Combination of cardioprotective glucose-lowering drugs and statins on cardiovascular mortality in diabetes: a nationwide cohort study

AIMS: In individuals with type 2 diabetes, we tested the hypothesis that a combination of a cardioprotective glucose-lowering drug, either a sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist, and statin is associated with a lower risk of cardiovascular mortality than either drug alone. METHODS AND RESULTS: From 2012 through 2021 in an active comparator cohort design, 75 285 individuals in Denmark with type 2 diabetes on metformin monotherapy were followed from the date when they initiated a second-line glucose-lowering therapy. Treatment categories were: (i) dipeptidyl peptidase-4 inhibitor, reference, (ii) dipeptidyl peptidase-4 inhibitor and statin, (iii) cardioprotective glucose-lowering drug, and (iv) cardioprotective glucose-lowering drug and statin. The primary outcome was cardiovascular mortality. Secondary outcomes were mortality by other causes, all-cause mortality, and atherosclerotic cardiovascular disease (ASCVD). During mean follow-up of 3.2 years, 5764 individuals died, 1301 by a cardiovascular cause. Compared with the dipeptidyl peptidase-4 inhibitor alone, adjusted hazard ratios for cardiovascular mortality were 0.54 (95% confidence interval: 0.45-0.65) for the combination of cardioprotective glucose-lowering drug and statin, 0.73 (0.64-0.84) for dipeptidyl peptidase-4 inhibitor and statin, and 0.67 (0.53-0.85) for cardioprotective glucose-lowering drug alone. Corresponding hazard ratios for all-cause mortality were 0.63 (0.58-0.69), 0.78 (0.73-0.83), and 0.77 (0.70-0.86), and for ASCVD 0.61 (0.54-0.68), 0.72 (0.65-0.78), and 0.80 (0.71-0.90), respectively. CONCLUSION: In individuals with type 2 diabetes, treatment with a combination of cardioprotective glucose-lowering drug and statin was associated with a lower risk of cardiovascular mortality than using either drug alone.