Treatment of drug-resistant hypercholesterolemia

INTRODUCTION — Hypercholesterolemia, and in particular, an elevated level of serum (or plasma) low-density lipoprotein cholesterol (LDL-C), is associated with an increased risk of adverse cardiovascular events. Lipid lowering drug therapy, particularly with statins, is indicated to decrease the risk of cardiovascular events in most individuals with established atherosclerotic cardiovascular disease and in many who are at high risk. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Summary and recommendations' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Statins are the preferred therapy for most patients requiring treatment of dyslipidemia and in particular those with an elevated LDL-C. The goals of therapy are discussed elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

If after treatment with the maximal tolerated dose of statin the patient has not achieved the desired LDL-C reduction, a number of other agents are available with varying levels of evidence for clinical benefits. These agents include nicotinic acid (niacin), bile acid sequestrants, ezetimibe, and bempedoic acid and their use is discussed elsewhere. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".)

However, some patients, including young individuals with severe hypercholesterolemia, such as occurs in familial hypercholesterolemia, are unable to sufficiently lower their LDL-C to values with the use of these drugs. In addition some patients cannot receive high-intensity statin therapy due to statin related adverse effects. These individuals remain at high risk for cardiovascular events. For some of these, PCSK9 inhibition may be the next logical step in escalating their treatment and may be sufficiently effective, so that therapies already tried as adjuncts to statin therapy can be discontinued.

This topic will discuss therapeutic options for these individuals, including PCSK9 inhibition, low-density lipoprotein (LDL) apheresis, lomitapide, bempedoic acid, evinacumab, as well as a number of procedures that are rarely performed such as partial ileal bypass surgery, liver transplantation, and portacaval shunting.

LDL-C GOALS — The desirable on-treatment level of low-density lipoprotein cholesterol (LDL-C) varies based on the patient’s risk of cardiovascular disease (CVD) events related to coexisting risk factors and the absence or presence of established CVD. In all patients, lifestyle modification and treatment with the maximal tolerated dose of statin (and possibly other medical therapy) should be tried. The goals of LDL-C lowering are discussed separately. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Dyslipidemia in children and adolescents: Management" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

REFERRAL TO A SPECIALIST — In patients who have drug-resistant hypercholesterolemia, management decisions may be complicated. We recommend that they be referred to a physician who has substantial expertise in managing such individuals.

PHARMACOLOGIC THERAPIES

PCSK9 inhibitors — Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease produced predominantly in the liver that leads to the degradation of hepatocyte low-density lipoprotein (LDL) receptors and increased LDL-cholesterol (LDL-C) levels. Therapies that lower circulating PCSK9 levels significantly lower LDL-C levels. This category of therapy, including PCSK9 antibodies and siRNA (RNAi) inhibitors of PCSK9 synthesis such as inclisiran, is discussed separately. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

The role of PCSK9 inhibition in patients with established cardiovascular disease is discussed elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

The potential role of PCSK9 inhibition in patients with homozygous familial hypercholesterolemia is discussed separately [1] (see "Familial hypercholesterolemia in adults: Treatment"). Most studies report that the LDL-C reduction with PCSK9 inhibitors is 50 percent less in patients with homozygous familial hypercholesterolemia than heterozygous familial hypercholesterolemia [2].

ANGPTL3 Antibodies — Angiopoietin-like 3 protein (ANGPTL3) inhibits endothelial lipase and lipoprotein lipase [1]. The fully human monoclonal antibody evinacumab that binds circulating ANGPTL3 significantly lowers LDL-C by an LDL receptor independent pathway [3,4].

Treatment with evinacumab has been shown to be effective in homozygous familial hypercholesterolemia regardless of the amount of residual LDL receptor activity. This agent is approved in the United States for treatment of hypercholesterolemia in patients with homozygous familial hypercholesterolemia. The medication is administered intravenously (15 mg/kg) every four weeks.

Bempedoic acid — Bempedoic acid is discussed separately. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bempedoic acid'.)

Lomitapide — In December of 2012, the United States Food and Drug Administration (FDA) approved the use of lomitapide for patients with homozygous familial hypercholesterolemia (FH), a rare inherited disorder that is estimated to occur in about one in a million individuals [5]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Familial combined hyperlipidemia'.)

The United States product information for lomitapide carries a boxed warning regarding a serious risk of liver toxicity, as its use is associated with liver enzyme abnormalities. Lomitapide may be embryotoxic; women of child-bearing potential should have a negative pregnancy test before starting treatment and use effective contraception during treatment. The drug is also associated with a risk of severe diarrhea. This adverse event may be mitigated by adherence to a strict low fat diet.

For patients with homozygous FH, we suggest adding lomitapide to treatment with a low-fat diet, lipid-lowering drugs including statins, and treatment with LDL apheresis or liver transplantation. For these patients who are not candidates for or refuse LDL-apheresis or liver transplantation, lomitapide should be considered as additional pharmacological therapy. (See 'LDL apheresis' below.)

Lomitapide is an inhibitor of microsomal triglyceride transfer protein, which transfers triglycerides onto apolipoprotein B as part of the assembly of very low-density lipoprotein within the liver [6]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Endogenous pathway of lipid metabolism'.)

The efficacy and safety of microsomal triglyceride transfer protein inhibition with the oral drug lomitapide have been evaluated in three small clinical studies:

●In a study of six patients with homozygous FH, lomitapide (at doses ranging between 0.03 and 1 mg/kg of body weight per day) decreased LDL-C by 51 percent and apolipoprotein B by 56 percent from baseline values [6].

●A subsequent phase 2 study took into account the side effects of lomitapide noted above. In this trial, 84 patients with moderate hypercholesterolemia (LDL-C 130 to 250 mg/dL [3.4 to 6.5 mmol/L]) were randomly assigned to ezetimibe, escalating doses of lomitapide (5, 7.5, and 10 mg per day), or ezetimibe plus escalating doses of lomitapide [7]. After 12 weeks, LDL-C was lowered by 20, 30 (on 10 mg lomitapide), and 46 percent in the three groups, respectively. Lomitapide also reduced HDL-C by 6 percent and apolipoprotein B by 24 percent.

●In an open-label, phase 3, nonrandomized, dose-escalating study, 29 patients with homozygous FH over the age of 18 were treated with lomitapide at a median dose of 40 mg daily [8]. Most patients received high-dose statin, and 18 patients underwent regular apheresis. After 26 weeks of therapy, LDL-C was reduced by approximately 50 percent from baseline (from 336 to 166 mg/dL [8.7 mmol/L to 4.3 mmol/L]).

In all three studies, the most common adverse events were gastrointestinal symptoms, increased liver aminotransferase levels (about 40 percent), and hepatic fat accumulation (about 8 percent). These side effects were dose-dependent. With regard to hepatic fat accumulation, one study showed stabilization at 30 percent after three years of therapy [8].

Lomitapide is started at 5 mg daily taken orally two or more hours after the evening meal. The dose may be increased after two weeks to 10 mg per day and, based upon tolerability and response, further gradual increases may be made at intervals of four weeks or more, up to the maximum daily dose of 60 mg [9].

Lomitapide is a substrate of cytochrome P450 3A4 (CYP3A4) hepatic metabolism and itself is an inhibitor CYP3A4 metabolism and P-glycoprotein efflux transporters; based upon its metabolic and hepatic effects, numerous significant drug interactions involving lomitapide are anticipated. As examples, the daily dose of lomitapide is limited to 30 mg when taken with weak CYP3A4 inhibitors (eg, amlodipine, atorvastatin, and ranolazine), and use of lomitapide with moderate to strong inhibitors of CYP3A4 is contraindicated. A list of CYP3A4 inhibitors is provided separately in the table (table 1). Specific interactions may be determined by use of the drug interactions program.

In the United States, lomitapide prescribing is restricted to physicians registered in a risk evaluation and mitigation strategy program whose requirements include: limiting use to patients with a diagnosis of homozygous FH, and excluding pregnancy and significant hepatic impairment (Child-Pugh B or C) prior to beginning treatment; the program also emphasizes close monitoring, including baseline and regular hepatic function tests (ie, at least monthly for first year) and educating patients about maintaining a diet supplying less than 20 percent of total calories as fat to reduce hepatic fat accumulation.

NONPHARMACOLOGIC THERAPIES

LDL apheresis — Some patients at very high risk for serious cardiovascular events have not achieved their desired low-density lipoprotein cholesterol (LDL-C) reduction with standard lipid lowering therapy. LDL apheresis, which is approved by the United States Food and Drug Administration, has been recommended by some experts for these individuals. Patients who might be potential candidates include: those with coronary artery disease (CAD) and LDL-cholesterol levels greater than 200 mg/dL after standard therapy; and those without established CAD, but at high risk due to an LDL-cholesterol level greater than 300 mg/dL after dietary and pharmacologic intervention, particularly those who have additional risk such as first-degree relatives with premature CAD, high lipoprotein (a), or high-risk medical condition [10]. Individuals with homozygous familial hypercholesterolemia (FH) usually are treated with LDL apheresis. We believe that clinical judgment plays an important role in the decision to use this burdensome therapy in these patients with or at high risk for cardiovascular disease. (See "Lipoprotein(a)".)

Procedure — LDL apheresis refers to the extracorporeal removal of circulating apo B-containing lipoproteins, including LDL, lipoprotein (a), and very low-density lipoprotein (VLDL). There are multiple apheresis methods, including dextran sulphate cellulose adsorption, heparin-induced extracorporeal LDL cholesterol precipitation, immunoadsorption, and double filtration plasma pheresis of lipoproteins [11]. The procedure is performed weekly or biweekly, determined in part by the rate at which LDL levels return to baseline after therapy. It is available at a limited number of centers and cost is in the range of 3000 to 4000 United States dollars per session.

Efficacy and safety — LDL apheresis lowers LDL-C acutely by 50 to 76 percent [12,13]. However, the time averaged exposure to LDL-C is more likely a better measure of efficacy than the single post-treatment value. This number is calculated using multiple between treatment values. While the optimal time-averaged LDL-C reduction is not known, a 30 percent reduction after six months and 38 percent after 18 months in the absence of statin therapy has been reported [14]. Patients with higher baseline lipid levels appear to have a relatively greater response to this therapy [15]. The range of time for return to baseline level of LDL-C varies between four days and three to four weeks.

The most frequent side effects include hypotension, anemia, nausea, flushing, and headache. Venous access is necessary and many patients require construction of an arteriovenous fistula or placement of a central venous port, which increases the long-term complications [11]. (See "Central venous access in adults: General principles".)

Outcomes — No study has demonstrated significantly improved survival with LDL apheresis [16]. Some studies, which are limited by multiple potential sources of bias, the use of suboptimal doses of statins, or the enrollment of small numbers of patients, have suggested evidence of benefit for outcomes such as myocardial infarction. For example, in an observational study of 130 patients with heterozygous familial hypercholesterolemia (FH) who were treated with either LDL apheresis plus statin therapy (n = 43) or statin therapy (n = 87), there was a significantly lower rate of total coronary events (nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and death from coronary heart disease) in the LDL apheresis group (10 versus 36 percent, respectively) at six years [17].

At least eight studies that evaluated angiographic parameters have evaluated the ability of LDL apheresis to reverse or delay the progression of atherosclerosis. Most of the patients in these studies had heterozygous FH; a few were homozygotes. Six of these studies were observational and in the aggregate did not show convincing evidence of regression [18]. The two trials which randomly assigned patients to either LDL apheresis plus drug therapy or to drug therapy (simvastatin or simvastatin plus a bile acid sequestrant) alone did not show any significant difference in angiographic outcome:

●The Familial Hypercholesterolemia Regression Study randomly assigned 39 patients with heterozygous FH and coronary disease to biweekly LDL-apheresis plus simvastatin (40 mg/day) or to the same dose of simvastatin plus colestipol (20 g/day) [19]. Repeat coronary angiography at approximately two years showed no difference in the mean change in luminal diameter but some secondary angiographic end points were biased in favor of drug therapy.

●The LDL-Apheresis Atherosclerosis Regression Study (LAARS) randomly assigned 42 patients with severe primary hypercholesterolemia (31 patients with heterozygous FH) and coronary atherosclerosis to biweekly LDL-apheresis plus simvastatin (40 mg/day) or to simvastatin alone [20]. At two years, the mean reduction in LDL-C was 63 and 47 percent, respectively. There was no difference in the degree of coronary atherosclerosis between the two groups. Repeat angiography at about two years revealed no difference within or between the two groups in the degree of coronary atherosclerosis, although more minor lesions disappeared in the apheresis group. LAARS also noted an improvement in regional myocardial perfusion in patients treated with apheresis [21] while another report showed improved endothelial function after a single apheresis [22].

Traditional coronary angiography is a relatively blunt outcome measure; several studies have demonstrated improvement in the following cardiovascular effects of LDL apheresis: endothelial function [22], coronary vasodilation [23], microvascular flow [24], and myocardial perfusion [15,25].

The literature contains a number of case reports of children with homozygous FH undergoing LDL apheresis, many of whom had regression of xanthomata [18]. The safety and efficacy of long-term LDL-apheresis was evaluated in a study of 11 children with severe genetic hypercholesterolemia (including children with homozygous FH) who were treated for 2 to 17 years [26]. There were no cardiac deaths, non-fatal myocardial infarctions, or coronary revascularization procedures. Regression of established coronary artery lesions, as well as prevention of the development of new aortic and coronary lesions, was demonstrated.

Clinical use — As no study has demonstrated improved survival with LDL apheresis, and because there are known side effects and patient burden, related to venous access, frequent long visit, and high cost, experts vary in their recommendations for initiation of this therapy and insurers have widely varying thresholds for reimbursement.

We believe LDL apheresis should be considered as an effective method of lowering LDL-C when the patient may experience substantial benefits. Benefit is likely to be greatest when an individual will be or has been exposed to very high LDL-C for many years; this can be thought of as the lifetime risk. We refer very few adult patients with heterozygous FH for the procedure (and no children). We think it is reasonable to consider LDL apheresis in homozygotes or those with analogous phenotypes such as compound heterozygotes if the patient has been treated with diet and pharmacotherapy and if LDL-C remains above the following cut-points:

●LDL-C ≥160 mg/dL in children (age less than 18 years) with established atherosclerotic CVD.

●LDL-C ≥250 mg/dL in children without established atherosclerotic CVD

●LDL-C ≥160 to 190 mg/dL in adults with established CVD

●LDL-C ≥190 mg/dL in adults without established CVD. A recommendation for the use of LDL-apheresis in these individuals should take into account not only the absolute LDL-C level, but also the presence or absence of other cardiovascular risk factors as well as the age of the patient. We consider recommending the procedure for younger individuals and other risk factors with an LDL-C of 190 mg/dL or higher, whereas our threshold for such a recommendation would be significantly higher for a patient without other risk factors or who was older than 50 years.

Recommendations of others — The 2016 European Society of Cardiology/European Atherosclerosis Society Guideline for the management of dyslipidemias recommends LDL apheresis for those with homozygous familial hypercholesterolemia [27].

The Third Report of the National (United States) Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report did not discuss LDL apheresis, in part because they were not intended to address patients with severe hypercholesterolemia associated with defined genetic disorders [28].

The 2011 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents makes the following statement: “Children with homozygous familial hypercholesterolemia (FH) and extremely elevated LDL-cholesterol levels (500 mg/dL) have undergone effective LDL lowering therapy with biweekly LDL apheresis under the care of lipid specialists in academic medical centers” [29].

The National Lipid Associated Expert Panel on FH list the following as possible indications for LDL apheresis in patients who, after six months, do not have an adequate response to maximum tolerated drug therapy [15,30]:

●Functional homozygous FH patients with LDL-C ≥300 mg/dL (or non-high density lipoprotein cholesterol [HDL-C] 330 mg/dL).

●Functional heterozygous FH patients with LDL-C ≥300 mg/dL (or non-HDL cholesterol 330 mg/dL and 0 to 1 risk factors).

●Functional heterozygous FH patients with LDL-C ≥200 mg/dL (or non-HDL cholesterol 230 mg/dL) and high-risk characteristics such as ≥2 risk factors or high lipoprotein (a) ≥50 mg/dL using an isoform insensitive assay.

●Functional heterozygous FH patients with LDL-C ≥160 mg/dL (or non-HDL cholesterol 190 mg/dL) and very high-risk characteristics such as established coronary heart disease, other cardiovascular disease, or diabetes.

Liver transplantation — Liver transplantation is a procedure that has been used in familial hypercholesterolemia homozygous patients to provide the functional hepatic low-density lipoprotein (LDL) receptors that these patients lack. Multiple case reports of children as young as five years of age have demonstrated that successful transplantation leads to normalization of LDL cholesterol (LDL-C) levels beginning as early as five days after surgery [31-34]. For individuals with end-stage coronary artery disease, heart-liver transplant has been described [35,36].

We believe that liver transplantation is a reasonable treatment option for patients with homozygous familial hypercholesterolemia who do not have optimal LDL-C levels after treatment with maximal tolerated cholesterol lowering therapy and for whom receiving regular LDL-apheresis is not possible.

Partial ileal bypass surgery — The efficacy of partial ileal bypass surgery was best assessed in the POSCH trial [37-39]. The study population consisted of 838 patients, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years. The following benefits were noted in those treated with surgery compared to the controls [37]:

●A 23 percent reduction in the serum total cholesterol concentration (181 versus 236 mg/dL [4.71 versus 6.14 mmol/L]).

●A 38 percent reduction in serum LDL-cholesterol.

●A nonsignificant reduction in overall mortality and mortality due to coronary heart disease.

●A significant 35 percent reduction in the combined end point of death due to coronary heart disease and confirmed nonfatal myocardial infarction.

●A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group.

These benefits persisted for five years after the trial (total mean follow-up 14.7 years) with significant reductions in cardiovascular and overall mortality, confirmed nonfatal myocardial infarction, incidence of coronary artery revascularization and onset of clinical peripheral vascular disease [39].

The most common side effect of partial ileal bypass was diarrhea. Other problems included occasional kidney stones, gallstones, and intestinal obstruction [37].

For these reasons, and because newer, less burdensome treatments are available, we do not recommend partial ileal bypass surgery for patients with drug-resistant hypercholesterolemia.

Portacaval shunt — We do not recommend portacaval shunting for patients with drug-resistant hypercholesterolemia, except perhaps for those who cannot be transplanted or treated with LDL apheresis. Portacaval shunting has been evaluated in a limited number of cases [40,41]. One case report described a six-year-old girl with homozygous familial hypercholesterolemia (FH) [40]. Before surgery, the rate of synthesis of low-density lipoprotein (LDL) was fourfold higher than in normolipidemic subjects and the fractional catabolic rate for LDL was reduced to 33 percent of control values. Five months after shunt surgery, the rate of LDL synthesis had declined by 48 percent. This caused a 39 percent reduction in the plasma LDL-cholesterol concentration despite a modest decrease in LDL catabolism. The mechanism of benefit was not well understood. Potential complications include hepatic encephalopathy and pulmonary hypertension [13].

POTENTIAL FUTURE APPROACHES — There are a few drugs under development that could be used in advance of the procedural interventions described in this topic to achieve desirable low-density lipoprotein cholesterol (LDL-C) levels.

Gene therapy — Gene therapy, supplying the normal LDL receptor gene for the treatment of familial hypercholesterolemia (FH), has been tested in mice and human subjects [42-44].

CETP inhibition — Inhibitors of cholesteryl ester transfer protein (CETP) significantly raise HDL-C levels. CETP inhibitors were tested and were found to be insufficiently effective to merit further development. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'CETP inhibition'.)

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: Secondary prevention of cardiovascular disease".)

SUMMARY AND RECOMMENDATIONS

●Background – Some patients, including young individuals with severe hypercholesterolemia such as occurs in severe or compound heterozygous or homozygous familial hypercholesterolemia (FH), are unable to lower their low-density lipoprotein-cholesterol (LDL-C) to values that approach prespecified targets with diet and established lipid lowering therapy, including statins. These individuals remain at high risk for cardiovascular events.

•Pharmacotherapy – Options include PCSK9 inhibition, lomitapide, bempedoic acid, and evinacumab. (See 'Pharmacologic therapies' above.)

•Nonpharmacologic therapy – This includes LDL apheresis and procedures used less often, including partial ileal bypass surgery, liver transplantation, and portacaval shunting. (See 'Nonpharmacologic therapies' above.)

●Adults with heterozygous FH – For adults with heterozygous FH who, after six months of dietary and optimal drug therapy, including the use of PCSK9 inhibitors, have an LDL-C above 300 mg/dL (7.17 mmol/L), and have no established cardiovascular disease, or above 200 mg/dL (5.17 mmol/L) in the presence of established cardiovascular disease, we suggest low-density lipoprotein (LDL) apheresis (Grade 2C). (See 'LDL apheresis' above.)

We recognize that there are multiple factors that should be part of the decision to begin LDL apheresis. We believe it is reasonable to begin such therapy with LDL-C values as low as 160 mg/dL (4.10 mmol/L) in adults with heterozygous FH with evidence of advanced atherosclerotic cardiovascular disease. In addition, we believe it is reasonable to consider the use of LDL apheresis in selected patients with even lower LDL-C levels who have documented progression of their atherosclerotic disease.

●Patients with homozygous FH – For patients with homozygous FH who are on maximal medical therapy and have the following LDL-C values, we suggest either LDL-apheresis or liver transplantation (Grade 2C). The decision between the two should be based on issues of availability, patient preference, and expertise in performing liver transplantation (including operative mortality) (see 'LDL apheresis' above and 'Liver transplantation' above):

•LDL-C ≥160 mg/dL in children (age less than 18 years) with established atherosclerotic CVD

•LDL-C ≥250 mg/dL in children without established atherosclerotic CVD

•LDL-C ≥160 to 190 mg/dL in adults with established CVD

•LDL-C ≥190 mg/dL in adults without established CVD

●Refractory hypercholesterolemia – FH patients without cardiovascular disease who do not achieve LDL-C <200 mg/dL (5.17 mmol/L) or those with established disease who do not achieve an LDL-C <160 mg/dL (4.10 mmol/L) after optimal drug therapy and LDL-apheresis, we suggest adding lomitapide (Grade 2C). For patients who are not candidates for or refuse LDL-apheresis or liver transplantation, lomitapide should be considered as additional pharmacologic therapy.