Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin has demonstrated consistent reductions in risk for cardiovascular (CV) death/ hospitalization for heart failure (HF) and progression of kidney disease, regardless of baseline concomitant use of various CV agents commonly prescribed for HF and kidney disease in patients with type 2 diabetes (T2D), with significant decreases in risk for both even in individuals who are receiving angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs), beta-blockers, and diuretics. These findings were published in JAMA Cardiology.
A prespecified secondary analysis (ClinicalTrials.gov Identifier: NCT01730534) of the randomized, double-blind, multinational Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial was conducted. In DECLARE-TIMI 58, treatment with dapagliflozin vs placebo was assessed in patients with T2D and either atherosclerotic CV disease (ASCVD) or multiple risk factors for ASCVD and a creatinine clearance of 60 mL/min or higher. The DECLARE-TIMI 58 trial was conducted between May 2013 and September 2018. Data derived from the analysis were evaluated between February 2021 and May 2022.
Investigators sought to evaluate whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without the background utilization of CV medications that are commonly used for HF and kidney disease among patients with T2D. The main outcome measures included the composite of CV death or hospitalization for HF; hospitalization for HF alone; and a kidney-specific composite outcome that comprised a persistent 40% or more decrease in estimate glomerular filtration rate [eGFR], end-stage kidney disease, and kidney-related death.
In the prespecified secondary analysis, patients were stratified according to baseline use of the following CV medications: ACE inhibitors, beta-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). Among a total of 17,160 patients in DECLARE-TIMI 58, at baseline, 13,950 used ACE inhibitors/ARBs, 9030 utilized beta-blockers, 6205 used diuretics, and 762 utilized MRAs.
Results of the study show that changes in eGFR and blood pressure at 48 months with dapagliflozin vs placebo does not differ significantly regardless of concurrent treatment being used. Despite background use of selected agents, however, dapagliflozin therapy is associated with consistent reductions in risk for CV death/hospitalization for HF, hospitalization for HF alone, and the kidney-specific composite outcome (hazard ratio [HR] range, 0.50; 95% CI, 0.39-0.63 to HR 0.82; 95% CI, 0.72-0.95; P >.05 for each interaction).
Among 4243 participants being treated with ACE inhibitors/ARBs plus beta-blockers plus diuretics, dapagliflozin reduces the risk for CV death/hospitalization for HF by 24% (HR, 0.76; 95% CI, 0.62-0.93) and of the kidney-specific composite outcome by 38% (HR, 0.62; 95% CI, 0.44-0.87). Further, no significant treatment interactions are reported with the concomitant CV medications for the adverse events of volume depletion, acute kidney injury, or hyperkalemia (HR range, 0.12; 95% CI, 0.02-0.99 to HR, 1.04; 95% CI, 0.83-1.32; P >.05 for each interaction).
Among the limitations of the study is the fact that the trial is not powered to detect event reductions in individual subgroups, based on the background utilization of CV medications and treatment multiplied by subgroup interactions between the subgroups. Additionally, the researchers are unable to explore the treatment interaction across a range of doses and change in dosage in the various medications utilized during the trial, because they did not record the dose used of each medication.
“These data support efforts to develop and implement strategies to optimize the use of SGLT2 inhibitors in a broad range of patients with type 2 diabetes regardless of background therapy,” the study authors noted.
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Oyama K, Raz I, Cahn A, et al. Efficacy and safety of dapagliflozin according to background use of cardiovascular medications in patients with type 2 diabetes: a prespecified secondary analysis of a randomized clinical trial. JAMA Cardiol. Published online July 20, 2022. doi:10.1001/jamacardio.2022.2006