Advertisement

Pharmacologic Approaches to Weight Management: Recent Gains and Shortfalls in Combating Obesity

  • Katherine H. Saunders
  • Rekha B. Kumar
  • Leon I. Igel
  • Louis J. Aronne
Clinical Trials and Their Interpretations (J. Kizer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Clinical Trials and Their Interpretations

Abstract

Obesity is a growing epidemic in the USA with over one third of adults presently classified as obese. Obesity-related comorbidities include many leading causes of preventable death such as heart disease, stroke, type 2 diabetes, and certain types of cancer. Modest weight loss of 5–10 % of body weight is sufficient to produce clinically relevant improvements in cardiovascular disease risk factors among patients with overweight and obesity. Until recently, there were limited pharmacologic options approved by the Food and Drug Administration to treat obesity. Phentermine/topiramate ER and lorcaserin were approved in 2012, and naltrexone SR/bupropion SR and liraglutide 3.0 mg were approved in 2014. This article reviews recent literature in the field of Obesity Medicine and highlights important findings from clinical trials. Future directions in the pharmacologic management of obesity are presented along with new diabetes medications that promote weight loss and reduce cardiovascular mortality.

Keywords

Obesity Weight loss Weight management Pharmacotherapy Clinical trials Type 2 diabetes 

Notes

Compliance with Ethical Standards

Conflict of Interest

Katherine H. Saunders and Leon I. Igel declare that they have no conflict of interest.

Rekha B. Kumar declares personal fees for being a speaker for Jansen Pharmaceuticals and is a shareholder in Zafgen and Myos Corporation.

Louis J. Aronne declares consultant/advisory board work with Jamieson Labs, Pfizer Inc, Novo Nordisk A/S, Eisai, VIVUS, GI Dynamics, JOVIA Health, and Gelesis. He is a shareholder of Zafgen, Gelesis, Myos Corporation, and Jamieson Labs, and he is on the Board of Directors of MYOS Corporation and Jamieson Labs. He has received research funding from Aspire Bariatrics and Eisai.

Human and Animal Rights and Informed Consent

All studies by Louis J. Aronne involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written, informed consent was obtained from all participants.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ogden CL, Carroll MD, Fryar CD, Flegal KM. Prevalence of obesity among adults and youth: united states, 2011–2014. NCHS Data Brief. 2015;219:1–8.PubMedGoogle Scholar
  2. 2.
    Ogden CL, Flegal KM. Changes in terminology for childhood overweight and obesity. Natl Health Stat Report. 2010;25:1–5.PubMedGoogle Scholar
  3. 3.
    Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood). 2009;28(5):w822–31.CrossRefGoogle Scholar
  4. 4.
    Trogdon JG, Finkelstein EA, Hylands T, Dellea PS, Kamal-Bahl SJ. Indirect costs of obesity: a review of the current literature. Obes Rev. 2008;9(5):489–500.CrossRefPubMedGoogle Scholar
  5. 5.
    Thompson D, Edelsberg J, Kinsey KL, Oster G. Estimated economic costs of obesity to U.S. business. Am J Health Promot. 1998;13:120–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Wolf AM, Colditz GA. The cost of obesity: the US perspective. Pharmacoeconomics. 1994;5:34–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Lovren F, Teoh H, Verma S. Obesity and atherosclerosis: mechanistic insights. Can J Cardiol. 2015;31(2):177–83.CrossRefPubMedGoogle Scholar
  8. 8.
    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;S1550-4131(16):30053–5.Google Scholar
  9. 9.
    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(7):1481–6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    The Look AHEAD Research Group. The look AHEAD study: A description of the lifestyle intervention and the evidence supporting it. Obesity. 2006;14:737–52.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Diabetes Prevention Program (DPP) Research Group. The diabetes prevention program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25:2165–71.CrossRefGoogle Scholar
  12. 12.
    Hinkle W, Cordell M, Leibel R, Rosenbaum M, Hirsch J. Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans. PLoS One. 2013;8(3):e59114.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rosenbaum M, Goldsmith R, Bloomfield D. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005;115(12):3579–86.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. Am J Clin Nutr. 2008;88(4):906–12.PubMedGoogle Scholar
  15. 15.••
    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. This publication denotes the first clinical practice guidelines for the management of adults with overweight and obesity. These guidelines were drafted by a task force of experts from the American College of Cardiology, American Heart Association and The Obesity Society.CrossRefPubMedGoogle Scholar
  16. 16.••
    Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62. This publication denotes the first clinical practice guidelines for the pharmacologic management of obesity. These guidelines were drafted by an Endocrine Society-appointed task force of experts, and were co-sponsored by the European Society of Endocrinology and The Obesity Society.CrossRefPubMedGoogle Scholar
  17. 17.
    American Medical Association. Policy H-440.842. Recognition of Obesity as a Disease. 2013.Google Scholar
  18. 18.
    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(2):330–42.CrossRefGoogle Scholar
  19. 19.
    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 randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341–52.CrossRefPubMedGoogle Scholar
  20. 20.
    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(2):297–308.CrossRefPubMedGoogle Scholar
  21. 21.
    Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245–56.CrossRefPubMedGoogle Scholar
  22. 22.
    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(10):3067–77.CrossRefPubMedGoogle Scholar
  23. 23.
    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(7):1426–36.CrossRefGoogle Scholar
  24. 24.
    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(9741):595–605.CrossRefPubMedGoogle Scholar
  25. 25.
    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(5):935–43.CrossRefGoogle Scholar
  26. 26.
    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(1):110–20.CrossRefGoogle Scholar
  27. 27.
    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(12):4022–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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(1):11–22.CrossRefPubMedGoogle Scholar
  29. 29.
    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(7):687–99.CrossRefPubMedGoogle Scholar
  30. 30.
    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(11):1443–51.CrossRefGoogle Scholar
  31. 31.
    Thomas EA, Mcnair B, Bechtell JL, Ferland A, Cornier MA, Eckel RH. Greater hunger and less restraint predict weight loss success with phentermine treatment. Obesity (Silver Spring). 2016;24(1):37–43.CrossRefGoogle Scholar
  32. 32.
    Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med. 2005;353(20):2111–20.CrossRefPubMedGoogle Scholar
  34. 34.
    Digenio AG, Mancuso JP, Gerber RA, Dvorak RV. Comparison of methods for delivering a lifestyle modification program for obese patients: a randomized trial. Ann Intern Med. 2009;150(4):255–62.CrossRefPubMedGoogle Scholar
  35. 35.
    Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hughes TE, Kim DD, Marjason J, Proietto J, Whitehead JP, Vath JE. Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Obesity (Silver Spring). 2013;21(9):1782–8.Google Scholar
  37. 37.
    Kim DD, Krishnarajah J, Lillioja S, et al. Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial. Diabetes Obes Metab. 2015;17(6):566–72.CrossRefPubMedGoogle Scholar
  38. 38.
    Zafgen Inc. Zafgen’s pivotal phase 3 trial of beloranib in Prader-Willi syndrome achieves co-primary efficacy endpoints. http://ir.zafgen.com/releasedetail.cfm?ReleaseID=950876. Accessed February 26, 2016.
  39. 39.
    Zafgen Inc. Zafgen announces positive results from phase 2 clinical trial of beloranib in hypothalamic injury associated obesity. http://ir.zafgen.com/releasedetail.cfm?releaseid=889999. Accessed March 8, 2016.
  40. 40.
    Zafgen, Inc. Zafgen provides clinical update on Beloranib. http://ir.zafgen.com/releasedetail.cfm?releaseid=945102. Accessed February 26, 2016.
  41. 41.
    Lomaira KVK Tech, Inc. http://kvktech.com/lomaira/ Accessed Feburary 27, 2016.
  42. 42.
    Smith SR, Garvey WT, Greenway F, et al. Combination Weight Management (WM) Pharmacotherapy with Lorcaserin (LOR) and Immediate Release (IR) Phentermine (phen) [abstract]. Poster presented at Obesity Week. Boston; 2014.Google Scholar
  43. 43.
    Aronne LJ. A practical guide to drug-induced weight gain. Minneapolis: McGraw-Hill; 2002.Google Scholar
  44. 44.
    Top-Line Data Show CV Benefit for Liraglutide in Type 2 Diabetes. Miriam E Tucker. Medscape Medical News. WebMD LLC. http://www.medscape.com/viewarticle/859905. Accessed March 8, 2016.
  45. 45.•
    Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. EMPA-REG OUTCOME is the first trial investigating a medication for type 2 diabetes which demonstrates both weight loss and improved cardiovascular outcomes in high-risk patients.CrossRefPubMedGoogle Scholar
  46. 46.
    Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349–57.CrossRefPubMedGoogle Scholar
  47. 47.
    Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–74.CrossRefPubMedGoogle Scholar
  48. 48.
    Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–82.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Katherine H. Saunders
    • 1
  • Rekha B. Kumar
    • 1
  • Leon I. Igel
    • 1
  • Louis J. Aronne
    • 1
  1. 1.Comprehensive Weight Control Center, Division of Endocrinology, Diabetes and MetabolismWeill Cornell MedicineNew YorkUSA

Personalised recommendations