Increased Serious Heart Failure Incidence With Pioglitazone

According to a new report in Diabetes Care, pioglitazone use is associated with an increased incidence of serious heart failure, but still provides clinical benefits, with no evidence that it increases subsequent mortality and morbidity

"Although there is an increased risk of CHF with pioglitazone, our analysis of serious heart failure events in PROactive showed that when serious heart failure does develop in pioglitazone-treated patients with type 2 diabetes and existing macrovascular disease, it does not increase (and may even decrease) risk of mortality or morbidity," Dr. Erland Erdmann from Universitaet zu Koeln, Germany, told Reuters Health.

Dr. Erdmann and colleagues studied investigator-reported heart failure rates and the treatment effect on sequelae after serious heart failure in more than 5200 patients with type 2 diabetes and preexisting cardiovascular disease in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive).

Serious heart failure was reported in 41% more patients in the pioglitazone group than in the placebo group, the investigators say.

Elevated creatinine level, diuretic use, LDL cholesterol above 3 mmol/L, previous myocardial infarction, and diabetes duration of at least 10 years were additional significant predictors of serious heart failure.
Serious heart failure occurred more frequently among patients treated with insulin, the authors report, but the use of pioglitazone did not further elevate the risk among insulin-treated patients.

Fatal heart failure events were no more common among pioglitazone patients than among placebo patients, the researchers note, and pioglitazone patients had lower rates of all-cause mortality, nonfatal myocardial infarction, and stroke than did placebo patients.

Pioglitazone-treated patients were also more likely to develop non-serious heart failure and edema than were placebo-treated patients.

"Because the rates for the composite endpoint subsequent to a report of serious heart failure were similar between pioglitazone and placebo," the authors write, "the cardiovascular benefits observed in PROactive with pioglitazone were not diminished by the increased incidence of heart failure."

"The mechanisms of action behind the fluid retention with thiazolidinediones remain unclear," the investigators continue, "although it has been suggested that peroxisome proliferator-activated receptor-gamma may regulate sodium reabsorption in the cortical collecting ducts via stimulation of epithelial sodium channel activity."

"The long-term study of pioglitazone use and heart failure, funded by the American Diabetes Association, argues against the possibility that thiazolidinediones cause heart failure," the researchers add.

"PROactive demonstrated the macrovascular ischemic safety profile of pioglitazone in patients with type 2 diabetes who are at high risk for cardiovascular events," Dr. Erdmann said.

"As a cardiologist, I have no reservations in its use in this condition when correctly and appropriately prescribed….When considering the appropriate therapeutic strategy for patients, the potential benefits and risks should be fully considered based on the evidence for both efficacy and safety," he concluded.
Diabetes Care Nov, 2007;30:2773-2778.

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FACT:
Beta blockers and risk of new-onset diabetes: Previous studies have shown that beta blockers and diuretics, the most commonly used treatments for hypertension, can cause metabolic derangements leading to increased risk of new-onset diabetes mellitus. There are, however, conflicting results. This month sees a meta-analysis which aims to explore the role of beta blockers in the risk of new-onset diabetes mellitus in patients with hypertension. Of 805 randomized controlled trials of beta blockers in patients with hypertension, twelve studies, evaluating 94,492 patients, fulfilled the inclusion criteria of the meta-analysis. It was shown that beta blocker therapy for hypertension is associated with increased risk of new-onset diabetes compared with non-diuretic antihypertensive drugs, and also compared with placebo. It was also shown that in comparison with other antihypertensive agents, the antihypertensive efficacy of beta blockers was inferior.

American Journal of Cardiology,100 (1254-1262): Bangalore S, Parkar S, Grossman E, Messerli F A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus