Takeda and GSK Challenge Latest Data Linking TZDs To Cardiovascular Events
Takeda and GlaxoSmithKline are disputing the findings of a Canadian study published in the December 12 issue of the Journal of the American Medical Association linking thiazolidinediones to cardiovascular events.
Results from a population-based, retrospective analysis conducted by the Toronto-based Institute for Clinical Evaluative Sciences (ICES) included more than 12,000 older patients with diabetes who received treatment with Avandia (rosaglitazone) and Lilly/Takeda's Actos (pioglitazone).
Concerns over cardiovascular risks with the type 2 diabetes drugs culminated in a label change for Avandia in November that expanded its "black box" warnings ("The Pink Sheet" DAILY, Nov. 14, 2007).
In addition to the boxed warning on congestive heart failure that was applied to the entire thiazolidinedione class in August, FDA required GSK add language on a meta-analysis of 42 clinical studies, most of which compared rosiglitazone to placebo, showing rosiglitazone is associated with increased risk of myocardial ischemic events such as angina or myocardial infarction.
The agency also requested that GSK undertake a long-term outcomes study to address outstanding safety questions.
The ICES analysis included information from Ontario-based health databases on diabetes patients 66 years or older who were treated with at least one oral hypoglycemic agent between 2002 and 2005 and who were followed up until March 2006.
During a median follow-up of 3.8 years, 7.9 percent of patients had a hospital visit for congestive heart failure, 7.9 percent had a visit for acute myocardial infarction and 19 percent died.
Treatment with TZD monotherapy was associated with a significantly increased risk of congestive heart failure (78 cases), acute myocardial infarction (65), and death (102 cases) compared with other oral hypoglycemic agent combination therapies
"The increased risk of congestive heart failure, acute myocardial infarction, and mortality associated with TZD use appeared limited to rosiglitazone," Lorraine Lipscombe, et al., write.
"Although the point estimate for pioglitazone does not favor a comparable increased risk [of CHF], we had limited power to explore the association between outcomes and pioglitazone use because of smaller numbers of patients receiving this agent," they add.
"As observed in the CHF analysis, the association between AMI and TZD monotherapy appeared to be limited to rosiglitazone," the authors state, noting 53 of the 65 MI cases were associated with Avandia.
Both GSK and Takeda challenged the population-based nature of the study.
In an interview with "The Pink Sheet" DAILY, Takeda Senior Director of Diabetes Robert Stanheimer said, "The best type of study to be done is a prospective trial and we have done one with Actos ... called Proactive. I think anytime you do what's called a real-life study or an observational trial, there may be some concerns with the validity of the results."
Referring to the ICES analysis, Stanheimer noted that the results with Actos are consistent with what Takeda has seen in other studies.
"What we're seeing in the JAMA article is a consistency with our other data, that is, there was no increase in total macro-vascular events or mortality with Actos. That is consistent with our prospective trial as well," he said.
In a statement, GSK said that the analysis by ICES has "significant limitations and generates misleading conclusions regarding acute myocardial infarction and death."
GSK added that the authors' conclusions are inconsistent with more robust evidence from large, long-term, prospective clinical studies such as the firm's ADOPT and RECORD trials.
"These long-term trials in diabetic patients comparing rosiglitazone to other oral anti-diabetic medicines show no increased risk for cardiovascular events compared to other commonly used medications, other than the well known risk of CHF with TZDs," according to GSK.
GSK also pointed to the fact that the ICES analysis represents an older, select group of patients with advanced diabetes and a higher baseline risk for cardiovascular disease.
In response to the article, FDA said: "This study in JAMA is one of what we expect to be many attempts to better characterize the risk profile of TZDs, much like others already published."
"This new study we have just seen today does not change FDAs recommendations. ...FDA is continuing to monitor and review all available data related to this class of drugs TZDs and cardiac risk, including this study."
- Anthony Vecchione (pharmasia@elsevier.com)
This article is reprinted from "The Pink Sheet" DAILY – Dec. 13, 2007.
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