Sunday, November 11, 2007

Latest analyses raise more questions about rosiglitazone, pioglitazone

Latest analyses raise more questions about rosiglitazone, pioglitazone

Meta-analysis outlined 18% reduction in MI with pioglitazone.

by Katie Kalvaitis
Cardiology Today STAFF WRITER

November 2007

Two meta-analyses published in the Journal of the American Medical Association have continued to fan the fires surrounding rosiglitazone and pioglitazone.

Sonal Singh, MD, and colleagues reported that rosiglitazone (Avandia, GlaxoSmithKline) raised the risk of MI by 42%. In a separate meta-analysis, A. Michael Lincoff, MD, and colleagues reported that pioglitazone (Actos, Takeda) lowered the risk for MI, stroke and death by 18%.

However, both diabetes drugs were associated with significant increases in HF. With rosiglitazone, the risk was doubled, and with pioglitazone, it increased by 41%.

“Cardiovascular disease is the most common major problem among patients with diabetes; it is generally what they die from,” Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic, told Cardiology Today. “As cardiologists we are looking for agents that improve that outcome on diabetes.”

Long-term risk

“Our study adds to the debate about rosiglitazone,” Singh, assistant professor of internal medicine at Wake Forest University School of Medicine, Winston-Salem, North Carolina, said in an interview.

The researchers’ meta-analysis included four randomized, controlled trials of rosiglitazone for treatment or prevention of type 2 diabetes, with at least 12 months’ follow-up and monitored cardiovascular adverse events (n=6,421 were assigned rosiglitazone; n=7,870 were in the control group).

There were 94 reports of MI among rosiglitazone-treated patients compared with 83 in the control group (RR=1.42; 95% CI, 1.06-1.91).

These findings were nearly identical to the 43% increased risk for non-fatal MI, as reported by Steven E. Nissen, MD, and Kathy Wolski, MPH, in May.

Yet, these results are different from those previously reported, Singh said. “[Nissen] recorded a nonsignificant increase in cardiovascular death, and we did not see an increase from the evidence we gathered,” he said.

Previous analyses of glitazones, including rosiglitazone and muraglitazar, have suggested an increased cardiovascular risk.

Protective effects

“The natural question was: Is pioglitazone also associated with increased cardiovascular risk?” Lincoff said. “In fact, we found just the opposite – there is more of a protective effect.”

They analyzed 19 randomized, double blind, controlled trials of pioglitazone using patient-level data transferred by Takeda (n=16,390).

Death, MI or stroke was reported in 375 of 8,554 patients (4.4%) who received pioglitazone, compared with 450 of 7,836 (5.7%) who received control therapy.

Interestingly, Lincoff said, pioglitazone increased the risk for serious HF without an associated increase in mortality.

“If this class of drugs is deemed appropriate, then pioglitazone is certainly a preferred agent,” he said.

“The two thiazolidinediones currently marketed have strikingly different profiles in their effects on ischemic cardiovascular outcomes. Both agents reduce blood glucose levels and HbA1c to a similar degree, and both appear to cause excess heart failure risk; however, their effects on cardiovascular ischemic events differ based on the currently available data,” Daniel H. Solomon, MD, MPH, and Wolfgang C. Winkelmayer, MD, ScD, wrote in an accompanying editorial.

According to a press release issued by GlaxoSmithKline, the JAMA meta-analyses “do not confirm a difference in the safety profile of rosiglitazone and pioglitazone,” and “do not yield data robust enough to guide doctors in selecting appropriate diabetes treatment for their patients.”

On the other hand, the meta-analysis by Lincoff et al is consistent with other studies on pioglitazone that have shown no evidence of increased risk for MI, stroke or death, according to a press release issued by Takeda.

In July, an FDA advisory panel voted that rosiglitazone should remain on the market, despite evidence of increased risk for MI. Both rosiglitazone and pioglitazone now contain a black box warning regarding the risk for HF.

“We may have to look in the direction of other treatments,” Singh said. “Older agents (metformin and second generation sulfonylureas) may be equally efficacious without these long-term adverse effects.”

For more information:

Lincoff MA, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2007;298:1180-1188.

Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone. JAMA. 2007;298:1189-1195.

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