Lowering LDL cholesterol:
where ezetimibe fits

What ezetimibe does

Ezetimibe is a nonstatin drug that reduces the cholesterol absorbed from the intestine. IMPROVE-IT tested it in combination with a statin, so every outcome result we cite for ezetimibe comes from adding it to a statin (Cannon 2015).

IMPROVE-IT: the outcome trial

IMPROVE-IT randomized 18,144 patients hospitalized for an acute coronary syndrome within the previous 10 days to simvastatin 40 mg with ezetimibe 10 mg, or to simvastatin with placebo. The median time-weighted average LDL was 53.7 mg/dL with the combination and 69.5 mg/dL with simvastatin alone (P<0.001).

The primary endpoint, a composite of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization after 30 days, or stroke, occurred at 7 years in 32.7% of the combination group and 34.7% of the simvastatin group. The absolute difference was 2.0 percentage points (hazard ratio 0.936, 95% CI 0.89 to 0.99). Rates of muscle, gallbladder and liver adverse effects, and of cancer, were similar in the two groups.

What the LDL drop means

Average LDL was about 23% lower with the combination (53.7 vs 69.5 mg/dL). This is our calculation from the trial's averages; the trial did not report this percentage. The authors concluded that adding ezetimibe to a statin resulted in incremental LDL lowering and improved cardiovascular outcomes.

The outcome benefit was modest in absolute terms: 2 percentage points over seven years, in patients who had just been hospitalized with an acute coronary syndrome.

Coenzyme Q10 in heart failure

Q-SYMBIO randomized 420 adults with moderate to severe heart failure to 100 mg of coenzyme Q10 three times a day or placebo, on top of standard care, for 2 years. The short-term endpoints at 16 weeks were not significant. The long-term composite of major adverse cardiovascular events occurred in 15% of the CoQ10 group and 26% of the placebo group (hazard ratio 0.50, 95% CI 0.32 to 0.80) (Mortensen 2014). This is one trial in heart failure, not evidence for prevention in people without it.

Coenzyme Q10 and statin muscle symptoms

A 2018 meta-analysis of 12 randomized trials (575 patients) found that CoQ10 reduced muscle pain and other statin-associated muscle symptoms compared with placebo (Qu 2018). A 2020 systematic review of 7 trials (321 patients) found no benefit for myalgia (weighted mean difference -0.42, 95% CI -1.47 to 0.62) and no improvement in staying on statin therapy (Kennedy 2020). The trials are small, and the two reviews disagree.

What this does not say

• IMPROVE-IT studied ezetimibe added to simvastatin 40 mg after an acute coronary syndrome. It does not show the same outcome benefit in people without a recent event.
• The LDL drop is a laboratory result. A lower LDL does not guarantee a lower risk for every person.
• The benefit is small in absolute terms, and it was seen with one fixed combination of doses.
• The coenzyme Q10 trials used specific doses and products. Ours may differ, and the results are averages for those groups, not predictions for one person.

Sources

1. 1.Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372:2387-2397. Cannon CP et al., N Engl J Med, 2015
2. 2.Mortensen SA et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO. JACC Heart Fail. 2014;2:641-649. Mortensen SA et al., JACC Heart Fail, 2014
3. 3.Qu H et al. Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2018;7:e009835. Qu H et al., J Am Heart Assoc, 2018
4. 4.Kennedy C et al. Effect of Coenzyme Q10 on statin-associated myalgia and adherence to statin therapy: A systematic review and meta-analysis. Atherosclerosis. 2020;299:1-8. Kennedy C et al., Atherosclerosis, 2020