A major study has found promising results for the safety of a weight-loss drug available online in the UK.
It says the drug, which works by suppressing appetite, does not put people at greater risk of heart issues.
But experts emphasise the importance of long-term lifestyle changes in achieving effective weight loss.
Lorcaserin has been available online in the US for several years under the name Belviq, but it has yet to be approved for use in Europe.
A weight-loss pill has been hailed as a potential “holy grail” in the fight against obesity after a major study showed it did not increase the risk of serious heart problems.
Researchers say lorcaserin is the first weight-loss drug to be deemed safe for heart health with long-term use. Taken twice a day, the drug is an appetite suppressant which works by stimulating brain chemicals to induce a feeling of fullness.
A US study saw 12,000 people who were either obese or overweight given the pills or a placebo – with those who took the drug shedding an average of 4kg (9lbs) in 40 months.
Further analysis showed no big differences in tests for heart valve damage.
Tam Fry, of Britain’s National Obesity Forum, said the drug is potentially the “holy grail” of weight-loss medicine.
“I think it is the thing everybody has been looking for,” he said.
“I think there will be several holy grails, but this is a holy grail and one which has been certainly at the back of the mind of a lot of specialists for a long time.
“But all of the other things apply – lifestyle change has got to be root and branch part of this.”
Prof Jason Halford, an obesity expert at the University of Liverpool, told the Daily Telegraph newspaper that the drug’s availability in the UK would depend on whether it is approved by National Health Service regulators.
“We don’t have any appetite suppressants available on the NHS. We have a massive great gap between lifestyle modification and surgery,” he said.
“At the moment you either get support and advice, or you get to surgery – there is nothing in between. This could be widely prescribed if it is approved by Nice (the National Institute of Health and Care Excellence) in the UK.”
The Food and Drug Administration, the US medicines watchdog, approved lorcaserin’s use in some adults in 2012.
The drug has been on sale there since 2013 under the name Belviq, where it costs $220- 290 (£155-225) a month.
The study into its long-term effects was led by Dr Erin Bohula, a cardiovascular medicine expert at the Harvard-affiliated Brigham and Women’s Hospital.
“Patients and their doctors have been nervous about using drugs to treat obesity and for good reason. There’s a history of these drugs having serious complications,” she said.
As well as affecting the heart, there are concerns weight-loss drugs can lead to mental health issues.
The results of the study into lorcaserin were discussed at the European Society of Cardiology in Munich on Sunday and have been published by the New England Journal of Medicine.
The researchers found after one year 39% of participants given lorcaserin had lost at least 5% of their starting weight, compared with 17% of those given placebo. Analysis also showed fewer people taking lorcaserin developed diabetes, 8.5% compared with 10.3% on placebo.
Tests for heart valve damage were done on 3,270 participants, but no significant differences in rates were identified.
Suicidal thoughts or behaviour were reported in 21 people taking lorcaserin compared with 11 people given placebo, however those taking the weight-loss drug had a history of depression.
The researchers said: “Among overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors who were being treated with dietary and exercise interventions, those who received lorcaserin had better long-term rates of weight loss than those who received placebo at a median follow-up of 3.3 years.
“The higher weight-loss rates were achieved without an accompanying increase in the risk of cardiovascular events.”
Weight-Loss Drug Lorcaserin Clears Cardiovascular Safety Hurdle: CAMELLIA-TIMI 61
Whether the data are enough to change hearts and minds of doctors willing to prescribe the drug for modest weight loss is another question, however.
MUNICH, Germany—A drug already approved in the United States for weight loss in overweight and obese patients does not increase the risk of cardiovascular events, according to the results of a large safety study.
Importantly, in a subset of patients who underwent echocardiographic follow-up, CAMELLIA-TIMI 61 investigators did not observe any of the valve problems that have plagued anti-obesity agents in the past.
“The history with weight-loss agents has been very challenging,” lead investigator Erin Bohula, MD, DPhil (Brigham and Women’s Hospital, Boston, MA). “There have been a number approved for use and then found to have major safety signals and removed. And obesity is clearly a global problem—the rates overall have tripled in the last 40 years. In the US, for example, obesity rates are around 40% so it is a major problem. This is the first time in a rigorous outcomes study we’ve been able to document cardiovascular safety, and for that reason I think it is a milestone and it’s important for patients and providers.”
Presenting the results during a press conference at the European Society of Cardiology Congress 2018, Bohula said lifestyle modification remains the cornerstone of weight-loss therapy for all patients, but adherence is challenging. Having a safe pharmacologic agent is useful and a “step forward” in the field, she said.
Lorcaserin (Belviq, Eisai/Arena Pharmaceuticals), a selective agonist of 5-hydroxytryptamine 2C serotonin receptor (5-HT2C) that modulates appetite, was approved by the US Food and Drug Administration (FDA) in 2012 as an adjunct to a calorie-reduced diet and increased physical activity for weight management. In several trials to date—BLOSSOM, BLOOM, and BLOOM-Diabetes Mellitus—treatment with lorcaserin resulted in better sustained weight loss compared with placebo.
However, given the history of weight-loss drugs, particularly first-generation antiobesity agents such as dexfenfluramine and fenfluramine that increased the risk of pulmonary hypertension and valve problems, determining the long-term safety of lorcaserin was critical, according to investigators.
Other weight-loss agents have faced setbacks, too. Rimonabant was safe from a cardiovascular perspective, but was pulled from several markets, including Europe, because of serious neuropsychiatric side effects (it was never approved in the US), while a cardiovascular safety study testing a naltrexone/bupropion combination (Contrave, Takeda Pharmaceuticals), broke down over leaked interim results, although the drug remains on the market.
Modest Weight Loss With Lorcaserin
In the CAMELLIA-TIMI 61 study, which was presented as a late-breaking clinical trial and published August 26, 2018, in the New England Journal of Medicine, investigators randomized 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to treatment with lorcaserin or placebo. Among the treated patients, 75% had established cardiovascular disease, 68% had coronary artery disease, and 40% had a prior MI. Additionally, 57% had diabetes mellitus, and nearly one-third were diagnosed with prediabetes.
The median weight and body mass index of the treated patients was 102 kg (224 lbs) and 35 kg/m2, respectively. After 1 year, weight loss in the lorcaserin- and placebo-treatment groups was 4.2 and 1.4 kg, respectively (P < 0.001). Overall, 38.7% and 14.6% of the lorcaserin-treated patients achieved a weight loss of at least 5% and 10% of their body weight, respectively, compared with 17.4% and 4.8% of patients in the placebo group, (P < 0.001 for both).
After 3.3 years of follow-up, major cardiovascular events—defined as cardiovascular death, MI, or stroke—occurred in 6.1% of the lorcaserin-treated patients and 6.2% of patients treated with placebo (HR 0.99; 95% CI 0.85-1.14). In an extended analysis of major cardiovascular events to include heart failure, unstable angina, or coronary revascularization, there was also no significant difference between the two treatment groups. Patients treated with lorcaserin were more likely to discontinue treatment, mainly because of headaches and nausea. There was no signal of cancer or serious neuropsychiatric side effects.
As part of the trial, investigators conducted an echocardiographic substudy in 3,270 patients to assess new or worsening FDA-defined valvulopathy at 1 year. Overall, there was no difference between the two study arms (1.8% with lorcaserin vs 1.3% in the placebo group; P = 0.24). None of the patients with valvulopathy were hospitalized or required treatment. The change in pulmonary artery systolic blood pressure at 1 year was also similar between the two groups.
To TCTMD, Bohula said that none of the 30 patients who developed valvulopathy in the study period with lorcaserin had symptoms or required valve repair or replacement. Moreover, the numerical increase in the lorcaserin arm was largely attributable to new-onset, mild aortic insufficiency. When compared with historical experience, Bohula said the development of symptomatic valve problems with prior agents typically occurred in the first year of treatment.
“At least the severity of what we’re seeing does not seem to correspond with what we’ve seen with the prior agents,” said Bohula.
Although the results are reassuring, Stephan Achenbach, MD (University of Erlangen, Germany), who chaired the press conference, said physicians have been burned by weight-loss agents in the past. Physicians don’t even know the details of the older trials, but the image of damaged valves is firmly lodged in their memory. “We’re so scared of the old drugs and valve damage,” he told TCTMD. “That’s what we all have in our minds. . . . So this is a relief. This is a drug that is safe.”
Kurt Huber, MD (Sigmund Freud University Medical School, Vienna, Austria), who was not involved in the study, also said the results are reassuring, but questioned whether the follow-up is sufficient to identify long-term side effects, particularly valve-related problems. “It’s safe for a bit more than 3 years,” he told TCTMD, “but what happens when we double the length of treatment?”
In an editorial, Julie Ingelfinger, MD, and Clifford Rosen, MD (Tufts University School of Medicine, Boston, MA), state that lorcaserin may be best used on a cautious basis according to the needs of individual patients. They advise continued follow-up, particularly since the drug is likely to be used for many years to maintain weight loss.
Potential Clinical Experiences
Speaking with the media, Bohula acknowledged that weight loss with lorcaserin is limited, especially when compared with bariatric surgery. In the first year, the between-group weight-loss difference was just 2.8 kg, but it was sustained during the 3.3 years follow-up. Trials to date with other weight-loss agents have only followed patients for 1 to 2 years, she said.
“It is modest, but it is something on top of diet and lifestyle, and it’s sustainable,” said Bohula. “And that’s the challenge—very often diet and lifestyle is not sustainable. We usually see some nadir in weight at 6 months and then people tend to regain [weight], and possibly regain [more] from where they started out. So something that helps maintain that weight loss for a longer period of time is something that moves the needle.”
To TCTMD, Huber cautioned that the modest weight loss was largely observed in the first year and the clinical significance of the change is unknown. “The drug supports things, but it doesn’t really help to lose weight in the range that is necessary,” said Huber. Lifestyle, he suggested, really needs to be altered for significant weight loss so a drug that helps patients lose weight in the first year could help patients get more active to make more sustained long-term changes. “Whether you should take it for a very long time is another question,” he said.
For Achenbach, it was slightly disappointing that treatment with lorcaserin didn’t lower the risk of cardiovascular events given the weight loss. “Is this a cosmetic drug now? It makes you thinner, but it doesn’t lower your risk of heart attack,” he commented to TCTMD. “Maybe we need to wait longer? Maybe the positive cardiovascular effects won’t occur in 3 years, but maybe they’ll take 5 or 10 years before they occur.”
Based on CAMELLIA-TIMI 61, Achenbach said he is comfortable enough with the safety data to keep a patient on lorcaserin if they were taking it, but he wouldn’t start a patient on the drug given the modest weight loss and absence of cardiovascular benefit. In addition to weight loss, Bohula noted there were improvements in systolic blood pressure, heart rate, and a 19% reduction in new-onset diabetes. The full metabolic data will be presented next month at the European Association for the Study of Diabetes (EASD) meeting in Berlin, Germany.
In the United States, weight-loss agents, including lorcaserin, are used infrequently, largely stemming from the poor safety profiles and/or lack of data. Without evidence of safety, physicians are reluctant to prescribe the drugs—they know the history and it scares them, said Bohula—and patients are reluctant to take them.
“I think these are important findings, where we can now confidently say that [lorcaserin] is safe in terms of major adverse cardiovascular events,” said Bohula. “I suspect there might be physicians and patients who are more inclined to use this pharmacologic agent going forward.”
- Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcasersin in overweight or obese patients . N Engl J Med. 2018
- Ingelfinger JR, Rosen CJ. Lorcaserin—elixir or liability. N Engl J Med. 2019;
- Obesity and overweight fact sheet. Geneva: World Health Organization, 2016(http://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight). Google Scholar
- Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016. JAMA 2018;319:1723–1725.
- The GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13–27. Web of Science / Medline / Google Scholar
- Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013;309:71–82. Crossref / Web of Science / Medline / Google Scholar
- Bray GA, Heisel WE, Afshin A, et al. The science of obesity management: an Endocrine Society scientific statement. Endocr Rev 2018; 39:79–132. Crossref / Medline / Google Scholar
- Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society. Circulation 2014;129:Suppl 2:S102–S138. Crossref / Web of Science / Medline / Google Scholar
- Garvey WT, Garber AJ, Mechanick JI, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract 2014;20:977–989. Crossref / Medline / Google Scholar
- Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997;337:581–588. Full Text / Web of Science / Medline / Google Scholar
- James WPT, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010;363:905–917. Full Text / Web of Science / Medline / Google Scholar
- Topol EJ, Bousser MG, Fox KA, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 2010;376:517–523. Crossref / Medline / Google Scholar
- Brashier DB, Sharma AK, Dahiya N, Singh SK, Khadka A. Lorcaserin: a novel antiobesity drug. J Pharmacol Pharmacother 2014;5:175–178. Crossref / Medline / Google Scholar
- Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245–256. Full Text / Web of Science / Medline / Google Scholar
- Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 2011;96:3067–3077. Crossref / Medline / Google Scholar
- O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 2012;20:1426–1436. Crossref / Web of Science / Medline / Google Scholar
- Bohula EA, Scirica BM, Fanola C, et al. Design and rationale for the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial. Am Heart J 2018;202:39–48. Crossref / Medline / Google Scholar
- Leblanc ES, O’Connor E, Whitlock EP, Patnode CD, Kapka T. Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155:434–447. Crossref / Medline / Google Scholar
- Hiatt WR, Thomas A, Goldfine AB. What cost weight loss? Circulation 2012;125:1171–1177. Crossref / Medline / Google Scholar
- Nissen SE, Wolski KE, Prcela L, et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA 2016;315:990–1004. Crossref / Medline / Google Scholar
- Vorsanger MH, Subramanyam P, Weintraub HS, et al. Cardiovascular effects of the new weight loss agents. J Am Coll Cardiol 2016;68:849–859. Crossref / Medline / Google Scholar
- Jordan J, Astrup A, Engeli S, Narkiewicz K, Day WW, Finer N. Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity. J Hypertens 2014;32:1178–1188. Crossref / Medline / Google Scholar
- Sjöström L, Narbro K, Sjöström CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741–752. Full Text / Web of Science / Medline / Google Scholar
- Guidance for industry: developing products for weight management. Rockville, MD: Food and Drug Administration, 2007 (https://www.fda.gov/downloads/Drugs/Guidances/ucm071612.pdf / ). Google Scholar
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322. Full Text / Web of Science / Medline / Google Scholar
- Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56–65. Crossref / Web of Science / Medline / Google Scholar
- Sundström J, Bruze G, Ottosson J, Marcus C, Näslund I, Neovius M. Weight loss and heart failure: a nationwide study of gastric bypass surgery versus intensive lifestyle treatment. Circulation 2017;135:1577–1585. Crossref / Medline / Google Scholar
- Zhou X, Yu J, Li L, et al. Effects of bariatric surgery on mortality, cardiovascular events, and cancer outcomes in obese patients: systematic review and meta-analysis. Obes Surg 2016;26:2590–2601. Crossref / Medline / Google Scholar
- The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154. Web of Science / Medline / Google Scholar
- Meltzer HY, Roth BL. Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype-targeted drugs. J Clin Invest 2013;123:4986–4991. Crossref / Medline / Google Scholar
- Thomsen WJ, Grottick AJ, Menzaghi F, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 2008;325:577–587. Crossref / Web of Science / Medline / Google Scholar
- Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016. JAMA 2018;319:1723–1725. Crossref