Lipids: from statin-first to ApoB-target combination therapy
The lipid ladder as the NHS funds it and as the evidence points: NICE NG238 and ESC/EAS 2025 targets side by side, the 50% rule for combination from the outset, ezetimibe, bempedoic acid, PCSK9 antibodies and inclisiran with their NICE thresholds, statin intolerance done properly, triglycerides and icosapent ethyl, familial hypercholesterolaemia and lipoprotein(a). About 60 minutes, for GPs, GP trainees, pharmacists, nurses, advanced clinical practitioners and physician associates. A 10-item knowledge check is marked on our learning platform; pass at 70% and a numbered, verifiable Certificate of CPD (1 hour) from New Vision University (UK) is issued to you.
Living Certificate · reviewed and kept current
Last editorial review: awaiting clinical sign-off · Next scheduled refresh: 12 months after sign-off.
The Golden Triangle for the topic taught here: fixed to the topic, and re-examined when its knowledge, evidence or real-world sources change.
Golden Triangle
Dyslipidaemia (raised cholesterol)
Knowledge Green · Evidence Green · Real-world Red
Not yet at the Equinox · UK (NHS England) · as of 7 October 2026 · How the triangle works
A 67-year-old man "on the maximum statin"
Mr D, 67, had a non-ST-elevation myocardial infarction six months ago. The discharge letter put him on atorvastatin 80 mg, aspirin, ticagrelor, ramipril, bisoprolol and dapagliflozin; he has type 2 diabetes (HbA1c 52 mmol/mol) and eGFR 64. At the practice's post-infarct review his non-fasting lipids read total cholesterol 4.0, HDL-C 1.0, LDL-C 2.1, triglycerides 2.0 mmol/L. The note says "on max statin, lipids improved, recall 12 months".
He is above every target that applies to him: NICE NG238 asks for LDL-C of 2.0 mmol/L or below (non-HDL 2.6 or below) in secondary prevention; ESC/EAS (goals unchanged from 2019 in the 2025 update) asks for below 1.4 with a 50% reduction in a man with an infarct and diabetes. The CVRM-HF clinic adds ezetimibe 10 mg, rechecks at ten weeks (LDL-C 1.7, non-HDL 2.6), measures ApoB (0.82 g/L) and Lp(a) once (32 nmol/L), and notes that inclisiran under NICE TA733 would only be available if the LDL-C stayed at 2.6 mmol/L or more despite maximum tolerated therapy, which it never was. At LDL-C 1.7 he meets the NICE target (2.0; non-HDL 2.6) but not the ESC/EAS target (below 1.4); no further LDL-lowering rung is NICE-funded, so the clinic documents adherence and a shared decision. A fasting triglyceride of 1.7 mmol/L or more on a statin with established disease would make him eligible for icosapent ethyl under TA805; today's 2.0 was non-fasting and needs a fasting repeat, and the decision is then taken with him. That ladder, and where the NHS funding gates sit on it, is this module.
By the end of this module you will be able to…
Targets: lower, earlier, in combination
Four guidelines that agree on direction and differ on numbers, and the rule that tells you when a statin alone will not be enough.
NICE NG238 (December 2023), the ESC/EAS 2025 focused update, DCRM 2.0 (2024) and the 2026 ACC/AHA multisociety guideline all aim to lower LDL-C further in high-risk patients. ESC/EAS and DCRM 2.0 favour early, intensive lowering with combination therapy where the gap to target is large; NICE starts a high-intensity statin and escalates, and its 2.0 mmol/L target is explicitly set by cost-effectiveness. In the UK the NICE targets govern what the NHS funds; the ESC/EAS targets tell you where the evidence points for the patient in front of you. NICE 'very high risk' for the PCSK9 antibodies (recurrent events, or events in more than one vascular bed) is a funding definition, not an ESC/EAS risk category.
| Setting | NICE NG238 (2023) | ESC/EAS 2025 | ACC/AHA 2026 (US) |
|---|---|---|---|
| Primary prevention | Atorvastatin 20 mg at QRISK3 ≥ 10%; aim non-HDL reduction > 40% | By SCORE2/SCORE2-OP class: very high LDL-C < 1.4 and ≥ 50% reduction; high < 1.8 and ≥ 50% reduction; moderate < 2.6; low < 3.0 (may be considered). Goals unchanged from 2019 | PREVENT-based; LDL-C < 1.8 at high (≥ 10%) risk or CAC 100–299; < 2.6 in diabetes aged 40–75 (< 1.8 with multiple risk factors) |
| Secondary prevention | Atorvastatin 80 mg; LDL-C ≤ 2.0 or non-HDL ≤ 2.6 | Very high risk: LDL-C < 1.4 and ≥ 50% reduction; non-HDL-C < 2.2 and ApoB < 0.65 g/L (2019 secondary goals, not restated in 2025) | Very-high-risk ASCVD < 1.4 (non-HDL < 2.2); other secondary prevention < 1.8 |
| Extreme risk (a DCRM 2.0 category; not used by NICE or ESC/EAS) | No separate category | No separate category; goals unchanged from 2019. LDL-C < 1.0 may be considered after a second vascular event within 2 years on maximally tolerated statin (2019, class IIb). DCRM 2.0: extreme < 1.4, extreme-plus < 1.04 for events despite LDL-C < 1.4; ApoB < 0.8 very high, < 0.7 extreme (expert suggestion) | No separate category; very-high-risk goals (< 1.4, non-HDL < 2.2) |
The 50% rule. A statin at maximum tolerated dose lowers LDL-C by about 50%; ezetimibe adds about 20%; a PCSK9 inhibitor or inclisiran adds about 50% more. If the reduction needed to reach target is more than 50% (the baseline is more than twice the target), a statin alone will not get there, and starting dual therapy (statin plus ezetimibe) from the outset is favoured by ESC/EAS 2025 and DCRM 2.0. A very-high-risk patient with LDL-C 4.2 mmol/L and a target below 1.4 needs a 67% fall, which a statin alone will not deliver.
Checkpoint 1 · Post-infarct on atorvastatin 80 mg: LDL-C 2.1, non-HDL 3.0. At target?
No, by NICE (LDL-C ≤ 2.0, non-HDL ≤ 2.6) and by ESC/EAS (< 1.4). Add ezetimibe and recheck at 8–12 weeks.
The ladder, and the NICE gates on each rung
Statin, ezetimibe, bempedoic acid, PCSK9 antibodies, inclisiran: what each adds and who the NHS funds.
| Rung | What it adds | NICE position and who qualifies |
|---|---|---|
| 1 · High-intensity statin | ≥ 40% LDL-C reduction: atorvastatin 20 mg (primary) or 80 mg (secondary); rosuvastatin 10–20 mg the alternative (NG238 high-intensity range 10–40 mg; 40 mg restricted, Lesson 3) | NG238 baseline: full lipid profile, diabetes status, renal function, transaminases (TSH if thyroid symptoms); repeat full lipid profile and transaminases at 2 to 3 months, transaminases at 12 months; CK only for muscle symptoms |
| 2 · Ezetimibe 10 mg | About 20% more; no renal adjustment; single-tablet combinations with atorvastatin or rosuvastatin | TA385 and NG238: add when the target is not reached on the maximum tolerated statin; the routine second step |
| 3 · Bempedoic acid 180 mg | About 20%; liver-only ATP-citrate lyase inhibitor, no muscle effect; 13% fewer major events in CLEAR Outcomes | TA694: with ezetimibe when statins are contraindicated or not tolerated and ezetimibe alone is insufficient. Watch uric acid and tendon rupture |
| 4a · PCSK9 antibodies (alirocumab, evolocumab) | About 50–60% more; alirocumab or evolocumab (NICE-recommended evolocumab dose 140 mg every 2 weeks); initiation usually via the lipid clinic (local policy, not a TA requirement) | TA393/394: only with the company discount and only when LDL-C stays persistently above the threshold despite maximal tolerated lipid-lowering therapy (maximum dose reached or titration limited by intolerance). Non-familial: above 4.0 with CVD at high risk (ACS, revascularisation, CHD, ischaemic stroke or PAD); above 3.5 at very high risk (recurrent events, or events in more than one vascular bed). Heterozygous FH: above 5.0 without CVD, above 3.5 with CVD |
| 4b · Inclisiran 284 mg | About 50%; siRNA against hepatic PCSK9; day 0, 3 months, then every 6 months; practice-deliverable | TA733: secondary prevention only: a history of ACS, revascularisation, coronary heart disease, ischaemic stroke or peripheral arterial disease and LDL-C persistently ≥ 2.6 mmol/L despite maximum tolerated lipid-lowering therapy (ezetimibe first is standard practice, not a TA733 condition); research only if no previous event. ORION-4 outcomes due 2026–27 |
| 5 · Icosapent ethyl 2 g twice daily | Residual triglyceride-related risk; 25% fewer events in REDUCE-IT | TA805: established CVD, fasting triglycerides ≥ 1.7 mmol/L on a statin, LDL-C above 1.04 and up to 2.60 mmol/L; repeat a non-fasting result of 1.7 or more fasting before applying it (Lesson 4) |
Even-handed pharmacology. Atorvastatin is the statin NICE NG238 tells you to offer (20 mg for primary prevention, 80 mg for secondary prevention, a lower dose if there are interactions, a high risk of adverse effects or the person prefers it). Rosuvastatin (10–40 mg) is in the same high-intensity group and is the NG238 switch if atorvastatin causes adverse effects. Simvastatin, pravastatin and fluvastatin are medium- or low-intensity doses in NG238; pitavastatin is not classified. Alirocumab and evolocumab are equivalent; inclisiran is not a prerequisite for them nor they for it. Evinacumab (NICE TA1002, for homozygous FH from age 12) and lomitapide are specialist drugs for homozygous FH. Fibrates have no event benefit on top of a statin.
The gap between evidence and funding. ESC/EAS suggests that an LDL-C below 1.0 mmol/L may be considered after a second vascular event within two years on maximal therapy, yet NICE's PCSK9 gates are LDL-C thresholds (2.6 for inclisiran; above 3.5 for the antibodies at very high risk). A man with recurrent infarction and peripheral arterial disease at LDL-C 1.6 on statin plus ezetimibe is above his ESC/EAS goal (below 1.4) with no funded LDL-lowering rung. If his fasting triglycerides are 1.7 mmol/L or more, icosapent ethyl (TA805) is the one funded next step, and it addresses triglyceride-related risk, not LDL-C; otherwise the honest UK response is adherence, maximal oral therapy and a lipid-clinic conversation about individual funding or trial access. Say so to the patient.
Checkpoint 2 · LDL-C 2.8 after six months on atorvastatin 80 mg plus ezetimibe, post-infarct, adherent. Next rung?
Inclisiran under TA733 (qualifying event and LDL-C persistently ≥ 2.6 despite maximum tolerated lipid-lowering therapy): loading dose, three months, then six-monthly in the practice. A PCSK9 antibody would need an LDL-C persistently above 4.0 (above 3.5 only at very high risk: recurrent events, or disease in more than one vascular bed).
Statin intolerance and monitoring, properly
Most reported intolerance is not; the N-of-1 approach, the transaminase and CK rules, and the interactions that matter.
The N-of-1 framework
In SAMSON, 90% of the symptom burden attributed to statins recurred on placebo. Before declaring intolerance: confirm symptoms on three different statins at different doses with resolution on stopping, and document the NG238 strategies (1.9.2–1.9.3: stop and retry, a different statin in the same intensity group, a lower dose, a lower-intensity statin); try a hydrophilic statin (rosuvastatin, pravastatin) or alternate-day dosing; check vitamin D, thyroid function and interacting drugs; reframe with the patient. True intolerance then earns the alternative ladder: ezetimibe plus bempedoic acid (TA694), then, or alternatively, inclisiran or a PCSK9 antibody within their thresholds.
Monitoring rules (NICE NG238 and SmPC)
Full lipid profile and transaminases at 2 to 3 months, transaminases again at 12 months (NG238 1.11.1–1.11.2); do not routinely exclude from a statin people whose transaminases are raised but below three times the upper limit (1.5.6). The atorvastatin SmPC contraindicates unexplained persistent rises above three times the limit and advises dose reduction or withdrawal if such a rise persists. CK only for unexplained muscle symptoms, not in asymptomatic people: if CK is above five times the limit before starting, repeat after 7 days and do not start if still above; symptoms with CK below five times are unlikely to be due to the statin (NG238 1.5.7, 1.11.3–1.11.5). Do not stop a statin because of a rise in glucose or HbA1c (1.11.6). Then an annual lipid profile and medication review.
Interactions. Simvastatin and atorvastatin are CYP3A4 substrates: macrolides, azoles, diltiazem, verapamil, ciclosporin and grapefruit raise levels (simvastatin is capped at 20 mg with amlodipine or diltiazem). Systemic fusidic acid must not be given with any statin or within 7 days of stopping fusidic acid: suspend the statin for the course (rhabdomyolysis, some fatal). Gemfibrozil is contraindicated with simvastatin and not recommended with rosuvastatin; simvastatin is also contraindicated with ciclosporin, danazol, erythromycin, clarithromycin and azole antifungals. Rosuvastatin: in patients of Asian ancestry (including South Asian, where exposure is about 1.3-fold higher; about 2-fold in East Asian groups) start at 5 mg and do not use 40 mg; the 40 mg dose is also contraindicated with CrCl below 60, hypothyroidism, alcohol misuse, previous statin or fibrate myopathy or a concomitant fibrate, and is a last titration step in severe hypercholesterolaemia at high risk with specialist supervision. Ciclosporin is contraindicated; ticagrelor and protease inhibitors raise exposure. Colchicine with a statin raises myopathy risk. Bempedoic acid raises simvastatin and pravastatin levels (cap simvastatin at 20 mg).
Checkpoint 3 · ALT 62 (upper limit 40) at three months on atorvastatin 20 mg, no symptoms, non-HDL down 44%. Stop?
No. Below three times the upper limit, asymptomatic: continue, recheck at 12 months. The non-HDL response shows the dose is right.
Triglycerides: two different problems
Severe hypertriglyceridaemia is a pancreatitis problem; mild elevation on a statin with cardiovascular disease is an icosapent ethyl question.
Above 10 mmol/L: prevent pancreatitis
Repeat a fasting triglyceride after 5 days and within 2 weeks (sooner if symptomatic); stop alcohol; restrict refined carbohydrate and fat; intensify glycaemic control; review secondary causes and drugs (thiazides, beta-blockers, oestrogens, retinoids, antipsychotics); safety-net for abdominal pain. NICE NG238 1.4.6–1.4.7: urgent specialist review above 20 mmol/L not explained by alcohol or poor glycaemic control; between 10 and 20, seek specialist advice if above 10 on the fasting repeat. A fibrate to lower pancreatitis risk is a specialist-guided option from DCRM 2.0 (above 5.7 mmol/L), not NICE: prefer fenofibrate and avoid gemfibrozil with a statin (simvastatin is capped at 10 mg with fibrates other than gemfibrozil or fenofibrate; rosuvastatin 40 mg is contraindicated with any fibrate). NG238 1.12.2 and 1.12.7 advise against routine fibrates and statin-fibrate combinations to prevent CVD. A statin follows for cardiovascular risk once the triglycerides are under control.
Fasting triglycerides 1.7 mmol/L or more on a statin with cardiovascular disease: icosapent ethyl (TA805)
NICE TA805 recommends icosapent ethyl 2 g twice daily as an add-on to a statin for established cardiovascular disease with fasting triglycerides of 1.7 mmol/L or more and LDL-C above 1.04 and up to 2.60 mmol/L (a non-fasting result of 1.7 or more is repeated fasting before TA805 is applied); REDUCE-IT showed a 25% relative reduction in major events (the mineral-oil placebo debate is acknowledged; the totality of evidence supports use in the NICE-recommended group, secondary prevention). Counsel on atrial fibrillation and bleeding; stop other omega-3 supplements. Fibrates lower triglycerides but add no event benefit on top of a statin.
Checkpoint 4 · Type 2 diabetes, triglycerides 18 mmol/L, 30 units of alcohol a week, HbA1c 78, asymptomatic. First move?
Fasting repeat within 5 days to 2 weeks (sooner if symptomatic), alcohol cessation, carbohydrate and fat restriction, glycaemic intensification and a review of secondary causes, with a pancreatitis safety-net and specialist advice if still above 10 mmol/L; a fibrate is a specialist-guided option. Not icosapent ethyl, which is for residual risk at fasting triglycerides of 1.7 mmol/L or more in established disease.
Familial hypercholesterolaemia and lipoprotein(a)
The two inherited problems that a risk calculator hides, and what to do about each today.
Familial hypercholesterolaemia (NICE CG71)
CG71 1.1.1: suspect FH with total cholesterol above 7.5 mmol/L or a personal or family history of premature coronary disease; search records for people under 30 with total cholesterol above 7.5 and 30 or over with above 9.0 (1.1.2). Confirm with Simon Broome (total cholesterol above 7.5 or LDL-C above 4.9, with tendon xanthomata for definite FH) or the Dutch Lipid Clinic score (1.1.5), with two LDL-C measurements and secondary causes excluded (1.1.4, 1.1.9). Do not use a risk tool (CG71 1.1.12; NG238 1.1.9). Start a high-intensity statin aiming for at least a 50% LDL-C reduction; add ezetimibe; refer to the FH specialist service for DNA testing, which leads cascade testing of first- and second-degree (and, when possible, third-degree) relatives. In a woman of childbearing age, discuss contraception and pregnancy plans before starting: statins are stopped if pregnancy is possible and 3 months before conception (NG238 1.5.9–1.5.10; CG71 1.4.2–1.4.3). PCSK9 antibodies for heterozygous FH at LDL-C persistently above 5.0 (3.5 with cardiovascular disease) despite maximal tolerated lipid-lowering therapy under TA393/394. About 1 in 250 people has FH; most are undiagnosed.
Lipoprotein(a)
Consider measuring once in every adult (ESC/EAS 2025, DCRM 2.0), and especially in anyone with FH, premature family history, calcific aortic stenosis or events despite controlled LDL-C. ESC/EAS 2025 treats above 50 mg/dL (105 nmol/L) as a risk-enhancing level, affecting roughly one adult in five; the EAS 2022 consensus and the 2026 ACC/AHA guideline use 125 nmol/L (50 mg/dL). NICE has no Lp(a) recommendation. Statins barely move it; PCSK9 inhibitors and inclisiran lower it modestly. Lp(a)-lowering has not yet been shown to reduce events: the first outcome trial, Lp(a)HORIZON (pelacarsen), was negative at topline in September 2026 and other siRNA and antisense trials continue; none is UK-licensed. Act by optimising LDL-C and ApoB, treating blood pressure and cascade-testing relatives. F1 covers the risk framing.
Checkpoint 5 · Woman aged 38: total cholesterol 9.2, LDL-C 6.4 (confirmed on repeat, secondary causes excluded), father's infarct at 48, tendon xanthomata. QRISK3?
Not needed. This is definite familial hypercholesterolaemia (Simon Broome: total cholesterol above 7.5 or LDL-C above 4.9 with tendon xanthomata): high-intensity statin now for a 50% reduction, discussion of contraception and pregnancy plans before starting, and referral to the FH specialist service for genetic testing, which leads cascade testing of relatives.
Running it: the search, inclisiran in the practice, and the lipid clinic
Where the untreated patients are, how the practice delivers the newer rungs, and when to refer.
Three searches
Inclisiran in primary care
Inclisiran was designed for primary-care delivery: a subcutaneous dose at day 0 and three months, then every six months. No inclisiran-specific monitoring is required; check a full lipid profile (and transaminases) 2 to 3 months after starting (NG238 1.11.1), then at the annual medication review. Set it up as a recall like a vaccination; the twice-yearly visit is also the adherence check for the oral therapy it sits on. Record the TA733 eligibility (a qualifying previous cardiovascular event and LDL-C ≥ 2.6 despite maximum tolerated lipid-lowering therapy) in the notes.
When to refer to the lipid clinic
Suspected familial hypercholesterolaemia (genetic testing, cascade); LDL-C persistently above the TA393/394 thresholds for a PCSK9 antibody despite maximal tolerated lipid-lowering therapy; evidence target unmet with no funded LDL-lowering rung (recurrent events or polyvascular disease); confirmed statin intolerance with LDL-C still above target on ezetimibe plus bempedoic acid; triglycerides above 20 mmol/L not explained by alcohol or poor glycaemic control, or above 10 on a fasting repeat after the measures in Lesson 4; suspected homozygous FH or lipoprotein disorders in the young.
Practice task
Run search 1 this week: count the patients on your CVD register whose latest LDL-C is above 2.0 mmol/L and who are not on ezetimibe. Record the number and your first ten actions in the reflection box below; it prints on your certificate.
Checkpoint 6 · The one search that most improves outcomes from lipid management?
The CVD register by latest LDL-C or non-HDL, statin intensity and ezetimibe status: the secondary-prevention gap, treated from the list.
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New Vision University (UK)
Acumen Focus · CVRM-HF Foundation series · delivered by MD Acumen Ltd
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Acumen Focus F2 · Lipids: from statin-first to ApoB-target combination therapy
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Authored by Prof Rajesh Varma · MD Acumen Ltd · mdacumen.com
CPD authorised by Prof Rajesh Varma, Convenor for CPD, New Vision University (UK)
Signed against: NICE NG238 (December 2023) · ESC/EAS 2025 · ACC/AHA 2026 · NICE TA385, TA694, TA393/394, TA733, TA805, TA1002 · NICE CG71 · DCRM 2.0 (2024)
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F2 is the lipid pillar of the CVRM-HF Foundation series (F1 cardiometabolic risk · F2 lipids · F3 type 2 diabetes · F4 heart failure · F5 kidney disease · F6 obesity and MASLD). Complete all six for the series certificate (6 CPD); the series counts as recognised prior learning for the Certificate of Advanced Studies in CVRM-HF.
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