Abstract
The management of obesity remains a major challenge. Dietary therapy often fails,
whereas bariatric surgery, although successful, is demanding and applicable to a limited
number of patients. Drug therapy has had many setbacks over the past 20 years because
of serious adverse effects; however, several new drugs for the treatment of obesity
are either licensed in some parts of the world, submitted for registration, or completing
phase III trials. These include combinations (at low dose) of existing drugs, eg,
bupropion + naltrexone (Contrave), phentermine + topiramate (Qsymia), higher doses
of existing drugs licensed for other indications (liraglutide, 3 mg), and new entities
(lorcaserin).
We discuss the challenges and opportunities for obesity pharmacotherapy and review
in detail the efficacy of the new drugs regarding weight loss and both desirable and
potential undesirable cardiovascular (CV) and metabolic risk factors. Substantial
barriers remain, even if the drugs are approved, in successfully integrating these
agents into weight management practice, largely related to cost, patient acceptability,
and clinician willingness to be engaged in obesity treatment. Although hard clinical
outcome benefit (at least for CV outcomes) has yet to be established, obesity pharmacotherapy
may soon address many of the challenges in the clinical management of obesity, although
newer and better drug combinations and more evidence of benefit from appropriately
designed outcome trials is needed.
Résumé
La prise en charge de l’obésité demeure un enjeu majeur. La thérapie nutritionnelle
échoue souvent, tandis que la chirurgie bariatrique, malgré son succès, est exigeante
et praticable que chez un nombre limité de patients. La pharmacothérapie a subi plusieurs
revers au cours des 20 dernières années en raison d’effets indésirables sérieux. Cependant,
plusieurs nouveaux médicaments pour le traitement de l’obésité sont soit homologués
dans certaines parties du monde, soit soumis à l’homologation ou en cours d’achèvement
d’essais cliniques de phase III. De ce nombre, citons les combinaisons (à faible dose)
de médicaments existants, par exemple le bupropione + la naltrexone (Contrave), la
phentermine + le topiramate (Qsymia), des doses plus élevées de médicaments existants
homologués pour d’autres indications (le liraglutide, 3 mg) et de nouvelles substances
(la lorcasérine).
Nous discutons des enjeux et des possibilités de la pharmacothérapie contre l’obésité
et passons minutieusement en revue l’efficacité des nouveaux médicaments quant à la
perte de poids, aux facteurs de risque cardiovasculaire (CV) et métabolique désirables
et indésirables potentiels. Même si les médicaments sont approuvés, il reste d’importants
obstacles à surmonter pour réussir l’intégration de ces agents à la pratique pour
la prise en charge du poids, en grande partie liés au coût, à l’acceptabilité des
patients et à la bonne volonté du clinicien de s’impliquer dans le traitement de l’obésité.
Bien que les avantages tangibles des résultats cliniques (du moins en ce qui concerne
les résultats CV) n’aient pas encore été établis, la pharmacothérapie contre l’obésité
pourra bientôt relever les nombreux défis de la prise en charge clinique de l’obésité.
Cependant, de plus récentes et de meilleures combinaisons de médicaments et plus de
données probantes sur les avantages provenant d’essais cliniques bien conçus sont
nécessaires.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2014; 384: 766-781
- Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies.Lancet. 2009; 373: 1083-1096
- A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2224-2260
- Lifelong patterns of BMI and cardiovascular phenotype in individuals aged 60-64 years in the 1946 British birth cohort study: an epidemiological study.Lancet Diabetes Endocrinol. 2014; 2: 648-654
- The disproportionate economic burden associated with severe and complicated obesity: a systematic review.Obes Rev. 2013; 14: 883-894
- Low-calorie diets and sustained weight loss.Obes Res. 2001; 9: 290S-294S
- Feasibility and indicative results from a 12-month low-energy liquid diet treatment and maintenance programme for severe obesity.Br J Gen Pract. 2013; 63: e115-e124
- The clinical effectiveness and cost-effectiveness of long-term weight management schemes for adults: a systematic review.Health Technol Assess. 2011; 15: 1-182
- Very-low-calorie diets and sustained weight loss.Obes Res. 2001; 9: 295S-301S
- Long-term weight-loss maintenance: a meta-analysis of US studies.Am J Clin Nutr. 2001; 74: 579-584
- Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study.Lancet Diabetes Endocrinol. 2014; 2: 474-480
- Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment.Diabetes Care. 2013; 36: 2175-2182
- Effects of bariatric surgery on mortality in Swedish obese subjects.N Engl J Med. 2007; 357: 741-752
- Bariatric surgery and long-term cardiovascular events.JAMA. 2012; 307: 56-65
- Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials.BMJ. 2013; 347: f5934
- First report from the American College of Surgeons Bariatric Surgery Center Network: laparoscopic sleeve gastrectomy has morbidity and effectiveness positioned between the band and the bypass.Ann Surg. 2011; 254 (discussion 20-2): 410-420
- Weight recidivism post-bariatric surgery: a systematic review.Obes Surg. 2013; 23: 1922-1933
- 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children.CMAJ. 2007; 176: S1-13
- The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery.Diabetes Care. 2010; 33: 1438-1442
- Impact of weight-loss medications on the cardiovascular system: focus on current and future anti-obesity drugs.Am J Cardiovasc Drugs. 2007; 7: 273-288
- Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.N Engl J Med. 2013; 369: 145-154
- Expectations for weight loss and willingness to accept risk among patients seeking weight loss surgery.JAMA Surg. 2013; 148: 264-271
- The role of patients' expectations and goals in the behavioral and pharmacological treatment of obesity.Int J Obes (Lond). 2007; 31: 1739-1745
- Willingness to pay for obesity pharmacotherapy.Obesity (Silver Spring). 2012; 20: 2019-2026
Brown A, Brown I. Patients’ experiences of prescribed anti-obesity drugs and perceptions of support from primary care: a qualitative study. Available at: http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=7831300&fileId=S1463423610000083. Accessed July 7, 2014.
- Effectiveness of interventions for reducing diabetes and cardiovascular disease risk in people with metabolic syndrome: systematic review and mixed treatment comparison meta-analysis.Diabetes Obes Metab. 2012; 14: 616-625
European Medicines Agency. Committee For Medicinal Products For Human Use (CHMP). Guideline on clinical evaluation of medicinal products used in weight control, November 2007. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003264.pdf. Accessed September 3, 2014.
- Food and Drug Administration's obesity drug guidance document: a short history.Circulation. 2012; 125: 2156-2164
- Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects.N Engl J Med. 2010; 363: 905-917
- Effect of bypassing the proximal gut on gut hormones involved with glycemic control and weight loss.Surg Obes Relat Dis. 2012; 8: 371-374
- Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial.Diabetes Obes Metab. 2012; 14: 523-530
- Changes in body weight and blood pressure: paradoxical outcome events in overweight and obese subjects with cardiovascular disease.Int J Obes (Lond). 2014; 38: 1165-1171
- Anti-obesity drugs: past, present and future.Dis Model Mech. 2012; 5: 621-626
- Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass.Diabetologia. 2012; 55: 1890-1901
- Use of prescription antiobesity drugs in the United States.Pharmacotherapy. 2013; 33: 1299-1307
- Comparison of metabolic effects of surgical-induced massive weight loss in patients with long-term remission versus non-remission of type 2 diabetes.Obes Surg. 2012; 22: 910-917
- Obesity in Europe—does anybody care?.Expert Opin Pharmacother. 2013; 14: 971-973
- Systematic review: an evaluation of major commercial weight loss programs in the United States.Ann Intern Med. 2005; 142: 56-66
- Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice.Int J Obes (Lond). 2005; 29: 1153-1167
- Long-term drug treatment for obesity: a systematic and clinical review.JAMA. 2014; 311: 74-86
- Predictors of attrition in bariatric aftercare: a systematic review of the literature.Obes Surg. 2012; 22: 1640-1647
- “Obesity is a disease”: examining the self-regulatory impact of this public-health message.Psychol Sci. 2014; 25: 997-1002
- Early weight loss while on lorcaserin, diet, and exercise as a predictor of week 52 weight-loss outcomes.Obesity (Silver Spring). 2014; 22: 2137-2146
- Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect.J Clin Invest. 2014; 124: 2456-2463
- The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. III: the mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion.Psychopharmacology (Berl). 1995; 121: 364-372
- Multicenter, placebo-controlled trial of lorcaserin for weight management.N Engl J Med. 2010; 363: 245-256
- 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
- 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
- XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.Diabetes Care. 2004; 27: 155-161
- Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP).Obesity (Silver Spring). 2012; 20: 330-342
- 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: 1341-1352
- Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2010; 376: 595-605
- A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II).Obesity (Silver Spring). 2013; 21: 935-943
- Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial.Obesity (Silver Spring). 2011; 19: 110-120
- Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes.Diabetes Care. 2013; 36: 4022-4029
- Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.Int J Obes (Lond). 2012; 36: 843-854
- Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomized study.Int J Obes (Lond). 2013; 37: 1443-1451
Novo Nordisk. Press release. Phase 3a data from largest trial with liraglutide 3 mg demonstrated significantly greater weight loss versus placebo for adults with obesity. Available at: http://www.novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=20525a92-b397-4b81-866d-42aae458100f. Accessed July 29, 2014.
- Efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled trials (RCTs) and narrative review on short-term RCTs.Obes Rev. 2013; 14: 383-392
Novo Nordisk. Press release. New phase 3a liraglutide 3 mg data showed positive impact on cardiovascular risk markers and fewer people progressing to prediabetes compared with placebo in adults with obesity. Available at: http://www.novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=7bfc8e14-21ef-4104-8782-a106be319479. Accessed July 29, 2014.
- Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials.Circ Cardiovasc Imaging. 2013; 6: 560-567
- Eating behavior and glucagon-like peptide-1-producing cells in interposed ileum and pancreatic islets in rats subjected to ileal interposition associated with sleeve gastrectomy.Obes Surg. 2013; 23: 39-49
- How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number.Surgery. 2007; 142: 74-85
- Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.Synapse. 2001; 39: 32-41
- Pharmacologic treatment options for obesity: what is old is new again.Curr Hypertens Rep. 2013; 15: 182-189
- Topiramate: a new potential pharmacological treatment for obesity.Obes Res. 2004; 12: 167S-173S
- Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors.Prog Retin Eye Res. 2000; 19: 87-112
- GABA(A) receptors in the lateral hypothalamus as mediators of satiety and body weight regulation.Brain Res. 2009; 1262: 16-24
- Topiramate: long-term maintenance of weight loss induced by a low-calorie diet in obese subjects.Obes Res. 2004; 12: 1658-1669
- Topiramate: effects on cognition in patients with epilepsy, migraine headache and obesity.Ther Adv Neurol Disord. 2013; 6: 211-227
- Neuropsychiatric adverse effects of centrally acting antiobesity drugs.CNS Neurosci Ther. 2011; 17: 490-505
- 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
- The Learn Program for Weight Management.American Health Publishing Co, Euless, TX2000
- Cardiovascular safety of phentermine alone. Cardiovascular safety of phentermine alone and in combination with topiramate.Obesity Facts. 2012; 5: 204
- Effects of phentermine and extended-release topiramate alone and in combination on cardiovascular risk factors. Poster 697.Diabetalogia. 2012; 55: S285
- Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity.J Hypertens. 2014; 32: 1178-1188
- Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance.Am J Physiol Endocrinol Metabl. 2012; 303: E122-E131
- Weight loss and cardiovascular risk reduction over 2 years with controlled-release phentermine- topiramate.J Am Coll Cardiol. 2011; 57: E545
- Efficacy of bupropion and predictors of successful outcome in a sample of French smokers: a randomized placebo-controlled trial.Addiction. 2004; 99: 1206-1218
- Bupropion treatment of olanzapine-associated weight gain: an open-label, prospective trial.J Clin Psychopharmacol. 2006; 26: 409-413
- Bupropion SR enhances weight loss: a 48-week double-blind, placebo- controlled trial.Obes Res. 2002; 10: 633-641
- A controlled trial of naltrexone in obese humans.Int J Obes (Lond). 1985; 9: 347-353
- Effect of naltrexone on senile dementia of the Alzheimer type.J Neurol Neurosurg Psychiatry. 1985; 48: 1169-1171
- Rational design of a combination medication for the treatment of obesity.Obesity (Silver Spring). 2009; 17: 30-39
Orexigen. Press release. Orexigen announces successful interim analysis of Contrave light study. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1879629&highlight. Accessed July 21, 2014.
- Incretin-based therapies for type 2 diabetes mellitus.Nat Rev Endocrinol. 2009; 5: 262-269
- Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.BMJ. 2012; 344: d7771
- Incretin hormones and the satiation signal.Int J Obes (Lond). 2013; 37: 1161-1168
- Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase.Drug Metab Dispos. 2010; 38: 1944-1953
- Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.Lancet. 2009; 374: 1606-1616
- First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery.Diabetes Care. 2009; 32: 375-380
- Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes.Diabetes Care. 2013; 36: 3276-3282
- Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial.Am Heart J. 2013; 166: 823-830.e5
- Tolerability of nausea and vomiting, and associations with weight loss, in a randomized trial of liraglutide in obese, non-diabetic adults.Int J Obes (Lond). 2013; 38: 689-697
- Cardiovascular biology of the incretin system.Endocr Rev. 2012; 33: 187-215
- A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe?.Diabetes Care. 2013; 36: 2118-2125
- Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?.BMJ. 2013; 346: f3680
- Vagal nerve dissection during pouch formation in laparoscopic Roux-Y-gastric bypass for technical simplification: does it matter?.Obes Surg. 2009; 19: 412-417
Article Info
Publication History
Published online: November 13, 2014
Accepted:
November 3,
2014
Received:
August 1,
2014
Footnotes
See page 149 for disclosure information.
Identification
Copyright
© 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
