28-09: Treatment of High LDL Cholesterol

Reduction of LDL cholesterol with statins is just one part of a program to reduce the risk of CVD. Other measures—including diet, exercise, smoking cessation, hypertension control, diabetes control, and antithrombotic therapy—are also of central importance. For example, exercise (and weight loss) may reduce the LDL cholesterol and increase the HDL. Quitting smoking reduces the effect of other cardiovascular risk factors (such as a high cholesterol level); it may also increase the HDL cholesterol level. Modest alcohol use (1–2 ounces a day) also raises HDL levels and may have a salutary effect on CHD rates.

The use of medications to raise the HDL cholesterol has not been demonstrated to provide additional benefit. For example, cholesteryl ester transfer protein inhibitors are a class of medicines being investigated to raise HDL levels; however, agents in this class have not been shown to be effective in so doing. The addition of niacin to statins has also been carefully studied in the AIM-HIGH study and the HPS2-THRIVE study in patients at high risk for CVD and shown not to produce any further benefit (ie, to decrease parameters of cardiovascular risk).

Studies of nonhospitalized adults have reported only modest cholesterol-lowering benefits of individual dietary therapies, typically in the range of a 5–10% decrease in LDL cholesterol, and even less over the long term. The effect of diet therapies, however, may be additive; some patients will have striking reductions in LDL cholesterol—up to a 25–30% decrease—whereas others will have clinically important increases. Thus, the results of diet therapy should be assessed about 4 weeks after initiation.

Several nutritional approaches to diet therapy are available. Most Americans currently eat over 35% of calories as fat, of which 15% is saturated fat. A traditional cholesterol-lowering diet recommends reducing total fat to 25–30% and saturated fat to less than 7% of calories, with complete elimination of trans fats. These diets replace fat, particularly saturated fat, with carbohydrate. Other diet plans, including the Dean Ornish Diet and most vegetarian diets, restrict fat even further. Low-fat, high-carbohydrate diets may, however, result in insulin resistance and reductions in HDL cholesterol.

An alternative strategy is the Mediterranean diet, which maintains total fat at approximately 35–40% of total calories but replaces saturated fat with monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. This diet is equally effective at lowering LDL cholesterol, and is less likely to lead to reductions in HDL cholesterol. Several studies have suggested that this diet may also be associated with reductions in endothelial dysfunction, insulin resistance, and markers of vascular inflammation and may result in better resolution of the metabolic syndrome than traditional cholesterol-lowering diets. A clinical trial demonstrated reduced cardiovascular events in persons on a Mediterranean diet supplemented with additional nuts or extra-virgin olive oil compared to persons on a less intensive standard Mediterranean diet.

Other dietary changes may also result in beneficial changes in blood lipids. Soluble fiber, such as that found in oat bran or psyllium, may reduce LDL cholesterol by 5–10%. Plant stanols and sterols can reduce LDL cholesterol by 10%. Intake of garlic, soy protein, vitamin C, and pecans may also yield modest reductions of LDL cholesterol. Because oxidation of LDL cholesterol is a potential initiating event in atherogenesis, diets rich in antioxidants, found primarily in fruits and vegetables, may be helpful (see Chapter 29). Studies have suggested that when all of these elements are combined into a single dietary prescription, the impact of diet on LDL cholesterol may approach that of statin medications, lowering LDL cholesterol by close to 30%.

There are seven classes of medications currently available for consideration in patients who require drug treatment of an elevated cholesterol (statins, ezetimibe, PCSK9 inhibitors, omega-3 fatty acids, bile-acid–binding resins, fibrates, and niacin). As discussed above, statins are the cornerstone of nearly all medical regimens, and current guidelines define four groups of patients who benefit from statin medications (adults with diabetes mellitus, those with existing ASCVD, LDL cholesterol greater than 190 mg/dL, or 10-year risk of ASCVD greater than 7.5%). For LDL cholesterol, the evidence is strongest for ezetimibe and PCSK9 inhibitors; for triglycerides, the evidence is strongest for adding prescription-grade omega-3 fatty acid preparations. There is less evidence for cholesterol absorption inhibitors, fibrates, and niacin. Bempedoic acid, an inhibitor of adenosine triphosphate citrate lyase (ACL)—the enzyme two steps upstream from HMG-CoA reductase, the target of statins—was approved by the FDA in 2020 and represents a new option for LDL lowering (~17%) in patients with statin intolerance.

A. Statins (Hydroxymethylglutaryl-Coenzyme A [HMG-CoA] Reductase Inhibitors)

The statins (HMG-CoA reductase inhibitors) work by inhibiting the rate-limiting enzyme in the formation of cholesterol. Cholesterol synthesis in the liver is reduced, with a compensatory increase in hepatic LDL receptors (so that the liver can take more of the cholesterol that it needs from the blood) and a reduction in the circulating LDL cholesterol level by 50% or more at the highest doses. There are also modest increases in HDL levels, substantial decreases in triglyceride levels, and marked reductions in high-sensitivity C-reactive protein levels.

The 2018 AHA/ACC/Multi-society guidelines divide statins into two categories: “high-intensity” and “moderate-intensity” statins (Table 28–2). High-intensity statins lower LDL cholesterol by approximately 50%. Examples include high-dose atorvastatin 40–80 mg/day and rosuvastatin 20–40 mg/day (Table 28–3). Moderate-intensity statins lower LDL cholesterol by approximately 30–50%. Examples include simvastatin 20–40 mg/day, pravastatin 40–80 mg/day, and lovastatin 40 mg/day, as well as low-dose atorvastatin 10–20 mg/day and rosuvastatin 5–10 mg/day. All statins are given once daily in the morning or evening.

Statin-associated muscle aches, with normal serum creatine kinase levels, occur in up to 10% of patients, and often such patients can tolerate the statin upon rechallenge. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) is a useful tool to help differentiate statin-related symptoms from symptoms unrelated to statins. More serious, but very uncommon, muscle disease includes myositis and rhabdomyolysis, with moderate and marked elevations of serum creatine kinase levels, respectively. Such muscle disease occurs more often when the statin is taken with niacin or a fibrate, as well as with erythromycin, antifungal medications, nefazodone, or cyclosporine. Simvastatin at the highest approved dose (80 mg) is associated with an elevated risk of muscle injury or myopathy; this dose should be used only in patients who have been taking simvastatin at a lower dose for longer than 1 year without muscle toxicity. Liver disease, with elevations of serum transaminases, is another uncommon side effect of statin therapy and is again more common in patients who are also taking fibrates or niacin. Manufacturers of statins recommend monitoring liver enzymes before initiating therapy and as clinically indicated thereafter; current guidelines do not recommend routine monitoring. Liver failure can occur but is extremely uncommon. Finally, statin therapy is associated with a 10% increase in risk of developing diabetes mellitus in at-risk individuals (eg, those with the metabolic syndrome).

B. Ezetimibe

Ezetimibe inhibits the intestinal absorption of dietary and biliary cholesterol across the intestinal wall by inhibiting a cholesterol transporter. The dose of ezetimibe is 10 mg/day orally. Ezetimibe reduces LDL cholesterol between 15% and 20% when used as monotherapy, reduces high-sensitivity C-reactive protein, and can further reduce LDL in patients taking statins in whom the therapeutic goal has not been reached. While beneficial effects of ezetimibe monotherapy on cardiovascular outcomes are available from only a large open-label trial, the double-blind IMPROVE-IT trial showed that adding ezetimibe to a statin resulted in a small incremental 5–10% relative risk reduction in detrimental cardiovascular outcomes. At the end of 7 years of study, patients taking ezetimibe-simvastatin had a 2% absolute reduction in cardiovascular events compared to patients taking simvastatin alone. Current guidelines recommend adding ezetimibe therapy to maximally tolerated statin therapy in patients at high risk for CVD whose LDL cholesterol remains above the treatment threshold of 70 mg/dL.

C. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

PCSK9 inhibitors are fully human monoclonal antibodies that inhibit PCSK9-mediated LDL-receptor degradation and lower LDL cholesterol levels by 50–60% and lipoprotein(a) by up to 20–30%. Two agents, alirocumab and evolocumab, are approved for use in the United States for patients with familial hypercholesterolemia or CVD who require additional lowering of LDL cholesterol. The medications are injected subcutaneously every 2–4 weeks. No significant increase in adverse events has been observed compared to placebo. The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial compared evolocumab with placebo in 27,564 patients with established atherosclerotic disease already taking statin therapy; participants were monitored for a median of 2.2 years. LDL cholesterol was reduced by 59%. Patients receiving the evolocumab plus statin had a 15% reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization and a 20% reduction in the secondary outcome of cardiovascular death, myocardial infarction, or stroke. The ODYSSEY-OUTCOMES study randomized 18,924 patients with recent acute coronary syndrome to alirocumab or placebo, demonstrating a 15% reduction in the primary composite cardiovascular endpoint and a 15% reduction in all-cause mortality in secondary statistical testing after median 2.8-year follow-up.

However, despite encouraging results from multiple clinical trials, initial cost-effectiveness models suggested that PCSK9 inhibitors were not cost-effective. After marked price reductions in 2018 and 2019, PCSK9 inhibitors are closer to being cost-effective; however, guidelines suggest that their relatively high cost must still remain part of the consideration regarding their use. Current guidelines recommend addition of PCSK9 inhibitors to statins at maximally tolerated doses in patients at very high risk for CVD when on-treatment LDL cholesterol remains above 70 mg/dL (or above 100 mg/dL in patients with familial hypercholesterolemia). Patients considered to be at very high-risk for CVD include those with recent acute coronary syndrome within 12 months; multiple prior myocardial infarctions or strokes; significant unrevascularized coronary artery disease; and polyvascular disease (coronary plus cerebrovascular or peripheral vascular disease).

In late 2020, the FDA will consider approval of a novel PCSK9 inhibitor called inclisiran that uses silencing RNA technology to reduce PCSK9 protein production by the liver, enabling dosing every 6 months.

D. Omega-3 Fatty Acid Preparations

Omega-3 fatty acids are essential fatty acids that must be consumed in the diet and are a prominent feature of Mediterranean-style diets. In pharmacologic doses, omega-3 fatty acid preparations can lower triglycerides by up to 30%, with modest reductions in apolipoprotein-B–containing lipoproteins and high-sensitivity C-reactive protein. Pharmacologic therapy should be differentiated from dietary omega-3 fatty acid supplements. The former is an FDA-approved product usually given at a much higher dose; dietary supplements are variable, the supporting evidence is much weaker, and they are not currently regulated.

There is modest evidence from meta-analyses that omega-3 fatty acid supplementation reduces myocardial infarctions, though with no reduction in total or cardiovascular mortality. Omega-3 ethyl esters have not been associated with cardiovascular event reduction when added to statin therapy.

In contrast, icosapent ethyl, which is a highly purified eicosapentaenoic acid (EPA) only preparation, was shown to reduce cardiovascular deaths, nonfatal myocardial infarctions, nonfatal strokes, coronary revascularizations, and unstable angina by 25% in statin-treated patients with triglycerides greater than 135 mg/dL in the 8179 person REDUCE-IT randomized clinical trial compared to a mineral oil placebo. The mechanism of action of icosapent ethyl is not yet clear but likely involves multiple mechanisms beyond lipid lowering, including antiplatelet activity, anti-inflammatory activity, and arrhythmia prevention. In 2019, the FDA granted icosapent ethyl a broad indication for CVD event lowering in patients with triglycerides over 150 mg/dL and either established CVD or diabetes mellitus plus two or more additional risk factors for CVD.

E. Bile Acid–Binding Resins

The bile acid–binding resins include cholestyramine, colesevelam, and colestipol. In the pre-statin era, treatment with these agents reduced the incidence of coronary events in middle-aged men by about 20%, with no significant effect on total mortality. The resins work by binding bile acids in the intestine. The resultant reduction in the enterohepatic circulation causes the liver to increase its production of bile acids, using hepatic cholesterol. Thus, hepatic LDL receptor activity increases, with a decline in plasma LDL levels. The triglyceride level tends to increase in some patients treated with bile acid–binding resins; these resins should be used with caution in patients with elevated triglycerides and not at all in patients who have triglyceride levels above 500 mg/dL. The clinician can anticipate a reduction of 15–25% in the LDL cholesterol level, with insignificant effects on the HDL level.

The usual dose of cholestyramine is 12–36 g of resin per day in divided doses with meals, mixed in water or, more palatably, juice. The dose of colestipol is 20% higher (each packet contains 5 g of resin). The dose of colesevelam is 625 mg, 6–7 tablets per day.

These agents often cause gastrointestinal symptoms, such as constipation and gas. They may interfere with the absorption of fat-soluble vitamins (thereby complicating the management of patients receiving warfarin) and may bind other drugs in the intestine. Concurrent use of psyllium may ameliorate the gastrointestinal side effects.

F. Fibric Acid Derivatives

The fibrates are peroxisome proliferative-activated receptor-alpha (PPAR-alpha) agonists that result in significant reductions of plasma triglycerides and increases in HDL cholesterol. They reduce LDL levels by about 10–15% (although the result is variable) and triglyceride levels by about 40% and raise HDL levels by about 15–20%. The fibric acid derivatives or fibrates approved for use in the United States are gemfibrozil and fenofibrate. Ciprofibrate and bezafibrate are also available for use internationally.

Gemfibrozil monotherapy reduced CHD rates in hypercholesterolemic middle-aged men free of coronary disease in the Helsinki Heart Study. The effect was observed only among those who also had lower HDL cholesterol levels and high triglyceride levels. In a Veteran Affairs study, gemfibrozil monotherapy was also shown to reduce cardiovascular events in men with existing CHD whose primary lipid abnormality was a low HDL cholesterol. There was no effect on all-cause mortality.

However, fibrates have not been shown to reduce cardiovascular events in all statin-treated patients with CVD or diabetes. For example, in the ACCORD study, addition of fenofibrate to statin in patients with diabetes and mild triglyceride elevations resulted in no benefit.

The usual dose of gemfibrozil is 600 mg once or twice a day. Side effects include cholelithiasis, hepatitis, and myositis. The incidence of the latter two conditions may be higher among patients also taking other lipid-lowering agents. Fenofibrate, 48–145 mg daily, can be used and has slightly fewer side effects than gemfibrozil. Resins are the only lipid-modifying medication considered safe in pregnancy.

G. Niacin (Nicotinic Acid)

Niacin was the first lipid-lowering agent that was associated with a reduction in total mortality in a long-term follow-up of a secondary prevention trial in middle-aged men with previous myocardial infarction. A meta-analysis of 10 randomized trials using niacin in the pre-statin era showed a 27% reduction in cardiovascular events.

Niacin reduces the production of VLDL particles, with secondary reduction in LDL and increases in HDL cholesterol levels. The average effect of full-dose niacin therapy is a 15–25% reduction in LDL cholesterol and a 25–35% increase in HDL cholesterol. Full doses are required to obtain the LDL effect, but the HDL effect is observed at lower doses, eg, 1 g/day. Niacin also reduces triglycerides and can lower lipoprotein(a) (Lp[a]) levels. Intolerance to niacin is common; only 50–60% of patients can take full doses. Niacin causes a prostaglandin-mediated flushing that patients may describe as “hot flashes” or pruritus. It can be decreased with aspirin (81–325 mg/day) or other nonsteroidal anti-inflammatory agents taken an hour before niacin dosing. Extended-release niacin is better tolerated by most patients. Niacin can also exacerbate gout and peptic ulcer disease. Niacin may increase blood sugar in some patients.

There is very little evidence to support the use of niacin in the modern era. In two large pivotal clinical trials, AIM-HIGH and HPS2-THRIVE, extended-release niacin did not reduce cardiovascular events when added to statin therapy in high-risk patients. Therefore, niacin should be rarely used.

For patients who require a lipid-modifying medication, an HMG-CoA reductase inhibitor (statin) is recommended. In patients with CVD, this should be at its maximally tolerated dose.

Combination therapy is indicated for (1) patients with familial hypercholesterolemia with on-treatment LDL cholesterol that is above 100 mg/dL; (2) patients with existing CVD with on-treatment LDL cholesterol that remains above 70 mg/dL; (3) many high-risk patients with triglycerides greater than 150 mg/dL or non-HDL cholesterol greater than 100 mg/dL.

Patients with heterozygous familial hypercholesterolemia or premature CVD may need two or more medications to get below the treatment threshold, while those without CVD (primary prevention) less commonly need multiple medications. The 2018 AHA/ACC/Multi-society guidelines recommend addition of ezetimibe in high-risk patients, while reserving PCSK9 inhibitor therapy for very high-risk patients or those taking maximally tolerated statin therapy and ezetimibe with LDL cholesterol still not below 70 mg/dL (Figure 28–2). Notably, the 2019 European Society of Cardiology guidelines have endorsed an LDL cholesterol treatment goal of less than 55 mg/dL in very high risk patients. Other guidelines, including the American Diabetes Association and the National Lipid Association, have endorsed the use of icosapent ethyl in high-risk patients with CVD or diabetes and on-treatment triglycerides greater than 150 mg/dL.

Patients with homozygous familial hypercholesterolemia may need plasmapheresis and/or special lipid-lowering therapies uniquely approved for this population (Table 28–3).