INTRODUCTION — Lipid (or lipoprotein) altering agents encompass several classes of drugs including statins, cholesterol absorbing inhibitors, fibric acid derivatives, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, nicotinic acid, and others. These drugs differ with respect to mechanism of action and to the degree and type of lipid altering.
Most patients for whom a prescription drug therapy is deemed advisable will have an elevation in their low-density lipoprotein cholesterol (LDL-C) level and a statin is the established first line therapy. Other lipid lowering drugs are used to augment statin effects on LDL-C, substitute for statins when that class cannot be used, or to treat non-LDL-C disorders, primarily hypertriglyceridemia. The decision to use a non-statin drug can be influenced by clinical parameters other than the lipid values themselves.
The characteristics, efficacy, and safety of the lipid-lowering drugs other than the statins and PCSK9 inhibitors will be reviewed here. The efficacy of statins and PCSK9 inhibitors is discussed elsewhere. (See "Statins: Actions, side effects, and administration" and "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)
Additionally, therapeutic decision making in patients with elevated lipid levels is discussed in detail separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
MECHANISMS OF BENEFIT — The mechanisms of benefit seen with these drugs are incompletely understood. Potential mechanisms include regressions of atherosclerosis, plaque stabilization, reversal of endothelial dysfunction, inhibition of inflammatory pathways, and decreased thrombogenicity. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
While the drugs discussed in this topic, as well as the statins and PCSK9 inhibitors, lower LDL-C to variable degrees, it has not yet been established that LDL-C lowering is the only mechanism by which these drugs lead to improved patient outcomes . There are numerous in vitro studies that suggest statins have pleiotropic effects that could affect the atherosclerosis process beyond their LDL-C lowering effect.
DOSING REGIMENS/SIDE EFFECTS — Conventional dosing regimens and common adverse reactions are summarized in a table (table 1).
IMPACT ON LIPID VALUES — The range of expected changes in the lipid profile with these drugs are summarized in a table (table 2).
Ezetimibe — Ezetimibe is a cholesterol absorption inhibitor that impairs dietary and biliary cholesterol absorption at the brush border of the intestine . It is the most commonly prescribed LDL-C lowering agent after statins. Addition discussion of the clinical use of ezetimibe are presented separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
Its mechanism involves inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein, which is expressed both in the intestine and the liver, with this inhibition resulting in a net decrease in cholesterol absorption from the intestine [3-5]. A genetic study found an association between having a single inactivating mutation (heterozygous state) for NPC1L1 and lower LDL-C, and also lower risk of developing coronary heart disease (CHD), providing biologic support that a medication that blocks NPC1L1 might be expected to reduce the risk of CHD .
In two randomized, double-blind, placebo-controlled trials, ezetimibe at a dose of 10 mg/day reduced LDL-C by approximately 17 percent [7,8]. However, the reduction in LDL-C is bimodal with one in eight patients experiencing an average 36 percent reduction in LDL-C. The hyper-responsiveness to ezetimibe occurs in patients who lack the common NPC1L1 haplotype 1735C-25342A-27677T . Ezetimibe is also effective as adjunctive therapy to a statin [10-14]; in one study, a 10 mg dose of ezetimibe lowered LDL-C by 14 percent below the LDL lowering effect of simvastatin .
IMPROVE-IT, the first large trial to directly assess clinical outcomes with ezetimibe plus a statin compared with a statin alone, found that after a median follow-up of six years, patients with an acute coronary syndrome randomized to ezetimibe/simvastatin had a lower rate of the primary composite cardiovascular outcome (cardiovascular death, myocardial infarction, hospital admission for unstable angina, coronary revascularization 30 or more days after randomization, or stroke) than those randomized to simvastatin alone (hazard ratio [HR] 0.94, 95% CI 0.89-0.99; seven-year event rates 32.7 versus 34.7 percent) . All-cause mortality (HR 0.99) and cardiovascular mortality (HR 1.00) were not reduced. Adverse events were similar in the two arms. The benefits on cardiovascular end points provide support for LDL-C lowering with this drug. (See "Low density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome", section on 'Ezetimibe' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
Randomized trials, such as the SHARP trial in patients with chronic kidney disease, found reductions in cardiovascular end points with the combination of ezetimibe and simvastatin compared with placebo . However, trials of this sort cannot be used to demonstrate additional clinical benefit from ezetimibe beyond what would be expected with a statin alone.
A trial of the combination of simvastatin and ezetimibe in patients with aortic stenosis, SEAS, found an increased risk of cancer and cancer death in the active treatment arm . Statins do not appear to increase the risk of cancer, which raised the possibility that ezetimibe treatment could cause cancer. Because of this concern, an interim analysis of two other trials of simvastatin and ezetimibe (IMPROVE-IT and SHARP) was performed . This analysis found no increased risk of incident cancer but a trend toward an increase in cancer deaths. However, an early increase in cancer deaths in a trial without an increase in incident cancer would be somewhat unusual. We feel the observed effects on cancer and cancer deaths are most likely due to chance. In a preliminary report of the final analysis of the SHARP trial, there continued to be no increase in cancer incidence with ezetimibe but there was a statistically nonsignificant increase in cancer deaths (3.2 versus 2.8 percent) ; the final analysis of IMPROVE-IT showed no increase in cancer (10.2 percent in each arm) .
The precise role of ezetimibe relative to other lipid lowering drugs is unclear. Similar reductions in LDL-C can often be achieved simply by maximizing the dose of statins. As an example, one randomized trial found that the reduction in LDL-C concentration was the same with atorvastatin 10 mg plus ezetimibe as with atorvastatin 80 mg alone; however, adding ezetimibe to atorvastatin 80 mg did result in an additional 9 percent reduction in LDL-C concentration . Ezetimibe plus atorvastatin also produced a greater reduction in serum C-reactive protein than atorvastatin alone.
Ezetimibe may be helpful for avoiding high doses of statins (and potentially increased susceptibility to muscle injury) in patients who do not meet cholesterol goals on low-dose statin therapy alone. (See "Statin muscle-related adverse events".)
Gemfibrozil and fenofibrate have been noted to increase ezetimibe levels [20,21], although the clinical significance of this is uncertain. Ezetimibe and fenofibrate have been safely used in combination [22,23], and we use this combination clinically.
Bempedoic acid — Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3methylglutarly-CoA reductase (the target of statins) in the cholesterol biosynthesis pathway (see "Statins: Actions, side effects, and administration", section on 'Mechanism of action'). Bempedoic acid alone or in combination with statin or ezetimibe lowers LDL-C as well as other atherogenic proteins [24-26].
Bempedoic acid may be used in statin-intolerant patients who require modest lipid lowering, but side effects must be monitored.
In a trial of 13,970 patients who were unable or unwilling to take statins due to adverse effects and had or were at high risk for cardiovascular disease, patients were assigned either bempedoic acid 180 mg daily or placebo . The following findings were noted after 40 months of follow-up:
●People assigned bempedoic acid compared with placebo had lower rates of these outcomes:
•Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization was lower (11.7 versus 13.3 percent; HR 0.87; 95% CI 0.79-0.96).
•Composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (8.2 versus 9.5 percent); fatal or nonfatal myocardial infarction (3.7 versus 4.8 percent); and coronary revascularization (6.2 versus 7.6 percent).
●People assigned bempedoic acid had similar rates of fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause compared with placebo.
●People assigned bempedoic acid had higher rates of gout (3.1 versus 2.1 percent) and cholelithiasis (2.2 versus 1.2 percent). Rates of serum creatinine, uric acid, and hepatic-enzyme levels were also modestly higher in those assigned bempedoic acid.
In 2019, two smaller randomized trials that evaluated the safety and LDL-C-lowering efficacy of this drug were published. In both trials, patients with either established cardiovascular disease or heterozygous familial hypercholesterolemia were randomly assigned to bempedoic acid (180 mg once daily) or placebo in a 2:1 ratio and followed for 52 weeks:
●The CLEAR Harmony trial enrolled 2230 patients taking maximally-tolerated doses of a statin that included 6.6 percent taking low-intensity statin therapy, 43.5 percent taking moderate-intensity statin therapy, and 49.9 percent taking high-intensity statin therapy . Baseline LDL-C had to be above 70 mg/dL.
The primary endpoint of safety (any adverse event) was similar in the two groups (78.5 versus 78.7 percent, respectively), as was the endpoint of serious adverse events (14.5 versus 14.0, respectively). The most common adverse events included nasopharyngitis, myalgia, and upper respiratory tract infection after 52 weeks of therapy. At week 12, bempedoic acid reduced the mean LDL-C by 19.2 mg per deciliter (0.50 mmol per liter), representing a change of -16.5 percent from baseline (difference versus placebo in change from baseline, -18.1 percent; p<0.001). There was a trend toward a greater LDL-C lowering response of bempedoic acid patients receiving low- to moderate-intensity statin (-20.0 percent) compared with high-intensity statin (-17.5 percent).
●The CLEAR Wisdom trial enrolled 779 patients receiving maximally-tolerated lipid-lowering therapies and whose baseline LDL-C was at least 100 mg/dL . The primary efficacy endpoint of the percent change from baseline to week 12 in LDL-C was significantly lower with bempedoic acid compared with placebo (-15.1 versus 2.4 percent; 97.6 versus 122.8 mg/dL, respectively). Adverse events were similar to CLEAR Harmony and included an elevated uric acid level in a higher percent of patients with active treatment (4.2 versus 1.9 percent).
We measure serum uric acid and stabilize patients with active gout before starting bempedoic acid.
In February 2020, the US Food and Drug Administration (FDA) approved the drug for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C . A combination single tablet of bempedoic acid-ezetimibe has also been approved.
Monoclonal antibody against ANGPTL3 — Angiopoietin-like proteins (ANGPTLs) are regulators of lipoprotein metabolism. ANGPTL3 is a hormone produced by the liver that inhibits lipoprotein lipase, an enzyme that breaks down plasma triglycerides (see "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Endogenous pathway of lipid metabolism'). In addition, it lowers LDL-C using a low-density lipoprotein-independent mechanism .
Evinacumab is a fully human monoclonal antibody against ANGPTL3, and it has been shown to significantly decrease LDL-C when given either subcutaneously or intravenously. A 2020 phase 2 trial randomly assigned 272 patients with refractory hypercholesterolemia and either heterozygous familial hypercholesterolemia (FH) or non-heterozygous FH with clinical atherosclerotic cardiovascular disease to various doses of evinacumab or placebo . All patients were treated with a PCSK9 inhibitor and a statin at a maximum-tolerated dose, with or without ezetimibe. At week 16, evinacumab significantly reduced LDL-C by 50 percent with intravenous (IV) administration (15 mg/kg IV every four weeks) and 56 percent with subcutaneous administration (450 mg subcutaneously every week). Through its effects on endothelial lipase, evinacumab reduces hepatic very-low-density lipoprotein cholesterol production and secretion and, consequently, LDL-C . (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Very low-density lipoprotein'.)
The potential use of monoclonal antibodies to decrease ANGLPT3 in patients with homozygous FH is discussed separately. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Homozygous individuals'.)
Fibrates — We do not recommend fibrate therapy, also known as "fibrates" or "fibric acid," to lower LDL-C or to raise high-density lipoprotein cholesterol (HDL-C) in the absence of hypertriglyceridemia. Fibrates lower triglyceride levels by as much as 50 percent and reduce LDL particle number, but the available evidence does not support their routine use as add-on drugs to statin therapy . Unlike statins, which have demonstrated clinical efficacy across a broad range of LDL-C levels, fibrates have shown reductions in cardiovascular events primarily in subsets of patients with high triglycerides (above 200 mg/dL [2.2 mmol/L]) and/or low HDL-C (below 40 mg/dL [1.0 mmol/L]) [35-37]. However, a prospective randomized, placebo-controlled trial of pemafibrate in dyslipidemic patients was unaccompanied by a reduction in cardiovascular outcomes . Thus, we do not recommend fibrates for cardiovascular event reduction. The potential role for fibrate therapy in patients with hypertriglyceridemia to prevent acute pancreatitis is discussed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Fibrates'.)
The impact of fibrates on the lipid profile are a reduction of serum triglycerides by as much as 50 percent and an elevation of HDL-C by 5 to 20 percent (table 2) [37,39]. Increases in HDL-C of as much as 20 percent are seen in patients with very high triglyceride levels (>500 mg/dL [5.7 mmol/L]), while increases of 5 percent are more typical with fibrate monotherapy in patients with lower triglyceride levels. Fibrates reduce LDL particle number (mean decrease of 10 percent) despite a mild increase in LDL-C (mean increase of 6 percent) [40-43]. Fibrates have variable effects on serum lipoprotein(a) (Lp(a)): In one study, as an example, bezafibrate reduced serum Lp(a) by approximately 26 percent overall and by 39 percent in patients with values above 30 mg/dL , but most studies show no effect on Lp(a) levels.
Nicotinic acid (niacin) — Nicotinic acid (niacin) is uncommonly used as therapy for patients with elevated LDL-C. Other therapies such as ezetimibe or a PCSK9 inhibitor are added to statin therapy in patients for whom a further reduction in LDL-C is needed. While nicotinic acid raises HDL-C significantly, there is no evidence that this use leads to improved patient outcomes [45-47]. In addition, the use of nicotinic acid is often limited by poor tolerability, and there are concerns about the safety of nicotinic acid as well as its efficacy for clinical end points.
Niacin lowers lipoprotein(a) (Lp(a)) levels by an average 25 percent , and thus it is used for patients with Lp(a) excess and hypercholesterolemia who have elevated LDL-C levels on treatment with maximum tolerated statin therapy plus ezetimibe . (See "Lipoprotein(a)", section on 'Next steps' and "Lipoprotein(a)", section on 'Rarely used drugs'.) There is no evidence that a reduction in Lp(a) with niacin reduces clinical events.
Large randomized trials of niacin in patients with low HDL-C levels and LDL-C levels of around 70 mg/dL have raised serious concerns about its safety and efficacy in combination with statin therapy, and by extension concerns about niacin monotherapy:
●The AIM-HIGH trial of 3414 patients with established cardiovascular disease, low HDL-C, elevated triglycerides, and treated with a statin (mean LDL-C of 70 mg/dL) found no additional benefit to treatment with extended-release niacin . The study was stopped early for futility and because of a concern about increased numbers of ischemic strokes in patients treated with niacin, which were not significantly different from placebo after final adjudication. However, HDL-C levels in the "placebo" arm (which received 100 to 200 mg of niacin daily) increased more than expected, which may have reduced the ability of the trial to detect a real benefit with niacin therapy. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
The AIM-HIGH trial does not answer the question of whether niacin would be of value in patients on statin therapy but much higher initial LDL-C levels.
●HPS2-THRIVE randomly assigned 25,673 adults ages 50 to 80 with vascular disease to receive extended–release niacin 2 grams daily plus laropiprant (to reduce flushing from niacin) or placebo; all patients received simvastatin 40 mg daily, and if LDL-C reduction was inadequate with simvastatin, ezetimibe 10 mg daily was added . After a median follow-up of 3.9 years, there was no reduction with niacin/laropiprant in the primary end point of first major vascular event (13.2 versus 13.7 percent; risk ratio [RR] 0.96, 95% CI 0.90-1.03) and there was also no benefit for this end point in the subgroup of patients with low HDL-C and elevated triglycerides. There was a statistically nonsignificant increase in mortality (6.2 versus 5.7 percent, RR 1.09, CI 0.99-1.21). Additionally, and despite the run-in period, there was an increase in serious adverse events. These included myopathy (RR 3.54), but with a much greater increased risk in patients from study centers in China (RR 5.2) than in Europe (RR 1.5), gastrointestinal side effects, and rash. Niacin/laropiprant worsened glucose control with both an increase in new cases of diabetes (RR 1.32) and serious disturbance in diabetes control (11.5 versus 7.5 percent, RR 1.55; most of these led to hospitalization). Additionally, there were unanticipated increases in serious infections (8.0 versus 6.6 percent; RR 1.22, CI 1.12-1.34) and bleeding (2.5 versus 1.9 percent; RR 1.38, CI 1.17-1.62).
Niacin was administered with laropiprant in HPS2-THRIVE, and so it is not possible to completely sort out the effects that might have been due to laropiprant, particularly with regard to the unexpected findings of excess bleeding and infection. However, given the results of HPS2-THRIVE, infection and bleeding were subsequently analyzed in AIM-HIGH, which studied niacin without laropiprant . Infections were increased with niacin (8.1 versus 5.8 percent; p = 0.008), and there were only small numbers to assess rates of bleeding (3.4 versus 2.9 percent; p = 0.36). This explanation for the observation of an increased infection risk is not known .
Given these results of these randomized trials, we would not administer niacin to most patients receiving statin therapy. Exceptions to this general approach would include patients at extremely high cardiovascular risk such as homozygous or heterozygous familial hypercholesterolemia patients who are not at goal with maximum dosage statin plus ezetimibe or colesevelam, particularly if they have Lp(a) excess and a family history of early onset of atherosclerotic cardiovascular disease. Patients who are unable to take other lipid-lowering therapies may consider long-term niacin therapy if their LDL-C is significantly elevated and is lowered substantially by a trial of niacin treatment.
While niacin can raise HDL-C, we generally do not recommend efforts to do so. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'Role of niacin, fibrates, or estrogen'.)
Use — The HDL-C raising properties of nicotinic acid occur with dosages as low as 1 to 1.5 g/day . In contrast, the very-low-density lipoprotein cholesterol and LDL-C lowering effects are typically seen with higher doses (3 g/day) [45,47]. In one study, for example, nicotinic acid in a dose of 500 mg three times daily raised HDL-C by 20 percent but reduced LDL-C by only 5 percent. In comparison, a higher dose of 1.5 g three times daily produced more prominent changes of 33 percent (HDL-C elevation) and 23 percent (LDL-C reduction). At higher doses, nicotinic acid can also lower Lp(a) levels by as much as 35 percent .
For those patients in whom niacin is chosen, therapy with crystalline nicotinic acid is initiated at 100 mg three times daily and gradually increased to the targeted dosage as tolerated . (See 'Bile acid sequestrants' below.)
Extended-release niacin, is a controlled release formulation of nicotinic acid that is administered once daily. It is initiated at a dose of 500 mg nightly for one month and the dosage is titrated to 1000 mg. The standard dosage is 1 to 2 grams nightly. It is advised that the medication be given with a night-time snack, but our experience suggests improved tolerability with dosing after the evening meal.
Side effects — The use of nicotinic acid is often limited by poor tolerability. At standard doses (1.5 to 4.5 g/day), flushing occurs in 80 percent of patients taking the crystalline preparation, and pruritus, paresthesias, and nausea each occur in about 20 percent . Symptoms after a dose of nicotinic acid can last from 10 to 20 minutes up to several hours.
With the crystalline preparation, pretreatment with aspirin (325 to 650 mg) 30 minutes prior to dosing or ibuprofen (200 mg) 60 minutes prior to dosing can minimize flushing and other prostaglandin-mediated side effects associated with niacin. This adverse reaction often diminishes in 7 to 10 days, gradually improving over time. Symptoms may recur episodically on a stable dose or with dose titration. Nicotinic acid is better tolerated when ingested with food, which minimizes gastrointestinal side effects.
Flushing appears to be less common with controlled-release Niaspan. In one study of 269 patients receiving a median dose of 2000 mg/day for 48 weeks, 4.8 percent discontinued the drug because of flushing . In another report in which both formulations were given in a dose of 1500 mg/day for four months, Niaspan was accompanied by fewer flushing episodes per month (1.9 versus 8.6) . A newer formulation of Niaspan (coated caplets) appears to further reduce flushing .
Laropiprant is a highly selective prostaglandin D2 receptor 1 antagonist that can decrease niacin-induced flushing [56,57]. It has not been approved in the United States, and this agent was withdrawn from the market worldwide after the results of HPS2-THRIVE. (See 'Nicotinic acid (niacin)' above.)
Additionally, although the absolute increase in risk appears to be small, these results suggest that niacin may increase the risk of myopathy in patients receiving simvastatin, and perhaps other statins (see "Statin muscle-related adverse events", section on 'Concurrent drug therapy'). This increased risk may be a particular concern in patients from China, and we suggest avoiding the combination of simvastatin and niacin in Chinese patients and only using niacin with caution in patients receiving other statins. (See "Statin muscle-related adverse events", section on 'Niacin'.)
Elevations in hepatocellular enzymes are also common with nicotinic acid and may lead to severe hepatotoxicity, jaundice, and fulminant hepatitis. The onset of hepatocellular injury is not predictable; therefore, regular monitoring of biochemical studies is mandatory. Crystalline niacin is preferred to most sustained-release preparations, since the former is associated with a greater hypolipidemic effect and seemingly less hepatotoxicity [46,58]. An exception may be extended release Niaspan, which has been found to minimally raise transaminases in clinical trials, but not cause significant hepatotoxicity .
Other important problems with nicotinic acid include :
●Nicotinic acid can increase glucose levels, particularly at moderate to high doses . As a result, hyperglycemia may develop in susceptible patients and the glycemic state may be worsened in those already being treated for overt diabetes mellitus [61,62]. This effect appears to be greatest with some extended-release preparations, and minimized with crystalline niacin and perhaps Niaspan. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
●Nicotinic acid can induce hyperuricemia and precipitate acute gouty arthritis; it should therefore be avoided in any patient with a history of gout.
●Nicotinic acid can produce hypotension in subjects treated with vasodilators, and can exacerbate unstable angina pectoris .
●Nicotinic acid causes a dose-dependent elevation in plasma homocysteine levels that may negate its favorable effects on the lipid profile in certain subsets of patients . (See "Overview of homocysteine".)
●As discussed above, nicotinic acid appears to increase the risk of infection and perhaps bleeding. (See 'Nicotinic acid (niacin)' above.)
Bile acid sequestrants — Bile acid sequestrants are rarely used for elevated LDL-C. This category of drug includes cholestyramine, colestipol, and colesevelam . These agents bind bile acids in the intestine, resulting in interruption of the reabsorption of bile acids which is usually 90 percent efficient. The ensuing reduction in the cholesterol pool lowers intrahepatic cholesterol, which promotes the synthesis of apo B/E (LDL) receptors. The apo B/E (LDL) receptors bind LDL from the plasma, causing a further reduction in blood cholesterol. The bile acid sequestrants also induce a minimal elevation in HDL-C . (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)
Low doses (8 g/day of cholestyramine or 10 g/day of colestipol) can reduce LDL-C by 10 to 15 percent. A more pronounced reduction (about 24 percent) can be achieved at maximal recommended doses (24 and 30 g/day, respectively). A similar reduction in LDL-C can be achieved with 1.5 to 4.5 g/day of colesevelam [65,67].
Bile acid sequestrants are also effective when used in combination with statins or nicotinic acid in patients with markedly elevated plasma levels of LDL-C. As an example, bile acid sequestrants and statins have synergistic actions to lower LDL-C (about 50 percent) and raise HDL–C (11 to 18 percent) [68-70]. Maximal doses of bile acid sequestrants with nicotinic acid (4 g/day) can reduce LDL-C by 32 percent and elevate HDL-C by 43 percent .
In addition to the relatively minor (compared with statin) effect on LDL-C, the use of a bile acid sequestrant is often limited by side effects. The major adverse reactions are gastrointestinal, including nausea, bloating, cramping, and an increase in liver enzymes; colesevelam is better tolerated and less likely to cause gastrointestinal side effects . Bile acid sequestrants can also bind to and impair the absorption of other drugs, such as digoxin, warfarin, and fat soluble vitamins (table 1). This effect can be minimized by administering the other drugs one hour before or four hours after the bile acid sequestrants.
Probucol — Probucol is of historical interest. It modestly lowers LDL-C, but more prominently reduces HDL-C (table 2). It is not available for clinical use. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Lipoproteins and atherosclerosis'.)
Estrogen replacement therapy — We do not prescribe estrogen replacement therapy (ERT) for the purpose of improving the lipid profile. ERT in postmenopausal women may lead to reductions in LDL-C (15 percent) and Lp(a) (20 percent) and elevations in HDL-C (10 to 15 percent) and triglycerides (24 percent) [71-74]. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Lipids'.)
It had been thought that these lipid changes might contribute to a cardioprotective effect of estrogen replacement therapy. However, such a benefit was not confirmed in the Women's Health Initiative, mostly of primary prevention, and the HERS trials of secondary prevention. Estrogen-progestin replacement had no cardioprotective effect and may have produced harm. (See "Menopausal hormone therapy and cardiovascular risk".)
Thyromimetics — Eprotirome appears to be able to reduce serum lipid levels. Long-term studies with clinical end points are required to determine whether eprotirome provides clinical benefits in patients with hypercholesterolemia.
Eprotirome is a thyroid hormone analog that has minimal uptake in nonhepatic tissue . A trial in 184 patients, nearly all without known cardiovascular disease, who were receiving statin therapy but had an LDL-C ≥116 mg/dL (3.0 mmol/L) randomly assigned patients to three different doses of eprotirome or to placebo . After 12 weeks, eprotirome reduced LDL-C in a dose-dependent fashion; at a dose of 100 mcg daily, LDL-C was reduced by 32 percent, compared with a 7 percent reduction with placebo. Similar changes were seen in levels of triglycerides, lipoprotein(a), and apolipoprotein B. Clinical end points were not assessed, and, over the 12 weeks, eprotirome did not appear to produce clinical hyperthyroidism, hypothyroidism, or have adverse effects on the heart or bone; some patients treated with eprotirome did have elevations in serum aminotransferase levels.
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".)
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●Although statins are the preferred therapy for most patients requiring treatment of dyslipidemia, other agents are available with varying levels of evidence for clinical benefits. (See "Statins: Actions, side effects, and administration".)
●In patients who do not achieve the desired low-density lipoprotein cholesterol (LDL-C) goal with statin therapy, we add ezetimibe more frequently than any other lipid altering drug. (See 'Ezetimibe' above.)
●The principal use of fibrate therapy is in the management of patients with hypertriglyceridemia. (See "Hypertriglyceridemia in adults: Management", section on 'Fibrates'.)
ACKNOWLEDGMENT — The UpToDate editorial staff thank John J P Kastelein, MD, PhD, FESC, who contributed to an earlier version of this topic review.
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