The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients

Abstract

OBJECTIVEThe aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSThis randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA 1c 6.5-10.5% (48-91 mmol/mol) and ‡3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [ 18 F]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTSAfter 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA 1c 20.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (23.74%, P < 0.01), liver volume (20.10 L, P < 0.05), visceral adipose tissue volume (20.35 L, P < 0.01), interleukin-6 (21.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (296 ng/L, P = 0.03). CONCLUSIONSIn this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.Clinical trial reg. no. NCT02426541, clinicaltrials .gov This article contains Supplementary Data online at

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

“…However, the absence of studies on dose dependency and headto-head comparisons does not allow any conclusions about drug-specific effects at present. As indicated in other NAFLD trials (22,23), the guideline-based dietary counseling for all groups could have been responsible for the higher rates of LFC improvement observed in the placebo groups of this study and one previous (8) but not in other SGLT2i trials (6,9).…”

“…Recent randomized controlled trials demonstrated that SGLT2is can induce a reduction of LFC compared with baseline (6-9), but only one trial also reported a statistically significant effect on LFC compared with placebo (6). The magnitude of the reduction in LFC may depend on trial medication and design; duration of the intervention; cohort characteristics, such as NAFLD status, T2D duration, glycemic control, and sex distribution; and, finally, statistical power (22,23).…”

“…Sodium-glucose cotransporter 2 inhibitors (SGLT2is) not only improve glycemia by increasing urinary glucose excretion but also reduce body weight and blood pressure (4) and improve cardiovascular and renal outcomes (5). Some open-label and placebo-controlled studies have reported that SGLT2is may also alleviate NAFLD (6,7), while canagliflozin and dapagliflozin trended toward decreased liver fat content (LFC) compared with placebo (8,9). Body weight loss and glycated hemoglobin (HbA 1c ) reduction may be mainly responsible for LFC reduction with canagliflozin (8,10), but empagliflozin (EMPA) could improve NAFLD independently of body weight and glycemia (7,11).…”

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…However, their impact on liver histology remains to be established. Table summarizes several recent RCTs in NAFLD . Taken together, this class has been remarkably consistent in causing a 2% to 3% decrease in total body weight (1.5‐3.0 kg) and in lowering plasma aminotransferases with a placebo‐corrected reduction in intrahepatic triglyceride content of 10%‐30%.…”

“…Table 2 summarizes several recent RCTs in NAFLD. [43][44][45][46][47] Taken together, this class has been remarkably consistent in causing a 2% to 3% decrease in total body weight (1.5-3.0 kg) and in lowering plasma aminotransferases with a placebo-corrected reduction in intrahepatic triglyceride content of 10%-30%. However, decreases in intrahepatic triglyceride content must be interpreted with caution because changes in liver fat on imaging may or may not reliably correlate with necroinflammation or fibrosis on histology.…”