**Background:** Statin therapy is a cornerstone for secondary prevention in patients with coronary artery disease (CAD), especially those with diabetes mellitus (DM). High-intensity statin therapy is strongly recommended, but concerns about side effects, including new-onset DM, often lead to underuse and poor adherence. The LODESTAR trial previously showed that a treat-to-target LDL-C strategy (goal 50-70 mg/dL) was non-inferior to high-intensity statin therapy for 3-year composite outcomes in CAD patients. This pre-specified analysis evaluated whether this treatment effect differs by DM status.
**Methods:** This was a pre-specified analysis of the LODESTAR trial, an investigator-initiated, multicenter, randomized, open-label, noninferiority trial conducted at 12 centers in South Korea. Between September 9, 2016 and November 27, 2019, 4400 patients with documented CAD were enrolled. Patients were randomized 1:1 to a treat-to-target strategy (target LDL-C 50-70 mg/dL, with statin dose titration) or high-intensity statin therapy (fixed high-intensity dose). The presence of DM at baseline was defined by history, antidiabetic medication use, fasting glucose ≥126 mg/dL, or HbA1c ≥6.5%. The primary outcome was the 3-year composite of all-cause death, myocardial infarction, stroke, or coronary revascularization. Secondary outcomes included new-onset DM, hospitalization for heart failure, and safety endpoints. Statistical analyses used Cox regression and Kaplan-Meier methods, with p-values for interaction between DM status and treatment strategy.
**Key Results:** Of 4400 patients, 1468 (33%) had DM at baseline. Baseline characteristics were well-balanced between treatment groups within DM strata, except for a higher proportion of chronic kidney disease in the high-intensity statin group among DM patients (15.0% vs 11.2%, p=0.04). Median follow-up was 3.0 years. Among patients with DM, the primary outcome occurred in 10.5% of the treat-to-target group vs 11.1% of the high-intensity statin group (HR 0.94, 95% CI 0.69-1.29, p=0.70). Among patients without DM, rates were 6.9% vs 7.5% (HR 0.93, 95% CI 0.71-1.21, p=0.58). There was no significant interaction between DM status and treatment strategy (p for interaction = 0.94). Individual components of the primary outcome were also comparable. Mean LDL-C levels over 3 years did not differ significantly between strategies in DM patients (64.9 vs 63.7 mg/dL, p=0.19) or non-DM patients (70.4 vs 70.4 mg/dL, p=0.97). The proportion achieving LDL-C <70 mg/dL was similar. In patients without DM, new-onset DM occurred in 8.4% (treat-to-target) vs 10.4% (high-intensity) (HR 0.79, 95% CI 0.62-1.01, p=0.06), and new-onset DM requiring medication was significantly lower in the treat-to-target group (5.1% vs 7.4%, HR 0.68, 95% CI 0.51-0.92, p=0.01). Other safety outcomes were comparable.
**Clinical Implications:** This pre-specified analysis demonstrates that a treat-to-target LDL-C strategy (goal 50-70 mg/dL) is comparable to high-intensity statin therapy for 3-year cardiovascular outcomes in CAD patients, regardless of diabetes status. Importantly, among patients without DM, the treat-to-target approach was associated with a significantly lower risk of new-onset DM requiring medication, suggesting a potential safety advantage. These findings support the use of a treat-to-target strategy as a reasonable alternative to fixed high-intensity statin therapy, particularly in patients where concerns about new-onset DM or drug intolerance exist. The study also highlights that achieving optimal LDL-C reduction often requires combination therapy (e.g., ezetimibe), as less than half of DM patients in the treat-to-target group received high-intensity statins. Limitations include the open-label design, the target LDL-C of <70 mg/dL (now considered less stringent than current European guidelines of <55 mg/dL), and the subgroup nature of the analysis, which may lack power for definitive conclusions.