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

EXECUTIVE SUMMARY

BACKGROUND

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

overweight and obesity in many populations. In the VA healthcare system, the prevalence of 

diabetes was 20% in fiscal year 2000 and is now estimated at nearly 25%. 

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

(CVD), recent trials show that intensive glucose lowering does not reduce the risk of CVD death 

or all-cause mortality although it reduces the risk of microvascular complications (nephropathy, 

retinopathy and neuropathy) and possibly non-fatal myocardial infarction. Intensive glucose 

control also increases the risk of hypoglycemic episodes. Several recent meta-analyses of the 

trials comparing intensive to conventional glucose control concluded that intensive control 

is associated with a 2-2.5 fold increased risk of severe hypoglycemia. The reviews however 

have not included smaller randomized trials, trials focused on the comparison of specific drug 

regimens, and non-randomized trials. We conducted the current review to provide broader 

insight into the incidence of, the risk factors for, and the clinical and social impact of severe 

hypoglycemia in adults with type 2 diabetes treated with glucose lowering medications.

The key questions were as follows: In adults with type 2 diabetes treated with one or more 

hypoglycemic agents:

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)?

METHODS

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

November 2011 using standard search terms. Studies were eligible if they involved adults with 

type 2 diabetes, were published in the English language and reported outcomes of interest. 

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

was not limited to randomized controlled trials (RCTs). We obtained additional articles from a 

search of the Cochrane Library, other systematic reviews, reference lists of pertinent studies, 

reviews, editorials and expert consultation. We defined severe hypoglycemia as an episode with 

typical symptoms resolving after treatment administered by another person.

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 
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Predictors and Consequences of Severe Hypoglycemia 

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

potentially relevant abstracts were retrieved for further review. For Key Questions #1 and #2, we 

excluded studies with fewer than 500 patients or duration less than 6 months. We also excluded 

studies if the medications involved were not FDA approved. For Key Question #3, there were no 

restrictions on sample size or study duration.

Study characteristics, patient characteristics, and outcomes were extracted by investigators and 

trained research associates under the supervision of the Principal Investigator. We assessed study 

quality according to established criteria for randomized trials and non-randomized trials.

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 

or clinical topic, and drew conclusions based on qualitative synthesis of the findings or pooled 

results, where appropriate. We identified and highlighted findings from veteran populations. 

PEER REVIEW

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

Reviewer comments were addressed and our responses may be found in Appendix C.

RESULTS

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.

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 most of the 60 reviewed studies, 

particularly those of metformin monotherapy (<1%), glucagon-like peptide-1 (GLP-1) analogs 

(< 1%), dipeptidyl-peptidase-4 (DPP-4) inhibitors (<1%), insulin detemir (<1%), glinides (0%) 

and thiazolidinediones (TZDs) (<1%). Annual rates of severe hypoglycemia were greater than 

1% for sulfonylureas and the following insulin preparations: neutral protamine Hagedorn (NPH), 

glargine, lispro and glulisine. Some of the highest rates of severe hypoglycemia were seen in 

trials of intensive glucose control.

We reviewed an additional 16 studies to gain a broader population-based perspective on 

incidence of symptomatic hypoglycemia (defined more broadly than “severe”): 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 
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Predictors and Consequences of Severe Hypoglycemia 

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

symptomatic hypoglycemia varied widely from 1% to 17%, likely due to a wide range of study 

designs, populations, and lengths of follow-up. 

Limitations

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. Furthermore, 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.

Discussion

The incidence of severe hypoglycemia ranges from 0-3% per year for adults with type 2 diabetes 

on hypoglycemic medications. Incidence is highest in studies of people on insulins, sulfonylureas 

and regimens targeting intensive control of hemoglobin A1c (HbA1c) levels. Risk is negligible 

for people on metformin, GLP-1 analogs, DPP-4 inhibitors, glinides and TZDs. The incidence 

was more than 2-fold greater among patients undergoing intensive control compared with 

conventional control. The most important limitation of the data is that they were mostly derived 

from industry funded randomized trials of highly selected populations. A review of survey data 

from more representative populations suggests that the incidence of symptomatic hypoglycemia 

may be more common than reported in these trials. 

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, comorbidities, 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.

Independent risk factors for severe hypoglycemia in persons with type 2 diabetes on 

hypoglycemic medication include: intensive glycemic 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. 

Limitations

We were unable to pool results across studies due to the heterogeneity of the study designs, 

analytical methods and risk factors assessed. Furthermore, the data are relatively sparse and 

almost certainly reflect publication bias.
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Predictors and Consequences of Severe Hypoglycemia 

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

Discussion 

The literature in this area is relatively sparse. We did not identify any other systematic reviews 

that evaluated risk factors for severe hypoglycemia in people with type 2 diabetes, although our 

findings are generally consistent with what has been summarized elsewhere. The most important 

limitation of the data is that there is likely publication bias since negative analyses are less likely 

to be published. In addition several potential risk factors (e.g., recent hospital discharge, smoking 

status, polypharmacy, alcohol consumption) have not been adequately evaluated.

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 53 studies (in 59 articles) that provided outcomes data from patients who 

experienced severe hypoglycemia. Overall, we found good evidence for an increased risk of 

the following outcomes: all-cause mortality, neurological events (other than non-fatal stroke), 

hospital and emergency department utilization and decreased quality of life. We found limited 

data about non-fatal MI, non-fatal stroke, cognitive decline, motor vehicle accidents, falls and 

traumatic injuries, work productivity and other medical service utilization. 

Limitations

Few studies that address outcomes of severe hypoglycemic episodes include appropriate control 

groups. In addition, many outcomes of interest were not widely reported.

Discussion

Episodes of severe hypoglycemia may be a marker of serious illness and observed clinical 

outcomes may be due to illness rather than severe hypoglycemia. Similarly, it is unclear whether 

severe hypoglycemia contributes to cognitive decline or whether individuals experience more 

episodes of severe hypoglycemia as a result of cognitive decline. 

FUTURE RESEARCH RECOMMENDATIONS 

Key Question #1 and Key Question #2: 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 should 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 #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.