Managed Care - October 2008 - (Page 42) TABLE 2 PROactive: CHF data Pioglitazone Any report of heart failure* Heart failure not leading to hospitalization* Heart failure needing hospitalization Fatal heart failure† *Not adjudicated †Adjudicated cause of death. Placebo 198 (8%) 90 (3%) 108 (4%) 22 (1%) P value <.0001 .003 .007 .634 281 (11%) 132 (5%) 149 (6%) 25 (1%) patients taking pioglitazone vs placebo (P<0.0001). Although more pioglitazone-treated patients required hospitalization for CHF (P=0.007), there was no statistically significant difference between patients treated with pioglitazone vs placebo for fatal heart failure (P=0.63). This may be of particular interest in light of the excess mortality that patients with type 2 diabetes experience with heart failure as compared to patients without diabetes (see figure 3). Furthermore, the previously referenced meta-analysis of pioglitazone trials confirmed the increase in CHF with pioglitazone use, but also demonstrated that there was no increase in mortality associated with this CHF (Lincoff 2007). With regard to the thiazolidinediones, then, cardiac issues can be understood to include both macrovascular events and CHF. Lipid-lowering properties should be taken into consideration too since they may directly impact cardiac pathology. The effects on lipids of rosiglitazone and pioglitazone were compared in a 24-week, head-tohead study that included 735 patients with type 2 diabetes, fasting triglyceride levels between 150 and 600 mg/dL, and fasting LDL-cholesterol levels below 130 mg/dL. Although both agents provided equivalent glycemic control, results regarding lipid parameters were markedly different. With pioglitazone, fasting triglyceride levels decreased from baseline by 51.9 mg/dL (12 percent) as compared with a 13.1 mg/dL (14.9 percent) increase from baseline with rosiglitazone (P<0.001). Both agents increased HDL-cholesterol, although the increase was greater for pioglitazone (5.2 mg/dL) as compared with rosiglitazone (2.4 mg/dL)(P<0.001). Non-HDL cholesterol levels also differed. Rosiglitazone-treated patients experienced a significant increase in non-HDL cholesterol of 25.7 mg/dL from baseline to the end of treatment, whereas the increase in non-HDL cholesterol was 3.6 mg/dL for patients treated with pioglitazone (P<0.001). The difference in LDLcholesterol was significant too, with a 21.3 mg/dL (23.3 percent) increase in LDL-cholesterol with rosiglitazone, and a 12.3 mg/dL (15.7 percent) increase with pioglitazone (P<0.001) (Goldberg 2005). It is clear that important distinctions exist between drugs in the same class that can influence physician drug choice. The CHF associated with thiazolidinediones seems to be a class effect specific to actions of PPARγ on a renal sodium receptor; CHF is typically clinically mild and does not result in excess cardiac mortality. However, differences between agents in lipid effects and with regard to macrovascular outcomes may be related to properties of specific agents within the class. A novel treatment approach may focus on treating the pathophysiology of diabetes, namely, treating both insulin resistance and β-cell dysfunction. Table 3 prioritizes goals of dia- FIGURE 3 Kaplan-Meier plot showing reduced survival among diabetic heart failure patients relative to non-diabetic heart failure patients 1.0 0.8 Survival proportion Median survival in diabetics = 3.62 years Median survival in non-diabetics = 5.42 years 0.6 Non-DM 0.4 DM 0.2 0.0 0 2 4 6 Time (years) 8 10 12 Source: Varela-Roman A, et al. Influence of diabetes on the survival of patients hospitalized with heart failure: a 12-year study. Eur. J. Heart Failure. 2005;7:859–864. 42 MANAGED CARE / OCTOBER 2008
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