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

Abstract

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.

Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors

“…Though our experimental groups are comparable regarding mean age, 5 patients in the AKI group were 75 years or older, as compared with 1 patient, only, in the non-AKI group. Though this difference falls short of statistical significance, it is in line with our concept of the role of medullary hypoxia and with the recently reported trend of increased rate of dehydration and AKI among patients in this age group, noted by sub-group evaluation of the DECLAIR safety analysis [36].…”

Sodium–glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes

“…On the other hand, specific trials that evaluated both the efficacy and safety of SGLT-2i in older patients with T2D, especially in those > 75 years, are still lacking and only very limited data are available from observational studies [57]. The post-hoc analysis of both EMPA-REG [58] and DECLARE [59] trials confirms that the efficacy/safety profile of these two SGLT-2i is unchanged by age, even with some signal of greater efficacy in patients older than 65 years of age. In particular, a significant interaction (P = 0.01) was reported in EMPA-REG trial [58] regarding the primary cardiovascular composite end point with better results in patients with T2D aged ≥ 65 years versus < 65 years.…”

“…The results of post-hoc analyses [58,59] or real-world databases [71] are reassuring about both the efficacy and safety of SGLT-2i in older patients with T2D, for whom the choice of the optimal drug is often limited by subjective (health state of patient) and objective (side effects of the antihyperglycemic drug) considerations. SGLT-2is can be used as an add-on therapy in selected and healthy older patients with T2D, especially those who are overweight and have uncontrolled hypertension.…”

Cardiovascular outcomes and safety with linagliptin, a dipeptidyl peptidase‐4 inhibitor, compared with the sulphonylurea glimepiride in older people with type 2 diabetes: A subgroup analysis of the randomized CAROLINA trial

“…CAROLINA is the longest randomized, double‐blind, multinational CVOT of a glucose‐lowering drug and the only study to have had an active comparator from a different, frequently used class, as well as a relatively large number of participants aged over 65 and 75 years. The few other analyses of elderly patient outcomes from recent CVOTs have mostly been limited to comparisons with placebo 9,38–42 . The present study therefore expands the evidence base for glucose‐lowering treatment of older people.…”