Dyslipidemia
Contents. #Definition · #Atherogenic targets — LDL-C, non-HDL-C and ApoB · #Screening and diagnosis · #Treatment goals by risk category · #Lifestyle · #Agents at a glance · #Hypertriglyceridaemia · #Lipoprotein(a) · #Emerging therapies · #Contradictions / Open Questions
Detailed pages. concepts/Dyslipidemia-Management — the drugs and the order to use them in: statin intensity, ezetimibe, PCSK9 agents, bempedoic acid, inclisiran, statin intolerance, secondary prevention and special populations.
Definition
Dyslipidaemias are disorders of blood lipid levels: elevated LDL-C and total cholesterol, hypertriglyceridaemia, and elevated lipoprotein(a). Management targets atherogenic lipoprotein reduction to lower ASCVD risk and, separately, prevention of acute pancreatitis in severe hypertriglyceridaemia.
The 2026 ACC/AHA guideline is the current comprehensive framework and moves the target beyond LDL-C alone to non-HDL-C and ApoB, adopting PREVENT for risk estimation, reinstating absolute LDL-C and non-HDL-C goals, recommending universal Lp(a) measurement for adults, and codifying ApoB as a marker to guide intensification (sources/lipid-aha-2026, rating: very high). ESC 2025 keeps its 2019 targets unchanged and concentrates on which agents to use, when to start them, and in whom (sources/lipid-esc-2025, rating: very high).
Key Concepts
Atherogenic targets — LDL-C, non-HDL-C and ApoB
- LDL-C measures cholesterol mass within LDL particles. Non-HDL-C (total cholesterol minus HDL-C) measures cholesterol across all atherogenic particles — LDL, VLDL remnants, IDL and Lp(a) — and predicts ASCVD better than LDL-C alone. It is reportable from any standard panel at no extra cost (sources/lipid-aha-2026, rating: very high).
- ApoB counts atherogenic particles directly: every LDL, VLDL, IDL and Lp(a) particle carries exactly one ApoB molecule. A given LDL-C can therefore conceal a high particle number (small dense LDL, more particles per unit cholesterol) or a low one; discordance is most common in cardiometabolic-kidney syndrome, triglycerides ≥150 mg/dL and diabetes (sources/lipid-aha-2026).
- The causal case rests on genetics, not just trials. Mendelian randomisation and naturally occurring PCSK9 loss-of-function variants show LDL-C lowering is causally and monotonically related to CHD risk reduction; PCSK9 loss-of-function carriers have up to 88% lower lifetime CHD risk (sources/verve102-pcsk9-nejm-2026, rating: high). PCSK9 biology, remnant atherogenicity and ApoC-III are covered on concepts/PCSK9-Inhibitors, concepts/Hypertriglyceridemia-Management and concepts/Atherosclerosis-Pathophysiology.
Screening and diagnosis
- Adults: lipid profile from age 19, repeated at least every 5 years, more often with additional risk factors. Children: universal screen at 9–11; cascade screening from age ≥2 where there is premature ASCVD or familial hypercholesterolaemia (sources/lipid-aha-2026, rating: very high).
- Fasting is not routinely required, but is preferred when triglycerides are ≥400 mg/dL, there is a family history of dyslipidaemia, or a known triglyceride metabolism disorder (sources/lipid-aha-2026).
- Estimate LDL-C with Martin/Hopkins or Sampson/NIH, not Friedewald. Martin/Hopkins markedly reduces LDL-C/ApoB discordance at low LDL-C and elevated triglycerides — only about 2% of patients with LDL-C <70 mg/dL by Martin/Hopkins had ApoB above target (sources/lipid-aha-2026).
- Measure ApoB to guide intensification, not to diagnose. COR 2a in adults already on lipid-lowering therapy with ASCVD, cardiometabolic-kidney syndrome, type 2 diabetes and/or elevated triglycerides, once LDL-C and non-HDL-C goals are met; COR 2b in adults not yet on therapy as a risk enhancer (sources/lipid-aha-2026).
- Advanced lipoprotein testing (NMR, gel electrophoresis) is not recommended for routine use. Dietary supplements — fish oil, red yeast rice, berberine, garlic, cinnamon, turmeric, plant sterols — produce no significant LDL-C reduction against placebo; COR 3: No Benefit, and ESC 2025 recommends against them outright (COR III B) (sources/lipid-aha-2026, sources/lipid-esc-2025).
Treatment goals by risk category
Sorted by LDL-C goal, strictest first; rows sharing a goal are ordered by indication.
| Risk category | LDL-C goal | Non-HDL-C goal | Guideline |
|---|---|---|---|
| Severe hypercholesterolaemia, LDL-C ≥190 mg/dL (4.9 mmol/L) | <55 mg/dL (1.4 mmol/L) with ASCVD; <70 mg/dL (1.8 mmol/L) if FH or additional risk; <100 mg/dL (2.6 mmol/L) otherwise | — | AHA COR 1 |
| Very strict control | |||
| ASCVD, very high risk | <55 mg/dL (1.4 mmol/L) and ≥50% reduction | <85 mg/dL (2.2 mmol/L) | ESC I A; AHA COR 2a |
| CAC ≥1000 AU | <55 mg/dL (1.4 mmol/L) | <85 mg/dL (2.2 mmol/L) | AHA COR 1 |
| Strict control | |||
| ASCVD, not very high risk | <70 mg/dL (1.8 mmol/L) | <100 mg/dL (2.6 mmol/L) | ESC I A; AHA COR 2a |
| CAC 300–999 AU | <70 mg/dL (1.8 mmol/L); consider intensifying to <55 mg/dL (1.4 mmol/L) | — | AHA COR 1 / 2a |
| CAC 100–299 AU or ≥75th centile | <70 mg/dL (1.8 mmol/L) | — | AHA COR 1 |
| Diabetes with multiple risk factors | <70 mg/dL (1.8 mmol/L) and ≥50% reduction | <100 mg/dL (2.6 mmol/L) | AHA COR 2a |
| Primary prevention, high (≥10%) | <70 mg/dL (1.8 mmol/L) | <100 mg/dL (2.6 mmol/L) | AHA |
| Normal control | |||
| CAC 1–99 AU or <75th centile | <100 mg/dL (2.6 mmol/L) | — | AHA COR 2a |
| Diabetes 40–75 y, no ASCVD | <100 mg/dL (2.6 mmol/L) and 30–49% reduction | <130 mg/dL (3.4 mmol/L) | AHA COR 1 |
| Primary prevention, intermediate (5–<10%) | <100 mg/dL (2.6 mmol/L) | <130 mg/dL (3.4 mmol/L) | AHA |
| Primary prevention, borderline (3–<5%) | <100 mg/dL (2.6 mmol/L) | <130 mg/dL (3.4 mmol/L) | AHA |
| Primary prevention, moderate risk by SCORE2 | <100 mg/dL (2.6 mmol/L) | — | ESC IIa A |
ESC states its targets in mmol/L and ACC/AHA in mg/dL; both are shown throughout. Cholesterol converts at 38.67 mg/dL per mmol/L, which also holds for non-HDL-C.
Sources for the table: ACC/AHA primary prevention, secondary prevention, CAC and diabetes goals (sources/lipid-aha-2026, rating: very high); ESC targets (sources/lipid-esc-2025). CAC of 0 with no higher-risk conditions supports deferring therapy and reassessing in 3–7 years (COR 2a), and incidental CAC on a non-cardiac CT should inform the decision (COR 1) (sources/lipid-aha-2026).
Very high risk ASCVD means ≥2 major ASCVD events, or 1 major event plus ≥2 high-risk conditions — recurrent ACS within 12 months, prior MI, ischaemic stroke, symptomatic PAD, age ≥65, FH, prior CABG/PCI, diabetes, hypertension, CKD (eGFR 15–59), current smoking, LDL ≥100 on maximum statin plus ezetimibe, or heart failure (sources/CCS-AHA-2023, rating: very high).
The <55 versus <70 question has one direct RCT. Ez-PAVE randomized 3,048 South Korean patients with established ASCVD to intensive (target <55) or conventional (target <70) therapy for a median of 3.0 years, open-label. Achieved LDL-C was 56 versus 66 mg/dL. The primary composite (cardiovascular death, nonfatal MI, nonfatal stroke, any revascularisation, unstable angina hospitalisation) occurred in 6.6% versus 9.7%, HR 0.67 (95% CI 0.52–0.86; P=0.002). The benefit was carried by revascularisation (HR 0.63) and nonfatal MI (HR 0.46); cardiovascular death (31 vs 29 all-cause deaths), nonfatal stroke and unstable angina hospitalisation were individually null. Only 60.8% of the intensive arm reached target (sources/intensive-ldl-ezpave-nejm-2026, rating: high).
Lifestyle
- Dietary pattern: emphasise fruit, vegetables, nuts, legumes, wholegrains and fibre; replace saturated and trans fats with mono- and polyunsaturated fats (Mediterranean, DASH, vegetarian). Replacing saturated fat with polyunsaturated fat lowers LDL-C — a causal risk factor — and is associated with reduced CHD risk (sources/diet-aha-2026, rating: very high).
- Fish oil supplements are not dietary fish. Supplements do not reduce cardiovascular risk in otherwise healthy adults and may increase AF; non-fried seafood is associated with fewer cardiovascular events and less MI. Icosapent ethyl is a prescription drug with its own indication and its own risks, not a supplement (sources/diet-aha-2026).
- Exercise and weight: ≥150 minutes/week of moderate-to-vigorous aerobic activity plus resistance training twice weekly; weight loss lowers triglycerides and modestly lowers LDL-C. The quantified contributions of each lifestyle factor are on concepts/Lifes-Essential-8.
- Dietary pattern detail, including ultraprocessed food and the comparative evidence across DASH, Mediterranean and vegetarian patterns, is on concepts/Heart-Healthy-Dietary-Patterns.
- Supplements do not substitute for therapy — see the COR 3 recommendation under Screening and diagnosis above.
Agents at a glance
| Class | LDL-C reduction | Route | Detail |
|---|---|---|---|
| High-intensity statin | ≥50% | Oral | concepts/Dyslipidemia-Management |
| Moderate-intensity statin | 30–49% | Oral | concepts/Dyslipidemia-Management |
| Ezetimibe | 18% alone; +25% with statin | Oral daily | concepts/Dyslipidemia-Management |
| PCSK9 mAb | 45–64% | SC 2–4 weekly | concepts/PCSK9-Inhibitors |
| Inclisiran | 48–52% | SC 6-monthly | entities/Inclisiran |
| Bempedoic acid | 21–24% alone; +17–18% with statin | Oral daily | concepts/Dyslipidemia-Management |
| Bile acid sequestrants | 10–27% | Oral | concepts/Dyslipidemia-Management |
| Obicetrapib (investigational) | ~30% add-on | Oral daily | concepts/CETP-Inhibitors |
| Olezarsen (FCS only) | −43.5% triglycerides | SC monthly | concepts/APOC3-Inhibition |
| Icosapent ethyl | −15 to −61% triglycerides | Oral | concepts/Hypertriglyceridemia-Management |
Reduction figures are the ACC/AHA class summary (sources/lipid-aha-2026, rating: very high). The order in which these are added, the evidence behind each step, and the management of statin intolerance are on concepts/Dyslipidemia-Management — in summary: high-intensity statin first, ezetimibe second, PCSK9 mAb only after maximum statin plus ezetimibe, with bempedoic acid and inclisiran reserved for when those fail or cannot be used.
Hypertriglyceridaemia
- Lifestyle first, at every level: reduce added sugar, refined carbohydrate, saturated fat and alcohol; 5–10% weight loss; ≥150 minutes/week of moderate aerobic exercise (sources/lipid-aha-2026, rating: very high).
- Triglycerides 150–499 mg/dL: statins lower triglycerides by 10–30%; the priority remains ASCVD risk reduction rather than the triglyceride number itself.
- Triglycerides 500–999 mg/dL: add fenofibrate (preferred over gemfibrozil, fewer interactions) or prescription omega-3 fatty acids to reduce pancreatitis risk (COR 2a) (sources/lipid-aha-2026).
- Triglycerides ≥1000 mg/dL: very-low-fat diet (<10–15% of calories), alcohol and added sugar eliminated, fibrate or omega-3, dietitian referral (COR 1). Gemfibrozil must never be combined with a statin because of myopathy risk.
- Familial chylomicronaemia syndrome: ACC/AHA 2026 gives olezarsen COR 1 on BALANCE; ESC 2025 gives volanesorsen COR IIa B on APPROACH (77% triglyceride reduction, fewer pancreatitis episodes, thrombocytopenia requiring monitoring). Different molecules, different regulators — access decides (sources/lipid-aha-2026, sources/lipid-esc-2025).
- Icosapent ethyl is COR 2b in ACC/AHA 2026 and COR IIa B in ESC 2025 for adults ≥50 with ASCVD or diabetes plus a risk factor, triglycerides 150–499 and LDL-C <100 on a statin. REDUCE-IT showed 25% MACE reduction; the mineral oil placebo is disputed and incident AF is increased.
- Fibrates and niacin produce no ASCVD event reduction when added to a statin (ACCORD-LIPID, HPS2-THRIVE, PROMINENT). Full detail: concepts/Hypertriglyceridemia-Management.
Lipoprotein(a)
- Lp(a) ≥125 nmol/L (50 mg/dL) is a risk-enhancing factor, conferring roughly 1.4-fold risk; the gradient continues upward, with ≥430 nmol/L equivalent to heterozygous FH (sources/lipid-aha-2026, rating: very high).
- ACC/AHA 2026 recommends measuring Lp(a) in all adults once. Statins do not lower it and may raise it slightly and non-significantly.
- In ASCVD with elevated Lp(a) and goals not met on maximum statin, a PCSK9 mAb is COR 1 — it lowers Lp(a) as well as LDL-C. No Lp(a)-specific therapy has outcomes evidence yet. See concepts/Lipoprotein-a.
Emerging therapies
- Obicetrapib (CETP inhibitor) reduced LDL-C by 32.6 percentage points between groups on top of maximum therapy and lowered Lp(a) 33.5% in BROADWAY; the cardiovascular outcomes trial is ongoing. Not approved, not guideline-recommended (sources/obicetrapib-broadway-nejm-2025, rating: high). See concepts/CETP-Inhibitors.
- VERVE-102, a single-infusion PCSK9 base editor, reduced PCSK9 88% and LDL-C 62% (−78 mg/dL) at 1.0 mg/kg in the Heart-2 phase 1 study, durable to ≥18 months. Phase 1, n=35, no placebo, no outcomes (sources/verve102-pcsk9-nejm-2026, rating: high). See concepts/Lipid-Gene-Therapy.
- Olezarsen at 50–80 mg monthly lowered triglycerides 58–61 percentage points in moderate hypertriglyceridaemia (ESSENCE-TIMI 73b) with LDL-C unchanged and no outcome data (sources/olezarsen-essence-timi73b-nejm-2025, rating: high). See concepts/APOC3-Inhibition.
- Evinacumab (ANGPTL3 inhibition) remains the option in homozygous FH where LDL-receptor-dependent strategies fail. See concepts/ANGPTL3-Inhibition.
Contradictions / Open Questions
- Ez-PAVE's benefit is driven by a procedure-sensitive endpoint in an open-label trial. Revascularisation (HR 0.63) and nonfatal MI carried the composite, while cardiovascular death, stroke and unstable angina hospitalisation were individually null. In an open-label study, a physician's knowledge of the assigned LDL-C target could reasonably lower the threshold for referral to angiography. Only 60.8% of the intensive arm reached <55 mg/dL at three years, which dilutes rather than exaggerates the contrast — but the headline HR 0.67 should be read as the best achievable result under restricted PCSK9 inhibitor access, not as a clean target effect (sources/intensive-ldl-ezpave-nejm-2026, rating: high).
- Ez-PAVE enrolled only Korean patients. East Asian populations often achieve higher statin exposure at equivalent doses and may reach goals more readily, and three years is short for mortality endpoints to separate. Whether the <55 target's advantage transfers at the same magnitude to European or North American ASCVD populations is untested (sources/intensive-ldl-ezpave-nejm-2026).
- ApoB is codified as an intensification marker, but neither guideline in this wiki states a numeric ApoB goal. ACC/AHA 2026 makes measurement COR 2a once LDL-C and non-HDL-C goals are met, and states that ApoB predicts risk better than LDL-C when they discord. The commonly quoted equivalents — ApoB <80 mg/dL for an LDL-C goal of <70, ApoB <65 for <55 — are arithmetically reasonable but are not stated in either source, and this page therefore does not table them as goals (sources/lipid-aha-2026).
- Icosapent ethyl is graded differently by the two societies for the same trial. ACC/AHA 2026 gives COR 2b; ESC 2025 gives COR IIa B. The difference is entirely a weighting of the REDUCE-IT mineral oil placebo controversy — whether a placebo that worsened the control arm's lipids inflated the 25% MACE reduction — and the neutral STRENGTH trial does not resolve it. The discordance is more informative than either grade: it marks the point where two expert panels read the same evidence differently.
- Statin use in pregnancy has been liberalised by one regulator and ignored by one guideline. The FDA removed pregnancy as a contraindication in 2024 and ACC/AHA 2026 reflects this; ESC 2025 does not address it. Statins should still be avoided during lactation. For a pregnant patient with severe hypertriglyceridaemia the guidance is better settled — fibrates after the first trimester or high-dose omega-3 (COR 2a) — than for a pregnant patient with familial hypercholesterolaemia.
- The threshold for starting lipid-lowering therapy below age 30 remains extrapolated. Thirty-year risk estimates are now available and identify young people at high lifetime risk, but trial evidence for treatment initiation at that age is sparse, and the decision rests on FH status and LDL-C magnitude rather than on a randomized comparison.
- Familial chylomicronaemia syndrome has two guideline-recommended drugs that are not interchangeable. ACC/AHA 2026 recommends olezarsen (FDA-approved) at COR 1; ESC 2025 recommends volanesorsen (EMA-approved) at COR IIa B. Both are antisense oligonucleotides against ApoC-III with different approvals, different dosing and different toxicity — volanesorsen requires platelet monitoring. Region-specific formulary access, not evidence, determines the choice (sources/lipid-aha-2026, sources/lipid-esc-2025).
- Statins reduce nonfatal events at age ≥70 without extending disability-free survival. STAREE is now the randomized answer to the treatment question at ≥70, and the answer is narrower than the one the guidelines imply: major cardiovascular events fell (HR 0.70) while disability-free survival (HR 0.94), dementia and all-cause death were unchanged, and cardiovascular death was identical. Meanwhile ACC/AHA still describes age >75 as "can be considered" while the trial enrolled from ≥70. The drug-level detail and the safety table are on concepts/Dyslipidemia-Management (sources/lipid-staree-nejm-2026, rating: very high).
- No Lp(a)-specific therapy has outcome data. The genetic and epidemiological case for Lp(a) as a causal risk factor is strong, but every Lp(a)-lowering agent currently in development is awaiting its outcomes trial; the only Lp(a) lowering with proven benefit is incidental to PCSK9 inhibition.
Connections
- Related to concepts/Dyslipidemia-Management — the detailed page: escalation order, statin intensity, nonstatin agents, secondary prevention, special populations, STAREE.
- Related to concepts/ASCVD-Risk-Assessment — PREVENT equations and SCORE2/SCORE2-OP determine who is eligible for primary prevention and at what intensity.
- Related to concepts/Lipoprotein-a — measurement, risk quantification and the Lp(a) therapeutic pipeline.
- Related to concepts/Familial-Hypercholesterolemia — the most severe LDL-C disorder, with its own targets and cascade screening.
- Related to concepts/Hypertriglyceridemia-Management — the full triglyceride framework and APOC3 inhibition.
- Related to concepts/PCSK9-Inhibitors — FOURIER and ODYSSEY outcomes, inclisiran trials, HoFH dosing.
- Related to concepts/Heart-Healthy-Dietary-Patterns — the dietary pattern underlying every pharmacological step.
- Related to entities/Heart-Failure — statins are considered in HFrEF; heart failure is itself a high-risk feature in the very-high-risk definition.
- Related to entities/Atrial-Fibrillation — icosapent ethyl and fish oil supplements both carry AF risk.
- Related to concepts/CETP-Inhibitors and concepts/Lipid-Gene-Therapy — the two emerging oral and single-infusion routes.