Jürgen Harreiter1, Ivica Just2,3, Michael Leutner1, Magdalena Bastian1, Helmut Brath4, Christian Schelkshorn5, Radka Klepochova2,3, Martin Krššák2,3, Alexandra Kautzky-Willer1. 1. Gender Medicine Unit, Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria. 2. Department of Biomedical Imaging and Image-Guided Therapy, High-Field MR Center, Medical University of Vienna, Vienna, Austria. 3. Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna, Vienna, Austria. 4. Diabetes Outpatient Clinic, Health Centre Favoriten, Vienna, Austria. 5. Department of Medicine, State Hospital Stockerau, Stockerau, Austria.
Abstract
AIMS: To investigate the potential synergistic effects of combined exenatide (EXE) and dapagliflozin (DAPA) versus (PLAC) placebo and DAPA on hepatocellular lipid (HCL) reduction after 24 weeks of treatment. MATERIALS AND METHODS:Thirty patients with type 2 diabetes were randomized to weekly EXE and daily DAPA (n = 16) or weekly PLAC and daily DAPA (n = 14). Inclusion criteria were glycated haemoglobin (HbA1c) 48 to 97 mmol/mol (6.5-11%), age 18 to 75 years, body mass index (BMI) ≥25 kg/m2 and metformin ≥1000 mg. The primary endpoint, HCL levels, were measured at baseline and after 24 weeks of treatment using magnetic resonance spectroscopy. Between-group effects were analysed using general linear models, adjusted for baseline outcome variables, age, sex and BMI. Within-group differences were assessed using a paired t-test. RESULTS: After 24 weeks, HCLs were reduced in both treatment groups (absolute change from baseline: EXE + DAPA -4.4%, 95% confidence interval [CI] -8.2, -0.7, P < 0.05; PLAC + DAPA -3.9%, 95% CI -6.0, -1.7, P < 0.01; relative change: EXE + DAPA -35.6%, PLAC + DAPA -32.3%) with no difference between groups. Similar findings were observed for subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). HbA1c (EXE + DAPA -17.8 mmol/mol, [95% CI -24.8, -10.8], P <0.001; PLAC + DAPA -6.9 mmol/mol, [95% CI -10.5, -3.3], P = 0.001) and fasting glucose significantly decreased in both groups, although EXE + DAPA achieved better glycaemic control than PLAC + DAPA (adjusted difference: HbA1c -6.0 mmol/mol [95% CI -9.7, -2.2], P < 0.01). Body weight was reduced in both treatment groups (EXE + DAPA -7.3 kg, 95% CI -9.9, -4.8, P <0.001; PLAC + DAPA -4.6 kg, 95% CI -7.4, -1.8, P <0.01) with comparable results between groups. Changes in HCLs and weight, hip and waist circumference, VAT and SAT were positively associated. CONCLUSION: After 24 weeks, HCLs were significantly but comparably reduced in the EXE + DAPA and PLAC + DAPA groups, despite significantly better glycaemic control in the combined group EXE + DAPA. Changes in HCLs were associated with weight loss and reduction of visceral adiposity, but not with glucose control. Further studies are necessary to evaluate possible additional long-term effects of a combined treatment.
RCT Entities:
AIMS: To investigate the potential synergistic effects of combined exenatide (EXE) and dapagliflozin (DAPA) versus (PLAC) placebo and DAPA on hepatocellular lipid (HCL) reduction after 24 weeks of treatment. MATERIALS AND METHODS: Thirty patients with type 2 diabetes were randomized to weekly EXE and daily DAPA (n = 16) or weekly PLAC and daily DAPA (n = 14). Inclusion criteria were glycated haemoglobin (HbA1c) 48 to 97 mmol/mol (6.5-11%), age 18 to 75 years, body mass index (BMI) ≥25 kg/m2 and metformin ≥1000 mg. The primary endpoint, HCL levels, were measured at baseline and after 24 weeks of treatment using magnetic resonance spectroscopy. Between-group effects were analysed using general linear models, adjusted for baseline outcome variables, age, sex and BMI. Within-group differences were assessed using a paired t-test. RESULTS: After 24 weeks, HCLs were reduced in both treatment groups (absolute change from baseline: EXE + DAPA -4.4%, 95% confidence interval [CI] -8.2, -0.7, P < 0.05; PLAC + DAPA -3.9%, 95% CI -6.0, -1.7, P < 0.01; relative change: EXE + DAPA -35.6%, PLAC + DAPA -32.3%) with no difference between groups. Similar findings were observed for subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). HbA1c (EXE + DAPA -17.8 mmol/mol, [95% CI -24.8, -10.8], P <0.001; PLAC + DAPA -6.9 mmol/mol, [95% CI -10.5, -3.3], P = 0.001) and fasting glucose significantly decreased in both groups, although EXE + DAPA achieved better glycaemic control than PLAC + DAPA (adjusted difference: HbA1c -6.0 mmol/mol [95% CI -9.7, -2.2], P < 0.01). Body weight was reduced in both treatment groups (EXE + DAPA -7.3 kg, 95% CI -9.9, -4.8, P <0.001; PLAC + DAPA -4.6 kg, 95% CI -7.4, -1.8, P <0.01) with comparable results between groups. Changes in HCLs and weight, hip and waist circumference, VAT and SAT were positively associated. CONCLUSION: After 24 weeks, HCLs were significantly but comparably reduced in the EXE + DAPA and PLAC + DAPA groups, despite significantly better glycaemic control in the combined group EXE + DAPA. Changes in HCLs were associated with weight loss and reduction of visceral adiposity, but not with glucose control. Further studies are necessary to evaluate possible additional long-term effects of a combined treatment.