9.2 Management of abnormal lipid metabolism		COR	LOE
New recommendation	For patients with non-cardioembolic IS or TIA with LDL-C levels ≥2.6 mmol/L (100 mg/dL), high-intensity statin therapy is recommended to reduce the risk of stroke recurrence.	I	A
	The SPARCL trial included adults with ischaemic or haemorrhagic stroke (or TIA, presumably owing to atherosclerotic causes) and an LDL-C level of 100–190 mg/dL.245 Eligible patients were randomised to atorvastatin 80 mg or placebo. The result revealed that in patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and cardiovascular events (atorvastatin group 11.2% vs placebo group 13.1%, adjusted HR 0.84, 95% CI 0.71 to 0.99). The secondary analysis of the SPARCL trial explored the effects of treatment in SPARCL subjects with type 2 diabetes mellitus or metabolic syndrome (MetS).246 This exploratory analysis found no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or MetS.
New recommendation	High-intensity statin therapy is recommended for patients with non-cardioembolic IS or TIA with intracranial and extracranial atherosclerosis. If necessary, combination therapy with ezetimibe should be considered to achieve LDL-C levels below 1.8 mmol/L (70 mg/dL) or to reduce LDL-C levels by 50% or more, aiming to lower the risk of stroke and cardiovascular events.	I	A
	The TST trial included adults with cerebral infarction or high-risk TIA, and a clear indication for statin therapy. Eligible patients were randomly assigned to an LDL-C target of <70 mg/dL vs 90–110 mg/dL.146 To achieve the assigned LDL-C targets, statin therapy was intensified, and ezetimibe was added if necessary. Patients who achieved a target LDL-C level of less than 70 mg/dL had a lower risk of subsequent cardiovascular events compared with those who had a target range of 90–110 mg/dL (8.5% vs 10.9%, HR 0.78, 95% CI 0.61 to 0.98).
Revised	For patients with IS or TIA, if their LDL-C levels remain above 1.8 mmol/L despite receiving maximum tolerated statin therapy, combination treatment with ezetimibe is recommended.	I	B
	The IMPROVE-IT trial involved adult patients with acute coronary syndrome to compare the cardiovascular risk of the combination of simvastatin and ezetimibe with simvastatin and placebo. The result indicated that when added to statin therapy, ezetimibe resulted in the incremental lowering of LDL-C levels and improved cardiovascular outcomes (HR 0.94, 95% CI 0.89 to 0.99).247
Revised	For extremely high-risk patients who had an IS (stroke plus another major atherosclerotic cardiovascular disease (ASCVD) event or stroke plus multiple high-risk factors), if LDL-C levels remain above 1.8 mmol/L despite receiving maximum tolerated statin and ezetimibe combination therapy, the use of PCSK9 inhibitors is recommended to prevent ASCVD events.	IIa	B
	The FOURIER trial involved patients with ASCVD (including stroke) with LDL-C levels of 1.8 mmol/L or higher who received statin therapy.248 Patients were randomly assigned to receive evolocumab or a matching placebo. The result showed that relative to placebo, evolocumab treatment significantly reduced the risk of the primary endpoint (9.8% vs 11.3%, HR 0.85, 95% CI 0.79 to 0.92, p<0.001).
New recommendation	For patients who cannot tolerate statins or have contraindications to statin therapy, the use of PCSK9 inhibitors or ezetimibe may be considered.	IIb	B
	The ODYSSEY ALTERNATIVE trial compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance.249 The results showed that alirocumab reduced the mean LDL-C levels by 45.0% vs 14.6% with ezetimibe (mean difference 30.4%, p<0.001). Skeletal muscle-related events were less frequent with alirocumab versus atorvastatin (HR 0.61, 95% CI 0.38 to 0.99, p=0.042).
New recommendation	For patients who had an IS or TIA with concurrent hypercholesterolaemia, the effectiveness of LDL-C-lowering medications and lifestyle adjustments should be assessed after 4–12 weeks of statin therapy based on the fasting lipid levels and safety indicators (liver transaminases and creatine kinase). Subsequently, medication adherence and safety should be monitored every 3–12 months as needed, considering medication adjustments.	I	A
	Lifestyle changes and statin therapy are often implemented together in the management of hypercholesterolaemia.250 The maximum percentage change in lipid levels typically occurs within 4–12 weeks after initiating statin therapy, at which time drug efficacy or initial adherence to therapy can be evaluated. The most frequent adverse effect of statin therapy is myopathy. Increased levels of liver enzymes may occur during statin therapy and are usually reversible. Periodical remeasurements of these indicators can confirm adherence to lipid-lowering therapy.251
New recommendation	For patients who had an IS or TIA with fasting TG ≥135 mg/dL (1.52 mmol/L), who have received moderate or high-intensity statin therapy, an HbA1c level <10%, and no history of pancreatitis, atrial fibrillation, or severe heart failure, treatment with icosapent ethyl (2 g two times per day) can reduce the risk of stroke recurrence.	IIa	B
	The REDUCE-IT trial randomised 8179 patients with ASCVD, including a history of IS or TIA (70%) or diabetes with other risk factors (30%), to icosapent ethyl 2 g two times per day plus statin versus statin alone.252 Enrolment criteria included fasting TG of 135–499 mg/dL and LDL-C of 41–100 mg/dL on statin dose for ≥4 weeks. Over a median follow-up of 4.9 years, the trial revealed a 25% reduction (17.2% vs 22.0%, HR 0.75, 95% CI 0.68 to 0.83, p<0.001) in the primary endpoint of major adverse cardiovascular events with icosapent ethyl treatment compared with the control group. The JELIS trial involved Japanese patients with hypercholesterolaemia with serum total cholesterol of 6.5 mmol/L or higher.253 Patients with hypercholesterolaemia were randomly assigned to receive eicosapentaenoic acid (EPA) with statin (EPA group) or statin alone (no EPA group). In the secondary prevention subgroup, stroke occurred in 48 (10.5%) of 457 no EPA group and in 33 (6.8%) of 485 EPA group, showing a 20% relative reduction in recurrent stroke in the EPA group (HR 0.80, 95% CI 0.640 to 0.997).