Evolving Targets for LDL-Cholesterol Reduction

Introduction to LDL-Cholesterol Reduction Targets

The American College of Cardiology recommends that for patients at very high risk, the target LDL-C level should be <70 mg/dL or a reduction of ≥50% from baseline, based on evidence that every 1.0 mmol/L reduction in LDL-C is associated with a 20-25% reduction in major cardiovascular events 1, 2, 3, 4, 6
The European Heart Journal guidelines suggest that for subjects at very high risk, the target LDL-C level should be <1.8 mmol/L (70 mg/dL) or a reduction of ≥50% from baseline, with a reduction of 1.0 mmol/L of LDL-C associated with a 20-25% reduction in cardiovascular mortality and non-fatal myocardial infarction 3

The Adult Treatment Panel III initially established a target LDL-C level of <100 mg/dL for patients at high risk, representing the minimum level supported by clinical evidence available at the time, and achievable with standard doses of statins in about half of high-risk patients 1, 2, 4, 5
However, ATP III explicitly indicated that 100 mg/dL was a minimum target, not the level of maximum benefit, with recent studies confirming that there is no threshold below which further reductions in risk are not obtained 1, 2, 4

The Heart Protection Study demonstrated that patients with baseline LDL-C <116 mg/dL, and even <100 mg/dL, achieved significant reductions in risk with statin therapy, with intensive therapy with atorvastatin 80 mg reducing major cardiovascular events by 16% compared to pravastatin 40 mg over 2 years 2, 4, 5, 6
The PROVE IT trial showed that intensive therapy with atorvastatin 80 mg, which reduced median LDL-C to 62 mg/dL, was associated with a 16% reduction in major cardiovascular events compared to pravastatin 40 mg, which achieved 95 mg/dL, over 2 years 2, 4, 6

Recent clinical trials with statins have not identified significant adverse effects from reducing LDL-C, with the risk-benefit ratio remaining favorable for achieving very low LDL-C levels 2, 4, 6, 5
Some epidemiological studies suggested associations between very low cholesterol and increased total mortality or cerebral hemorrhage, but recent clinical trials have not confirmed these findings 2, 4, 6

The optional target of <70 mg/dL is recommended for patients at very high risk, defined as those with established cardiovascular disease plus multiple major risk factors, poorly controlled risk factors, or multiple factors of the metabolic syndrome 2, 4, 6, 5