With a 13 year dry-spell in terms of new obesity drugs on the market, the FDA is making up for lost time - Belviq was approved at the end of June and Qysmia was approved just last week. Qysmia (originally called Qnexa) is a combination of phentermine, a stimulant with similar chemical properties to amphetamines, and topiramate, an anticonvulsant. We have no idea how to pronounce it but it has shown some promising results and (hopefully!) reduced side effect profile compared with its predecessors (1).
We left off last week with the removal of fen-phen from the marketplace in 1997, which did little to deter the release of new medications. This week we will cover contemporary anti-obesity medications, both approvals and scandals.
1996: Olestra (Olean), a poorly-absorbed fat and oil substitute made from sucrose, is approved as a food additive. Now famous for potato chips with the warning “may cause diarrhea and fecal incontinence” and concerns regarding fat-soluble vitamin deficiency, Olestra is still an approved food additive in the US today, though few companies add the product to foods given its reputation. It is also used as a paint additive and mechanical lubricant! Yum!
1997: Sibutramine (Meridia) is approved by the FDA. Sibutramine’s mechanism of action is the inhibition of neurotransmitter reuptake – namely serotonin, dopamine and norepinephrine – in brain synapses. Higher circulating levels of these neurotransmitters in the brain were associated with satiety, weight loss and improved glycemic control in clinical trials (2,3).
1999: Orlistat (Xenical), a fat absorption-blocking medication, is approved by the FDA. By blocking the fat-digesting enzyme lipase, orlistat reduces fat absorption, and thereby caloric intake. Gastrointestinal side effects, such as steatorrhea and fecal urgency, are significant in those taking orlistat though seem to abate with time (4). A low-fat diet is crucial for success and side-effect management.
2002: Ralph Nader (yes, that Ralph Nader!) and Public Citizen health advocacy group petition the FDA to withdraw sibutramine given rising concerns over long-term health consequences.
2004: Ephedra sinica (ephedrine), a plant-extracted dietary supplement with potent thermogenic and stimulant effects, is banned by the FDA. Although unregulated in its use as a “natural” weight loss aide, as purported use in asthma and hypertension, concerns regarding side effects similar to DNP (as discussed last week) including heart attack, stroke and death prompt the FDA to intervene.
2006: Initial conditional approval for appetite-reducing Rimonabant (a cannibinoid antagonist) granted and medication goes to 6- and 12-month safety reviews before entering the marketplace, though begins use in the UK as a prescription anti-obesity medication.
2007: Lower-dose orlistat, marketed as Alli, is approved for over-the-counter (read: without prescription) use in the US. Alli is still not available OTC in Canada, despite availability in Australia and the EU.
The Sibutramine Cardiovascular OUTcomes (SCOUT) study results are released, indicating that “six-week treatment with sibutramine appears to be efficacious, tolerable and safe in this high-risk population for whom sibutramine is usually contraindicated” (5). Pretty short timeframe to establish safety!
2010: New study from SCOUT investigators links meridia with an increased risk of nonfatal stroke and heart attack in those with preexisting cardiovascular disease (7). As a result, the medication is withdrawn from the market.
FDA issues revised safety labeling for orlistat indicating risk of rare but severe liver injury.
Application for Belviq approval is denied by the FDA arising from concerns that harm may outweight benefit – preliminary research suggested an increased risk of heart-valve dysfunction (similar to its predecessors) and tumours in animal studies, despite only modest weight loss success.
Application for Qysmia (then called Qnexa) is denied by the FDA given concerns regarding risk of birth defects should a woman become pregnant while taking the medication.
2011: Public Citizen group petition the FDA to remove orlistat and Alli from the marketplace given concerns regarding risk of pancreatitis and liver damage, though research results suggest liver damage is rare and routine monitoring of liver function is a part of prescription protocols.
2012: Belviq and Qysmia are approved after some initial false-starts. Long-term cardiovascular outcome studies investigating safety are ongoing.
No Baloney’s advice. Pretty interesting 15 years! While this may paint a less-than-rosy picture of anti-obesity medications, we are by no means suggesting that pharmacological agents have no place in obesity management. We are, however, highlighting the fact that the same caveat always applies – “to be used with diet and exercise”. It is never a matter of simply popping a pill.
Recent reviews suggest that weight loss success has been most successful in medications that have been pulled from the market (8-10) – greater weight loss = higher risk of health consequences? Despite some recent public health concerns regarding orlistat and risk of liver injury, it is one of the rare medications that seems to NOT be associated with increased risk of heart disease (8-10).
As will all medications, it is important to have a discussion with your doctor regarding your options vis a vis your current health – from good ol’ fashioned diet and exercise with and without the addition of medication to (hopefully) boost chances of success all the way to bariatric surgery, which is acknowledged as the most drastic but successful strategy. While there are likely new medications on the horizon of approval, like exenatide, bupropion and zonisamide/naltrexone, and gut-hormones like PYY, none are free of risk or a guarantee of success.
- Garvey WT, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012; 95:297-308.
- Lean ME. Sibutramine–a review of clinical efficacy. Int J Obes Relat Metab Disord 1997;21 Suppl 1:S30-6.
- Cole JO, et al. Sibutramine: a new weight loss agent without evidence of the abuse potential associated with amphetamines. J Clin Psychopharmacol 1998;18:231-6.
- Sjöström L, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998; 352:167-72.
- Torp-Pedersen C, et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J 2007; 28:2915-23.
- Samat A, et al. Rimonabant for the treatment of obesity. Recent Pat Cardiovasc Drug Discov 2008;3:187-93.
- James WP, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010 Sep 2;363(10):905-17.
- Gray LJ, et al. A systematic review and mixed treatment comparison of pharmacological interventions for the treatment of obesity. Obes Rev 2012; 13:483-98.
- Derosa G, Maffioli P. Anti-obesity drugs: a review about their effects and their safety. Expert Opin Drug Saf 2012; 11:459-71.
- Kang JG, Park CY. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab J 2012; 36:13-25.