Weight Loss Associated with Sodium-glucose Co-transporter 2 Inhibitor
Keywords:
weight loss, SGLT2 inhibitor, obesity, diabetes mellitus, anti-obesity drugAbstract
Sodium-glucose co-transporter 2 inhibitor (SGLT2-i) is an oral hypoglycemic drug with a proven advantage regarding weight reduction effects in type 2 diabetes patients. By its main mechanism, it increases urinary glucose loss which can cause negative energy balance hence weight loss. Other mechanisms that might play roles in its weight-losing effect include loss of extracellular fluid by transient increase of urinary output, increase body lipid oxidation, and increase metabolism by inducing the fat-browning(burning?) process. The magnitude of SGLT2-i-induced weight loss usually ranges from 1-3 kg, which is commonly observed within the first 6 months of prescription. Then the rate of weight loss gradually declines afterward to reach a plateau after 6 months to 1 year. Fat mass loss contributes a major proportion in body weight loss whereas muscle and bone mass losses are minute. Adherence to diet control, SGLT2-i dosage increment, or a combination with GLP-1 RA should be considered to achieve greater weight loss effect. Currently, SGLT2-i has not been approved as an anti-obesity drug in patients without type 2 diabetes mellitus.
References
Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia. 2018;61(10):2079–86.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 26;373(22):2117–28.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 17;377(7):644–57.
Cai X, Ji L, Chen Y, Yang W, Zhou L, Han X, et al. Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: A meta-analysis. J Diabetes Investig. 2017;8(4):510–7.
Association AD. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes—2020. Diabetes Care. 2020;43(Supplement 1):S98–110.
Walter CP, Bleske BE, Dorsch MP. Pharmacotherapy for weight loss: the cardiovascular effects of the old and new agents. J Clin Pharm Ther. 2014;39(5):475–84.
Lingvay I, Catarig A-M, Frias JP, Kumar H, Lausvig NL, le Roux CW, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(11):834–44.
Del Prato S, Nauck M, Durán-Garcia S, Maffei L, Rohwedder K, Theuerkauf A, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17(6):581–90.
Sasaki T, Sugawara M, Fukuda M. Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: the components of weight loss in Japanese patients with type 2 diabetes mellitus) Study. J Diabetes Investig. 2019;10(1):108–17.
Yamamoto C, Miyoshi H, Ono K, Sugawara H, Kameda R, Ichiyama M, et al. Ipragliflozin effectively reduced visceral fat in Japanese patients with type 2 diabetes under adequate diet therapy. Endocr J. 2016;63(6):589–96.
Kawata T, Iizuka T, Iemitsu K, Takihata M, Takai M, Nakajima S, et al. Ipragliflozin improves glycemic control and decreases body fat in patients with type 2 diabetes mellitus. J Clin Med Res. 2017;9(7):586–95.
Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159–69.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.
Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium–glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1730–5.
Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang S-S, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087–95.
Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, et al. SGLT2 Inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine. 2017;20:137–49.
Xu L, Nagata N, Chen G, Nagashimada M, Zhuge F, Ni Y, et al. Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. BMJ Open Diabetes Res Care. 2019;7(1):e000783.
Sakai S, Kaku K, Seino Y, Inagaki N, Haneda M, Sasaki T, et al. Efficacy and safety of the SGLT2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus stratified according to baseline body mass index: Pooled analysis of data from 52-Week phase III trials. Clinical Therapeutics. 2016;38(4):843-862.e9.
Iemitsu K, Iizuka T, Takihata M, Takai M, Nakajima S, Minami N, et al. Factors influencing changes in hemoglobin A1c and body weight during treatment of type 2 diabetes with ipragliflozin: Interim analysis of the ASSIGN-K study. J Clin Med Res. 2016;8(5):373–8.
Inagaki N, Goda M, Yokota S, Maruyama N, Iijima H. Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52-week open-label study. Expert Opin Pharmacother. 2015;16(11):1577–91.
Cai X, Yang W, Gao X, Chen Y, Zhou L, Zhang S, et al. The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: A meta-analysis. Obesity. 2018;26(1):70–80.
Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes, Obesity and Metabolism. 2010;12(6):510–6.
Cai X, Yang W, Gao X, Chen Y, Zhou L, Zhang S, et al. The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: A meta-analysis. Obesity (Silver Spring). 2018;26(1):70–80.
Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35(7):1473–8.
Wilding JPH, Woo V, Rohwedder K, Sugg J, Parikh S, Dapagliflozin 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014;16(2):124–36.
Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37(7):1815–23.
Ludvik B, Frías JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370–81.
Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(5):356–67.
Jabbour SA, Frías JP, Guja C, Hardy E, Ahmed A, Öhman P. Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly, or dapagliflozin, added to metformin monotherapy, on body weight, systolic blood pressure, and triglycerides in patients with type 2 diabetes in the DURATION-8 study. Diabetes Obes Metab. 2018;20(6):1515–9.
Harashima S-I, Inagaki N, Kondo K, Maruyama N, Otsuka M, Kawaguchi Y, et al. Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52-week, open-label, phase IV study. Diabetes Obes Metab. 2018;20(7):1770–5.
Fulcher G, Matthews DR, Perkovic V, de Zeeuw D, Mahaffey KW, Mathieu C, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):82–91.
Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, et al. Pooled analysis of phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93(1):231–44.
Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138(15):1537–50.
Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962–71.
Kashiwagi A, Takahashi H, Ishikawa H, Yoshida S, Kazuta K, Utsuno A, et al. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes Obes Metab. 2015;17(2):152–60.
Haneda M, Seino Y, Inagaki N, Kaku K, Sasaki T, Fukatsu A, et al. Influence of renal function on the 52-week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clin Ther. 2016;38(1):66-88.e20.
Brown E, Wilding JPH, Barber TM, Alam U, Cuthbertson DJ. Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: Mechanistic possibilities. Obesity Reviews. 2019;20(6):816–28.
Suzuki M, Takeda M, Kito A, Fukazawa M, Yata T, Yamamoto M, et al. Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models. Nutr Diabetes. 2014;4:e125.
Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity. 2012;20(8):1645–52.
Hamamoto H, Noda M. Body weight gain and hyperphagia after administration of SGLT-2 inhibitor: A Case Report. Am J Case Rep. 2015;16:863–7.
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190–5.
Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity. 2014;22(4):1042–9.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guidance on clinical evaluation of medicinal products used in weight control. 2007. Available at http://www.emea.europa.eu
Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). Draft. Guidance for industry. Developing products for weight management. 2007. Available at http://www.fda.gov/cder/guidance/ 7544dft.pdf
Hollander P, Bays HE, Rosenstock J, Frustaci ME, Fung A, Vercruysse F, et al. Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes: A randomized clinical trial. Diabetes Care. 2017;40(5):632–9.
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