Pioglitazone Use and Heart Failure in Patients With Type 2 Diabetes and Preexisting Cardiovascular Disease

Abstract

OBJECTIVE— PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS— PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II–IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS— More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS— Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal

“…However, although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with T2DM and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure [40]. Overall, the cardiovascular benefits seen with pioglitazone appear to outweigh the cardiovascular risks [41,42].…”

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes

“…Individuals within the upper two tertiles for baseline endotrophin serum levels (tertile two, 6.3-7.7 ng/ml and tertile three, ≥7.8 ng/ml) were four times more likely to respond to treatment, compared with patients in the lower tertile (≤6.2 ng/ml baseline serum endotrophin). Since the glitazones are associated with safety concerns, such as non-fatal heart failure and bone fractures [15,[27][28][29][30][31], identification of individuals who will gain the most benefit from treatment and also the fewest AEs is crucial for the continued use of these drugs, which are still considered highly effective insulin sensitisers. Participants in the upper two tertiles who responded to treatment with a reduction in FPG and HbA 1c levels were at a reduced risk of developing lower leg oedema, a major AE associated with glitazone treatment.…”

Rehabilitation of pioglitazone

“…However, these cases were not adjudicated and it is noteworthy that individuals with CHF did not experience any increase in mortality: to the contrary, overall mortality and cardiovascular events tended to be decreased. 9,26 These results suggest that the cardiovascular benefits of pioglitazone become evident once the excess fluid is diuresed. The sodium retention responds well to distally acting diuretics such as spironolactone or triamterene.…”

“…25 The fluid retention associated with pioglitazone treatment is related to the drug's sodium retentive effect on the kidney and recognition of fluid retention (oedema) and institution of diuretic therapy will prevent any cardiac decompensation. 26 In PROactive the incidence of CHF in pioglitazone-treated subjects was increased. However, these cases were not adjudicated and it is noteworthy that individuals with CHF did not experience any increase in mortality: to the contrary, overall mortality and cardiovascular events tended to be decreased.…”