Lemons for Obesity
Authors: Michael S. Lauer
Journal: Annals of Internal Medicine (2012)

Ideas and Opinions17 July 2012Lemons for ObesityFREEMichael S. Lauer, MDMichael S. Lauer, MDFrom the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-157-2-201207170-00438 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail On 22 February 2012, the U.S. Food and Drug Administration (FDA) convened a panel for advice on a proposed antiobesity medication called "Qnexa." Qnexa, manufactured by Vivus Inc., is a combination of phentermine, which is already approved as a diet suppressant, and topiramate, an antiseizure agent. Clinical trials demonstrated that Qnexa can lead to 10% weight loss in obese adults, but in 2010 an FDA panel recommended against approval because of safety concerns. Now, on February 22, Vivus was prepared to respond to 2 top safety worries: increased teratogenic risk for cleft lip and palette, and increased risk for cardiovascular events stemming from increases in heart rate. After reviewing documents and hearing a number of presentations, 20 FDA panelists voted in favor of approval and 2 voted against. I was 1 of the 2 (1).My thoughts about Qnexa, and obesity medications in general, derive in part from 2 classic Nobel prize–winning publications from the 1970s. In 1970, George Akerlof wrote about the market for bad cars, otherwise known as "lemons" (2). Suppose used car buyers have reason to believe that 75% of cars are good and 25% are lemons; buyers know that some owners want to sell their cars because they've discovered many problems. A good car, which we'll call "a peach," is worth $20 000, a lemon only $5000. A prospective buyer has a big problem in being unable to distinguish peaches from lemons, whereas owners have no trustworthy way to communicate their inside knowledge. The buyer's problem, which Akerlof referred to as information asymmetry, leads to a low offer of, say, $16 250. Owners of peaches will refuse "low-ball" offers of less than $20 000, whereas sellers of lemons will gladly accept. However, the buyer will wonder why an owner would accept a low offer for a peach, suspecting that the car is in fact a lemon. The buyer will revise his or her offer down, say, to $12 500, making owners of peaches even less willing to sell. Over time, the only cars that will sell will be lemons—peaches will be driven out of the market. Because of information asymmetry, Akerlof argued, bad products drive out good ones.If we think about the history of obesity medications, we've seen plenty of lemons. Ephedra, Fen-phen, phenylpropanolamine, and sibutramine had to be withdrawn from the market because of cardiovascular toxicity. Rimonabant was approved for sale in Europe, but was never approved in the United States because of severe psychiatric side effects. At this time, Xenical is the only drug that is FDA-approved for obesity, and its use is limited by abdominal discomfort and steatorrhea. Why so many lemons? And what about Qnexa? Is it another lemon, or is it the peach we all want?On 22 February, Vivus submitted a lengthy document that included its syntheses of cardiovascular data to the FDA panel (3). The company noted that the drug increases heart rate by a modest degree while improving other cardiovascular biomarkers, including blood pressure and high-sensitivity C-reactive protein. Of 2581 patients enrolled in the company-sponsored "safety set" trials who were randomly assigned to Qnexa, 6 had myocardial infarction and 1 had a stroke, whereas among 1742 patients assigned to placebo, 1 died from an out-of-hospital cardiac arrest and 4 had strokes. On the basis of these 12 major adverse cardiovascular events, the company reported a hazard ratio of 0.84 with a confidence range of 0.26 to 2.64 (3). The company wrote, "Considering the overall absence of excess major adverse cardiovascular events in subjects in this program who received treatment with Qnexa, the lack of a direct relationship between major adverse cardiovascular events and heart rate changes, and the beneficial effects of Qnexa in models of cardiovascular risk that include heart rate, it does not appear that the small heart rate increase observed with Qnexa treatment can be associated with an increased risk for major cardiovascular events" (3).I disagreed, arguing that it is impossible to draw any conclusions about Qnexa's clinical cardiovascular effects based on a tiny sample of only 12 events and a confidence range that stretches from 80% protection to nearly a 3-fold increase in risk. I believe that if the public were to "buy" Qnexa after FDA approval, it would run the risk for severe, even fatal, consequences from another diet lemon. Why?This brings me to the second classic publication from the 1970s, namely Tversky and Kahneman's description of biases and heuristics that lead to inappropriate conclusions (4). People have an "illusion of validity," thinking that 1 outcome is "representative" of what they're actually interested in. In clinical research, we call this problem "excess reliance on surrogates." We've seen numerous examples of failed surrogates, cases in which drugs seemed to do good things (like reduce blood sugar, increase high-density lipoprotein cholesterol, and improve left ventricular ejection fraction) yet, once rigorously tested in trials with large numbers of hard clinical events, turn out to be dangerous. We cannot assume that just because a drug reduces weight and improves some biomarkers that it will be safe, let alone beneficial.Tversky and Kahneman also described "insensitivity to prior probability of outcomes," in which people do not properly take into account preexisting data while attempting to interpret new data. In clinical research, we call this failure to employ "Bayesian thinking." We know that increased heart rate may reflect adverse autonomic nervous system effects that may increase the risk for fatal arrhythmias (5). We also know that prior obesity medications reduced weight at the price of unacceptable side effects. Taking history into account, we should be concerned about a proposed obesity medication that increases heart rate, especially considering that it may be used in tens of millions of people, many of whom are already burdened with cardiovascular risk factors.Finally, Tversky and Kahneman described "insensitivity to sample size." People assume that observations seen in small samples automatically translate to correct inferences about the general universe. We cannot assume that an absence of excess cardiovascular events in small trials—trials that yielded only 12 outcome events—means that we can confidently conclude that Qnexa is safe. In modern biostatistical terms, we express that uncertainty with the confidence interval.What's the information asymmetry? Consumers, and indeed many physicians, are not able to judge the value of a proposed obesity drug because they do not appreciate the problems with surrogates, the importance of prior probabilities, and the extreme uncertainties inherent in small numbers. Manufacturers and the FDA are aware of these problems (or at least, they should be), but they have no good way to communicate with most physicians and patients who are limited by statistical innumeracy (6–9). The result is that, absent rigorous FDA oversight, we wind up with obesity drugs that reduce weight but increase cardiovascular risk.So what to do? We can resolve the information asymmetry by insisting on a large-scale, preapproval cardiovascular outcomes trial of Qnexa. It would be too risky to rely on postapproval surveillance or to hope that a rigorous trial could be conducted in a timely manner. If Qnexa prevents cardiovascular events, or at least doesn't increase the risk for them, in a preapproval trial, then we will all know that we have the peach we've been waiting for.References1. Roan S. FDA advisors endorse weight-loss drug Qnexa. Los Angeles Times. 23 February 2012. Accessed at articles.latimes.com/2012/feb/23/health/la-he-qnexa-fda-20120223 on 8 March 2012. Google Scholar2. Akerlof GA. Market for lemons—quality uncertainty and market mechanism. Quarterly Journal of Economics. 1970;84:488-500. CrossrefGoogle Scholar3. Vivus. VI-0521 (Qnexa®) Advisory Committee Briefing Document. NDA 022580. 22 February 2012. Accessed at www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM292317.pdf on 8 March 2012. Google Scholar4. Tversky A, Kahneman D. Judgment under uncertainty—heuristics and biases. Science. 1974;185:1124-31. CrossrefMedlineGoogle Scholar5. Lauer MS. Autonomic function and prognosis. Cleve Clin J Med. 2009;76 Suppl 2 S18-22. [PMID: 19376976] CrossrefMedlineGoogle Scholar6. Reyna VF, Nelson WL, Han PK, Dieckmann NF. How numeracy influences risk comprehension and medical decision making. Psychol Bull. 2009;135:943-73. [PMID: 19883143] CrossrefMedlineGoogle Scholar7. Gigerenzer G, Gaissmaier W, Kurz-Milcke E, Schwartz LM, Woloshin S. Helping doctors and patients make sense of health statistics. Psychol Sci Publ Interest. 2008;8:53-96. CrossrefGoogle Scholar8. Wegwarth O, Schwartz LM, Woloshin S, Gaissmaier W, Gigerenzer G. Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med. 2012;156:340-9. [PMID: 22393129] LinkGoogle Scholar9. Moyer VA. What we don't know can hurt our patients: physician innumeracy and overuse of screening tests. Ann Intern Med. 2012;156:392-3. [PMID: 22393136] LinkGoogle Scholar Comments0 CommentsSign In to Submit A Comment Franz H. Messerli,† Sripal Bangalore,* Seth Uretsky†† St. Luke's Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, New York. * Cardiac Catheterization Laboratory, The Leon H. Charney Division of Cardiology, New York 9 August 2012 Letter to the Editor: Lemons for obesity. In his eloquent editorial Dr. Lauer (1) criticizes physician's "excess reliance on surrogates." because it not uncommonly leads to surrogate failure. Drugs seem to do good things like reduce blood pressure and glycemia or increase HDL cholesterol but fail to reduce morbidity and mortality or worse, may even hasten demise. From a strictly cardiocentric point of view indexes of overweight and obesity can be considered as surrogate endpoints and as such are occasionally prone to failure (2). However, obesity cannot be put on an equal footing with the above completely asymptomatic surrogate endpoints. For most patients HDL cholesterol is a somewhat esoteric concept making for interesting topic at a cocktail party. In contrast, obesity remains a major opprobrium in our society to the extent that some patients gladly would trade a few months of life expectancy for a more slender body habitus. Regardless of whether and how it affects cardiovascular risk, a weight loss of 10% as was observed with Qnexa can be uplifting and greatly improve quality of life in an obese patient (3). In contrast we have no way of knowing what an increase of average heart rate by 1.5 bpm as was also seen with Qnexa will engender in terms of life expectancy. Heart rate does not always inversely correlate with cardiovascular morbidity and mortality and just as are other surrogates, may be prone to failure. (4). Unfortunately the meager outcome data in the NDA of Qnexa with only 12 outcome events do not allow us to establish a clear risk benefit ratio. Thus as Dr. Lauer appropriately states, we are at this juncture not sure whether we are dealing with a peach or a lemon. Given such uncertainty we should perhaps err on the cautious side and remember Hemingway's dictum on the heart (5): "It is just a muscle. Only it is the main muscle. It works as perfectly as a Rolex Oyster Perpetual. The trouble is you cannot send it to the Rolex representative when it goes wrong. When it stops, you just don't know the time. You're dead". Drs. Messerli, Bangalore and Uretsky report no potential conflicts of interest. References 1. Lauer MS. Lemons for obesity. Ann Intern Med. 2012 Jul 17;157(2):139-40. 2. Uretsky S, Messerli FH, Bangalore S, Champion A, Cooper-Dehoff RM, Zhou Q, Pepine CJ. Obesity paradox in patients with hypertension and coronary artery disease. Am J Med. 2007 Oct;120(10):863-70. 3. Imayama I, Alfano CM, Kong A, Foster-Schubert KE, Bain CE, Xiao L, Duggan C, Wang CY, Campbell KL, Blackburn GL, McTiernan A. Dietary weight loss and exercise interventions effects on quality of life in overweight/obese postmenopausal women: a randomized controlled trial. Int J Behav Nutr Phys Act. 2011 Oct 25;8:118. 4. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker-induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol. 2008 Oct 28;52(18):1482-9. 5. Hemingway, Ernest. Across the River and Into the Trees. Charles Scribner's Sons. September 1950. Enrique J., Sanchez-Delgado, Director of Medical EducationHospital Metropolitano Vivian Pellas, Managua, Nicaragua18 April 2012 How to identify cardiovascular risk with obesity drugs before events How to identify cardiovascular risk with obesity drugs before eventsThe lesson has been clear with anterior cases of drugs for obesity. If they reduce weight, but produce increases in resting heart rate and/or blood pressure, or produce important cognitive or mood disorders, and more important, if the balance of the PULSE MASS INDEX or the PULSE MASS PRESSURE PRODUCT is not reduced, the continuation of their use should be discouraged.In the case of rimonabant, I sent a letter to Lancet mentioning the reasons why it should be discontinued, one year before the EMA decided to take it out from the market (the letter was not published then, but latter in the BMJ).If the Body Mass Index and the Resting Heart Rate, are elevated (the PULSE MASS INDEX), the probability to have a high risk in the Framingham Risk Score, or elevated risk of mortality, is very high (1).Measure the PULSE MASS PRESSURE PRODUCT (Body Mass Index by Resting Heart Rate by Systolic Blood Pressure). If over 200000 pay attention, if over 240000, the probability of a high cardiovascular risk is clearly elevated and the obesity drug, Qnexa or any other, will probably produce a higher incidence of cardiovascular events.In this context, the use of weekly injections of exenatide in obese diabetic or pre-diabetic patients looks promising.Prof. Enrique Sanchez-Delgado, MD Internal Medicine- Clinical Pharmacology Hospital Metropolitano Vivian Pellas Managua, NicaraguaRef. 1. E. Sanchez-Delgado. Lancet.Volume 353, Number 9156,13 March 1999Conflict of Interest:None declared dhastagir, sheriff d, professor of biochemistryfaculty of Medicine. Benghazi University, Benghazi10 April 2012 Apples for obesity will be better than Lemons An apple a day keeps a doctor away is one saying followed by an aspirin a day keep the coronary artery disease away. Now the need for drugs for obesity control push drug manufacturers and scientists look for a drug that will help obesity prevention. Daedalus effect that every clinical decision carries a risk associated with it. This is true for every clinical situation or therapy. Prudence must prevail over irrational need or corporate culture.ds sheriffConflict of Interest:None declared Author, Article, and Disclosure InformationAuthors: Michael S. Lauer, MDAffiliations: From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland.Disclaimer: The views expressed here are those of the author and do not necessarily reflect the views of the National Heart, Lung, and Blood Institute or of the Patient-Centered Outcomes Research Institute.Disclosures: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0689.Corresponding Author: Michael S. Lauer, MD, 6701 Rockledge Drive, Room 8128, Bethesda, MD 20892; e-mail, lauerm@nhlbi.nih.gov. Author Contributions: Conception and design: M.S. Lauer.Drafting of the article: M.S. Lauer.Critical revision of the article for important intellectual content: M.S. Lauer.Final approval of the article: M.S. Lauer.Obtaining of funding: M.S. Lauer.Administrative, technical, or logistic support: M.S. Lauer.This article was published at www.annals.org on 10 April 2012. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe role of fibroblast growth factor 21 in diabetes and its complications: A review from clinical perspectiveCosa c'è all'orizzonte della farmacologia dell'obesitàTime series analyses of the effect of FDA communications on use of prescription weight loss medicationsScientific integrity and the market for lemonsA long journey to effective obesity treatments: is there light at the end of the tunnel? 17 July 2012Volume 157, Issue 2Page: 139-140KeywordsClinical trialsDrugsFood and Drug AdministrationHeartHeart rateMyocardial infarctionObesityOverweightSafetyWeight loss ePublished: 17 July 2012 Issue Published: 17 July 2012 PDF downloadLoading ...