Intensive vs More Intensive Lipid-Lowering Therapy and Plaque Regression in Statin-Naive Patients

Importance: Prior imaging studies (predominantly using intravascular ultrasound) have demonstrated modest plaque regression with lipid-lowering therapy in stable coronary artery disease (CAD). The effect of initiating intensive lipid-lowering therapy on coronary plaque regression across the entire coronary tree in treatment-naive patients remains uncertain. Objective: To report the prespecified secondary imaging end points of the FLOWPROMOTE trial by comparing the effects of intensive vs more intensive lipid-lowering therapy on plaque regression in statin-naive patients with stable CAD and to assess the association between achieved low-density lipoprotein cholesterol (LDL-C) levels and plaque regression. Design, Setting, and Participants: FLOWPROMOTE was a multicenter randomized clinical trial enrolling statin-naive patients with newly diagnosed stable CAD, defined by a coronary computed tomography angiography (CTA) stenosis greater than 50% and fractional flow reserve CT less than or equal to 0.80. Coronary CTA was performed at baseline and repeated at 9 and 18 months. Study data were analyzed from February 2025 to January 2026. Interventions: Patients were randomized to intensive lipid-lowering therapy (atorvastatin 40 mg) or more intensive lipid-lowering therapy (rosuvastatin 40 mg plus ezetimibe 10 mg) for 18 months. Main Outcomes and Measures: Prespecified secondary end points included changes in total plaque volume (TPV), noncalcified plaque volume (NCPV), and calcified plaque volume (CPV) across all coronary vessels at 9 and 18 months compared with baseline. Results: A total of 104 patients (mean [SD] age, 64 [9] years; 82 male [79%]) were included in this analysis, with 52 patients in the intensive group and 52 patients in the more intensive group. LDL-C levels decreased from 119.7 to 69.5 mg/dL (-38%) with intensive therapy and from 127.4 to 42.5 mg/dL (-65%) with more intensive therapy (between-group P < .001). At 18 months, both TPV and NCPV decreased in both groups, with significantly greater regression in the more intensive-therapy group. TPV was reduced by -69.8 mm3 (-21.1%) with more intensive therapy vs -39.0 mm3 (-13.6%) with intensive therapy (between-group difference, -30.9 mm3; 95% CI, -57.2 to -4.5 mm3; P = .02), and NCPV was reduced by -82.3 mm3 (-28.2%) vs -53.5 mm3 (-20.0%), respectively (between-group difference, -28.9 mm3; 95% CI, -53.2 to -4.6 mm3; P = .02). CPV increased similarly in both groups. Regression of TPV occurred in 90% of patients receiving more intensive therapy compared with 76% receiving intensive therapy (47 of 52 [90%] vs 38 of 51 [75%]; P = .05), and regression of NCPV was observed in 98% vs 77% (51 of 52 [98%] vs 39 of 51 [77%]; P =.001). Lower achieved LDL-C levels were linearly associated with greater regression of TPV and NCPV. Conclusions and Relevance: This secondary analysis of the FLOWPROMOTE randomized clinical trial demonstrated that in statin-naive patients with CAD, more intensive lipid-lowering therapy was associated with significantly greater regression of total and noncalcified coronary plaque burden compared with intensive therapy. The extent of plaque regression was related to achieved LDL-C levels, supporting the potential for partial reversal of coronary atherosclerosis with intensive lipid reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04737408.