Novel Lipid-Lowering Agents and Stroke Prevention:
New Tools, New Targets

Discussions of new ways to prevent stroke often focus primarily on antithrombotic agents, with less attention paid to the variety of ways hyperlipidemia can be treated. This review article covers the evidence for established lipid-lowering therapies for primary and secondary stroke prevention as well as current research on novel lipid-lowering agents and their effects on stroke risk.

Statins, the mainstay of lipid-lowering therapy, lower serum low-density lipoprotein cholesterol (LDL-C) levels by reducing cholesterol synthesis through inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme. Effective reduction of serum LDL-C levels also can be achieved with agents targeting other steps in cholesterol synthesis or inhibiting intestinal absorption of cholesterol or by inhibiting proprotein convertase subtilisin/kexin 9 (PCSK9) with monoclonal antibodies or with small interfering RNA (siRNA) molecules preventing cholesterol synthesis. Other agents lower serum triglyceride or lipoprotein(a) (Lp[a]) levels. Figure 1 provides a summary of the pathways and molecules targeted by these pharmacologic tools, and the Table summarizes the existing evidence regarding the lipid-lowering effects of these agents.

Medical therapies for stroke/cardiovascular disease prevention should be used in conjunction with lifestyle changes, including dietary and physical activity modifications. A meta-analysis studying dietary factors and stroke risk found a linear dose-response relationship with a 32% (95% CI, 0.56–0.82) and 11% (95% CI, 0.81–0.98) decrease in stroke risk for every 200 g/day increase in fruit and vegetable consumption, respectively.¹ Because of the numerous studies showing the cardiovascular benefits of healthful lifestyle modifications, the 2021 American Heart Association (AHA) stroke guidelines recommend low-salt and Mediterranean diets in addition to supervised exercise for stroke risk reduction.²

Statins

Treatment with statin medications lowers LDL-C levels through inhibition of HMG-CoA reductase and is a well-established therapy for both primary and secondary stroke prevention. AHA guidelines for treatment of hyperlipidemia for primary stroke prevention recommend statin medication for individuals estimated to have a 10-year risk of cardiovascular events exceeding 7.5%.³ The Cholesterol Treatment Trialists’ Collaboration conducted a meta-analysis of 26 randomized control trials (RCTs) including 5 trials of more versus less intensive statin doses and 21 trials of statin versus placebo.⁴ This meta-analysis found a 1.07 mmol/L reduction in LDL-C levels and a 20% risk reduction in ischemic stroke in statin-treated groups compared with placebo (95% CI, 0.72–0.89).⁴ In the more versus less statin groups, the study reported a 0.51 mmol/L reduction in LDL-C levels and a 16% risk reduction in ischemic stroke with higher statin regimens (95% CI, 0.71–0.99).⁴ Statins are an effective first-line treatment for lowering LDL-C levels with clear benefit for primary stroke prevention.

Statins also have an important role in secondary stroke prevention. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial randomly assigned 4731 participants with a history of stroke or transient ischemic attack (TIA) within 1 to 6 months before study entry, all of whom had LDL-C levels of 100 to 190 mg/dL and no known coronary heart disease, to 80 mg of atorvastatin daily or placebo.⁵ Atorvastatin reduced risk of nonfatal or fatal stroke (hazard ratio [HR], 0.84 [95% CI, 0.71–0.99]) and risk of ischemic stroke (HR, 0.78 [95% CI, 0.66–0.94]).⁵ This study confirmed that statins provide long-term morbidity and mortality benefits after stroke, making them a powerful agent for secondary stroke prevention.

Ezetimibe

Although statins are highly effective at lowering LDL-C levels, not all individuals can achieve LDL-C goals with statin monotherapy because of adverse side effects that can be caused by higher doses of statins. Therefore, the 2021 AHA guidelines recommend adding ezetimibe (Zetia; Merck & Co, Rahway, NJ) to a statin, if needed, to achieve a goal LDL-C level <70 mg/dL in people with ischemic stroke or TIA and atherosclerotic disease.² Ezetimibe is an agent that decreases cholesterol absorption by inhibiting the Niemann-Pick C1-like 1 (NPC1L1) protein on the brush border of small intestinal epithelial cells. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT, NCT00202878) studied the effects of simvastatin 40 mg and ezetimibe 10 mg daily compared with simvastatin and placebo in 18,144 individuals who were hospitalized for acute coronary syndrome within the past 10 days and had LDL-C levels of 50 to 100 mg/dL (if on lipid-lowering therapy) or 50 to 125 mg/dL (if not on lipid-lowering therapy).⁶ The results showed that at 1 year, there was a 24% further lowering of LDL-C levels with the addition of ezetimibe to simvastatin.⁶ There was also a 21% reduction in risk of ischemic stroke in the simvastatin–ezetimibe group (HR, 0.79 [95% CI, 0.67–0.94]).⁶ Thus, evidence suggests that ezetimibe can decrease stroke risk when added to moderate-intensity statin treatment in individuals with evidence of atherosclerotic disease.

The Treat Stroke to Target (TST, NCT01252875) trial tested ezetimibe’s effects after stroke.⁷ In this study, individuals with a history of ischemic stroke in the past 3 months or TIA within the previous 15 days and evidence of atherosclerotic disease were randomly assigned to a target LDL-C level of <70 or 100±10 mg/dL using statin or ezetimibe, or both, as needed.⁷ The results showed that participants in the <70 mg/dL group who were also on dual therapy had a reduced risk of major cardiovascular events (HR, 0.59 [95% CI, 0.38–0.90]) and reduced risk of cerebral infarction and urgent carotid and cerebral artery revascularization (HR, 0.57 [95% CI, 0.33–0.97]) compared with all individuals in the 100±10 mg/dL group.⁷ The TST trial was the basis for the AHA-recommended LDL-C goal of <70 mg/dL and demonstrated the effectiveness of adding ezetimibe to statin therapy for secondary stroke prevention.

PCSK9 Inhibitors: Monoclonal Antibodies

PCSK9 is an enzyme involved in the regulation of LDL receptors. PCSK9 binds to an extracellular region on LDL receptors, promoting their endocytosis and breakdown in lysosomes.⁸ Evolocumab (Repatha; Amgen, Thousand Oaks, CA) and alirocumab (Praluent; Regeneron, Tarrytown, NY) are monoclonal antibodies that target and inhibit PCSK9, preventing the binding of PCSK9 to LDL receptors, ultimately promoting the recycling of LDL receptors back to the cell surface to clear LDL from the serum.⁸ The 2021 AHA guidelines recommend using either evolocumab or alirocumab as a third-line treatment for individuals with ischemic stroke who are at very high risk and have an LDL-C level >70 mg/dL on maximally tolerated statin and ezetimibe therapy.² This guideline is based on the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER, NCT01764633) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes, NCT01663402) trials.^9,10

The FOURIER trial randomized 27,564 participants with atherosclerotic cardiovascular disease on statin or ezetimibe therapy and LDL-C level ≥70 mg/dL to evolocumab or placebo. The authors reported a 59% mean reduction in LDL-C levels in the evolocumab group at 48 weeks.⁹ The trial also found that evolocumab significantly reduced the primary end point of the composite risk of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization (HR, 0.85 [95% CI, 0.79–0.92]). There was a 21% reduction in the risk of all strokes (HR, 0.79 [95% CI, 0.66–0.95]), a 25% reduction in ischemic stroke risk (HR, 0.75 [95% CI, 0.62–0.92]), and a 23% reduction in risk of ischemic stroke or TIA (HR, 0.77 [95% CI, 0.65–0.92]) in the evolocumab-treated group.⁹ Of the 19% of individuals who had a history of an ischemic stroke before randomization, evolocumab decreased the risk of the primary outcome (HR, 0.85 [95% CI, 0.72–1.00]). Evolocumab also reduced postrandomization total stroke, ischemic stroke, and the composite of ischemic stroke or TIA to a similar degree, regardless of history of previous stroke. Out of the 503 strokes that occurred in the FOURIER trial, 34 were recurrent strokes in 32 individuals after an initial stroke. There were 10 fewer recurrent strokes in the evolocumab group compared with the placebo group.¹¹ The results of the FOURIER trial support the use of evolocumab for both primary and secondary stroke prevention.

The ODYSSEY Outcomes trial studied the effects of alirocumab versus placebo in 18,924 participants with previous acute coronary syndrome who had LDL-C levels >70 mg/dL on the maximum tolerated dose of statin therapy. At 4 months, the LDL-C levels of the alirocumab group were on average 62% lower than those of the placebo group. Alirocumab decreased the risk of the primary end point (HR, 0.85 [95% CI, 0.78–0.93]) and the risk of fatal or nonfatal ischemic stroke (HR, 0.73 [95% CI, 0.57–0.93]).¹⁰ The effect of alirocumab on stroke was consistent regardless of history of previous stroke (P_interaction = 0.37).¹² These studies show that PCSK9 monoclonal antibodies are effective LDL-C–lowering therapies for reducing the risk of stroke.

PCSK9 Inhibition by RNA Interference With Inclisiran

Inclisiran (Leqvio; Novartis, Cambridge, MA) is an siRNA that recruits the RNA-induced silencing complex and binds to and breaks down PCSK9 mRNA. Inclisiran is administered twice yearly as a subcutaneous injection. Three phase 3 placebo-controlled trials have evaluated inclisiran in individuals with high risk of cardiovascular events and elevated LDL-C levels despite receiving maximally tolerated doses of statins.¹³ A pooled analysis of these trials found that at 3 months, inclisiran lowered LDL-C levels by 50.6% compared with placebo.¹³ There was also a 25% risk reduction in major adverse cardiovascular events in the inclisiran group (HR, 0.75 [95% CI, 0.60–0.94]). However, there was no effect on fatal or nonfatal stroke risk (HR, 0.80 [95% CI, 0.39–1.67]).¹³ Despite its ability to lower LDL-C levels significantly in combination with statins, inclisiran does not yet have a proven beneficial effect on stroke risk.

Lowering LDL-C Levels With Bempedoic Acid

Bempedoic acid is an oral inhibitor of ATP citrate lyase, an enzyme involved in the cholesterol synthesis pathway.¹⁴ Unlike statins, bempedoic acid is a prodrug that is activated in the liver, reducing the potential for adverse effects on muscles. In the Cholesterol Lowering via Bempedoic Acid (CLEAR, NCT02993406) trial, 13,970 participants with high risk of cardiovascular disease who were not on statin therapy were randomized to bempedoic acid or placebo. After 6 months, there was a 21% greater reduction in LDL-C level in the bempedoic acid group compared with the placebo group. The primary end point of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or coronary revascularization was significantly lower with bempedoic acid than placebo (HR, 0.87 [95% CI, 0.79–0.96]). However, bempedoic acid had no significant effects on the risk of fatal or nonfatal stroke (HR, 0.85 [95% CI, 0.67–1.07]).¹⁴ More study is needed to determine the role of bempedoic acid in stroke prevention.

ANGPTL3 Inhibition

Angiopoietin-like protein 3 (ANGPTL3) is a liver-derived protein that inhibits lipoprotein lipase and endothelial lipase, enzymes that normally metabolize very-low-density lipoprotein into remnants that can be cleared through reuptake by the liver. Evinacumab-dgnb (Evkeeza; Regeneron; Tarrytown, NY) is a monoclonal antibody targeting ANGPTL3 that has been shown to lower LDL-C levels by 47% and to lower apolipoprotein B and non–high-density lipoprotein cholesterol levels significantly in phase 3 trials in individuals with familial hypercholesterolemia.¹⁵ Evinacumab has been approved in the United States as an adjunct to other LDL-C–lowering therapies in individuals with familial hypercholesterolemia. ARO-ANG3 (Arrowhead Pharmaceuticals, Pasadena, CA) is an antisense oligonucleotide (ASO) that binds to ANGPTL3 mRNA in the hepatocyte nucleus. In a small sample of healthy participants, ARO-ANG3 significantly reduced triglyceride, LDL-C, very-low-density lipoprotein, and apolipoprotein B levels.¹⁶ Data regarding cardiovascular outcomes with these therapies, including stroke, may become available over the next 2 to 4 years.¹⁷

Triglyceride-Lowering Therapies

Hypertriglyceridemia is a risk factor for cardiovascular events in people with atherosclerotic disease. Icosapent ethyl ([IPE], Vascepa; Amarin, Dublin, Ireland) is a highly purified eicosapentaenoic acid ethyl ester that is thought to lower risk of vascular events through pleiotropic effects, including lowering triglyceride levels, inhibiting platelet aggregation, and stabilizing lipid membranes. In the Reduction of Cardiovascular Events With Icosapent Ethyl–Interventional Trial ([REDUCE-IT], NCT01492361), 8179 participants who had cardiovascular disease or diabetes and other risk factors, were on statin therapy, and had a fasting triglyceride level of 135 to 499 mg/dL and LDL-C level of 41 to 100 mg/dL were randomized to IPE or placebo.¹⁸ IPE was shown to decrease triglyceride levels by 18.3% in 1 year and reduced the risk of the primary end point of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina (HR, 0.75 [95% CI, 0.68–0.83]). IPE also reduced the risk of fatal or nonfatal stroke (HR, 0.72 [95% CI, 0.55–0.93]) and ischemic stroke (HR, 0.64 [95% CI, 0.49–0.85]). The rate of atrial fibrillation was significantly higher in the IPE group compared with the placebo group (5.3% versus 3.9%). Based on the study results, the 2021 AHA guidelines recommend IPE treatment for individuals with ischemic stroke or TIA with a triglyceride level of 135 to 499 mg/dL, LDL-C level of 40 to 100 mg/dL, and no history of atrial fibrillation or heart failure.² Studies on niacin and fibrates for stroke prevention have yielded negative results; however, IPE is an effective treatment for stroke risk reduction.

Pemafibrate (Parmodia; Kowa Company Ltd., Aichi, Japan) is a new peroxisome proliferator-activated receptor a (PPARa) modulator with many metabolic effects (see Figure 1), including triglyceride-lowering. However, despite decreasing triglyceride levels by 31% in 4 months, pemafibrate was found to have no effect on cardiovascular risk, including stroke.¹⁹

Volanesorsen (Waylivra; Akcea Therapeutics, subsidiary of Ionic Pharmaceuticals, Carlsbad, CA) and olezarsen (Ionis Pharmaceuticals, Carlsbad, CA) are both ASOs targeting the mRNA of apolipoprotein C3 (ApoC3), a major protein component of triglyceride-rich chylomicrons that inhibits lipoprotein lipase.²⁰ A pooled analysis of 4 RCTs reported that volanesorsen lowered triglyceride levels by 73%.²¹ Another RCT found up to 60% triglyceride reduction in the olezarsen-treated group.²² Ongoing early-phase clinical trials are investigating an siRNA targeting ApoC3 called ARO-APOC3 (Arrowhead Pharmaceuticals, Pasadena, CA).¹⁷ Studies on cardiovascular outcomes are needed to evaluate the effectiveness of these novel therapies.

Lp(a)-Targeted Therapies

Lipoprotein(a) (Lp[a]) is a form of LDL-C that is a known risk factor for atherosclerosis. A recent meta-analysis found that Lp(a) was significantly associated with risk of ischemic stroke and large artery atherosclerosis.²³ Therapies under development have been reported to lower Lp(a) levels by 80% to 100%, including pelacarsen (Ionis Pharmaceuticals, Carlsbad, CA),²⁴ an ASO, as well as the siRNAs olpasiran (Amgen, Thousand Oaks, CA)²⁵ and SLN360 (Silence Therapeutics, Hoboken, NJ).²⁶ These therapies are undergoing phase 3 trials, and cardiovascular outcomes will become available between 2025 and 2027.¹⁷

Summary

Evidence has shown that lowering lipid levels leads to reduced risk of ischemic stroke. The literature supporting statins and ezetimibe as effective therapies for primary and secondary prevention of stroke is robust. Newer trials have established the monoclonal PCSK9 antibodies evolocumab and alirocumab as well as IPE as powerful adjuncts to statins in reducing stroke risk. Whereas phase 3 trials for inclisiran, bempedoic acid, and pemafibrate have not yet indicated effectiveness in stroke prevention, trials focusing on effects of these agents in secondary prevention among people who have experienced a stroke have yet to be reported. Research into other new agents targeting ANGPTL3, Lp(a), and ApoC3 is underway to provide evidence in people at high risk of stroke. The existing evidence can support an algorithm for lipid control that starts with high-intensity statin therapy and ezetimibe as first-line and second-line therapies, and incorporates PCSK9 inhibitors, IPE, and bempedoic acid as additional therapies to consider in specific cases (Figure 2). The emergence of several powerful new agents targeting serum lipid levels provides hope for new stroke prevention tools to become available in upcoming years.