Dapagliflozin added to metformin reduces perirenal fat layer in type 2 diabetic patients with Obesity

Abstract

Sodium-glucose co-transporters type 2 inhibitors (SLGT2i) are highly effective in controlling type 2 diabetes, mainly by inducing net glucose output at the proximal renal tubule, but reported beneficial cardiovascular effects suggest broader actions on insulin resistance. Weight loss may be initially explained by glycosuria net caloric output and secondary volumetric excretion, but its maintenance is mainly due to loss of visceral fat mass. Structured ultrasound (US) imaging of abdominal adipose tissue (“eco-obesity”) is a recently described, noninvasive, easily reproducible methodology used to measure 5 consecutive layers of abdominal fat (superficial subcutaneous (SS), deep subcutaneous (DS), preperitoneal (PP), omental (Om) and right perirenal (RK), not assessable by DEXA or CT scan. PP, Om and RK are predictors of metabolic syndrome (MS) with defined cut-off points. To assess the effect of SLGT2i effect on every fat depot we enrolled 29 patients with type 2 Diabetes (HbA1c 6,5–9%) and Obesity (IMC > 30 Kg/m2) in an open-label, randomized, single-center, phase IV trial (EudraCT: 2019-000979-16): the Omendapa trial. Diabetes was diagnosed < 12 months before randomization and all patients were treatment naïve. 14 patients were treated with metformin alone (cohort A) and 15 were treated with metformin + dapaglifozin (cohort B). Anthropometric measures and laboratory tests for glucose, lipid profile, insulin, HOMA, leptin, ultrasensitive-CRP and microalbuminuria (MAL) were done at baseline, 3rd and 6th months. At 6th month, weight loss was − 5.5 ± 5.2 Kg (5.7% from initial weight) in cohort A and − 8.4 ± 4.4 Kg (8.6%) in cohort B. Waist circumference showed a -2.7 ± 3.1cm and − 5.4 ± 2.5cm reduction, respectively (p = 0.011). Both Metformin (-19.4 ± 20.1mm; -21.7%) alone or combined with Dapaglifozin (-20.5 ± 19.4mm; -21.8%) induced significant Om fat reduction. 13.3% of cohort A patients and 21.4% of cohort’s B reached Om thickness below the cut-off for MS criteria. DS, PP, Om and RK fat thickness showed significant reduction within the Met + Dapa group, whereas only DS and RK fat reduced with metformin alone. RK fat relative change was significantly higher in cohort B group compared to cohort A at both kidneys. Om fat loss correlated with leptin, CRP and MAL and RK fat loss correlated with HOMA-IR, only in the Met + Dapa group. US is a useful clinical tool to assess pharmacological efficacy to reduce ectopic fat depots. Both Metformin and Dapaglifozin induce fat loss in layers involved with MS (Om) but combined treatment is particularly effective in RK fat layer reduction and correlates with cardiovascular risk markers. Perirenal fat should be considered as a potential target for cardiovascular dapaglifozin beneficial effects.