LDL cholesterol causes most heart disease and some strokes. The first line treatment for high LDL cholesterol after diet and exercise is statins, which I reviewed in my last post. Statins have a far lower burden of side effects than many believe and any reduction in LDL cholesterol – no matter how low or high it already is – reduces heart disease risk.
For people who have already adopted a healthy lifestyle and maxed out their statin dose – whether that means they’re taking a high dose or none at all due to (rare!) side effects – what comes next? Ezetimibe. Most blood cholesterol is produced in the liver, but some comes from food. Ezetimibe inhibits the intestines from absorbing dietary cholesterol.
In this post I’ll argue that ezetimibe is an effective tool for preventing heart disease that – like its more famous cousin the statin – is underappreciated. Ezetimibe got off to a rocky start when sequential studies raising hopes, dashing them, then resurrecting them.
The progression from taking a cholesterol-lowering drug to preventing heart disease proceeds in a few steps over ever longer time scales. First, the cholesterol benefit can be measured in as little as two weeks. Second, the thickness of artery walls show a difference in a year or two. Third, after four or five years of treatment people on these drugs experience fewer heart attacks or similar bad outcomes. I’ll now walk through three sets of studies, each longer and larger than the last, that measure the effect of ezetimibe at each of those stages.
Step One – Ezetimibe and LDL Cholesterol
The Ezetimibe Study Group published this trial in 2002 and this trial in 2003. They randomly assigned patients to one of four groups with different treatments for 12 weeks: a placebo, a statin, ezetimibe, or ezetimibe plus a placebo. The studies both found that ezetimibe on its own lowers LDL cholesterol about half as much as a statin on its own. The incremental effect of adding ezetimibe to the statin had a smaller, but still meaningful effect. Hopes were high for an addition to the anti-cholesterol toolbox.
Step Two – Ezetimibe and Arterial Thickness
A measurement called a carotid intima-media thickness test (CIMT) measures the thickness of the artery wall. An increasing CIMT result is the intermediate step between high LDL cholesterol and heart disease. The ENHANCE trial, published in 2008, followed on the earlier tests of Ezetimibe and cholesterol by checking for improvement in CIMT. The trial followed 700 patients for two years, with half assigned to statin alone and half assigned to a statin and ezetimibe.
The ENHANCE trial confirmed the LDL lowering effect of ezetimibe but, in a disappointment, found no benefit for thickening of the artery wall. Use of ezetimibe fell by half in the year after this study came out. The outcome came as such a shock that many heart disease researchers were driven mad. They started wondering if statins actually reduce heart disease by a mechanism other than lowering LDL cholesterol. Such a result would have upended decades of work on the mechanisms of heart disease.
Step 3. Ezetimibe and Heart Disease
Seven years after the ENHANCE trial, the larger and longer IMPROVE-IT trial, with 18,000 patients followed for six years, measured the effect of ezetimibe on patients who had been admitted to the hospital for heart problems within the 10 days prior to enrollment. The trial randomly broke the patients into two groups: one received a statin and a placebo, the other received a statin and ezetimibe.
The study confirmed the results of the prior two sets, that adding ezetimibe further lowered LDL cholesterol by about half as much as a statin. But unlike the ENHANCE trial that looked at patients’ arteries, this trial found that there was a direct benefit of ezetimibe on heart disease risk. Just like the LDL lowering, the effect wasn’t huge, just a 6.4% relative risk reduction. This pair of results – a small decrease in LDL and a proportional decrease in heart disease risk – restored sanity to the earth. It confirmed that the heart protection offered by statins is, in fact, because of their LDL lowering effect.
When this trial started, guidelines called for patients at high risk of heart disease to target an LDL cholesterol below 70 mg/dl. Patients in the control group on statins alone achieved LDL cholesterol of 69.9 mg/dl and the treatment group got all the way down to 53.2 mg/dl, demonstrating there is further benefit to even more lowering of LDL cholesterol. This self-described “expert analysis” from the American College of Cardiology argues that with this study, we know “The Lower the LDL-C, the Better” (title case because that’s the title). American and European guidelines updated after the publication of this study both suggested adding ezetimibe to high-intensity statins for high-risk patients. The Europeans go further, specifically recommending a target LDL of under 55 mg/dl, whereas the Americans stick with 70.
Ezetimibe vs Statins for Liver (Non-)Side Effects
When people start taking statins, they typically see increases in liver function tests that would be alarming if they weren’t on statins. But these tests in people on statins rarely indicate a liver problem. This review article describes statin-induced liver damage as a myth and this paper describes efforts to get doctors to order fewer wasteful liver function tests for people on statins. In any case, if a patient gets a concerning liver function test, they can simply stop taking statins and the tests go back to normal.
For people still worried about the effect of statins on the liver, the Ezetimibe Study Group found that side effects of ezetimibe were indistinguishable from placebo. Whereas less than 1% of patients on statins had abnormal results for tests of liver function, zero patients on ezetimibe did. The much larger IMPROVE-IT trial also checked for differences in liver function tests and didn’t find any impact.
Ezetimibe vs Statins for Muscle (Non-)Side Effects
Although statins are widely reported to cause muscle problems, I reviewed in my last post the evidence that the rate of statin-caused muscle problems is roughly 1 in 10,000 patient-years. Just like the liver tests, the rare muscle problems are cured by ending statin therapy. And also like the liver tests, the early studies of ezetimibe showed exactly 0 patients with muscle problems and the IMPROVE-IT didn’t find any difference between treatment and control.
Ezetimibe and Diabetes
The main reason not to give everyone statins is that they raise the risk of type 2 diabetes (T2D) by about 1 in 1,000 patient-years. The mechanism for the T2D risk isn’t understood. If it’s a direct consequence of low LDL, as some have speculated, then ezetimibe should have the same side effect.
An analysis of new-onset T2D in the IMPROVE-IT trial reported no statistically significant increase. More specifically, their point estimate was a 4% increase in risk, but the 95% confidence interval included the possibility of no increase. Just because the study wasn’t able to show statistical significance for an increase in T2D risk doesn’t mean there isn’t one. This meta-analysis of statins found that they increase the risk of T2D by 9%. Not to over-complicate things, but if ezetimibe lowers LDL cholesterol about half as much as a statin…and it also increases the risk of T2D about half as much as a statin… it sure seems like there’s something there. I wish someone would do a meta-analysis of LDL lowering and T2D risk. My guess is there’s a connection independent of whether the LDL lowering is caused by statins, ezetimibe, or newer drugs. If we could put more precise numbers on the risk as a function of LDL cholesterol we could do a better job of recommending which low-risk patients should start statin therapy.
Ezetimibe for Low-Risk Patients
One unanswered question I have after researching this post is why expert guidelines suggest adding ezetimibe for high-risk patients only after they’ve maxed out their statin dose. The IMPROVE-IT trial was a study of high-risk patients, so narrowly interpreted it only shows that ezetimibe is good for those patients. But all the evidence we have suggests that the benefit of statins or ezetimibe – whether you’re a 40-year-old with slightly elevated cholesterol or an 80-year-old recovering from a heart attack – comes from LDL lowering. Ezetimibe lowers LDL about half as much as a moderate-dose statin with a lower burden of side effects. Wouldn’t it make sense to start low-risk patients on ezetimibe and then add a statin later?