Fixed-dose vs loose-dose combination antidiabetic therapy and cardiorenal outcomes in type 2 diabetes: a nationwide comparative effectiveness study.

Background: Combination therapy is gaining attention in type 2 diabetes management due to its potential to reach glycaemic goals within a shorter period. However, the long-term comparative cardiorenal effectiveness of fixed- versus loose-dose combinations remains unclear. This study aimed to assess whether oral antidiabetic fixed-dose combination (FDC) therapy is associated with improved cardiorenal outcomes in adults with type 2 diabetes compared with loose-dose combination (LDC) therapy. A secondary objective was to evaluate the mediating role of medication adherence in these associations.

Methods: This population-based, new-user, active-comparator cohort study used Swedish national registers. Propensity score matching without replacement was applied. Study outcomes included acute myocardial infarction, atrial fibrillation, unstable angina, heart failure, ischaemic stroke, and eGFR < 30 ml/min/1.73m². Associations with cardiorenal outcomes were assessed using Cox regression. Adherence was defined as the proportion of days covered > 80% during the first year.

Results: The median follow-up time was 4.0 years for cardiovascular outcomes and 3.8 years for kidney outcomes. In the matched cohort (mean age 62 years; 67% male), FDC users had higher treatment adherence (68.6 vs. 46.5%). FDC was associated with a lower rate of heart failure (HR = 0.88; 95% CI 0.79, 0.99), with adherence mediating 47% of this association. In people aged ≥ 65 years, FDC was associated with a lower rate of heart failure (HR = 0.79; 95% CI 0.69, 0.91). The observed association was attenuated with further matching for diabetes duration or when drugs were matched at the ATC code level. No associations between FDC use and other outcomes were identified.

Conclusions: FDC therapy in people with type 2 diabetes was associated with a lower rate of heart failure, particularly in older adults. Higher medication adherence appeared to mediate nearly half of this association.