Adipositas - Ursachen, Folgeerkrankungen, Therapie 2021; 15(03): 130-137
DOI: 10.1055/a-1491-5805
Review

Medikamentöse Adipositastherapie – Chancen und Perspektiven

Drug Therapy for Obesity – Chances and Perspectives
Anne Lautenbach
1   Endokrinologie und Diabetologie, Universitäres Adipositas Centrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
,
Jens Aberle
1   Endokrinologie und Diabetologie, Universitäres Adipositas Centrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
,
Sebastian M. Meyhöfer
2   Institut für Endokrinologie & Diabetes, Universität Lübeck, Lübeck, Deutschland
3   Deutsches Zentrum für Diabetesforschung, Neuherberg, Deutschland
,
Svenja Meyhöfer
2   Institut für Endokrinologie & Diabetes, Universität Lübeck, Lübeck, Deutschland
3   Deutsches Zentrum für Diabetesforschung, Neuherberg, Deutschland
4   Medizinische Klinik 1, Universitätsklinikum Schleswig-Holstein Campus Lübeck, Lübeck, Deutschland
› Author Affiliations

Zusammenfassung

Medikamentöse Therapiestrategien sind dringend erforderlich, um Adipositas-assoziierte Begleiterkrankungen langfristig reduzieren und verhindern zu können. Mit einer Gewichtsabnahme um 10% kann bereits eine Reduktion kardiovaskulärer Endpunkte erreicht werden. Als medikamentöse Therapieoption stehen aktuell in Deutschland der Lipaseinhibitor Orlistat sowie der GLP-1 Rezeptor-Agonist (GLP-1RA) Liraglutid zur medikamentösen Langzeittherapie der Adipositas zur Verfügung. Perspektivisch könnten zukünftig noch weitere Therapieoptionen zur Verfügung stehen, mit denen eine effektive Gewichtsreduktion erzielt werden kann. Semaglutid ist bereits als GLP-1RA zur Therapie des Typ 2 Diabetes zugelassen und zeigt, neben einer effektiven HbA1c-Senkung, eine deutliche Gewichtsreduktion. Im Fokus aktueller Adipositasforschung stehen zudem die Multi-Agonisten auf GLP-1-Basis, die balanziert an Rezeptoren mehrerer gastrointestinaler Peptide binden. So zeigen klinische Studien bspw. mit einem dualen Agonisten aus GLP1 und GIP (Glucose-dependent insulinotropic peptide) vielversprechende Körpergewichts-reduzierende Effekte. Weitere Forschungsansätze medikamentöser Therapieoptionen zur Gewichtsreduktion basieren u. a. auf Glukagon-Analoga, PYY und Amylin, aber auch auf Kombinationstherapien wie Leucin-Metformin-Sildenafil. Neben einer Verringerung der Nahrungsaufnahme werden derzeit zudem Therapieansätze zur Steigerung des Energieumsatzes, z. B. über die Aktivierung des braunen Fettgewebes, intensiv beforscht. In diesem Übersichtsartikel werden aktuelle sowie mögliche zukünftige Therapieoptionen zur Gewichtsreduktion in der Therapie der Adipositas zusammengefasst.

Abstract

Therapy strategies are required to reduce and prevent obesity-associated comorbidities. Weight loss of 10% leads to a significant reduction in cardiovascular endpoints. In Germany, the lipase inhibitor orlistat and the GLP-1 receptor agonist (GLP-1RA) liraglutide are currently approved and available for long-term therapy of obesity. However, current research point to more oral and subcutaneous therapy options for effective weight loss in the future. Semaglutide is already approved as GLP-1RA for the treatment of type 2 diabetes and significantly reduces HbA1c-levels and body weigth. Current research also focuses on multi-agonists based on GLP-1, which are binding in a balanced way to receptors of gastrointestinal peptides. Further obesity research is based on glucagon analogues, gastrointestinal peptide hormones such as PYY and amylin, as well as on combination therapies such as leucine-metformin-sildenafil. In addition, increasing energy expenditure by activation of brown adipose tissue is in the focus of current research for weight reduction. This review summarizes current and possible future treatment options for obesity.



Publication History

Article published online:
24 September 2021

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  • Literatur

  • 1 Bentham J, Di Cesare M, Bilano V. et al Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. The Lancet 2017; 390: 2627-2642
  • 2 The GBD 2015 Obesity Collaborators. Health Effects of Overweight and Obesity in 195 Countries over 25 Years New England Journal of Medicine 2017. 377: 13-27
  • 3 Gregg E, Jakicic J, Blackburn G. et al Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial The Lancet Diabetes and Endocrinology 2016. 4: 913-921
  • 4 Dansinger ML, Gleason JA, Griffith JL. et al Comparison of the Atkins, Ornish, Weight Watchers, and Zone Diets for weight loss and heart disease risk reduction: A randomized trial. Journal of the American Medical Association 2005; 293: 43-53
  • 5 Lean ME, Leslie WS, Barnes AC. et al Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet 2018; 391: 541-551
  • 6 Dansinger ML, Gleason JA, Griffith JL. et al Comparison of the Atkins, Ornish, Weight Watchers, and Zone Diets for Weight Loss and Heart Disease Risk Reduction: A Randomized Trial. JAMA 2005; 293: 43
  • 7 Dombrowski SU, Knittle K, Avenell A. et al Long term maintenance of weight loss with non-surgical interventions in obese adults: Systematic review and meta-analyses of randomised controlled trials BMJ (Online). 2014; 348
  • 8 Wing RR, Bahnson JL, Bray GA. et al Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the look AHEAD trial. Archives of Internal Medicine 2010; 170: 1566-1575
  • 9 Toplak H, Woodward E, Yumuk V. et al 2014 EASO Position Statement on the Use of Anti-Obesity Drugs. Obesity Facts 2015; 8: 166-174
  • 10 Interdisziplinäre S3-Leitlinie “Prävention und Therapie der Adipositas”: Version 2.0 (April 2014). 2014. https://www.awmf.org/leitlinien/detail/ll/050-001.html Letzter Zugriff: 23.08.2021
  • 11 Wadden TA, Walsh OA, Berkowitz RI. et al Intensive Behavioral Therapy for Obesity Combined with Liraglutide 3.0 mg: A Randomized Controlled Trial. Obesity 2019; 27: 75-86
  • 12 Fachinformation Tenuate® Retard. 2018
  • 13 Hutton B, Fergusson D. Changes in body weight and serum lipid profile in obese patients treated with orlistat in addition to a hypocaloric diet: A systematic review of randomized clinical trials. Vol. 80, American Journal of Clinical Nutrition. American Society for Nutrition 2004; 1461-1468
  • 14 CHMP. Fachinformation Xenical
  • 15 Padwal RS, Rucker D, Li SK. et al Long-term pharmacotherapy for obesity and overweight. Cochrane Database of Systematic Reviews 2003; 4: Art. No.: CD004094 https://doi.org/10.1002/14651858.CD004094.pub2
  • 16 Secher A, Jelsing J, Baquero AF. et al The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. Journal of Clinical Investigation 2014; 124: 4473-4488
  • 17 Pi-Sunyer X, Astrup A, Fujioka K. et al A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine 2015; 373: 11-22
  • 18 le Roux CW, Astrup A, Fujioka K. et al 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet (London, England) 2017; 389: 1399-1409
  • 19 Marso SP, Daniels GH, Frandsen KB. et al Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine 2016; 375: 311-322
  • 20 Davies MJ, Aronne LJ, Caterson ID. et al Liraglutide and cardiovascular outcomes in adults with overweight or obesity: A post hoc analysis from SCALE randomized controlled trials. Diabetes, Obesity and Metabolism 2018; 20: 734-739
  • 21 Wilding JPH, Batterham RL, Calanna S. et al Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine 2021; 384: 989-1002
  • 22 Wadden TA, Bailey TS, Billings LK. et al Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults with Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA-Journal of the American Medical Association 2021; 325: 1403-1413
  • 23 Muscelli E, Mari A, Casolaro A. et al Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients. Diabetes. 2008; 57: 1340-1348
  • 24 Liu C, Li C, Cai X. et al Discovery of a novel GLP-1/GIP dual receptor agonist CY-5 as long-acting hypoglycemic, anti-obesity agent. Bioorganic Chemistry 2021; 106: 104492 DOI: 10.1016/j.bioorg.2020.104492.
  • 25 Gautier J-F, Choukem S-P, Girard J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab 2008; 34: 65-72
  • 26 Alvarez E, Martinez MD, Roncero I. et al The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 2005; 92: 798-806
  • 27 Frias JP, Nauck MA, Van J. et al Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018; 392: 2180-2193
  • 28 Eli Lilly and Company. Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes (04.03.2021). Im Internet. https://www.prnewswire.com/news-releases/tirzepatide-achieved-superior-a1c-and-body-weight-reductions-across-all-three-doses-compared-to-injectable-semaglutide-in-adults-with-type-2-diabetes-301239948.html Stand: NA
  • 29 Kleinert M, Sachs S, Habegger KM. et al Glucagon Regulation of Energy Expenditure Int J Mol Sci. 2019; 20: 5407
  • 30 Kim JK, Kim J, Lee SM. et al 991-P: Potential of a Novel Long-Acting Glucagon Analog, HM15136, for the Treatment of Obesity Diabetes. 2019; 68: 991-P DOI: 10.2337/db19-991-P.
  • 31 Eriksson O, Haack T, Hijazi Y. et al Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes. Sci Rep 2020; 10: 16758
  • 32 Lafferty RA, Flatt PR, Irwin N. Emerging therapeutic potential for peptide YY for obesity-diabetes. Peptides 2018; 100: 269-274
  • 33 Zac-Varghese S, De Silva A, Bloom SR. Translational studies on PYY as a novel target in obesity. Current Opinion in Pharmacology 2011; 11: 582-585
  • 34 Christensen RM, Juhl CR, Torekov SS. Benefit-Risk Assessment of Obesity Drugs: Focus on Glucagon-like Peptide-1 Receptor Agonists. Drug Saf. 2019; 42: 957-971
  • 35 Boyle CN, Lutz TA, Le Foll C. Amylin–Its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Molecular. Metabolism 2018; 8: 203-210
  • 36 Mollet A, Gilg S, Riediger T. et al Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats. Physiology & Behavior 2004; 81: 149-155
  • 37 Liberini CG, Koch-Laskowski K, Shaulson E. et al Combined Amylin/GLP-1 pharmacotherapy to promote and sustain long-lasting weight loss. Sci Rep 2019; 9: 8447
  • 38 Enebo LB, Berthelsen KK, Kankam M. et al Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. The Lancet 2021; 397: 1736-1748
  • 39 Zemel MB, Kolterman O, Rinella M. et al Randomized Controlled Trial of a Leucine-Metformin-Sildenafil Combination (NS-0200) on Weight and Metabolic Parameters. Obesity 2019; 27: 59-67
  • 40 Noureddin M, Loomba R. Editorial: role of leucine-metformin-sildenafil combination in the treatment of nonalcoholic fatty liver disease (NAFLD). Aliment Pharmacol Ther. 2018; 48: 378-379
  • 41 Nahon KJ, Janssen LGM, Sardjoe Mishre ASD. et al The effect of mirabegron on energy expenditure and brown adipose tissue in healthy lean South Asian and Europid men. Diabetes Obes Metab. 2020; 22: 2032-2044
  • 42 Cypess AM, Weiner LS, Roberts-Toler C. et al Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015; 21: 33-38
  • 43 Loh RKC, Formosa MF, La Gerche A, Reutens AT, Kingwell BA, Carey AL. Acute metabolic and cardiovascular effects of mirabegron in healthy individuals. Diabetes Obes Metab. 2019; 21: 276-284
  • 44 Beiroa D, Imbernon M, Gallego R. et al GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK. Diabetes 2014; 63: 3346-3358
  • 45 Sjöstrom L, Narbro K, Sjöström D. et al Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects. N Engl J Med. 2007; 357: 741-752