Hypercholesterolemia

Bempedoic acid

Bempedoic acid is a prodrug that is converted to bempedoyl-CoA, its active form, in the liver. It inhibits adenosine triphosphate-citrate lyase, an enzyme in the cholesterol biosynthesis pathway, upstream to 3-hydroxy-3-methylglutaryl-CoA reductase (target of statins). Similarly to statins, bempedoic acid inhibits cholesterol biosynthesis, triggering an up-regulation of the expression of low-density lipoprotein (LDL)-receptor, which ultimately leads to increasing clearance of LDL particles and lowering of LDL-cholesterol (LDL-C). Unlike statins, however, bempedoic acid is not activated in skeletal muscles, thus making it theoretically less prone to be associated with muscular adverse effects. In the phase 3 CLEAR Wisdom trial, 779 patients with a history of atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia with LDL-C ≥70 mg/dL (≥1.8 mmol/L) despite maximally tolerated lipid-lowering therapy were randomized to bempedoic acid versus placebo for 12 weeks. Bempedoic acid was associated with a 15% reduction in LDL-C from baseline at 12 weeks.[113] In the CLEAR Outcomes trial, statin-intolerant patients receiving bempedoic acid had a 21.7% reduction in LDL-C at 6 months, compared with 0.6% reduction with placebo, and also had a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).[114][115] An associated reduction in major cardiovascular events was also seen in a subgroup of participants without previous cardiovascular event (primary prevention).[116] In the US, bempedoic acid is approved as an adjunct to diet, either alone or in combination with other LDL-C lowering therapies, for the treatment of adults with primary lipidemia including heterozygous familial hypercholesterolemia. It is also approved in the US to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take statin therapy with established cardiovascular disease, or a high risk for a cardiovascular disease event but without established cardiovascular disease. Based on the CLEAR Outcomes trial, bempedoic acid is now indicated as the first nonstatin LDL-C lowering medication for primary prevention patients, broadening the treatable population to approximately 70 million individuals in the US. In Europe, bempedoic acid is approved for the treatment of adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia. It is also approved in Europe for the treatment of adults with established or at high risk for atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels. In the UK, the National Institute for Health and Care Excellence (NICE) recommends bempedoic acid in combination with a statin or a statin plus other lipid-lowering therapies in patients unable to reach LDL‑C goals with the maximum tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in patients who cannot tolerate or cannot be given statins.[117]

Inclisiran

Inclisiran is a small interfering RNA drug that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in the liver. This drug has a long duration of action, which allows for dosing at long intervals. In the ORION-1 phase 2 clinical trial, 501 individuals with elevated LDL-C despite maximally tolerated statin therapy were given one dose or two doses (baseline and 90 days) or placebo. The time-averaged reduction in LDL-C levels over 1 year ranged from 30% to 39% after a single dose and from 30% to 46% after two doses.[118] Sustained reductions in LDL-C and PCSK9 concentrations over 4 years were seen with inclisiran in the ORION-1 open-label extension (ORION-3) and it was well tolerated.[119] The ORION-9 phase 3 randomized controlled trial, which included 482 adults with heterozygous familial hypercholesterolemia found that those who received inclisiran had significantly lower levels of LDL-C than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile.[120] ORION-10 and ORION-11 were randomized controlled trials that included patients with ASCVD and patients with ASCVD risk equivalent; both studies found around 50% reduction in LDL-C in patients who received inclisiran, compared with placebo; however more injection-site adverse events occurred with inclisiran.[121] A prespecified analysis of ORION-11, assessing efficacy in primary prevention in those at risk of ASCVD, found that inclisiran was well tolerated with significant reductions in LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and apoB.[122] One pooled analysis of ORION-9, ORION-10, and ORION-11 suggested potential benefits in reducing major cardiovascular events, but this awaits confirmation in larger outcome trials.[123] A post hoc analysis of ORION-1, -3, -5, -9, -10, -11, and ongoing ORION-8 trials demonstrated that long-term treatment with inclisiran was well tolerated, without new safety signals, and showed that serious or discontinuation-inducing treatment-emergent adverse events (TEAE), hepatic, muscle, and kidney events, incident diabetes, and elevations of creatine kinase or creatinine accrued at a comparable rate between inclisiran and placebo for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran, and treatment-induced antidrug antibodies were uncommon.[124] The VICTORION-INITIATE trial, a phase 3b study, demonstrated that an “inclisiran first” strategy, where inclisiran was added immediately upon failure to reach LDL-C <70 mg/dL (<1.8 mmol/L) despite maximally tolerated statins, led to significantly greater reductions in LDL-C compared with usual care (60.0% vs. 7.0%; P <0.001).[125] The ORION-5 trial, a phase 3, multicenter study, assessed the efficacy, safety, and tolerability of inclisiran in patients with homozygous familial hypercholesterolemia. Despite substantial lowering of PCSK9 levels, inclisiran did not significantly reduce LDL-C levels compared with placebo, but it was well-tolerated with no significant differences in adverse events between the groups.[126] A cardiovascular outcomes trial (ORION-4) to determine the efficacy of inclisiran is also recruiting patients. In the US, inclisiran is approved as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia including heterozygous familial hypercholesterolemia, to reduce LDL-C. In Europe, inclisiran is approved for the treatment of adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia. In the UK, NICE recommends inclisiran for treating primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia as an adjunct to diet in adults. It is recommended only if there is a history of cardiovascular events and LDL-C concentrations are persistently 100 mg/dL (2.6 mmol/L) or more, despite maximum tolerated lipid-lowering therapy.[127]

Evinacumab

Evinacumab is a fully human monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3), a secreted protein expressed in the liver, which increases plasma concentrations of LDL-C (independent of LDL-receptor activity), triglycerides, and HDL-C. In the US and Europe, evinacumab is approved as an adjunct to other LDL-C lowering therapies for the treatment of adults and children (ages 5 years and older in the US and ages 12 years and older in Europe) with homozygous familial hypercholesterolemia. It is also being investigated as a treatment for refractory hypercholesterolemia, in those with or without heterozygous FH. In one phase 2 randomized open-label trial, evinacumab was associated with sustained reductions in LDL-C and was generally well tolerated.[128]

Sebelipase alfa in lysosomal acid lipase deficiency

Lysosomal acid lipase is an enzyme that is involved in metabolizing endocytosed lipid particles. Lysosomal acid lipase deficiency is a rare and under-appreciated disorder that causes cirrhosis and severe dyslipidemia. The safety and effectiveness of enzyme-replacement therapy with sebelipase alfa has been studied in a phase 3 multicenter randomized controlled trial of 66 children and adults with lysosomal acid lipase deficiency.[129] Among the participants, 58% had baseline LDL-C levels ≥190 mg/dL and 31% had biopsy-proven cirrhosis. Sebelipase alfa was administered intravenously every other week for 20 weeks with a primary end point of alanine aminotransferase normalization. During follow-up there was normalization in the alanine aminotransferase level in 31% of participants in the sebelipase alfa group versus 7% in the control group (P = 0.03), with mean changes from baseline of -58 U/L versus -7 U/L (P <0.001). There were also significant improvements in lipid levels and hepatic fat content, with similar proportions of adverse events between groups. As such, sebelipase alfa therapy appears a promising therapy for some patients with lysosomal acid lipase.

Emerging treatments

Your Organizational Guidance

Bempedoic acid

Inclisiran

Evinacumab

Sebelipase alfa in lysosomal acid lipase deficiency