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Next Gen Weight-loss Drugs and CV Risk

Next Gen Weight-loss Drugs and CV Risk

  • Safety concerns have historically overshadowed the benefits of weight loss drugs.
  • Majority of weight-loss drugs have been withdrawn from market, failed to received regulatory approval based on public safety concerns (CV, CNS, psychological effects) Lifestyle modification can result in ↓ 2.0-3.0 kg over 36 months; newer weight loss drugs often can bring about ↓ 3.0-9.0 kg. (1) Newer drugs showing some promise; have shown beneficial effects on some cardiometabolic parameters (total cholesterol, HDL, LDL, TGs, BP) in clinical trials. 2012 FDA mandate: Obesity drugs must be tested for CV safety whether or not risk is deemed likely or was apparent in early testing. CNS modifiers, fat absorption modifiders, gut hormone analogs are showing some promise.
  • Phentermine-topiramate (Qsymia)(2) Suppresses appetite via amphetamine effects; topiramate, anti-epileptic; mechanism for weight control unclear. FDA approved: 2012, not yet approved in Canada, Europe. Serious risks include cognitive deficits, metabolic acidosis, birth defects. Cardiac: clinical trials suggest ↑ HR; Endocrine Society—do not use in patients with Hx of heart disease, ucontrolled HTN. (3) Aqclaim cardiac safety trial ongoing.
  • Lorcaserin (Belviq) (2) CNS modifier. Selective serotonin 2c (5ht-2c) receptor activator, suppresses appetite. FDA approved: 2012, Canadian approval pending; EMA denied based on ↑ cancers, potential risk for valvular disease in rodents (not seen in human studies to date). Cardiac: Endocrine Society—lorcaserin OK in patients with Hx of heart disease vs sympathomimetics.(3) Camellia cardiac safety trial ongoing.
  • Naltrexone-bupropion (Contrave) (2) CNS modifier. Bupropion stimulates POMC neurons, naltrexone inhibits the opioid-mediated area of the POMC system, and both medications may affect the dopamine reward system. FDA approved: 2014. Possible increased risk of neuropsychiatric events, seizures. Cardiac: Contrave linked to ↑ HR vs placebo; Endocrine Society—do not use as first line in patients with cardiac dysfunction. (3) Light Study cardiovascular safety trial is underway.
  • Orlistat (Xenical, Alli [OTC]) Fat-absorption inhibitor. Pancreatic lipase inhibitor, decreases fat absorption. 90% of patients discontinue orlistat after ≥1 years for GI side effects, malabsorption of fat soluble vitamins. Total cholesterol, LDL, systolic and diastolic BP shown to improve with long-term use, but no hard endpoint CV outcomes available. The American Heart Association, American College of Cardiology, Endocrine Society, Canadian Diabetes Association: orlistat can be used to optimize blood glucose control and manage weight in patients with and without diabetes. (3-5)
  • Liraglutide (Saxenda) Gut hormone analog. GLP-1 receptor agonist, increases insulin sensitivity, suppresses appetite, delays gastric emptying. FDA, EMA, Health Canada approved: T2DM in 2009-2010. FDA, Health Canada approved: obesity 2015. Cardiometabolic: Consistent demonstration of cardioprotective effects in lower doses (1.2/1.8 mg); long-term cardiometabolic safety data at 3.0 mg not available. LEADER cardiac safety trial ongoing.
  • Take Home Points Public safety concerns about weight loss drugs have hindered their use, but newer drugs may result in greater weight loss than standard lifestyle modification Consider non-sympathomimetic agents like lorcaserin or orlistat for patients with a history of cardiovascular dysfunction or uncontrolled hypertension Consider GLP-1 agonist liraglutide as first-line in patients with diabetes; patients with both diabetes and CVD might also do well Overall there is little long-term safety data on MACE and mortality of newer generation weight loss medications; cardiac safety trials are ongoing

The anti-obesity drug graveyard holds headstones etched with familiar old names including Fen-Phen, aminorex, rimonabant, ephedrine, sibutramine, phenylpropanolamine, and more. Pulmonary hypertension, valvular heart disease, strokes, depression, and suicide are just some of the side effects that forced the withdrawal of all of them from US and European markets.

It’s this legacy that weight-loss drug wannabes must overcome to win approval today.

Have a look (in 8 slides) at which drugs have made it and how their CV risks compare.


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1. Hainer V1, Hainerová IA. Do we need anti-obesity drugs? Diabetes Metab Res Rev. 2012;Suppl 2:8-20. doi: 10.1002/dmrr.2349.

2. Wharton S, Serodio KJ. Next generation of weight management medications: implications for diabetes and CVD risk. Curr Cardiol Rep. 2015;17:35. doi: 10.1007/s11886-015-0590-z.

3. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342-62. doi: 10.1210/jc.2014-3415. Epub 2015 Jan 15.

4. Ransom T, Goldenberg R, Mikalachki A, et al. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Reducing the risk of developing diabetes. Can J Diabetes. 2013;37 Suppl 1:S16-9. doi: 10.1016/j.jcjd.2013.01.013. Epub 2013 Mar 26.

5. Jensen MD, Ryan DH, Apovian CM, Ard JD, 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;(25 Suppl 2):S102-38. doi: 10.1161/ Epub 2013 Nov 12.


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