Abstract Body (Do not enter title and authors here): Introduction:
Cardioprotective glucose-lowering drugs including sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, and lipid-lowering statins are both aimed at preventing morbidity and mortality in individuals with type 2 diabetes. The importance of combining cardioprotective glucose-lowering drugs and statins in a real-world setting is unknown, and this was never tested in a 2-by-2 randomized trial.

Hypotheses:
We tested the hypothesis that combination of cardioprotective glucose-lowering drug and statin is associated with lower risk of all-cause mortality than using either drug alone.

Aims:
We investigated the association with all-cause mortality of combined treatment of cardioprotective glucose-lowering drug with statin versus either drug alone versus no drugs, in a nationwide real-world setting.

Methods:
From January 2013 through December 2021, we identified all individuals with type 2 diabetes living in Denmark. We categorized four groups according to treatment status: i) both cardioprotective glucose-lowering drug and statin, ii) cardioprotective glucose-lowering drug alone, iii) statin alone, and iv) neither cardioprotective glucose-lowering drug nor statin. First, using a simple cohort design, we followed 197,507 individuals with type 2 diabetes from January 2015 through December 2021. Second, using a time-varying cohort design, we followed all 354,979 individuals with type 2 diabetes and updated their treatment and covariate status annually from 2013 through 2021. All-cause mortality was assessed from the nationwide Danish Central Person Registry, which is 100% complete.

Results:
During mean follow-ups of 6.1 and 6.0 years, 50,571 and 80,712 individuals died in the simple and time-varying cohorts. Compared with nonusers of cardioprotective glucose-lowering drug or statin, the multivariable adjusted hazard ratios of all-cause mortality were 0.60 (95% confidence interval: 0.57–0.63) for combined use of cardioprotective glucose-lowering drug and statin, 0.76 (0.74–0.77) for treatment with statin alone, and 0.76 (0.70–0.82) for treatment with cardioprotective glucose-lowering drug alone. Corresponding values in the time-varying cohort were 0.43 (0.42-0.45), 0.63 (0.62-0.64), and 0.61 (0.58-0.64), respectively.

Conclusions:
In individuals with type 2 diabetes, treatment with a cardioprotective glucose-lowering drug and statin in combination was associated with a lower risk of all-cause mortality than using either drug alone.