Sodium-glucose co-transporter 2 (SGLT2) inhibitors are glucose-lowering drugs that reduce plasma glucose levels by inhibiting glucose and sodium reabsorption in the kidneys, thus resulting in glucosuria. Their effects consequently include reductions in HbA1c, blood glucose levels, and blood pressure, but also reductions in body weight and adiposity. The ability to reduce body weight is consistently observed in individuals taking SGLT2 inhibitors, but this weight loss is moderate due to counter-regulatory mechanisms striving to maintain body weight. This has prompted exploration of SGLT2 inhibitors in combination with other agents acting via decreased food intake, e.g., glucagon-like peptide 1 receptor agonists (GLP1-RAs). The bodyweight effects are promising, and together with the signs of prevention of cardiovascular and renal events, such combinations including SGLT2 inhibitors are appealing. The weight loss is clinically important, as most individuals with type 2 diabetes are overweight or obese, but also because there is an unmet need for safe, effective, and durable weight loss interventions in obese individuals without diabetes.
AimsTo explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes.Materials and methodsIn this single‐centre, double‐blind trial, we randomized 50 obese adults without diabetes (aged 18–70 years; body mass index 30–45 kg/m2) to oral dapagliflozin 10 mg once daily plus subcutaneous long‐acting exenatide 2 mg once weekly or placebo. MRI was used to assess change in body composition. Participants were instructed to follow a balanced diet and exercise moderately.ResultsOf 25 dapagliflozin/exenatide‐ and 25 placebo‐treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was −4.13 kg (95% confidence interval −6.44, −1.81; P < .001), which was mostly attributable to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% of participants achieved ≥5% body weight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P < .01). The difference in SBP change for dapagliflozin/exenatide versus placebo was −6.7 mm Hg. As expected, nausea and injection‐site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only two and three participants, respectively, discontinued because of adverse events.ConclusionsCompared with placebo, dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes.
PurposeHere, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1.MethodsHuman SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 non-diabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes.ResultsFKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake.ConclusionsFKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.
AimsDapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes.Materials and methodsObese adults without diabetes (N = 50; aged 18‐70 years; body mass index, 30‐45 kg/m2) were initially randomized to double‐blind oral dapagliflozin 10 mg once daily plus subcutaneous long‐acting exenatide 2 mg once weekly or to placebo. They entered an open‐label extension from 24 to 52 weeks during which all participants received active treatment.ResultsOf the original 25 dapagliflozin + exenatide‐treated and 25 placebo‐treated participants, respectively, 21 (84%) and 17 (68%) entered the open‐label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (−4.5 and −5.7 kg), total adipose tissue volume (−3.8 and −5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (−9.8 and −12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo → dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection‐site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event‐related withdrawals between placebo and active treatment periods was observed.ConclusionsDapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes.
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