Background: Genetic studies consistently demonstrate that individuals born with reduced Cholesteryl Ester Transfer Protein (CETP) activity experience lower rates of atherosclerotic vascular disease throughout their lives. In contrast, short-term randomized controlled trials of CETP inhibitors have yielded mixed results, with only one of four trials reporting a reduction in clinical events. Several theories have been proposed to explain this discrepancy, but none fully account for the central mechanism of atherosclerosis: the cumulative lifetime exposure to circulating low-density lipoprotein (LDL) particles in the arterial walls. Objectives: We aimed to reconcile these conflicting findings by examining the relationship between cumulative LDL exposure and atherosclerosis risk across both genetic studies and clinical trials. Methods: We analyzed 679 carriers of CETP protein-truncating variants (resulting in reduced or non-functional CETP protein) and 505,837 non-carriers in a population with 95,568 atherosclerosis events. Additionally, we assessed treatment effects relative to cumulative LDL reductions in 34 cardiovascular prevention trials involving 328,036 participants and 53,161 events. Results: Heterozygous CETP protein-truncating variant carrier status reduced atherosclerotic disease risk (odds ratio, 0.70; 95% confidence interval, 0.57– 0.85; P=5×10-4). In clinical trials, we observed a significant interaction between the magnitude and duration of LDL lowering on treatment effects (hazard ratio, 0.69 per 10–mmol/L× years; 95% confidence interval, 0.52– 0.90; P=0.007), supporting that reducing cumulative LDL exposure is key to lowering cardiovascular risk. When comparing genetics with trial outcomes, accounting for differences in timing, duration, and follow-up, we observed consistent effects on atherosclerosis-related events per LDL years across genetic and pharmacological CETP inhibition, as well as with statins, ezetimibe, PCSK9 inhibitors, and familial hypercholesterolemia-associated variants (hazard ratio, 0.74 and 0.69 per 10–mmol/L×years, respectively). This suggests that CETP inhibition reduces cardiovascular risk primarily through LDL. Notably, several trials failed to achieve sufficient cumulative LDL reduction to impact clinical events, and this was not unique to CETP inhibitors. Conclusion: Our findings indicate that future CETP inhibitor trials achieving substantial and sustained LDL reduction will demonstrate efficacy in preventing cardiovascular events. These results highlight the importance of long-term LDL lowering and support further investigation of CETP inhibition as a strategy for cardiovascular prevention.

Fredrik Landfors is a part-time clinical scientist at Lipigon Pharmaceuticals AB. John J.P. Kastelein is the chief scientific officer of NewAmsterdam Pharma N.V. Elin Chorell has no conflicts of interest to declare.

This work was supported by grants from the Northern Sweden Heart Fund, and received financial support from New Amsterdam Pharma Company N.V.

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This study analyzed data from the UK Biobank under Application Number 148828. The North West Multi-centre Research Ethics Committee (MREC) gave ethical approval for this work that covers all research undertaken using the UK Biobank resource (REC reference: 16/NW/0274). All participants provided written informed consent at recruitment. This research was conducted in accordance with the principles of the Declaration of Helsinki.

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