The LDL (low-density lipoprotein)
hypothesis postulates that excess LDL cholesterol causes atherosclerotic
cardiovascular disease. This implies that lowering LDL levels should also
reduce adverse cardiovascular events.
The evidence for this hypothesis is based
on data from animal and epidemiologic human studies as well as clinical trials
involving both statins and non-statin lipid-modifying agents. A meta-analysis
conducted with more than 90,000 participants in 14 randomized statin trials, Cholesterol Treatment Trialists' Collaborators
(CTTC) reported that on an average, a reduction of 1 mmol per liter in LDL
cholesterol levels cuts the risk of adverse cardiac events by 23% over a period
of 5 years.
In an editorial published in The New England Journal of Medicine
2015, Jarcho and Keaney analyze the reports of the IMPROVE-IT study in favour
of the LDL hypothesis. The IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy
International Trial) aims
at comparing ezetimibe/simvastatin
combination therapy with
simvastatin alone in high-risk patients with severe coronary syndromes. The
results of the study confirmed that combining a non-statin lipid-lowering drug
with a statin
can have additional benefits in lowering LDL cholesterol levels
thereby reducing adverse
cardiovascular events. The addition of a non-statin agent (ezetimibe) to statin
therapy reduced the absorption of cholesterol
from the gastrointestinal tract and lowered LDL cholesterol by 24%.
In the IMPROVE-IT trial, 18, 144 patients
with acute coronary syndrome were randomly assigned to either simvastatin (40
mg) plus ezetimibe
(10 mg) or to simvastatin (40 mg) plus placebo.
After 1 year, the mean LDL cholesterol level was 53.2 mg per decilitre in the
simvastatin-plus-ezetimibe group and 69.9 mg per decilitre in the simvastatin
monotherapy group. The primary endpoint in the trial was a range of adverse
cardiovascular events like myocardial infarction, unstable angina
death or nonfatal strokes. After 7 years, the rate of the primary endpoint was
lower by 2.0 percentage points in the simvastatin-plus-ezetimibe group.
The results of IMPROVE-IT provide hope to
patients who do not respond sufficiently well to statin therapies. While the
2013 cholesterol treatment guidelines of the American College of Cardiology and
the American Heart Association do not recommend specific agents to reduce LDL
levels, it acknowledges the need to add a non-statin agent when patients do not
respond to statin therapy alone.
The IMPROVE-IT study also suggests that
reduction in LDL cholesterol is beneficial, regardless of the agent used. The
recent development of PCSK9 inhibitors is highlighted. These agents enable LDL
clearance from blood circulation and reduce LDL cholesterol by almost 60%.
Clinical trials with these agents are in process.
IMPROVE-IT does not specifically prove
unique benefits of ezetimibe, rather it suggests that reduction in LDL
cholesterol by any mechanism is useful to prevent adverse cardiovascular
Jarcho, A. John & Keaney, F. John.
(2015). "Proof That Lower Is Better LDL Cholesterol and IMPROVE-IT". New England Journal of Medicine
2015: 372:2448-2450. DOI: 10.1056/NEJMe1507041. Retrieved on 21 September 2015