A large-scale analysis has revealed that patients with blocked arteries should be treated immediately with a combination of a statin and ezetimibe, rather than statins alone, to lower levels of low-density lipoprotein cholesterol (LDL-C). This approach could prevent thousands of deaths each year from heart attacks, strokes, and other cardiovascular diseases.
According to the Global Burden of Disease and the American Heart Association, high LDL-C was responsible for 4.5 million deaths worldwide in 2020, with the highest mortality rates in Eastern Europe and Central Asia.
Published in Mayo Clinic Proceedings, the analysis examined data from 108,353 high-risk patients across 14 studies. These patients had either already suffered a heart attack or stroke or were at very high risk.
The study found that adding ezetimibe to a high-dose statin resulted in a 19% reduction in the risk of death from any cause, a 16% reduction in deaths from cardiovascular causes, an 18% reduction in major adverse cardiovascular events and a 17% reduction in the risk of stroke. The combination therapy significantly lowered LDL-C levels by an extra 13 mg/dL compared to statins alone. This improved the likelihood of achieving the target LDL-C level of less than 70 mg/dL by 85%.
These benefits were even more pronounced in the network meta-analysis, which allows direct comparison of different treatment regimens. It showed a 49% reduction in all-cause mortality and a 39% reduction in major cardiovascular events (MACE) compared to high-dose statin therapy alone.
The study confirmed that the combination therapy is both safe and effective, with no significant increase in adverse events. Patients receiving moderate-intensity statin plus ezetimibe had a 44% lower risk of discontinuing treatment compared to those on high-dose statins alone.
For years, there has been debate over whether doctors should prescribe combination therapy immediately or wait to see if statin monotherapy sufficiently lowers cholesterol after at least two months. This study confirms that combination therapy should be initiated immediately as the gold standard for treating very high-risk patients. Simply adding ezetimibe to a statin right away—rather than waiting—leads to better LDL-C control and significant reductions in cardiovascular events and deaths.
Unlike newer cholesterol-lowering drugs, ezetimibe is affordable and does not require additional funding or insurance reimbursement. Prof. Toth notes that adopting this approach could reduce the frequency of first and subsequent heart attacks and strokes, as well as complications like heart failure—conditions that place a heavy financial burden on healthcare systems worldwide.
Cardiovascular disease kills 20 million people a year worldwide. If combination therapy were universally adopted, it could prevent over 330,000 deaths annually among patients who have already suffered a heart attack—including nearly 50,000 deaths in the U.S. alone. We strongly recommend that combination therapy be included in all future treatment guidelines.
These findings reinforce the principle of ‘the lower, the better, for longer’ when it comes to LDL-C levels. But just as importantly, they highlight that ‘the earlier, the better’—starting combination therapy immediately after diagnosis is critical for preventing complications and saving lives.
Source: Mayo Clinic Proceedings
Image Credit: iStock
References:
Banach M et al. (2025) Impact of Lipid-Lowering Combination Therapy With Statins and Ezetimibe vs Statin Monotherapy on the Reduction of Cardiovascular Outcomes: A Meta-analysis. Mayo Clinic Proceedings.
