Are there non-statin options that work as well for prevention?

The short version: ezetimibe and PCSK9 inhibitors reduce heart attacks and strokes when added to a statin, but none of them have been shown to keep you alive longer than a statin alone.

The evidence for non-statin options comes from large trials, but almost all of them were run on top of a statin, not instead of one. A 2019 meta-analysis of 9 trials with over 100,000 patients found that adding ezetimibe or a PCSK9 inhibitor to a statin cut cardiovascular events by 18% and heart attacks by 16% [1]. But all-cause mortality was not significantly reduced: the odds ratio was 0.94 with a confidence interval that crossed 1.0 [1]. A 2024 narrative review of the same trials confirmed this pattern: ezetimibe, PCSK9 inhibitors, and bempedoic acid all reduced composite cardiovascular endpoints but did not reduce cardiovascular death [24]. The only add-on therapy that did reduce cardiovascular death was icosapent ethyl (a high-dose fish oil), with a hazard ratio of 0.80 [24].

The 2025 Korean cohort study in people with diabetes is worth a close look. It compared a lower-intensity statin plus ezetimibe against a high-intensity statin alone [3]. The combination reduced major cardiovascular events by 33% in primary prevention and 20% in secondary prevention. But again, all-cause death was not different: hazard ratio 0.93 in primary prevention, 1.01 in secondary prevention [3]. The combination did cause fewer liver and diabetes-related hospitalizations than the high-dose statin, which is a real advantage [3].

The PCSK9 inhibitors are powerful: they drop LDL by about 60% [4]. But the FOURIER trial, which was funded by Amgen, found that evolocumab did not reduce cardiovascular death (HR 1.05) [24]. The ODYSSEY trial, funded by Sanofi, found the same for alirocumab (HR 0.88, not significant) [24]. These are expensive drugs, around $5,000 to $14,000 per year, and the evidence that they extend life is missing.

For people who cannot tolerate statins, bempedoic acid is an option. The CLEAR Outcomes trial, funded by Esperion, found it reduced composite cardiovascular events but not cardiovascular death (HR 1.04) [24]. It also raises uric acid and gout risk [17].

My call: if you are already on a statin and still having events, adding ezetimibe or a PCSK9 inhibitor will lower your LDL and reduce your risk of another heart attack or stroke, but the evidence does not show it will help you live longer. For statin-intolerant patients, bempedoic acid or icosapent ethyl are reasonable alternatives, but again the mortality benefit is absent or limited to one drug. Confidence: moderate.