Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial.

AIMS: Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death. METHODS AND RESULTS: DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo. CONCLUSION: In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.

Sustained 52-week efficacy and safety of triple therapy with dapagliflozin plus saxagliptin versus dual therapy with sitagliptin added to metformin in patients with uncontrolled type 2 diabetes.

AIMS: To compare the efficacy and safety of an intensification strategy of early triple combination therapy with dapagliflozin (DAPA) plus saxagliptin (SAXA) to a dual therapy strategy with sitagliptin (SITA) in patients with type 2 diabetes who are inadequately controlled with metformin (MET) monotherapy. MATERIALS AND METHODS: This multinational, active-controlled, parallel-group phase 3b trial randomized 461 patients, at least 18 years of age, with glycated haemoglobin (HbA1c) of 8%-10.5% (64-91 mmol/mol), to either DAPA plus SAXA or SITA, added to MET, for a 26-week double-blind treatment period and an extension of a 26-week blinded treatment period. RESULTS: Mean (± SD) baseline HbA1c was 8.8% ± 0.9% (73.0 ± 9.3 mmol/mol). DAPA plus SAXA (n = 232) provided a greater reduction from baseline in HbA1c at Weeks 26 and 52 compared with SITA (n = 229) (adjusted mean ± SE change, Week 26: -1.41 ± 0.07% vs -1.07 ± 0.07% [-15.4 ± 0.8 mmol/mol vs 11.7 ± 0.8 mmol/mol]; P = 0.0008; Week 52: -1.29 ± 0.08% vs -0.81 ± 0.09% [14.1 ± 0.9 mmol/mol vs 8.9 ± 1.0 mmol/mol]). The between-group difference in adjusted mean (95% CI) change from baseline in HbA1c increased from -0.34 (-0.54, -0.14) at Week 26 to -0.48 (-0.71, -0.25) at Week 52. DAPA plus SAXA was generally well tolerated and the incidence of adverse events was similar in both treatment arms. CONCLUSIONS: Early intensification to triple therapy with DAPA plus SAXA results in better, more durable glycaemic control than addition of SITA only (dual therapy) in patients with high HbA1c levels who are uncontrolled with MET monotherapy.

Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes.

OBJECTIVE: To compare the efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin vs glimepiride as add-on to metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 52-week, multicentre, double-blind, active-controlled study (NCT02471404) randomized (1:1:1) patients (n = 939; HbA1c 7.5%-10.5%) on metformin monotherapy (≥1500 mg/day) to add-on dapagliflozin 10 mg, dapagliflozin 10 mg plus saxagliptin 5 mg, or glimepiride 1 to 6 mg (titrated). The primary efficacy end point was change in HbA1c from baseline to Week 52. RESULTS: Baseline mean age, diabetes duration and HbA1c were 58.4 years, 7.0 years and 8.3%, respectively. Adjusted mean HbA1c change from baseline was -1.20% with dapagliflozin plus saxagliptin and -0.82% with dapagliflozin, vs -0.99% with glimepiride (mean dose at Week 52, 4.6 mg). Changes in body weight (-3.2 kg and -3.5 kg vs +1.8 kg) and systolic blood pressure (SBP; -6.4 mm Hg and -5.6 mm Hg vs -1.6 mm Hg) were significantly greater with dapagliflozin plus saxagliptin and dapagliflozin than with glimepiride. FPG decreased significantly with dapagliflozin plus saxagliptin compared with glimepiride (-2.1 mmol/L vs -1.5 mmol/L) and was similar with dapagliflozin (-1.6 mmol/L) compared with glimepiride. Confirmed incidence of hypoglycaemia was lower with dapagliflozin regimens than with glimepiride (0 and 1 vs 13 patients) and fewer patients required rescue. Genital infections were more frequent with dapagliflozin; other AE profiles were similar. CONCLUSIONS: Dapagliflozin, saxagliptin and metformin improved glycaemic control compared with glimepiride plus metformin; add-on of dapagliflozin alone showed efficacy similar to that of glimepiride. Both dapagliflozin regimens decreased body weight and SBP, with a lower incidence of hypoglycaemia compared with glimepiride.