Ezetimibe Plus Moderate Statin a Welcome Alternative for High-Dose Monotherapy

A combination of ezetimibe and a moderate-intensity statin seems to be a good alternative to high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD), results of the randomized RACING trial indicate.

The findings could be helpful in getting patients to goal while reducing side effects associated with the stronger statin doses, investigators say.

Through 3 years in the trial, the rate of CV death, major CV events, or nonfatal stroke was 9.1% with dual therapy and 9.9% with high-intensity statin monotherapy, a difference (-0.78%; 90% CI -2.39-0.83) that met criteria for noninferiority with a margin of 2.0.

The ezetimibe-based combo had an advantage, however, when it came to the magnitude of the reduction in LDL cholesterol and to tolerability, with a lower rate of discontinuation or dose reduction of the study drug in response to intolerance or adverse events (4.8% vs 8.2%; P < 0.0001).

Currently, international guidelines—including those from the American Heart Association, the American College of Cardiology, and their partners—recommend maxing out the dose of a statin before considering the addition of nonstatin therapies like ezetimibe for patients who still have high LDL cholesterol levels.

It might be time to tweak those recommendations, said RACING researchers led by Byeong-Keuk Kim, MD, PhD, and Sung-Jin Hong, MD (both Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea).

Trials like this, like some of the new PCSK9 inhibitor trials, give us the armamentarium we need to start rethinking the guidelines and saying maybe the most important thing is getting the LDL down by whatever means we can. Alison Bailey

“Our results support recommending the addition of ezetimibe for patients who are taking moderate-intensity statins at a maximal tolerance,” the authors write. “Moreover, these findings suggest that ezetimibe combination therapy might be considered earlier in the use of moderate-intensity statin therapy rather than doubling the statin dose for patients at high risk of adverse effects or statin intolerance with high-intensity statin therapy.”

Alison Bailey, MD (Centennial Heart at Parkridge, Chattanooga, TN), who was on the writing committee for the US cholesterol guidelines, agreed that it could be time to take a fresh look at some of the existing guidance.

“In the United States, we woefully undertreat ASCVD patients who are at the highest risk . . . and it’s probably because of some of the inflexibility in the guidelines,” she commented to TCTMD. “And so I think trials like this, like some of the new PCSK9 inhibitor trials, give us the armamentarium we need to start rethinking the guidelines and saying maybe the most important thing is getting the LDL down by whatever means we can.”

The RACING results were published online this week in the Lancet.

The RACING Trial

Prior research—including a 2014 meta-analysis—has shown that ezetimibe plus lower-intensity statin therapy provides a greater reduction in LDL cholesterol than does higher-intensity statin monotherapy. And it’s expected that avoiding higher doses of statins will cut down on some of the associated side effects.

Until RACING, however, no randomized trials have assessed the longer-term impact this approach has on clinical outcomes in patients with established ASCVD. Both IMPROVE-IT and HIJ-PROPER evaluated the effect of adding ezetimibe to statins, but those trials used a placebo and moderate-intensity statin as comparators, respectively, not a high-intensity statin dose as monotherapy.

The RACING trial, conducted at 26 centers in South Korea, included 3,780 patients with ASCVD (mean age 64 years; 25% women). Investigators randomized them to once-daily ezetimibe 10 mg plus rosuvastatin 10 mg or rosuvastatin 20 mg. The most-common lipid-lowering regimens used before study entry were a high-intensity statin (38%), a moderate-intensity statin (36%), and a moderate-intensity statin plus ezetimibe (13%).

The primary endpoint was a composite of CV death, major CV events (coronary or peripheral revascularization or CV hospitalization), or nonfatal stroke at 3 years. The noninferiority of combination therapy was consistent across subgroups, and there no significant differences between trial arms for any of the individual outcomes.

During the study period, the median LDL-cholesterol concentration was lower with ezetimibe-based therapy than with high-intensity statin monotherapy (58 vs 66 mg dL), and patients receiving the combination were more likely to achieve a level below 70 mg/dL at 1 year (73% vs 55%), 2 years (75% vs 60%), and 3 years (72% vs 58%; P < 0.0001 for all).

The larger reduction is likely “because combination therapy can provide dual action (with a different mechanism) for lowering LDL cholesterol, particularly inhibition of synthesis and intestinal absorption,” senior author Myeong-Ki Hong, MD, PhD (Severance Hospital, Yonsei University College of Medicine), said via email.

‘Really Exciting’ Results

Bailey said this trial was long overdue. “Anything that gives us an additional way to lower LDL and have the same or similar clinical outcomes, with lower side effects of therapy, is a really exciting thing in the world of ASCVD prevention,” she said.

The RACING results were better than expected, because it wasn’t previously clear that a combination of ezetimibe and a moderate-intensity statin would provide clinical outcomes similar to what can be achieved with a high-intensity statin. “I think that’s reassuring and exciting, because I see a lot of patients who have side effects to therapy,” Bailey commented.

In an accompanying editorial, Layla Abushamat, MD, and Christie Ballantyne, MD (both Baylor College of Medicine, Houston, TX), question whether writers of cholesterol guidelines should start considering treatment approaches like those seen in hypertension, for which first-line therapy with multiple drugs is now common.

“Is it time for a paradigm shift in the management of lipids toward an approach with combination therapy as an initial treatment option that is more similar to the treatment of hypertension?” they ask.

Indeed, Bailey said, it is time to start conversations along those lines. Though RACING is the first trial with a moderate-to-large sample size to explore the impact of combination lipid-lowering therapy with ezetimibe on longer-term clinical outcomes, there are data from trials adding PCSK9 inhibitors to statins that suggest benefits as well.

RACING will get people talking about earlier consideration of combination lipid-lowering therapy, although other trials with more-diverse study populations will likely be needed before big changes come to the guidelines, Bailey said. “But I think this has to come into play and I think it will definitely affect clinical practice.”

She stressed the importance of lowering LDL cholesterol using multiple methods: “We should always focus on lifestyle strategies that have been proven to be effective, like diet and exercise, as well as maximizing drug therapy that is tolerated and acceptable to the patient.”