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Purpose: The objective of this investigation is to examine the benefits and potential risks of these drugs in individuals by varying baseline low-density lipoprotein cholesterol (LDL-C) values, utilizing the concept of the number needed to treat (NNT)., Methods: We extensively searched electronic databases, such as PubMed, EMBASE, Cochrane, and Web of Science, up to 6 August 2023. Baseline LDL-C values were stratified into four categories: < 100, 100-129, 130-159, and ≥ 160 mg/dL. Risk ratios (RRs) and NNT values were computed., Results: This analysis incorporated data from 46 randomized controlled trials (RCTs), encompassing a total of 237,870 participants. The meta-regression analysis demonstrated an incremental diminishing risk of major adverse cardiovascular events (MACE) with increasing baseline LDL-C values. Statins exhibited a significant reduction in MACE [number needed to treat to benefit (NNTB) 31, 95% confidence interval (CI) 25-37], but this effect was observed only in individuals with baseline LDL-C values of 100 mg/dL or higher. Ezetimibe and PCSK9 inhibitors also were effective in reducing MACE (NNTB 18, 95% CI 11-41, and NNTB 18, 95% CI 16-24). Notably, the safety outcomes of statins and ezetimibe did not reach statistical significance, while the incidence of injection-site reactions with PCSK9 inhibitors was statistically significant [number needed to treat to harm (NNTH) 41, 95% CI 80-26]., Conclusion: Statins, ezetimibe, and PCSK9 inhibitors demonstrated a substantial capacity to reduce MACE, particularly among individuals whose baseline LDL-C values were relatively higher. The NNT visually demonstrates the gradient between baseline LDL-C and cardiovascular disease (CVD) risk., Systematic Review Registration: Registration: PROSPERO identifier number: CRD42023458630., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD)., Methods: A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges's g and a Mantel-Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events., Results: The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= - 0.41; CI - 0.63 to - 0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: - 0.81; CI - 1.52 to - 0.10; P = 0.02)., Conclusion: This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Familial hypercholesterolemia is a common genetic condition that significantly increases an individual's risk of cardiovascular events such as heart attack, stroke, and cardiac death and is a candidate for population-wide screening programs. Economic analyses of strategies to identify and treat familial hypercholesterolemia are limited by a lack of real-world cost estimates for screening services and medications for reducing cardiovascular risk in this population., Methods: We estimated the cost of lipid panel testing in patients with hyperlipidemia and the cost of statins, ezetimibe, and PCKS9 inhibitors in patients with familial hypercholesterolemia from a commercial claims database and report costs and charges per panel and prescription by days' supply., Results: The mean cost for a 90-day supply for statins was $183.33, 2.3 times the mean cost for a 30-day supply at $79.35. PCSK9 inhibitors generated the highest mean costs among medications used by patients with familial hypercholesterolemia., Conclusions: Lipid testing and lipid-lowering medications for cardiovascular disease prevention generate substantial real-world costs which can be used to improve cost-effectiveness models of familial hypercholesterolemia screening and care management., (© 2024. Italian Society of Hypertension.)

Aim: We aimed to assess the cost effectiveness of four different lipid-lowering strategies for primary prevention of coronary heart disease initiated at ages 30, 40, 50, and 60 years from the UK National Health Service perspective., Methods: We developed a microsimulation model comparing the initiation of a lipid-lowering strategy to current standard of care (control). We included 458,692 participants of the UK Biobank study. The four lipid-lowering strategies were: (1) low/moderate-intensity statins; (2) high-intensity statins; (3) low/moderate-intensity statins and ezetimibe; and (4) inclisiran. The main outcome was the incremental cost-effectiveness ratio for each lipid-lowering strategy compared to the control, with 3.5% annual discounting using 2021 GBP (£); incremental cost-effectiveness ratios were compared to the UK willingness-to-pay threshold of £20,000-£30,000 per quality-adjusted life-year., Results: The most effective intervention, low/moderate-intensity statins and ezetimibe, was projected to lead to a gain in quality-adjusted life-years of 0.067 per person initiated at 30 and 0.026 at age 60 years. Initiating therapy at 40 years of age was the most cost effective for all lipid-lowering strategies, with incremental cost-effectiveness ratios of £2553 (95% uncertainty interval: 1270, 3969), £4511 (3138, 6401), £11,107 (8655, 14,508), and £1,406,296 (1,121,775, 1,796,281) per quality-adjusted life-year gained for strategies 1-4, respectively. Incremental cost-effectiveness ratios were lower for male individuals (vs female individuals) and for people with higher (vs lower) low-density lipoprotein-cholesterol. For example, low/moderate-intensity statin use initiated from age 40 years had an incremental cost-effectiveness ratio of £5891 (3822, 9348), £2174 (772, 4216), and was dominant (i.e. cost saving; -2,760, 350) in female individuals with a low-density lipoprotein-cholesterol of ≥ 3.0, ≥ 4.0 and ≥ 5.0 mmol/L, respectively. Inclisiran was not cost effective in any sub-group at its current price., Conclusions: Low-density lipoprotein-cholesterol lowering from early ages is a more cost-effective strategy than late intervention and cost effectiveness increased with the increasing lifetime risk of coronary heart disease., (© 2023. Crown.)

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials., (© 2023. The Author(s).)

Background: Despite treatment with statins, dyslipidaemia patients with elevated cholesterol- and triglyceride-levels remain at high residual risk for major adverse cardiovascular events (MACE). New lipid-lowering drugs must prevent the occurrence of MACE and exhibit cost-effectiveness for their successful adoption to clinical practice., Objective: To assess the cost effectiveness of icosapent ethyl, fenofibrate, ezetimibe, evolocumab, and alirocumab in combination with statins compared to statin monotherapy for cardiovascular prevention from the perspective of UK's National Health Service., Methods: A Markov model simulated the progression of cardiovascular disease and MACE, including myocardial infarction, stroke, angina pectoris, and coronary revascularisation, in dyslipidaemia patients. The model was populated with cardiovascular outcome trial data for each drug. Cost and utility data were extracted from peer-reviewed literature. The incremental cost-effectiveness ratio (ICER) is reported per quality-adjusted life years (QALY) gained in 2021 Great Britain Pounds (£)., Results: For primary cardiovascular prevention, icosapent ethyl increased QALYs by 0.79 and costs by £15,421 compared to statin monotherapy (ICER = £19,485/QALY). Fenofibrate yielded 0.62 additional QALYs at cost-savings of - £6127 (ICER = - £9932/QALY). For secondary prevention, the omega-3 fatty acid icosapent ethyl extended QALYs by 0.98 at costs of £12,981 compared to statin monotherapy (ICER = £13,285/QALY). Fenofibrate added 0.85 QALYs whilst saving - £637 (ICER = - £7472/QALY). Ezetimibe increased QALYs by 0.60 at cost reductions of - £2529 (ICER = - £4231/QALY). PCSK9 inhibitors provided QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER = £85,193/QALY) and alirocumab (ICER = £54,211/QALY), respectively. At a willingness-to-pay threshold of £25,000/QALY, there is a probability of 100% for icosapent ethyl (98% in primary prevention) and 0% for PCSK9 inhibitors to be cost effective in secondary prevention., Conclusions: Icosapent ethyl is cost effective for primary and secondary cardiovascular prevention at an annual price of £2064 in the UK. For PCSK9 inhibitors, price discounts or prescription restrictions are necessary to achieve cost effectiveness., (© 2022. The Author(s).)

Peripheral artery disease (PAD) is the occlusion or narrowing of the arteries supplying the lower extremities. Peripheral artery disease has been estimated to affect approximately 240 million people worldwide, approximately 70% of whom are within low- or middle-income countries. Due to the ageing population and diabetes epidemic, the prevalence of PAD is rapidly rising. The symptoms of PAD are heterogeneous and thus a high index of suspicion is needed to prevent delays in diagnosis and treatment. Measurement of ankle brachial pressure index or arterial duplex ultrasound are traditionally used to diagnose PAD. Patients with PAD have a high risk of major adverse cardiovascular events. Early diagnosis and implementation of secondary cardiovascular prevention is therefore critical. This includes therapies to reduce low-density lipoprotein cholesterol, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, blood-pressure reducing medications and anti-thrombotic drugs. Treatments to facilitate smoking cessation and control blood sugar if relevant and an exercise programme are also critical in reducing cardiovascular risk. Currently, these treatments are not well implemented. This review summarises the clinical presentation, risk factors and medical management of PAD. Global efforts are needed to reduce the burden from the growing PAD epidemic by implementing best practices and improving outcomes through further research., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.

Background: Several clinical trials have investigated the effect of statin/ezetimibe combination therapy on secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in the Asian population., Objective: This study aimed to summarize study results regarding the effect of statin/ezetimibe combination therapy on lipid parameters and highly sensitive C-reactive protein (HsCRP) biomarkers in ASCVD patients from Asian countries., Methods: We searched the PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar databases for relevant papers published from 2008 to June 2020. We included randomized controlled trials (RCTs) that (1) were conducted in ASCVD patients in Asian countries; (2) examined the effects of statin/ezetimibe combination therapies compared with a control group; and (3) reported sufficient data on lipid parameters and HsCRP biomarkers. The results were reported as weighted mean differences (WMDs) with 95% confidence intervals (CI) using random-effects models. Funnel plots and Egger's regression test were used to assess publication bias., Results: Twenty-four RCTs were reviewed and 20 were included in the meta-analysis. A total of 4344 participants were included (n = 2197 in the intervention group and n = 2147 in the control group), and the intervention durations ranged from 6 weeks to 3.6 years. Ezetimibe coadministered with statin therapy, compared with control treatment, significantly reduced low-density lipoprotein cholesterol (LDL-C; n = 20 studies) [WMD  - 0.39 mmol/L, 95% CI - 0.73 to - 0.05; p < 0.001], triglycerides (TG; n = 18 studies) [WMD - 0.23 mmol/L, 95% CI - 0.33 to - 0.13; p < 0.001], and total cholesterol (TC; n = 17 studies) [WMD - 0.31 mmol/L, 95% CI - 0.45 to - 0.17; p < 0.001). Although the effect of statin/ezetimibe combinations on high-density lipoprotein cholesterol (HDL-C; n = 17 studies) [WMD 0.02 mmol/L, 95% CI - 0.05 to 0.09; p < 0.001) was very minimal and no effect was observed on HsCRP levels (n = 11 studies)., Conclusions: Our study found that statin/ezetimibe combinations reduced LDL-C, TC, and TG levels but had minimal effects on HDL-C and no effect HsCRP biomarkers in ASCVD patients. The statin/ezetimibe therapy enabled a more effective reduction in LDL-C levels; however, the duration of the treatment was suboptimal.

Rosuvastatin/ezetimibe combines two lipid-lowering agents: rosuvastatin, an HMG-CoA reductase inhibitor (i.e. statin) with particularly strong inhibitory effects on hepatic cholesterol synthesis, and ezetimibe, which inhibits the intestinal absorption of cholesterol. A fixed-dose combination (FDC) of rosuvastatin/ezetimibe is indicated as an adjunctive therapy to diet for the management of primary hypercholesterolemia in adults in numerous countries worldwide. In well-designed clinical trials evaluating the therapeutic efficacy of rosuvastatin/ezetimibe administered as either separate agents or as an FDC, rosuvastatin/ezetimibe was significantly more effective than rosuvastatin monotherapy (including at double the dose of rosuvastatin) or simvastatin/ezetimibe in reducing low-density lipoprotein cholesterol (LDL-C) and total cholesterol in adults with hypercholesterolemia. Furthermore, rosuvastatin/ezetimibe enabled significantly higher proportions of patients to achieve recommended LDL-C levels than rosuvastatin monotherapy or simvastatin/ezetimibe. Rosuvastatin/ezetimibe did not significantly differ from rosuvastatin monotherapy with respect to incidences of treatment-related or serious adverse events in these short-term trials and displayed a similar safety profile to simvastatin/ezetimibe. While additional cardiovascular outcomes data and head-to-head comparisons with atorvastatin/ezetimibe would be of interest, rosuvastatin/ezetimibe is a potent and generally well-tolerated drug combination that extends the range of options available for the pharmacological management of primary hypercholesterolemia in adults.

Pooled data from randomized clinical trials on lipid-lowering therapy have provided valuable information and clinical insights. Although cardiovascular disease is a common cause of death, mortality data have rarely been prominent in key lipid trials. The 4S, LIPID and HPS trials were the first to demonstrate a reduction in overall mortality. Lower- versus higher-intensity statin trials and non-statin lipid-lowering trials with ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors proved that additional lipid lowering significantly reduces the occurrence of cardiovascular events. However, only the ODYSSEY OUTCOMES trial showed a reduction in all-cause mortality. The aim of the present narrative review was to contrast these results with those of other key lipid trials: those assessing statins compared with placebo, those evaluating intensive- versus moderate-intensity lipid-lowering therapy and, finally, those investigating non-statin lipid-lowering therapies.

Background and Objective: Cardiovascular (CV) diseases represent a major cause of death and severe medical condition worldwide. Different therapeutic options are available to control low-density lipoprotein cholesterol (LDL-C) level in order to prevent CV events. In recent years, two new drugs were approved for patients who are unable to reduce circulating LDL-C with the current therapies: evolocumab and alirocumab (proprotein convertase subtilisin/kexin type nine [PCSK9] inhibitors). This study was aimed to characterise patients who started treatment with PCSK9 inhibitors in the Tuscany region of Italy during the first year of public healthcare service reimbursement and to describe the pattern of PCSK9 inhibitor use in the first 6 months of treatment., Methods: Patients on PCSK9 inhibitor treatment in Tuscany (3.7 million inhabitants) from 07/2017 to 06/2018 were selected from regional healthcare administrative databases. Concomitant use of lipid-lowering therapies (LLTs), adherence and persistence during the 6 months preceding the first PCSK9 inhibitor dispensing, as well as comorbidities since 1996, were described. In the first 6 months of PCSK9 inhibitor treatment, adherence, persistence and concomitant LLTs were assessed., Results: There were 269 (176 evolocumab, 93 alirocumab) new users of PCSK9 inhibitors. Patients (mean age of 59.1 years) were mainly male (71.0%) in secondary prevention (70.2%) and affected by familial hypercholesterolaemia (53.5%). Sixty-six patients (24.5%) had diabetes mellitus and 12 (4.5%) chronic renal failure. In the 6 months prior to the first PCSK9 inhibitor administration, 61.3% of patients received at least one prescription of ezetimibe or high-intensity statins and 45.7% were persistent to these drugs. During follow-up, 79.9% of patients were adherent to PCSK9 inhibitor and 73.3% were persistent., Conclusions: During the first year of availability, the rate of prescription of PCSK9 inhibitors appears below expectations. Patients were mainly in secondary prevention and had been slightly persistent to previous LLTs. During follow-up, the PCSK9 inhibitor monotherapy showed high levels of adherence and persistence. This real-world study sets the stage for future longer-term investigations useful to improve our knowledge on the appropriateness, drug access and public healthcare sustainability of PCSK9 inhibitors.

The objective of this study was to review available health economic evaluations of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. These drugs reduce low-density lipid cholesterol levels and cardiovascular risk, but their cost effectiveness has been questioned. We searched Medline and Embase for economic evaluations in any language at any time. Studies were included if they analysed any PCSK9 inhibitor compared with either statin alone or in combination with ezetimibe or any other therapy considered standard prior to the introduction of PCSK9 inhibitors. We found ten full health economic evaluations of PCSK9 inhibitors, two from Europe and eight from the United States (US). Six of the eight from the US were from two different consortia that analysed PCSK9 inhibitors at different stages through the development of evidence. All studies generally reported incremental cost-effectiveness ratios above suggested thresholds for cost effectiveness, except one study from Spain. The results of this review indicate that PCSK9 inhibitors in general are not cost effective at the current prices, but lower prices may change the results.

Background and Aims: Ezetimibe reduces plasma low-density lipoprotein cholesterol (LDL-C) levels by up to 20%. However, its effect on plasma lipoprotein(a) [Lp(a)] concentrations in patients with primary hypercholesterolemia has not been defined., Objective: Therefore, we performed a systematic review and meta-analysis to assess this effect based on the available randomized controlled trials (RCTs)., Methods: We searched the PubMed and SCOPUS databases from inception until 28 February 2017 to identify RCTs that investigated the effect of ezetimibe monotherapy on plasma Lp(a) concentrations in patients with primary hypercholesterolemia. We pooled mean percentage changes in plasma Lp(a) concentrations as a mean difference (MD) with a 95% confidence interval (CI)., Results: Seven RCTs with 2337 patients met the selection criteria and were included in the analysis. Overall pooled analysis suggested that ezetimibe 10 mg significantly reduced plasma Lp(a) concentrations in patients with primary hypercholesterolemia by - 7.06% (95% CI - 11.95 to - 2.18; p = 0.005) compared with placebo. No significant heterogeneity was observed (χ 2  = 5.34; p = 0.5). Excluding one study from the analysis resulted in insignificant differences between the two groups (p = 0.2). Meta-regression did not find a significant association between the mean percentage changes in Lp(a) and other potential moderator variables, which included the mean percentage changes of LDL-C concentrations (p = 0.06) and baseline Lp(a) mean values (p = 0.46)., Conclusions: Ezetimibe monotherapy (10 mg/day) showed a small (7.06%) but statistically significant reduction in the plasma levels of Lp(a) in patients with primary hypercholesterolemia. According to current literature, this magnitude of reduction seems to have no clinical relevance. However, further studies are warranted to clarify the mechanism mediating this effect of ezetimibe and to investigate its efficacy in combination with other drugs that have shown promise in lowering Lp(a) levels.

The use of low-density lipoprotein cholesterol (LDL-C)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statin therapy, one of the cornerstones for the prevention and treatment of cardiovascular disease (CVD), has been demonstrated to be effective in lowering LDL-C levels and in reducing the risk for CVD and is generally well-tolerated. However, compliance with statins remains suboptimal. One of the main reasons is limitations by adverse events, notably myopathies, which can lead to non-compliance with the prescribed statin regimen. Reducing the burden of elevated LDL-C levels is critical in patients with CVD as well as in patients with very high baseline levels of LDL-C (e.g. patients with familial hypercholesterolaemia), as statin therapy is insufficient for optimally reducing LDL-C below target values. In this review, we discuss alternative treatment options after maximally tolerated doses of statin therapy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. Difficult-to-treat patients may benefit from combination therapy with ezetimibe or a PCSK9 inhibitor (evolocumab or alirocumab, which are now available). Updates of treatment guidelines are needed to guide the management of patients who will best benefit from these new treatments.

Evolocumab (Repatha(®)) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference -54.8 to -76.3%) and/or ezetimibe (treatment difference -36.9 to -47.2%) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ≈30% vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins.

Background and Aim: The increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) leads to low-density lipoprotein (LDL) receptor degradation. Statins significantly reduce LDL-cholesterol levels, but upregulate PCSK9. This study evaluated the effect of ezetimibe monotherapy or ezetimibe in combination with a statin on serum levels of PCSK9 in patients with type 2 diabetes and hypercholesterolemia., Methods: Ezetimibe treatment was given to ten patients with diabetes without statin therapy and ten patients with statin therapy. Plasma levels of PCSK9 were examined at baseline and 24 weeks after treatment., Results: At baseline, PCSK9 concentrations in patients with statin therapy were significantly higher than those in patients without statin use and in control subjects [median (25th-75th percentile) 411 (272-467) and 382 (356-453) ng/mL, respectively, p < 0.01]. After ezetimibe treatment for 24 weeks, LDL-cholesterol, triglyceride and remnant-like lipoprotein cholesterol were significantly decreased in both groups. However, PCSK9 concentration did not change compared with baseline measurements in both groups. The percentage change in LDL-cholesterol after ezetimibe therapy for 24 weeks was not correlated with the percentage change in PCSK9 concentration., Conclusion: Ezetimibe may reduce LDL-cholesterol levels without affecting PCSK9 in patients with type 2 diabetes and hypercholesterolemia.