Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: A randomized cross-over clinical study.

AIM: To evaluate the albuminuria-lowering effect of dapagliflozin, exenatide, and the combination of dapagliflozin and exenatide in patients with type 2 diabetes and microalbuminuria or macroalbuminuria. METHODS: Participants with type 2 diabetes, an estimated glomerular filtration rate (eGFR) of more than 30 ml/min/1.73m2 and an urinary albumin: creatinine ratio (UACR) of more than 3.5 mg/mmol and 100 mg/mmol or less completed three 6-week treatment periods, during which dapagliflozin 10 mg/d, exenatide 2 mg/wk and both drugs combined were given in random order. The primary outcome was the percentage change in UACR. Secondary outcomes included blood pressure, HbA1c, body weight, extracellular volume, fractional lithium excretion and renal haemodynamic variables as determined by magnetic resonance imaging. RESULTS: We enrolled 20 patients, who completed 53 treatment periods in total. Mean percentage change in UACR from baseline was -21.9% (95% CI: -34.8% to -6.4%) during dapagliflozin versus -7.7% (95% CI: -23.5% to 11.2%) during exenatide and -26.0% (95% CI: -38.4% to -11.0%) during dapagliflozin-exenatide treatment. No correlation was observed in albuminuria responses between the different treatments. Numerically greater reductions in systolic blood pressure, body weight and eGFR were observed during dapagliflozin-exenatide treatment compared with dapagliflozin or exenatide alone. Renal blood flow and effective renal plasma flow (ERPF) did not significantly change with either treatment regimen. However, all but four and two patients in the dapagliflozin and dapagliflozin-exenatide groups, respectively, showed reductions in ERPF. The filtration fraction did not change during treatment with dapagliflozin or exenatide, and decreased during dapagliflozin-exenatide treatment (-1.6% [95% CI: -3.2% to -0.01%]; P = .048). CONCLUSIONS: In participants with type 2 diabetes and albuminuria, treatment with dapagliflozin, exenatide and dapagliflozin-exenatide reduced albuminuria, with a numerically larger reduction in the combined dapagliflozin-exenatide treatment group.

Effects of Semaglutide on Albuminuria and Kidney Function in People With Overweight or Obesity With or Without Type 2 Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials.

OBJECTIVE: These post hoc analyses of the Semaglutide Treatment Effect in People with obesity (STEP) 1-3 trials (NCT03548935, NCT03552757, and NCT03611582) explored the effects of semaglutide (up to 2.4 mg) on kidney function. RESEARCH DESIGN AND METHODS: STEP 1-3 included adults with overweight/obesity; STEP 2 patients also had type 2 diabetes. Participants received once-weekly subcutaneous semaglutide 1.0 mg (STEP 2 only), 2.4 mg, or placebo for 68 weeks, plus lifestyle intervention (STEP 1 and 2) or intensive behavioral therapy (STEP 3). Changes in urine albumin-to-creatinine ratio (UACR) and UACR status from baseline to week 68 were assessed for STEP 2. Changes in estimated glomerular filtration rate (eGFR) were assessed from pooled STEP 1-3 data. RESULTS: In STEP 2, 1,205 (99.6% total cohort) patients had UACR data; geometric mean baseline UACR was 13.7, 12.5, and 13.2 mg/g with semaglutide 1.0 mg, 2.4 mg, and placebo, respectively. At week 68, UACR changes were -14.8% and -20.6% with semaglutide 1.0 mg and 2.4 mg, respectively, and +18.3% with placebo (between-group differences [95% CI] vs. placebo: -28.0% [-37.3, -17.3], P < 0.0001 for semaglutide 1.0 mg; -32.9% [-41.6, -23.0], P = 0.003 for semaglutide 2.4 mg). UACR status improved in greater proportions of patients with semaglutide 1.0 mg and 2.4 mg versus placebo (P = 0.0004 and P = 0.0014, respectively). In the pooled STEP 1-3 analyses, 3,379 participants had eGFR data; there was no difference between semaglutide 2.4 mg and placebo in eGFR trajectories at week 68. CONCLUSIONS: Semaglutide improved UACR in adults with overweight/obesity and type 2 diabetes. In participants with normal kidney function, semaglutide did not have an effect on eGFR decline.

Individual variability in response to renin angiotensin aldosterone system inhibition predicts cardiovascular outcome in patients with type 2 diabetes: A primary care cohort study.

AIMS: To assess variability in systolic blood pressure (SBP) and albuminuria (urinary albumin creatinine ratio [UACR]) responses in patients with type 2 diabetes mellitus initiating renin angiotensin aldosterone system (RAAS) inhibition, and to assess the association of response variability with cardiovascular outcomes. MATERIAL AND METHODS: We performed an observational cohort study in patients with type 2 diabetes who started RAAS inhibition between 2007 and 2013 (n = 1600). Patients were identified from general practices in the Netherlands. Individual response in SBP and UACR was assessed during 15 months' follow-up. Patients were categorized as: good responders (∆SBP <0 mm Hg and ∆UACR <0%); intermediate responders (∆SBP <0 mm Hg and ∆UACR >0% or ∆SBP >0 mm Hg and ∆UACR <0%); or poor responders (∆SBP >0 mm Hg and ∆UACR >0%). Multivariable Cox regression was performed to test the association between initial RAAS inhibition response and subsequent cardiovascular outcomes. RESULTS: After starting RAAS inhibition, the mean SBP change was -13.2 mm Hg and the median UACR was -36.6%, with large between-individual variability, both in SBP [5th to 95th percentile: 48.5-20] and UACR [5th to 95th percentile: -87.6 to 171.4]. In all, 812 patients (51%) were good responders, 353 (22%) had a good SBP but poor UACR response, 268 (17%) had a good UACR but poor SBP response, and 167 patients (10%) were poor responders. Good responders had a lower risk of cardiovascular events than poor responders (hazard ratio 0.51, 95% confidence interval 0.30-0.86; P = .012). CONCLUSIONS: SBP and UACR response after RAAS inhibition initiation varied between and within individual patients with type 2 diabetes treated in primary care. Poor responders had the highest risk of cardiovascular events, therefore, more efforts are needed to develop personalized treatment plans for these patients.