I’m Sticking with Ezetimibe

Despite the Conspiracy Theories

My post, cited below, on the statin rule of six is my most frequently read post, but not everyone agrees with my use of ezetimibe.

A clinician (whose name I won’t use because I was unable to contact him to obtain permission) wrote:

Paul, on ezetimibe, you write that: "The IMPROVE-IT or “Improved Reduction of Outcomes: Vytorin Efficacy International Trial” randomized patients with an acute coronary syndrome to simvastatin 40 mg/day with or without ezetimibe. The study was criticized because it had to be extended to a median follow-up of 6 years to accrue a sufficient number of cardiac events." No. IMPROVE-IT is important because it PROVED that ezetimibe does NOTHING for patients that are under 75 years of age or are not diabetic. See the subgroup analysis that they originally hid away at the back of their original 2015 Supplemental Appendix and didn't discuss. (And it was worse if you were male and/or from North America...). The vast majority of those prescribed ezetimibe, i.e. non-diabetics under 75 years of age, will receive absolutely no benefit from it, just poly-pharmacy. This was made clearer in the more extensive 2019 IMPROVE-IT analysis in "Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial," PMID 31314050. *** See the Kaplan-Meier curves in its Figure 1. *** You gotta be over 75 (or diabetic) to get any benefit from ezetimibe. (Which makes sense due to ezetimibe's mechanism-of-action. Think of all those useless prescriptions written and $$$ billions made by hiding this..!) IMPROVE-IT was a large-scale, long-term, hard-outcome randomized controlled trial on a relevant population, the strongest type of scientific proof on efficacy--or non-efficacy--that we can have. You either practice Evidence-Based Medicine--or you don't. (See, also, Figure 2 of PMID 29677301.)

My Response: I appreciate this clinician’s taking the time to comment. He is partly correct. If you look at the benefit from ezetimibe, it was almost entirely due to a remarkable reduction in risk in patients over 75. This was presented in a subsequent evaluation of the IMPROVE-IT study (1). In fact, you only needed to treat 11 patients aged 75 years and older to prevent one cardiovascular event, but you need to treat 125 patients < 75 years to prevent an event. But this was discovered in a not-prespecified, post-hoc analysis. The original pre-specified analysis was to examine results among three age groups: 65, 65 to 74, and 75 years or older. This analysis observed no significant differences. So, if we are being strict in our analyses, the examination of just two age groups is not pre-specified, and if we strictly practice evidence based medicine, we must rely on the original conclusion, which is that ezetimibe produced a 2% absolute reduction in cardiovascular events from 34.7 to 32.7% (p=0.016). That would make it a highly effective medication, especially since all patients were treated with 40 or 80 mg of simvastatin, and had reasonable LDL-C levels without ezetimibe. Specifically, LDL-C in IMPROVE-IT with or without ezetimibe were 53.7 and 69.6 mg/dL, respectively

But the clinician’s point is interesting and important. I am not sure why there is this difference in response between older and younger patients. I originally thought it may indicate that older patients absorb more cholesterol so that blocking its absorption produced a bigger effect, but there was no difference in the cholesterol reduction among the three age groups when ezetimibe was added (-27.8, -27.7, - 28.6 mg/dl)(1).

But older patients were also not the only subgroup to benefit from ezetimibe. Subjects with diabetes, prior coronary artery bypass graft surgery, prior stroke, or higher Thrombolysis in Myocardial Infarction (TIMI) Risk Scores for Secondary Prevention also had large absolute reductions in cardiovascular events.(1) In other words, the riskiest patients seemed to benefit the most. That is usually seen with effective treatments.

In addition, adding ezetimibe produces large reductions in LDL-C. Ezetimibe alone reduces LDL-C about 20% and about 24% when added to a statin. So which other effective “polypharmacy” would we prefer to reach an LDL-C goal, a generic ezetimibe costing little or a PCSK-9 costing considerably more ? Or do we think that LDL-C is not the culprit in atherosclerosis? Ezetimibe increases LDL-C receptor activity, and drugs that increase LDL-C receptor activity reduce cardiac events. (2)

I also do not see a conspiracy or even the hiding of data. As for the figure 2 cited by the clinician, that shows no reduction in total mortality with ezetimibe, but remember that many of these subjects were older, and that “nobody gets out alive” - everyone has to die. Consequently, I prefer figure 4 which presents cardiovascular mortality and shows a reduction in cardiovascular mortality with ezetimibe. (3)

So, I am sticking with ezetimibe, but I appreciate the chance to discuss it.

1. Bach RG, et al. Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2019 Sep 1;4(9):846-854. PMID: 31314050

2. .Sabatine MS, Wiviott SD, Im K, Murphy SA, Giugliano RP. Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: a meta-analysis. JAMA Cardiol. 2018;3(9):823-828.

3. Navarese FP, et al. Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering- A Systematic Review and Meta-analysis, JAMA. 2018 Apr 17;319(15):1566–1579. PMID: 29677301

#ezetimibe #heartdisease #cholesterol #cardiacdisease #IMPROVEIT