Another CETP Inhibitor, Yet Another Negative Study

Summary and Comment |
May 17, 2017

Another CETP Inhibitor, Yet Another Negative Study

  1. Harlan M. Krumholz, MD, SM

Despite improved laboratory values, a cholesterol ester transfer protein inhibitor had no clinical effect.

  1. Harlan M. Krumholz, MD, SM

Cholesterol ester transfer protein (CETP) inhibitors have failed to improve outcomes despite their marked effects on reducing LDL cholesterol and raising HDL cholesterol. In the ACCELERATE trial, researchers have tested yet another CETP inhibitor, evacetrapib, against placebo among patients with high-risk vascular disease who were receiving standard therapy.

This industry-sponsored, international trial randomized 12,092 patients, one third of whom had an acute coronary syndrome 6 months before randomization. Almost all patients were receiving statins at randomization.

The study was stopped early because of futility, at a median follow-up of 28 months. Mean LDL cholesterol levels were significantly different between groups, with a decrease of 31% with evacetrapib and an increase of 6% with placebo. The mean HDL cholesterol level increased significantly more in the evacetrapib group than in the placebo group (133% vs. 2%). However, the groups had similar results on the primary composite endpoint — death from cardiovascular causes, myocardial infarction, coronary revascularization, stroke, or hospitalization for unstable angina — 12.9% with evacetrapib and 12.8% with placebo.


We can add this CETP inhibitor to the list of drug failures. People may focus on the failure of raising HDL cholesterol, but what I find remarkable is that a drug that lowers LDL cholesterol by 31% does not budge cardiovascular risk. The reason that lowering LDL cholesterol in this case does not reduce risk is unknown. We await the trial results of yet another CETP, anacetrapib. Meanwhile, the lesson here is that not all drugs producing favorable changes in lab results also improve outcomes; you need to do the study to be sure.

Editor Disclosures at Time of Publication

  • Disclosures for Harlan M. Krumholz, MD, SM at time of publication Consultant / Advisory board United Healthcare; Element Science; Aetna; IBM Watson Equity ImageCor; Me2Health Grant / Research support Agency for Healthcare Research and Quality; Food and Drug Administration; Robert Wood Johnson Foundation; Medtronic; SI-Bone; Johnson & Johnson; Centers for Medicare & Medicaid Services Editorial boards; American Journal of Managed Care; American Journal of Medicine; Critical Pathways in Cardiology; Current Cardiovascular Risk Reports; JACC: Cardiovascular Imaging;Circulation: Cardiovascular Quality and Outcomes; Circulation; JAMA; The Lancet; New England Journal of Medicine


Reader Comments (7)

Rajeev Gupta, MD, DM Physician, Cardiology, Mediclinic Al Jowhara hospital, Al Ain, UAE

The ASCVD is much more beyond just cholesterol. I think, time will prove (like for Hypertension sugar is more harmful than salt), sugar and refined carbohydrates are much more harmful than cholesterol. Statins benefit via. their pleiotropic effects more that cholesterol-lowering effect.

CARLO SAITTO Physician, Epidemiology/Statistics

May be the issue is timing and progress of coronary involvement. Once the coronary arteries are affected and the inflammatory response is on, lowering LDL cholesterol becomes increasingly ineffective. Tis study is dealing with established coronary disease patients in whom the role of inflammation is probably preponderant. It would be interesting to look at young high LDL cholesterol, high risk patients to evaluate whether CETP inhibitors prevent plaques building and coronary disease.

Paul DeGange R. N. Nurse/NP/PA, Other

Findings like this are not uncommon. It has been acknowledged for years that improving blood lipid values with medication does not reduce all cause mortality. Perhaps it is time to reexamining the lipid hypothesis and consider that elevated cholesterol levels may not be a causative factor in cardiovascular disease.

Robert Teets MBA Other, Other, Retired

My lay opinion is that the Medication did exactly what it was designed to do, Lower LDL and RAISE HDL. Cholesterol isn't the only factor in CHD. Was the vascular condition of the subjects in the study evaluated before and after the study? If so how? CT calcium scoring, invasive coronary angiography or was the how you feeling method used. If lowering LDL and raising HDL had no effect maybe the concept that cholesterol has a significant factor in reducing overall events is wrong. I think a better factor to look at would be did the medication reduce future events for a majority of the study group by reducing plaque buildup. If that is the case the medication would be a success. I have been part of a Clinical Trial that was considered a failure, yet I went from walking on a tread mill for 4 minutes 30 seconds to over 10 minutes at two years and I didn’t follow protocols to the letter. The medication did exactly what it was being evaluated for and deemed a failure. How about clinical trials look to the success side for everyone instead of whether is prevents a person of unknown vascular condition from suffering a adverse event not related to the study.

Clifford Hansen

It seems I keep seeing studies where cholesterol values do not line up with expected end points. In fact some, especially with older people, seem to have an inverse relationship. Perhaps the only reason the JUPITER trial showed a positive result was because they only tested on those with high inflammation markers (hsCRP above 2 with an average over 4.5 if memory serves me), and that the inflammation markers were significantly improved with the drug.

Maybe we should be looking at inflammation lowering (hsCRP in particular) in addition to or possibly even instead of cholesterol in terms of changing outcomes.

Norman Miller MD, PhD, DSc Physician, Preventive Medicine, Oxford PharmAssist Ltd (UK)

The failure of CETP inhibitors to prevent CVD despite lowering LDL does not contradict the HDL hypothesis but supports it as they raise HDL cholesterol by disrupting a key step in reverse cholesterol transport. As I pointed out three years ago, six out of six prospective cohort studies found CVD incidence to be negatively associated with CETP activity or concentration. See . Let's hope the massive LDL-lowering effect of anacetrapib overcomes the negative impact on HDL metabolism to achieve a net reduction of CVD.

Charles Matheson, Pharm D Other, Internal Medicine, Forsyth Medical Center

Could it be that cardiovascular ds is NOT caused by high LDL and low HDL levels as we have been "taught" all these years?? The problem is not elevated cholesterol, but more likely sugar (overconsumption).

But of course, the pharmaceutical industry has too much invested in the cholesterol theory, and the manufacturers of sugar are deeply invested in deflecting blame. Until such time, we'll continue to watch our patients suffer disease (and profit off of it).

Your Comment

(will not be published)

Filtered HTML

  • Allowed HTML tags: <a> <em> <strong> <cite> <blockquote> <code> <ul> <ol> <li> <dl> <dt> <dd>
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Do you have any conflict of interest to disclose?
This question is for testing whether you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

* Required

Reader comments are intended to encourage lively discussion of clinical topics with your peers in the medical community. We ask that you keep your remarks to a reasonable length, and we reserve the right to withhold publication of remarks that do not meet this standard.

PRIVACY: We will not use your email address, submitted for a comment, for any other purpose nor sell, rent, or share your e-mail address with any third parties. Please see our Privacy Policy.