The therapeutic core of the guidelines is not "prescribe a statin" but reach a target proportionate to the risk. The intensity of LDL-C lowering in the 2025 focused update is still determined by the level of risk. The principle "the earlier and lower, the better" for ACS is formulated in the same place, with reference to the vulnerability of the first year after the event.
The steps the student is required to reproduce in order.
- Non-pharmacological measures. ESC/EAS 2019: a dietary pattern low in saturated fat, whole grains, vegetables, fruit, fish. Kazakhstan Ministry of Health protocol No. 196: moderate-intensity exercise ≥30 minutes a day even without excess weight; a diet following the Mediterranean pattern (the appendix on diet). Supplements without proven safety and effect are class III B (ESC/EAS 2025). Red yeast rice: Commission Regulation (EU) 2022/860 of 1 June 2022 prohibits a portion for daily consumption containing 3 mg or more of monacolins from red yeast rice; an individual portion must provide less than 3 mg.
- Statin at the maximally tolerated dose. Kazakhstan Ministry of Health protocol No. 196: I, A. High-intensity regimen (LDL-C reduction ≥50%): atorvastatin 40–80 mg, rosuvastatin 20–40 mg. Moderate-intensity (30–50%): atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg. ESC CCS 2024 for everyone with CCS: a high-intensity statin up to the highest tolerated dose to reach the target.
- If the target is not reached — ezetimibe. Kazakhstan Ministry of Health protocol: I, B. IMPROVE-IT (Cannon C.P. et al., N Engl J Med 2015;372:2387–2397): 18 144 patients hospitalised with ACS in the preceding 10 days, simvastatin 40 mg ± ezetimibe 10 mg; primary endpoint at 7 years 32.7% versus 34.7% (absolute difference 2.0 percentage points; HR 0.936; 95% CI 0.89–0.99; P=0.016).
- If the target is still not reached in very high risk — a PCSK9 inhibitor (alirocumab, evolocumab) or inclisiran (siRNA against PCSK9). Kazakhstan Ministry of Health protocol: secondary prevention I, A; primary prevention at very high risk I, C. Alirocumab 75 or 150 mg every 2 weeks (or a monthly regimen); evolocumab 140 mg every 2 weeks or monthly. Inclisiran — the advantage of a once-every-6-months regimen in low adherence (the protocol's wording). Inclisiran MACE outcomes are still awaited in 2025 (ORION-4, NCT03705234; VICTORION-2 PREVENT, NCT05030428 — reports in 2026 and 2027, ESC/EAS 2025).
- Bempedoic acid — an inhibitor of ATP citrate lyase. ESC/EAS 2025: recommended for patients who cannot take a statin, to reach the target (I B); addition to the maximally tolerated statin ± ezetimibe may be considered at high/very high risk (IIa C). CLEAR Outcomes (Nissen S.E. et al., N Engl J Med 2023;388:1353–1364): 13 970 patients unable to tolerate recommended statin doses (6992 bempedoic acid, 6978 placebo); 69.9% in secondary prevention; median follow-up 40.6 months. Mean baseline LDL-C 139.0 mg/dL in both groups; by 6 months the difference versus placebo was 29.2 mg/dL (≈0.75 mmol/L), the observed difference in percentage reduction was 21.1 percentage points in favour of bempedoic acid. Four-component MACE was reduced (11.7% versus 13.3%; HR 0.87; 95% CI 0.79–0.96; P=0.004); cardiovascular death was not reduced (HR 1.04; 95% CI 0.88–1.24). On top of a statin, LDL-C reduction of the order of 18%; in fixed combination with ezetimibe, of the order of 38% (review estimates for the 2025 focused update). Reversible increase in uric acid: caution in gout, but gout is not an absolute contraindication.
- Homozygous FH: evinacumab IIa B from 5 years of age if the target is not reached.
When to start a combination right away. ESC/EAS 2025 for ACS: intensification during hospitalisation is recommended for those already on lipid-lowering therapy (I C); starting a combination of a high-intensity statin with ezetimibe during hospitalisation should be considered in treatment-naïve patients if a statin is unlikely to be sufficient to reach the target (IIa B). Kazakhstan Ministry of Health protocol No. 196, text of the treatment section: with a significant elevation of LDL-C in very-high-risk patients (above 4.0 mmol/L), consider statins and ezetimibe, preferably in a single tablet, as first line; with an elevation above 5.0 mmol/L at extreme or very high risk, consider initial prescription of a statin, ezetimibe and a PCSK9 inhibitor or inclisiran as first line.
Primary prevention, when the drug is already class I (ESC/EAS 2025, I A): very high risk and LDL-C ≥1.8 mmol/L or high risk and LDL-C ≥2.6 mmol/L — despite optimisation of non-pharmacological measures.
The boundary of the lesson. The course does not set out the management of complete statin intolerance as a separate discipline and does not claim that inclisiran has already proven a reduction in MACE: by the date of the 2025 focused update there were no outcome trials yet. It does not claim that bempedoic acid reduces cardiovascular death: in CLEAR Outcomes there was no effect on CV death (HR 1.04; 95% CI 0.88–1.24).