Cleveland, OH - The same group from the Cleveland Clinic that helped start the Vioxx controversy is now calling for a delay in the approval of a new diabetes drug because of concerns that it may increase major cardiovascular events.

The drug, muraglitazar (Pargluva, in joint development by Merck and Bristol-Myers Squibb), is the first dual-peroxisome proliferator-activated receptor (PPAR) agonist to be developed. It was recommended for approval by the FDA endocrinologic and metabolic drugs advisory committee by an 8:1 vote last month for use in controlling blood glucose levels in patients with type 2 diabetes.

But two Cleveland Clinic cardiologists, Drs Steven Nissen and Eric Topol, analyzed data from the studies presented at that advisory committee meeting (and published on the FDA's website) and found that patients treated with muraglitazar had a more than twofold increase in the risk of death, MI, or stroke compared with patients receiving placebo or another PPAR agonist, pioglitazone. Muraglitazar patients also had an increased risk of transient ischemic attack and heart failure. They report their findings in an "emergency paper" published in the Journal of the American Medical Association today.

Nissen explained to heartwire how the situation had come about. Because he was aware that dual PPARs had had toxicity issues in the past—Merck's first dual agent was dropped early on because of malignancy concerns, and muraglitazar itself has had issues with edema and heart failure—Nissen was interested in the studies presented to the FDA advisory committee. These studies were published on the FDA website in advance of the meeting, and Nissen saw that they suggested an excess of serious cardiovascular events. "I thus assumed that the FDA advisory committee would not recommend approval of the drug, so I was stunned when they voted for approval. I thought there could be a potential public-health catastrophe here," he told heartwire.

So Nissen called in the help of statistician Kathy Wolski, also named as an author of the current paper, and together they went through all the data that had been made public. They found a 2.23-fold increased risk of the composite of death/MI/stroke and a 2.62 fold increase in the risk of death/MI/stroke/CHF/TIA, both of which were statistically significant. Nissen commented: "We knew we were in a race against time, as the advisory committee had recommended approval, so we rapidly wrote a manuscript and I invited Eric Topol to be a coauthor to give advice and help us put it all together, and we sent the paper to JAMA on October 10 stressing the importance of quick publication."

Nissen also noted that Merck and Bristol-Myers Squibb received an approvable letter for muraglitazar on Tuesday of this week but that the letter also called for more safety data.

Asked why the advisory committee voted for approval if there were such obvious safety concerns, Nissen said he did not know. "I don't think the advisory committee did a very good job. The meeting finished at 2 in the afternoon, and that's unusual—they normally go on much later. They obviously failed to probe the data adequately. If I had been on that advisory committee, the meeting definitely wouldn't have finished at 2 pm and I would have strongly urged for a vote against approval."

The difference is this time the genie is still in the bottle.

He added that it was important that members of FDA advisory committees do not just accept the company's presentation. "You should probe and probe because you are responsible for public safety." he commented to heartwire.

This is not the first time Nissen and Topol have taken on the FDA. They were key players in the removal of Vioxx from the market and challenged decisions made by the FDA on that drug. Nissen pointed out that the difference this time is that the drug is not yet on the market and they hope to prevent another Vioxx-type crisis. "The difference is this time the genie is still in the bottle," he said.

In the paper, the researchers explain their analysis. They reviewed all trials of muraglitazar performed in diabetic patients submitted to the FDA. They excluded from the analysis patients treated with the higher 10-mg and 20-mg doses of muraglitazar because further development of these dosages was terminated after a phase 2 trial demonstrated a high incidence of peripheral edema. The remaining patients consisted of 2374 participants given 5 mg/day or less of muraglitazar and 1351 given placebo or pioglitazone.

They used the composite of death/MI/stroke as their primary end point, as they say this is "the most widely accepted composite end point." But they note that other end points using narrower definitions or broader composites showed similar risks.

"The consistency in magnitude and direction of the adverse effects across multiple cardiovascular end points reduce the likelihood that these findings result from chance alone. These results are particularly concerning because the significant excess of adverse events was observed after only limited drug exposure, ranging from 24 to 104 weeks. Moreover, patients who are enrolled in clinical trials often constitute the lowest-risk strata of patients, and the real-world exposure would likely substantially amplify the risk. Taken as a whole, these data demonstrate that it is likely that muraglitazar, if approved by the FDA, would constitute an unacceptable patient hazard," Nissen et al write.

In an accompanying editorial, Dr James Brophy (McGill University Health Centre, Montreal, QC) points out that there could also be concerns about cancer with muraglitazar, given that other dual PPAR agonists have had to be dropped from development because of carcinogenicity issues [2]. He notes: "The sponsor's presentation to the advisory committee concluded that cancer rates were not increased. However, 34 cancers were reported among 3125 patients in the muraglitazar group for an incidence of 9.8 per 1000 patient-years, whereas one cancer was reported among 528 placebo patients, or an incidence rate of 3.0 per 1000 patient-years. Although the confidence intervals overlap, this is a worrisome observation that requires immediate further study, as a very large increase in cancer risk cannot be excluded with the limited available data."

Brophy also lists eight "specific methodological decisions in the sponsor's FDA application that may foster an illusion of safety." These include the following:

1. Selecting a study population unlikely to have adverse outcomes but nonrepresentative of potential future users (eg, exclusion of elderly patients, even though more than one third of type 2 diabetes occurs in this group).
2. Conducting underpowered studies, increasing the failure rate to detect meaningful safety differences.
3. In contrast to efficacy determinations, reporting individual rather than composite safety outcomes to decrease the likelihood of establishing statistical significance.
4. Limiting preapproval peer-review publication of results so as to minimize scrutiny and debate of both methods and results.
5. Evoking biological implausibility of safety concerns by the use of surrogate measures implying safety.
6. Recording outcomes only in patients who are fully compliant with prescribed treatment because this self-selected group will likely have fewer adverse events.
7. Ignoring the totality of the evidence by excluding consideration of confirmatory safety signals seen in studies of similar molecules.
8. Diverting attention to unproven but potential benefits by concentrating on reductions in surrogate laboratory values (eg, hemoglobin A1_c) rather than in meaningful patient health outcomes.

Brophy concludes: "Although muraglitazar may yet prove to be a valuable addition to the clinical armamentarium, the meticulous examination of the current evidence by Nissen and colleagues should focus serious attention on the potential cardiovascular risks of this drug. Residual safety concerns surrounding carcinogenicity also have not been completely resolved. The question now is, which safety message will the FDA buy?"

In an interview with heartwire, Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) agreed that the analysis from the Cleveland Clinic raised legitimate questions about muraglitazar, but he did not feel it was time to adopt a new standard by which all
new diabetes drugs should be required to specifically prove cardiovascular safety as a unique adverse end point among all the safety indicators currently required by the FDA. The safety of diabetes drugs should be evaluated from an overall benefit/safety consideration. "If you're talking about a prediabetes condition in people with or without cardiovascular disease, then I think it's reasonable to require clinical trials with cardiac end points before approving a drug targeting glucose metabolism. It's a stretch to assume you can treat prediabetes specifically to prevent cardiovascular disease. On the other hand, we have not yet reached a point where we can say that all new drugs in diabetes are going to have to specifically jump through the hoop of a cardiovascular end-point trial." As to whether muraglitazar should be approved now, Grundy said, "I am not sufficiently familiar with the totality of the available database to make a judgment call."