J Korean Med Assoc.  2019 Nov;62(11):588-597. 10.5124/jkma.2019.62.11.588.

Mechanisms of action and clinical applications of anti-obesity drugs currently available in Korea

• Kim KK

• KMID: 2462242
• DOI: http://doi.org/10.5124/jkma.2019.62.11.588

Abstract

Over the last 5 years, the Korean Ministry of Food and Drug Safety has approved four anti-obesity drugs for long-term weight management. In this review, the mechanisms of action and clinical applications of lorcaserin, naltrexone/bupropion, liraglutide, and phentermine/topiramate have been clarified. Lorcaserin stimulates proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons in the arcuate nucleus. Naltrexone/bupropion reduces body weight by controlling the hedonic reward system of food intake. The hypophagic effect of liraglutide depends on the direct activation of the proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons and indirect suppression of neuropeptide Y/agouti-related peptide neurons through gammaaminobutyric acid-dependent signaling, with an additional thermogenic effect. Phentermine/topiramate induces weight loss by elevating the norepinephrine levels in the hypothalamus, reducing energy deposition in the adipose tissue and skeletal muscle, and elevating the corticotropin-releasing hormone in the hypothalamus. In patients with high cardiovascular risks or type 2 diabetes mellitus, lorcaserin and liraglutide are appropriate. In patients with mood disorders, naltrexone/bupropion could be considered as the first choice of therapy. Notably, lorcaserin and liraglutide are neutral in the aspect of sleep disorder. In case of obese individuals with obstructive sleep apnea, liraglutide or phentermine/topiramate would be selected as the treatment option. These four drugs should be used after considering the patients' co-morbidities of obesity.

Keyword

Anti-obesity agents; Pharmacology; Hypothalamus

MeSH Terms

Adipose Tissue
Anti-Obesity Agents*
Arcuate Nucleus of Hypothalamus
Body Weight
Corticotropin-Releasing Hormone
Diabetes Mellitus, Type 2
Eating
Humans
Hypothalamus
Korea*
Liraglutide
Mood Disorders
Muscle, Skeletal
Neurons
Neuropeptides
Norepinephrine
Obesity
Pharmacology
Reward
Sleep Apnea, Obstructive
Sleep Wake Disorders
Weight Loss
Anti-Obesity Agents
Corticotropin-Releasing Hormone
Liraglutide
Neuropeptides
Norepinephrine

Reference

1. Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Med. 2016; 14:191.

2. Kim KK. Safety of anti-obesity drugs approved for long-term use. Korean J Obes. 2015; 24:17–27.

3. Volkow ND, Wang GJ, Baler RD. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci. 2011; 15:37–46.

4. Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science. 2005; 307:1909–1914.

5. Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron. 2011; 69:664–679.

6. Rossi MA, Stuber GD. Overlapping brain circuits for homeostatic and hedonic feeding. Cell Metab. 2018; 27:42–56.

7. Breisch ST, Zemlan FP, Hoebel BG. Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine. Science. 1976; 192:382–385.

8. Saller CF, Stricker EM. Hyperphagia and increased growth in rats after intraventricular injection of 5,7-dihydroxytryptamine. Science. 1976; 192:385–387.

9. Fletcher PJ, Burton MJ. Microstructural analysis of the anorectic action of peripherally administered 5-HT. Pharmacol Biochem Behav. 1986; 24:1133–1136.

10. Blundell JE, Latham CJ. Serotonergic influences on food intake: effect of 5-hydroxytryptophan on parameters of feeding behaviour in deprived and free-feeding rats. Pharmacol Biochem Behav. 1979; 11:431–437.

11. Guy-Grand B, Crepaldi G, Lefebvre P, Apfelbaum M, Gries A, Turner P. International trial of long-term dexfenfluramine in obesity. Lancet. 1989; 2(8672):1142–1145.

12. Voigt JP, Fink H. Serotonin controlling feeding and satiety. Behav Brain Res. 2015; 277:14–31.

13. Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones Z, Liu HY, Zigman JM, Balthasar N, Kishi T, Lee CE, Aschkenasi CJ, Zhang CY, Yu J, Boss O, Mountjoy KG, Clifton PG, Lowell BB, Friedman JM, Horvath T, Butler AA, Elmquist JK, Cowley MA. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron. 2006; 51:239–249.

14. Pecina S, Smith KS. Hedonic and motivational roles of opioids in food reward: implications for overeating disorders. Pharmacol Biochem Behav. 2010; 97:34–46.

15. Bermudez-Silva FJ, Cardinal P, Cota D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J Psychopharmacol. 2012; 26:114–124.

16. Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuno F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015; 519:45–50.

17. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusll N, Fowler JS. Brain dopamine and obesity. Lancet. 2001; 357:354–357.

18. Campana B, Brasiel PG, de Aguiar AS, Dutra SC. Obesity and food addiction: similarities to drug addiction. Obes Med. 2019; 16:100136.

19. Beeler JA, Faust RP, Turkson S, Ye H, Zhuang X. Low Dopamine D2 receptor increases vulnerability to obesity via reduced physical activity, not increased appetitive motivation. Biol Psychiatry. 2016; 79:887–897.

20. Spiegel TA, Stunkard AJ, Shrager EE, O'Brien CP, Morrison MF, Stellar E. Effect of naltrexone on food intake, hunger, and satiety in obese men. Physiol Behav. 1987; 40:135–141.

21. Atkinson RL, Berke LK, Drake CR, Bibbs ML, Williams FL, Kaiser DL. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther. 1985; 38:419–422.

22. Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKen-ney J, O'Neil PM. Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res. 2002; 10:633–641.

23. Kim KK. Understanding the mechanism of action and clinical implications of anti-obesity drugs recently approved in Korea. Korean J Fam Med. 2019; 40:63–71.

24. Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD, Dunayevich E. COR-I Study Group. 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.

25. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018; 27:740–756.

26. Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS, Hansen G, Grove KL, Pyke C, Raun K, Schaffer L, Tang-Christensen M, Verma S, Witgen BM, Vrang N, Bjerre Knudsen L. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014; 124:4473–4488.

27. Jelsing J, Vrang N, Hansen G, Raun K, Tang-Christensen M, Knudsen LB. Liraglutide: short-lived effect on gastric emptying-long lasting effects on body weight. Diabetes Obes Metab. 2012; 14:531–538.

28. Gentilella R, Pechtner V, Corcos A, Consoli A. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev. 2019; 35:e3070.

29. Kastin AJ, Akerstrom V, Pan W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci. 2002; 18:7–14.

30. Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012; 13:33.

31. Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M. OBES-002 Study Group. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004; 28:1399–1410.

32. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, Tam PY, Troupin B, Day WW. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012; 20:330–342.

33. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, Andreasen AH, Jensen CB, DeFronzo RA. NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015; 314:687–699.

34. O'Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, Raether B, Anderson CM, Shanahan WR. 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.

35. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR. Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010; 363:245–256.

36. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean MEJ, Niskanen L, Rasmussen MF, Rissanen A, Rossner S, Savolainen MJ, Van Gaal L. NN8022-1807 Investigators. 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.

37. Larsen JR, Vedtofte L, Jakobsen MSL, Jespersen HR, Jakobsen MI, Svensson CK, Koyuncu K, Schjerning O, Oturai PS, Kjaer A, Nielsen J, Holst JJ, Ekstrom CT, Correll CU, Vilsboll T, Fink-Jensen A. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with zchizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017; 74:719–728.

38. Blackman A, Foster GD, Zammit G, Rosenberg R, Aronne L, Wadden T, Claudius B, Jensen CB, Mignot E. SCALE study group. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016; 40:1310–1319.

39. 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 obstructive sleep apnea in obese adults. Sleep. 2012; 35:1529–1539.