A massive trial on a new cholesterol medication: CETP inhibitor

Cholesteryl ester transfer protein (CETP) is an important component of lipid metabolism. It helps exchange triglycerides and cholesterol between HDL and atherogenic particles (LDL, IDL and VLDL). Reduction or inhibition of CETP leads directly to both higher HDL-cholesterol and lower atherogenic particle concetrations. In principle, these lipid profile modifications are expected to reduce cardiovascular outcomes. 

To date, three CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) tested in clinical trials were either not effective in reducing CV outcomes or caused major adverse events. The current study published in NEJM September 2107 paints a different picture: anacetrapib 100 mg once daily lowered coronary events by 10% in patients with established CVD being treated with high intensity statin (atorvastatin/lipitor). Authors attribute these benefits primarily to non-HDL reduction of 17 mg/dL. Although HDL increased by 43 mg/dL, it is not considered causative or therapeutic.

Some unforeseen outcomes with anacetrapib were the subtle increase in systolic blood pressure of 0.7 mmHg, slight decrease in kidney function and lower incidence of new-onset type 2 diabetes. 

Study results are of major significance for several reasons. Some adults with very high baseline CVD risk (ex. prior myocardial infarction) still have residual chance for more coronary events even when receiving a high intensity statin such as atrovastatin or rosuvastatin. Thus an add-on medication like  anacetrapib could be useful. Importantly, results were derived from a massive amount of data involving ~30,000 participants over a 4 year period. Participants' baseline LDL-cholesterol (~60) and non-HDL-cholesterol (~90) were well controlled and balanced across study groups.

Given poor outcomes from other sister medications, I suspect more research is needed to fully elucidate the benefit/harm ratio for CETP inhibitors, and particularly for anacetrapib.

GT

 


N E J M

Reveal

September 2017

Background: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of LDL-cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.

Methods: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg/dL, a mean non-HDL cholesterol level of 92 mg/dL, and a mean HDL cholesterol level of 40 mg/dL. The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients).

The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.

Results:

During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91, p=0.004).

The relative difference in risk was similar across multiple prespecified subgroups.

At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg/dL in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg/dL (0.44 mmol per liter), a relative difference of −18%.

There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.

Conclusions:

Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. 


More from the publication:

Evidence from large-scale, randomized trials has shown that each reduction of 40 mg/dL (1 mmol/L) in the level of low-density lipoprotein (LDL) cholesterol reduces the risk of coronary events (including coronary death, myocardial infarction, and revascularization procedures) and ischemic stroke by approximately one quarter during each year after the first year of administration. Moreover, further reductions in LDL cholesterol levels have been shown to produce additional reductions in cardiovascular risk. Nevertheless, these risks remain high among persons with atherosclerotic vascular disease. Although higher levels of high-density lipoprotein (HDL) cholesterol are associated with a lower risk of vascular events, previous trials have not shown that raising HDL cholesterol levels reduces risk.

Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides between HDL particles and atherogenic particles containing apolipoprotein B in the blood. Pharmacologic inhibition of CETP can produce substantial increases in HDL cholesterol levels, along with reductions in levels of non-HDL cholesterol (particularly LDL cholesterol). However, previous randomized clinical outcomes trials of CETP inhibitor therapy were stopped after approximately 2 years of follow-up because of either hazards associated with the therapy or an apparent lack of efficacy.

Anacetrapib is a potent CETP inhibitor that has been found to have an acceptable side-effect profile in previous, smaller studies. Here, we report the findings of the phase 3 Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL) trial, which assessed the clinical efficacy and safety of anacetrapib (at a dose of 100 mg once daily) for approximately 4 years among more than 30,000 patients with preexisting atherosclerotic vascular disease who were receiving effective statin therapy.

In this randomized trial, we found that the addition of the CETP inhibitor anacetrapib at a dose of 100 mg daily to intensive statin therapy for approximately 4 years resulted in a lower incidence of major coronary events than the addition of placebo among patients with preexisting atherosclerotic vascular disease, despite very well-controlled baseline LDL cholesterol levels (mean, 61 mg per deciliter [1.58 mmol per liter]). The proportional risk reductions appeared to be larger with more prolonged follow-up.

Our trial has a number of strengths that facilitated assessments of both efficacy and safety, including recruitment of a large number of patients, high treatment adherence, follow-up for a median of more than 4 years, and a large number of clinical outcomes. Our results contrast with those reported from clinical outcome trials of other CETP inhibitors:

The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was terminated early because of excess risks of cardiac events and death with torcetrapib, findings that have been attributed to off-target drug effects.  Subsequently, the Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome (Dal-OUTCOMES) trial and the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) were both stopped early after approximately 2 years of treatment because of an apparent lack of efficacy.

Dalcetrapib is a relatively weak CETP inhibitor that does not lower LDL cholesterol at the dose tested in Dal-OUTCOMES, whereas evacetrapib has effects on blood lipid levels similar to those of anacetrapib. However, ACCELERATE differed from our trial in several ways. In particular, it involved fewer patients (12,092 vs. 30,449), a shorter treatment period (median, 26 months vs. 50 months), and fewer primary cardiovascular outcomes (1555 vs. 3443).

Our trial results suggest that the full effects of anacetrapib may take at least a year of treatment to emerge. A similar pattern has been observed in randomized trials of other lipid-lowering drugs. Consequently, the follow-up duration of just over 2 years in ACCELERATE may have been too short to allow an effect on vascular events to emerge.

It is not possible to determine the mechanism by which anacetrapib reduced the risk of major coronary events in this trial. On the basis of evidence from trials of statin therapy, the lower level of non-HDL cholesterol (by 17 mg per deciliter) in the anacetrapib group than in the placebo group as seen in our trial would be anticipated to result in a 10% relative reduction in the risk of coronary death or myocardial infarction, a finding that is entirely consistent with the 11% reduction that we observed.

This result reduces the likelihood that other actions of anacetrapib played a major role in modifying the risk of coronary events.

In particular, the higher mean level of HDL cholesterol in the anacetrapib group (by 43 mg per deciliter) does not appear to have had as large an effect on coronary events as would be anticipated on the basis of observational studies. Analyses of genetic variants in CETP also indicate that differences in coronary risk are related largely to differences in LDL cholesterol levels. LDL cholesterol levels were particularly well controlled among the patients throughout our trial.

The beneficial effects of anacetrapib may be greater among patients with higher baseline LDL cholesterol levels, in whom the absolute reductions in LDL cholesterol levels may be greater.

During a median of 4 years of follow-up, anacetrapib treatment was not associated with any of the previously hypothesized adverse effects of very low levels of cholesterol (e.g., reduced cognitive function, increased cancer incidence, or nonvascular death). Unlike previous and much smaller studies of anacetrapib, our trial showed a slightly higher level of systolic blood pressure (0.7 mm Hg) in the anacetrapib group than in the placebo group, a difference that was similar in magnitude to effects reported for dalcetrapib and evacetrapib but much smaller than the increase of 5 mm Hg seen with torcetrapib. 

In addition, the risk of the development of an eGFR < 60 was slightly higher. As has been observed with torcetrapib and evacetrapib (but not with dalcetrapib), anacetrapib was associated with a lower incidence of new-onset diabetes, which contrasts with the small increase seen with statins or, to a greater extent, niacin.

Our trial has certain limitations. LDL cholesterol levels were very well controlled, and the median follow-up was only 4 years, so our findings may not be generalizable to patients with longer-term use of anacetrapib and those with higher LDL cholesterol levels. Anacetrapib continues to accumulate in adipose tissue with prolonged administration, and although plasma levels fall substantially after cessation of treatment, levels in adipose tissue decline only minimally after 1 year. No substantial safety issues were identified during the trial, but follow-up for clinical outcomes in trial patients is being continued for at least an additional 2 years after the end of the treatment period to assess longer-term safety, as well as efficacy.

In conclusion, we found that the addition of the CETP inhibitor anacetrapib to intensive statin treatment in patients with atherosclerotic vascular disease resulted in a significantly lower incidence of major coronary events than the addition of placebo during 4 years of treatment.