Effects of SGLT-2 inhibitors on adipose tissue distribution in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials

Abstract

Objective Sodium-glucose cotransporter-2 (SGLT-2) inhibitors therapies were reported to affect adipose tissue distribution. However, the available evidence about the effect of SGLT-2 inhibitor on adipose tissue is contradictory. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of SGLT-2 inhibitors on adipose tissue distribution in patients with type 2 diabetes mellitus (T2DM). Methods RCTs on SGLT-2 inhibitors on adipose distribution affect in patients with T2DM published in full-text journal databases such as PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched. The fixed or random effect model was used for meta-analysis, the I2 test was used to evaluate the heterogeneity between studies, and the sensitivity analysis and subgroup analysis were used to explore the source of heterogeneity. Funnel chart and Begg’s test were used to estimate publication bias. Results Overall, 18 RCTs involving 1063 subjects were evaluated. Compared with placebo or other hypoglycemic drugs, SGLT-2 inhibitors significantly reduced visceral adipose tissue (standard mean deviation [SMD] = − 1.42, 95% confidence interval [CI] [− 2.02, − 0.82], I2 = 94%, p < 0.0001), subcutaneous adipose tissue (SMD = − 1.21, 95% CI [− 1.99, − 0.42], I2 = 93%, p = 0.003), ectopic liver adipose tissue (SMD = − 0.70, 95% CI [− 1.20, − 0.20], I2 = 73%, p = 0.006). In addition, body weight (mean deviation [MD] = − 2.60, 95% CI [− 3.30, − 1.89], I2 = 95%, p < 0.0001), waist circumference (MD = − 3.65, 95% CI [− 4.10, − 3.21], I2 = 0%, p < 0.0001), and body mass index (BMI) (MD = − 0.81, 95% CI [− 0.91, − 0.71], I2 = 23%, p < 0.0001) were significantly decreased. However, epicardial fat tissue showed an insignificant reduction (SMD = 0.03, 95% CI [− 0.52, 0.58], I2 = 69%, p = 0.71). Subgroup analysis revealed that appropriate treatment duration (16 – 40 weeks) or young patients with nonalcoholic fatty liver disease (NAFLD) and obesity were the decisive factors for SGLT-2 inhibitors to effectively reduce visceral and subcutaneous adipose tissues. Conclusions Our meta-analysis provides evidence that in patients with T2DM, SGLT-2 inhibitors significantly reduce visceral adipose tissue, subcutaneous adipose tissue, and ectopic liver fat, especially in young T2DM patients with NAFLD and high BMI. Appropriate dosing time (16–40 weeks) may have a more significant and stable beneficial effect on VAT and SAT reduction.

Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease

“…SGLT2 inhibitors may offer advantages to patients with diabetic NAFLD due to their known ability to induce weight loss and lower glucose . SGLT2 inhibitors redistribute visceral, subcutaneous, and ectopic fat (eg, liver fat) depots . SGLT2 inhibitors facilitate glucose loss through the kidney, which provokes a fastinglike state and activates catabolic pathways in the liver and visceral adipose tissues .…”

Epicardial adipose tissue, metabolic disorders, and cardiovascular diseases: recent advances classified by research methodologies

“…In the past decade, four types of interventions have been proposed to reduce EAT volume, including exercise interventions, dietary interventions, bariatric surgery, and pharmaceutical interventions 129–134 (Figure 3). There have been a number of well‐designed tables summarizing related clinical studies in recent systematic reviews 134–142 …”

Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes

“…Clinical evidence demonstrated that the SGLT-2I could exert progressive BMI reduction at 12 (MD = − 0.52 kg/m 2 ), 24 (MD = − 0.73 kg/m 2 ), 52 (− 0.93 kg/m 2 ), and 104 (− 1.22 kg/m 2 ) weeks [ 59 ]. Further body composition studies showed that within the duration of treatment, lean body mass remained stable [ 64 ], while fat depletion in subcutaneous, visceral, and liver/ectopic sites were all significant [ 65 ]. Specifically, the SGLT-2I could deplete liver fat via glucose deprivation (as de novo lipogenesis accounts for one-fourth of hepatic FA content in MASLD) [ 66 ] and glucose deprivation-boosted hepatic FA β-oxidation.…”

“…The SCD2023 recommends that a SGLT-2I should be included in the treatment regimen for patients with T2DM and established cardiovascular/renal disease or risks [ 67 ], as the major CVOTs indicated that risks of MACE (HR = 0.89) and cardiovascular death or hospitalization for heart failure (HR = 0.77) were all significantly reduced in patients with T2DM receiving SGLT-2I treatment [ 68 ••], though the SGLT-2I is associated with a statistically but not clinically significant increase in total plasma cholesterol (MD = 0.003 mmol/L) [ 69 ] and an insignificant depletion in epicardial fat [ 65 ]. Moreover, a pooled analysis of 31 RCT (including all up-to-date CVOT) demonstrated that compared with placebo or no therapy, the SGLT-2I could also significantly reduce the incidence of total (risk ratio (RR) = 0.83) and serious (RR = 0.75) atrial fibrillation [ 70 ].…”