Dapagliflozin Reduces Fat Mass without Affecting Muscle Mass in Type 2 Diabetes

Seigo Sugiyama, Hideaki Jinnouchi, Noboru Kurinami, Kunio Hieshima, Akira Yoshida, Katsunori Jinnouchi, Hiroyuki Nishimura, Tomoko Suzuki, Fumio Miyamoto, Keizo Kajiwara, Tomio Jinnouchi, Seigo Sugiyama, Hideaki Jinnouchi, Noboru Kurinami, Kunio Hieshima, Akira Yoshida, Katsunori Jinnouchi, Hiroyuki Nishimura, Tomoko Suzuki, Fumio Miyamoto, Keizo Kajiwara, Tomio Jinnouchi

Abstract

Aim: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy has been demonstrated to improve glycemic control and reduce body weight and fat mass in type 2 diabetes mellitus (T2DM). Here, our aim was to investigate the effects of SGLT2i dapagliflozin-treatment on body muscle mass and muscle fat content in patients with T2DM.

Methods: We prospectively recruited uncontrolled (hemoglobin A1c [HbA1c] ＞7%) Japanese T2DM patients who had a body mass index (BMI) ＜35 kg/m2. Patients were treated with dapagliflozin (5 mg/day) or non-SGLT2i medicines for six months to improve HbA1c. We investigated changes in body composition using bioelectrical impedance analysis and changes in psoas muscle mass using abdominal computed tomography (CT).

Results: Subjects were 50 T2DM patients (72% male) with a mean age of 56.1 years, mean BMI of 27.1 kg/m2 and mean HbA1c of 7.9%. HbA1c, body weight, and BMI were significantly decreased in both treatment groups, and the HbA1c decrease was not significantly different between groups. Dapagliflozin treatment significantly decreased body weight and total fat mass without affecting skeletal muscle mass. The absolute change in soft lean mass and skeletal muscle mass was not significantly different between groups. Dapagliflozin treatment did not significantly decrease psoas muscle index, and the absolute change in this index was not significantly different between groups. Dapagliflozin therapy also produced a significant increase in CT radiation attenuation in the third lumbar paraspinal muscles compared with non-SGLT2i therapy.

Conclusions: Treatment with dapagliflozin for six months significantly improved glycemic control and reduced body weight without reducing muscle mass in T2DM patients.

Keywords: Fat mass; Muscle mass; Sarcopenia; Sodium-glucose co-transporter 2 inhibitor; Type 2 diabetes.

Conflict of interest statement

Dr. Seigo Sugiyama has received Speaker's Bureau from MSD, Inc., AstraZeneca Pharmaceuticals LP, Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Novo Nordisk Inc., Daiichi-Sankyo Co., Ltd., and Boehringer Ingelheim Pharmaceuticals, Inc.

Dr. Hideaki Jinnouchi has received Consultant from Sanofi U.S., and Novo Nordisk Inc.; Research support from Eli Lilly Japan K.K., Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd., GlaxoSmithKline, Takeda Pharmaceutical Company Limited, Daiichi- Sankyo Co., Ltd., Taisho Pharmaceutical Co., Ltd., Astellas Pharma US, Inc., and AstraZeneca Pharmaceuticals LP; Speaker's Bureau from Sanofi U.S., Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, Astellas Pharma US, Inc., Mitsubishi Tanabe Pharma Corporation, Daiichi-Sankyo Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals, Novartis Pharmaceuticals Corporation, AstraZeneca Pharmaceuticals LP, MSD, Inc., and Mochida Pharmaceutical Co., Ltd.

All other authors declare that they have no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Dot plot of soft lean mass before and after 6 months of dapagliflozin or non-sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy as measured using a bioelectrical impedance analyzer Soft lean mass of each patient before and after each therapy presented as a dot plot, with black circles and bars representing the mean and standard error of the mean, respectively.
Fig. 2.
Fig. 2.
Dot plot of skeletal muscle mass before and after 6 months of dapagliflozin or non-sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy as measured using a bioelectrical impedance analyzer Skeletal muscle mass of each patient before and after each therapy presented as a dot plot, with black circles and bars representing the mean and standard error of the mean, respectively.
Fig. 3.
Fig. 3.
Dot plot of the psoas muscle index before and after 6 months of dapagliflozin or non-sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy as assessed by abdominal computed tomography Psoas muscle index of each patient before and after each therapy presented as a dot plot, with black circles and bars representing the mean and standard error of the mean, respectively.

References

    1. Scheen AJ, Van Gaal LF: Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol, 2014; 2: 911-922
    1. Shulman GI: Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med, 2014; 371: 1131-1141
    1. Bianchi L, Volpato S: Muscle dysfunction in type 2 diabetes: a major threat to patient's mobility and independence. Acta Diabetol, 2016; 53: 879-889
    1. Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S: Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab, 2012; 97: 1020-1031
    1. Tanizawa Y, Kaku K, Araki E, Tobe K, Terauchi Y, Utsunomiya K, Iwamoto Y, Watada H, Ohtsuka W, Watanabe D, Suganami H. Tofogliflozin and Study g: Long-term safety and efficacy of tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open-label, randomized controlled trials. Expert Opin Pharmacother, 2014; 15: 749-766
    1. Blonde L, Stenlof K, Fung A, Xie J, Canovatchel W, Meininger G: Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgrad Med, 2016; 128: 371-380
    1. Goring S, Hawkins N, Wygant G, Roudaut M, Townsend R, Wood I, Barnett AH: Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis. Diabetes Obes Metab, 2014; 16: 433-442
    1. Vivian EM: Dapagliflozin: a new sodium-glucose cotransporter 2 inhibitor for treatment of type 2 diabetes. Am J Health Syst Pharm, 2015; 72: 361-372
    1. Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjostrom CD, Sugg J, Parikh S: 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: 159-169
    1. Kostev K, Pscherer S, Rist R, Busch S, Scheerer MF: Changes in Glycemic Control and Body Weight After Initiation of Dapagliflozin or Basal Insulin Supported Oral Therapy in Type 2 Diabetes. J Diabetes Sci Technol, 2016; 1932296816688011
    1. Scheerer MF, Rist R, Proske O, Meng A, Kostev K: Changes in HbA1c, body weight, and systolic blood pressure in type 2 diabetes patients initiating dapagliflozin therapy: a primary care database study. Diabetes Metab Syndr Obes, 2016; 9: 337-345
    1. Hesselink MK, Schrauwen-Hinderling V, Schrauwen P: Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol, 2016; 12: 633-645
    1. Fujita Y, Inagaki N: Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: Clinical data and mechanism of action. J Diabetes Investig, 2014; 5: 265-275
    1. Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T, Nakano Y, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T, Ogawa Y: Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol, 2017; 16: 32
    1. Cetrone M, Mele A, Tricarico D: Effects of the antidiabetic drugs on the age-related atrophy and sarcopenia associated with diabetes type?. Curr Diabetes Rev, 2014; 10: 231-237
    1. Malavolti M, Mussi C, Poli M, Fantuzzi AL, Salvioli G, Battistini N, Bedogni G: Cross-calibration of eight-polar bioelectrical impedance analysis versus dual-energy X-ray absorptiometry for the assessment of total and appendicular body composition in healthy subjects aged 21–82 years. Ann Hum Biol, 2003; 30: 380-391
    1. Kurinami N, Sugiyama S, Yoshida A, Hieshima K, Miyamoto F, Kajiwara K, Jinnouchi T, Jinnouchi H: Correlation of body muscle/fat ratio with insulin sensitivity using hyperinsulinemic-euglycemic clamp in treatment-naive type 2 diabetes mellitus. Diabetes Res Clin Pract, 2016; 120: 65-72
    1. Wannamethee SG, Atkins JL: Muscle loss and obesity: the health implications of sarcopenia and sarcopenic obesity. Proc Nutr Soc, 2015; 74: 405-412
    1. Hamaguchi Y, Kaido T, Okumura S, Kobayashi A, Hammad A, Tamai Y, Inagaki N, Uemoto S: Proposal for new diagnostic criteria for low skeletal muscle mass based on computed tomography imaging in Asian adults. Nutrition, 2016; 32: 1200-1205
    1. Aubrey J, Esfandiari N, Baracos VE, Buteau FA, Frenette J, Putman CT, Mazurak VC: Measurement of skeletal muscle radiation attenuation and basis of its biological variation. Acta Physiol (Oxf), 2014; 210: 489-497
    1. Brons C, Grunnet LG: MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander? Eur J Endocrinol, 2017; 176: R67-R78
    1. Traina SB, Slee A, Woo S, Canovatchel W: The Importance of Weight Change Experiences for Performance of Diabetes Self-Care: A Patient-Centered Approach to Evaluating Clinical Outcomes in Type 2 Diabetes. Diabetes Ther, 2015; 6: 611-625
    1. Obata A, Kubota N, Kubota T, Iwamoto M, Sato H, Sakurai Y, Takamoto I, Katsuyama H, Suzuki Y, Fukazawa M, Ikeda S, Iwayama K, Tokuyama K, Ueki K, Kadowaki T: Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice. Endocrinology, 2016; 157: 1029-1042
    1. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, Sica D, Rothenberg P, Plum-Morschel L: 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: 1087-1095
    1. Solini A: Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Acta Diabetol, 2016; 53: 863-870
    1. Hirose S, Nakajima S, Iwahashi Y, Seo A, Takahashi T, Tamori Y: Impact of the 8-week Administration of Tofogliflozin for Glycemic Control and Body Composition in Japanese Patients with Type 2 Diabetes Mellitus. Intern Med, 2016; 55: 3239-3245
    1. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E: Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care, 2015; 38: 1730-1735
    1. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA: Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest, 2014; 124: 509-514
    1. Komiya H, Mori Y, Yokose T, Kurokawa N, Horie N, Tajima N: Effect of intramuscular fat difference on glucose and insulin reaction in oral glucose tolerance test. J Atheroscler Thromb, 2006; 13: 136-142
    1. Sano M, Meguro S, Kawai T, Suzuki Y: Increased grip strength with sodium-glucose cotransporter 2. J Diabetes, 2016; 8: 736-737
    1. Ribola FA, Cancado FB, Schoueri JH, De Toni VF, Medeiros VH, Feder D: Effects of SGLT2 inhibitors on weight loss in patients with type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci, 2017; 21: 199-211
    1. Hsu WC, Araneta MR, Kanaya AM, Chiang JL, Fujimoto W: BMI cut points to identify at-risk Asian Americans for type 2 diabetes screening. Diabetes Care, 2015; 38: 150-158

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