Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes - A Systematic Review of the Evidence (Paperback)

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. 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. More recently, it was estimated that nearly 25% of veterans receiving care in the VA have diabetes. 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 (ACCORD, ADVANCE and VA-DT), 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) and possibly non-fatal myocardial infarction. 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. 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. 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 less than 7% is recommended only for those with no microvascular complications and a life expectancy of greater than 10 years. 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. 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)?