Pargluva® made by Merck and Co. Inc. and Bristol-Myers Squibb, may be delayed in coming to market by 2 years if additional safety studies are required by the FDA. Pargluva was going to be the first to reach the market of a class of drugs called glitizars, which reduce insulin resistance and control fats in the blood. And just last month, a scientific panel appointed by the FDA voted 8-1 urging approval of the drug, which lowers blood sugar and certain blood fats, as a stand-alone treatment.
From a report issued last week by the AMA, the FDA was encouraged to delay approval until additional safety studies completed. A new medication under review by the Food and Drug Administration that may regulate blood glucose levels and have a beneficial effect on blood cholesterol and lipid levels for patients with Type 2 diabetes appears to increase the risk for major adverse cardiovascular events and death, according to a new study in the Journal of the American Medical Association.
The study and an accompanying editorial were released last week online at www.jama.com because of their timeliness and potential importance for public health.
The medication, muraglitazar, is in a class of drugs called dual peroxisome proliferator-activated receptors (PPARs), that affect lipid levels and glycemic control in diabetic patients.
The studies on muraglitazar were reviewed by an FDA advisory committee on September 9, 2005, resulting in a vote of 8 to 1 recommending approval for its use as a monotherapy in controlling blood glucose levels in patients with type 2 diabetes. On October 18, 2005, the FDA issued an "approvable letter" for muraglitazar, indicating that the drug could be approved once the FDA receives and reviews additional information.
The researchers analyzed the muraglitazar trials performed in diabetic patients, publicly released by the sponsor and FDA for the advisory panel meeting. The documents provided data for five clinical trials that assessed safety and efficacy in diabetic patients. The researchers restricted their analysis to treatment groups using muraglitazar doses of 5 mg/d or less.
The analysis yielded 2,374 patients exposed to muraglitazar and 1,351 patients exposed to other agents, of which 823 received pioglitazone (a currently available PPAR) and 529 placebo. The patients were relatively young (average age 55 years or less) and obese (average body mass index greater than 30). The studies included both men and women participants and the diabetes control among the participants was relatively poor.
"In the muraglitazar-treated patients, death, MI (heart attack), or stroke occurred in 35 of 2,374 (1.47%) patients compared with 9 of 1,351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls)," the authors found.
"The results of this analysis are concerning," the authors write. "For the most widely accepted composite end point of death, MI (heart attack), and stroke the RR (relative risk) for muraglitazar was 2.23. Other end points using narrower definitions (including only cardiovascular death) or broader composites (including CHF [congestive heart failure] and TIA [transient ischemic attack] events) showed similar risks." The researchers note that the results are particularly concerning because the excess of adverse events was observed after the study participants had limited drug exposure ranging from 24 to 104 weeks.
The researchers state that "atherosclerotic cardiovascular disease is particularly common in patients with type 2 diabetes, representing the cause of death in approximately 80% of diabetic patients. Thus, any drug used to treat diabetes requires careful scrutiny for its effects on atherosclerosis-related outcomes, such as MI and stroke." The researchers also note there are some limitations to their analysis as they did not have access to original trial databases.
"Nonetheless, some important conclusions are warranted. Muraglitazar appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment. The estimated magnitude of this risk is substantial with RRs indicating a doubling for irrevocable, major end points and composite outcomes. The consistency of these RRs suggests that this result is not due to chance. Accordingly, muraglitazar should not be used or approved to treat patients with diabetes until an appropriate dedicated trial to assess cardiovascular outcomes is performed," the authors conclude.
In an accompanying editorial, James M. Brophy, MD, FRCP, PhD, from McGill University, Montreal, Canada, writes, "muraglitazar is the first dual PPAR agonist to be considered for general marketing both as mono and combined therapy by the U.S. Food and Drug Administration. Given the emerging epidemic of diabetes, it is easy to understand the enthusiasm for this new class of drugs."
"Last month, a FDA advisory committee reviewed muraglitazar’s efficacy and safety data and recommended approval. However, in this issue of JAMA, Nissen and colleagues have re-analyzed this data and challenge the advisory board’s recommendation."
In addition to underscoring the cardiovascular risks evident in the analysis by Nissen et al, Dr. Brophy notes that carcinogenicity (cancer) also has been a concern in animal studies involving other PPAR agonists.
"While the manufacturer’s presentation to the advisory committee concluded that cancer rates were not increased, there were 34 cancers reported in the muraglitazar group and one in the control group."
He goes on to question some of the methodological decisions in the sponsor’s FDA application that "may foster an illusion of safety" including the selection of the study population that is not representative of potential future users; underpowered studies increasing the failure rate to detect meaningful safety differences; and concentrating on reductions in surrogate laboratory values rather than in meaningful patient health outcomes.
"In conclusion, while muraglitazar may yet prove to be a valuable addition to our clinical armamentarium, Nissen and colleagues are to be congratulated for their meticulous examination of the current evidence and for drawing our attention to its potential cardiovascular risks. Residual safety concerns surrounding carcinogenicity also have not been completely resolved. The question now is which safety message will the FDA buy?"
JAMA. 2005. Available at www.JAMA.com
DID YOU KNOW:
One in four African American women older than age 55 reported as having Type 2 diabetes. Type 2 diabetes has reached epidemic status among African-American women. This rate is two times higher than in white American women. In the last 12 years the percentage of African Americans with diabetes has doubled from 8.9% to18.2%. African-American women are twice as likely as white women to be diagnosed with diabetes and once diagnosed African-American women are more likely to experience severe complications, such as kidney disease and blindness. Diabetes with its related complications is the fourth leading cause of death in the African-American community and the fifth leading cause nationwide. CDC