Abstract
BACKGROUND: Results of cardiovascular outcome trials enabled a shift from "treat-to-target" to "treat-to-benefit" paradigm in the management of type 2 diabetes (T2D). However, studies validating such approach are limited. Here, we examined whether treatment according to international recommendations for the pharmacological management of T2D had an impact on long-term outcomes. METHODS: This was an observational study conducted on outpatient data collected in 2008-2018 (i.e. prior to the "treat-to-benefit" shift). We defined 6 domains of treatment based on the ADA/EASD consensus covering all disease stages: first- and second-line treatment, intensification, use of insulin, cardioprotective, and weight-affecting drugs. At each visit, patients were included in Group 1 if at least one domain deviated from recommendation or in Group 2 if aligned with recommendations. We used Cox proportional hazard models with time-dependent co-variates or Cox marginal structural models (with inverse-probability of treatment weighing evaluated at each visit) to adjust for confounding factors and evaluate three outcomes: major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular mortality (HF-CVM), and all-cause mortality. RESULTS: We included 5419 patients, on average 66-year old, 41% women, with a baseline diabetes duration of 7.6 years. Only 11.7% had pre-existing cardiovascular disease. During a median follow-up of 7.3 years, patients were seen 12 times at the clinic, and we recorded 1325 MACE, 1593 HF-CVM, and 917 deaths. By the end of the study, each patient spent on average 63.6% of time in Group 1. In the fully adjusted model, being always in Group 2 was associated with a 45% lower risk of MACE (HR 0.55; 95% C.I. 0.46-0.66; p < 0.0001) as compared to being in Group 1. The corresponding HF-CVM and mortality risk were similar (HR 0.56; 95%CI 0.47-0.66, p < 0.0001 and HR 0.56; 95% C.I. 0.45-0.70; p < 0.0001. respectively). Sensitivity analyses confirmed these results. No single domain individually explained the better outcome of Group 2, which remained significant in all subgroups. CONCLUSION: Managing patients with T2D according to a "treat-to-benefit" approach based international standards was associated with a lower risk of MACE, heart failure, and mortality. These data provide ex-post validation of the ADA/EASD treatment algorithm.