Additional Low-density Lipoprotein Cholesterol Lowering Research Articles

Evolocumab (Repatha)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform nonbinding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses Evolocumab (Repatha) 140 mg/mL, prefilled syringea and autoinjector, subcutaneous injection 120 mg/mL, automated mini-doser with prefilled cartridge, subcutaneous injection. Indication: Evolocumab is indicated for the reduction of elevated low-density-lipoprotein cholesterol (LDL-C) in adult patients with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH] and atherosclerotic cardiovascular disease [ASCVD]): as an adjunct to diet and statin therapy, with or without other lipid-lowering therapies, in patients who require additional lowering of LDL-C as an adjunct to diet, alone or in combination with nonstatin lipid-lowering therapies, in patients for whom a statin is contraindicated

12369 Clinical Experience With Inclisiran At An Academic Center

Abstract Disclosure: L. Chavez Marin: None. M. Gonzalez: None. M.F. Linton: None. B.G. Carranza Leon: None. Background: Inclisiran, a small interfering RNA (siRNA) molecule designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), is the only siRNA approved for management of elevated low-density lipoprotein cholesterol (LDL-C) in both primary (for patients with familial hypercholesterolemia) and secondary prevention of cardiovascular disease. In clinical trials, Inclisiran has been shown to reduce LDL-C by more than 50% in populations at high cardiovascular risk. However, real world data about its tolerability and efficacy is still limited. Methods: We conducted an electronic medical record search to identify subjects who were prescribed Inclisiran at a lipid clinic within Vanderbilt University Medical Center (Nashville, USA). Subjects were included if they received at least one dose of Inclisiran and had pre- and post- LDL-C levels. Subjects taking other LDL-C lowering medications like statins, ezetimibe, bempedoic acid, and PCSK-9 inhibitors were included. Pre- and post- LDL-C averages were calculated and analyzed with 95% confidence intervals. The reasons for medication discontinuation were also examined. Results: Out of 69 subjects identified, only 19 met criteria for inclusion, while 32 never received a dose due to cost burden and insurance denial. The other 18 subjects were not included due to inadequate lab results at the time of data collection. In subjects who received at least one dose of Inclisiran, average pre-LDL-C was 142 mg/dL [CI: 34.7] while post-LDL-C was 77 mg/dL [CI: 24.0], notable for a 46% decrease in LDL-C levels. These subjects were also receiving another lipid lowering agent, like a statin, or had previously used a monoclonal antibody-PCSK-9 inhibitor. Those without prior use of PCSK-9 inhibitors were also analyzed. Average pre-LDL-C was 109.5 mg/dL [CI: 15.8] while post-LDL-C was 39.8 mg/dL [CI: 17.2], which revealed a 64% decrease in LDL-C levels. The main reason for discontinuation of Inclisiran was insurance denial followed by individual preference. Only one subject discontinued Inclisiran due to experiencing a generalized rash. Conclusions: Inclisiran is an effective and overall well-tolerated medication indicated for the management of elevated LDL cholesterol. Our study revealed that for individuals with above goal LDL-C, despite maximum tolerated therapy with a statin, additional LDL-C lowering benefits can be seen with Inclisiran use. However, insurance approval and cost burden seem to be the main barriers for access. Presentation: 6/3/2024

Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.

Lerodalcibep, a novel small recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 ml SC dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep was evaluated in heterozygous familial hypercholesterolaemia (HeFH) patients requiring additional LDL-C lowering. Patients were randomized 2:1 to monthly SC injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the percent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L] lerodalcibep reduced LDL-C, compared to placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean(SE); 95% CI -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < 0.0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended ESC LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. Lerodalcibep, a novel anti-PCSK9 small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with HeFH with a safety profile similar to placebo.

Characterization of Inclisiran Use in Real World: Prescription Data from Germany

<h3>Lead Author's Financial Disclosures</h3> Raquel Lahoz is an employee of Novartis Pharma AG, Basel, Switzerland, and owns Novartis shares. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Despite the availability of effective low-density lipoprotein cholesterol (LDL-C) lowering drugs, ∼80% of patients with established ASCVD fall short of achieving and maintaining LDL-C levels <70 mg/dL, highlighting the need for innovative new LDL-C lowering therapies. Inclisiran is a novel small-interfering RNA (siRNA) that effectively reduces circulating LDL-C. Administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months, inclisiran has been approved by the European Medicines Agency (EMA) in December 2020 for adult patients with hypercholesterolemia as an adjunct to diet who require additional lowering of LDL-C despite receiving other lipid-lowering therapies and by the Food and Drug Administration (FDA) in December 2021. <h3>Objective/Purpose</h3> This study aimed to assess real-world patient characteristics, adherence and persistence for patients being initiated with inclisiran in Germany. <h3>Methods</h3> This retrospective non-interventional study used the IQVIA LRx prescription database and included adult patients being initiated with inclisiran treatment between February 2021 and October 2021 with a 6-month lookback period. For the adherence and persistence analyses, a subgroup of patients with a first inclisiran prescription recorded between February and June 2021 was selected, allowing for at least 4 months follow-up, up to October 2021. <h3>Results</h3> A total of 697 patients receiving at least one dose of inclisiran between February- October 2021 were included in this study. Mean age of patients was 63 years (50% females) and 81% were ≥ 55 years old. Majority of patients were prescribed inclisiran by their nephrologists (42%) and cardiologists (30%). Of the 334 patients receiving their first inclisiran dose between February-June 2021, the second dose was also recorded for 257 (77%) patients until the time of the analysis; median time between the two doses was 3 months and 91% (233) of patients received the second dose within 4 months of treatment initiation. <h3>Conclusions</h3> This study shows early results from one of the first real-world studies describing the characteristics of patients being initiated with inclisiran with majority returning for their second dose within 4 months. Future real-world studies with longer follow-up are needed to evaluate the long-term adherence and persistence as well as effectiveness of inclisiran.

LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments

BackgroundThe 2019 European guidelines (ESC/EAS) for the treatment of dyslipidaemias recommend more aggressive targets for low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH). Current lipid-lowering treatment is often inadequate to achieve these targets. MethodsData from the HELLAS-FH registry were analysed to assess achievement of LDL-C targets in adults with FH based on the 2019 ESC/EAS guidelines. In patients who had not achieved LDL-C target, the maximally reduced LDL-C value was calculated after theoretical switch to rosuvastatin/ezetimibe 40/10 mg/day. The percentage of patients who remained candidates for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) was then calculated. ResultsPatients (n = 1694, mean age 50.8 ± 14.7 years) had LDL-C levels 242 ± 71 mg/dL (6.3 ± 1.8 mmol/L) at diagnosis. Most treated patients were receiving statins (97.5%) and about half were on additional ezetimibe (47.5%). Based on the 2019 ESC/EAS guidelines the percentage of patients achieving LDL-C goals was only 2.7%. Following theoretical up titration to rosuvastatin/ezetimibe 40/10 mg, LDL-C target achievement rate would increase to 5.9%. In this scenario, most patients (55.9%) would be eligible for PCSK9i treatment. Following theoretical administration of a PCSK9i, LDL-C target achievement rate would rise to 57.6%. However, 42.4% of patients would still be eligible for further LDL-C lowering treatment. ConclusionsMost FH patients do not reach new LDL-C targets even if on maximum intensity statin/ezetimibe treatment. In this case, more than half of FH patients are candidates for PCSK9i therapy and a considerable proportion may still require additional LDL-C lowering.

Greater than expected reduction in low-density lipoprotein-cholesterol (LDL-C) with bempedoic acid in a patient with heterozygous familial hypercholesterolemia (HeFH)

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that reduces levels of low-density lipoprotein-cholesterol (LDL-C) in the plasma by inhibition of cholesterol synthesis in hepatic cells, which leads to up-regulation of hepatic LDL receptors. Bempedoic acid is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. In this case study, we describe a patient with HeFH who had a prior excellent response to statin but unable to take the same, and a less than expected response to PCSK9i, in whom initiation of bempedoic acid led to a substantial reduction of LDL-C. Our findings suggest that patients who are quite responsive to statins may also be quite responsive to bempedoic acid, a medication that works in the same biochemical pathway as HMG-CoA reductase inhibitors. Additionally, this medication may be particularly effective at lowering LDL-C among individuals not on background statin therapy.

Bempedoic Acid for Heterozygous Familial Hypercholesterolemia: From Bench to Bedside.

Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.

Bempedoic Acid: a cholesterol lowering agent with a novel mechanism of action

ABSTRACT Introduction Dyslipidemia is a common condition that increases the risk of heart diseases and stroke. High levels of low-density lipoprotein-cholesterol (LDL-C) are correlated with a higher risk for heart disease. A drug class known as ‘statins’ is the gold standard for LDL-C-lowering, but its use in some patients is limited by its adverse effects of myalgias and myopathies. Use of other LDL-C-lowering agents is frequently limited by cost and degree of efficacy. Additionally, many high-risk atherosclerotic cardiovascular disease patients fail to meet LDL-C goals despite maximally tolerated statin therapy with or without the addition of a non-statin agent. Areas Covered This review covers the pharmacology, pharmacokinetics, clinical trials, and clinical implications of bempedoic acid. A PubMed search was conducted using the terms bempedoic, bempedoic acid, Nexletol, ETC-1002, and adenosine triphosphate citrate lyase inhibitor. Additional data were obtained from the prescribing information and relevant guidelines. All clinical trials were included. Expert Opinion Bempedoic acid has not been shown to cause myalgias or myopathies and is likely to be competitively affordable compared to other LDL-C-lowering agents. Bempedoic acid has been shown to be superior compared to placebo and provides additional LDL-C lowering on top of maximally tolerated statin therapy or combined with ezetimibe alone.

Role of Bempedoic Acid in Dyslipidemia Management.

Statins remain the preferred agent to reduce low-density lipoprotein cholesterol (LDL-C) and lower atherosclerotic cardiovascular disease (ASCVD) risk. Additional nonstatin agents are recommended to further lower LDL-C among patients at high-risk of ASCVD or those with heterozygous familial hypercholesterolemia, despite statin therapy. Patients unable to tolerate recommended doses of statin therapy due to adverse effects, including statin-associated muscle symptoms, may also require additional nonstatin agents to lower LDL-C and ASCVD risk. Bempedoic acid is a first-in-class, once-daily oral agent, recently approved as monotherapy and in combination with ezetimibe, as an adjunct to maximally tolerated statin therapy in patients with ASCVD or heterozygous familial hypercholesterolemia who require additional LDL-C lowering. Its novel mechanism is reported to avoid adverse muscle symptoms associated with statins. The effectiveness and safety of bempedoic acid and bempedoic acid/ezetimibe combination have been reported in multiple phase 2 and 3 trials. In this review, we report the lipid-lowering effects associated with bempedoic acid, and the safety profile from multiple clinical trials. Based on available data, bempedoic acid significantly lowers LDL-C and other atherogenic lipoprotein measures, and high-sensitivity C-reactive protein when added to background lipid-lowering therapy in patients with and without statin intolerance. Overall safety of bempedoic acid seems to be comparable to placebo, except for increased serum uric acid and tendon rupture. Ongoing clinical trials assessing the long-term safety and cardiovascular outcomes will provide additional insight into the role of bempedoic acid as an adjunct lipid-lowering medication.

Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials

An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options. The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)-citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%-28.5% vs placebo. This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180mg of bempedoic acid (n=2424) or placebo (n=1197) once daily for 12 to 52weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests. Of 3621 patients (the median drug exposure: 363days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups. Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT.

Bempedoic acid for the treatment of dyslipidemia

Cardiovascular disease (CVD) is the leading cause of death worldwide and one key factor associated with the increased CVD risk is dyslipidemia. Statin therapy remains the first-line treatment to manage dyslipidemia, yet many patients do not achieve optimal low-density lipoprotein-cholesterol (LDL-C) levels even after taking moderate- or high-intensity statins; therefore, additional, non-statin therapy is often needed. Bempedoic acid is a prodrug that, once activated, decreases LDL-C levels by the inhibition of adenosine triphosphate citrate lyase in the liver. Five clinical trials have demonstrated the safety and efficacy of bempedoic acid and the bempedoic acid/ezetimibe combination in lowering LDL-C in patients with atherosclerotic CVD and heterozygous familial hypercholesterolemia and also in high-risk primary prevention, and statin-intolerant patients. Bempedoic acid has been demonstrated to lower LDL-C levels by 15–25% in clinical trials and up to 38% when combined with ezetimibe. In 2020, the FDA approved bempedoic acid. Furthermore, the combination of bempedoic acid with ezetimibe is FDA approved for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic CVD who require additional LDL-C lowering after maximally tolerated statin therapy. The ongoing CLEAR OUTCOMES trial aims to evaluate whether bempedoic acid can reduce cardiovascular events in patients with statin intolerance and results will be available in the next 3 years. This outcomes trial will be pivotal for determining the role of bempedoic acid in the non-statin lipid-lowering armamentarium.

A Meta-Analysis Assessing Additional LDL-C Reduction from Addition of a Bile Acid Sequestrant to Statin Therapy

BackgroundStatins are the first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C). However, there are secondary prevention patients who are either intolerant to maximal statin therapy or do not get adequate effects from a high-intensity statin. While data exist for the additional LDL-C-lowering effects of ezetimibe, there are no data on additional LDL-C lowering of bile acid sequestrants when combined with statin therapy. The purpose of this study was to quantify the LDL-C-lowering effects of bile acid sequestrants when added to statin therapy. MethodsDatabases (Medline via PubMed, Embase, and the Cochrane Library) were searched for randomized controlled trials comparing statin therapy to statin therapy with the addition of bile acid sequestrants. Nine studies were included in the meta-analysis. A meta-regression was performed to estimate the mean difference in LDL-C between the 2 groups. ResultsWithout controlling for other variables, data suggest that combining statin with bile acid sequestrant increases the percentage change in LDL-C by 16.2 points, on average, compared with statin use alone. ConclusionIn patients unable to tolerate an adequate statin dosage, bile acid sequestrants offer a viable alternative with additional LDL-C-lowering benefit.

Bempedoic acid: effect of ATP-citrate lyase inhibition on low-density lipoprotein cholesterol and other lipids.

Bempedoic acid is a new, first-in-class oral ATP-citrate lyase (ACLY) inhibitor that has to be converted to its CoA thioester before it inhibits ACLY. This conversion only occurs in the liver and not in skeletal muscle. This may explain why, unlike the statins, bempedoic acid does not cause myalgia. Bempedoic acid given at a dosage of 180 mg orally once daily produces a highly significant reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and importantly also in high-sensitivity C-reactive protein. It has recently been approved by both the Food and Drug Administration (FDA) and the European Commission for use in adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-C, and for the treatment of adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, respectively.

P828Low-density lipoprotein cholesterol lowering therapy and target level attainment after a recent myocardial infarction - nationwide cohort study

Abstract Background Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease after a myocardial infarction (MI). The European Society of Cardiology (ESC) guidelines recommend lipid lowering therapy to reach LDL-C treatment targets after an MI. Purpose To assess LDL-C target level attainment according to the ESC guidelines among patients with a recent MI in Sweden. Methods We used data from nationwide registers in Sweden and included patients aged 18–74 years admitted to a hospital with MI (1 January 2013–1 October 2016). Among patients who were alive and had LDL-C data available, we assessed LDL-C target achievement at 6–10 weeks (n=21,505) and 12–14 months (n=17,957) after the MI by category of lipid lowering therapy (no statin; low/moderate-intensity statins; high-intensity statins; any statin plus ezetimibe). The target was defined as an LDL-C of &lt;1.8 mmol/L and a ≥50% reduction from the baseline if LDL-C was 1.8–3.5 mmol/L and the patient was not already receiving statins. Results Most patients were treated with high-intensity statin monotherapy (84.2% and 72.0%) or any statin with ezetimibe (2.1% and 10.4%) at 6–10 weeks and 12–14 months after the MI, respectively. In total, 37.7% (6–10 weeks) and 38.3% (12–14 months) had attained their LDL-C target. The proportion of patients attaining their LDL-C target at 6–10 weeks was 12% (no statin), 30% (low/moderate-intensity statins), 39% (high-intensity statins), and 49% (any statin plus ezetimibe). The corresponding numbers at 12–14 months were 16% (no statin), 29% (low/moderate-intensity statins), 39% (high-intensity statins), and 58% (any statin plus ezetimibe). A total of 11.8% at 6–10 weeks and 12.3% at 12–14 months reached an LDL-C level of &lt;1.8 mmol/L, but did not reach their LDL-C target level due to the ≥50% reduction criteria. (Figure 1) Figure 1 Conclusions In this large population-based study using nationwide data, more than half of patients with a recent MI did not achieve the ESC guidelines LDL-C target levels, despite a large proportion with high-intensity statin therapy. In patients treated with statins and ezetimibe, four out of ten did not reach the ESC LDL-C target level. Our findings indicate that there may be a need for additional LDL-C lowering therapy if the target level is to be attained in all patients. Acknowledgement/Funding This project was supported by funding from Merck Sharp &amp; Dohme.

Adding ezetimibe to statin therapy: latest evidence and clinical implications.

BackgroundStatins are the hypolipemic treatment of choice for hyperlipidemia with confirmed atherosclerotic cardiovascular disease (ASCVD) protective effect, proven even in normolipemic patients. But in rare situations, even with a high-dose treatment regimen, or maximally tolerated statin dose treatment, treatment targets of low-density lipoprotein cholesterol (LDL-C), according to the risk profile of the patient, cannot be achieved. Combination therapy with ezetimibe is an effective treatment choice, as it is one of the few hypolipemic drugs with proven ASCVD protective effect.AimIn this review, we address the question of therapeutic efficacy and safety of ezetimibe in combination therapy with statins, as expressed through its hypolipemic and vasoprotective effects and its potential side effects.MethodsWe conducted a literature review of English articles through PubMed, PubMed Central, and Cochrane for randomized clinical trials, retrospective analyses, meta-analyses, and review articles by using key words: ezetimibe, statins, combination therapy, adverse effects. We analyzed data on ezetimibe–statin combination therapy in terms of hypolipemic efficacy, ASCVD risk reduction, and adverse effects.ResultsStatins have been proven to be very effective in reducing ASCVD risk, with no apparent threshold at which LDL-C lowering is not associated with reduced risk. Yet, a significant on-treatment residual risk of major cardiovascular (CV) events still exists according to meta-analyses of statin trials. Findings like this point to the unmet needs of the patients on statin treatment. The unmet needs in terms of LDL-C targets and ASCVD risk reduction raise the question of statin combination therapy. Ezetimibe is a cholesterol-lowering drug from the class of cholesterol absorption inhibitors, with the potency to decrease LDL-C by about 10–18% and Apo B by 11–16%, while in combination therapy with statins, an additional LDL-C lowering of 25% or total LDL-C lowering of 34–61% is observed. The effects on LDL-C and other lipoprotein (LP) fractions are translated by ASCVD risk reduction. Ezetimibe is one of the few hypolipemic medications that leads to additional ASCVD risk reduction when added to statin therapy. Present data on ezetimibe support the existence of pleotropic anti-inflammatory and antioxidative effects, in addition to its hypolipemic effect, which are responsible for this added ASCVD risk reduction on top of statin monotherapy. Ezetimibe, in combination therapy with a maximal or maximally tolerated statin therapy, is used in patients who fail to achieve target LDL-C levels with statin monotherapy. In combination with low-to-moderate statin dose treatment, or with second- or third-line statins, ezetimibe is used in situations of statin-associated muscle symptoms. The combination therapy is relatively safe.ConclusionEzetimibe add-on to statin combination therapy is an effective treatment option that leads to additional LDL-C lowering – recommended in situations where, with a maximal or maximally tolerated statin monotherapy treatment regimen, LDL-C targets cannot be achieved. It leads to additional ASCVD risk reduction, without raising significant safety concerns.

Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study

Background and aimsPatients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering. MethodsThis phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C. ResultsThe study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; −23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (−23.6%), total cholesterol (−18.0%), apolipoprotein B (−19.3%), and high-sensitivity C-reactive protein (−31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups. ConclusionsBempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.

Abstract P275: Prescription of PCSK9 Inhibitors in the United States, by Patient, Provider, and Payer Characteristics, 2016

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved in 2015 for use by adults with familial hypercholesterolemia (FH) or clinical atherosclerotic cardiovascular disease (ASCVD) requiring additional low-density lipoprotein cholesterol lowering beyond use of diet modification and maximally tolerated statin therapy. This study describes the patient, provider and payer related characteristics of prescriptions filled for this new class of injectable medication during 2016. Methods: 2016 quarterly state-level prescription data were obtained from Symphony Health Solution’s PHAST 2.0. PHAST 2.0 includes data on over 90% of prescriptions filled from US retail and mail order pharmacies and, along with market purchasing data, are used to calculate state and national estimates. PCSK9 inhibitor fills among adults aged ≥18 years were characterized by quarter, patient age, provider type, and payer type. Per-capita fill rates across US states and total and patient spending per 30-day supply were calculated. Results: In 2016, 216,082 PCSK9 inhibitor prescriptions were filled. The number of fills per quarter increased from 20,348, in Q1, to 83,812, in Q4, and fill totals were greatest among those aged 65-74 years (39.3% of fills) (Figure). Cardiologists prescribed the majority of fills (60.5%). Commercial payers (43.3%) and Medicare (43.1%) were the most frequent payers. State per-capita fill rates (per 100,000) ranged from 12.1, in WY, to 191.9, in LA (median: 69.1). Total spending per 30-day supply was $951; patient spending was $58 per 30-day supply. Conclusion: Quarterly fills for PCSK9 inhibitors quadrupled during 2016, with substantial variation in per-capita fill rates across states. Cardiologists prescribed the majority of fills, which aligns with their indicated use among adults with FH or ASCVD. Total spending per 30-day supply was considerable. Tracking of prescribing trends for these medications is warranted as additional information about their efficacy becomes available.

Prescribing Patterns of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in Eligible Patients With Clinical Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia

Two proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are approved for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who require additional low-density lipoprotein cholesterol (LDL-C) lowering. This retrospective study sought to determine differences between eligible patients who were prescribed and those who were not prescribed a PCSK9 inhibitor. Patients from an electronic medical record database were included in the analysis, and their demographic, clinical, and treatment characteristics were evaluated. Of 368,624 PCSK9 inhibitor-eligible patients, 1,752 (<0.5%) received a PCSK9 inhibitor prescription. Patients who received a PCSK9 inhibitor were more frequently associated with a higher cardiovascular disease risk category and a higher baseline LDL-C level (139.4 vs 103.5 mg/dl; p <0.0001) compared with those who did not. Patients with a PCSK9 inhibitor prescription were significantly more likely to be on ezetimibe, alone or in combination with a statin, at baseline compared with those without (29% vs 5%; p <0.0001). The use of a PCSK9 inhibitor was very low in the 2 groups of patients identified as PCSK9 inhibitor-eligible based on the American College of Cardiology Expert Consensus Decision Pathway. In conclusion, this study demonstrates that most PCSK9 inhibitor-eligible patients do not receive a PCSK9 inhibitor prescription, highlighting that many high-risk patients could benefit from additional LDL-C lowering with a PCSK9 inhibitor.

Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11–17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55–75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use.Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0620-7) contains supplementary material, which is available to authorized users.

Patient Characteristics and Real-World Treatment Patterns Among Early Users of PCSK9 Inhibitors.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce low-density lipoprotein cholesterol (LDL-C) levels and are approved for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional LDL-C lowering. Our objective was to characterize patients receiving PCSK9i medications in real-world practice and describe physician-reported treatment patterns among dyslipidemia patients using PCSK9i or other lipid-lowering therapy. We analyzed data from a point-in-time Adelphi dyslipidemia disease-specific programme (DSP) survey conducted in the USA in 2016. Physicians provided treatment history, laboratory values, patient characteristics, and comorbidities for treated patients. To ensure sufficient numbers of PCSK9i-treated patients, we conducted systematic oversampling of patients being prescribed PCSK9i. Outcomes included patient characteristics and physician-reported treatment patterns. The DSP included 159 physicians, who provided information on 1522 patients (304 PCSK9i; 1218 non-PCSK9i). Mean±standard deviation (SD) baseline LDL-C levels were 180.0±39.7mg/dl for PCSK9i patients and 159.2±40.5mg/dl for non-PCSK9i patients. Prior statin use was reported in 69.1% of PCSK9i patients and 19.5% of non-PCSK9i patients, and physician-reported statin intolerance was observed in 31.6% of PCSK9i and 5.3% of non-PCSK9i patients. Use of statins only was reported in 40.5% of PCSK9i and 88.8% of non-PCSK9i patients. The most common physician-reported reasons for change to PCSK9i were lack of efficacy (70.2%) and muscle-related symptoms (myalgia 28.6%; myopathy 11.1%). Physicians surveyed appeared to prescribe PCSK9i medications appropriately. PCSK9i-treated patients had higher rates of cardiovascular comorbidities and physician-determined statin intolerance, had higher LDL-C levels, and received more lines of therapy than non-PCSK9i patients.