medwireNews: A post-hoc analysis of the DECLARE-TIMI 58 trial suggests that the sodium-glucose cotransporter (SGLT)-2 inhibitor dapagliflozin has a favorable safety profile in a broad population of patients with type 2 diabetes.
“The DECLARE-TIMI 58 study is the largest and longest CV [cardiovascular] outcome study conducted with an SGLT2 inhibitor and included a heterogeneous population of patients with type 2 diabetes,” which ranged “from those with increased age and at least one additional CV risk factor to those with established atherosclerotic cardiovascular disease,” say Avivit Cahn (Hadassah Hebrew University Hospital, Jerusalem, Israel) and fellow researchers.
In their safety analysis, the team investigated the occurrence of serious adverse events (AEs), AEs leading to drug discontinuation, and AEs of special interest among 17,143 individuals treated with dapagliflozin or placebo during a median follow-up of 4.2 years, with a focus on “potential safety concerns related to the SGLT2-inhibitors class.”
Cahn and colleagues report in Diabetes, Obesity and Metabolism that dapagliflozin was “well tolerated […] overall and across multiple and clinically relevant subgroups.”
Acute kidney injury (AKI) events occurred significantly less frequently among people treated with dapagliflozin versus placebo, with rates of 1.5% and 2.0%, respectively, and a hazard ratio (HR) of 0.69. These results remained consistent in subgroup analyses, including by age, sex, medication use, and comorbidities.
Serious AEs of AKI were also significantly less common among individuals treated with dapagliflozin compared with placebo (0.8 vs 1.2%; HR=0.64), as were rates of major hypoglycemia (0.7 vs 1.0%; HR=0.68) and bladder cancer (0.3 vs 0.5%; HR=0.57).
On the other hand, Cahn and team found that diabetic ketoacidosis (DKA) events were significantly more common among dapagliflozin- versus placebo-treated patients (0.3 vs 0.1%). However, they stress that DKA “was a rare event,” with 29 occurrences of definite or probable DKA reported in 27 patients in the dapagliflozin group and 12 episodes in 12 patients in the placebo arm.
Genital infections leading to discontinuation of the study drug were more likely to occur in people taking dapagliflozin than those given placebo, with 74 versus seven patients, respectively, experiencing such infections. The researchers say that this finding is “consistent with the known safety profile of SGLT2 inhibitors.”
They report that “[t]here were no differences in other key safety outcomes” in the study, and “[n]o subgroup with significant baseline risk for any complication has been identified.” Rates of amputation, urinary tract infection, fracture, and overall malignancy were comparable in the dapagliflozin and placebo groups.
“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,” say Cahn and team.
They caution, however, that their post-hoc analysis “was not powered to detect differences in relatively rare safety events,” and that their findings have limited generalizability to real-world patients not meeting the inclusion criteria for DECLARE-TIMI 58.
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