Applied Evidence

Obesity: When to consider medication

J Fam Pract. 2017 October;66(10):608-616

From The Journal of Family Practice | 2017;66(10):608-616.

References

1. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481-1486.

2. Magkos F, Fraterrigo G, Yoshino J. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23:591-601.

3. 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. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023.

4. Sumithran P, Predergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365:1597-1604.

5. Greenway FL. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond). 2015;39:1188-1196.

6. Fothergill E, Guo J, Howard L, et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity (Silver Spring). 2016;24:1612-1619.

7. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342-362.

8. Saunders KH, Shukla AP, Igel LI, et al. Pharmacotherapy for obesity. Endocrinol Metab Clin North Am. 2016;45:521-538.

9. Saunders KH, Kumar RB, Igel LI, et al. Pharmacologic approaches to weight management: recent gains and shortfalls in combating obesity. Curr Atheroscler Rep. 2016;18:36.

10. US Food and Drug Administration. Drug approval package. Qsymia. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022580Orig1s000_qsymia_toc.cfm. Accessed August 28, 2017.

11. Arena Pharmaceuticals. Arena Pharmaceuticals and Eisai announce FDA approval of BELVIQ® (lorcaserin HCl) for chronic weight management in adults who are overweight with a comorbidity or obese. Available at: http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=687182. Accessed August 28, 2017.

12. Drugs.com. Contrave approval history. Available at: https://www.drugs.com/history/contrave.html. Accessed August 28, 2017.

13. US Food and Drug Administration. Drugs@FDA: FDA approved drug products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=206321. Accessed August 28, 2017.

14. Igel LI, Kumar RB, Saunders KH, et al. Practical use of pharmacotherapy for obesity. Gastroenterology. 2017;152:1765-1779.

15. Adipex-P package insert. Available at: http://www.iodine.com/drug/phentermine/fda-package-insert. Accessed August 28, 2017.

16. Ionamin package insert. Available at: http://druginserts.com/lib/rx/meds/ionamin/. Accessed August 28, 2017.

17. Lomaira package insert. Available at: https://www.lomaira.com/Prescribing_Information.pdf. Accessed August 28, 2017.

18. Suprenza package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202088s001lbl.pdf. Accessed August 28, 2017.

19. Aronne LJ, Wadden TA, Peterson C, et al. Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity (Silver Spring). 2013;21:2163-2171.

20. Alli package labeling. Available at: http://druginserts.com/lib/otc/meds/alli-1/. Accessed August 28, 2017.

21. Xenical package insert. Available at: https://www.gene.com/download/pdf/xenical_prescribing.pdf. Accessed August 28, 2017.

22. Torgerson JS, Hauptman J, Boldrin MN, et al. 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.

23. Qsymia package insert. Available at: https://www.qsymia.com/pdf/prescribing-information.pdf. Accessed August 28, 2017.

24. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.

25. 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 randomized, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341-1352.

26. Garvey WT, Ryan DH, Look M, et al. 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.

27. Belviq package insert. Available at: https://www.belviq.com/-/media/Files/BelviqConsolidation/PDF/Belviq_Prescribing_information-pdf.PDF?la=en. Accessed August 28, 2017.

28. 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.

29. 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.

30. 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.

31. Contrave package insert. Available at: https://contrave.com/wp-content/uploads/2017/05/Contrave_PI.pdf. Accessed August 28, 2017.

32. Greenway FL, Fujioka K, Plodkowski RA, et al. 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.

33. Apovian CM, Aronne L, Rubino D, et al. 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.

34. Wadden TA, Foreyt JP, Foster GD, et al. 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.

35. Hollander P, Gupta AK, Plodkowski R, et al. 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.

36. Saxenda package insert. Available at: http://www.novo-pi.com/saxenda.pdf. Accessed August 28, 2017.

37. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11-22.

38. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes randomized clinical trial. JAMA. 2015;314:687-699.

39. Wadden TA, Hollander P, Klein S, et al. 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.

40. Saunders KH, Igel LI, Aronne LJ. An update on naltrexone/bupropion extended-release in the treatment of obesity. Expert Opin Pharmacother. 2016. [Epub ahead of print]

41. Thomas CE, Mauer EA, Shukla AP, et al. Low adoption of weight loss medications: a comparison of prescribing patterns of antiobesity pharmacotherapies and SGLT2s. Obesity (Silver Spring). 2016;24:1955-1961.

42. Qsymia Risk Evaluation and Mitigation Strategy (REMS). VIVUS, Inc. Available at: http://www.qsymiarems.com. Accessed January 16, 2017.

43. Zinman B, Wanner C, Lachin JM, et al. Empaglifozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.

44. US Food and Drug Administration. FDA announces withdrawal fenfluramine and dexfenfluramine (Fen-Phen). Available at: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm. Accessed August 28, 2017.

45. Belviq XR package insert. Available at: https://www.belviq.com/-/media/Files/BelviqConsolidation/PDF/belviqxr_prescribing_information-pdf.PDF?la=en. Accessed January 16, 2017.

46. Smith SR, O’Neil PM, Astrup A. 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.

47. 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.

48. Madsen LW, Knauf JA, Gotfredsen C, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology. 2012;153:1538-1547.

49. Fujioka K, O’Neil PM, Davies M, et al. Early weight loss with liraglutide 3.0 mg predicts 1-year weight loss and is associated with improvements in clinical markers. Obesity (Silver Spring). 2016;24:2278-2288.

CASE 2 Norman S, a 52-year-old overweight man (BMI 29 kg/m²) with type 2 diabetes, hyperlipidemia, osteoarthritis, and glaucoma, has recently hit a plateau with his weight loss. He lost 45 pounds secondary to diet and exercise, but hasn’t been able to lose any more. He also struggles with constant hunger. His medications include metformin 1000 mg bid, atorvastatin 10 mg/d, and occasional acetaminophen/oxycodone for knee pain until he undergoes a left knee replacement. Laboratory values are normal except for a hemoglobin A1c of 7.2%.

Mr. S is afraid of needles and cannot tolerate stimulants due to anxiety. Which medication is an appropriate next step for this patient?

Discussion

Lorcaserin is a good choice for this patient who is overweight and has several weight-related comorbidities. He has worked hard to lose a significant number of pounds, and is now at high risk of regaining them. That’s because his appetite has increased with his new exercise regimen, but his energy expenditure has decreased secondary to metabolic adaptation.

Narrowing the field. Naltrexone SR/bupropion SR cannot be used because of his opioid use. Phentermine/topiramate ER is contraindicated for patients with glaucoma, and liraglutide 3 mg is not appropriate given the patient’s fear of needles.

He could try orlistat, especially if he struggles with constipation, but the gastrointestinal adverse effects are difficult for many patients to tolerate. While not an antiobesity medication, a sodium-glucose co-transporter 2 (SGLT2) inhibitor could be prescribed for his diabetes and may also promote weight loss.⁴³

An appealing choice. The glucose-lowering effect of lorcaserin could provide an added benefit for the patient. The BLOOM-DM (Behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus) study reported a mean reduction in hemoglobin A1c of 0.9% in the treatment group compared with a 0.4% reduction in the placebo group,³⁰ and the effect of lorcaserin on A1c appeared to be independent of weight loss.

Mechanism of action: Cause for concern? Although lorcaserin selectively binds to serotonin 5-HT2C receptors, the theoretical risk of cardiac valvulopathy was evaluated in phase III studies, as fenfluramine, a 5-HT2B-receptor agonist, was withdrawn from the US market in 1997 for this reason.⁴⁴ Both the BLOOM (Behavioral modification and lorcaserin for overweight and obesity management) and BLOSSOM (Behavioral modification and lorcaserin second study for obesity management) studies found that lorcaserin did not increase the incidence of FDA-defined cardiac valvulopathy.^28,29

Formulations/adverse effects. Lorcaserin is available in 2 formulations: 10-mg tablets, which are taken twice daily, or 20-mg XR tablets, which are taken once daily. Both are generally well tolerated.^27,45 The most common adverse event reported in phase III trials was headache.^28,30,43 Discontinue lorcaserin if the patient does not lose 5% of his initial weight after 12 weeks, as weight loss at this stage is a good predictor of longer-term success.⁴⁶

Some patients don’t respond. Interestingly, a subset of patients do not respond to lorcaserin. The most likely explanation for different responses to the medication is that there are many causes of obesity, only some of which respond to 5-HT2C agonism. Currently, we do not perform pharmacogenomic testing before prescribing lorcaserin, but perhaps an inexpensive test to identify responders will be available in the future.

References

4. Sumithran P, Predergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365:1597-1604.

5. Greenway FL. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond). 2015;39:1188-1196.

6. Fothergill E, Guo J, Howard L, et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity (Silver Spring). 2016;24:1612-1619.

7. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342-362.

8. Saunders KH, Shukla AP, Igel LI, et al. Pharmacotherapy for obesity. Endocrinol Metab Clin North Am. 2016;45:521-538.

9. Saunders KH, Kumar RB, Igel LI, et al. Pharmacologic approaches to weight management: recent gains and shortfalls in combating obesity. Curr Atheroscler Rep. 2016;18:36.

10. US Food and Drug Administration. Drug approval package. Qsymia. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022580Orig1s000_qsymia_toc.cfm. Accessed August 28, 2017.

12. Drugs.com. Contrave approval history. Available at: https://www.drugs.com/history/contrave.html. Accessed August 28, 2017.

14. Igel LI, Kumar RB, Saunders KH, et al. Practical use of pharmacotherapy for obesity. Gastroenterology. 2017;152:1765-1779.

15. Adipex-P package insert. Available at: http://www.iodine.com/drug/phentermine/fda-package-insert. Accessed August 28, 2017.

16. Ionamin package insert. Available at: http://druginserts.com/lib/rx/meds/ionamin/. Accessed August 28, 2017.

17. Lomaira package insert. Available at: https://www.lomaira.com/Prescribing_Information.pdf. Accessed August 28, 2017.

18. Suprenza package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202088s001lbl.pdf. Accessed August 28, 2017.

19. Aronne LJ, Wadden TA, Peterson C, et al. Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity (Silver Spring). 2013;21:2163-2171.

20. Alli package labeling. Available at: http://druginserts.com/lib/otc/meds/alli-1/. Accessed August 28, 2017.

21. Xenical package insert. Available at: https://www.gene.com/download/pdf/xenical_prescribing.pdf. Accessed August 28, 2017.

23. Qsymia package insert. Available at: https://www.qsymia.com/pdf/prescribing-information.pdf. Accessed August 28, 2017.

24. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.

27. Belviq package insert. Available at: https://www.belviq.com/-/media/Files/BelviqConsolidation/PDF/Belviq_Prescribing_information-pdf.PDF?la=en. Accessed August 28, 2017.

28. 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.

29. 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.

31. Contrave package insert. Available at: https://contrave.com/wp-content/uploads/2017/05/Contrave_PI.pdf. Accessed August 28, 2017.

33. Apovian CM, Aronne L, Rubino D, et al. 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.

36. Saxenda package insert. Available at: http://www.novo-pi.com/saxenda.pdf. Accessed August 28, 2017.

37. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11-22.

38. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes randomized clinical trial. JAMA. 2015;314:687-699.

40. Saunders KH, Igel LI, Aronne LJ. An update on naltrexone/bupropion extended-release in the treatment of obesity. Expert Opin Pharmacother. 2016. [Epub ahead of print]

42. Qsymia Risk Evaluation and Mitigation Strategy (REMS). VIVUS, Inc. Available at: http://www.qsymiarems.com. Accessed January 16, 2017.

43. Zinman B, Wanner C, Lachin JM, et al. Empaglifozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.

45. Belviq XR package insert. Available at: https://www.belviq.com/-/media/Files/BelviqConsolidation/PDF/belviqxr_prescribing_information-pdf.PDF?la=en. Accessed January 16, 2017.

46. Smith SR, O’Neil PM, Astrup A. 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.

47. 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.

Obesity: When to consider medication

References

Discussion

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Commentary

Is obesity a disease?