Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study.

AIMS: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium-glucose co-transporter-2 inhibitor class. METHODS: In the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug. RESULTS: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. CONCLUSIONS: Dapagliflozin was well tolerated. The long duration and large number of patient-years in DECLARE-TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin.

Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE-TIMI 58 Study.

OBJECTIVE: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively). CONCLUSIONS: The overall efficacy and safety of dapagliflozin are consistent regardless of age.

DECLARE-TIMI 58: Participants' baseline characteristics.

AIM: To describe the baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) trial, the pivotal study conducted to assess cardiovascular (CV) outcomes with dapagliflozin. METHODS: The DECLARE-TIMI 58 trial will analyse 17 160 patients with type 2 diabetes randomized to treatment with dapagliflozin (10 mg/d) or matching placebo. We analysed their baseline characteristics. RESULTS: The participants' mean ± SD age was 63.8 ± 6.8 years, 62.6% were male, and their mean ± SD diabetes duration was 11.8 ± 7.8 years, glycated haemoglobin 8.3% ± 1.2% (67 mmol/mol ± 9.7 mmol/mol) and body mass index 32.1 ± 6.0 kg/m2 . Randomization included 6971 (40.6%) patients with atherosclerotic CV disease (CVD), and 10 189 (59.4%) patients with multiple risk factors (MRF) for CVD (defined as men age ≥ 55 years or women ≥60 years, with at least one of dyslipidaemia, hypertension or smoking). Patients with CVD compared with patients with MRF were younger (62.5 ± 8.1 vs 64.7 ± 5.6 years), more frequently male (72.1% vs 56.1%), less often used metformin (74.6% vs 81.2%), more often used insulin (44.2% vs 36.4%), and more frequently used statins, aspirin, clopidogrel and ß-blockers (82.2%, 71.1%, 24.7% and 66.6% vs 63.7%, 39.1%, 1.5% and 32.3%, respectively). CONCLUSION: The DECLARE-TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin in addition to standard of care, on CV outcomes in a broad patient population with type 2 diabetes and CVD or MRF for CVD.