Written by: Dr. Robert Kleiman, Chief Medical Officer & Vice President, Global Cardiology
Obesity is one of the nation’s largest health problems and has grown into a major epidemic. Over the past 20 years, obesity rates in the US have continued to dramatically increase. According to the Centers for Disease Control and Prevention, more than one-third of U.S. adults and approximately 17% (or 12.5 million) of children and adolescents aged 2—19 years are obese.1 Overweight and obese individuals are at increased risk for many diseases and chronic health conditions, including: hypertension, osteoarthritis, dyslipidemia, type 2 diabetes, heart disease, stroke, liver and gallbladder disease, sleep apnea and respiratory problems, and certain cancers (i.e. pancreas, kidney, prostate, endometrial, breast, and colon).2 A 2009 study by the Centers for Disease Control and Prevention, along with RTI International, demonstrated the economic burden of obesity and estimated that medical costs were as high as $147 billion annually, which accounted for approximately 10% of all medical spending.3
To date, there aren’t any satisfactorily safe and effective obesity drugs commercially available. Many potential weight-loss drugs have either failed or been abandoned by drug development companies and there have been several obesity drugs withdrawn from the market due to safety concerns and adverse side effects. There is a huge opportunity for pharmaceutical sponsors to make a significant impact on the lives of obese people with long-term drug therapy. However, there have obviously been several challenges, mounting concerns and an increasing number of hurdles required to continue development programs and ultimately gain regulatory approval for any new weight-loss drugs. In 1997, two popular anti-obesity drugs, Fen Phen and Redux, were pulled from the market by the FDA because of potentially life-threatening heart valve damage. Also, in 2010, the obesity drug Meridia was recalled for causing an increased risk of stroke and heart attack in populations already prone to these dangerous cardiovascular events.
Currently, there are three obesity drugs (QNEXA, Lorcaserin, and Contrave) which are again seeking regulatory approval after being previously rejected by US regulators over safety concerns. To put the challenge here into perspective, the FDA has not approved a new prescription drug for long-term weight since Xenical (orlistat), over a decade ago in 1999. Xenical has demonstrated to be minimally effective and presents significant side effects which have inhibited its use over time. In general, weight loss has been tied to positive effects on the heart, but the few trials conducted on the long-term heart safety of obesity drugs have shown to actually increase heart risks, or have little to no effect on heart health. It is clear that the FDA will no longer approve a drug for the masses based on a small treatment benefit and without evidence of future improvement on patient health. In clinical trials, Contrave raised pulse rates and blood pressure slightly, a warning sign that the drug might increase the risk of heart attacks, strokes or other cardiovascular problems. Consequently, the FDA told the drug maker that it must first do a cardiac safety study to prove Contrave does not increase the risk of adverse cardiovascular events in order to gain regulatory approval.
The FDA has clearly been grappling with cardiovascular risks in obesity drugs and on March 29th, 2012, the FDA Endocrinology and Metabolic Drugs Advisory Committee, after hearing from experts in obesity, diabetes, cardiology and statistics, recommended that drug companies be required to submit phase II or III data to prove absence of cardiovascular risk for new obesity drugs, even if clinical trials do not initially show evidence of precipitating cardiovascular events. Obesity trials should randomize about 3000 subjects to the active drug and at least 1500 subjects to a placebo for one year of treatment. The FDA requires that patients in phase III obesity drug trials have a body-mass index (BMI) of at least 30 (or 27 plus comorbidities). The drug should demonstrate either mean efficacy—a >5% difference in weight loss between treatment and placebo—or categorical efficacy—at least 35% of treated patients lose >5% of their baseline body weight, approximately double the proportion in the placebo group.4 In addition to these already established requirements to prove efficacy, almost all committee members agreed that the major adverse cardiac event (MACE) data should come from either cardiovascular-outcome trials or meta-analyses. While not an easy decision, torn between recommending the new safety requirements, which could dampen research efforts, or not extending the safety requirement, which could potentially expose millions of people who would be eligible to take these drugs to serious adverse events, 17 to 6 voted in favor of the new suggested requirements. As you may recall, back in 2008, FDA advisors had a similar kind of discussion regarding the cardiovascular safety of diabetes drugs and the FDA later published its 2008 guidance for industry. The new recommendations for obesity drugs to enrich phase II and III clinical trials by including older, sicker individuals with cardiovascular risk factors have mirrored those in the 2008 advisory. Although not required, the FDA usually follows panel recommendations. This news could and will likely affect the drug makers of QNEXA and Lorcaserin, which are also vying to get their obesity drug to market in the near future.
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Stay tuned for more news on any further recommendations or official guidances from the FDA regarding cardiac safety in obesity drugs. If you have any questions for Dr. Kleiman, please visit our website at http://www.ert.com/contact-ert/ or write your questions/comments below.
For more information on ERT’s Cardiac Safety Solutions, please visit: http://www.ert.com/cardiac-safety
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