Drug therapy for obesity in the Russian Federation: pharmacoepidemiological study

Objective: аssessment of orlistat, liraglutide and sibutramine consumption in the Russian Federation as drugs recommended by the Russian clinical guidelines for the pharmacotherapy of obesity.

Material and methods. From IQVIA database, the information was selected on retail sales and procurement of the specified drugs at the expense of the federal and regional budgets in the period of 2011–2021. The consumed volumes of each drug were recalculated into the number of defined daily doses (DDDs) for each international nonproprietary name in accordance with the World Health Organization methodology.

Results. It was demonstrated that over a 10-year period there was a tendency to reduce the consumption of drugs for the treatment of obesity from 83.03 million DDDs in 2011 to 71.7 million in 2021. Sibutramine consumption dominated throughout the observation period: its share ranged from 76% to 84%. The proportion of people receiving obesity pharmacotherapy in the Russian Federation was about 0.5%. Herewith 58–66% of DDDs sales took place in 3 regions: Moscow, Moscow Region and Saint Petersburg.

Conclusion. Low efficacy, high frequency of adverse effects, frequent weight gain after therapy termination, as well as low orientation of doctors to the need for pharmacotherapy are probably the main factors determining the low prevalence of using drugs for the treatment of obesity in Russia.

1. World Health Organization. Obesity and overweight. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/ (accessed 16.04.2022).

2. Health care in Russia 2021. Available at: https://rosstat.gov.ru/folder/210/document/13218 (in Russ.) (accessed 16.04.2022).

3. Wilson P., D’Agostino R., Sullivan L., et al. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med. 2002; 162 (16): 1867–72. https://doi.org/10.1001/archinte.162.16.1867.

4. Poirier P., Giles T., Bray G., et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006; 113 (6): 898– 918. https://doi.org/10.1161/CIRCULATIONAHA.106.171016.

5. Manninen P., Riihimäki H., Heliövaara M., Mäkelä P. Overweight, gender, and knee osteoarthritis. Int J Obes Relat Metab Disord. 1996; 20 (6): 595–7.

6. Ferini-Strambi L., Fantini M.L., Castronovo C. Epidemiology of obstructive sleep apnea syndrome. Minerva Med. 2004; 95 (3): 187–202.

7. Basen-Engquist K., Chang M. Obesity and cancer risk: recent review and evidence. Curr Oncol Rep. 2011; 13 (1): 71–6. https://doi.org/10.1007/s11912-010-0139-7.

8. Tremmel M., Gerdtham U.G., Nilsson P.M., Saha S. Economic burden of obesity: a systematic literature review. Int J Environ Res Public Health. 2017; 14 (4): 435. https://doi.org/10.3390/ijerph14040435.

9. Puhl R., Heuer C. The stigma of obesity: a review and update. Obesity (Silver Spring). 2009; 17 (5): 941–64. https://doi.org/10.1038/oby.2008.636.

10. Colman E. Food and Drug Administration's Obesity Drug Guidance Document: a short history. Circulation. 2012; 125 (17): 2156–64. https://doi.org/10.1161/CIRCULATIONAHA.111.028381.

11. Astrup A. Drug management of obesity – efficacy versus safety. N Engl J Med. 2010; 363 (3): 288–90. https://doi.org/10.1056/NEJMe1004076.

12. Adan R.A. Mechanisms underlying current and future anti-obesity drugs. Trends Neurosci. 2013; 36 (2): 133–40. https://doi.org/10.1016/j.tins.2012.12.001.

13. Obesity. Guidelines. 2020. Available at: https://edu.endocrincentr.ru/sites/default/files/recommendation_pdf/kr28.pdf (in Russ.) (accessed 16.04.2022).

14. Order of the Government of the RF of 23.12.2021 No. 3781-r. Available at: http://publication.pravo.gov.ru/Document/View/0001202112290013 (in Russ.) (accessed 16.04.2022).

15. Khera R., Murad M.H., Chandar A.K., et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016; 315 (22): 2424– 34. https://doi.org/10.1001/jama.2016.7602.

16. Nelson D.L., Gehlert D.R. Central nervous system biogenic amine targets for control of appetite and energy expenditure. Endocrine. 2016; 29 (1): 49–60. https://doi.org/10.1385/endo:29:1:49.

17. McMahon F.G., Fujioka K., Singh B.N., et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Intern Med. 2000; 160 (14): 2185–91. https://doi.org/10.1001/archinte.160.14.2185.

18. Smith I.G., Goulder M.A. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract. 2001; 50 (6): 505–12.

19. Fujioka K., Seaton T.B., Rowe E., et al. Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2000; 2 (3): 175–87. https://doi.org/10.1046/j.1463-1326.2000.00081.x.

20. Jame W., Caterson I., Coutinho W., et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010; 363 (10): 905–17. https://doi.org/10.1056/NEJMoa1003114.

21. Kang J.G., Park C.Y. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab J. 2012; 36 (1): 13–25. https://doi.org/10.4093/dmj.2012.36.1.13.

22. Drent M.L., Larsson I., William-Olsson T., et al. Orlistat (Ro 180647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obes Relat Metab Disord. 1995; 19 (4): 221–6.

23. Davidson M.H., Hauptman J., DiGirolamo M., et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999; 281 (3): 235–42. https://doi.org/10.1001/jama.281.3.235.

24. Hollander P.A., Elbein S.C., Hirsch I.B., et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. 1-year randomized double-blind study. Diabetes Care. 1998; 21 (8): 1288–94. https://doi.org/10.2337/diacare.21.8.1288.

25. Zelber-Sagi S., Kessler A., Brazowsky E., et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006; 4 (5): 639–44. https://doi.org/10.1016/j.cgh.2006.02.004.

26. McDuffie J.R., Calis K.A., Booth S.L., et al. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy. 2002; 22 (7): 814–22. https://doi.org/10.1592/phco.22.11.814.33627.

27. Drucker D.J. The biology of incretin hormones. Cell Metab. 2006; 3 (3): 153–65. https://doi.org/10.1016/j.cmet.2006.01.004.

28. Sisley S., Gutierrez-Aguilar R., Scott M., et al. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest. 2014; 124 (6): 2456–63. https://doi.org/10.1172/JCI72434.

29. Prigeon R.L., Quddusi S., Paty B., D’Alessio D.A. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab. 2003; 285 (4): E701–7. https://doi.org/10.1152/ajpendo.00024.2003.

30. González N., Acitores A., Sancho V., et al. Effect of GLP-1 on glucose transport and its cell signalling in human myocytes. Regul Pept. 2005; 126 (3): 203–11. https://doi.org/10.1016/j.regpep.2004.10.002.

31. Willms B., Werner J., Holst J.J., et al. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996; 81 (1): 327–32. https://doi.org/10.1210/jcem.81.1.8550773.

32. Timmers L., Henriques J.P., de Kleijn D.P., et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 2009; 53 (6): 501–10. https://doi.org/10.1016/j.jacc.2008.10.033.

33. Hui H., Farilla L., Merkel P., Perfetti R. The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. Eur J Endocrinol. 2002; 146 (6): 863–9. https://doi.org/10.1530/eje.0.1460863.

34. Agersø H., Jensen L.B., Elbrønd B., et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002; 45 (2): 195– 202. https://doi.org/10.1007/s00125-001-0719-z.

35. Degn K.B., Juhl C.B., Sturis J., et al. One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alphaand beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004; 53 (5): 1187–94. https://doi.org/10.2337/diabetes.53.5.1187.

36. Vilsbøll T., Zdravkovic M., Le-Thi T., et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007; 30 (6): 1608–10. https://doi.org/10.2337/dc06-2593.

37. Bettge K., Kahle M., Abd El Aziz M.S., et al. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes Obes Metab. 2017; 19 (3): 336–47. https://doi.org/10.1111/dom.12824.

38. 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. https://doi.org/10.1056/NEJMoa1411892.

39. IQVIA Russia and CIS. Available at: https://www.iqvia.com/ru-ru/ locations/russia (in Russ.) (accessed 16.04.2022).

40. WHO Collaborating Centre for Drug Statistics Methodology. ATC/ DDD Index 2018. Available at: https://www.whocc.no/atc_ddd_index/ (accessed 16.04.2022).

41. WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment. 2022. Available at: https://www.whocc.no/filearchive/publications/2022_guidelines_web.pdf (accessed 16.04.2022).

42. Dedov I.I., Shestakova M.V., Galstyan G.R. The prevalence of type 2 diabetes mellitus in the adult population of Russia (NATION study). Diabetes Mellitus. 2016; 19 (2): 104–12 (in Russ.). https://doi.org/10.14341/DM2004116-17.

43. Federal State Statistics Service. Population of the Russian Federation by gender and age as of January 1, 2016. Available at: https://gks.ru/bgd/regl/B16_111/Main.htm (in Russ.) (accessed 16.04.2022).

44. Xia Y., Kelton C.M., Guo J.J., et al. Treatment of obesity: pharmacotherapy trends in the United States from 1999 to 2010. Obesity (Silver Spring). 2015; 23 (8): 1721–8. https://doi.org/10.1002/oby.21136.

45. Thomas C.E., Mauer E.A., Shukla A.P., et al. Low adoption of weight loss medications: a comparison of prescribing patterns of antiobesity pharmacotherapies and SGLT2s. Obesity (Silver Spring). 2016; 24 (9): 1955–61. https://doi.org/10.1002/oby.21533.

46. Colbert J.A., Jangi S. Training physicians to manage obesity – back to the drawing board. N Engl J Med. 2013; 369 (15): 1389–91. https://doi.org/10.1056/NEJMp1306460.

47. Jensen M.D., Ryan D.H., Apovian C.M., 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. Circulation. 2014; 129 (25 Suppl. 2): S102–38. https://doi.org/10.1161/01.cir.0000437739.71477.ee.

48. Sjöström L., Lindroos A.K., Peltonen M., et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004; 351 (26): 2683–93. https://doi.org/10.1056/NEJMoa035622.

49. Pories W.J., Swanson M.S., MacDonald K.G., et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995; 222 (3): 339–52. https://doi.org/10.1097/00000658-199509000-00011.

50. Carlsson L.M., Peltonen M., Ahlin S., et al. Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012; 367 (8): 695–704. https://doi.org/10.1056/NEJMoa1112082.

51. Russian National Bariatric Registry. Available at: https://bareoreg. ru/ (in Russ.) (accessed 16.04.2022).

52. Robinson M.K. Surgical treatment of obesity – weighing the facts. N Engl J Med. 2009; 361 (5): 520–1. https://doi.org/10.1056/NEJMe0904837.

53. Marcotte E., Chand B. Management and prevention of surgical and nutritional complications after bariatric surgery. Surg Clin North Am. 2016; 96 (4): 843–56. https://doi.org/10.1016/j.suc.2016.03.006.

54. Shikora S.A., Kruger R.S. Jr., Blackburn G.L. Best practices in policy and access (coding and reimbursement) for weight loss surgery. Obesity (Silver Spring). 2009; 17 (5): 918–23. https://doi.org/10.1038/oby.2008.573.

55. Decree of the Government of the RF of 28.12.2021 No. 2505 “On the Program of state guarantees of free medical care to citizens for 2022 and for the planning period of 2023 and 2024”. Available at: https://base.garant.ru/403335795/ (in Russ.) (accessed 16.04.2022).