3B-06 - Timing of antidiabetic medication initiation and risk of major adverse cardiovascular events and mortality: A target trial emulation with clone-censor-weight approach

Background: In individuals above the diagnostic threshold for type 2 diabetes (T2D), timely initiation of antidiabetic medication (ADM) is critical for early glycemic control and reducing long-term cardiovascular risk. However, evidence regarding the impact of earlier initiation of ADM on the risk of cardiovascular events and mortality remains limited.

Objectives: To assess the association between the timing of ADM initiation and risk of major adverse cardiovascular events (MACE) and mortality in individuals with HbA1c ≥ 6.5%.

Methods: We used health screening records from a tertiary hospital linked to national health insurance claims in Korea (2013-2022). Individuals with HbA1c ≥ 6.5% were included, with the date of their first-ever HbA1c ≥ 6.5% as cohort entry date (CED). Using the clone-censor-weight approach, eligible individuals were replicated and assigned to one of three treatment groups at CED: ADM initiation within 6 months (early), 12 months (delayed), or no initiation during the 5-year follow-up (control). Individuals were censored if they deviate from the assigned group. Time-varying inverse probability of censoring weights were estimated using a pooled logistic regression model. The co-primary outcomes were 3-point MACE (myocardial infarction, stroke, and all-cause mortality) and all-cause mortality. We calculated 5-year absolute risk, risk difference (RD), and risk ratio (RR) using survival probabilities derived from the cumulative baseline hazard function of weighted Cox models. We performed 1000-sample non-parametric bootstrapping to obtain 95% confidence intervals (CI).

Results: Among 10,474 participants (mean age 47.8 years; 74.2% males) cloned into three treatment strategies, 2,923 (27.9%) adhered to early group, 4,178 (39.9%) adhered to delayed group, and 4,020 (38.4%) adhered to control group. The 5-year absolute risk of MACE was 0.55% in early group, 0.77% in delayed group, and 0.80% in control group. Compared to control, the weighted 5-year RD and RR were -0.24% (95% CI, -0.65% to 0.25%) and 0.69 (0.37-1.40) in early group, and -0.03% (-0.42% to 0.44%) and 0.96 (0.59-1.79) in delayed group, respectively. For the all-cause mortality, the 5-year risk was 0.25% in early group, 0.32% in delayed group, and 0.46% in control group. Compared to control, the weighted 5-year RD and RR were -0.21% (95% CI, -0.50% to 0.08%) and 0.54 (0.24-1.26) in early group, and -0.14% (-0.43% to 0.14%) and 0.69 (0.34-1.43) in delayed group, respectively.

Conclusions: Earlier ADM initiation after exceeding diagnostic threshold for T2D was associated with a trend for lowered risks of MACE and mortality, though the results were not statistically significant. Further studies are warranted to clarify the potential benefits of timely treatment initiation.