Rosiglitazone and cardiovascular outcomes: is there a clear answer?

D iabetes mellitus is a common chronic disease that is characterized and defined by an elevated glucose level and that has grown in prevalence by 75% in the United States during a 20-year period ending in 2010. 1 The exact reason for this rising prevalence is not known with certainty; however, a large body of evidence implicates changes in weight, caloric consumption, reduced physical activity, and migration to urban versus rural dwellings. Regardless of the reasons for this growth, epidemiological studies and analyses of administrative databases have repeatedly shown that people with diabetes mellitus are 2 to 3 times more likely to experience fatal and nonfatal cardiovascu-lar outcomes than people without diabetes mellitus. 2 This high risk was the basis for the intentional inclusion of ambulatory adults with diabetes mellitus in a large number of recent cardio-vascular outcomes trials that either recruited large subpopula-tions or people with diabetes mellitus or were wholly restricted to people with diabetes mellitus. These trials showed that therapies that were shown to be cardioprotective in people without diabetes mellitus will also reduce cardiovascular outcomes in ambulatory people with diabetes mellitus. These include blood pressure lowering, 3 low-density lipoprotein lowering with statins, 4 angiotensin-converting enzyme inhibitors 5 or angioten-sin receptor blockers, 6 and bypass surgery. 7 During the same period, other therapies were shown to have a neutral effect on cardiovascular outcomes in people with diabetes mellitus, including vitamin E, 8 omega 3 fatty acids, 9 and basal insulin. Implementation of the results of these trials may account for the decline in absolute risk of cardiovascular outcomes and death in people with diabetes mellitus over time. However, both the inability of these trials to reduce this risk to levels seen in people without diabetes mellitus 6 and the inability of traditional risk factors to completely explain the high cardiovascular risk associated with diabetes mellitus points to additional factors that are unique to people with diabetes mellitus. The many studies showing that different measures of glucose elevation above normal (including hemoglobin A1c levels and fasting, postload, and random glucose levels) independently predict incident cardiovascular outcomes strongly implicate an elevated glucose level or some factor tightly linked to an elevated glucose level. 2,13 Moreover, a recent report showing that genetic variants that predict elevated random glucose levels also predict cardiovascular outcomes further highlights the importance of dysglycemia or genetically determined biological abnormalities closely linked to dysglycemia in the …