Anti-Obesity Medications: Qsymia(TM)Thursday, October 3, 2013
In our review of the literature on new and emerging anti-obesity drugs, published in Nature Endocrine Reviews, we next turn our attention to the fixed combination of phentermine and control-release topiramate, recently launched in the US under the trade name Qsymia.
The amphetamine analogue phentermine has been around for use as an appetite suppressant for decades and is by the far the most widely used anti-obesity drug in the US and is generally prescribed in doses ranging between 15.00 and 37.5 mg. Its anorexic effect is attributed to its sympathomimetic action, which however also accounts for the most common adverse effects: high blood pressure, tachycardia, restlessness and insomnia. Furthermore, tolerance can develop with long-term use, which is therefore generally recommended to be used for 12 weeks (which of course makes little sense, given the chronic nature of obesity).
Topiramate, the other component of this combination has been approved in the USA for epilepsy treatment since 1996 and since 2004 for the prevention of migraines. For these indications doses range from 100 to 400 mg per day. Although the precise mechanisms by which topiramate exerts its antiobesity effect are incompletely understood, its efficacy seems to be related to a number of pathways: reduction in compulsive or addictive food craving via antagonism of α‑amino‑3-hydroxy‑5-methyl‑4-isoxazolepropionic acid (AMPA) receptors and kainate receptors, decreased lipogenesis and modification of food taste via inhibition of carbonic anhydrase isoenzymes as well as increased energy expenditure via activation of γ‑aminobutyric acid (GABA) receptors. Common dose-dependent adverse effects, include paraesthesia, fatigue, dysgeusia (distortion of taste), difficulty with concentration and mood changes. There is also concern about teratogenicity of topiramate when taken during pregnancy.
Qsymia takes advantage of the synergistic effects of phentermine and topiramate, resulting in clinically relevant weight loss at doses of the individual components that are substantially lower than those of phentermine and topiramate when used as monotherapy. Thus, the recommended dose of 7.5/46 mg Qsymia, combines phentermine and topiramate at doses that are about 25% and 12% of the maximum dose of these compounds approved for other uses, respectively. Given that most of the adverse effects of these compounds are dose-dependent, the substantially lower dose of these drugs in this combination, significantly reduces the likelihood of side effects.
The 2012 FDA approval of phentermine–topiramate CR was based on data from four phase II studies that used commercially available tablets of phentermine and topiramate (separately ingested) and three phase III trials that used fixed-dose combinations of these two agents, administered as a single tablet, involving over 4,500 participants. In our review, we describe and discuss details of each of these studies.
At the highest dose of 15/92 mg, the average placebo-adjusted weight loss was about 8-10% of initial weight with favourable effects on blood pressure and other cardiometabolic risk factors. Overall, almost four times as many participants achieved a clinically meaningful weight loss of 5% or greater compared to placebo (~65% vs. ~17).
The safety profile of phentermine-topiramate CR reported in these trials was essentially what one may expect from the known profiles of the individual components: apart from paraesthesia (~20%), dry mouth (~20%), and constipation (~15%). Furthermore, participants receiving high-dose phentermine–topiramate CR had a fourfold to sevenfold higher probability than those receiving placebo to discontinue treatment owing to a mental-health-related adverse event, such as anxiety, insomnia or depression. Cognitive disorders (confusion, disorientation and mental impairment) were also more frequent in patients receiving active treatment than in those on placebo (7.6% versus 1.5%); these symptoms were commonly reported within the first month of treatment and seemed to be dose-related.
There was also a statistically significant increase in heart rate (1.7 bpm) in the high-dose groups, the clinical significance of which remains unclear.
Given the previously noted concerns around possible teratogenicity of topiramate, in women of child-bearing potential, a pregnancy test is recommended before start as well as use of effective contraception and monthly pregnancy testing with immediate discontinuation of treatment in case of pregnancy.
As with all of the new obesity drugs discussed in our review – uncertainty exists as to the long-term benefits (beyond weight loss).
In the case of Qsymia, a long-term cardiovascular outcome trial with ‘hard endpoints” in well over 10,000 participants is currently in preparation and expected to commence early next year.
Disclaimer: Neither phentermine and topiramate nor the combination are currently approved for obesity treatment in Canada. I have received honoraria from the makers of Belviq (and other anti-obesity drugs) for consultation and research.
Rueda-Clausen CF, Padwal RS, & Sharma AM (2013). New pharmacological approaches for obesity management. Nature reviews. Endocrinology, 9 (8), 467-78 PMID: 23752772