Managed Care - October 2008 - (Page 41) of death, myocardial infarction, or stroke. These observations have engendered much discussion about the cardiac safety of thiazolidinediones as a class. Congestive heart failure (CHF, inability of the heart to function efficiently as a pump), heart failure, weight gain, and edema are wellrecognized classwide side effects of the thiazolidinediones. In considering the cardiac safety profiles of thiazolidinediones, then, it is critical to distinguish between macrovascular events, such as myocardial infarction, and CHF. Thiazolidinediones are known to increase plasma volume through a direct effect on the kidney, a consequence of PPARγ-induced excess sodium resorption, but without a direct effect on cardiac tissue (Zhang 2005, Guan 2005). Macrovascular events represent a consequence of acute loss of blood flow to critical tissue, often resulting in permanent loss of function. Among the thiazolidinediones, there seems to be marked differences with regard to these issues. In the PROactive trial, over 5,200 patients with type 2 diabetes and a prior history of macrovascular disease were randomized to receive either pioglitazone or placebo in addition to their current treatment regimens. Patients were followed for a mean of 2.85 years. Treatment groups were similar with regard to demographic, physical, and laboratory parameters. Ninety-six percent of patients in the study were treated with blood glucose lowering agents including sulfonylureas, metformin, and insulin. Ninety-five percent were taking cardiovascular medications that included β-blockers, ACE inhibitors, calcium channel blockers, diuretics, lipid lowering agents, and antiplatelet medications. The pri- mary efficacy endpoint was time from randomization to first occurrence of any event: all-cause mortality, nonfatal myocardial infarction, acute coronary syndrome, cardiac intervention including cardiac artery bypass graft or percutaneous coronary intervention, stroke, above the ankle amputation, bypass surgery, or revascularization of the leg. There was no statistically significant difference between pioglitazone and placebo for the 3-year incidence of first cardiovascular event, and no increase in mortality or total macrovascular events with pioglitazone (Charbonnel 2004). Meta-analysis of 19 randomized studies of pioglitazone further demonstrated that pioglitazone use is associated with decreased risk of ischemic cardiovascular events (Lincoff 2007). Table 2 demonstrates that reports of CHF were more common among FIGURE 2 Algorithm for the metabolic management of type 2 diabetes Diagnosis Lifestyle intervention + metformin No Add basal insulin • Most effective No A1C ≥7% Intensify insulin No A1C ≥7% Yes* No A1C ≥7% Add sulfonylurea • Least expensive A1C ≥7% Yes* No Yes* Add glitazone • No hypoglycemia A1C ≥7% Yes* Add glitazone Yes* Add basal insulin No Add sulfonylurea† A1C ≥7% Yes* Add basal or intensify insulin Intensive insulin + metformin +/– glitazone ADA = American Diabetes Association Lifestyle intervention should be reinforced at every visit. *A1C should be checked every 3 months until it is <7% and then at least every 6 months. †Although 3 oral agents can be used, initiation and intensification of insulin therapy is preferred based on efficacy and cost. Adapted with permission from the American Diabetes Association OCTOBER 2008 / MANAGED CARE 41
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