Cardioprotective glucose-lowering drugs, statins, and risk of first-time atherosclerotic cardiovascular disease in Denmark: a nationwide cohort study.

Background: We hypothesized that combining cardioprotective glucose-lowering drugs, i.e. sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists, and statins is associated with lower risk of first-time atherosclerotic cardiovascular disease (ASCVD) than using either drug alone. Methods: We identified and followed individuals in Denmark with type 2 diabetes and without preexisting ASCVD from 2012 to 2021. In an active comparator design, individuals initiating a cardioprotective glucose-lowering drug or a dipeptidyl peptidase-4 inhibitor ± statin were compared: i) dipeptidyl peptidase-4 inhibitor (N = 12,298/59,795; 21%), ii) cardioprotective glucose-lowering drug (N = 16,357/59,795; 27%), iii) dipeptidyl peptidase-4 inhibitor plus statin (N = 14,823/59,795; 25%), and iv) cardioprotective glucose-lowering drug plus statin (N = 16,317/59,795; 27%). Also, in a time-varying design with annually updated covariates we compared: i) no cardioprotective drug (N = 113,669/277,747; 41%), ii) cardioprotective glucose-lowering drug (N = 12,225/277,747; 4%), iii) statin (138,405/277,747; 50%), and iv) cardioprotective glucose-lowering drug plus statin (N = 13,448/277,747; 5%). The primary outcome was ASCVD (myocardial infarction, coronary revascularization, stroke, peripheral arterial disease, or coronary death). Findings: In the active comparator and time-varying cohorts during mean follow-ups of 3.2 and 5.9 years, 2546/59,795 (4%) and 28,044/277,747 (10%) developed ASCVD. In the active comparator cohort, multivariable adjusted hazard ratios of ASCVD were 0.87 (95% confidence interval: 0.76-0.98) for cardioprotective glucose-lowering drug, 0.69 (0.63-0.77) for statin, and 0.64 (0.56-0.73) for combined treatment compared with dipeptidyl peptidase-4 inhibitor. Corresponding values in the time-varying cohort were 0.94 (0.89-1.01), 0.70 (0.68-0.72), and 0.67 (0.64-0.70), respectively. Interpretation: In individuals with type 2 diabetes without preexisting ASCVD, statin was associated with substantially lower risk of ASCVD than cardioprotective glucose-lowering drug, while combination of the two drug classes was associated with similar ASCVD risk as statin alone. Funding: Danish Cardiovascular Academy and Danish Heart Foundation.