Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease

INTRODUCTION — 

Patients with atherosclerotic cardiovascular disease (ASCVD) are at high risk for future ASCVD events. Therapy to reduce the risk of subsequent ASCVD events in patients with ASCVD is referred to as secondary prevention. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

This topic will review our treatment approach to lowering low-density lipoprotein cholesterol (LDL-C) for secondary ASCVD prevention and supporting evidence.

Related topics include:

●Other aspects of secondary prevention. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

●Primary prevention applies to patients without ASCVD. Although some individuals without ASCVD have risk factors that result in a 10-year risk of ASCVD events of more than 20 percent, which approaches event rates in those with established ASCVD, primary prevention recommendations apply. The approach to primary prevention of ASCVD is discussed in detail separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

●Familial hypercholesterolemia. (See "Familial hypercholesterolemia in adults: Treatment".)

●LDL-C lowering after an acute coronary syndrome. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".)

IDENTIFICATION OF ASCVD — 

Patients with established ASCVD have clinical ASCVD and/or unequivocal imaging evidence of ASCVD [1,2]. This includes patients with one or more of the following conditions:

●Coronary artery disease (including stable angina or prior acute coronary syndrome, myocardial infarction [MI], or coronary revascularization). (See "Chronic coronary syndrome: Overview of care" and "Acute coronary syndrome: Terminology and classification".)

●Ischemic stroke or transient ischemic attack of atherosclerotic origin. (See "Pathophysiology of ischemic stroke".)

●Atherosclerotic aortic or peripheral arterial disease. (See "Epidemiology, risk factors, pathogenesis, and natural history of thoracic aortic aneurysm and dissection" and "Overview of abdominal aortic aneurysm" and "Overview of lower extremity peripheral artery disease".)

●Imaging evidence of atherosclerotic disease, including incidentally noted obstructive (≥50 percent) coronary or carotid atherosclerotic plaque on diagnostic imaging. (See "Approach to the patient with suspected angina pectoris" and "Evaluation of carotid artery stenosis".)

In studies of ASCVD risk and outcomes, ASCVD is commonly defined to include a subset of the above conditions, such as cardiovascular death, MI, and ischemic stroke.

BASELINE LABORATORY TESTS — 

In patients with ASCVD, we obtain baseline laboratory tests to assess lipid levels and baseline tests for statin therapy (since such therapy is indicated in all patients with ASCVD).

●Lipid levels – We measure serum total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride levels. Measurement methods are discussed in detail separately. (See "Measurement of blood lipids and lipoproteins", section on 'LDL cholesterol'.)

Management of hypertriglyceridemia in patients with ASCVD is discussed separately. (See "Hypertriglyceridemia in adults: Management".)

●Baseline tests for statin therapy – Baseline tests prior to starting statin therapy include serum creatine kinase, serum aminotransferase levels (alanine aminotransferase and aspartate aminotransferase), and thyroid stimulating hormone level. (See "Statins: Actions, side effects, and administration".)

GENERAL APPROACH — 

(algorithm 1)

Key components of therapy — We treat all patients with known ASCVD with counseling to promote proven lifestyle interventions, evidence-based management of major nonlipid ASCVD risk factors (including hypertension and diabetes mellitus) and lipid-lowering therapy (usually with a high-intensity statin), irrespective of baseline LDL-C [3]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

Lifestyle modification — In all adults, the following lifestyle modifications are important for reducing ASCVD risk and optimizing overall health and should be pursued apart from whether they reduce LDL-C, as discussed separately (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Lifestyle modifications'):

●Physical activity – The role of physical activity in reducing ASCVD risk is discussed separately. One of the benefits of exercise is that it can improve an individual’s lipid profile by reducing serum triglycerides and increasing serum high-density lipoprotein (HDL) cholesterol, and may modestly lower LDL-C. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Effects of exercise on lipoproteins and hemostatic factors", section on 'Influence of exercise on lipids and lipoproteins'.)

●Healthy diet – The components of a healthy diet are discussed separately. (See "Healthy diet in adults".)

Dietary modifications can reduce ASCVD risk through reduction of LDL-C, reduction of blood pressure, and reduction of body weight. In patients with high LDL-C, we obtain a dietary history to identify specific patterns that can raise LDL-C (eg, ketogenic or paleolithic diets). If the patient is on such a diet, we counsel the patient to alter their diet to one that is more heart healthy, as discussed separately. (See "Lipid management with diet or dietary supplements".)

●Healthy weight – For patients with a body mass index in the overweight or obesity range, management includes counseling on weight loss goals, diet and exercise, and other treatments, as discussed separately. (See "Obesity in adults: Overview of management".)

●Smoking cessation – This is a key intervention to reduce ASCVD risk for current smokers, as discussed separately. (See "Overview of smoking cessation management in adults".)

LDL-C lowering rationale — A key intervention for secondary ASCVD prevention is treatment to lower elevated levels of LDL-C since LDL-C plays a key role in the pathogenesis of ASCVD. LDL-C lowering can reduce the risk of ASCVD events and in some populations can reduce the risk of all-cause mortality. (See "Pathogenesis of atherosclerosis", section on 'Dyslipidemia'.)

Regardless of a person’s baseline ASCVD risk and LDL-C baseline levels, most therapies that lower LDL-C lead to a clinically important reduction in the risk of ASCVD events, including MI and ischemic stroke [4]. Therefore, regardless of their baseline LDL-C, individuals with ASCVD should be treated with lipid-lowering therapy, as described below. (See 'Initial drug therapy to reduce LDL-C' below and 'Subsequent LDL management' below.)

INITIAL DRUG THERAPY TO REDUCE LDL-C — 

(algorithm 1)

Initial therapy — For all individuals with ASCVD, we recommend lifelong high-intensity statin therapy (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg) (table 1) rather than moderate-intensity statin [5-9]. For most patients, we use the highest approved dose. High-intensity statin therapy achieves an average of 50 percent LDL-C lowering [10,11]. (See 'Rationale for high-intensity statin therapy' below and "Statins: Actions, side effects, and administration".)

For patients who do not tolerate the highest approved doses, the maximally tolerated dose of a statin should be used. Management of statin intolerance is discussed below. (See 'Managing statin intolerance' below.)

Dose adjustment in older adults and in those with chronic kidney disease is discussed below. (See 'Older patients (age >75 years)' below and 'Chronic kidney disease' below.)

Management of drug-drug interactions is discussed separately. (See 'Chronic kidney disease' below and "Statins: Actions, side effects, and administration", section on 'Drug interactions'.)

For LDL-C <170 mg/dL — For most patients with serum LDL-C<170 mg/dL (4.4 mmol/L), we start with statin monotherapy, as described above. (See 'Initial therapy' above.)

For LDL-C ≥170 mg/dL — Patients with serum LDL-C ≥170 mg/dL (4.4 mmol/L) are likely to require combination therapy of a high-intensity statin plus another lipid-lowering agent (eg, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor, or bempedoic acid) to reach their treatment goal. High-intensity statins alone achieve an average 50 percent LDL-C lowering. Therefore, high-intensity statin monotherapy is unlikely to sufficiently lower LDL-C in patients with levels ≥170 mg/dL (4.4 mmol/L) to attain a goal of either <55 mg/dL (1.3 mmol/L) for patients with ASCVD with conditions associated with largest benefit from intensification of LDL lowering or <70 mg/dL (1.8 mmol/L) for other patients with ASCVD. (See 'LDL-C goal' below.)

Combination therapy can be achieved by first starting with a statin and adding an additional agent at a later time or by starting with a statin plus a second agent [12]. We most often prescribe the statin first and then add the second agent in the event a side effect occurs and a change in drug regimen is needed. However, the approach is individualized based upon the patient’s LDL-C level and their ASCVD risk. (See 'Role of combination therapy' below and 'Patients not at goal LDL-C' below.)

Of note, an untreated LDL-C level of ≥190 mg/dL (4.9 mmol/L) is among the clinical features that suggest familial hypercholesterolemia, which is an indication for intensive lipid lowering. Diagnosis and management of familial hypercholesterolemia are discussed separately. (See "Familial hypercholesterolemia in adults: Overview" and "Familial hypercholesterolemia in adults: Treatment".)

Statin efficacy — Statins are preferred as initial treatment for lipid lowering in secondary prevention due to their efficacy for preventing ASCVD events and good safety profile. They have greater LDL-C lowering than ezetimibe and are significantly less costly and easier to use than PCSK9 inhibitors. In addition, they have been used for over 30 years with an excellent safety profile.

In a 2010 meta-analysis of 26 trials (nearly 170,000 patients) of statin therapy, using a wide range of doses and baseline LDL-C levels, there was an approximate 22 percent reduction in the rate of major vascular events per 40 mg/dL (1 mmol/L) decrease in LDL-C [6]. Vascular events included any coronary event, coronary revascularization, or stroke. In the subgroup of patients with prior coronary artery disease, statins reduced vascular events compared with placebo (annual event rate 5.6 versus 4.5; rate ratio [RR] 0.79; 95% CI 0.76-0.82). In patients with noncoronary ASCVD, the risk of vascular events was also reduced (annual event rate 3.7 versus 3.1; RR 0.81; 95% CI 0.71-0.92). In this analysis, an LDL-C reduction of 80 to 120 mg/dL (2 to 3 mmol/L) was associated with a 40 to 50 percent ASCVD relative risk reduction.

Rationale for high-intensity statin therapy — Trials comparing high- versus less-intensity statin therapy have shown the safety and efficacy of a high-intensity statin therapy approach. A meta-analysis of secondary prevention trials showed that high-intensity versus non-high-intensity statin therapy reduced major vascular events and vascular mortality but not all-cause mortality [6]. Two such trials include:

●PROVE-IT – In a trial of people hospitalized for an acute coronary syndrome within the preceding 10 days (ie, patients at very high risk), 4162 participants were randomly assigned to 40 mg of pravastatin daily (standard therapy) or 80 mg of atorvastatin daily (intensive therapy) [13] and followed for a composite outcome of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. Rates of the primary endpoint at two years were lower in the intensive therapy group (26.3 versus 22.4; hazard ratio [HR] 0.84; 16 percent risk reduction; 95% CI 5-26.3).

The median LDL-C level achieved was 95 mg/dL (2.46 mmol/L) in the standard-dose pravastatin group and 62 mg/dL (1.60 mmol/L) in the high-dose atorvastatin group.

The rates of discontinuation of treatment at one and two years because of an adverse event, patient preference, or for other reasons were similar in the two treatment groups (33 versus 30.4 percent at two years).

●TNT – In this trial, 10,001 patients with stable coronary heart disease (ie, patients with predominantly high rather than very high risk) and LDL-C levels of less than 130 mg/dL (3.4 mmol/L) were randomly assigned to either 80 or 10 mg of atorvastatin per day and followed for the occurrence of a first major cardiovascular event, defined as death from coronary heart disease, nonfatal nonprocedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke [14]. After a mean of 4.9 years, the primary composite outcome occurred in fewer patients assigned to 80 versus 10 mg of atorvastatin (8.7 versus 10.9 percent; HR 0.78; 95% CI 0.69-0.89, relative risk reduction 22 percent). There was no difference between the two treatment groups in overall mortality.

The mean achieved LDL-C levels in the 80 mg atorvastatin group was 77 mg/dL (2 mmol/L) versus 101 mg/dL (2.6 mmol/L) in the 10 mg atorvastatin group.

Rates of adverse events related to treatment were higher in the 80 versus 10 mg atorvastatin groups (8.1 versus 5.8 percent). The respective rates of discontinuation were also higher due to treatment-related adverse events (7.2 and 5.3 percent).

Managing statin intolerance

●Intolerance of high-intensity statin therapy – Patients who are unable to tolerate the highest approved dose of high-intensity statin therapy should take the maximum tolerated dose.

In patients with intolerance to a high-intensity statin, we attempt treatment with moderate-intensity statin plus ezetimibe. This approach is supported by the findings of an open-label trial in 3780 patients with ASCVD who were randomly assigned to moderate-intensity statin (rosuvastatin 10 mg) plus ezetimibe (10 mg) or high-intensity statin (rosuvastatin 20 mg) [15]. At each year of follow-up, LDL-C concentrations <70 mg/dL were more frequently observed in patients assigned to combination therapy compared with high-dose statin monotherapy. The three-year composite endpoint of cardiovascular disease, major cardiovascular events, or nonfatal stroke occurred at similar rates in patients treated with combination therapy versus statin monotherapy (9.1 versus 9.9 percent). Discontinuation or dose reduction of the study drug due to statin intolerance that can develop at moderate to high doses were less frequent with combination therapy compared with high-dose statin monotherapy group (4.8 versus 8.2 percent). (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)

●Intolerance of moderate-intensity statin therapy – In patients who do not tolerate one statin at moderate-intensity dose because of unacceptable myopathy, clinicians should try another statin that may be better tolerated or alternative dosing regimens (eg, dosing every other day), such as using low doses of rosuvastatin. Statin intolerance is identified when there are unacceptable statin-associated side effects (eg, unacceptable myalgia) with at least two statin therapies, including one attempt at the lowest daily dose approved by the US Food and Drug Administration and a trial of an alternative dosing regimen. (See "Statin muscle-related adverse events", section on 'Switching statins' and "Statin muscle-related adverse events", section on 'Alternate-day dosing'.)

●Intolerance of any statin therapy – For patients who cannot tolerate any statin therapy, we generally start with ezetimibe monotherapy and then add either bempedoic acid or a PCSK9 inhibitor, depending on how far the patient’s LDL-C level is above goal.

•Ezetimibe – In randomized placebo-controlled trials, ezetimibe 10 mg daily reduced LDL-C by approximately 17 percent [16,17], although the reduction in LDL-C is bimodal with one in eight patients experiencing an average 36 percent reduction in LDL-C. Ezetimibe was well tolerated in clinical trials. Ezetimibe monotherapy [18] (or in combination with a statin [19]) reduces the risk of cardiovascular events, as discussed separately. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)

•Bempedoic acid – Bempedoic acid may be used in statin-intolerant patients who require modest lipid lowering. Bempedoic acid plus ezetimibe therapy reduces LDL-C by approximately 40 percent. Bempedoic acid monotherapy reduces LDL-C by a mean of approximately 20 percent and reduces the risk of cardiovascular events, as discussed separately [20]. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bempedoic acid'.)

However, bempedoic acid use is associated with risk of side effects, including hyperuricemia-induced acute gouty arthritis and cholestasis. We recommend screening for hyperuricemia and gout prior to initiation of bempedoic acid. It is also reasonable to check kidney function after initiation of bempedoic acid.

•PCSK9 inhibitor – PCSK9 inhibitor reduces LDL-C by approximately 60 percent and reduces the risk of ASCVD events, as discussed separately. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

•Bile acid sequestrant – Bile acid sequestrant (eg, colesevelam) is a rarely used alternative agent to lower LDL-C for patients who are statin intolerant if ezetimibe, bempedoic acid, and PCSK9 inhibitors are all not tolerated and/or not available. These agents can lower LDL-C by about 13 to 30 percent [21]. The large size and number (six) of pills needed and gastrointestinal side effects have limited widespread use of bile sequestrants (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bile acid sequestrants'.)

SUBSEQUENT LDL MANAGEMENT — 

(algorithm 2)

Monitoring therapy — We check LDL-C approximately four to six weeks after initiation or change in treatment [22]. LDL-C levels are monitored to determine if the LDL-C goal has been achieved, to evaluate adherence with LDL-C-lowering therapy, and to help motivate patients to remain adherent.

After goal LDL-C has been reached and/or maximal combination therapy has been prescribed, measurement every 12 months is reasonable in patients who seem adherent to lifestyle modifications and pharmacotherapy to evaluate adherence or to comply with reimbursement specifications. More frequent lipid monitoring is reasonable if the patient is at risk for medication nonadherence and/or has comorbidities that require more frequent monitoring, eg, hyperglycemia and monitoring of blood pressure.

LDL-C goal — For patients with ASCVD, the LDL-C treatment goal is based upon whether the patient has one or more characteristics associated with greatest benefit from intensification of LDL-lowering therapy.

Patients with largest benefit from intensified therapy — Patients with one or more of the following conditions have been shown to derive the largest benefit from intensification of LDL-C lowering therapy. The following list is modified from the list in the 2021 Canadian Cardiovascular Society guidelines for management of dyslipidemia for the prevention of cardiovascular disease in adults [2]. For patients with these conditions, we suggest an LDL-C goal of <55 mg/dL (1.4 mmol/L). Aggressive lipid lowering in these patients is expected to yield the largest absolute benefit which will usually outweigh risks and adverse effects of lipid-lowering medications [23]. (See 'Side effects and interactions' below.)

●Recent acute coronary syndrome (ACS; this includes MI and unstable angina)

•Hospitalized ACS to 12 months post-index ACS event

●Clinically evident ASCVD and any of the following:

•Diabetes mellitus

•Polyvascular disease (vascular disease in ≥2 arterial beds)

•Symptomatic peripheral arterial disease

•Recurrent MI

•MI in the past two years

•Previous coronary artery bypass graft surgery

•Heterozygous familial hypercholesterolemia

Management of LDL-C in patients with recent ACS is discussed in detail separately. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".)

Management of LDL-C in patients with familial hypercholesterolemia is discussed separately. (See "Familial hypercholesterolemia in adults: Treatment".)

Other patients with ASCVD — For patients with ASCVD who do not have one of the conditions listed above (see 'Patients with largest benefit from intensified therapy' above), we suggest an LDL-C goal of <70 mg/dL (1.8 mmol/L). Among those included in the high-risk group are patients with chronic stable coronary artery disease with no prior history of MI and no atherosclerosis involving another vascular bed. This includes patients with prior unstable angina occurring more than 12 months prior to the risk assessment.

Evidence on LDL-C targets — Most [24,25], but not all [26], analyses have suggested a continuous log-linear benefit on ASCVD event reduction with LDL-C lowering. As an example, an analysis suggested a reduction in ASCVD outcomes down to levels ≤20 mg/dL in patients treated with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition [27].

While clinical trials have not investigated a specific LDL-C target, trials of PCSK9 inhibitors and ezetimibe have demonstrated that these therapies reduce ASCVD events while achieving a mean LDL-C level below 55 mg/dL (1.4 mmol/L) [28,29]:

●FOURIER trial – In this trial, in patients with established ASCVD on statin therapy, the achieved median LDL-C at 48 weeks was 30 mg/dL (0.78 mmol/L) in the group randomly assigned to evolocumab (a PCSK9 inhibitor) versus 86 mg/dL (2.2 mmol/L) in the placebo arm [29].

PCSK9 inhibitor reduced the composite outcome cardiovascular death, MI, or stroke (annualized incidence per 100 person-years 2.05 versus 2.58; hazard ratio [HR] 0.80, 95% CI 0.68-0.93). PCSK9 inhibitor reduced the risk of MI (3.4 versus 4.6 percent; HR 0.73, 95% CI 0.65-0.82) and of stroke (1.5 versus 1.9 percent; HR 0.79, 95% CI 0.66–0.95) compared with placebo. Death from any cause was similar in the two groups. (3.2 versus 3.1 percent). Cardiovascular death was also similar in the two groups (1.8 versus 1.7 percent). This trial is discussed in detail separately. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Clinical effect'.)

●IMPROVE-IT trial – In this trial, 18,144 patients with recent ACS were randomly assigned to simvastatin plus ezetimibe or simvastatin plus placebo. The achieved LDL-C values were 54 mg/dL (1.4 mmol/L) for the statin plus ezetimibe group versus 69 mg/dL (1.8 mmol/L) for the group assigned to statin monotherapy [28].

The addition of ezetimibe was associated with a reduced risk of the composite outcome of cardiovascular death, major coronary events, or stroke at seven years: 31.9 versus 36 percent (adjusted HR 0.79, 95% CI 0.69-0.91). The addition of ezetimibe reduced the risk of MI (13.1 versus 14.8 percent; HR 0.87, 95% CI 0.80-0.95) and ischemic stroke (3.4 versus 4.1 percent; HR 0.79, 95% CI 0.67-0.94). Death from any cause was similar in the two groups (15.4 versus 15.3 percent), as was cardiovascular death (6.9 versus 6.8 percent). This trial is discussed further separately [28]. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".)

Limited evidence is available on LDL-C targets for secondary ASCVD event prevention:

●Treat Stroke to Target (TST) – The TST trial supports an approach of treating to an LDL-C target <70 mg/dL (1.8 mmol/L) versus a more lenient target. This trial randomly assigned 2680 patients with recent ischemic stroke or transient ischemic attack to a low target LDL-C <70 mg/dL (1.8 mmol/L) or a higher target of 90 to 110 mg/dL (2.3 to 2.8 mmol/L) [30]. Patients were treated with a statin, ezetimibe, or both. After a mean follow-up of 3.5 years, the group assigned to an LDL-C target of <70 mg/dL (1.8 mmol/L) had lower rates of a composite of cardiovascular events (ischemic stroke, MI, urgent coronary or carotid revascularization, or death from cardiovascular causes) compared with those assigned the higher LDL-C target (8.5 versus 10.9 percent; HR 0.78; 95% CI 0.61- 0.98). The rates of individual endpoints trended similarly, though differences were not statistically significant, including cardiovascular death (1.5 versus 2.2; HR 0.69; 95% CI 0.40-1.18) and MI or urgent revascularization (1.4 versus 2.2 percent; HR 0.64; 95% CI 0.37-1.13).

●LODESTAR – The efficacy of a treat-to-target approach was assessed by the LODESTAR trial in which 4400 patients with coronary artery disease were randomly assigned to either an LDL-C target strategy for statin therapy (with an LDL-C target of 50 to 70 mg/dL) or high-intensity statin treatment (which consisted of rosuvastatin 20 mg daily or atorvastatin 40 mg daily) [31].

•The achieved LDL-C in the treat-to-target and high-intensity statin groups were similar (69.1 versus 68.4 mg/dL). The two treatment groups had similar composite outcomes of death, MI, stroke, or coronary revascularization after three years (8.1 versus 8.7 percent) [31].

•One limitation of this study was the relatively low rate of achievement of LDL-C <70 mg/dL in the treat-to-target group, which was similar to the rate in the high-intensity statin group at two and three years (both approximately 60 percent), but lower than the rate in the high-intensity statin group at six weeks and three months.

•More patients in the high-intensity statin group were receiving high-intensity statins at three years compared with those in the treat-to-target group (89 versus 56 percent). Although more patients in the treat-to-target group were on combination therapy with ezetimibe (20 versus 11 percent at three years), the use of this agent was lower than expected given guidelines for treat-to-target therapy.

●Additional support for an LDL-C target <70 mg/dL – Other trials such as PROVE IT, which is described above (see 'Patients with largest benefit from intensified therapy' above), studied two intensities of statin therapy in patients with recent ACS [13]). These studies indirectly support a targeted approach whereby different intensities of statin therapy targeting <70 versus <100 mg/dL were used. More intensive therapy achieving an average LDL-C <70 mg/dL was associated with greater ASCVD risk reduction. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".)

Other approaches — Similar criteria for stratifying LDL-C goals for secondary prevention of ASCVD have been included in major society guidelines, including the 2018 multispecialty guideline on management of cholesterol and the Canadian Cardiovascular Society guidelines [2,10].

The European Society of Cardiology guidelines for CVD prevention recommend using the SMART Risk Score tool (available online and as an app), which estimates 10-year ASCVD risk (MI, stroke, or CVD death) for individuals with stable ASCVD [1,32]. These guidelines also suggest estimation of individual residual lifetime (until 90 years) ASCVD risk and benefit of risk factor treatment in individuals with established ASCVD [1,33].

Managing treatment response and noncompliance — The generally expected response to high-intensity statin monotherapy (or moderate-intensity statin plus ezetimibe) is an approximately 50 percent LDL-C reduction. High-intensity statin plus ezetimibe is expected to lower LDL-C approximately 60 percent [34].

If LDL-C reduction is substantially less than expected, possible intolerance or nonadherence to treatment (lifestyle modification and drug therapy) should be carefully explored prior to considering escalation of therapy. (See 'Role of combination therapy' below.)

Nonadherence to statin therapy is common among patients with ASCVD [35,36]. A pharmacy database in the United States showed that among over 200,000 patients with a recent acute MI, over 20 percent of patients discontinued statin therapy within one year after initiating treatment [35]. A Canadian study of over 58,000 older patients showed that two-year discontinuation rates were even higher for patients >66 years of age with ACS (60 percent) or chronic coronary syndrome (64 percent) [36].

Several strategies to enhance adherence to lipid-lowering therapies have been shown to be effective including educational tools for patients and physicians, pharmacy-based programs to help patients with prescription refills (including reminders and delivery by mail), and use of telemedicine to overcome geographical and transportation barriers [37]. Strategies to address nonadherence are discussed separately. (See "Adherence to lipid-altering medications and recommended lifestyle changes".)

Patients not at goal LDL-C — For patients not at their LDL-C goal after four to six weeks of high-intensity (or maximal tolerated intensity) statin therapy, we suggest addition of a second LDL-C-lowering drug (algorithm 2). Patients with ASCVD with conditions associated with largest benefit from intensification of LDL-C lowering and those with higher LDL-C levels are more likely to benefit from combination therapy. (See 'Role of combination therapy' below.)

The magnitude of LDL-C elevation above goal that triggers additional LDL-C-lowering therapy will vary from patient to patient, depending on an individualized assessment of many factors such as overall cardiovascular risk, likely adherence with a regimen including additional therapy, and comorbidities. Clinicians should consider referring their patient to a lipid specialist if management or decision making has become difficult.

LDL-C ≤25 percent above goal — If a patient on initial LDL-lowering therapy is within 25 percent above their goal LDL-C:

●If taking the maximal tolerated intensity of statin therapy, ezetimibe is added, which can provide approximately 20 percent additional LDL-C lowering.

●If taking the maximal tolerated intensity of statin plus ezetimibe (or ezetimibe alone due to statin intolerance), a PCSK9 inhibitor or bempedoic acid is added.

LDL-C is rechecked after four to six weeks on the new regimen. If the LDL-C remains above goal, options include adding a PCSK9 inhibitor, if not yet taking one. (See 'Role of combination therapy' below.)

LDL-C >25 percent above goal — For patients whose LDL-C is >25 percent above their goal LDL-C after four to six weeks of high-intensity (or maximal tolerated intensity) statin, add a PCSK9 inhibitor. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Clinical effect'.)

After four to six weeks of the new regimen, the clinician can reevaluate the LDL-C value and determine if addition of ezetimibe is needed to achieve the goal in a three-drug regimen.

Refractory high LDL-C — Patients who have not achieved their LDL-C goal using a combination of LDL-lowering agents (statin, ezetimibe, bempedoic acid, or a PCSK9 inhibitor) should be referred to a clinician who specializes in the treatment of complex lipid disorders. (See "Treatment of drug-resistant hypercholesterolemia".)

Role of combination therapy — The clinical evidence supporting the combination of statin plus ezetimibe or statin plus PCSK9 inhibitor is stronger than for the combination of statin plus bempedoic acid:

●Ezetimibe plus statin – This combination causes greater LDL-C lowering and ASCVD event reduction compared with statin therapy alone [19], as discussed separately. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome", section on 'Ezetimibe'.)

•Moderate-intensity statin therapy causes an approximately 40 percent reduction in LDL-C as compared with an approximately 52 percent reduction in LDL-C with moderate-intensity statin plus ezetimibe therapy [34].

•High-intensity statin therapy causes an approximately 50 percent reduction in LDL-C as compared with an approximately 60 percent reduction in LDL-C with high-intensity statin plus ezetimibe therapy [34].

●PCSK9 inhibitor plus statin – PCSK9 inhibitors were generally well tolerated in clinical trials. This combination causes greater LDL-C lowering and ASCVD event reduction compared with statin therapy alone, as discussed separately. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Clinical effect'.)

•Moderate-intensity statin plus PCSK9 inhibitor causes an approximately 76 percent reduction in LDL-C [34]. Moderate-intensity statin plus ezetimibe and PCSK9 inhibitor causes an approximately 81 percent reduction in LDL-C.

•High-intensity statin plus PCSK9 inhibitor causes an approximately 80 percent reduction in LDL-C [34]. High-intensity statin plus ezetimibe and PCSK9 inhibitor causes an approximately 84 percent reduction in LDL-C.

●Bempedoic acid plus statin – The combination of statin plus bempedoic acid causes greater LDL-C lowering than statin therapy alone. Clinical trials have shown that bempedoic acid monotherapy reduces the risk of ASCVD events, but the clinical effect of statin plus bempedoic acid has not been established. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bempedoic acid'.)

•Moderate-intensity statin plus bempedoic acid causes an approximately 50 percent reduction in LDL-C.

•High-intensity statin therapy plus bempedoic acid causes an approximately 60 percent reduction in LDL-C.

●Role of combination tablets – Fixed-dose combination tablets are available to reduce medication burden (cost and inconvenience) for patients who require two or more LDL-C-lowering drugs. These include ezetimibe-simvastatin and bempedoic acid-ezetimibe tablets. However, high-intensity statin therapy cannot be achieved with ezetimibe-simvastatin.

SIDE EFFECTS AND INTERACTIONS — 

Side effects and drug interactions vary among various statins and other lipid-lowering medications (table 2). Management of drug-drug interactions and monitoring for side effects are discussed separately. (See "Statins: Actions, side effects, and administration" and "Statin muscle-related adverse events" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Adverse effects'.)

Serious adverse reactions to LDL-C-lowering therapies are rare. LDL-C lowering is associated with a relatively low incidence of adverse outcomes (eg, muscle symptoms and new-onset diabetes with statins) [6,38]. The adverse effects of statins are discussed in detail separately. (See "Statins: Actions, side effects, and administration" and "Statin muscle-related adverse events".)

While there are theoretical concerns about lowering LDL-C to levels that are uncommonly seen in untreated individuals, the preponderance of evidence suggests that doing so is not associated with adverse effects over a 5- to 10-year period.

The safety of low LDL-C <30 mg/dL (0.78 mmol/L) has been assessed in multiple trials studying high-intensity statin and combination therapies of ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor with statin. In each of these trials, there was no increase in side effects or adverse effects, and adjusted rates of cardiovascular disease events were lower in the more intensive versus less intensive therapy groups. Relevant findings are summarized as follows:

●In a prespecified analysis of the IMPROVE-IT trial, patients achieving an LDL-C less than 30 mg/dL (0.78 mmol/L) at one month had a similar safety profile over six years, compared with patients achieving higher LDL-C concentrations [28]. Safety events studied included muscle, hepatobiliary, and neurocognitive events; hemorrhagic stroke; heart failure; cancer; and noncardiovascular death.

●In trials of PCSK9 inhibitors, patients had achieved levels of LDL-C of 30 and 40 mg/dL, and no increase in adverse effects were seen in the randomized groups versus placebo. Furthermore, an analysis of achieved LDL-C found no increase in adverse events even down to LDL-C levels <20 mg/dL [27,39].

●There is no evidence of adverse effects of very low LDL-C values (but these lower values are associated with lower cardiovascular event rates) [40]. A study of over 3000 patients taking alirocumab found that individuals with on-therapy LDL-C levels of <25 mg/dL did not have an increased rate of adverse events compared with those with higher LDL-C levels during a median drug exposure of about 1.5 years [41].

In addition, patients with total deficiency of PCSK9 (due to pathogenic variants) with LDL-C levels in the range of 15 mg/dL (0.39 mmol/L) are described in case reports. These patients do not appear to have any adverse clinical effects from these extremely low LDL-C levels [42]. Thus, no safety issue (but lower cardiovascular event rates) has been seen with very low LDL-C values. (See "Low LDL-cholesterol: Etiologies and approach to evaluation", section on 'Other genetic conditions'.)

SPECIAL POPULATIONS

Older patients (age >75 years) — The benefit from LDL-C-lowering therapy on ASCVD secondary prevention extends to healthy individuals 75 years of age or older, and the prevalence of side effects is relatively low. Absolute ASCVD risk is higher in older adults, and the absolute ASCVD risk reduction with LDL-C-lowering therapy is greater in older adults. Therefore, we generally take the same approach to LDL-C lowering for older compared with younger patients.

However, older people often have multiple comorbidities and take multiple medications, making them more vulnerable to adverse events. Therefore, shared decision-making is important prior to initiating therapy given the benefits versus risks of LDL-C-lowering therapy. Consideration of potential drug-drug interactions and patient preferences are important. (See "Drug prescribing for older adults", section on 'Drug-drug interactions' and "Statins: Actions, side effects, and administration", section on 'Drug interactions'.)

●Statins – Use of high-intensity statin in older adults is based on the comparable relative event reduction shown in randomized trials comparing older and younger individuals presenting with an acute coronary syndrome (ACS) or other ASCVD (such as stable coronary artery disease). Although fewer patients >75 years of age were enrolled in statin clinical trials, a benefit of statin therapy has been identified in the subgroup of adults >75 years old [6]. Absolute ASCVD risk is much higher in older individuals, so the number of events potentially prevented by LDL-C lowering is greater than for younger individuals.

Several randomized studies have evaluated older individuals, including those >75 years of age, and have shown that statins are generally safe in older people, although the risk of myopathy and rhabdomyolysis may be higher than in younger adults [43]. Statin-related myopathy and rhabdomyolysis are rare conditions. (See "Statin muscle-related adverse events" and "Statins: Actions, side effects, and administration", section on 'Side effects'.)

Some experts initiate statin therapy in older individuals with a moderate- rather than high-intensity statin based on concern for a greater likelihood of side effects from age-related hepatic and kidney dysfunction (table 1). For older individuals not started on high-intensity statin, a reasonable approach is to uptitrate or switch to high-intensity statin within three months if the patient tolerates a moderate dose.

●Ezetimibe – A substantially greater absolute benefit from adding ezetimibe was seen in those >75 years of age compared with those <75 years old in the IMPROVE IT trial in patients with recent ACS [44]. The absolute benefit over six-year follow-up was 8.7 versus 0.9 percent, respectively. The EWTOPIA 75 ASCVD primary prevention trial in patients >75 years also identified benefit of ezetimibe in this age group [18].

●PCSK9 inhibitor – Older patients with ASCVD appear to benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In an analysis of 27,564 patients with ASCVD enrolled in the FOURIER trial, earlier initiation of evolocumab reduced the rate of the primary composite endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for stable angina, or coronary revascularization) in patients ≥75 years of age (hazard ratio [HR] 0.79; 95% CI 0.64-0.97) [45]. An analysis of the ODYSSEY OUTCOMES trial showed similar findings with alirocumab [46]. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome", section on 'PCSK9 inhibitors'.)

Chronic kidney disease — For most patients with CVD and chronic kidney disease (CKD), including stage 4 or 5 disease (table 3), we attempt to lower the LDL-C with statin therapy.

●End-stage kidney disease patients on dialysis – This is discussed in detail separately. (See "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)", section on 'Lipid modification'.)

●Patients receiving a transplanted kidney – Kidney transplant recipients with established ASCVD should receive maximal tolerated intensity statin therapy, similar to nontransplant patients with established ASCVD, as discussed separately. (See "Lipid abnormalities after kidney transplantation".)

●Nondialysis patients with chronic kidney disease – For patient with CKD who are not on dialysis, and with known ASCVD, our approach to LDL-C lowering is similar to that in the general population, with some caveats. When statin therapy is chosen, maximal-dose atorvastatin is preferred for most of these patients, as atorvastatin is not dependent on kidney function for its metabolism and excretion. With other statins, we use a low to moderate dose because there is some level of kidney excretion. (See "Lipid management in patients with nondialysis chronic kidney disease", section on 'Secondary prevention: Patients with CKD and established atherosclerotic cardiovascular disease'.)

•Ezetimibe – In patients with CKD, no dose adjustment is needed.

•Bempedoic acid – No dose adjustment is needed for patients with CKD. Bempedoic acid use may worsen kidney function in some patients.

•Use of PCSK9 inhibitors – Subgroup analyses of large, randomized trials show that this class of drugs is both effective and safe in patients with ≥stage 3 CKD [47,48]. This is described in detail separately. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Renal impairment'.)

Data in patients with higher stages of CKD (ie, lower estimated glomerular filtration rate) are scant. Although the FOURIER trial of PCSK9 inhibitors included 208 patients with stage 4 CKD [48], the study was not sufficiently powered to draw firm conclusions in the subgroup of patients with stage 4 and 5 CKD. Thus, the role of PCSK9 in the management of lipids and cardiovascular diseases or risks in ≥stage 4 CKD is unclear.

In the FOURIER trial, the absolute reduction in cardiovascular events with evolocumab therapy was greater with more advanced CKD [48] Absolute risk reductions at 30 days for the secondary endpoint (composite of cardiovascular death, MI, or stroke) were -2.5 percent (95% CI -0.4 to -4.7 percent) for ≥stage 3 CKD compared with -1.7 percent (95% CI 0.5 to -2.8 percent) with preserved kidney function. There were no differences in the primary endpoint (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) for patients with advanced kidney disease versus preserved renal function.

Pregnancy and lactation — We do not start or continue statin therapy during pregnancy or if the patient is lactating [49].

If a patient is on a statin and becomes pregnant or is breastfeeding, we recommend stopping the statin. We do not counsel termination of the pregnancy. Statins may not be uniformly teratogenic; however, few interventional studies have been conducted and data are somewhat mixed. The United States Food and Drug Administration has updated statin labels to note the safety of stopping the statin as soon as pregnancy is found.

●A meta-analysis of nine studies (two clinical trials and seven observational studies) found that among those taking statin therapy in pregnancy, the following was observed [50]:

•Increased rates of spontaneous abortion in 8422 participants (odds ratio [OR] 1.36, 95% CI 1.10-1.68)

•No increase in odds of stillbirth in 2350 participants (OR 1.30, 95% CI 1.30 0.56-3.02)

•Trend towards increased odds of induced abortion in 8422 participants (OR 2.08, 95% CI 0.81-5.36)

•Trend towards reduced rate of preterm delivery in 483 participants (OR 0.47, 95% CI 0.06-3.70)

●In a nested case-control study of 1.4 million pregnant patients in Taiwan, the perinatal outcomes of 469 patients on statins during pregnancy were compared with 4690 controls [51]. Statin use was not associated with congenital defects but was associated with increased risk of preterm labor, low birth weight, and lower Apgar score (preterm risk ratio [RR] 1.51, 95% CI 1.05-2.16; low birth weight RR 1.99, 95% CI 1.46-2.71; lower one-minute Apgar score RR 1.83, 95% CI 1.04-3.20).

More prospective clinical trial safety data are needed before we can safely advocate the use of statins in pregnant people with ASCVD.

We do not use ezetimibe in pregnant people, as it has not been extensively studied in pregnancy and therefore may have risks associated with its use. No data are available about use of PCSK9 inhibitors in pregnancy.

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: High cholesterol and lipid treatment options (Beyond the Basics)")

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults" and "Society guideline links: Secondary prevention of cardiovascular disease".)

SUMMARY AND RECOMMENDATIONS

●Rationale – Patients with atherosclerotic cardiovascular disease (ASCVD) are at high risk for ASCVD events. Treatment to lower low-density lipoprotein cholesterol (LDL-C) is a key measure for secondary prevention of ASCVD events. (See 'LDL-C lowering rationale' above.)

●Initial management (algorithm 1)

•Lifestyle modification – We counsel all patients with ASCVD to undertake lifestyle interventions associated with improved clinical outcomes. (See 'General approach' above.)

•Statin therapy – For patients with ASCVD, we recommend lifelong high-intensity statin therapy (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg) rather than moderate-intensity statin (Grade 1B). Patients with LDL-C ≥170 mg/dL are candidates for early combination LDL-lowering therapy. (See 'Initial therapy' above and 'For LDL-C ≥170 mg/dL' above and 'Role of combination therapy' above.)

•Statin intolerance – For patients who do not tolerate high-intensity statin, the maximally tolerated dose of a statin should be used. Moderate-intensity statin plus ezetimibe is an alternative for patients with ASCVD who do not tolerate a high-intensity statin. (See 'Managing statin intolerance' above.)

For patients with ASCVD who do not tolerate any statin regimen, we generally start with ezetimibe monotherapy and then add either bempedoic acid or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, depending on how far the patient’s LDL-C level is above goal.

●Subsequent management (algorithm 2)

•Goal LDL-C – The goal LDL-C is selected based upon whether or not the patient has any of the conditions associated with largest benefit from intensification of statin therapy. (See 'Patients with largest benefit from intensified therapy' above.)

-For patients with ASCVD with one or more conditions associated with largest benefit from intensification of statin therapy, we suggest an LDL-C goal of <55 mg/dL (1.4 mmol/L). (See 'Patients with largest benefit from intensified therapy' above.)

-For other patients with ASCVD, we suggest an LDL-C goal of <70 mg/dL (1.8 mmol/L). (See 'Other patients with ASCVD' above.)

•Monitoring therapy – We check LDL-C approximately four to six weeks after initiation or change in treatment. If the degree of LDL-C reduction is less than expected, statin adherence and tolerance should be explored. (See 'Monitoring therapy' above.)

•Safety – LDL-C lowering, including to lower values that are rarely seen in the general population, has been associated with few to no significant adverse outcomes. (See 'Side effects and interactions' above.)

●Patients not at LDL-C goal with initial therapy – For patients not at their LDL-C goal after four to six weeks of adherence to high-intensity (or maximal tolerated) statin therapy, we suggest addition of a second LDL-C-lowering drug (Grade 2B) (algorithm 2). Patients with conditions associated with largest benefit from intensification of LDL-C lowering and those with higher LDL-C levels are more likely to benefit from combination therapy. (See 'Patients not at goal LDL-C' above.)

•LDL-C ≤25 percent above goal – If a patient is ≤25 percent above their goal LDL-C on maximal tolerated statin therapy, ezetimibe is added, and the level is rechecked after four to six weeks to confirm if the goal has been achieved. If the LDL-C remains above goal, options include adding a PCSK9 inhibitor. (See 'Role of combination therapy' above.)

•LDL-C >25 percent above goal – For patients whose LDL-C remains >25 percent above their goal on statin therapy, a PCSK9 inhibitor is added. Recheck LDL-C four to six weeks after adding the second agent, and if not at goal, consider adding a third agent (eg, ezetimibe). (See 'LDL-C >25 percent above goal' above.)

●Refractory high LDL-C – Patients who have not achieved their LDL-C goal using statin therapy (as tolerated) plus ezetimibe, bempedoic, and/or a PCSK9 inhibitor should be referred to a clinician who specializes in the treatment of complex lipid disorders. (See "Treatment of drug-resistant hypercholesterolemia".)

●Special populations – The approach to LDL-C lowering differs during pregnancy and lactation and in individuals with chronic kidney disease (CKD). (See 'Special populations' above.)