Twenty-year epidemiologic study on LDL-C levels in relation to the risks of atherosclerotic event, hemorrhagic stroke, and cancer death among young and middle-aged population in China

•The lower the low-density lipoprotein cholesterol (LDL-C) in a range of 40–160 mg/dL, the lower the long-term atherosclerotic cardiovascular disease risk. •Lower LDL-C was not associated with the long-term risk of cancer death in Chinese. •LDL-C <70 mg/dL increased risk of hemorrhagic stroke for uncontrolled hypertension. •LDL-C 70–99 mg/dL may be a proper level for all individuals in primary prevention. Background Lowering elevated low-density lipoprotein cholesterol (LDL-C) levels is a key strategy in primary prevention of atherosclerotic cardiovascular disease (ASCVD), but the optimal LDL-C level is not well established in Chinese. Objective We aimed to search for the LDL-C level that associated with the lowest long-term ASCVD risk without excess risk of other life-threatening diseases. Methods Totally 20,954 participants aged 35–64 years were followed up for about 20 years. Cumulative and relative risks of ASCVD, hemorrhagic stroke, and cancer death, according to baseline LDL-C levels, were calculated using modified Kaplan-Meier and Fine & Gray models, considering competing risks. Preventable ASCVD cases against increased harms were estimated by simulation, replacing elevated LDL-C levels with lower LDL-C levels in the risk prediction models for individuals with different ASCVD risk. Results The lower the baseline LDL-C, the lower the 20-year risk of ASCVD in participants with LDL-C levels ranging from the lowest category (<40 mg/dL) to the highest (≥160 mg/dL). We found no association between lower LDL-C levels and long-term risk of cancer death. If all people with LDL-C ≥130 mg/dL were assumed to have the LDL-C level <70 mg/dL and other risk factors remained unchanged, a substantial number of ASCVD cases would be preventable. However, for uncontrolled hypertensive patients, the LDL-C level <70 mg/dL would have extra harm from hemorrhagic stroke. Conclusion Participants with baseline LDL-C <40 mg/dL had the lowest ASCVD risk. An excess risk of hemorrhagic stroke was observed in patients with uncontrolled hypertension and LDL-C <70 mg/dL. LDL-C 70–99 mg/dL had reasonably low ASCVD risk without excess risk of other life-threatening diseases. Lowering elevated low-density lipoprotein cholesterol (LDL-C) levels is a key strategy in primary prevention of atherosclerotic cardiovascular disease (ASCVD), but the optimal LDL-C level is not well established in Chinese. We aimed to search for the LDL-C level that associated with the lowest long-term ASCVD risk without excess risk of other life-threatening diseases. Totally 20,954 participants aged 35–64 years were followed up for about 20 years. Cumulative and relative risks of ASCVD, hemorrhagic stroke, and cancer death, according to baseline LDL-C levels, were calculated using modified Kaplan-Meier and Fine & Gray models, considering competing risks. Preventable ASCVD cases against increased harms were estimated by simulation, replacing elevated LDL-C levels with lower LDL-C levels in the risk prediction models for individuals with different ASCVD risk. The lower the baseline LDL-C, the lower the 20-year risk of ASCVD in participants with LDL-C levels ranging from the lowest category (<40 mg/dL) to the highest (≥160 mg/dL). We found no association between lower LDL-C levels and long-term risk of cancer death. If all people with LDL-C ≥130 mg/dL were assumed to have the LDL-C level <70 mg/dL and other risk factors remained unchanged, a substantial number of ASCVD cases would be preventable. However, for uncontrolled hypertensive patients, the LDL-C level <70 mg/dL would have extra harm from hemorrhagic stroke. Participants with baseline LDL-C <40 mg/dL had the lowest ASCVD risk. An excess risk of hemorrhagic stroke was observed in patients with uncontrolled hypertension and LDL-C <70 mg/dL. LDL-C 70–99 mg/dL had reasonably low ASCVD risk without excess risk of other life-threatening diseases.