A Systematic Review: Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes
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 FY2000 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 does reduce the risk of microvascular complications and, possibly, non-fatal myocardial infarction. However, intensive glucose control also increases the risk of hypoglycemic episodes. Three recent studies suggest intensive control is associated with a 2 to 2.5 fold increased risk of severe hypoglycemia. Reviews of these studies have not included smaller randomized trials, trials comparing specific drug regimens, or non-randomized trials.
Investigators at the VA Evidence-based Synthesis Program in Minneapolis, MN conducted a review of the literature from 1950 through November 2011. This review sought 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 who are treated with glucose-lowering medications. After screening more than 2,300 articles, 127 references were included in the current review to address the following key questions:
What is the incidence of severe hypoglycemia in adults with type 2 diabetes who are on one or more hypoglycemic agents?
The most important limitation of the data is that they were derived mostly 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 higher than reported in these trials.
The incidence of severe hypoglycemia ranges from 0% to 3% per year for adults with type 2 diabetes who are on hypoglycemic medications. However, the incidence was more than 2-fold greater among patients undergoing intensive control compared with conventional control.
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.
What are the risk factors for severe hypoglycemia in adults with type 2 diabetes who are on one or more hypoglycemic agents (e.g., demographics, co-morbidities, diabetes treatment regimen, other medication use, goal and achieved HbA1c)?
- Investigators identified 12 studies that reported multivariate adjusted risk factor analyses for severe hypoglycemia in adults with type 2 diabetes on hypoglycemic mediations. Since these 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.
Independent risk factors associated with 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 were not consistently associated with risk, but in the two largest studies, higher age and lower BMI were significantly associated with higher risk.
What is the effect of severe hypoglycemia on other outcomes in adults with type 2 diabetes who are on one or more hypoglycemic agents (e.g., quality of life, mortality, morbidity, utilization)?
Investigators identified 53 studies that provided outcomes data from patients who experienced severe hypoglycemia. Overall, they found good evidence that hypoglycemia is associated with 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.
They found limited data on non-fatal MI, non-fatal stroke, cognitive decline, motor vehicle accidents, falls and traumatic injuries, work productivity, and other medical service utilization.
The authors of the review made several recommendations for future research to address current gaps. Larger, population-based prospective studies should enroll patients taking a variety of hypoglycemic agents and employ accurate methods for ascertaining incidence of severe hypoglycemia. Moreover, these 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, diabetic complications). To better define the consequences of severe hypoglycemia, future studies should be prospective, use a uniform and generally accepted definition of severe hypoglycemia, distinguish short- and long-term consequences, and include as controls people with medication-treated diabetes who have not experienced severe hypoglycemia.
Implications for Policymakers
Severe hypoglycemia can have devastating effects and is more likely to affect the VA population given its age and comorbidity profile (e.g., older and sicker). Overly aggressive A1c goals and performance measures should be avoided to minimize the risk of iatrogenic hypoglycemia in this vulnerable population.
A Cyberseminar session on this ESP Report will be held Monday, June 25 at 1:00pm (ET). To register, go to the HSR&D Cyberseminar web page.
This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers -- and to disseminate these reports throughout VA.
Bloomfield H, Greer N, Newman D, MacDonald R, Carlyle M, Fitzgerald P, Rutks I, and Wilt T. Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes: A Systematic Review of the Evidence. VA-ESP Project #09-009; 2012.
View the full report online: http://vaww.hsrd.research.va.gov/publications/esp/hypoglycemia-2012.cfm (intranet only)
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