Drug-induced weight gain: Rethinking our choices

,; ,; ,; ,

Applied Evidence

Drug-induced weight gain: Rethinking our choices

J Fam Pract. 2016 November;65(11):780-782,784-786,788

PDF Download

References

1. Serretti A, Mandelli L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry. 2010;71:1259-1272.

2. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100:342-362.

3. Apovian CM, Aronne L, Powell AG. Clinical Management of Obesity. West Islip, NY: Professional Communications, Inc., 2015.

4. Aronne LJ. A Practical Guide to Drug-induced Weight Gain. Minneapolis, Minn: McGraw-Hill; 2002.

5. Leslie WS, Hankey CR, Lean ME. Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM. 2007;100:395-404.

6. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2016 executive summary. Endocr Pract. 2016;22:84-113.

7. Aronne LJ. Drug-induced weight gain: non-CNS medications. In: A Practical Guide to Drug-Induced Weight Gain. Minneapolis, Minn: McGraw-Hill: 2002:77-91.

8. Domecq JP, Prutsky G, Leppin A, et al. Clinical review: drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100:363-370.

9. Phung OJ, Scholle JM, Talwar M, et al. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303:1410-1418.

10. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.

11. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473–481.

12. Malin SK, Kashyap SR. Effects of metformin on weight loss: potential mechanisms. Curr Opin Endocrinol Diabetes Obes. 2014;21:323-329.

13. Igel LI, Sinha A, Saunders KH, et al. Metformin: an old therapy that deserves a new indication for the treatment of obesity. Curr Atheroscler Rep. 2016;18:16.

14. US Food and Drug Administration. FDA approves weight-management drug Saxenda. December 23, 2014. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm. Accessed October 1, 2016.

15. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol. 2012;8:495-502.

16. van de Laar FA, Lucassen PL, Akkermans RP, et al. Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care. 2005;28:154-163.

17. Hong ES, Khang AR, Yoon JW, et al. Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy in uncontrolled Korean type 2 diabetes: CSI study. Diabetes Obes Metab. 2012;14:795-802.

18. Arnolds S, Dellweg S, Clair J, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care. 2010;33:1509-1515.

19. Scheen AJ. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 2012;38:89-101.

20. Hollander PA, Levy P, Fineman MS, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care. 2003;26:784-790.

21. Aronne L, Fujioka K, Aroda V, et al. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab. 2007;92:2977-2983.

22. Saunders KH, Kumar RB, Igel LI, et al. Pharmacologic approaches to weight management: recent gains and shortfalls in combating obesity. Curr Atheroscler Rep. 2016;18:36.

23. Landsberg L, Aronne LJ, Beilin LJ, et al. Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment—a position paper of the Obesity Society and the American Society of Hypertension. Obesity (Silver Spring). 2013;21:8-24.

24. Messerli FH, Bell DS, Fonseca V, et al. Body weight changes with beta-blocker use: results from GEMINI. Am J Med. 2007;120:610-615.

25. Pischon T, Sharma AM. Use of beta-blockers in obesity hypertension: potential role of weight gain. Obes Rev. 2001;2:275-280.

26. Sharma AM, Pischon T, Hardt S, et al. Hypothesis: beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension. 2001;37:250-254.

27. Manrique C, Whaley-Connell A, Sowers JR. Nebivolol in obese and non-obese hypertensive patients. J Clin Hypertens (Greenwich). 2009;11:309-315.

28. Norris SL, Zhang X, Avenell A, et al. Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(1):CD004096.

29. Rosenzweig-Lipson S, Beyer CE, Hughes ZA, et al. Differentiating antidepressants of the future: efficacy and safety. Pharmacol Ther. 2007;113:134-153.

30. Gadde KM, Xiong GL. Bupropion for weight reduction. Expert Rev Neurother. 2007;7:17-24.

31. Arterburn D, Sofer T, Boudreau DM, et al. Long-term weight change after initiating second-generation antidepressants. J Clin Med. 2016;5:piiE48.

32. US Food and Drug Administration. FDA approves weight-management drug Contrave. September 10, 2014. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm413896.htm. Accessed October 1, 2016.

Antidiabetic agents and weight

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶(TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²