Dyslipidaemia: LDL-C targets, statin intensity, ezetimibe and PCSK9 inhibitors

Overview and definitions

Abbreviations used on this page

^{[1] [3]}

• The 2025 ESC/EAS focused update explains why LDL-C is the target: it says atherosclerosis is caused by the progressive deposition of LDL-C and other ApoB-containing lipoproteins within the artery wall, which triggers inflammation and the formation and progression of plaque.^[2]
• The 2025 ESC/EAS update states that LDL-C, like other ApoB-containing lipoproteins, is a direct cause of ASCVD, so lowering plasma LDL-C should be the main focus for preventing atherosclerotic cardiovascular events.^[2]
• ESC/EAS 2019 adds that no level of LDL-C below which benefit ceases or harm occurs has been defined.^[1]

Classification: who is at which risk

• Every goal below hangs on a risk category, so start here.
• The 2025 ESC/EAS focused update presents updated definitions of very high, high, moderate and low risk using SCORE2/SCORE2-OP instead of SCORE for apparently healthy persons, and its Table 3 is intended to replace Table 4 of the 2019 guideline.^[2]
• The 2025 ESC/EAS update used a 2× multiplier to convert the previous SCORE-based thresholds into SCORE2- or SCORE2-OP-based thresholds for total CVD risk.^[2]

ESC/EAS 2025 cardiovascular risk categories

^[2]

• In ESC/EAS 2025 Table 3, significant plaque is typically defined by stenosis above 50%, a markedly elevated CAC score is exemplified by a score above 300, and target organ damage means microalbuminuria, retinopathy or neuropathy.^[2]

• Figure 1 of the 2025 update also draws an "extreme risk" box above very high risk: patients with ASCVD who have recurrent vascular events while taking maximally tolerated statin-based therapy, and patients with polyvascular (for example coronary and peripheral) arterial disease.^[2]

• ACC/AHA 2026 splits clinical ASCVD into very high risk and not very high risk using the event-and-feature definition above, and it expects most patients to land in the higher group: the majority of patients with clinical ASCVD are likely to be at very high risk.^[3]

• For primary prevention in adults aged 30 to 79 years without ASCVD or subclinical atherosclerosis and with LDL-C of 70 to 189 mg/dL (1.8–4.9 mmol/L), ACC/AHA 2026 recommends the PREVENT-ASCVD equations to estimate 10-year risk, categorised as low (below 3%), borderline (3% to below 5%), intermediate (5% to below 10%) or high (10% or more) (COR 1, LOE B-NR).^[3]

• Australia uses a five-year horizon: for people without known CVD, the 2023 Australian guideline for assessing and managing cardiovascular disease risk categorises risk with the Aus CVD Risk Calculator into low (below 5% over five years), intermediate (5% to below 10%) or high (10% or more).^[5]

^{[2] [1] [3] [4]}

Epidemiology and risk factors

• Risk from LDL-C accumulates over a lifetime: the 2025 ESC/EAS update says cumulative exposure to higher LDL-C at younger ages is associated with higher ASCVD risk later in life, and ACC/AHA 2026 opens its take-home messages with the instruction to treat dyslipidaemia earlier to reduce lifelong exposure to atherogenic lipoproteins.^[2][3]

Raised Lp(a) is common: the 2025 ESC/EAS update notes that levels above 50 mg/dL (105 nmol/L or more) affect at least 20% of the population.^[2] ACC/AHA 2026 adds that Lp(a) concentrations are mostly genetically determined by the LPA gene and that population distributions vary by ancestry, with the highest levels in people of African ancestry.^[3]

Pathophysiology: LDL particles, the LDL receptor and where each drug acts

• ESC/EAS 2019 describes statins as reducing hepatic cholesterol synthesis by competitively inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis.^[1]

• The fall in intracellular cholesterol increases LDL receptor expression on hepatocytes, so more LDL is taken up from the blood and plasma concentrations of LDL and other ApoB-containing lipoproteins, including TG-rich particles, decrease (ESC/EAS 2019).^[1]

• ESC/EAS 2019 explains that ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol at the brush border by interacting with the Niemann-Pick C1-like protein 1, without affecting absorption of fat-soluble nutrients; less cholesterol reaches the liver, which upregulates LDL receptor expression and clears more LDL.^[1]

• PCSK9 controls the receptor itself: ESC/EAS 2019 states that elevated PCSK9 concentration or function reduces LDL receptor expression by promoting lysosomal catabolism of the receptor, while lower PCSK9 concentration or function is related to lower plasma LDL-C.^[1]

• The 2025 ESC/EAS update describes inclisiran as a small interfering RNA molecule that inhibits the synthesis of PCSK9 and may represent an alternative approach to the PCSK9 monoclonal antibodies alirocumab and evolocumab.^[2]

The 2025 ESC/EAS update describes bempedoic acid as an oral small molecule that inhibits cholesterol synthesis by inhibiting ATP-citrate lyase, a cytosolic enzyme upstream of the HMG-CoA reductase pathway.^[2] The 2025 ESC/EAS update states that bempedoic acid is a prodrug whose activating enzyme (very long-chain acyl-CoA synthetase-1) is not expressed in skeletal muscle, and reports muscle-related adverse events similar to placebo.^[2]

ACC/AHA 2026 explains why ApoB adds information: LDL-C reflects the cholesterol mass within LDL particles, whereas ApoB directly measures atherogenic particle number, with 1 molecule per LDL, very-low-density lipoprotein and Lp(a) particle.^[3] ACC/AHA 2026 describes Lp(a) as an LDL-like particle that carries a single apolipoprotein(a) strand bound to its apoB-100 component.^[3]

• The benefit tracks the size of the LDL-C reduction: in the Cholesterol Treatment Trialists (CTT) meta-analysis reported by ESC/EAS 2019, each 1 mmol/L reduction in LDL-C with a statin or a more intensive statin regimen reduced major vascular events by about 22%, major coronary events by 23%, coronary death by 20%, total stroke by 17% and total mortality by 10% over 5 years.^[1]
• The CTT authors found no evidence of any threshold within the cholesterol range studied.^[11][1]
• The 2025 ESC/EAS update states that the clinical benefit depends on the achieved LDL-C reduction, so individuals with higher risk need more intense LDL-C lowering to reach the same absolute residual risk on treatment as those with lower risk.^[2]

^{[1] [2]}

Clinical presentation: how lipid problems reach you

• ACC/AHA 2026 recommends lipid-profile screening in adults beginning at age 19 years and at least every 5 years thereafter to identify treatable ASCVD risk, with frequent screening recommended for those with additional ASCVD risk factors (COR 1, LOE B-NR).^[3]

• ACC/AHA 2026 says complaints of myalgia or muscle weakness, or the fear of developing them, are the most frequently reported reasons for failure to tolerate or adhere to statin therapy.^[3]

• ACC/AHA 2026 says a statin-related cause is supported by new-onset bilateral, symmetrical, proximal muscle pain or weakness within weeks of starting or increasing a statin, typically resolving within a similar period after stopping and possibly recurring on rechallenge.^[3]

• ACC/AHA 2026 notes that these symptoms may occur with or without CK elevation.^[3]

Differential diagnosis

In adults with severe hypercholesterolaemia (LDL-C 190 mg/dL [4.9 mmol/L] or more), ACC/AHA 2026 recommends that secondary causes be excluded and addressed to reduce LDL-C (COR 1, LOE B-NR).^[3] The ACC/AHA 2026 footnote to that row defines severe hypercholesterolaemia as LDL-C above 190 mg/dL, non-HDL-C above 220 mg/dL and/or ApoB above 140 mg/dL.^[3]

^[3]

• For muscle symptoms on a statin, ACC/AHA 2026 says the symptoms may be due to the prescribed statin alone or to other explanations: altered statin metabolism through drug-drug interactions, excessive muscular activity, primary muscle or metabolic disorders, or patient expectation that the statin is responsible.^[3]
• ACC/AHA 2026 Table 24 lists diseases associated with myalgia or muscle weakness (for example fibromyalgia, polymyalgia rheumatica, polymyositis and primary myopathies) among the characteristics associated with an increased risk of statin-attributed muscle symptoms.^[3]

Clinical and bedside assessment: estimating risk

• Risk calculators are for people without ASCVD: ESC/EAS 2025 recommends SCORE2 and SCORE2-OP for apparently healthy people without established ASCVD, DM, CKD or genetic or rare lipid or blood pressure disorders and places documented ASCVD in its very high-risk category, and ACC/AHA 2026 recommends the PREVENT-ASCVD equations for adults aged 30 to 79 years without ASCVD or subclinical atherosclerosis and with LDL-C 70 to 189 mg/dL (1.8–4.9 mmol/L).^[2][3]

• The 2025 ESC/EAS update warns that SCORE2 and SCORE2-OP were derived in people without clinical ASCVD who were not on lipid-lowering therapy, so they should not be used for people with existing ASCVD or already on lipid-lowering therapy, nor to re-assess risk with lipid values obtained after treatment has started.^[2]
• The 2025 ESC/EAS update also notes that non-HDL-C (TC minus HDL-C) is used as an input in the SCORE2 and SCORE2-OP algorithms.^[2]

ACC/AHA 2026 states that, in general, PREVENT-ASCVD risk estimates tend to be 40% to 50% lower than 10-year estimates from the pooled cohort equations for the same risk factor profile.^[3]

• In Australia, the 2023 risk guideline recommends assessment in people without known CVD aged 45–79 years, people with diabetes from 35 years and First Nations people from 30 years.^[5]
• The 2023 Australian guideline allows reclassification for Indigenous status or ethnicity, eGFR, urine albumin to creatinine ratio, severe mental illness, CAC score and family history of premature CVD, particularly near a risk threshold.^[5]

Investigations

The lipid profile and how LDL-C is estimated

• ESC/EAS 2019 recommends LDL-C analysis as the primary lipid analysis method for screening, diagnosis and management (Class I, Level C).^[1]

• ACC/AHA 2026 recommends a standard nonfasting or fasting lipid profile in adults and children to document baseline levels, estimate ASCVD risk and guide initiation of lipid-lowering therapy (COR 1, LOE B-NR), and notes that nonfasting samples can be used for most individuals.^[3]

• When to fast (ACC/AHA 2026): with a family history of dyslipidaemia or premature ASCVD, a known or suspected disorder of TG metabolism, or a nonfasting TG of 400 mg/dL (4.5 mmol/L) or more, a fasting profile should be performed to estimate LDL-C more accurately (COR 1, LOE B-NR).^[3]

• Which equation (ACC/AHA 2026): the Martin/Hopkins or Sampson/National Institutes of Health equation is preferred over the Friedewald equation to estimate LDL-C (COR 1, LOE B-NR).^[3]

• Why not Friedewald (ACC/AHA 2026): it is prone to inaccuracies as TG rises and as LDL-C and non-HDL-C fall, and it cannot be used if TG is 400 mg/dL (4.5 mmol/L) or more.^[3]

• Non-HDL-C: ESC/EAS 2019 recommends non-HDL-C evaluation for risk assessment, particularly with high TG, DM, obesity or very low LDL-C (Class I, Level C); ACC/AHA 2026 recommends that non-HDL-C be reported for risk assessment and to guide initiation and monitoring of lipid-lowering therapy (COR 1, LOE B-NR).^[1][3]

• Advanced lipoprotein testing (ACC/AHA 2026): routine advanced lipoprotein testing to assess lipoprotein subclasses and parameters such as LDL particle size is not recommended to estimate ASCVD risk or guide initiation of lipid-lowering therapy (COR 3: No Benefit, LOE B-NR).^[3]

ApoB

• ESC/EAS 2019 recommends ApoB analysis for risk assessment, particularly with high TG, DM, obesity, metabolic syndrome or very low LDL-C, and says it can be used as an alternative to LDL-C, if available, as the primary measurement for screening, diagnosis and management, and may be preferred over non-HDL-C in people with high TG, DM, obesity or very low LDL-C (Class I, Level C).^[1]

• ACC/AHA 2026 is more targeted: in adults on lipid-lowering therapy, particularly those with ASCVD, cardiovascular-kidney-metabolic syndrome, type 2 diabetes and/or elevated TG, measuring ApoB is reasonable to guide further intensification once LDL-C and/or non-HDL-C goals are achieved (COR 2a, LOE B-NR).^[3]

• In adults not on therapy, ACC/AHA 2026 says ApoB measurement may be reasonable to enhance risk assessment, guide initiation and characterise inherited lipid disorders (COR 2b, LOE B-NR).^[3]

• ACC/AHA 2026 says clinically significant discordance often occurs when LDL-C is at goal but ApoB remains elevated above the treatment goal, indicating persistent atherogenic particle burden and a potential need to intensify therapy.^[3]

ESC/EAS 2019 secondary goals (defined by inference; moderate grading)

^[1]

• ESC/EAS 2019 says these secondary goals were defined by inference and have not been extensively studied in randomised trials; the non-HDL-C goal should be 0.8 mmol/L (30 mg/dL) higher than the corresponding LDL-C goal, and adjusting therapy to them may be considered in patients at very high risk after the LDL-C goal is achieved, although the clinical advantages of this approach for outcomes remain to be addressed.^[1]

Lipoprotein(a)

^{[1] [2] [3]}

• Do not convert Lp(a) units with confidence: ACC/AHA 2026 states that equivalence between nmol/L and mg/dL is approximate and that its risk table is a general guide that may differ in other populations.^[3]
• The 2025 ESC/EAS Figure 3 legend says risk of major cardiovascular events starts to rise slightly above 62 nmol/L (30 mg/dL) and more steeply at 105 nmol/L (50 mg/dL) or more.^[2]

Safety blood tests and monitoring on treatment

^{[1] [2] [3]}

• Monitoring matters because response varies: the 2025 ESC/EAS update stresses considerable inter-individual variability in LDL-C response to any drug or combination, which necessitates monitoring after any initiation or adaptation of therapy.^[2]
• ESC/EAS 2019 states that mild ALT elevation occurs in 0.5–2.0% of patients on statin treatment, more commonly with potent statins or high doses, and has not been shown to be associated with true hepatotoxicity.^[1]
• ESC/EAS 2019 adds that progression to liver failure is exceedingly rare, so routine monitoring of ALT during statin treatment is no longer recommended; its Table 13 keeps the ALT check before treatment and once 8–12 weeks after starting or a dose increase.^[1]

ESC/EAS 2019 Table 13 also covers abnormal results and at-risk patients:^[1]

• ALT elevated: if ALT is below 3× ULN, continue therapy and recheck liver enzymes in 4–6 weeks; if ALT rises to 3× ULN or more, stop lipid-lowering therapy or reduce the dose and recheck liver enzymes within 4–6 weeks; cautious reintroduction of therapy may be considered after ALT has returned to normal; if ALT remains elevated, check for other reasons.^[1]
• CK elevated: re-evaluate the indication for statin treatment. If CK is 4× ULN or more: above 10× ULN, stop treatment, check renal function and monitor CK every 2 weeks; below 10× ULN without symptoms, continue lipid-lowering therapy while monitoring CK between 2 and 6 weeks; below 10× ULN with symptoms, stop the statin and monitor normalisation of CK before rechallenge with a lower statin dose.^[1]
• If CK is below 4× ULN: without muscle symptoms, continue the statin, with the patient alerted to report symptoms and CK checked; with muscle symptoms, monitor symptoms and CK regularly; if symptoms persist, stop the statin, re-evaluate symptoms after 6 weeks and re-evaluate the indication for statin treatment.^[1]
• Be alert to myopathy and CK elevation in patients at risk, such as elderly patients, those on concomitant interfering therapy or multiple medications, those with liver or renal disease, and athletes; the guideline text adds that CK should be checked in patients at high risk for myopathy, such as the very elderly with comorbidities, patients with antecedents of muscle symptoms, or patients receiving interacting drugs.^[1]
• Regular checks of HbA1c or glucose should be considered in patients at high risk of developing diabetes and on high-dose statin treatment.^[1]

Management: the acute coronary syndrome admission

• The 2025 ESC/EAS update notes that patients with ACS are at particularly elevated risk of recurrent cardiovascular events, especially within the first year after hospital discharge.^[2]
• The 2025 ESC/EAS update proposes a strategy of early, intensive LDL-C lowering to be considered in all patients with ACS, with immediate statin initiation and combination with one or more non-statin classes with proven cardiovascular benefit as needed, depending on the patient's lipid-lowering therapy before the event.^[2]

The Medical Journal of Australia summary of that guideline justifies the target by stating that each 1.0 mmol/L LDL-C reduction is associated with a 20% lower risk of major cardiovascular events.^[4]

Management: definitive and stepwise LDL-C lowering

Step 1: set the goal for the risk category

• ESC/EAS 2019 explains the double requirement: it seems appropriate to reduce LDL-C as low as possible, at least in patients at very high risk, so a minimum 50% reduction is suggested together with reaching the tailored goal.^[1]
• The 2025 ESC/EAS update confirms that the LDL-C goals and the therapeutic guidance for each risk category have not changed from 2019.^[2]

Step 2: choose the statin dose that can deliver it

ESC/EAS 2019 recommends prescribing a high-intensity statin up to the highest tolerated dose to reach the goals set for the specific level of risk (Class I, Level A).^[1] ESC/EAS 2019 adds that response is variable, so uptitration of the statin dose may be required before additional LDL-lowering treatments are started.^[1] ESC/EAS 2019 also notes considerable interindividual variation in LDL-C reduction with the same dose of drug.^[1]

Statin intensity: expected LDL-C reduction and doses (ACC/AHA 2026)

^[3]

• ACC/AHA 2026 footnotes that these are population estimates and individual responses should be expected to vary, and that initiation of or titration to simvastatin 80 mg is not recommended by the US Food and Drug Administration because of the increased risk of myopathy, including rhabdomyolysis.^[3]
• ACC/AHA 2026 says certain populations, especially people of East Asian ancestry, may be more prone to side effects through inherited drug metabolism, so initial treatment should be with lower doses.^[3]

Step 3: add non-statin therapy when the goal is not reached

ESC/EAS 2019 notes that addition of a PCSK9 inhibitor directly to a statin is also feasible.^[1]

ACC/AHA 2026 explains the bempedoic acid grading: there are no outcome trials combining standard statin therapy with bempedoic acid, which is why it receives a Class 2a recommendation in ASCVD.^[3]

^[2]

The 2025 ESC/EAS Figure 2 also gives about 20% for ezetimibe alone, about 23% for bempedoic acid alone and about 38% for the two together.^[2]

^{[1] [3]}

Drugs and doses as the sources state them

LDL-C-lowering drugs: dosing and effect

^{[3] [1] [7] [2]}

Specific scenarios

Primary prevention under ACC/AHA 2026 (adults aged 30–79 years with LDL-C 70–189 mg/dL [1.8–4.9 mmol/L])

• Low 10-year risk (below 3%), aged 30–59 years, LDL-C below 160 mg/dL (4.1 mmol/L) and 30-year risk below 10%: counselling on health behaviours is recommended to reduce LDL-C and risk for ASCVD (COR 1, LOE A).^[3]
• Low 10-year risk but LDL-C 160–189 mg/dL (4.1–4.9 mmol/L) or 30-year risk 10% or more (aged 30–59 years): a moderate-intensity statin is reasonable to reduce cumulative exposure to atherogenic lipoproteins (COR 2a, LOE C-LD).^[3]
• Borderline 10-year risk (3% to below 5%) when a decision is made to start a statin: a moderate-intensity statin is reasonable to achieve a 30% to 49% LDL-C reduction and to reduce ASCVD risk (COR 2a, LOE A).^[3]
• Intermediate 10-year risk (5% to below 10%): at least a moderate-intensity statin is recommended to achieve a 30% to 49% reduction; at the higher end of the range, a high-intensity statin is beneficial to reduce LDL-C by 50% or more (COR 1, LOE A).^[3]
• Borderline or intermediate 10-year risk on a statin: it is reasonable to treat to LDL-C below 100 mg/dL (2.6 mmol/L) and non-HDL-C below 130 mg/dL (3.4 mmol/L) to reduce ASCVD risk (COR 2a, LOE B-NR).^[3]
• High 10-year risk (10% or more) when lipid-lowering therapy is started: high-intensity statin therapy is recommended to achieve an LDL-C reduction of 50% or more to reduce the risk of ASCVD (COR 1, LOE A); when a decision to start a statin is made, treating to LDL-C below 70 mg/dL (1.8 mmol/L) and non-HDL-C below 100 mg/dL (2.6 mmol/L) to reduce ASCVD risk is reasonable (COR 2a, LOE B-R).^[3]
• High 10-year risk on maximally tolerated statin with that goal not achieved: adding ezetimibe is reasonable (COR 2a, LOE B-R); with or without ezetimibe, adding a PCSK9 mAb or bempedoic acid may be reasonable (COR 2b, LOE B-NR).^[3]
• Untreated LDL-C below 70 mg/dL (1.8 mmol/L) and non-HDL-C below 100 mg/dL (2.6 mmol/L) without additional risk factors: starting therapy for primary prevention is unlikely to reduce ASCVD risk (COR 3: No Benefit, LOE B-NR).^[3]

Primary prevention in Australia (2023 risk guideline)

The 2023 Australian guideline for assessing and managing cardiovascular disease risk says blood pressure-lowering and lipid-modifying pharmacotherapies should be prescribed for high-risk and considered for intermediate-risk individuals, unless contraindicated or clinically inappropriate.^[5] Its categories are five-year risks from the Aus CVD Risk Calculator: intermediate is 5% to below 10% and high is 10% or more over five years.^[5]

Subclinical coronary atherosclerosis: men aged 40 or more, women aged 45 or more (ACC/AHA 2026)

• CAC score 1000 AU or more: LDL-C-lowering therapy, with consideration of a statin first line, is recommended to achieve a 50% or greater LDL-C reduction and a goal below 55 mg/dL (1.4 mmol/L), with non-HDL-C below 85 mg/dL (2.2 mmol/L) (COR 1, LOE B-NR).^[3]
• CAC score 300 to 999 AU: LDL-C-lowering therapy, with consideration of a statin first line, is recommended to achieve a 50% or greater lowering in LDL-C and a goal below 70 mg/dL (1.8 mmol/L), with non-HDL-C below 100 mg/dL (2.6 mmol/L) (COR 1, LOE B-R).^[3]

Severe hypercholesterolaemia and familial hypercholesterolaemia

• ACC/AHA 2026 defines severe hypercholesterolaemia in its row footnote as LDL-C above 190 mg/dL, non-HDL-C above 220 mg/dL and/or ApoB above 140 mg/dL, and recommends maximally tolerated statin therapy (COR 1, LOE B-R).^[3]

• LDL-C 190 mg/dL (4.9 mmol/L) or more without clinical ASCVD, additional risk factors, HeFH or subclinical atherosclerosis: on maximally tolerated statin, adding ezetimibe, a PCSK9 mAb and/or bempedoic acid is recommended to achieve a goal of LDL-C below 100 mg/dL (2.6 mmol/L) and non-HDL-C below 130 mg/dL (3.4 mmol/L) and to reduce ASCVD risk (ACC/AHA 2026, COR 1, LOE B-NR).^[3]

• LDL-C 190 mg/dL (4.9 mmol/L) or more without clinical ASCVD but with clinical or genetic HeFH, additional risk factors or documented coronary calcification, on maximally tolerated statin: adding these agents to achieve LDL-C below 70 mg/dL (1.8 mmol/L) and non-HDL-C below 100 mg/dL (2.6 mmol/L) is recommended to lower LDL-C and reduce ASCVD risk (ACC/AHA 2026, COR 1, LOE B-R).^[3]

• LDL-C 190 mg/dL (4.9 mmol/L) or more with clinical ASCVD, on maximally tolerated statin: adding these agents is recommended to achieve LDL-C below 55 mg/dL (1.4 mmol/L) and non-HDL-C below 85 mg/dL (2.2 mmol/L), to lower LDL-C and reduce ASCVD risk (ACC/AHA 2026, COR 1, LOE B-R).^[3]

• Severe hypercholesterolaemia, with or without clinical ASCVD, and LDL-C 100 mg/dL (2.6 mmol/L) or more despite maximally tolerated statin with or without ezetimibe: inclisiran is reasonable to lower LDL-C (ACC/AHA 2026, COR 2a, LOE B-R); the row footnote says cardiovascular outcomes trials are pending, that it is indicated only to lower LDL-C and that it is considered a second-line PCSK9 inhibitor at this time.^[3]

• ESC/EAS 2025 Table 3 places FH with ASCVD or with another major risk factor at very high risk, and FH without other major risk factors at high risk.^[2]

• Homozygous FH responds differently: ESC/EAS 2019 notes that receptor-deficient HoFH responds poorly to PCSK9 inhibition, and the 2025 update reports that evinacumab, an antibody against angiopoietin-like 3, has shown potential benefits with a reduction of LDL-C close to 50% in patients with homozygous FH, in whom statins and PCSK9 inhibitors have little efficacy.^[1][2]

Diabetes without ASCVD (ACC/AHA 2026)

• Aged 40–75 years: moderate-intensity statin therapy is indicated to achieve a 30% to 49% LDL-C reduction and a goal of LDL-C below 100 mg/dL (2.6 mmol/L) and non-HDL-C below 130 mg/dL (3.4 mmol/L), to reduce ASCVD risk (COR 1, LOE A).^[3]
• Aged 40–75 years with multiple ASCVD risk factors: high-intensity statin therapy is reasonable to achieve a 50% or greater reduction and LDL-C below 70 mg/dL (1.8 mmol/L) with non-HDL-C below 100 mg/dL (2.6 mmol/L) (COR 2a, LOE B-R).^[3]
• With statin-attributed side effects: ezetimibe and/or bempedoic acid or a PCSK9 mAb is recommended (COR 1, LOE B-R).^[3]

Recurrent events despite treatment

• ESC/EAS 2019 says that for patients with ASCVD who have a second vascular event within 2 years while taking maximally tolerated statin-based therapy, an LDL-C goal below 1.0 mmol/L (below 40 mg/dL) may be considered (Class IIb, Level B).^[1]
• The 2025 ESC/EAS update's Figure 1 places these patients, with those who have polyvascular arterial disease, in its "extreme risk" box.^[2]

Elevated Lp(a)

• The 2025 ESC/EAS update says it has yet to be shown whether lowering Lp(a) reduces the risk of ASCVD and aortic valve stenosis progression, and that the extent of Lp(a) lowering required for clinical benefit is also not known.^[2]

• In the absence of specific Lp(a)-lowering therapies, the update says early risk factor management and more intensive LDL-C lowering is reasonable, considering both absolute cardiovascular risk and Lp(a) levels.^[2]

• The 2025 ESC/EAS update reports that statins had no effect on Lp(a) concentrations in individual-level data from seven randomised, placebo-controlled statin outcome trials, and that injectable RNA-based therapies in trials lower Lp(a) by 80%–98%.^[2]

• ACC/AHA 2026: with elevated Lp(a) (125 nmol/L or more, or 50 mg/dL or more), optimal early control of modifiable cardiovascular risk factors is recommended to reduce ASCVD risk (COR 1, LOE B-NR).^[3]

• ACC/AHA 2026: with clinical ASCVD and elevated Lp(a), not at LDL-C and non-HDL-C treatment goals on maximally tolerated statin, adding a PCSK9 mAb with proven cardiovascular benefit is recommended to achieve treatment goals and reduce ASCVD risk (COR 1, LOE B-R).^[3]

• Lp(a) lowering with PCSK9 inhibitors: ACC/AHA 2026 gives about 15% to 30% for PCSK9 inhibitors (monoclonal antibodies and small interfering RNA), and ESC/EAS 2019 reports about 30–40% with PCSK9 monoclonal antibodies from pooled results of phase II trials.^[3][1]

• ACC/AHA 2026 notes that lifestyle management minimally affects Lp(a) because it is mostly genetically determined.^[3]

Complications and pitfalls

Statin-associated muscle symptoms and statin intolerance

ESC/EAS 2019 reports a 10–15% frequency of statin-associated muscle symptoms in observational studies, but no or only a slightly increased frequency in statin-allocated groups of blinded placebo-controlled trials.^[1] ESC/EAS 2019 reports the ASCOT-LLA conclusion that a nocebo effect may partly explain the difference, and ACC/AHA 2026 calls patient expectation that statins are responsible the "drucebo effect".^[1][3]

• ACC/AHA 2026 says the patient's willingness to restart an alternate statin, take less than daily dosing of a long-acting statin, or add non-statin therapies should be explored, to align lipid-lowering therapy with their estimated ASCVD risk.^[3]
• ESC/EAS 2019 reports a considerable LDL-C-lowering effect from alternative dosing, such as every other day or twice a week with atorvastatin or rosuvastatin, and says this should be considered in high-risk patients who cannot take daily doses, although no clinical endpoint trials are available.^[1]

^{[1] [2] [3]}

• ACC/AHA 2026 Table 24 lists characteristics associated with an increased risk of statin-attributed muscle symptoms: age 65 years or more, low body mass index, female sex, obesity, hypothyroidism, diabetes, chronic liver disease, CKD, alcohol consumption, vigorous exercise and high-dose statin therapy.^[3]
• ACC/AHA 2026 Table 24 adds diseases associated with myalgia or muscle weakness, drugs affecting statin metabolism and gene variants affecting statin metabolism (for example SLCO1B1).^[3]

Other adverse effects and interactions

• Statins (ACC/AHA 2026 Table 25): myalgia with a normal CK is common and dose-related; contraindications are acute liver failure, decompensated cirrhosis, lactation and severe underlying neuromuscular disease (for example dermatomyositis or muscular dystrophy); myositis or myopathy with concerning symptoms or objective weakness is rare, rhabdomyolysis is rare and immune-mediated necrotising myopathy is very rare.^[3]
• New diabetes (ESC/EAS 2019): the guideline reports that patients on statins have been shown to have an increased risk of dysglycaemia and type 2 diabetes, that several studies have shown this to be a consistent, dose-related effect, and that the number needed to cause one case has been estimated as 255 over 4 years of statin treatment.^[1]
• Liver (ESC/EAS 2019): mild ALT elevation occurs in 0.5–2.0% of patients on statins, more commonly with potent statins or high doses, and has not been shown to be associated with true hepatotoxicity; because progression to liver failure is exceedingly rare, routine monitoring of ALT during statin treatment is no longer recommended, while Table 13 keeps the ALT check before treatment and once 8–12 weeks after starting or a dose increase.^[1]
• Interactions (ESC/EAS 2019): all currently available statins except pravastatin, rosuvastatin and pitavastatin undergo major hepatic metabolism through cytochrome P450 enzymes.^[1]
• Ezetimibe (ACC/AHA 2026 Table 25): typically well tolerated; not recommended in moderate or severe hepatic impairment; persistent transaminase elevations (above 3 times ULN) can occur when it is added to a statin; the table advises monitoring hepatic transaminase levels before and after starting statin with ezetimibe combination therapy.^[3]
• PCSK9 monoclonal antibodies: ACC/AHA 2026 lists injection-site reactions as the common side effect and rare hypersensitivity reactions; ESC/EAS 2019 lists itching at the injection site and flu-like symptoms among the most frequently reported side effects.^[3][1]
• Bempedoic acid: ACC/AHA 2026 reports elevated blood urea nitrogen, creatinine and uric acid, with urate monitoring needed in preexisting untreated hyperuricaemia; in CLEAR Outcomes, gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%) were more frequent than with placebo.^[3][9]
• Inclisiran (ACC/AHA 2026 Table 25): injection-site reactions are the common side effect; hypersensitivity reactions are rare.^[3]

Pitfalls examiners use

• Recalculating SCORE2 on treatment: the 2025 ESC/EAS update says SCORE2 and SCORE2-OP should not be used to re-assess risk with lipid values obtained after starting guideline-recommended therapy.^[2]
• Trusting a Friedewald LDL-C when it is very low or TG is high: ACC/AHA 2026 says the equation is prone to inaccuracies as TG rises and as LDL-C and non-HDL-C fall.^[3]
• Expecting a statin to treat Lp(a): the 2025 ESC/EAS update reports no effect of statins on Lp(a) in pooled trial data.^[2]
• Quoting one Lp(a) threshold for everyone: ESC/EAS 2025 uses above 50 mg/dL (105 nmol/L), while ACC/AHA 2026 uses 125 nmol/L or 50 mg/dL.^[2][3]
• Treating inclisiran as an outcome-proven drug: the 2025 ESC/EAS update says its two outcome trials are ongoing and expected to report in 2026 and 2027.^[2]

Prognosis and follow-up

The CTT meta-analysis (Lancet 2010) found that each 1.0 mmol/L reduction in LDL-C reduced the annual rate of major vascular events by just over a fifth.^[11][1] Across all 26 CTT trials, all-cause mortality fell by 10% per 1.0 mmol/L LDL-C reduction, with no significant effect on cancer deaths or other non-vascular deaths, even at low LDL-C.^[11][1] ACC/AHA 2026 reports that even when baseline LDL-C was below 2 mmol/L (77 mg/dL), a further 1 mmol/L reduction was associated with a 21% reduction in ASCVD risk.^[3]

• Follow-up: ACC/AHA 2026 says clinicians should perform a lipid profile 4 to 12 weeks after initiation or dose adjustment and every 6 to 12 months thereafter to assess efficacy and adherence (COR 1, LOE A); ESC/EAS 2019 Table 13 advises 8 (±4) weeks after starting treatment, 8 (±4) weeks after each adjustment until the goal is achieved, and annually once at target.^[3][1]

Special populations

Older adults

^{[1] [3]}

Chronic kidney disease

^{[1] [3]}

Pregnancy and lactation

The two bodies differ in emphasis, so state each separately. ESC/EAS 2019 says lipid-lowering drugs should not be given when pregnancy is planned, during pregnancy or while breastfeeding, although bile acid sequestrants and/or LDL apheresis may be considered in severe FH.^[1]

• ACC/AHA 2026: people of childbearing age with hypercholesterolaemia who are not at high ASCVD risk and plan pregnancy should stop statin therapy 1 to 2 months before attempting to become pregnant or as soon as pregnancy is discovered, to avoid uncertain risks to the fetus (COR 1, LOE C-LD).^[3]
• ACC/AHA 2026: in pregnant or lactating individuals with hypercholesterolaemia but without hypertriglyceridaemia, bile acid sequestrants are reasonable to lower LDL-C (COR 2a, LOE C-EO).^[3]
• ACC/AHA 2026: in pregnant individuals with FH or a history of clinical ASCVD, continuing a statin to lower LDL-C and ASCVD risk may be reasonable after an individualised benefit-risk discussion (COR 2b, LOE C-LD); its footnote says a hydrophilic statin such as pravastatin should be considered if the benefit of continued statin therapy is judged greater than the potential risk, based on results from available clinical trials.^[3]
• ACC/AHA 2026 Table 20: avoid ezetimibe in pregnancy because of insufficient data regarding risk to the fetus, and avoid it during lactation; the guideline also notes that the US Food and Drug Administration has removed pregnancy as a contraindication to statin therapy.^[3]

Evidence, guidelines and regional differences

• The current documents are the 2019 ESC/EAS guideline with its 2025 focused update, whose new recommendations add to and whose changed recommendations replace the 2019 ones, and the 2026 ACC/AHA multisociety guideline, which retires and replaces the 2018 cholesterol guideline.^[2][3]

^{[1] [11] [6] [7] [8] [9] [10]}

Where the guidelines differ

^{[2] [3] [5] [1] [4]}

Exam pearls

References11ShowHide

1. [1]Mach F, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J, 2020.PMID 31504418
2. [2]Mach F, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J, 2025.PMID 40878289
3. [3]Blumenthal RS, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2026.PMID 41824590
4. [4]Brieger DB, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian Clinical Guideline for Diagnosing and Managing Acute Coronary Syndromes 2025. Med J Aust, 2026.PMID 41693087
5. [5]Nelson MR, et al. 2023 Australian guideline for assessing and managing cardiovascular disease risk. Med J Aust, 2024.PMID 38623719
6. [6]Cannon CP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med, 2015.PMID 26039521
7. [7]Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med, 2017.PMID 28304224
8. [8]Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med, 2018.PMID 30403574
9. [9]Nissen SE, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med, 2023.PMID 36876740
10. [10]Ray KK, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med, 2020.PMID 32187462
11. [11]Baigent C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet, 2010.PMID 21067804