Drug combinations in the treatment of obesity: the past and present

Czech version

Authors: V. Hainer
Authors‘ workplace: Centrum pro diagnostiku a léčbu obezity ; Ředitelka: doc. RNDr. Běla Bendlová, CSc. ; Endokrinologický ústav, Praha
Published in: Prakt. Lék. 2017; 97(3): 109-116
Category: Reviews

Overview

Withdrawal of several anti-obesity drugs from the market and inappropriate demands of drug regulating agencies with regard to the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. Since 2010, only lipase inhibitor orlistat remained available for the long-term treatment of obesity in the Czech Republic. Nevertheless, recently developed anti-obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, improvement of cardio-metabolic health risks, safety and tolerability. The use of drug combinations in obesity management began in the eighties when two drug combinations (as ephedrine/caffeine mixture) in decreased doses were recommended to increase both the safety and efficacy of the treatment. However, it should be seriously considered that drug combinations may not only lead to increased efficacy but in some cases (as with fenfluramine/phentermine combination) also to enhancement of side effects. A short outline of anti-obesity drug combinations used or investigated in the past is provided. Curently two combination drugs are available for the long-term treatment of obesity: phentermine/topiramate in the United States (U.S.) and naltrexone/bupropion in both the U.S. and Europe, including the Czech Republic. Treatment with naltrexone/bupropion, used as indicated by the drug labelling and in combination with comprehensive lifestyle modification, leads to a significantly higher weight loss compared to diet and exercise intervention alone. Moreover, naltrexone/bupropion combination facilitates weight loss maintenance and improves lipid profile and glucose homeostasis as well as a quality of life in the treated overweight and obese patients. The drug is safe and well tolerated when indications and contraindications are taken into accout. It is emphasized that the treatment with anti-obesity agents should be interrupted in non-responders, i.e. in those who did not achieve weight loss ≥ 5,0% after 4-month of the drug administration.

Keywords:
combined anti-obesity agents – ephedrine/caffeine – fenfluramine/phentermine – phentermine/topiramate – naltrexone/bupropion – efficacy – safety

Sources

1. World Health Organization. Obesity and overweight. Fact sheet, updated June 2016. Dostupný z: http://www.who.int/mediacentre/fact sheets/fs.311/en/

2. Kunešová M, Müllerová D, Hainer V. Epidemiologie a zdravotní rizika obezity. In: Hainer V. a kol. Základy klinické obezitologie. Praha: Grada Publishing 2011; 15–34.

3. Sigmund E, Baďura P, Vokáčová J, Sigmundová D. Matčina obezita a nadměrné sledování televise výrazně zvyšují šanci nadváhy/obesity u předškoláků. Prakt. Lék. 2016; 96(6): 255–260.

4. Horton ES. Effects of lifestyle changes to reduce risks of diabetes and associated cardiovascular risks: results from large scale efficacy trials. Obesity (Silver Spring) 2009; 17(Suppl 3): S43–S48.

5. Freemark M. Pharmacotherapy of childhood obesity. An evidence based conceptual approach. Diabetes Care 2007; 20(2): 395–402.

6. The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145–154.

7. Hainer V, Kunešová M. Farmakoterapie obezity. In: Kunešová M. a kol. Základy obezitologie. Praha: Galén 2016; 139–144.

8. Hainer V, Aldhoon Hainerová I. Do we need antiobesity drugs? Diabetes Metab Res Rev 2012; 28(Suppl 2): 8–20.

9. Doležalová K. Bariatrická léčba obezity. In: Kunešová M. a kol. Základy obezitologie. Praha: Galén 2016; 145–154.

10. Hainer V. Overview of new antiobesity drugs. Expert Opin Pharmacother 2014; 15(14): 1975–1978.

11. Jones BJ, Bloom SR. The new era of drug therapy for obesity: The evidence and the expectations. Drugs 2015; 75: 935–945.

12. Sari R, Balci MK, Cakir M, et al. Comparison of efficacy of sibutramine or orlistat versus their combination in obese women. Endocr Res 2004; 30(2): 159–167.

13. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581–588.

14. Breum L, Pedersen JK, Ahlstrom F, et al. A comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord 1994; 18(2): 99–103.

15. Molnár D, Torok K, Erhardt E, Jeges S. Safety and efficacy of treatment with an efedrine/caffeine mixture. The first double-blind placebo-controlled pilot study in adolescents. Int J Obes Relat Metab Disord 2000; 24(12): 1573–1578.

16. Liu AG, Smith SR, Fujioka K, Greenway FL. The affect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss. Obesity (Silver Spring) 2013; 21(10): 1991–1996.

17. Liu AG, Arceneaux III KP, Chu JT, et al. The effect of caffeine and albuterol on body composition and metabolic rate. Obesity (Silver Spring) 2015; 23(9): 1830–1835.

18. Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992; 51(5): 586–594.

19. Gadde KM, Yonish GM, Foust MS, et al. Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study. J Clin Psychiatry 2007; 68(8): 1226–1229.

20. Ravussin E, Smith SR, Mitchell JA, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 2009; 17(9): 1736–1743.

21. Aronne LJ, Halseth AE, Burns CM, et al. Enhanced weight loss following administration of pramlintide with sibutramine or phentermine in a multicenter trial. Obesity (Silver Spring) 2010; 18(9): 1739–1746.

22. Greenway FL, Pilson R, Ma T, Kung T. The impact of weight loss therapy on food cravings: an exploratory analysis from a 12-week pilot safety study with lorcaserin and phentermine. Obesity Week (TOS) 2015; [online]. Dostupný z: http://obesityweek.com/app/uploads/2015/11/11104-Wednesday-ObesityWeek-2015-TOS-Poster-Abstracts.pdf [Cit. 18.1.2017].

23. Field BCT, Wren AM, Peters V, et al. PYY3-36 and Oxyntomodulin can be additive in their effect on food intake in overwight and obese humans. Diabetes 2010; 59: 1635–1639.

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(2): 330–342.

25. Gadde KM, Allison DB, Ryan DH, et al. Effect 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): 1341–1352.

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(2): 297–308.

27. Winslow DH, Bowden CH, DiDonato KP, McCullough PA. A randomized double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of sleep apnea in obese adults. Sleep 2012; 35(11): 1529–1539.

28. Garvey WT, Ryan DH, Henry H, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care 2014; 37(4): 912–921.

29. Wang G-J, Tomasi D, Volkow ND, et al. Effect of combined naltrexone and bupropion therapy on the brain´s reactivity to food cues. Int J Obes 2014; 38: 682–688.

30. Greenway FL, Whitehouse MJ, Guttadauria M, et al. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring) 2009; 17(1): 30–39.

31. 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.

32. 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): 935–943.

33. Wadden TA, Foreyt JP, Foster GD, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an sdjunct to behavior modification: the COR-BMOD trial. Obesity 2011; 19(1): 110–120.

34. 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 patiens with type 2 diabetes. Diabetes Care 2013; 36(12): 4022–4029.

35. Apovian CM. Naltrexone/bupropion for the treatment of obesity and obesity with type 2 diabetes. Future Cardiol 2016; 12(2): 129–138.

36. Halseth A, Shan K, Walsh B, et al. Method-of-use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity. Obesity (Silver Spring) 2017; 25: 338–345.

37. Smith SR, Fujioka K, Gupta AK, et al. Combination therapy with naltrexone and bupropion for obesity reduces total and visceral adiposity. Diabetes Obes Metab 2013; 15(9): 863–866.

38. Kolotkin RL, Chen S, Klassen P, et al. Patient-reported quality of life in a randomized placebo-controlled trial of naltrexone/bupropion for obesity. Clin Obes 2015; 5(5): 237–244.

39. Nissen SE, Wolski KE, Prcela L, et al. Effect of naltrexone-bupropion on major averse cardiovascular events in overweight and obese patiens with cardiovascular risk factors: A randomized clinical trial. JAMA 2016; 315(10): 990–1004.

Labels

General practitioner for children and adolescents General practitioner for adults

Patient-centered care: general aspects and terminology challenges

Preeclampsia is not just a complication of pregnancy

The selected indicators of health status of the Czech population – results of EHES study 2014

Plant based diet in the prevention of civilization diseases

Comparison of palliative care in the Czech Republic and sub- Saharan Africa

Article was published in

General Practitioner

2017 Issue 3