Nota Medik
Dyslipidaemia: CV Risk, LDL-C Targets, Statins, Escalation & Doses
Contents
Dyslipidaemia in one place: who to screen, how to set the LDL-C target by CV risk, which drug to start, how to escalate, what to do when a statin isn't tolerated, and the usual doses. Based on the CPG Management of Dyslipidaemia (6th Edition, 2023).
Screening and definitions
- Lipid profile for everyone >30 years old.
- If LDL-C is at target and TG is low, repeat every 3 years; annually for very high or high risk (e.g. diabetes, family history of premature CVD).
- Non-fasting samples are fine. If TG >4.5 mmol/L, repeat the lipid panel fasting (the Friedewald LDL-C formula isn't valid above 4.5).
- Look for secondary causes (e.g. hypothyroidism, nephrotic syndrome, cholestatic liver disease) and treat them first; recheck lipids once euthyroid before starting lipid-lowering therapy.
Cut-offs the CPG uses for dyslipidaemia:
| Parameter | Dyslipidaemia if |
|---|---|
| Total cholesterol | >5.2 mmol/L |
| HDL-C | <1.0 mmol/L (male), <1.2 mmol/L (female) |
| Triglycerides | >1.7 mmol/L |
| LDL-C | Depends on CV risk (see the targets below) |
Remark: HDL-C / LDL-C = high- / low-density lipoprotein cholesterol.
CV risk and LDL-C targets
Patients with established CVD, CKD or diabetes are already very high or high risk. Everyone else is risk stratified with the Framingham General CVD risk score (10-year risk).
| Global risk | LDL-C to initiate drug therapy (mmol/L) | Target LDL-C (mmol/L) | Target non-HDL-C (mmol/L) |
|---|---|---|---|
| Low CV risk <10% 10-year CVD risk | Clinical judgement* | <3.0 | <3.8 |
Intermediate (moderate) CV risk
| >2.6* | <2.6 | <3.4 |
High CV risk
| >1.8 | ≤1.8 and a reduction of >50% from baseline | ≤2.6 and a reduction of >50% from baseline |
Very high CV risk
| >1.4 | ≤1.4 and a reduction of >50% from baseline | ≤2.2 and a reduction of >50% from baseline |
| Recurrent CV events within 2 years despite LDL-C <1.4 | <1.0 |
Remark: CV = cardiovascular; CVD = cardiovascular disease; CKD = chronic kidney disease; eGFR in mL/min/1.73 m²; non-HDL-C = total cholesterol - HDL-C. Adapted from Table 4, CPG Dyslipidaemia 2023. *After a therapeutic trial of 8-12 weeks of lifestyle changes and a discussion of the risk-benefit of drug therapy with the patient. **Lipid-lowering therapy isn't started in patients on dialysis, but continue it if they have CVD or were already on a statin before dialysis. All other CV risk factors should be treated to target.
- LDL-C is the primary target in both primary and secondary prevention. Both the absolute LDL-C reached and the percentage reduction matter: the lower, the better.
- Non-HDL-C (total cholesterol - HDL-C) is a secondary target in combined hyperlipidaemia, diabetes, cardiometabolic risk and CKD, and becomes the primary target when TG >4.5 mmol/L.
- Asymptomatic atherosclerosis upgrades the risk: ABI <0.9 or >1.40, positive stress test at ≤6 METs, coronary calcium ≥100 Agatston units (or >75th percentile), CT coronary plaque >50% stenosis, or carotid plaque ≥50% or >1.2 mm thick. Treat these patients to LDL-C <1.4 and a 50% reduction.
Which drug
Statins are the drug of first choice. Lifestyle changes (heart-healthy diet, 150-300 min/week of moderate exercise, stop smoking) come first and continue throughout.
| Pharmacotherapy | Indication | Grade | |
|---|---|---|---|
| Statins | Very high and high CV risk; intermediate (moderate) and low risk after lifestyle changes | I, A | |
| Statins | + ezetimibe | Failure to achieve LDL-C goals | I, A |
| Statins | + PCSK9 inhibitors | Familial hypercholesterolaemia; failure to achieve LDL-C goals | I, A |
| Statins | + PCSK9 inhibitors + ezetimibe | Failure to achieve LDL-C goals | I, A |
| Statins | + siRNA PCSK9 inhibitor (inclisiran) | Failure to achieve LDL-C goals | IIa, B |
| Statins | + siRNA PCSK9 inhibitor + ezetimibe | Failure to achieve LDL-C goals | IIa, B |
| Statins | + fibrates | Diabetes on maximally tolerated statin, at LDL-C target, but with low HDL-C and high TG | IIb, B |
| Ezetimibe | Statin intolerance | IIa, B | |
| PCSK9 inhibitors | Very high and high CV risk with statin intolerance | I, A | |
| Fibrates | Very high TG despite lifestyle changes | IIa, C | |
Remark: PCSK9 = proprotein convertase subtilisin/kexin type 9; siRNA = small interfering RNA; TG = triglycerides; HDL-C = HDL cholesterol. Adapted from Table 6, CPG Dyslipidaemia 2023. Ezetimibe + bempedoic acid is an option in statin-intolerant patients (IIa, B).
Secondary prevention: every patient with CVD gets lipid-lowering therapy, target LDL-C <1.4 mmol/L and a 50% reduction.
- Start a high-intensity statin on admission in all ACS, and before PCI or CABG, regardless of baseline cholesterol; continue indefinitely.
- Start a statin in everyone with previous non-cardioembolic ischaemic stroke or TIA.
Drug classes at a glance
| Drug class | Lipid effects | Side effects | Contraindications |
|---|---|---|---|
| Statins (HMG-CoA reductase inhibitors) | LDL-C ↓21-55% HDL-C ↑2-10% TG ↓6-30% | Myopathy; raised liver enzymes | Absolute: active or chronic liver disease. Relative: some interacting drugs (cyclosporin, macrolides, azole antifungals, protease inhibitors, CYP450 inhibitors) |
| Fibrates | LDL-C ↓20-35% (fenofibrate) HDL-C ↑6-18% TG ↓20-35% (up to 60% with fenofibrate) | Dyspepsia; cholelithiasis; myopathy | Absolute: severe hepatic or kidney disease. Relative: some interacting drugs (gemfibrozil and repaglinide) |
| PCSK9 inhibitors | LDL-C ↓48-71% Non-HDL-C ↓49-58% TC ↓36-42% | Injection-site swelling or rash; nasopharyngitis; limb pain; fatigue | Absolute: hypersensitivity |
| Ezetimibe (cholesterol absorption inhibitor) | LDL-C ↓10-18% alone; a further ↓25% with a statin, ↓20-22% with fenofibrate | Headache; abdominal pain; diarrhoea | Absolute: hypersensitivity. Relative: active liver disease or unexplained persistent raised transaminases |
| Inclisiran (siRNA) | LDL-C ↓50% | Injection-site reaction; arthralgia; UTI; headache | None listed |
| Bempedoic acid | LDL-C ↓25-30% alone; a further ↓20% with a statin, ↓40% with ezetimibe | Hyperuricaemia | Absolute: with simvastatin >20 mg or pravastatin >40 mg. Relative: hyperuricaemia, tendon rupture |
| Bile acid sequestrants | LDL-C ↓15-25% HDL-C ↑3-5% TG ↔ or ↑ | GI upset; constipation; reduced absorption of folate, fat-soluble vitamins and some drugs | Absolute: dysbetalipoproteinaemia, TG >4.5 mmol/L. Relative: TG >2.3 mmol/L |
| Nicotinic acid (niacin) | LDL-C ↓10-25% HDL-C ↑10-35% TG ↓20-30% | Flushing; hyperglycaemia; hyperuricaemia or gout; upper GI upset; hepatotoxicity (rare) | Absolute: chronic liver disease, severe gout. Relative: diabetes (high doses), peptic ulcer disease |
Remark: TC = total cholesterol; TG = triglycerides; CYP450 = cytochrome P450 enzymes; GI = gastrointestinal; UTI = urinary tract infection; ↓ = lowers, ↑ = raises, ↔ = no change. Adapted from Table 11, CPG Dyslipidaemia 2023 (data from short-term registration trials; real-world changes may be smaller).
Escalation
- Recheck the lipid profile 1-3 months after starting a statin and after every dose change.
- Not at target → up-titrate the statin to the maximum tolerated dose. Very high and high risk patients should be on a maximally tolerated statin.
- Still not at target → add a non-statin, in this order of evidence:
-
- ezetimibe
-
- PCSK9 inhibitor (± ezetimibe)
-
- inclisiran (± ezetimibe); don't combine inclisiran with a PCSK9 monoclonal antibody
-
- At target → keep the same statin dose; don't stop it. Repeat lipids every 6-12 months (more often if adherence or results are unstable).
Adding ezetimibe 10 mg to any statin dose lowers LDL-C by about another 25%, versus about 6% from doubling the statin dose.
Monitoring and safety
- ALT: at baseline and 1-3 months after starting or changing the dose. Stop if ALT >3× ULN on 2 occasions; cautious re-introduction is possible once normal. Mild baseline elevation (e.g. fatty liver) isn't a contraindication. Routine long-term ALT monitoring isn't needed.
- CK: only if myositis is suspected (not after vigorous exercise). Stop if CK >5× ULN on 2 occasions.
- New diabetes: statins slightly raise the risk (dose related), but the CV benefit far outweighs it. Screen for diabetes 6-12 monthly in those at high risk (elderly, metabolic syndrome, obesity, family history).
- Kidneys: no routine monitoring of renal function or proteinuria needed.
- Interactions: avoid statin + gemfibrozil (myopathy); take care with simvastatin >20 mg and CYP450 inhibitors.
De-escalation and statin intolerance
Treatment is life-long; reaching the target is not a reason to stop. Reduce or stop for adverse effects:
- Any adverse effect: reduce the dose or stop temporarily. Once symptoms or tests normalise, re-introduce at a lower dose; if it recurs, stop and use an alternative.
- Myalgia without CK rise (5-10% of patients): reduce the dose or stop if not tolerable or progressive.
- Suspected statin-associated muscle symptoms:
- Stop the statin for 2-3 weeks.
- Symptoms persist → probably not the statin; restart at the same dose.
- Symptoms resolve → try a lower dose or less-than-daily dosing (e.g. atorvastatin or rosuvastatin every other day or twice a week), or the highest tolerated dose + ezetimibe, or a PCSK9 inhibitor if indicated.
- 92% of statin-intolerant patients tolerate a second statin, and 73% a third.
- Elderly: start lower and titrate cautiously; reconsider treatment periodically. In secondary prevention, don't withhold based on age alone. In primary prevention over 80 years, benefit is uncertain: individualise and discuss with the patient and family.
- Dialysis: don't start a statin for primary prevention; continue if the patient has CVD or was already on one.
- Pregnancy, planning pregnancy or breastfeeding: avoid statins (if strongly indicated, a hydrophilic statin such as rosuvastatin is preferred). PCSK9 inhibitors cross the placenta and shouldn't be used in pregnancy.
High triglycerides
The primary target is still LDL-C; non-HDL-C becomes the secondary target when TG >2.3 and the primary target when TG >4.5 mmol/L.
Mild-moderate (TG >1.7 to <10 mmol/L):
- Lifestyle: weight loss, less simple carbohydrate and sugary drinks, less alcohol, stop smoking, control diabetes.
- After 4-12 weeks, reassess. Drug therapy for high CV risk, stepwise:
- intensify the statin (atorvastatin, rosuvastatin and pitavastatin lower TG most)
- + fibrate if TG is still high on optimal LDL-lowering therapy (caution: gemfibrozil + statin)
- omega-3: CV benefit uncertain, and high doses (4 g/day) nearly double the risk of AF
- In diabetes on a maximally tolerated statin with HDL-C ≤0.88 and TG ≥2.3 mmol/L, a fibrate may be considered.
Severe (TG >10 mmol/L): repeat fasting TG after 5 days to 2 weeks, look for secondary causes, and seek specialist advice if it stays >10. Very low carbohydrate and low-fat diet. Fibrates are for very high TG that doesn't respond to non-drug measures, to prevent pancreatitis.
Special groups
| Group | What the CPG recommends |
|---|---|
| Diabetes | Statin for everyone with diabetes over 40, whatever the baseline LDL-C. Not generally recommended in T2DM <21 years without clinical CVD. Target by CV risk. See Type 2 diabetes |
| Hypertension | Start a statin for primary prevention if LDL-C >3.4 mmol/L; otherwise use the Framingham score. See Hypertension |
| CKD (not on dialysis), stages 3-5 | Statin or ezetimibe/simvastatin for primary and secondary prevention. eGFR <60: start at a lower dose (doses below) and avoid statin + fibrate. Stages 1-2: assess with the Framingham score |
| Kidney transplant | Statin for all adult recipients |
| Heart failure | Statin if HF is due to CAD; not routinely in non-ischaemic HF |
| Thyroid disease | Treat the thyroid disorder first and reassess lipids once euthyroid |
| Cushing syndrome (persistent) | Statin whatever the CV risk; LDL-C target <1.8 mmol/L |
| HIV / psychiatric disorders | LDL-C is the primary target; statins first; watch for drug interactions with ART |
Remark: CKD = chronic kidney disease; CVD = cardiovascular disease; HF = heart failure; CAD = coronary artery disease; ART = antiretroviral therapy.
Usual doses
Statins by intensity
| High intensity (LDL-C ↓ ≥50%) | Moderate intensity (LDL-C ↓ 30-<50%) | Low intensity (LDL-C ↓ <30%) |
|---|---|---|
| Atorvastatin 40-80 mg Rosuvastatin 20-40 mg | Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin 40 mg BD Pitavastatin 2-4 mg | Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg |
Remark: BD = twice daily. Adapted from Table 12, CPG Dyslipidaemia 2023 (daily doses). High intensity is for very high and high risk. Low intensity is generally used for primary prevention after lifestyle changes and a risk-benefit discussion.
Statins in CKD
| Agent | CKD stage 3a-5 (mg/day) |
|---|---|
| Atorvastatin | 20 |
| Fluvastatin | 80 |
| Lovastatin | Not studied |
| Pravastatin | 40 |
| Rosuvastatin | 10 |
| Simvastatin | 40 |
| Simvastatin/ezetimibe | 20/10 |
Remark: CKD = chronic kidney disease; KDIGO = Kidney Disease: Improving Global Outcomes. Adapted from Table 15, CPG Dyslipidaemia 2023 (from KDIGO 2013).
Non-statins
| Drug | Recommended dose |
|---|---|
| Ezetimibe | 10 mg daily. No adjustment for mild hepatic impairment or mild-moderate kidney disease; not recommended in moderate-severe hepatic impairment |
| Evolocumab | 140 mg SC every 2 weeks, or 420 mg SC monthly |
| Alirocumab | 75-150 mg SC every 2 weeks, or 300 mg SC monthly |
| Inclisiran | 284 mg SC once, again at 3 months, then every 6 months |
| Fibrates (adjust dose in CKD) | |
| Fenofibrate | 100 mg TDS, 145 mg daily (nanoparticles), or 160 mg daily (micronised) |
| Gemfibrozil | 600-1200 mg daily in divided doses, 30 minutes before meals (max 1.5 g/day). Not with statins |
| Bezafibrate | 200 mg daily, increasing gradually over 5-7 days to max 200 mg TDS (regular), or 400 mg daily (sustained release) |
| Ciprofibrate | 100 mg daily |
Remark: SC = subcutaneous; TDS = three times daily; CKD = chronic kidney disease. Adapted from Sections 7.2.2-7.2.5 and Table 13, CPG Dyslipidaemia 2023 (fibrate doses as stated in MIMS 2016-2017).
Sources
- National Heart Association of Malaysia, Ministry of Health Malaysia, Academy of Medicine of Malaysia. Clinical Practice Guidelines: Management of Dyslipidaemia, 6th Edition. 2023. Key Recommendations 1-18; Tables 4, 6, 11, 12, 13, 15; Sections 7.2, 11, 12. MOH