Clinical Review

Individualizing Treatment of Hyperglycemia in Type 2 Diabetes

Journal of Clinical Outcomes Management. 2017 January;24(1)

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Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.