Cut LDL-C for CV Risk-Reduction, but How Matters: Meta-Analysis

Patrice Wendling

October 17, 2016

BOSTON, MA — A recent meta-analysis that puts certain nonstatin therapies that work via the same mechanism on par with statins for reducing cholesterol and cardiovascular events is drawing mixed reviews from key opinion leaders[1].

Based on results from 49 studies conducted over the past 51 years, it showed that each 1-mmol/L (38.7-mg/dL) reduction in LDL-C was associated with a 23% lower relative risk (RR) of major vascular events with statins (RR 0.77, 95% CI 0.71–0.84; P<0.001) and 25% lower risk with intensive diet, bile-acid sequestrants, ileal bypass surgery, or ezetimibe (Zetia, Merck/Schering Plough)—all therapies that help clear cholesterol by upregulating the LDL receptor (RR 0.75, 95% CI 0.66-0.86; P=0.002).

Senior investigator Dr Marc Sabatine (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) told heartwire from Medscape, "Our data show that as you think about treatment you don't really want to focus just on a single line of therapy. It's not as simple as 'I've given a high-intensity statin, and now I'm done and don't need to think about the patient any further.' It needs to be focused on the patients and the goal, which is to reduce the risk factor, which is LDL cholesterol, and then one should use all the appropriate tools in one's armamentarium."

Asked to comment, Dr David Waters (University of California, San Francisco) told heartwire , "My main criticism was that I wanted the authors to make clear that yes, all these drugs work by the same mechanism and all of them reduce cholesterol and cardiovascular events, but in clinical practice we're not recommending people use ileal bypass to reduce cholesterol."

He also noted an advisory panel and the US Food and Drug Administration (FDA) itself did not accept an extended indication for the combination of ezetimibe and simvastatin (Vytorin, Merck) to reduce CV events in patients with coronary heart disease, although the European Medicines Agency did. The FDA's decision was based on results from the IMPROVE-IT trial, the only trial in the meta-analysis to evaluate ezetimibe.

It also included data from 25 statin trials, four dietary trials, two trials of bile-acid sequestrants, one of ileal bypass, nine fibrate trials, three trials with niacin, three with cholesteryl ester transfer protein (CETP) inhibitors, and two with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In all, there were 312,175 participants with 39,645 major vascular events followed for an average of 4.3 years.

The random-effects meta-regression analysis showed that niacin fell roughly along the regression line; fibrates fell slightly above the line, suggesting a larger risk reduction than expected; and CETP inhibitors fell well below the line, indicating no significant effect on vascular events, Sabatine said. The observed RR reductions in major vascular events associated with each 1-mmol/L reduction in LDL-C were 0.94, 0.88, and 1.01, respectively.

"I think the message there is if the drug mechanism isn't through upregulation of the LDL receptor, then all bets are off. You really need to view the individual class," he said.

In commenting to heartwire , Dr Henry Ginsberg (Columbia University Medical Center, NYC) said there was no surprise in the lack of effect with fibrates and niacin but dinged the authors for asserting that the effects of CETP inhibitors on LDL-C are not through the LDL-receptor pathway. He cited a recent mechanistic study by his team[2] showing that the CETP inhibitor anacetrapib (Merck), as monotherapy and in combination with a statin, reduces LDL cholesterol by increasing the fractional clearance rate, or the efficiency of LDL removal.

Bridging the 2013 Guideline Divide

Sabatine said the 2013 American College of Cardiology (ACC) and American Heart Association (AHA) cholesterol treatment guidelines shifted the focus from LDL targets to statins, but that the 2016 ACC expert consensus paper on nonstatin therapies is "starting to get to that idea that one maybe needs to return to the notion of targets and consider adding on additional therapy to get LDL lower."

Ginsberg, who was invited to pen a perspective on the 2013 guidelines[3], said the recent ACC consensus paper "goes a way to overcoming" the damage from the 2013 guidelines but added that "doctors need to get more good news about how you can add things and lower cholesterol, so this paper may make more of a good impression. It's a good add-on to IMPROVE-IT."

National Lipid Association chief science officer Dr Peter H Jones (Baylor College of Medicine, Houston, TX) told heartwire the meta-analysis reinforces the ACC consensus paper and will probably move into the next update or guideline.

"This kind of information is what they're using to build more of that evidence [base]; even though it may be more expert [opinion] or lower level, it's still important evidence for clinicians to know," he added.

On the other hand, Jones also said many of the nonstatin therapies are not in mainstream lipidology. "The bottom line is that niacin, fibrates, and probably bile-acid resins, diet, and ileal bypass are just not contemporary treatments. That's a weakness. It really boils down to statins have the benefit, ezetimibe, and then the possibility for PCSK9 inhibitors."

The PCSK9 inhibitors evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) were estimated to lower the risk of vascular events by 51% per 1-mmol reduction in LDL-C level (RR 0.49), according to the analysis, reported online September 27, 2016 in the Journal of the American Medical Association.

The authors noted that the PCSK9 inhibitors were analyzed separately because cardiovascular-outcomes trial data are not yet available. Results are eagerly anticipated next year, however, from the largest of these trials, Amgen's FOURIER trial of evolocumab, led by Sabatine and others.

"When these PCSK9 studies are positive—and they're almost certainly going to be positive, especially since the placebo groups have LDLs of about 85 to 90 and they're going to come down to 30 or 40—then the US guidelines have to somehow deal with this," Ginsberg said.

Finally, the investigators, led by Dr Michael Silverman (Brigham and Women's Hospital), conducted an analysis looking at where achieved LDL-C levels were in a group of patients in a trial arm and how that compared with the observed event rate. "And for that there was a nice linear relationship going down to even slightly below 60 mg/dL, reinforcing the notion that lower is better," Sabatine said.

Commenting on the meta-analysis to heartwire , Dr Frederick Masoudi (University of Colorado Hospital, Aurora) said, "From the perspective of a practicing cardiologist, this is not going to change my practice."

He noted that the finding of a relationship between the magnitude of LDL lowering and the risk of vascular events "is territory that's been looked at before" and that obvious differences in outcomes remain in terms of how one obtains an LDL level of a certain magnitude. The CETP inhibitors, he said, are a very good example of this in that they raise HDL quite a bit but also can lower LDL. Despite this fairly substantial impact on lipid levels, however, they have had no impact on outcomes and in one case, torcetrapib, was harmful.

Of the meta-analysis, Masoudi added, "Some might say 'Well, it's great support for this idea of treating more to targets,' but again that's really not a strategy that's been attempted in any of these trials," and so "I still think the guidelines provide great guidance. This doesn't call into question what I think is fairly sound guidance—the use of therapies that clearly improve patient outcomes."

Until PCSK9 inhibitors have clinical-trial evidence, Waters agreed that most people who need LDL lowering should be on a statin, the backbone of therapy in the guidelines.

"If my little old lady in clinic who doesn't like to take her statin and is yearning for something else hears a news report on this saying there are other ways to lower cholesterol and they're all equally good, she'll come back and say 'I've stopped my statin and I want you to give me one of those other treatments.' I think that would be a disservice to her and to a lot of people," he added.

For his part, Sabatine said, "I don't view this as an endorsement for any one drug, although I would argue that statins should always be first line. For the others, it's whatever it takes to get the LDL down and then pick the right drug for that patient."

Sabatine reported receiving institutional grant support from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, Bristol-Myers Squibb, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis, Poxel, Roche Diagnostics, Sanofi, and Takeda and serving as a consultant for Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, CVS Caremark, Intarcia, Ionis, the Medicines Company, Merck, MyoKardia, Pfizer, Quest Diagnostics, Sanofi, and Zeus Scientific. Disclosures for the coauthors are listed in the article. Ginsberg reported research grants from Merck and Sanofi-Regeneron; clinical-trial site participation for Merck and Amgen, and consulting for Merck, Sanofi-Regeneron, and Amgen. Jones reported serving on the scientific advisory boards for Amgen and Sanofi-Regeneron. Waters and Masoudi reported no relevant financial relationships.


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