Phentermine plus topiramate in the treatment of obesity

Phentermine plus topiramate in the treatment of obesity

Correspondence Science Photo Library pulmonary clearance of serotonin, and this might be the possible mechanism by which it can cause primary pulmon...

71KB Sizes 0 Downloads 13 Views

Correspondence

Science Photo Library

pulmonary clearance of serotonin, and this might be the possible mechanism by which it can cause primary pulmonary hypertension.2 The study by Gadde and colleagues lasted 1 year, hence exceeding the current recommendations on duration of therapy. No routine echocardiography was done, either at baseline or periodically during treatment. Despite some limitations, echocardiography is useful for measuring pulmonary pressure and for determining cardiac abnormalities in patients with pulmonary hypertension.4 Several centrally acting anorectic substances have been withdrawn from the market owing to cardiovascular toxicity in past years: aminorex, fenfluramine, sibutramine, and benfluorex.5 Before drawing definitive conclusions on the usefulness of the combination of phentermine and topiramate in the treatment of obesity, very robust evidence of its cardiovascular safety should be provided. We declare that we have no conflicts of interest.

Renato Bertini Malgarini, *Giuseppe Pimpinella [email protected] Agenzia Italiana del Farmaco (AIFA), 00187 Rome, Italy 1

2

3

4

5

Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: 1341–52. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine–phentermine N Engl J Med 1997; 337: 581–88. European Medicines Evaluation Agency. Final opinion of the Committee for Proprietary Medicinal Products in accordance with Article 12 of Directive 75/319/EC as amended. http:// www.ema.europa.eu/docs/en_GB/document_ library/Referrals_document/Anorectics_31/ WC500014209.pdf (accessed April 21, 2011). Janda S, Shahidi N, Gin K, et al. Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis. Heart 2011; 97: 612–22. Mullard A. Mediator scandal rocks French medical community. Lancet 2011; 377: 890–92.

The CONQUER trial1 assessed the efficacy of phentermine plus topiramate for weight loss. Kishore Gadde 126

and coauthors conclude that phentermine/topiramate “could be a valuable addition to the small arsenal of effective obesity treatments”. What they do not explain is that the US Food and Drug Administration (FDA) has already considered these data and has not approved phentermine/ topiramate for weight loss owing to substantial safety concerns. The results of this trial, formerly referred to as OB-303, have been publicly available since July, 2010, when the FDA considered Vivus’s bid to gain approval for phentermine/topiramate (Qnexa).2 In October, 2010, the FDA did not approve the new drug application, partly because of concerns about the potential teratogenicity of topiramate.3 If it were approved, phentermine/ topiramate could be prescribed to hundreds of thousands of women of childbearing age. It is striking that neither the authors of the CONQUER trial nor those of the accompanying Comment4 discuss the FDA’s decision or this major safety concern. The publication of clinical trials provides an opportunity to inform clinicians about the efficacy as well as the safety of novel treatments, and it is disappointing that the authors of this industry-sponsored study omitted an adequate discussion of the safety of phentermine/topiramate. I declare that I have no conflicts of interest.

Pieter A Cohen [email protected] Department of Medicine, Harvard Medical School and Cambridge Health Alliance, Somerville, MA 02139, USA 1

2

Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: 1341–52. Vivus. VI-0521 (Qnexa) Advisory Committee briefing document. NDA 022580. Endocrinologic and Metabolic Drugs Advisory Committee meeting. July 15, 2010. http:// www.fda.gov/downloads/advisorycommittees/ committeesmeetingmaterials/drugs/ endocrinologicandmetabolicdrugsadvisory committee/ucm218821.pdf (accessed April 17, 2011).

3

4

Vivus. FDA issues complete response letter to Vivus regarding new drug application for Qnexa. http://www.prnewswire.com/news-releases/ fda-issues-complete-response-letter-to-vivusregarding-new-drug-application-for-qnexa106157983.html (accessed June 28, 2011). Shah K, Villareal DT. Combination treatment to CONQUER obesity? Lancet 2011; 377: 1295–97.

Authors’ reply There is no clear evidence linking phentermine monotherapy (when not used in combination with fenfluramine or dexfenfluramine) to primary pulmonary hypertension or valvular heart disease. A prospective surveillance study1 of 579 patients—205 with primary pulmonary hypertension and 374 with secondary pulmonary hypertension—showed no relation between primary pulmonary hypertension and phentermine (odds ratio 0·6, 95% CI 0·2–2·2). With regard to valvular heart disease, the study by Connolly and colleagues cited by Renato Malgarini and Giuseppe Pimpinella showed an association in patients taking phentermine in combination with fenfluramine, but not phentermine monotherapy. A large population-based study2 showed an association between valvular heart disease and use of fenfluramine or dexfenfluramine alone or in combination with phentermine, but there were no cases of valvular heart disease among 862 patients who used phentermine alone. In a proof-of-concept trial,3 Gadde and colleagues examined echocardiographic changes in 100 patients who received phentermine alone (n=50) or in combination with topiramate (n=50) for 24 weeks, and found no treatmentemergent valvular heart disease; therefore, echocardiography was not incorporated into the larger study we reported in The Lancet. Additionally, a review by the US Food and Drug Administration (FDA) presented at an advisory committee meeting in July, 2010, stated that “neither mechanistic nor clinical evidence supports a causative role for phentermine in druginduced valvulopathy.”4 www.thelancet.com Vol 378 July 9, 2011