Effect of sodium-glucose transporter 2 inhibitors on sarcopenia in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

Abstract

ObjectiveSarcopenia has been recognized as the third category of disabling complications in patients with type 2 diabetes mellitus(T2DM), in addition to micro- and macrovascular complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are innovative glucose-lowering treatments that have been shown to reduce body weight and enhance cardiovascular and renal outcomes. However, there is vigilance that SGLT2 inhibitors should be taken cautiously because they target skeletal muscle and may raise the risk of sarcopenia. Herein, we conducted a meta-analysis of randomized controlled trials to evaluate the effects of SGLT2 inhibitors on sarcopenia in patients with T2DM.MethodRelevant studies were obtained from PubMed, Embase, Medicine, Cochrane, and Web of Science databases to determine eligible studies until February 2023, without any language restrictions. A random effects model was utilized irrespective of heterogeneity, and the I2 statistic was used to evaluate study heterogeneity. The differences in results were measured using the weighted average difference (WMD) of the continuous data, along with a 95% confidence interval (CI).ResultsA total of 25 randomized controlled trials with 2,286 participants were included. SGLT2 inhibitors significantly reduced weight-related changes and fat-related changes, including body weight(BW) (WMD= -2.74, 95% CI: -3.26 to -2.23, P<0.01), body mass index(BMI) (WMD= -0.72, 95% CI: -0.95 to -0.49, P<0.01), waist circumference(WC) (WMD= -1.60, 95% CI: -2.99 to -0.22, P=0.02), fat mass(FM)(WMD= -1.49, 95% CI: -2.18 to -0.80, P<0.01), percentage body fat(PBF) (WMD= -1.28, 95% CI: -1.83 to -0.74, P<0.01), visceral fat area(VFA)(WMD= -19.52, 95% CI: -25.90 to -13.14, P<0.01), subcutaneous fat area(SFA)(WMD= -19.11, 95% CI: -31.18 to -7.03, P=0.002), In terms of muscle-related changes, lean mass(LM)(WMD= -0.80, 95% CI: -1.43 to -0.16, P=0.01), and skeletal muscle mass(SMM) (WMD= -0.38, 95% CI: -0.65 to -0.10, P=0.007), skeletal muscle index(SMI) (WMD= -0.12, 95% CI: -0.22 to -0.02, P=0.02)were also significantly reduced. In addition, body water likewise decreased significantly (WMD=-0.96, 95% CI: -1.68 to -0.23, P=0.009).ConclusionsAs one of the most widely used hypoglycemic, SGLT2 inhibitors have beneficial effects on FM and BW weight loss in T2DM, such as BW, BMI, WC, FM, PBF, VFA, and SFA. However, the negative influence on muscle mass paralleled the reduction in FM and BW, and the consequent increased risk of sarcopenia warrants high attention, especially as patients are already predisposed to physical frailty.Clinical Trial Registrationhttps://www.crd.york.ac.uk/prospero/#myprospero, identifier PROSPERO (No.CRD 42023396278).

Dapagliflozin Improves Skeletal Muscle Insulin Sensitivity through SIRT1 activation Induced by Nutrient Deprivation State

“…Dapa treatment for ve weeks lead to adaptive changes in skeletal muscle substrate metabolism, favoring metabolism of fatty acids and ketone bodies [32] , and Dapa treatment for 14 days in insulin-resistant individuals improved fat oxidation in skeletal muscle and mimicked the effects of calorie restriction [33] . In accordance with previous results, we observed the metabolic bene ts of Dapa treatment, including decreases in body weight, body fat, and blood lipids, an increase in urine glucose concentration, an RQ value indicative of fat metabolism, and importantly, ketogenic effects; however, we did not observe a clear improvement in muscle mass, which has been controversial in previous research [34,35] .…”

“…SIRT1 also can regulate mitochondrial quality control by promoting mitochondrial biogenesis and facilitating the disposal of dysfunctional organelles [38] . Recent experimental evidence suggests that SGLT2 inhibitors have activating effects on SIRT1; the mechanism may involve inhibiting endoplasmic reticulum stress and oxidative stress or maintaining mitochondrial homeostasis [30][31][32][33][34][35][36][37][38][39][40][41] . We measured the RNA and protein expression levels of SIRT1 in muscle, and the results showed that it was signi cantly inhibited under high-fat diet-induced obesity conditions, while Dapa treatment had a bene cial effect.…”

Associations of medicine use and ejection fraction with the coexistence of frailty and sarcopenia in a sample of heart failure outpatients: a cross-sectional study

“…Mone et al reported that the SGLT2 inhibitor empagliflozin improved cognitive and physical functions [ 58 ] and mRNAs signature of endothelial dysfunction in frail diabetic patients with HFpEF [ 59 ]. However, a recent meta-analysis revealed that the use of SGLT2 inhibitors may increase the risk of sarcopenia in patients with type-2 diabetes [ 60 ]. Therefore, patients using SGLT2 inhibitors should be carefully monitored for unwanted outcomes related with muscle health.…”

Drug‐related sarcopenia as a secondary sarcopenia

“…Sodium-glucose cotransporter 2 inhibitors that decrease proximal tubular glucose reabsorption, not only reduce body weight and body fat, but meta-analyses have indicated that they also reduce lean body mass and skeletal muscle mass. 25,26 Sodiumglucose cotransporter 2 itself is not present in skeletal muscle, and its effects on skeletal muscle may be mediated by indirect systemic effects. Possible mechanisms include decreased uptake of glucose and amino acids and increased degradation of muscle proteins in skeletal muscle associated with decreased insulin secretion, but the detailed mechanisms remain unclear (Tables 2 and 3).…”

“…Sodium–glucose cotransporter 2 inhibitors that decrease proximal tubular glucose reabsorption, not only reduce body weight and body fat, but meta‐analyses have indicated that they also reduce lean body mass and skeletal muscle mass 25,26 . Sodium–glucose cotransporter 2 itself is not present in skeletal muscle, and its effects on skeletal muscle may be mediated by indirect systemic effects.…”