between 

14% and 23% of severe hypoglycemic episodes were treated in the emergency room.114, 133

Another cohort study reported that 31% of the patients enrolled, all of whom were eventually 

hospitalized, were treated first in the emergency department17 while a third found that 8% of 

patients were treated in either the emergency or primary care service, 36% were treated by 

an ambulance service and 55% required both ambulance and emergency or clinic service.25

Finally, over a mean follow-up of 2.5 years, insulin-treated diabetic individuals who experienced 

hypoglycemic episodes had higher rates of overall emergency department use (0.85 visits 

per year vs. 0.40 visits per year in insulin-treated diabetic individuals who did not have a 

hypoglycemic episode, p<0.01) with 53% of the excess visits due to hypoglycemia.118

Two cross-sectional studies (noted above) reported on rates of either hospitalization or 

emergency department visit (5.5% to 8%).78, 124 An additional cross-sectional study reported that 

six of the seven patients with severe hypoglycemia during a one month period required medical 

services including three emergency room visits.125

Accident/Trauma 

An evidence report prepared for the Federal Motor Carrier Safety Administration (FMCSA)134

focused on the risk of motor vehicle crashes in drivers with diabetes and the relationship with 

hypoglycemia. Based on data from 13 case-control studies of low to moderate quality, the 

conclusion was that the risk for crash among drivers with diabetes was higher than for those 

without diabetes (RR 1.19, 95% CI 1.08 to 1.31). Many of the studies enrolled only patients with 

type 1 diabetes and all but two were published before 2000. The strength of evidence was rated 

as weak. To look at the effect of hypoglycemia on driving ability, the review identified three 

studies of moderate quality, all with type 1 patients. All three involved induced hypoglycemia 

and simulated driving ability. Although driving ability was impaired, it was unclear which 

aspects of driving ability were most affected or at what level of hypoglycemia the impairments 

were evident. It is unknown whether data from driving simulators are predictive of crash risk in 

actual driving conditions. 

We identified several other studies related to motor vehicle operation that were either not 

included in the FMCSA review or were published after the review was completed. A casecontrol study identified 795 drivers who were reported (typically because of a motor vehicle 

crash, mandatory annual review for commercial vehicle license, license suspension appeal, or 

notifiable medical condition) to the Ontario Ministry of Transportation Medical Advisory Board 

and who had an underlying diagnosis of diabetes mellitus. The type of diabetes was not reported. 

Among the cases (57 drivers who had a crash), 60% reported experiencing severe hypoglycemia 

in the past 2 years compared to 27% of the controls (738 drivers with no crash) (OR 4.07, 95% 

CI 2.35 to 7.04). A lower HbA1c was also associated with an increased risk of crash even after 

adjusting for severe hypoglycemia (OR 1.25, 95% CI 1.02 to 1.55).129 A cross-sectional study of 

diabetic patients taking hypoglycemia-inducing medications found that among the 122 patients 

talking oral-antidiabetics (116 with type 2 diabetes, mean age 64.2 years), subjects reported two 

hypoglycemia-induced accidents per year driven. Among the 151 patients receiving conventional 

insulin therapy (109 with type 2 diabetes, mean age 59.0 years, treated with one or two 

injections of premixed insulin and may also be taking other oral antidiabetics), there were three 
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Predictors and Consequences of Severe Hypoglycemia 

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hypoglycemia-induced accidents per year driven. When asked if they refrained from driving due 

to fear of hypoglycemia events during driving, 0.8% of the oral medication group and 4.0% of 

the conventional insulin therapy group responded “yes.”121

Several studies reported on motor vehicle accidents but did not specifically relate the outcome 

to severe hypoglycemia. In the ACCORD study, there was no difference in incidence of motor 

vehicle accidents in which the patient was the driver (0.2% in intensive therapy, 0.3% in standard 

therapy, p=0.40).3

 A nested case-control study used an insurance registry of all eligible drivers 

ages 67 to 84 years, an accident report file, and a prescription drug database. The type of diabetes 

was not reported. Several medication regimens were associated with a borderline significant risk 

of an accident. A combination of sulfonylureas and metformin was used during the preceding 

month by 1.6% of those involved in a crash and 1.2% of the controls (adjusted rate ratio 1.3, 

95% CI 1.0 to 1.7). The adjusted rate ratio for any insulin use was 1.3 (95% CI 1.0 to 1.8). A 

dose-response effect was noted for users of a combination of sulfonylureas and metformin over 

the year preceding the index event.135

Six studies reported falls and bone injury data.17, 95, 97-99, 127 A cohort study of 45 patients with 

sulfonylurea-induced hypoglycemia requiring hospitalization reported that six (13%) had soft 

tissue injuries or fractures as a result of falls associated with hypoglycemia.17 A second cohort 

study of 126 type 2 diabetic patients hospitalized for severe hypoglycemia found that the 

percentage of patients who had experienced a fall was 21.5% with no difference between oral 

medication and insulin users.95 In a third cohort study, among patients hospitalized for severe 

hypoglycemia, bone injuries were reported in 7.3% of patients (9.9% of the insulin users, 0% of 

the oral medication users).98 A cohort study97 and a cross-sectional study99 reported “injury” in 

1.7% to 5% of patients who experienced severe hypoglycemia. In a case series brain trauma and 

skeletal injury were reported in 7% of patients.127

Quality of Life

Nine cross-sectional studies reported measures of quality of life. One study assessed healthrelated quality of life with the SF-36 and reported that scores for all domains were lowest for 

patients reporting severe hypoglycemia.120

Five studies (reported in six papers) assessed health utility/quality of life with the EuroQol-5 

Dimensions (EQ-5D). EQ-5D scores were lower for patients reporting severe hypoglycemia.81, 

82, 87, 119, 120, 126 Three studies reported data from the worry subscale of the Hypoglycemia Fear 

Survey-II (HFS-II). In two studies worry scores were highest for patients who reported severe/

very severe symptoms compared to those with lesser symptoms81, 126 while in the third study, 

there were no differences in worry score as severity increased.82 Both the quality of life and the 

worry scores were impacted by the frequency of severe hypoglycemia episodes.87

Two studies looked at anxiety and depression associated with severe hypoglycemia.122, 123 In one 

study, affective disorder, but not anxiety disorder, was found to be associated with a history of 

severe hypoglycemia in the prior 12 months.122 The second study found that a lifetime history of 

at least one episode of severe hypoglycemia was associated with symptoms of anxiety (p<0.001) 

but not depression.123
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Lifestyle changes made following an episode of severe hypoglycemia were the focus of one 

study.124 Patients reported more frequent testing of blood glucose, changes to insulin doses, 

greater fear of hypoglycemia, requests to have someone check on them, and additional concerns 

about driving. 

Other Outcomes

Cognitive Decline 

Cognitive decline was reported in two cohort studies. One of the studies followed patients 

to determine if the risk of dementia was increased in those with at least one episode of 

hypoglycemia requiring hospitalization or an emergency room visit.94 Patients who had 

experienced at least one episode of hypoglycemia during a 22 year period were evaluated for an 

additional mean of 3.8 years to determine whether they developed dementia. No patient had a 

diagnosis of dementia, mild cognitive impairment or general symptom memory loss at the time 

of the hypoglycemic episode(s). Among 1465 patients, the incidence of dementia was higher for 

patients who had at least one episode of hypoglycemia than for those who had no episodes (17% 

vs. 10%, p<0.001). The attributable risk of dementia in patients with one or more episodes of 

hypoglycemia was 2.4% per year (95% CI 1.7 to 3.0). In the adjusted model all patients with at 

least one episode of severe hypoglycemia were at increased risk for dementia (hazard ratio 1.4, 

95% CI 1.3 to 1.7 for one or more episodes).

In the second prospective study, a baseline assessment (the Mini-Mental State Examination and 

the Informant Questionnaire for Cognitive Decline in the Elderly) was completed on 302 patients 

age 70 and over. At 18 months, a repeat assessment was done on 205 patients (29 had died, 27 

had developed dementia and 41 declined the assessment). Thirty-three new cases of cognitive 

decline were identified (four cases of dementia and 29 cases of cognitive impairment without 

dementia). There was no significant difference in prior severe hypoglycemia (either self-reported 

or requiring medical assistance) between those who developed cognitive decline and those who 

did not.92

Productivity 

One cohort study and two cross-sectional studies reported on productivity. In the cohort study, 

insulin-treated patients with a medical claim coded for hypoglycemia were more likely to 

use short-term disability (47% vs. 32%, p<0.01) and to use more sick days (19.5 vs. 11.0, 

p<0.01) than insulin-treated patients with no claim for hypoglycemia. The analysis included 

patients with either type 1 or type 2 diabetes.118 In one cross-sectional study, a mean loss of 8.6 

productive days following hypoglycemia was reported for patients who experienced severe 

hypoglycemia; for those with mild or moderate hypoglycemia, the mean days lost was 2.7. 

In multivariate modeling, severity of hypoglycemia (along with frequency) was a significant 

predictor of productivity.120 A second study reported that 32% of patients who experienced severe 

hypoglycemia went home from school, work or other activities and 26% stayed home the next 

day.124
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Medical Resource Use 

Several studies reported on medical service use other than hospitalization or emergency room 

visits. A randomized trial reported that one of five patients on liraglutide (20%) who experienced 

severe hypoglycemia required medical assistance of some type.54 One cohort study reported that 

1.9% of the 2,417 patients studied required medical contact for hypoglycemia during the first 

year of insulin use. The number decreased to 0.4% by the fourth year of use.26 A cross-sectional 

study reported mean total resource use of 13.2 contacts with a health service provider among 

patients who reported severe hypoglycemia. For patients with mild or moderate hypoglycemia, 

the mean was 11.5 contacts.120 A second cross-sectional study reported eight nurse visits, three 

physician visits and one telephone contact with medical care among six patients who experienced 

severe hypoglycemia in a one-month period (number of events not reported).125 Another crosssectional study reported that 2.5% of the patients experiencing severe hypoglycemia had 

additional visits to their physicians while 0.4% had additional communication (non-visit).124

Two studies114, 133 that reported hypoglycemic events before and after conversion to a pen device 

reported significantly fewer physician visits (37.7% of hypoglycemic events before, 28.1% after; 

OR 0.39, 95% CI 0.24 to 0.64), no significant difference in outpatient visits (7.8% before, 12.2% 

after, OR 0.79, 95% CI 0.31 to 2.01), and significantly lower use of “other” (not emergency 

department, hospitalization, physician visits, or outpatient visits) health care resources (22.1% 

before, 16.5% after, OR 0.38, 95% CI 0.20 to 0.71) after conversion to the pen device.

Summary of Key Question #3 

We found good evidence for an increased risk of the following outcomes in patients who have 

experienced severe hypoglycemia: all-cause mortality, neurological events (other than nonfatal stroke), hospital and emergency department utilization and decreased quality of life. 

Severe hypoglycemia does not appear to be associated with short-term mortality. However, a 

history of severe hypoglycemia may contribute to increased long-term mortality. Neurological 

events, including coma, impaired consciousness, seizures and paralysis, were reported in seven 

randomized trials, three cohort studies and seven other studies. Few patients in the randomized 

trials experienced coma or loss of consciousness. However, in observational studies of patients 

presenting to an emergency department or admitted to a hospital, between 19% and 71% 

were in a coma. Hospitalization and emergency department utilization was reported in five 

randomized trials, nine cohort studies and three other studies with wide variation across studies. 

Although many of these studies lacked control groups, there is some evidence of increased 

emergency department visits and hospital admissions among patients who experience severe 

hypoglycemia. Data from eight cross-sectional studies suggest that patients who experience 

severe hypoglycemia generally report a lower quality of life and higher worry. 

We found limited data about many of our outcomes of interest including non-fatal MI, non-fatal 

stroke, cognitive decline, motor vehicle accidents, falls and traumatic injuries, work productivity 

and other medical service utilization. The available evidence suggests that non-fatal MI and 

stroke are unlikely consequences of severe hypoglycemia. There are mixed findings from two 

studies on development of cognitive decline or dementia in individuals with a history of severe 

hypoglycemia. Few studies have reported motor vehicle accident data specifically related to 

severe hypoglycemia. Falls and injuries are common consequences of severe hypoglycemia but 
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given the absence of appropriate control groups it is unclear if these outcomes are hypoglycemiarelated or simply reflect the age and co-morbidity burden of the population. The evidence 

suggests that individuals who experience episodes of severe hypoglycemia are more likely 

to miss days at work. Medical resource utilization findings are difficult to interpret without 

appropriate control group data.
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SUMMARY AND DISCUSSION

SUMMARY OF EVIDENCE BY KEY QUESTION

Key Question #1: What is the incidence of severe hypoglycemia in adults with 

type 2 diabetes on one or more hypoglycemic agents? 

Overall incidence of severe hypoglycemia was less than 1% in the majority of the 60 reviewed 

studies, particularly those of metformin (0-1.5%), GLP-1 analogs (< 1%), DPP-4 inhibitors 

(<1%), insulin detemir (<1%), glinides (0%) and TZDs (<1%). These rates are similar to the 

placebo or diet-only rates which were measured in three studies21, 29, 59, 136 with a pooled incidence 

of severe hypoglycemia of 0.6% (95% CI 0.3 to 1.2%) over a weighted mean follow-up time of 

7 years. These results are consistent with other high quality systematic reviews of exenatide,62, 

63 liragultide,63 sitagliptin,64 glinides71 and pioglitazone.70 These results are also consistent with 

a recent meta-analysis of a wide variety of OHAs that concluded that severe hypoglycemia did 

not “occur more often with any particular monotherapy or combination therapy” but that the 

sulfonylureas were the most likely to increase the risk.137 However, Bennett did not include 

insulins or intensive versus conventional control trials.

The treatment regimens with the highest risk were sulfonylureas, those targeting intensive 

control of HbA1c levels and insulin (in particular NPH, glargine, lispro, and glulisine). For the 

sulfonylureas the pooled incidence of severe hypoglycemia was 1.2% (95% CI 0.9 to 1.5%) over 

a weighted average follow-up time of 2.4 years. Due to limited data we were unable to determine 

incidence rates associated with individual sulfonylureas.

In the five trials that randomized participants to intensive versus conventional glycemic control3-5, 21, 

29, 30 the pooled incidence of severe hypoglycemia was 7.6% in the intensive group and 3.1% in the 

conventional group (RR 2.4, 95% CI 1.8 to 3.1, N= 27,644) over a weighted average follow up of 5.2 

years. This is consistent with four other high quality meta-analyses that included these RCTs and other 

studies and that reported a 2- to 2.5- fold increased risk of severe hypoglycemia in intensively treated 

patients, with 5 year incidence rates of 2-3% with conventional control and 5-7% with intensive 

control.8-11 A post-hoc analysis of the ACCORD data indicated that participants whose HbA1c did not 

drop to target levels promptly were at the highest risk. The authors concluded that clinicians should 

not continue to intensify glucose lowering regimens when initial efforts are unsuccessful.89

Insulin

There were only two trials of NPH monotherapy, one of which reported a 5 year incidence of 

11.1%35 and one a 6 month incidence of 2.3%.39 These results are consistent with two metaanalyses, one which identified no cases of severe hypoglycemia in 14 RCTs with an average 

follow-up of 40 weeks.69 The second reported an incidence of severe hypoglycemia of 2.6% 

in six studies with 1532 subjects followed for 6 months to 1 year.

66 Overall, it appears that the 

annual incidence of severe hypoglycemia in persons on NPH monotherapy is about 0-3%. 

For NPH with OHAs we documented a pooled incidence of severe hypoglycemia of 5% 

(95% CI 4.1 to 6.1%, N=3150), over a weighted average followup time of 1.2 years. This is 

consistent with the results of a large trial in which an insulin-based strategy to lower HbA1c to 
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Predictors and Consequences of Severe Hypoglycemia 

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less than 7% was associated with a 9.2% 5-year incidence rate58 and another systematic review 

which compared long-acting insulin analogues to NPH insulin with or without concomitant 

OHAs and reported a 6 month 2.7% incidence of severe hypoglycemia66 However, a review by 

Goudswaard,69 which investigated either insulin monotherapy or combinations of insulin plus 

OHAs, identified only one severe hypoglycemic episode in a patient on morning NPH plus a 

sulfonylurea. In this review, 12 unique studies reported rates of hypoglycemia, none of which 

were included in our review because either they enrolled fewer than 500 subjects, were not 

published in English or were less than 6 months in duration. 

Insulin detemir, a long-acting insulin analogue, was associated with a low incidence (<1%) of 

severe hypoglycemia, consistent with another systematic review (also including only studies 

of at least 6 months duration) which reported an incidence of 1.2% (7/578) in two studies.66

However, a third review reported an incidence of severe hypoglycemia of 3.0% in four RCTs 

with a total of 1247 patients.65 Since this review included studies as short as 12 weeks in duration 

and hypoglycemic episodes are known to occur more frequently during initiation of therapy, this 

may explain the discrepancy between the reviews. 

Insulin glargine was evaluated in eight studies. Results from three long term studies (pooled 

incidence 4.1%, 95% CI 1.9 to 8.4%, N=1223) and five short-term studies (pooled incidence 

1.6%, 95% CI 0.8 to 3.2%, N=13,088) are consistent with the findings of two other recent metaanalyses in which risk of severe hypoglycemia with glargine was found to be 3.2%65 and 1.9%.66

Among the short (or fast) acting insulin analogues (lispro, aspart, glulisine), for lispro, the 

pooled incidence of severe hypoglycemia was 3.6% (95% CI 2.3 to 5.4%, N=1198) over a 

weighted average follow-up time of 1.3 years. For aspart, the pooled incidence of severe 

hypoglycemia was 0.2% (95% CI 0.2% to 0.2%, N=54,425) over a weighted average followup time of 6 months; this analysis however was dominated by a very large observational study 

conducted in physician offices in 11 countries and funded by a pharmaceutical company.22 If 

the analysis is repeated without this study the incidence is 1.5% (95% CI 0.9 to 2.5%) over 

a weighted mean average follow-up of years 1.2 years. For glulisine (combined with NPH 

insulin) the incidence of severe hypoglycemia was 1.0% (95% CI 0.5 % to 2.1%, N=883) over a 

weighted average follow-up time of 6 months.

In a meta-analysis comparing these insulins with either non-insulin agents, premixed human 

insulin, or long-acting insulin analogues in adults with type 2 diabetes, Qayyum found that there 

was no significant difference in risk of serious hypoglycemia.138 A Canadian health technology 

report came to a similar conclusion, stating that there was no significant difference in severe 

hypoglycemia between treatment with human insulin or the insulin analogues.68 A Cochrane 

review reported a median incidence of 0.3 severe hypoglycemic episodes (range 0 to 30.3) per 

100 patient-years.67 The authors attributed the wide range to the inclusion of a single study with a 

very short duration of follow-up. 

Key Question #1 Extension

Of the additional 16 studies reviewed to gain a broader population-based perspective on incidence 

of severe hypoglycemia, 13 were survey studies reporting patient-recalled rates. Eleven of these 

asked patients to report on events in the past 6 months (N=6) to 1 year (N=5). In these 11 studies, 
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Predictors and Consequences of Severe Hypoglycemia 

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patient reported incidences of HA varied widely from 1% to 17%. Although hypoglycemic agents 

are among the most commonly implicated drugs in adverse event reports and ER visits (see Key 

Question #3 discussion), these data do not cast any light on incidence. In the two studies least 

likely to be affected by recall bias, one which recorded events within the past 2 weeks86 and the 

prospective study in Scotland,72 the incidence of symptomatic hypoglycemia was 14% over 2 

weeks in the former and 3% over one month in the latter. The discrepancy is likely due to Donnelly 

et al.’s more restrictive definition of hypoglycemia (HA as opposed to symptomatic only). 

VA Specific Data

Among the studies included herein, four reported specifically on VA patients.5, 30, 74, 75 In 

addition we identified two VA publications which did not meet our inclusion criteria. One was 

an unpublished abstract examining VA administrative data reporting that 22% of 1.4 million 

veterans with diabetes had a hypoglycemic associated medical encounter over 5 years. It is 

unclear from the abstract how the diagnoses were confirmed and what the severity of the 

episodes were. The second, published after our search was concluded, evaluated the incidence of 

hypoglycemia as determined by administrative records in 497,900 veterans aged 65 or older.139

That study found that 7.5% of subjects had one or more inpatient or outpatient visits in which a 

code for hypoglycemia was recorded over 24 months.

Although suggestive of increased rates of hypoglycemia among veterans with diabetes, it 

is difficult to derive definitive conclusions from these VA studies since there is substantial 

heterogeneity with respect to definitions of hypoglycemia, study design, subject inclusion 

criteria, treatment regimens and lengths of follow-up. 

Limitations of Available Studies

Much of the evidence comes from reports of RCTs funded by pharmaceutical companies 

which enroll highly selected populations and generally do not include those at highest risk for 

hypoglycemia. Second, the definitions of severe hypoglycemia varied among studies and there is 

likely substantial ascertainment bias, especially in the RCTs designed primarily to measure the 

benefits of specific drug regimens. Finally, there are few studies that investigated regular insulin, 

generally thought to be associated with high rates of hypoglycemia. 

Conclusion for Key Question #1 

The incidence of severe hypoglycemia is about 0-3% per year for adults with type 2 diabetes 

on hypoglycemic medications. Risk is highest for insulins, sulfonylureas and regimens 

targeting intensive control of HbA1c levels. Risk is lowest for metformin, GLP-1 analogs, 

DPP-4 inhibitors, glinides and TZDs. Since most of these data are derived from pharmaceutical 

company funded RCTS which enrolled highly selected populations, the generalizability of 

the results is unclear. Indeed, one small population based prospective study suggests that the 

incidence may be as high as 3% per month in community based subjects treated with insulin.72

Furthermore, several studies performed in VA suggest that incidence of hypoglycemia may be 

higher in this population. Larger population-based prospective studies of people on a variety 

of hypoglycemic agents that employ accurate methods for ascertaining incidence of severe 

hypoglycemia should be performed. 
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Even with this relatively low incidence of severe hypoglycemia, given the high prevalence of 

diabetes in the general population1

 and in the VA, there are likely tens of thousands of people in the 

US experiencing severe hypoglycemia every year. These episodes tend to be frightening, and may 

lead to more severe consequences (see Key Question #3 below) and to reluctance to pursue optimal 

blood sugar control.140 They may also be associated with significant costs to the health care system.141

Key Question #2: What are the risk factors for severe hypoglycemia in adults 

with type 2 diabetes on one or more hypoglycemic agents (e.g., demographics, 

co-morbidities, diabetes treatment regimen, other medication use, goal and 

achieved HbA1c)? 

We identified 14 articles from 12 studies that reported multivariate adjusted risk factor analyses 

for severe hypoglycemia in adults with type 2 diabetes on hypoglycemic mediations. Since these 

varied considerably with respect to risk factors evaluated (and their definitions), populations 

studied, and lengths of follow-up, the data were considered unsuitable for pooling. Transient 

causes (e.g., missed meal, excess exercise, alcohol use, acute infection) were not included.142

The factors evaluated in the 12 multivariate analyses are discussed below. In addition, genetic 

markers, marital status, smoking, alcohol consumption, polypharmacy, recent discharge from the 

hospital, congestive heart failure and use of ACE inhibitors were all identified in at least one of 

these 12 studies as independent risk factors for severe hypoglycemia. However, the findings for 

these risk factors were generally sparse, often conflicting, and ultimately inconclusive. 

Independent Risk Factors

Factors most consistently and independently associated with risk include: intensive glycemic 

control (discussed above under Key Question #1), history of hypoglycemia, renal insufficiency, 

history of microvascular complications, longer diabetes duration, lower education level, African 

American race and history of dementia. History of hypoglycemia unawareness, gender, age 

and BMI are not consistently associated with risk, although higher age and lower BMI were 

associated with higher risk in the two largest studies. 

Previous hypoglycemia which was evaluated in four studies, appears to be one of the strongest 

risk factors for a severe hypoglycemic event (three to nine-fold increased risk) and is often listed 

as a well known risk factor in reviews of this topic.142, 143 Repeated episodes of hypoglycemia 

are thought to lead to autonomic insufficiency, a state in which patients become unaware of 

the common symptoms of low blood sugar, such as palpitations and lightheadedness. This 

unawareness may then lead to failure to take corrective action resulting in more episodes, thus 

establishing a vicious cycle.144

Renal insufficiency was evaluated in seven studies, five of which found it to be a significant 

independent risk factor for severe hypoglycemia. The two studies that did not find a significant 

association were either very small102 or recorded very few episodes of severe hypoglycemia.100

Renal insufficiency is a well known risk factor for hypoglycemia; the reduced clearance 

of insulin in the diseased kidney causes relative hyperinsulinemia which can lead to 

hypoglycemia.141, 143 Hypoglycemia in renal insufficiency may also be due to reduced clearance 

of antidiabetic agents145 and a decrease in renal gluconeogenesis.146
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The relationship between renal insufficiency, hypoglycemic agents and incidence of severe 

hypoglycemia, however, is complicated. A nested case control study of 558 people with diabetes 

over the age of 65 on insulin, metformin or glyburide investigated whether renal function was 

an effect modifier for the association between glyburide or insulin use and hypoglycemia.147

Since the study did not distinguish between severe and other forms of hypoglycemia, it was 

not included in our review. Results indicated that while renal function did not significantly 

modify risk of glyburide associated hypoglycemia, risk of insulin-associated hypoglycemia was, 

unexpectedly, attenuated by renal dysfunction. 

The relationship between non-renal microvascular disease and severe hypoglycemia 

was evaluated in five studies. In three of the five studies, there were significant positive 

associations between peripheral neuropathy (or its manifestation, leg ulcerations) and risk of 

severe hypoglycemia with risk ratios in the 1.2 to 2.4 range; the largest of these three studies, 

ACCORD,3

 found the lowest risk. In a fourth study, “history of microvascular disease,” which 

also included renal disease, conferred a twofold increased risk of severe hypoglycemia (HR 

2.1, 95% CI 1.5 to 3).4 The pathophysiologic mechanism underlying this association is unclear. 

Although microvascular complications are an indicator of longstanding diabetes, duration of 

diabetes was often controlled for in these analyses. 

Diabetes duration was associated with a modestly increased risk for severe hypoglycemia in 

studies (with odds ratios of less than 2) and is thought to be due to the compromised ability of 

people with advanced type 2 diabetes to mount an appropriate counter-regulatory hormonal 

(insulin, epinephrine, and glucagon) response to low blood sugar.141, 143

Demographic variables such as African American race and lower education level were both 

independently associated with a modestly increased risk of severe hypoglycemia. In the studies 

that evaluated race, blacks were significantly more likely than whites to experience severe 

hypoglycemia, with relative risks of 1.4 to 2.0. This association was independent of other known 

risk factors, such as education, that may track with race.89

Four of five studies that evaluated education, reported significant positive associations between 

lower education level and risk of severe hypoglycemia. One of these found the risk associated 

with low literacy rates, a more specific construct than education level, was associated with close 

to a four-fold increased risk. However this study was a case-control study that included fewer 

than 300 subjects leading to wide confidence intervals around the odds ratio.104 It has been 

speculated that persons with low levels of education and literacy may not fully understand how 

to take their hypoglycemic medications or how to treat incipient hypoglycemia. 

Dementia was found to be an independent risk factor for severe hypoglycemia in two of three 

studies. As is expected based on sample size, the much larger of these two studies (N=11,140)4

found a modestly increased risk with a very tight confidence interval, whereas the smaller study 

(N=302),92 found a larger risk with a very wide confidence interval. The only study that did not 

find an association was very small.103 In addition, an article from ACCORD that was not included 

in our review because it was published in 2012, also found a significant association between poor 

cognitive function and risk of HMA.148 Dementia may increase the likelihood of errors in selfmedication and of inability to recognize and treat incipient hypoglycemia.141
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Risk Factors NOT Found to be Independently Associated with Risk 

Gender, age and low BMI were not consistently associated with risk, although age and low BMI 

were significantly predictive of risk of severe hypoglycemia in the two largest trials.3, 4 It has 

been suggested that older people may be at increased risk due to diminished counter-regulatory 

and autonomic system responses to low blood sugar149 and may be more likely to suffer from 

hypoglycemia unawareness.150 Low BMI may contribute to hypoglycemia because of poor 

nutrition, decreased glucose absorption, or erratic meal plans. In contrast to age and BMI, the 

results for gender were conflicting in the two large trials: ACCORD found that women were at 

modestly increased risk compared with men whereas ADVANCE found no significant difference 

between men and women. 

Impaired hypoglycemic awareness was only evaluated in one of our included studies.84 Although 

this study found a significant increased risk, it employed a weak study design (cross sectional) 

and had relatively few subjects (N=401). 

Other Literature

We did not identify any other systematic reviews that evaluated risk factors for severe 

hypoglycemia in people with type 2 diabetes. One literature survey included six prospective and 

five retrospective studies that enrolled at least 50 participants all on insulin followed for at least 6 

months.151 The risk factors identified included impaired hypoglycemia awareness, advanced age, 

longer duration of diabetes and of insulin therapy. HbA1c at baseline and dose of insulin were 

not found to increase risk. However this study included only insulin treated patients, did not limit 

its review to studies using multivariate analysis, and antedated publication of the three large trials 

of intensive versus conventional control. 

An unpublished abstract examining VA administrative data reported the following risk factors for 

an inpatient or outpatient diagnosis of hypoglycemia: prior hypoglycemia, history of ketoacidosis 

or hyperosmolar coma, high HbA1c levels, recent initiation of a new medication, recent 

hospitalization, use of secretagogues, insulin, fluoroquinolones or tricyclic antidepressants, 

higher age, low SES (which often correlates with education level) and unmarried status. It 

is unclear from the abstract how the diagnoses were confirmed and what the severity of the 

episodes were. In addition, a paper published after our literature search was concluded indicated 

that dementia and cognitive impairment were independent risk factors for hypoglycemia among 

older veterans,139 consistent with our findings. 

Limitations of Available Studies 

The data are relatively sparse and almost certainly reflect publication bias (negative analyses 

are less likely to be published). In addition we were unable to pool results across studies due to 

the heterogeneity of the study designs, analytical methods, and risk factors assessed. Finally, 

only two studies used negative binomial or zero inflated poisson16, 84, 93 methodology which may 

be less likely than standard regression techniques to yield spurious associations in situations in 

which there are frequent zero counts.152
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Predictors and Consequences of Severe Hypoglycemia 

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Conclusion for Key Question #2 

Independent risk factors for severe hypoglycemia in persons with type 2 diabetes on 

hypoglycemic medication include: intensive diabetes control, history of hypoglycemia, renal 

insufficiency, history of microvascular complications, longer diabetes duration, lower education 

level, African American race and history of dementia. Gender, age and BMI are not consistently 

associated with risk, although in the two largest studies, higher age and lower BMI were 

significantly associated with higher risk.

Key Question #3. What is the effect of severe hypoglycemia on other outcomes in 

adults with type 2 diabetes on one or more hypoglycemic agents (e.g., quality of 

life, mortality, morbidity, utilization)?

Severe hypoglycemia causes brain fuel deprivation that, if uncorrected, can lead to neurological 

compromise and death.143 There is uncertainty about a possible link between hypoglycemia 

and mortality, cardiovascular events, and other adverse health outcomes.153-155 Based on 

studies included in this review, we found no evidence of increased short-term mortality and 

limited evidence that a history of severe hypoglycemia increases long-term mortality. Few 

cardiovascular events were reported; coma and seizures were present in 5% to 71% of patients 

with severe hypoglycemia.

A recent study of over 850,000 patients found greater odds of an acute cardiovascular event 

during a one year period in type 2 diabetic patients who also experienced a hypoglycemic event 

(not necessarily severe) during that period (OR 1.79, 95% CI 1.69 to 1.89). The analysis included 

adjustment for baseline cardiovascular risk factors, comorbidities, and prior cardiovascular 

events (all of which were significantly more prevalent in the hypoglycemia group).156 In a study 

of adverse events reported to the Food and Drug Administration from 1998 through 2005, there 

were 9597 reports of insulin-associated disability or other serious but non-fatal outcome.157

However, in a study of patients hospitalized with acute MI, not all of whom had diabetes, 

spontaneous hypoglycemia in patients not treated with insulin was associated with increased 

risk for mortality; among patients treated with insulin, hypoglycemia was not associated with 

increased risk for mortality. This would suggest that hypoglycemia, itself, does not cause 

adverse events but is, instead, a marker of severe illness.158 People who are likely to experience 

hypoglycemia may also be likely to experience other serious health outcomes due to other risk 

factors.155

It is well known that cognitive and psychomotor function decline during a hypoglycemic 

episode.159, 160 Therefore, it is theorized that driving performance would be affected. However, 

whether severe hypoglycemia is associated with an increase in motor vehicle crashes is 

uncertain. Data from early studies are of questionable value as a result of improvements in 

methods for self-monitoring of blood glucose and changes in available medications.161 A more 

recent study found a nearly four-fold increased risk of a history of severe hypoglycemia in those 

who experienced a motor vehicle crash.129

Much of the information about driving performance is from laboratory studies where 

hypoglycemia is induced and driving simulators are used. In a recent study of 20 type 2 diabetic 

individuals with normal hypoglycemic awareness (mean age 52 years, all of whom had a driver’s 
37

Predictors and Consequences of Severe Hypoglycemia 

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license for at least 2 years), 11 of the 20 felt hypoglycemic. Of those 11, five (45%) said they 

would measure their blood glucose and six (55%) said they would not drive. Nine of the 20 

“maybe” felt hypoglycemic. Of those nine, three (33%) said they would drive, two (22%) said 

they would “maybe” drive, two (22%) said they would measure their glucose and two (22%) said 

they would not drive.130 It is unknown how results from studies of this type translate to actual 

driving performance or behavior. 

Long-term effects of hypoglycemia, especially repeated episodes of severe hypoglycemia, on 

cognitive performance are not fully understood.159, 160 Results, to date, in patients with type 2 

diabetes have been mixed.92, 94 The DCCT/EDIC trial in patients with type 1 diabetes found 

neither frequency of severe hypoglycemia nor initial treatment group assignment (intensive 

versus conventional therapy) were associated with cognitive decline over 18 years based on a 

battery of 17 tests representing eight cognitive domains.162 The ACCORD-MIND study reported 

no differences in cognitive outcomes between intensive treatment and standard treatment groups 

at 40 months. The authors did not relate their findings to the presence or absence of severe 

hypoglycemic episodes.163

Data from the Edinburgh Type 2 Diabetes Study were recently published.164 Participants, all age 

60 to75 years, were asked about severe hypoglycemic events. A history of severe hypoglycemia 

(one or more episodes) was associated with lower cognitive ability as reflected by the LetterNumber Sequencing test (p=0.03), the Trail-Making Test (p=0.004), and a composite score based 

on seven cognitive tests (p=0.04). Results were adjusted for prior cognitive ability, demographic 

characteristics and comorbid conditions. Similar findings were noted for the analysis based on 

severe hypoglycemia in the year preceding cognitive testing.

Potential reasons for differences across studies have been suggested in the literature. Many 

studies of cognitive function completed to date may not have sufficient follow-up time to 

adequately address long-term effects.159 Differences observed between studies may be due to 

differential effects of hypoglycemia on the brain in younger versus older people.160 Increased 

risk of dementia associated with type 2 diabetes may be due to other factors (e.g., depression, 

vascular disease, comorbid conditions and associated medications and genetic predisposition).165

Alternatively, an observed association between hypoglycemia and cognitive decline may be due 

to the fact that patients with cognitive decline may be less able to manage their diabetes and 

therefore may experience more hypoglycemic events.159

Hypoglycemia, particularly severe hypoglycemia, results in utilization of health care resources. 

In studies included in this review, we observed that between 0% and 31% of episodes of 

severe hypoglycemia were seen in an emergency department and between 0% and 33% of 

episodes resulted in hospital admission. Increased physician visits were also reported. A recent 

systematic review recommended increased hospitalization and primary care visits for posthypoglycemic patients.166 Citing the potential for repeat hypoglycemia, as reported in studies of 

post-hypoglycemic type 2 diabetes patients taking oral hypoglycemic agents and first treated for 

a hypoglycemic episode in a prehospital environment, the authors recommended conservative 

management (i.e., transportation of all patients to a hospital for observation and treatment). 

They also encouraged the development of evidence-based interventions to increase primary or 

specialty care visits by post-hypoglycemic patients. 
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Predictors and Consequences of Severe Hypoglycemia 

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In a study examining nationally representative data, Budnitz et al.167 estimated that insulin, 

metformin, glyburide and glipizide were implicated in 13%, 2.3%, 2.2%, and 1.5% of all 

emergency department visits in the United States in persons age 65 and older. These four were 

among the top 10 most commonly implicated medications.167 In a more recent study, this group 

estimated that insulin and oral hypoglycemic agents accounted for 25% of all adverse drug eventassociated emergency hospitalizations in the United States in 2007-2009.168 These studies did not 

link the emergency department visits or hospitalizations to episodes of severe hypoglycemia.

Limitations of Available Studies

Few studies that address outcomes of severe hypoglycemic episodes include appropriate control 

groups. In addition, many outcomes of interest were not widely reported.

Conclusion for Key Question #3

There is good data that severe hypoglycemia is associated with an increased risk of the following 

outcomes: all-cause mortality (particularly long-term), neurological events (other than non-fatal 

stroke), hospital and emergency department utilization, and decreased quality of life. There is limited 

data about many other outcomes of interest including non-fatal MI, non-fatal stroke, cognitive decline, 

motor vehicle accidents, falls and traumatic injuries, work productivity, and other medical service 

utilization. In the absence of appropriate control groups it is unclear if many of these outcomes are 

hypoglycemia-related or simply reflect the age and co-morbidity burden of the population. 

RECOMMENDATIONS FOR FUTURE RESEARCH

Key Question #1: Larger population-based prospective studies of people on a variety of 

hypoglycemic agents that employ accurate methods for ascertaining incidence of severe 

hypoglycemia should be performed. Studies need to control for or stratify outcomes by important 

patient, disease and comorbidity factors including: age, gender, race/ethnicity, socio-economic 

and marital status, disease duration and severity (e.g., HbA1c level, presence or absence of 

diabetic complications).

Key Question #2: Future research should include studies in VA patients and include the more 

intriguing possible risk factors including smoking or recent hospital discharge. In addition, future 

research may lead to the development of a risk factor index if outcomes are significant enough to 

warrant risk stratification.

Key Question #3: Future studies of outcomes associated with severe hypoglycemia should 

be prospective, use a uniform and generally accepted definition of severe hypoglycemia, and 

include, as controls, people with medication-treated diabetes who have not experienced severe 

hypoglycemia. Also, studies should clearly distinguish between short-term or episode-related 

versus long-term consequences. 

Specific future research needs include:

a. To clarify the association between hypoglycemia and cardiovascular events, research is 

needed to better understand the effects of hypoglycemia on blood constituents and the 
39

Predictors and Consequences of Severe Hypoglycemia 

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

vascular system and larger clinical trials are needed to determine whether hypoglycemia is 

a cause of cardiovascular events.153, 154 Better understanding of the role of hypoglycemia in 

patients already at risk for developing vascular disease is also needed.153

b. There is a need for a large-scale, prospective study of accident rates in patients with diabetes 

compared to appropriate control groups.161 Better understanding is needed of which driving 

skills are most likely to be affected by hypoglycemia, at what level of blood glucose driving 

impairments become observable, and whether results obtained in a laboratory translate to 

road conditions.134

c. Additional research is needed to assess the overall effect of hypoglycemia on patients 

with type 2 diabetes including quality of life outcomes (both work and recreational). To 

date, much of the research has focused on type 1 diabetes and the emphasis has been on 

hypoglycemia as a safety issue.169

d. To assess the effect of hypoglycemia on cognitive function, large-scale epidemiological 

studies with detailed phenotyping of clinical variables and randomized trials of interventions 

(therapeutic and preventive) that include cognitive testing and brain structure/function 

assessments are needed.165, 170
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Predictors and Consequences of Severe Hypoglycemia 

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