PCSK9 and ANGPTL3 Inhibitors in Homozygous Familial Hypercholesterolemia: A Meta-analysis of Randomized Clinical Trials.

Background Homozygous familial hypercholesterolemia (HoFH) is a genetic disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels, leading to early-onset atherosclerotic cardiovascular disease. The aim of this meta-analysis was to compare the efficacy of PCSK9 and ANGPTL3 inhibitors in patients with HoFH. Methods We systematically searched selected electronic databases until 30th November 2024. Main endpoint was the effect of lipid lowering therapy on lipid profile: total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and lipoproteins level levels. The secondary endpoint was adverse clinical effects. Results 12 trials (6 with PCSK9i and 6 with ANGPTL3i), involving a total of 392 patients with HoFH, were included in the meta-analysis. At a median follow-up of 12 months, the ANGPTL3i group demonstrated a greater reduction in mean TC [–4.27 mmol/L (165.1 mg/dL) vs. –1.37 mmol/L (52.9 mg/dL); p for subgroup <0.001], LDL-C [–3.51 mmol/L (135.7 mg/dL) vs. –1.81 mmol/L (69.9 mg/dL); p for subgroup <0.001], and TG [–0.61 mmol/L (54.1 mg/dL) vs. –0.21 mmol/L (18.6 mg/dL); p for subgroup <0.001], but a smaller impact on HDL-C compared to those treated with PCSK9i. Likewise, Apo-B reduced more with ANGPTL3i compared to PCSK9i [–0.81 g/L vs. –0.21 g/L; p < 0.001], but Apo-A and Lipoprotein (a) remained comparable between the two groups (p > 0.05 for both). The treatment-related adverse events and discontinuation rates were not different between groups (p > 0.05 for both). Conclusions PCSK9 inhibitors have significantly lower efficacy in reducing lipid levels in HoFH patients compared to ANGPTL3 inhibitors, particularly in children. Further clinical trials are needed to compare their effectiveness across different functional variations of LDL-C receptors in HoFH patients.Figure 1.Summary mean change of lipid p Figure 2.Graphical abstract

price tag raises concerns about affordability.

PCSK9 inhibition is an effective therapy to reduce LDL cholesterol (LDL-C) and cardiovascular events. A recent study shows that one or two doses of inclisiran, a long-acting synthetic small-interfering RNA (siRNA) that selectively targets hepatic PCSK9, causes a sustained reduction of plasma LDL-C for up to 6 months. Pending further studies of safety and efficacy, this may represent an important addition to the armamentarium for inhibiting PCSK9.

AimsHeterozygous familial hypercholesterolaemia (HeFH) is one of the most frequent monogenic disorders in the world, leading to premature atherosclerotic cardiovascular diseases. The aim of this meta-analysis was to evaluate the efficacy and safety of lipid-lowering therapy (LLT) and achievement of low density lipoprotein cholesterol (LDL-C) goal in children with HeFH.Methods and resultsThe main endpoint was efficacy of goal achievement for LDL-C and other lipid parameters: total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), apolipoprotein B, and lipoprotein(a), and the LLT safety [adverse events (AEs), including endocrine function, and growth indices]. The secondary endpoint was an effect of LLT on attainment of LDL-C goal treatment (<3.5 mmol/L/130 mg/dL). A total of 41 studies with 4667 paediatric patients at mean age 12.08 ± 2.4 years were included. Seventeen reported the efficacy and safety of LLT therapy compared to control, while the remaining assessed LLT through pre- and post-treatment. At median follow-up of 18.8 months, the group on LLT had significantly higher mean reductions of TC, LDL-C, TG, and increased HDL-C compared to control [−1.75 mmol/L (−67.7 mg/dL), −1.84 mmol/L (−71.2 mg/dL), −0.11 mmol/L (−9.74 mg/dL), 0.08 mmol/L (3.1 mg/dL), respectively, P < 0.001 for all]. In the subgroup analysis according to different types of LLT, we observed a significantly higher mean reduction of LDL-C by statin combined with ezetimibe treatment, followed by statins in monotherapy, PCSK9 inhibitors, and monotherapy with ezetimibe [−2.48 mmol/L (−95.9 mg/dL), −2.16 mmol/L (−83.5 mg/dL), −2.03 mmol/L (−78.5 mg/dL), and −1.50 mmol/L (−58 mg/dL), respectively, test for overall effect: P < 0.001]. The pooled LDL-C was reduced by 33.44% [−2.14 mmol/L (−82.8 mg/dL), P < 0.001] and failed to reach the goal treatment (<3.5 mmol/L) by 12.6% (95% CI, 12.4–12.9%). A total of 38.7% of children achieved the LDL-C goal, 23.9% fell short by up to 10%, 10.7% experienced moderate failure (were over the LDL-C target between >10% and 20%), and 26.7% failed by more than 20% to reach the LDL-C target. When comparing different regions, only Sweden and Greece achieved the LDL-C goal < 3.5 mmol/L in the follow-up. Netherlands, Norway, Poland, USA, UK, France, Spain, Belgium, and Austria required 2.2%, 3.4%, 3.5%, 8.9%, 10.2%, 11.2%, 11.2%, 15%, and 19.4% additional reduction in LDL-C respectively to achieve the LDL-C goal of < 3.5 mmol/L. All other countries required over 20% additional reduction in LDL-C to achieve the LDL-C goal. For other investigated countries, over 20% mean LDL-C reduction was required. All parameters related to endocrine function and demographic indices were unaffected by LLT therapy (P > 0.05). The AEs were not reported significantly higher when compared to the control, and the prevalence of therapy discontinuation was only 0.8%.ConclusionDespite the efficacy of LLT in children with HeFH and the low occurrence of discontinuation-related adverse events, achieving LDL-C treatment goals was relatively rare, with large differences between the investigated countries. These results underscore the importance of considering early combination therapy of statins and ezetimibe, and PCSK9 inhibitors (if available) to attain LDL-C goals effectively.

Joint statement from the European Atherosclerosis Society and European Society of Vascular Medicine focuses on patients with peripheral arterial disease

IntroductionAchieving target low-density lipoprotein-cholesterol (LDL-C) levels remains challenging when treating homozygous familial hypercholesterolemia (HoFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are prescribed in addition to statins and ezetimibe, but patients’ response varies and depends on residual low-density lipoprotein receptor (LDLR) function.MethodsA multicenter, retrospective observational analysis evaluated LDL-C target achievement in response to PCSK9i treatment in 28 patients with HoFH from the Middle East/North Africa region. Effect of genotype was investigated. Demographic and clinical information was retrospectively obtained from medical records. Patient response to PCSK9i treatment was assessed by calculating percentage changes in lipid levels from pre-PCSK9i treatment baseline to most recent follow-up visit where patients were recorded as receiving PCSK9i on top of standard of care lipid-lowering therapies (LLTs; i.e., statins/ezetimibe) and assessing European Atherosclerosis Society (EAS) target achievement up to January 31, 2022. Lowest LDL-C level while receiving PCSK9i was identified.ResultsThe cohort (n = 28) had a mean age (standard deviation; SD) of 22.8 (9.8) years (n = 28) and was 51% female (n = 27). Baseline LDL-C data were available in 24/28 (85.7%) patients (mean [SD] 14.0 [3.0] mmol/L). Median (interquartile range) duration of PCSK9i treatment was 12.0 months (4.0–19.1) months and mean (SD) % change in LDL-C after PCSK9i treatment was − 8.6% (12.1). LDL-C reduction from baseline was below 15% in 17/24 patients (70.8%). In the full cohort, mean (SD) minimum LDL-C during PCSK9i treatment was 11.9 (2.8; n = 28) mmol/L. No patient achieved EAS target LDL-C while receiving PCSK9i; genotype analysis suggested LDLR-null/null patients were most refractory to PCSK9i.ConclusionResponse to PCSK9i was minimal in this cohort of patients with HoFH. No patients achieved EAS LDL-C targets, and most failed to reach the EAS-recommended 15% LDL-C reduction for PCSK9i therapy continuation. These results suggest additional LLTs are necessary to achieve LDL-C targets in HoFH.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-023-02764-y.

Background and importanceThe proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i), evolocumab and alirocumab, approved by the European Medicines Agency in 2015, are a new approach in obtaining a large...

Homozygous familial hypercholesterolemia (HoFH) is an autosomal semidominant disorder characterized by extreme elevations in LDL-C (low-density lipoprotein cholesterol) and early-onset atherosclerotic cardiovascular disease. Evinacumab is a monoclonal antibody administered by monthly intravenous infusion that binds ANGPTL3 (angiopoietin-like 3) and when added to standard lipid-lowering therapies lowers LDL-C by ≈50% in HoFH clinical trials. Studies examining the real-world effectiveness and safety of evinacumab are limited. We performed a retrospective study to assess the effectiveness and safety of evinacumab in patients with HoFH in clinical practice at 6 US academic medical centers. The primary end point was the percent change in LDL-C from baseline to first follow-up and to the most recent follow-up after evinacumab initiation. Secondary end points were percent change in non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, total cholesterol, HDL-C, and achievement of an LDL-C <70 mg/dL. Adverse events were recorded. Twenty-four patients (mean age, 40 [range, 5-84] years) with HoFH were followed for a median of 48 weeks. Fifty percent were female, 66.7% had atherosclerotic cardiovascular disease, 87.5% were on a statin, 83.3% were on ezetimibe, 66.7% were on PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors), 24% were on lomitapide, and 33.3% were undergoing lipoprotein apheresis. Significant reductions in LDL-C, non-HDL-C, total cholesterol, triglycerides, and HDL-C were observed both at the first follow-up (4 weeks) and the most recent follow-up (48 weeks); mean±SEM percent change from baseline to the most recent follow-up was as follows: LDL-C, -53.2% (±4.1); non-HDL-C, -52.7% (±3.9); triglycerides, -47.4% (±5.1); total cholesterol, -48.9% (±4.0); and HDL-C, -30.2% (±4.1); P<0.001 for all. Significantly more patients achieved LDL-C <70 mg/dL after evinacumab was added. Nine (37.5%) patients reported adverse events during or following evinacumab infusions. Treatment was discontinued by 1 patient because of back pain. Across 6 US academic medical centers, evinacumab was generally well tolerated by patients with HoFH and lowered LDL-C by ≈50%, consistent with results from clinical trials.

Renal Impairment, Cardiovascular Disease, and the Short-Term Efficacy and Safety of PCSK9 Targeted by Inclisiran

Patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at high risk of atherosclerotic cardiovascular disease events. Treatment guidelines recommend intensive treatment in these patients. Variation in the use of lipid-lowering therapies (LLTs) in these patients in a national sample of cardiology practices is not known. Using data from the American College of Cardiology National Cardiovascular Data Registry-Practice Innovation and Clinical Excellence registry, we assessed the proportion of patients with LDL-C ≥190 mg/dL (n=49 447) receiving statin, high-intensity statin, LLT associated with ≥50% LDL-C lowering, ezetimibe, or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor between January 2013 and December 2016. We assessed practice-level rates and variation in LLT use using median rate ratio (MRR) adjusted for patient and practice characteristics. MRRs represent the likelihood that 2 random practices would differ in treatment of identical patients with LDL-C ≥190 mg/dL. The proportion of patients receiving a statin, high-intensity statin, LLT associated with ≥50% LDL-C reduction, ezetimibe, or PCSK9 inhibitor were 58.5%, 31.9%, 34.6%, 8.5%, and 1.5%, respectively. Median practice-level rates and adjusted MRR for statin (56% [interquartile range, 47.3%-64.8%]; MRR, 1.20 [95% confidence interval [CI], 1.17-1.23]), high-intensity statin (30.2% [interquartile range, 12.1%-41.1%]; MRR, 2.31 [95% CI, 2.12-2.51]), LLT with ≥50% LDL-C lowering (31.8% [interquartile range, 15.3%-45.5%]; MRR, 2.12 [95% CI, 1.95-2.28]), ezetimibe (5.8% [interquartile range, 2.8%-9.8%]; MRR, 2.42 [95% CI, 2.21-2.63]), and PCSK9 inhibitors (0.16% [interquartile range, 0%-1.9%]; MRR, 2.38 [95% CI, 2.04-2.72]) indicated significant gaps and >200% variation in receipt of several of these medications for patients across practices. Among those without concomitant atherosclerotic cardiovascular disease, even larger treatment gaps were noted (proportion of patients on a statin, high-intensity statin, LLT with ≥50% LDL-C reduction, ezetimibe, or PCSK9 inhibitor were 50.8%, 25.25%, 26.8%, 4.9%, and 0.74%, respectively). Evidence-based LLT use remains low among patients with elevated LDL-C with significant variation in care. System-level interventions are needed to address these gaps and reduce variation in care of these high-risk patients.

Article, see p 1931 > “It is always wise to look ahead, but difficult to look further than you can see.” > > —Winston Churchill The noteworthy article by Ray et al1 in this issue of Circulation provides a tantalizing glimpse into the future. It points to the potential of 2 nonstatins—alirocumab, a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, and ezetemibe—to reduce atherogenic lipoproteins with proportional reductions in major adverse cardiovascular events beyond that achieved with statins alone. The authors make an important observation: a continuous relationship exists between average on-treatment low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events. Moreover, they found no observed effect attenuation at low achieved levels of LDL-C <50 mg/dL. But their analysis is not conclusive. As the authors note, there are significant limitations due to a low number of events, the short trial duration (≤2 years), and, importantly, the post hoc nature of the analysis. On the other hand, if results from prospective outcome trials are in accord with these preliminary data, it will be appropriate to update current cholesterol guidelines. It is helpful to review what current guidelines stated. The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Cholesterol Guidelines (2013 GL) endorsed lifestyle as the foundation for atherosclerotic cardiovascular disease (ASCVD) prevention.2 The guideline panel proposed 3 critical questions to determine when and how pharmacologic treatment should be implemented. These critical questions generated a comprehensive search for high-quality randomized clinical trials (RCTs) or meta-analyses of these RCTs by an outside contractor chosen by the National Heart Lung Blood Institute. Low-quality studies were not allowed to contribute to the evidence. The panel then published their final recommendations under the auspices of the ACC and AHA. Other guidelines that adhered closely to the RCT evidence include the National Institutes of Clinical Excellence guidelines3 …

HomeCirculationVol. 135, No. 17Letter by Koh Regarding Article, “Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh From Department of Cardiovascular Medicine, Heart Center, Gachon University Gil Medical Center; and Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published25 Apr 2017https://doi.org/10.1161/CIRCULATIONAHA.116.026821Circulation. 2017;135:e1006–e1007To the Editor:In her recent article, Bittner discussed pleiotropic effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.1 PCSK9 is a serine protease that is secreted by the liver, binds to the low-density lipoprotein (LDL) receptor, and directs the LDL receptor toward lysosomal degradation. PCSK9 inhibitors achieve LDL-cholesterol (LDL-C) reductions of 45% to 60% and similarly LDL particle number, small and large LDL particles, and apolipoprotein B levels. The impact of PCSK9 inhibition is not limited to reduction in LDL-C but also affects other aspects of lipoprotein metabolism, inflammation, thrombosis, and immune function. PCSK9 inhibitors lower lipoprotein (a) by as much as 30% and variably reduce triglyceride-rich lipoproteins possibly through enhanced clearance by LDL receptors and very LDL (VLDL) receptors or by lowering production of triglyceride-rich lipoproteins. Thus, PCSK9 antibodies lower LDL-C and other atherogenic lipoproteins and seem to favorably affect the complex inflammatory and thrombotic mechanisms related to atherosclerosis progression and acute events. Therefore, broad effects of PCSK9 inhibitors on multiple physiological systems come with concerns about the potential for unintended effects.1On the other hand, subjects with genetic variants in PCSK9 or HMGCR with reduced LDL levels had similar decreases in cardiovascular disease (CVD) risk per unit decrease in LDL-C.2,3 In subjects with preexisting glucose intolerance, variants in both genes were associated with independent and additive effects to increase risk of diabetes mellitus (also associated with LDL lowering albeit with smaller effect size than CVD risk).2 PCSK9 inhibitors and statins use distinct mechanisms to lower LDL-C, the common downstream effect that is likely related to both protection against CVD and promotion of diabetes mellitus. Together, these data strongly support large clinical outcome studies to determine whether a further increase in diabetes mellitus occurs with statin therapy.These data provide insights into the potential adverse effects of LDL-C-lowering therapy. What should we target, CVD risk or diabetes mellitus? Because new-onset diabetes mellitus adds substantially to CVD risk, a dilemma exists with combination therapy of high-potency statins combined with PCSK9 inhibitors. Also, we should think about cost-effectiveness. PCSK9 inhibitors are expensive and would be unnecessary except in patients with a CVD event or familial hypercholesterolemia+inadequate lowering of LDL-C with statins with or without stain intolerance. Statins are important, but we should also endeavor to control residual risk because reduction of LDL-C prevents <50% of CVD events.We have proposed statins-based combined therapy to balance cardiometabolic benefits and risks of statins. Statins-based combined therapy would simultaneously prevent new-onset diabetes mellitus and improve cardiovascular outcome because of the beneficial effects of renin-angiotensin system or ezetimibe on insulin resistance and endothelial dysfunction.4,5 In this regard, combined therapy demonstrates additive/synergistic effects on endothelial dysfunction and insulin resistance in addition to lowering LDL-C levels and blood pressure when compared with either monotherapy in patients. This finding is mediated by both distinct and interrelated mechanisms.4,5Kwang Kon Koh, MD, PhDAcknowledgmentsI deeply appreciate Dr Robert H. Eckel, Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Denver, for his comment.DisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.

It has not been yet adequately addressed whether the addition of the nonstatin LDL-C (low-density lipoprotein cholesterol)-lowering agents on top of statins has the same magnitude of risk reduction in the cardiovascular events as compared with more-intensive statin therapy. We performed a systematic review and meta-analysis of RCTs (randomized controlled trials) comparing more- versus less-intensive lipid-lowering therapy (LLT) on clinical outcomes in patients with atherosclerotic cardiovascular risk. We included 23 studies involving 133 037 patients (more-intensive LLT: 67 691 patients and less-intensive LLT: 65 346 patients). We evaluated 3 types of more- versus less-intensive LLT including more versus less statins (57 672 patients), combination therapy of ezetimibe versus statins alone (20 688 patients), or a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor with statins versus statins alone (54 677 patients). The odds for major adverse cardiovascular events (MACE; equivalent to the composite of coronary heart death, nonfatal myocardial infarction, stroke, or coronary revascularization) were significantly lower in the more-intensive LLT group compared with the less-intensive LLT group in the entire study population (odds ratio, 0.84; 95% CI, 0.79-0.88; P<0.001), and in all the 3 categories of more-intensive LLT strategies (more-intensive statin therapy: odds ratio, 0.83; 95% CI, 0.76-0.90; P<0.001, ezetimibe: odds ratio, 0.90; 95% CI, 0.85-0.96; P<0.001, and PCSK9 inhibitors: odds ratio, 0.81; 95% CI, 0.73-0.90; P<0.001) with numerically greater relative odds reduction by more-intensive statin therapy and PCSK9 inhibitors than by ezetimibe. Odds reduction for MACE per 20 mg/dL LDL-C reduction was also different across the 3 types of more-intensive LLT (more-intensive statin therapy: 17.4%, ezetimibe: 11.0%, and PCSK9 inhibitors: 6.6%). In this meta-analysis, more-intensive LLT as compared with less-intensive LLT was associated with significant odds reduction for MACE in the entire study population and in all the 3 categories of more-intensive LLT such as more-intensive statin therapy, ezetimibe, and PCSK9 inhibitors. However, overall odds reduction for MACE and odds reduction for MACE per 20 mg/dL LDL-C reduction were different across the 3 types of more-intensive LLT. Registration: URLs: https://www.crd.york.ac.uk/PROSPERO/ and http://www.umin.ac.jp/ctr. Unique identifiers: PROSPERO: CRD42018081196, and UMIN-CTR: R000036229.

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors bring about a wide reduction in low-density lipoprotein (LDL) cholesterol, greater than that of other lipid-lowering agents. The aim of this metanalysis was assessment of the effects of PCSK9 inhibitors on glucose metabolism, LDL cholesterol, cardiovascular morbidity and mortality in individuals with and without diabetes. A Medline and Clinicaltrials.gov search for eligible studies published before 1 December 2017 was performed. All randomized trials comparing PCSK-9 inhibitors with placebo or active drugs were included. Primary endpoints included (a) incident diabetes, fasting glucose and HbA1c, (b) LDL cholesterol at endpoint in patients with diabetes and in the total sample, and (c) major cardiovascular events (MACE) and mortality in individuals with and without diabetes. A total of 38 trials was identified. The risk of incident diabetes was not increased by PCSK-9 inhibitors, vs placebo or any comparator. The reduction in LDL cholesterol vs placebo in patients with diabetes was 52.6 [41.3;63.8] mg/dL; the corresponding figure for all patients was 66.9 [62.4;71.3] mg/dL. Meta-regression analysis showed an inverse correlation between proportion of patients with diabetes and drug effect on LDL cholesterol in trials vs ezetimibe, but not in those vs placebo. In studies reporting data on MACE and mortality separately for individuals with and without diabetes, the effect of PCSK-9 did not appear to be affected by diabetes. PCSK-9 inhibitors do not affect glucose metabolism. Their efficacy on LDL cholesterol and MACE in patients with diabetes does not seem to be very dissimilar to that observed in non-diabetic participants.

Sex Differences in Cardiovascular Outcomes and Cholesterol-Lowering Efficacy of PCSK9 Inhibitors: Systematic Review and Meta-Analysis