INTRODUCTION — The management of the risk factors for atherosclerotic cardiovascular disease (CVD), of which elevated low density lipoprotein cholesterol (LDL-C) is one, is called primary prevention if this process is done in someone who has not previously experienced an atherosclerotic vascular event. The rationale for activities focused on LDL-C reduction is based upon epidemiologic data documenting a continuous, positive, graded relationship between LDL-C concentration and CVD events and mortality and evidence that lowering of LDL-C in patients across a broad range of LDL-C levels reduces the risk in patients with and without CVD [1-4]. (See "Overview of established risk factors for cardiovascular disease".)

Patients without known CVD are generally at much lower baseline risk of cardiovascular events than patients with known CVD. The decision as to whether LDL-C treatment should be recommended depends on a determination of global CVD risk, as the potential absolute risk reduction with treatment for hypercholesterolemia will usually be smaller than for patients with established CVD.

For the purpose of risk reduction in patients without manifest CVD, only management of an elevated LDL-C has been shown to be of clinical benefit. Management of elevated triglycerides or low high density lipoprotein cholesterol has not. (See "Hypertriglyceridemia in adults: Management", section on 'Summary and recommendations' and "HDL cholesterol: Clinical aspects of abnormal values", section on 'Summary and recommendations'.)

This topic reviews the evidence for treating patients with increased CVD risk due to elevated LDL-C but no known CVD or CVD equivalents. The management of patients with established disease is discussed separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

RATIONALE FOR LDL-C LOWERING IN PRIMARY PREVENTION — The preponderance of evidence from randomized trials that have evaluated the impact of LDL-C lowering (or the surrogate of total cholesterol) have demonstrated a reduction in cardiovascular disease events, irrespective of the pre-therapy LDL-C level. Among these events, it is the risk of myocardial infarction that is reduced the most.

Three very early trials of lipid altering therapy evaluated clofibrate [5,6], cholestyramine [7], or gemfibrozil [8]. They found no difference in coronary mortality and an increase in non-cardiovascular disease mortality (with the exception of cholestyramine). In contrast to the results seen with these early trials of non-statin lipid modifying agents, many large randomized trials of statin therapy have demonstrated reductions in myocardial infarction and cardiovascular mortality; no evidence of an increase in non-cardiovascular mortality has been seen. The following are representative studies:

●The West of Scotland Coronary Prevention Study (WOSCOPS) showed that cholesterol lowering with pravastatin (40 mg daily) for five years reduced both the number of nonfatal myocardial infarctions and coronary heart disease (CHD) mortality in middle-aged men with a serum LDL-C concentration above 155 mg/dL (4.0 mmol/L) (figure 1) [9]. LDL-C fell 26 percent from 192 to 142 mg/dL (5.0 to 3.7 mmol/L).There was a borderline (p = 0.051) 22 percent reduction in all-cause mortality. Extended follow-up of the trial examining outcomes 10, 15, and 20 years after the trial concluded found continued reductions in mortality in patients who had initially been assigned to receive pravastatin [10-13].

●The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) found that lovastatin (20 to 40 mg daily), which reduced the serum LDL-C concentration by 25 percent, reduced the incidence of a first major coronary event (unstable angina pectoris, fatal and nonfatal myocardial infarction, and sudden cardiac death) in low-risk men and women without clinical evidence of cardiovascular disease (CVD) and LDL-C levels near the average for the general population (150 mg/dL [3.9 mmol/L], range 130 to 190 mg/dL [3.4 to 4.9 mmol/L]) [14]. For every 1000 men and women treated with lovastatin for five years, 19 major coronary events, 12 myocardial infarctions, and 17 coronary revascularizations could be prevented. No effect was seen on all-cause mortality.

●The JUPITER trial of rosuvastatin 20 mg daily in healthy adult men and women with a C-reactive protein ≥2 mg/L and LDL-C levels below 130 mg/dL (3.4 mmol/L) found a marked reduction in the primary end point of first major cardiovascular events and all-cause mortality (HRs 0.56 and 0.80, respectively) [15]. The absolute benefit for the primary end point was 0.59 events per 100 person-years and for all-cause mortality was 0.25 deaths per 100 person-years. In JUPITER, the final LDL-C was 55 mg/dL (1.4 mmol/L) in the rosuvastatin group and 110 mg/dL (2.8 mmol/L) in the placebo group. This trial was stopped early for benefit, which may exaggerate the true level of benefit, particularly for the primary end point [16].

●In the HOPE-3 trial, 12,705 patients with at least one CVD risk factor were randomly assigned to rosuvastatin 10 mg or placebo daily [17]. The mean baseline LDL-C was about 128 mg/dL (3.3 mmol/L). The on-treatment LDL-C at one year was 39.6 mg/dL lower (1.02 mmol/L) in the rosuvastatin group. The primary composite outcome (death from CVD, nonfatal myocardial infarction, or nonfatal stroke) occurred less often with statin therapy (3.7 versus 4.8 percent; hazard ratio 0.76, 95% CI 0.64-0.91).

Multiple meta-analyses of clinical trials of LDL-C lowering therapy in patients with and without manifest CVD have been performed [18-20]. They have all found strong evidence of reductions in CVD events and CVD mortality [21]. Other meta-analyses have also found a reduction in the risk of all-cause mortality. In terms of individual components, all have found important reductions in myocardial infarction and in CHD mortality; reductions in stroke are somewhat smaller in magnitude but also clinically important [21].

A 2016 meta-analysis evaluated outcomes in over 300,000 individuals at a broad range of risk in 49 trials. The mean baseline LDL-C was 122 mg/dL (3.15 mmol/L). The following were found [22]:

●The relative risk for the end point of major vascular events (a composite of cardiovascular death, acute coronary syndrome, coronary revascularization, or stoke) per 38.7 mg/dL (1-mmol/L) reduction in LDL-C was 0.77 (95% CI 0.71-0.84) for statins and 0.75 (95% CI 0.66-0.86) for non-statin therapies.

●Among primary prevention trials (n = 8), the post-treatment LDL-C was positively correlated with CVD events, meaning that lower post-treatment LDLs were correlated with lower event rates and higher post-treatment LDL levels were correlated with higher event rates.

The most complete meta-analyses of primary prevention trials found a reduction in all-cause mortality benefit (relative risk 0.91) [18,19]. This relative reduction translated to a small absolute reduction in deaths of 0.09 percent per year (1.33 versus 1.42 percent per year) [18].

Taken together, the evidence demonstrates that lowering LDL-C with statin therapy for primary prevention is effective at reducing CVD events (mostly myocardial infarction) over a wide range of baseline LDL-C levels and lipid profiles, and produces a similar relative risk reduction to statin therapy in secondary prevention but a lower absolute reduction. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

LIFESTYLE MODIFICATION — It is reasonable to recommend that all patients, particularly those with high LDL-C, undergo lifestyle modifications such as weight loss in overweight patients, aerobic exercise, and eating diets lower in saturated fats (See "Healthy diet in adults".) The United Kingdom Lipid Clinics Programme study of 2508 subjects found that, with diet alone, 60 percent of subjects had a mean reduction in body weight of 1.8 percent, which was associated with 5 to 7 percent reductions in serum total and LDL-C [23]. In occasional patients with poor baseline diets, marked dietary change can lower LDL-C by as much as 30 percent [24]. (See "Lipid management with diet or dietary supplements".)

A study randomly assigned 180 postmenopausal women and 197 men with low levels of high-density lipoprotein cholesterol (HDL-C) and moderately-elevated levels of LDL-C to aerobic exercise, diet, diet plus exercise, or no treatment [25]. Although there were no significant changes in HDL-C in any group, there were significant reductions in LDL-C in both men and women (14.5 and 20 mg/dL [0.38 and 0.52 mmol/L], respectively) in the diet plus exercise group compared with control or diet alone and, in men, in the diet plus exercise group compared with exercise alone.

The individual response to a cholesterol-lowering diet depends upon many factors; some of the response is genetically determined, and increased body mass index is associated with less response to dietary change [26]. Patients who are referred to a dietitian may have greater success in the short term with lowering LDL-C compared with patients who receive dietary counseling by clinicians, although long-term compliance with dietary therapy is inadequate for both groups [27,28].

Despite these benefits on LDL-C in primary prevention, there is limited evidence that lifestyle modifications improve cardiovascular outcomes. In the Multiple Risk Factor Intervention Trial (MRFIT) in 12,866 high-risk men, an intervention that included dietary advice to reduce cholesterol levels did not significantly reduce coronary heart disease mortality (1.8 versus 1.9 percent) or all-cause mortality (4.1 versus 4.0 percent) [29]. However, the differences in achieved total cholesterol levels between the groups (generally 5 to 10 mg/dL [0.13 to 0.26 mmol/L]) were probably too small to expect significant effects on mortality.

INDICATIONS — Our approach (presented later in this section) to deciding when statin therapy should be recommended or offered to patients with an LDL-C >100 mg/dL (>2.59 mmol/L) is guided by assessment of cardiovascular disease risk (algorithm 1). (Related Pathway(s): Lipids: Management of LDL cholesterol for primary prevention of cardiovascular disease in adults.)

We acknowledge that there is a benefit from LDL-C lowering with statin therapy at virtually all levels of cardiovascular risk (see 'Rationale for LDL-C lowering in primary prevention' above). If statin therapy had no side effects and caused no financial burden, it might be reasonable to recommend it to virtually all at-risk individuals, similar to a healthy diet and exercise. In addition, the high burden and lifetime risk of cardiovascular disease in industrialized societies must be kept in mind.

However, most drugs come with burdens and cost, and these need to be a reasonably balanced with benefits. Since cardiovascular risk is on a continuum, the level of baseline risk above which statin therapy is reasonable is by definition arbitrary. Thus, for most patients who are neither at very high nor very low baseline risk, we emphasize the importance of discussing the benefits and costs of statin therapy with the individual patient.

It should be noted that our cut-off points for initiation of statin therapy differ somewhat from those found in the 2018 guideline from the American Heart Association/American College of Cardiology (and others) on the management of blood cholesterol [30]. This guideline states "In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8mmol/L), at a 10-year atherosclerotic cardiovascular disease risk of ≥7.5 percent, start a moderate-intensity statin if a discussion of treatment options favors statin therapy."

We believe that the cut-off points below will be easy for practitioners to use and will be reasonable to most patients.

●For most patients with an LDL-C >100 mg/dL (>2.59 mmol/L) and a 10-year cardiovascular disease (CVD) risk of 10 percent or greater, we initiate statin therapy. This approach may differ in specific populations, such as the very young, the very old, and those with diabetes. (See 'Specific populations' below.)

●For such patients with a 10-year risk between 5 and 10 percent, we present in some detail the potential benefits and costs/risks to patients (shared decision making).

In some of these patients, particularly those who are reluctant to start statin therapy, and particularly those who are closer to the 10 percent cut-off, we consider additional risk stratification such as with a calcium score or lipoprotein(a) level. In patients with a coronary artery calcium score suggesting atherosclerosis (100 Agatston units or higher) or an elevated lipoprotein (a) level, we usually recommend statin therapy. In those with a score of 0, we defer statin therapy. (See "Coronary artery calcium scoring: Image acquisition and clinical utilization", section on 'Asymptomatic patients' and "Lipoprotein(a)", section on 'Disease associations'.)

In patients with very high LDL-C levels (eg, >160 mg/dL [>4.14 mmol/L]), despite a calculated risk between 5.0 and 10 percent, we usually recommend statin therapy.

●For most patients with a 10-year risk less than 5 percent, we do not start statin therapy.

We agree with the 2018 American College of Cardiology/American Heart Association (and others) guideline on management of blood cholesterol, which states that other risk-enhancing factors may favor initiation of statin therapy [30]. Some of these factors include a family history of premature CVD, chronic kidney disease, or chronic inflammatory disorder (such as chronic human immunodeficiency viral infection).

We begin CVD risk evaluations and discussions at 20 years of age or at first encounter with the health care system beyond 20 years of age. Some of these individuals will have formal CVD risk assessments undertaken to help guide preventive care. In order to determine which patients should make an attempt to lower their LDL-C, their risk for the development of CVD events needs to be assessed using risk evaluation tools that take into account more than the baseline LDL-C. Cardiovascular risk should be calculated using validated risk models/calculators. Patients and their providers can then decide whether a 20 to 30 percent relative risk reduction, which is a reasonable expectation for statin therapy, translates into an absolute risk reduction large enough to be worth the cost, burdens, and potential side effects of daily therapy. Recommendations for the use of risk calculators are found elsewhere. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Our approach to ASCVD risk assessment' and "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

Although we recommend CVD risk calculation for most patients, this may be unnecessary for individuals with an LDL-C >190 mg/dL (>4.9 mmol/L), as we generally prescribe statin therapy for them. For young women of childbearing age with LDL-C >190 mg/dL (>4.9 mmol/L) who wish to become pregnant, a decision to initiate statin therapy demands a discussion of the potential risk of fetal abnormalities and the need for continuous effective contraception. Upon making a decision to conceive, we withdraw the statin for a minimum of three months. 

Many of the individuals with very high LDL-C will have heterozygous familial hypercholesterolemia. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Heterozygous individuals'.)

Lipid-lowering therapy with statins reduces relative cardiovascular risk by approximately 20 to 30 percent regardless of baseline LDL-C. (See 'Rationale for LDL-C lowering in primary prevention' above.) The absolute benefit of treatment will be proportional to the underlying absolute risk. It should be noted that statins have not been well-studied for such a benefit in patients with very low baseline LDL-C levels (eg, below 70 mg/dL [1.8 mmol/L]), but very few such patients would be expected to have a high enough absolute risk to justify statin therapy. Determining when the benefits of treatment outweigh its burdens (costs, adverse effects) requires determination of the patient's future CVD risk.

The following are two patient examples for which the decision to start statin therapy may differ despite both patients having the same baseline LDL-C:

●A 45-year-old non-smoking normotensive woman with an LDL-C of 180 mg/dL (4.7 mmol/L) and a high-density lipoprotein cholesterol (HDL-C) of 40 mg/dL (1.03 mmol/L) has a 10-year risk of a myocardial infarction of approximately 1 percent. This could likely be reduced by 0.2 to 0.3 percentage points if she were treated with a statin daily for 10 years.

●A 60-year-old non-smoking normotensive man with an LDL-C of 180 mg/dL (4.7 mmol/L) and an HDL-C of 40 mg/dL (1.03 mmol/L) has a 10-year risk of a myocardial infarction of approximately 12 percent. Use of a statin would reduce this risk to 8 to 9 percent, a 3 to 4 percentage point reduction.

Specific populations

Young patients — Statin therapy has been used since the mid-1980s. There are few data on the benefits or safety of statins over decades of therapy. It is also uncertain whether long-term treatment leads to better outcomes compared with postponing treatment until the patient's cardiovascular risk rises to an absolute level at which treatment becomes warranted. A full discussion regarding potential benefits and risks/costs with the patient (shared decision making) is important in these individuals. (See 'Indications' above.)

It should be noted that statins are contraindicated in pregnant women. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)

Older patients — We believe that the risk of myocardial infarction and stroke will be significantly lowered by statin therapy in elderly patients. The higher the risk of a cardiovascular disease (CVD) event, the more inclined we are to recommend statin therapy in the elderly [31]. On the other hand, the overall benefit from statin therapy in individuals with significant non-cardiovascular conditions and limited life expectancy (less than five years) is likely small. Some lipid experts do not initiate statin therapy in individuals older than 85 years or in individuals with advanced comorbid disease.

A continuous, positive, graded relationship between LDL-C concentration and CVD events and mortality includes patients over the age of 70 years (see 'Introduction' above). In a large, contemporary population of individuals aged 70 to 100 years without atherosclerotic cardiovascular disease (ASCVD) or diabetes at baseline and who were not taking statins, higher LDL-C was associated with a greatly increased absolute risk of myocardial infarction and ASCVD [32].

As few elderly patients were enrolled in randomized trials of statins, outcomes with therapy in this age group have not been as well studied. Since the rate of death from all causes increases with aging, it is difficult to demonstrate a benefit from statin therapy on mortality. The following three studies support LDL-C lowering in patients aged 75 years or older:

●A 2019 meta-analysis evaluated outcomes in 14,483 elderly individuals (among 186,854 participants) in primary and secondary prevention statin trials [33]. Statin therapy led to significant reductions in major cardiovascular events in these older patients. Although the relative risk was smaller than that for younger individuals, the greater absolute risk in older patients makes therapy a rational choice for some. Subsequent to the meta-analysis, a 2020 secondary analysis of a randomized trial evaluating aspirin in the elderly was published. It looked at outcomes in those individuals, who were ≥70 years of age, based on whether they were receiving statin at baseline (n = 5629) or not (n = 12,547). Over a median follow-up of 4.7 years, statin use was associated with lower risks for multiple cardiovascular outcomes (similar to the meta-analysis) and physical disability [34].

●A 2020 meta-analysis evaluated outcomes in 11,750 statin-treated patients (most of whom were included in the 2019 analysis directly above) and 9742 patients treated with non-statin therapy [35]. Patients were from primary and secondary prevention trials. LDL-C-lowering therapy significantly reduced the risk of major vascular events (a composite of cardiovascular death, MI, or other acute coronary syndrome; stroke; or coronary revascularization) by 26 percent per 1 mmol/L reduction in LDL-C (risk ratio 0.74, 95% CI 0.61-0.89).

●An observational study using propensity scoring found a significant decrease in the risk of all-cause and cardiovascular mortality when statin is started in elderly patients for primary prevention [36].

The decision to lower LDL-C in adults 75 years of age and older should be individualized and should occur after a full discussion of the potential benefits and costs. Shared decision making is important in this setting. Patients should consider the financial cost of statin therapy, as well as the potential burdens of multiple medications.

As discussed above, statin therapy is first-line treatment in older patients for whom LDL-C lowering is deemed appropriate. One randomized trial evaluated monotherapy with ezetimibe [37] (see "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'). Over 3700 patients were randomly assigned to receive ezetimibe or usual care. At a median follow-up of 4.1 years, ezetimibe reduced the incidence of the primary composite outcome of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke (hazard ratio 0.66, 95% CI 0.50-0.86). However, significant limitations of this trial, including its open-label design, premature terminations, and issues with follow-up, prevent us from considering ezetimibe as an alternative to statin in older patients. This trial provides weak evidence that ezetimibe may be a reasonable choice for primary prevention in statin-intolerant patients.

Patients with diabetes — The role of statin therapy in patients with diabetes is discussed separately. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Dyslipidemia'.)

INITIAL DRUG THERAPY — Several randomized trials have examined the effects of lipid-lowering pharmacologic therapy on cardiovascular disease (CVD) events. Most trials have compared a fixed dose of a single pharmacologic agent with placebo, with both groups receiving basic, limited lifestyle counseling. A moderate-dose statin is our initial therapy in most patients (algorithm 1). No trials that have evaluated effects on CVD events for primary prevention have tested any medication in combination with statins or treatment to specific LDL-C goals.

Ezetimibe has not been well studied in patients without cardiovascular disease. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors have not been adequately evaluated in primary prevention in patients without familial hypercholesterolemia (see "Familial hypercholesterolemia in adults: Treatment", section on 'Goal of therapy').

Their effects in secondary prevention suggest that they could be expected to reduce cardiovascular outcomes to a similar degree, as is seen with statin therapy (see "PCSK9 inhibitors: Pharmacology, adverse effects, and use"). However, their cost, the requirement for injections, and the lack of long-term safety data would make them an option only in the highest-risk primary prevention patients who are unable to tolerate statin therapy.

USE OF STATINS

Intensity — Moderate-intensity statin therapy includes daily treatment with:

●Lovastatin 40 to 80 mg

●Pravastatin 40 to 80 mg

●Simvastatin 20 to 40 mg

●Atorvastatin 10 to 20 mg

●Rosuvastatin 5 to 10 mg

High-intensity statin therapy includes daily treatment with:

●Atorvastatin 40 to 80 mg

●Rosuvastatin 20 to 40 mg

Dose — If a decision is made to treat with statins to achieve the 20 to 30 percent reduction in coronary heart disease events seen in most clinical trials, it may make sense to treat with the doses shown to be of benefit in clinical trials.

Statin doses that have been used in clinical trials of primary prevention include low- to-moderate-intensity (pravastatin 40 mg, lovastatin 20 to 40 mg, atorvastatin 10 mg, and rosuvastatin 10 mg) therapy. No trials have directly compared the effects of low-to-moderate- with high-intensity statin therapy for primary prevention.

When the decision is made to treat, we suggest starting treatment with a moderate dose of a statin, such as 20 mg of atorvastatin or 5 to 10 mg of rosuvastatin. It is reasonable to start with high-intensity statin therapy for patients assessed to be at particularly high risk, such as those with a 10-year risk of 20 percent or higher.

Side effects and intolerance — Long-term compliance is likely increased if the patient does not have a side effect on first use of the drug. Statin side effects and intolerance, which vary somewhat among the statins, are discussed in detail separately. (See "Statins: Actions, side effects, and administration".)

Some patients will not tolerate atorvastatin, rosuvastatin, pravastatin, or simvastatin (see 'Use of statins' above). Some lipid specialists prescribe fluvastatin or pitavastatin in patients intolerant to other members of the hydroxymethylglutaryl CoA reductase inhibitor class. However, these drugs are not commonly prescribed by non-specialists, as other statins offer either better LDL-C lowering or are more cost effective.

FOLLOW-UP — For most patients who have been started on moderate-dose statin therapy, we do not intensify therapy. There is little evidence to suggest that intensification provides a level of (absolute) benefit that warrants more aggressive LDL-C lowering. However, we acknowledge that some patients without established disease will be at very high risk for a cardiovascular disease event. For example, in those with an initial 10-year risk of greater than 20 percent, intensification of statin therapy may be reasonable. In such patients, we consider high-intensity statin therapy if the LDL-C is greater than 100 mg/dL (2.6 mmol/L) (see 'Intensity' above). We generally do not use ezetimibe or a PCSK9 inhibitor.

Our rationale to not intensify therapy beyond moderate-dose statin takes into account the following:

●Randomized trials comparing high- with lower-dose statin in secondary prevention have shown a modest benefit.

●There have been no randomized trials comparing high- with low- or moderate-intensity statin therapy for primary prevention.

●The baseline absolute risk of a future CVD event is higher in patients with established disease than those without. The relative risk reduction is the same at any baseline level of risk but the reduction in absolute risk with statin therapy is smaller in patients with lower baseline risk.

●Most benefit from statin therapy occurs with moderate-dose therapy. The increase in benefit is small when going from moderate- to high-dose statin.

●We pick a moderate- rather than a high-dose statin, as it effectively lowers LDL-C, has a low side effect profile, and because it is the dose used in primary prevention studies.

Measuring the LDL-C does not require fasting in most cases. However, in patients who have had prior significant elevation(s) of nonfasting triglyceride, a fasting LDL-C (calculated from the lipid profile) should be obtained. This will help to avoid miscalculation of the LDL-C. An alternative approach is to obtain a direct measurement of LDL-C. This approach can be chosen as long as the direct method is always used to assess LDL-C; switching between the calculated and direct measurements is not recommended.

In patients who do not tolerate statins, we do not routinely recommend non-statin lipid-lowering medication for primary prevention, unless the patient has LDL-C levels substantially higher than 190 mg/dL (4.9 mmol/L) or is at substantial risk (eg, a 10-year risk >20 percent). That is, no lipid-lowering therapy should be administered in patients who are intolerant of statins unless their LDL-C is very high. Potential interventions include lifestyle modification and, in higher-risk patients, antiplatelet therapy. (See 'Lifestyle modification' above and "Aspirin in the primary prevention of cardiovascular disease and cancer".)

In the highest-risk patients (10-year risk of events of approximately 20 percent or more), if statin myopathy has been carefully assessed (algorithm 2) and statin therapy is not possible, treatment with a PCSK9 inhibitor or ezetimibe is an option [38]. We recognize that PCSK9 antibodies are not approved for use in patients without established CVD in many geographies. (See 'Initial drug therapy' above.) As additional information becomes available on the long-term safety of these agents, more patients may become eligible for such treatment.

Assessing adherence — Some patients do not achieve appropriate LDL-C reduction due to non-adherence. It is important to ask about adherence at follow-up visits. Measuring LDL-C response may be helpful in determining whether patients are adherent to treatment.

The following may be useful when assessing compliance: Atorvastatin 10 mg is expected to give a 30 to 35 percent reduction, and 20 mg should give a 45 percent reduction; rosuvastatin 5 mg should give 30 percent reduction, and 10 mg should approach a 40 percent reduction; and moderate doses of lower potency statins such as lovastatin or pravastatin typically give 25 to 30 percent reduction.

Repeat LDL-C — LDL-C should be measured six to eight weeks after initiating statin therapy. Once an appropriate level of LDL-C reduction has been obtained (see 'Follow-up' above), the test can be repeated every 12 months thereafter, or as the clinical situation dictates. The main reason to periodically check LDL-C in treated patients is to evaluate compliance (see 'Assessing adherence' above). More frequent testing is reasonable when compliance is in doubt. For patients who have had no major change to their health status, LDL-C does not need to be repeated out of concern for safety or waning efficacy.

RECOMMENDATIONS OF OTHERS — Most societal guidelines recommend evaluating future cardiovascular disease (CVD) risk using a risk calculator and treating those patients at higher levels of risk. For patients with modestly elevated risk, shared decision making about treatment is warranted.

●Our recommendations for the management of LDL-C in patients for the purpose of primary prevention are generally consistent with those made in the 2018 American College of Cardiology/American Heart Association (and others) guideline on management of blood cholesterol [30]. Our cut-off points for initiation of statin therapy differ slightly. (See 'Indications' above.)

●In 2017, the American College of Cardiology updated its expert consensus document on the role of non-statin therapies [39]. Our recommendations are generally similar to those made in this consensus document.

●The United States Preventive Services Task Force recommends treatment of adults 40 to 75 with 10-year ASCVD risk greater than 10 percent and at least one CVD risk factor [21].

●Guidelines for lipid management for primary prevention of CVD from the United Kingdom's National Institute for Health and Clinical Excellence (NICE) state that patients with a 10-year risk of CVD of 10 percent or more should be offered statin therapy [40].

●The 2016 European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemias recommends using the SCORE system to assess the 10-year risk for fatal CVD (there is a conversion factor to obtain the risk of fatal plus nonfatal hard CVD events) [41]. For individuals with a <5 percent 10-year risk, lipid lowering therapy is generally not indicated. An LDL-C goal of 100 mg/dL (2.6 mmol/L) is suggested.

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: Primary prevention of cardiovascular disease" and "Society guideline links: Assessment of cardiovascular risk".)

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 lipid treatment options (Beyond the Basics)")

●Basics topics (see "Patient education: High cholesterol (The Basics)" and "Patient education: Can foods or supplements lower cholesterol? (The Basics)" and "Patient education: High triglycerides (The Basics)")

SUMMARY AND RECOMMENDATIONS

●We suggest that all patients with an elevated LDL-C be counseled to exercise, eat a prudent diet, and lose weight as appropriate (Grade 1B). (See 'Lifestyle modification' above.)

●We calculate a baseline risk for cardiovascular disease (CVD) events in all adult patients. (See 'Indications' above.)

●For patients with an LDL-C >100 mg/dL (2.6 mmol/L) and a greater than 10 percent risk of a CVD event within 10 years, we recommend statin therapy (Grade 1A). (See 'Rationale for LDL-C lowering in primary prevention' above and 'Indications' above and 'Initial drug therapy' above.)

For such patients with a 10-year risk between 5 and 10 percent, we present the potential benefits and costs/risks to patients (shared decision making).

●In primary prevention, when the decision is made to treat, we suggest treatment with a moderate dose of a statin such as atorvastatin 20 mg or 5 to 10 mg of rosuvastatin, rather than starting at a higher dose (Grade 2C). (See 'Dose' above.)

●Measuring LDL-C response at six weeks after initiating therapy and every 12 months thereafter may be helpful in assessing adherence to medication and diet. Occasionally, an LDL-C might drift upward in an adherent patient, such as a woman at menopause. In this situation, statin dose might be increased in an individual taking a moderate dose of a statin. (See 'Side effects and intolerance' above.)

●Some patients without established disease will be at very high risk for a CVD event (eg, those with a 10-year risk of greater than 20 percent). For such patients whose on-treatment LDL-C is greater than 100 mg/dL (>2.6 mmol/L), we treat with high-intensity statin therapy. (See 'Intensity' above.).

●For most primary prevention patients who do not tolerate statins, we suggest not routinely administering a non-statin lipid-lowering medication (Grade 2C). Potential interventions include lifestyle modification and, in higher-risk patients, antiplatelet therapy.

However, in patients with very high LDL-C levels and high CVD risk, we believe it is reasonable to consider a non-statin drug. (See 'Side effects and intolerance' above and 'Older patients' above.)

●In primary prevention patients who do not achieve a particular LDL-C level on statin therapy, we suggest not adding a non-statin lipid-lowering medication (Grade 2C). That is, the patient should be maintained on statin therapy as their only lipid-lowering medication. (See 'Follow-up' above.)

ACKNOWLEDGMENT — Michael Pignone, MD, MPH, was recently a member of the United States Preventive Services Task Force. The expressed opinions herein are those of Dr. Pignone and do not necessarily represent those of the United States Preventive Services Task Force.