The log-linear low-density lipoprotein (LDL) hypothesis suggests that relative risk reduction is constant but that there are diminishing absolute benefits. For example, reducing LDL cholesterol level by 0.78 mmol/L (30 mg/dL) is associated with a 24% relative risk reduction in all instances, but the amount of absolute benefit is much greater when LDL cholesterol level is reduced from 5.69 mmol/L (220 mg/dL) to 4.91 mmol/L (190 mg/dL) than from 2.59 mmol/L (100 mg/dL) to 1.81 mmol/L (70 mg/dL). Absolute benefit is also greater when higher-risk patients (top) compared with lower-risk patients (bottom) are being treated. The top panel predicts reduction in cardiovascular (CV) risk for a 65-year-old white woman with type 2 diabetes mellitus and systolic blood pressure of 145 mm Hg, high-density lipoprotein cholesterol level of 0.54 mmol/L (21 mg/dL), triglyceride level of 3.39 mmol/L (300 mg/dL), and hemoglobin A_1c level of 7%. The bottom panel predicts reduction in CV risk for a 60-year-old white woman with type 2 diabetes mellitus and systolic blood pressure of 125 mm Hg, high-density lipoprotein cholesterol level of 1.42 mmol/L (55 mg/dL), triglyceride level of 1.13 mmol/L (100 mg/dL), and hemoglobin A_1c level of 7%. To convert LDL cholesterol values to mmol/L, multiply by 0.02586.

No statistically or clinically significant difference was seen in relative benefit of statin therapy by low-density lipoprotein (LDL) cholesterol level at baseline or prerandomization LDL response. To convert LDL cholesterol values to mg/dL, divide by 0.02586.

*In this hypothetical example, megastatin reduces both cardiovascular (CV) risk and levels of low-density lipoprotein (LDL) cholesterol, but reduction of the latter is not related to megastatin's benefits. The maximum relative risk reduction (RRR) for CV events is achieved with 40 mg of megastatin, and maximum reduction in LDL cholesterol levels is achieved with 80 mg of megastatin. All results can be calculated from the assumptions in section A or can be obtained from the first author by request. The adjusted observational (cohort) analysis controls for dose of megastatin and finds that reaching the LDL cholesterol goal is not an independent predictor of degree of CV risk reduction. To convert LDL cholesterol values to mmol/L, multiply by 0.02586.

Top. Event rate assuming a single association between low-density lipoprotein (LDL) cholesterol and outcome. Bottom. The LDL–outcome associations found within each study. 4S= Scandinavian Simvastatin Survival Study; CARE= Cholesterol and Recurrent Events Study; HPS= Heart Protection Study; LIPID= Long-Term Intervention with Pravastatin in Ischaemic Disease Study; TNT= Treating to New Targets Study. To convert LDL cholesterol values to mmol/L, multiply by 0.02586.

Experiments (top) generally assess interventions but can rarely directly assess their mechanisms of action. Cohort analyses (bottom) can provide evidence for or against proposed mechanisms of action by examining whether a marker for the proposed mechanism of action (i.e., low-density lipoprotein [LDL] cholesterol level) is an independent predictor of lower risk after controlling for treatment exposure, adherence, and other known risk factors for the outcome being studied. CV= cardiovascular.