Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus.

Abstract

The burden of type 2 diabetes mellitus across the United States continues to increase. Today, ≈25.8 million Americans are affected by type 2 diabetes mellitus, and its incidence in the Medicare age group exceeds 25%. The number of newly diagnosed subjects with type 2 diabetes mellitus aged >20 years approximated 1.9 million in the year 2010 alone, and the direct and indirect costs of managing this disease entity for the year 2007 neared 174 billion US dollars.1 The worldwide prevalence of diabetes mellitus has also increased from 153 million in 1980 to an estimated 347million in 2008,2 with low- and middle-income countries accounting for 80% of the disease burden, a number that is expected to continue to rise exponentially over the next decade. Although diabetes mellitus is the most common cause of blindness, renal failure, and nontraumatic amputation in the United States, the predominant mechanism of death in this population is cardiovascular. The current dramatic increase in the prevalence of type 2 diabetes mellitus is therefore a harbinger for increasing cardiovascular morbidity and mortality in the decades ahead. In the original observations by Haffner and colleagues, the 7-year hazard for cardiovascular death in middle-aged Finns with long-standing diabetes mellitus and without a previous myocardial infarction was similar to that observed in patients without diabetes mellitus who had experienced a previous myocardial infarction.3 In Multiple Risk Factor Interventional Trial (MRFIT), the risk of cardiovascular death was tripled in men with diabetes mellitus despite an adjustment for other traditional risk factors.4 With the use of a data set of 820 900 subjects randomly assigned across 97 clinical trials, the Emerging Risk Factors Collaborators estimated that a diagnosis of diabetes mellitus in a middle-aged man or woman 50 years of age resulted in a decrease in survival of 5.8 …