New Gold Standard for Cholesterol Treatment Could Prevent 330,000 Deaths a Year

The largest study to date suggests that patients at high risk for heart attacks and strokes should begin immediate treatment with a combination of a statin and ezetimibe.

The largest study to date examining how best to lower “bad” cholesterol in patients with blocked arteries has found that starting treatment with a combination of a statin and the drug ezetimibe is significantly more effective than using statins alone. This approach could prevent thousands of deaths each year from heart attacks, strokes, and other cardiovascular conditions.

Published in Mayo Clinic Proceedings, the meta-analysis included data from 14 clinical trials involving 108,353 high-risk patients, those who had either experienced a heart attack or stroke or were at high risk of doing so. The results showed that combining ezetimibe with a high-dose statin led to a 19% reduction in all-cause mortality, a 16% reduction in cardiovascular deaths, and an 18% and 17% reduction in major cardiovascular events and strokes, respectively, compared to high-dose statin therapy alone.

The combination therapy also achieved significantly better cholesterol control, lowering LDL-C (low-density lipoprotein cholesterol) by an additional 13 mg/dL compared to statins alone. This improvement made it 85% more likely for patients to reach the recommended LDL-C target of less than 70 mg/dL.

Enhanced Outcomes with Network Meta-Analysis

“These results were even more pronounced in the network meta-analysis, which enables a direct comparison of different therapy regimens used in the study. This showed a 49% reduction in all-cause mortality and a 39% reduction in major adverse cardiovascular events, when compared to high dose statin therapy alone,” said the first author of the study, Maciej Banach, Professor of Cardiology at the John Paul II Catholic University of Lublin, Poland, and Adjunct Professor at the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, who also leads the International Lipid Expert Panel and the Blood Pressure Meta-analysis Collaboration group that carried out the study.

“The combination therapy is safe and efficacious; the risk of adverse events and the therapy discontinuation rate was comparable between groups. In the network meta-analysis, we showed a significant 44% reduction in the risk of discontinuation in those treated with moderately high-dose statin therapy plus ezetimibe versus a high-dose statin alone.”

Challenging Current Guidelines on Cholesterol Treatment

Until now, there have been inconsistent findings about whether or not combined cholesterol lowering therapy should be given to high risk patients immediately, even before they suffer a heart attack or stroke, or whether doctors should start these patients on a high dose statin first and monitor the effects on cholesterol levels after at least two months before deciding if the patients need ezetimibe as well.

Co-author of the study, Peter Toth, Professor of Clinical Family and Community Medicine, University of Illinois, and Adjunct Associate Professor of Medicine at Johns Hopkins University, USA, said: “This study confirms that combined cholesterol lowering therapy should be considered immediately and should be the gold standard for treatment of very high-risk patients after an acute cardiovascular event. Simply adding ezetimibe to statin therapy, without waiting for at least two months to see the effects of statin monotherapy, which is suboptimal in many patients, is associated with more effective LDL-C goal achievement and is responsible for significant incremental reductions in cardiovascular health problems and deaths.

“This approach does not require additional funding or reimbursement of new expensive drugs. In fact, it may translate into lower rates of first and subsequent heart attacks and stroke, and their complications like heart failure, which are extremely costly for all healthcare systems.”

According to the data from the Global Burden of Disease and the American Heart Association, deaths occurring as a result of high LDL-C alone are highest in Eastern Europe and Central Asia, and 4.5 million deaths worldwide were attributed to it in 2020.

Global Health Implications and Future Guidelines

Prof. Banach said: “Cardiovascular disease kills around 20 million people a year worldwide. Based on our previous analysis, we estimate that if combination therapy to reduce LDL-C was included in all treatment guidelines and implemented by doctors everywhere for patients with high cholesterol levels, it would prevent over 330,000 deaths a year among patients who have already suffered a heart attack, and almost 50,000 deaths alone in the USA. We recommend combination therapy should be considered the gold standard of treatment for these patients and included in all future treatment guidelines.”

Statins have been used safely for years. They help to lower LDL-C by reducing the production of it by the liver. Ezetimibe reduces the amount of cholesterol that the body takes from food by inhibiting the absorption of it in the intestines. Some patients do not respond adequately to statins and are prescribed ezetimibe in combination with a statin. High doses of statins are known as ‘high intensity’ statins and moderately high doses are known as ‘moderate intensity’ or ‘medium intensity’ statins.

Prof. Toth said: “Our findings underline the importance of the adages ‘the lower for better for longer’ but also the equally important ‘the earlier the better’ for treating patients at high risk of cardiovascular conditions and to avoid further medical complications and deaths.”

A strength of the study is its large size, as it includes the greatest number of patients studied so far. The patients were included in 14 studies, 11 of which were randomised controlled trials and three of which were cohort studies. Limitations relate mainly to the type of studies that were included in the meta-analysis, including their size and the observational nature of some of them.

Reference: “Impact of Lipid-Lowering Combination Therapy With Statins and Ezetimibe vs Statin Monotherapy on the Reduction of Cardiovascular Outcomes: A Meta-analysis” by Maciej Banach, Vikash Jaiswal, Song Peng Ang, Aanchal Sawhney, Novonil Deb, Pierre Amarenco, Dan Gaita, Zeljko Reiner, Ivan Pećin, Carl J. Lavie, Peter E. Penson and Peter P. Toth, 23 March 2025, Mayo Clinic Proceedings.