Obesity drugs: FDA says good guns or no guns

Ryan Novosad

Sara Brouse

Although it often seems as though there exists a pill to treat any disease, when it comes to obesity, this is not the case. Few drugs have dared enter the arena in the fight against obesity, and while overweight and/or obesity is rapidly becoming one of the most common comorbidities in the US, none of the available obesity medications approach the level of treatment success observed with antilipid, antihypertensive, antidiabetic agents or other agents used to treat common, chronic disorders. This, unfortunately, leaves clinicians with few options beyond the first line, non-pharmacologic treatment modalities (ie, diet and exercise) and bariatric surgery options, which while successful, can be associated with adverse outcomes, and the result may not be durable.

To further exacerbate the paucity of obesity treatment options, recent FDA rulings regarding both currently available and new drugs in the anti-obesity class have resulted in further limitations in the anti-obesity arsenal. FDA approval criteria, established in 2007, require that new weight-loss medications result in either at least 5% statistically significant, placebo-adjusted weight loss after 1 year or more than 35% of patients treated achieve more than 5% weight loss.

Sibutramine fails risk-benefit analysis

Sibutramine (Meridia, Abbott Laboratories), a centrally acting monoamine oxidase inhibitor approved in November 1997 for weight loss and weight-loss maintenance, was voluntarily withdrawn from the US market in October 2010 after the FDA requested its discontinuation. Sibutramine exerts its pharmacologic effect by enhancing adrenergic, serotonergic, and dopaminergic signaling in the brain, thus resulting in diminished hunger and increased satiety. While these effects result in weight loss, unfortunately, these effects likely contributed to the associated adverse event profile and recent demise. The SCOUT trial, which enrolled about 10,000 patients with CAD or at high CV risk, demonstrated a 16% increase in the risk for major adverse CV events (including death, resuscitated cardiac arrest, nonfatal stroke or nonfatal MI) in patients treated with sibutramine compared with those taking placebo (11.4% vs. 10%; HR=1.16; P=.02). Because the weight loss observed in this trial at 60 months was only about 2.5%, it was determined that the CV risks outweighed the potential for weight-loss benefit, and sibutramine was subsequently withdrawn from the market.

Safety concerns remain for phentermine/topiramate

Phentermine/topiramate (Qnexa, Vivus) is an investigational, combination product that was recently denied approval by the FDA based on concern regarding its adverse effect profile. Results from two phase 3 extension trials demonstrated significant weight loss, in the ballpark of 10% weight reduction in 52 weeks. However, although this weight-loss result suggests the possibility of benefit in terms of CV risk reduction in the long-term, it came at the expense of a number of side effects, including cognitive disorders (7.8%), metabolic acidosis (persistent bicarbonate from <21 to <17mEq/L), and increased heart rate (>20 bpm). The FDA has requested additional evidence of this new combination’s safety before re-review and/or approval.

Naltrexone/bupropion falls short

Naltrexone/bupropion (Contrave, Orexigen Therapeutics) is another combination product that is thought to exert its effect in a bimodal fashion, acting centrally on opioid receptors and dopamine levels, ultimately increasing satiety and decreasing food intake. It was thought that this synergistic approach would not only increase the weight-loss potential of each medication separately, but would possibly also serve as an attractive option to those resistant to other anti-obesity agents. Naltrexone/bupropion has shown promise in terms of statistically significant weight loss, demonstrating about 4% weight loss over that of placebo. However, this does not meet the current FDA requirement for weight-loss effect, and concerns regarding BP and heart rate elevations led the FDA to request an adequately powered long-term safety study before consideration for approval. After a request to market its drug only to low-CV-risk patients, which the FDA rejected, Orexigen Therapeutics opted to explore marketing opportunities outside of the US this past June and decided to forgo plans to seek approval for Contrave in the US at this time.

Safety cited for lorcaserin rejection

Lorcaserin (Lorqess, Arena Pharmaceuticals) is a selective agonist of 5-HT_2C. This selective serotonin stimulation results in suppression of appetite and induces a feeling of satiety and is thought to avoid the precipitation of cardiac valvular disease associated with activation of 5-HT_2B receptors (as seen with fenfluramine use). In a recent study of 3,182 patients, those treated with lorcaserin lost an average of 5.8% of their baseline body weight compared with 2.2% in those taking placebo. It was also noted that approximately 50% (lorcaserin group) compared with 20% (placebo group) had lost at least 5% of the baseline body weight at the end of 1 year, and significantly more patients in the lorcaserin group sustained their weight loss at the end of 2 years. Further improvements in CV risk seen in the lorcaserin group included statistically significant reductions in BMI, waist circumference, total and LDL, triglycerides, fasting glucose, and HbA1c. Despite these benefits, the FDA voted against approval due to concerns regarding safety (specifically, valvular disease, neuro-psychiatric-related adverse effects, and cancer risk observed in animal studies).

Physicians’ options limited

It is easy to see that in the realm of anti-obesity medications, it has been difficult to find a balance with regard to pharmacologic targets and/or mechanisms that are also clinically effective at weight reduction and safety. Even the currently available treatment options, including phentermine, diethylpropion, orlistat, benzphetamine, and phendimetrazine, are not without their drawbacks. Considering that the long-term goal of treating obesity is the prevention of morbidity and mortality, and considering several anti-obesity drugs have the potential to cause harm, it is apparent that there is a “call to arms” for new, innovative, novel treatment approaches. In the mean time, clinicians are left with lifestyle modification as the safest and most effective option — but only when incorporated as a way of life over the long-term. Getting patients to embrace exercise through rehab programs and healthier eating habits through dietary counseling is one effective way to see improved weight-loss success rates.

Ryan Novosad, PharmD, is PGY1 pharmacy practice resident at Huntsville Hospital, Huntsville, Ala. Sara Brouse, PharmD, is associate professor of pharmacy practice and vice chair for residency programs at Texas Tech University Health Sciences Center School of Pharmacy and Advanced Practice Pharmacist in Cardiology/Critical Care in Dallas.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor, department of pharmacotherapy and translational research, College of Pharmacy, and Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. For suggestions of future topics for this column, please contact Dr. Cooper-DeHoff, dehoff@cop.ufl.edu.

For more information:

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• James W. N Engl J Med. 2010;363:905-917.
• Kaplan L. Gastroenterol Clin N Am. 2010;39:69-79.
• Smith S. N Engl J Med. 2010;363:245-256.

Disclosure: Drs. Brouse, Cooper-DeHoff and Novosad report no relevant financial disclosures.