Reduction In LDL-C Levels Research Articles

First clinical experiences with inclisiran in a real-world setting

Inclisiran is the first-in-class small interfering RNA (siRNA) PCSK9 inhibitor. In clinical trials inclisiran showed effective and sustained LDL-C reduction of ±50%. As data in clinical setting are scarce, we aim to investigate the efficacy and safety in clinical practice. We describe a registry of consecutive patients who started with inclisiran at a lipid clinic of a university hospital. Patients were eligible if they fulfilled the reimbursement criteria in the Netherlands. Patients were included if they started with inclisiran as first line (group 1) or switched from PCSK9 monoclonal antibody (mAbs) to inclisiran (group 2). LDL-C levels were measured at 3 and 9 months after initiation of inclisiran. Median change of LDL-C levels was calculated on an individual and group level. We analysed 65 patients (36 women), median [25th percentile; 75th percentile] age of 63 [54; 68] years. Of these, 44 patients had both a 3 month and 9 month visit. At 3 months, patients who newly started inclisiran (group 1, n=45) showed a LDL-C decrease of 38 [-49;-33]%. Patients who used statins as co-medication (n=15) had a higher median LDL-C decrease compared to those without statin use (n=30; 45% vs 38%). However, patients who switched from mAbs to inclisiran (group 2, n=20) had an increase in LDL-C of 38 [+4; +97]%. Adverse effects associated with inclisiran were mild and consisted of mild injection site reactions. Efficacy was slightly less whereas safety results were similar at 9 months. Our initial experience of inclisiran in a clinical setting showed less reduction in LDL-C levels compared to clinical trials but a similar safety profile. Moreover, patients who switched from PCSK9 mAbs to inclisiran generally showed an increase in LDL-C levels implying that inclisiran is less potent in LDL-C reduction compared to PCSK9 mAbs.

Long-term safety and effectiveness of alirocumab and evolocumab in familial hypercholesterolemia (FH) in Belgium

Background: In 2019, the European Atherosclerosis Society (EAS) published updated guidelines, recommending even lower blood cholesterol targets than previously. In patients with familial hypercholesterolaemia (FH), who have very elevated blood cholesterol levels and are at (‘Very’) ‘High risk’ of atherosclerotic cardiovascular disease (ASCVD), this represents a real challenge. Anti-Proprotein convertase subtilisin/kexin type 9 monoclonal antibody (anti-PCSK9 mAb) has been commercially available for FH in Belgium since 2015. Our study aims to investigate the real-life efficacy of anti-PCSK9 mAb in FH patients. Method: We sourced patients from the EAS FH Studies Collaboration database (an international database on FH in which Belgium participates). We only retained patients using anti-PCSK9 mAb and followed at our Lipid Clinic. Results: Of the 239 subjects included in this study (mean age: 56 years), 85% were considered at ‘Very High Risk’ (56% with a history of ASCVD), the remaining 15% were at ‘High Risk’. The PCSK9 mAb treatment reduced LDL-C levels by 54% within the first year. This reduction was maintained over the follow-up (FU) period (3.0 ± 1.8 years). The EAS targets were reached in 50% of the subjects, 93% of whom were also treated with statins. The treatment was very well tolerated. At the end of the observation period, 96% patients continued receiving PCSK9 mAb. Conclusions: Anti-PCSK9 mAb are a safe and effective therapeutic option for lowering LDL-C levels in FH patients. It allowed a significant portion of our FH patients to reach their lipid targets, mainly in those with combined therapy with statin and/or ezetimibe.

Multizonal observational study conducted by clinical practitioners on Repatha® use in patients with hyperlipidemia (ZERBINI): Colombian results

BackgroundCardiovascular disease (CVD) represents the primary cause of death and disability globally, with elevated cholesterol as one of the leading risk factors for CVD. We describe the clinical characteristics, treatment patterns, and effectiveness of evolocumab in treating hyperlipidemia. MethodsObservational study conducted through a chart review of patients with hyperlipidemia receiving evolocumab as part of clinical management in Colombia. ResultsThis study included 115 patients treated with evolocumab. A total of 101 patients (87.8%) had a history of CVD, 13 (11.3%) familial hypercholesterolemia (FH), and 23 (20%) type 2 diabetes. Thirty-nine patients reported intolerance to any statin (33.9%). The median value of LDL-C before initiation of evolocumab was 147mg/dL (IQR: 122.5–183.7mg/dL). Within the first 3 months of treatment, LDL-C value dropped to a median value of 53mg/dL (IQR: 34.0–95.5mg/dL), showing a reduction of 63.9%. The median LDL-C values remained below 45mg/dL until the end of follow-up. Among the patients with available data, up to 61% achieved an LDL-C level below 55mg/dL at the 10–12-month follow-up. A total of 72% of patients were persistent with treatment. Safety results showed a low frequency of hospitalizations (≤2%) and treatment-emergent adverse drug reactions (5.2%). No serious adverse events were reported. ConclusionsEvolocumab was associated with reductions in LDL-C levels, with a relative decrease of 63.9% within the first 3 months of treatment. Low rates of interruptions due to adverse events and adequate medication persistence was reported.

ANMCO position paper on the management of hypercholesterolaemia in patients with acute coronary syndrome.

Patients suffering from acute coronary syndrome (ACS) present a high risk of recurrence and new adverse cardiovascular events after hospital discharge. Elevated plasma LDL-cholesterol (LDL-C) levels have been shown to be a causal factor for the development of coronary heart disease, and robust clinical evidence has documented that LDL-C levels decrease linearly correlates with a reduction in cardiovascular events. Recent studies have also demonstrated the safety and efficacy of an early and significant reduction in LDL-C levels in patients with ACS. In this position paper, Italian Association of Hospital Cardiologists proposes a decision algorithm on early adoption of lipid-lowering strategies at hospital discharge and short-term follow-up of patients with ACS, in the light of the multiple evidence generated in recent years on the treatment of hypercholesterolaemia and the available therapeutic options, considering current reimbursement criteria.

Abstract 105: Lipid Regulation of Senescent Effector CD8 T Cells in Type 2 Diabetes

Introduction: Atherosclerotic plaques from patients with Type 2 Diabetes (T2D) present a more severe pathology than non-T2D (ND) plaques and response to cholesterol-lowering is compromised. An increased level of circulating senescent CD8 T cells in T2D patients is associated with increased risk for myocardial infarction. However, whether senescent T cells infiltrate human atherosclerotic plaques and how they are regulated by lipid lowering is unknown. Hypothesis: Senescent CD8+ T cells are increased in atherosclerotic plaques and circulation of T2D, and are normalized by aggressive lipid lowering in T2D. Methods: We performed unbiased scRNA-seq analysis (75,049 total cells) of immune cells in plaques from T2D (n=12) and ND patients (n=10) to identify senescent T cells in human atherosclerotic plaques. Using CyTOF we tested the effect of aggressive lipid lowering on circulating CD8 T cells in T2D (n=16) and ND (n=6) patients. Results: We identified senescent T cells within atherosclerotic plaques and found that senescent CD8 T cells largely accumulate in plaques from T2D patients (p<0.001). Plaque CD8 T cells showed a terminally differentiated effector memory phenotype with high expression of CX3CR1 and low expression of SELL and CCR7 genes. CD8 T cell clusters express senescence markers ( B3GAT1,KLRG1,KLRD1,KLRF1 ) and presented senescence associated secretory phenotype with high expression of cytotoxic ( GZMB,PRF1,GNLY ) and proatherogenic ( IFNG,TNFA,CCL5 ) genes. CyTOF analysis showed higher levels of circulating senescent CD57+CD28-CD8 T cells in patients with T2D vs ND controls (p<0.001). Potent lipid lowering with PCSK9 inhibitor + statin/ezetimibe, which reduced LDL-C levels by >70% in all patients at 4 weeks, normalized the frequency of circulating senescent CD8 T cells (p<0.001) in T2D patients to the levels found in ND. Conclusion: Our results show that senescent CD8 T cells accumulated in blood and plaques of T2D patients and that potent lipid lowering diminished circulating aged CD8 T cells, suggesting that CD8 T cell senescence can be improved by aggressive lipid control in high-risk T2D subjects. Further analyses are needed to understand the role of lipid metabolism in the T cell senescence and the impact on atherosclerosis progression.

A comprehensive review of healthy effects of vegetarian diets

AimsA comprehensive review comparing the effect of vegetarian (V) and non-vegetarian (NV) diets on the major cardiometabolic diseases’ outcomes was performed. Data synthesisWe performed literature research (up to December 31, 2022) of the evidence separately for vascular disease (VD), obesity (OB), dyslipidemia (Dysl), hypertension (HPT), type 2 diabetes (T2D), metabolic syndrome (MetS), analyzing only cohort studies and randomized controlled studies (RCTs) and comparing the effect of V and NV diets. Cohort studies showed advantages of V diets compared to NV diets on incidence and/or mortality risk for ischemic heart disease, overweight and OB risk. Most cohort studies showed V had lower risk of HPT and lower blood pressure (BP) than NV and V diets had positive effects on T2D risk or plasma parameters. The few cohort studies on the risk of MetS reported mixed results. In RCTs, V diets, mainly low-fat-vegan ones, led to greater weight loss and improved glycemic control than NV diets and in the only one RCT a partial regression of coronary atherosclerosis. In most RCTs, V diets significantly reduced LDL-C levels (but also decreased HDL-C levels) and BP. ConclusionsIn this comprehensive review of the association between V diets and cardiometabolic outcomes, we found that following this type of diet may help to prevent most of these diseases. However, the non-uniformity of the studies, due to ethnic, cultural, and methodological differences, does not allow for generalizing the present results and drawing definitive conclusions. Further, well-designed studies are warranted to confirm the consistency of our conclusions.

Sex differences in efficacy and safety of PCSK9 monoclonal antibodies: A real-world registry

Background and aimsProprotein convertase subtilisin/kexin 9 monoclonal antibodies (PCSK9 mAbs) reduce low-density lipoprotein (LDL-c) with a favourable safety profile. Available data from PCSK9 antibody trials suggest LDL-c reduction is lower in women compared to men. Data in real-world setting is scarce. The aim of this study was to assess sex differences in efficacy and safety of PCSK9 antibodies in clinical care. MethodsAll patients starting with evolocumab or alirocumab in our lipid clinic were included in a prospective registry. We collected clinical information, including baseline and follow-up mean LDL-C levels after initiation of PCSK9 mAbs treatment. In addition, side effects and PCSK9 mAbs discontinuation were recorded. ResultsWe analysed 436 patients (209 women), mean age 58 ± 11 years. Women had higher baseline LDL-c levels compared to men (4.7 ± 1.6 mmol/L vs 4.1 ± 1.4 mmol/L, p < 0.01). PCSK9 mAbs resulted in less relative LDL-c reduction in women compared to men (50% vs 61% p<0.01), but equal absolute LDL-c reduction (respectively 2.3 ± 1.3 mmol/L vs 2.5 ± 1.1 mmol/L, p = 0.087). Women less often reached LDL-c target levels than men (50% vs 72%). No sex differences were observed in reporting of side effects (women 32% vs men 27% p = 0.26) or PCSK9 mAbs discontinuation (women 13% vs men 10%, p = 0.46). ConclusionsIn clinical practice, PCSK9 mAbs are less effective in reducing LDL-c levels in women compared to men and equally safe, implying the importance of sex differences in PCSK9 metabolism.

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment.

Familial hypercholesterolemia (FH) is a hereditary disorder that causes severely elevated low-density lipoprotein (LDL-C) levels, which leads to an increased risk for premature cardiovascular disease. A variety of genetic variants can cause FH, namely variants in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and/or LDL-receptor adaptor protein 1 (LDLRAP1). Variants can exist in a heterozygous form (HeFH) or the more severe homozygous form (HoFH). If affected individuals are diagnosed early (through screening), they benefit tremendously from early initiation of lipid-lowering therapy, such as statins, and cardiovascular imaging to detect possible atherosclerosis. Over the last years, due to intensive research on the genetic basis of LDL-C metabolism, novel, promising therapies have been developed to reduce LDL-C levels and subsequently reduce cardiovascular risk. Results from studies on therapies focused on inhibiting PCSK9, a protein responsible for degradation of the LDLR, are impressive. As the effect of PCSK9 inhibitors (PCSK9-i) is dependent of residual LDLR activity, this medication is less potent in patients without functional LDLR (e.g., null/null variant). Novel therapies that are expected to become available in the near future focused on inhibition of another major regulatory protein in lipid metabolism (angiopoietin-like 3 (ANGPTL3)) might dramatically reduce the frequency of apheresis in children with HoFH, independently of their residual LDLR. At present, another independent risk factor for premature cardiovascular disease, elevated levels of lipoprotein(a) (Lp(a)), cannot be effectively treated with medication. Further understanding of the genetic basis of Lp(a) metabolism, however, offers a possibility for the development of novel therapies.

ANMCO Position paper: Management of hypercholesterolemia in patients with acute coronary syndrome

Patients suffering from acute coronary syndromes (ACS) present a high risk of recurrence and new adverse cardiovascular events after hospital discharge. Elevated plasma LDL-cholesterol (LDL-C) levels have been shown to be a causal factor for the development of coronary heart disease, and robust clinical evidence has documented that a decrease of LDL-C levels correlates linearly with a reduction in cardiovascular events. Recent studies have also demonstrated the safety and efficacy of an early and significant reduction in LDL-C levels in patients with ACS.In this position paper, ANMCO proposes a decision algorithm on early adoption of lipid-lowering strategies at hospital discharge and short-term follow-up of patients with ACS, in the light of the multiple evidence generated in recent years on the treatment of hypercholesterolemia and the available therapeutic options, considering current reimbursement criteria.

Efficacy, safety, adherence and persistence of PCSK9 inhibitors in clinical practice: A single country, multicenter, observational study (AT-TARGET-IT)

Background and aimsProprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9i) are recommended in patients at high and very-high cardiovascular (CV) risk, with documented atherosclerotic CV disease (ASCVD), and for very-high risk patients with familial hypercholesterolaemia not achieving LDL-cholesterol (LDL-C) goal while receiving maximally tolerated dose of lipid-lowering therapy (LLT). However, single country real-life data, reporting the use of PCSK9i in clinical practice, are limited. Therefore, we designed AT-TARGET-IT, an Italian, multicenter, observational registry on the use of PCSK9i in clinical practice. MethodsAll data were recorded at the time of the first prescription and at the latest observation preceding inclusion in the study. Results798 patients were enrolled. The median reduction in LDL-C levels was 64.9%. After stratification for CV risk, 63.8% achieved LDL-C target; of them, 83.3% took LLTs at PCSK9i initiation and 16.7% did not. 760 patients (95.2%) showed high adherence to therapy, 13 (1.6%) partial adherence, and 25 (3.1%) poor adherence. At 6 months, 99.7% of patients enrolled in the study remained on therapy; there were 519 and 423 patients in the study with a follow-up of at least 12 and 18 months, respectively. Persistence in these groups was 98.1% and 97.5%, respectively. Overall, 3.5% of patients discontinued therapy. No differences in efficacy, adherence, and persistence were found between alirocumab and evolocumab. ConclusionsPCSK9i are safe and effective in clinical practice, leading to very high adherence and persistence to therapy, and achievement of recommended LDL-C target in most patients, especially when used as combination therapy.

Orange juice intake and lipid profile: a systematic review and meta-analysis of randomised controlled trials.

Dyslipidaemia is a metabolic anomaly which has been related to numerous morbidities. Orange juice (OJ) is a popular flavonoid-rich drink consumed worldwide. Due to the existing controversies regarding its impact on blood lipids, we decided to investigate the impact of OJ supplementation on lipid profile parameters. Major scientific databases (Cochrane library, Scopus, PubMed and Embase) were searched. Pooled effects sizes were reported as weighted mean difference (WMD) and 95% confidence intervals (CIs). Out of 6334 articles retrieved by the initial search, 9 articles met our inclusion criteria. Overall, supplementation with OJ did not exert any significant effects on blood levels of TG (WMD -1·53 mg/dl, 95% CI -6·39, 3·32, P = 0·536), TC (WMD -5·91 mg/dl, 95% CI -13·26, 1·43, P = 0·114) or HDL-C (WMD 0·61 mg/ dl, 95% CI -0·61, 1·82, P = 0·333). OJ consumption did reduce LDL-C levels significantly (WMD -8·35 mg/dl, 95% CI -15·43, -1·26, P = 0·021). Overall, we showed that the consumption of OJ may not be beneficial in improving serum levels of TG, TC or HDL-C. Contrarily, we showed that daily intake of OJ, especially more than 500 ml/d, might be effective in reducing LDL-C levels. In the light of the existing inconsistencies, we propose that further high-quality interventions be conducted in order to make a solid conclusion.

Reduction of cerebrovascular and peripheral events with PCSK9 inhibitors: Does it just depend on the lowering of the low-density lipoprotein?

Atherosclerotic cardiovascular disease is a systemic condition involving several vascular districts. The most involved vascular bed, beyond the coronary district, is represented by the peripheral arteries, whose involvement can give rise to cerebrovascular or peripheral events. PCSK9 inhibitors (PCSK9i) have established themselves as safe and effective drugs in reducing cholesterol linked to low-density lipoprotein (LDL-C), a causative factor of disease, with a consequent reduction in cardiovascular events. The two main studies on anti-PCSK9 antibodies, the FOURIER study for evolocumab and the ODYSSEY OUTCOMES study for alirocumab, highlighted the effectiveness in reducing LDL-C levels and its translation in a lower event rate of around 15%. Sub-analysis of these two trials showed how PCSK9i prevent cerebrovascular and/or peripheral events and how patients with already known cerebrovascular or peripheral disease benefit more from the action of these drugs than patients who do not have a widespread disease. Current evidence suggests that the preventive action of cerebrovascular and peripheral events is mainly expressed through reducing LDL-C levels. Although there are data regarding the association of PCSK9 levels and inflammatory status, propensity for thrombosis and platelet aggregation, these are currently less robust and do not justify a cardiovascular event reduction action that is independent of the action on LDL-C.

Comparing Simvastatin Monotherapy V/S Simvastatin-Ezetimibe Combination Therapy for the Treatment of Hyperlipidemia: A Meta-Analysis and Review.

Longstanding hyperlipidemia canincrease the risk of cardiovascular disease. Statins are currently the mainstay of treatment in hyperlipidemia. Combination therapy of statin with ezetimibe is only indicated for severe hypercholesterolemia and very high-risk atherosclerotic cardiovascular disease (ASCVD) population. There is a paucity of studies comparing statin monotherapy vs combination therapy with ezetimibe. This study aims to perform a meta-analysis of the existing literature and compare the effectiveness of statin monotherapy with statin-ezetimibe combination therapy in the management of hyperlipidemia. A systematic electronic search of the scientific literature was performed in PubMed, EMBASE, and Scopus. Only randomized controlled trials comparing simvastatin monotherapy vs simvastatin-ezetimibe combination therapy between the years 2000 and 2021 and published in English language were included. Fifteen studies were included in the final analysis. The main outcomes that were compared were a reduction in low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Our study showed that combination therapy led to a higher reduction of LDL-C (Mean difference: -20.22(-26.38, -14.07); P<0.0001) compared to monotherapy with a statin alone. There was no significant difference in the reduction of HDL-C values (Mean difference: -0.07(-0.45,0.32); P-0.04)between the two groups. Our study indicates that the combination therapy of simvastatin and ezetimibe is more effective in reduction of LDL-Clevels compared to simvastatin monotherapy alone. Currently, guidelines recommend combination therapy only for severe hypercholesterolemia and high-risk ASCVD patients, more studies are needed to study the effectiveness of simvastatin-ezetimibe combination therapy in low-risk ASCVD population.

High long-term persistence to evolocumab treatment regimens in European clinical practice: analysis of the HEYMANS registry

Abstract Background Lipid-lowering treatments (LLTs) require both adherence and persistence to the treatment regimen long-term to maximise treatment benefits. Small molecules require self-medication daily but therapies such as evolocumab are labelled for self-medication every 2 weeks or monthly. Limited data exist concerning the long-term persistence to evolocumab in routine clinical practice. Purpose Using data from the HEYMANS registry, the objective of this analysis was to evaluate persistence and discontinuation of evolocumab in Europe. Methods HEYMANS was a prospective registry including adults initiating evolocumab treatment in routine clinical practice in 12 European countries between August 2015 and June 2020. Originally designed to have up to 12 months of follow-up, the protocol was amended (February 2018) to extend follow-up for up to 30 months. Patients yet to complete 12 months follow-up at this date, were followed up for up to 30 months. Therefore, we analysed evolocumab discontinuation separately for the two time periods: 0–12 months (all), 12–30 months (subset). Results Of the 1951 total patients, 30 patients discontinued participation in the study before 12 months (evolocumab use still ongoing at study discontinuation). Therefore, evolocumab use status was determined for 1921 patients at 12 months. Of these, 1781 (92.7%), remained on evolocumab at 12 months of follow-up (Figure). At 12 months, LDL-C levels were reduced from baseline by a median of 58% (Q1, Q3: 41%, 69%). In total, 1136 patients were eligible for extended follow up after protocol amendment. Of these, 137 patients discontinued study participation before 30 months of follow-up (with evolocumab ongoing). Therefore, evolocumab use status was determined in 999 patients, of whom, 92.2% (921) remained on evolocumab treatment at 30 months of follow-up (Figure). The reductions in LDL-C levels seen at 12 months were sustained throughout the study, with patients continuing to achieve median LDL-C reductions of 58% (Q1, Q3: 42%, 70%) from baseline at 30 months of follow-up. Conclusions In this real-world study, representative of European practice, of patients who entered the extension phase, the proportion of patients who remained on evolocumab up to 30 months exceeded 90%, and treatment was associated with sustained LDL-C reductions. These data suggest that the self-administration regimen of evolocumab is both feasible and acceptable in general populations, providing long-term sustained, reductions in LDL-C with likely associated health benefits. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen (Europe) GmbH

Evolocumab treatment is associated with early and sustained reductions in low-density cholesterol (LDL-C) over 30 months: final results from the pan-European observational HEYMANS registry

Abstract Background Variability in LDL-C control at a population level associates with worse CV outcomes. This could in part be related to variations in patient adherence to self-administration regimens or variability in the response to a given therapy. Potent therapies such as PCSK9 inhibitors (PCSK9i) reduce cardiovascular events but some have questioned whether these therapies, which require dosing every 2 weeks, can offer sustained population level control of LDL-C. Purpose Using data from the HEYMANS registry, the objective of these analyses was to evaluate, at a population level, various metrics of variability in LDL-C reduction over time with evolocumab treatment. Methods HEYMANS was a prospective registry including adults initiating evolocumab treatment in clinical practice in 12 European countries between August 2015 to June 2020. Patient data were collected for ≤6 months before evolocumab initiation (baseline) and ≤30 months post initiation. LDL-C measurements were collected per clinical practice. At each 3-month time point in the study, we analysed median (and 95% CI) reductions in LDL-C, and the proportion of patients achieving ≥30% and ≥50% reductions in LDL-C from baseline. Results Data from 1951 patients were included in this final analysis (62% male, mean age 60 years, median baseline LDL-C 3.98 [Q1–Q3 3.17–5.07]) mmol/L). Most patients (85%) were receiving evolocumab for secondary prevention, with 40% not on oral LLT of whom the majority reported a history of statin intolerance. There was a median of 4 (Q1, Q3: 2, 6) LDL-C measurements per patient during follow-up. Within 3 months of initiating evolocumab treatment, LDL-C levels had reduced by a median of 58% and this reduction was maintained over 30 months (Figure 1). Among patients with an LDL-C value, ∼85% achieved a ≥30% reduction at each follow-up throughout the study, and ∼63% achieved a ≥50% reduction at each visit (Figure 2). Conclusions In European clinical practice, evolocumab treatment was associated with early and sustained reductions in LDL-C of over 30 months, with limited variability in LDL-C reductions at a population level. Within 3 months of treatment, evolocumab was associated with ∼58% reduction in LDL-C levels that was maintained throughout the study. These data should reassure the clinical community that meaningful, consistent additional reductions in LDL-C can be achieved with use of evolocumab. As greater use of combination therapies is required to achieve lower LDL-C goals, expanding the use of PCSK9i could provide improvements in population level control of LDL-C in European clinical practice. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen (Europe) GmbH

Persistence to long-term PCSK9 inhibitors treatment and its effectiveness in familial hypercholesterolemia: data from the SAFEHEART study

Abstract Background Most patients with heterozygous familial hypercholesterolemia (FH) do not achieve current LDL-C goals proposed by European guidelines with conventional lipid-lowering therapy (LLT). Chronic use of PCSK9 inhibitors (PCSK9i) have shown to reduce LDL-C levels up to 61% on top of statins. Persistence to chronic LLT is important to reduce the burden of atherosclerotic cardiovascular disease (ASCVD). Purpose To analyze persistence and effectiveness of PCSK9i in clinical practice setting in FH patients from the SAFEHEART register with long-term follow-up. Methods SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of FH. Follow-up is carried out every year through a standardized phone-call to collect clinical conditions, persistence to medications, lipid profile, and cardiovascular events. This study analyses subjects ≥18 years of age on stable LLT who have received PCSK9i. Results 696 individuals (46% females), median age 56.4 years (IQR 49–66) started with PCSK9i (49% alirocumab and 51% evolocumab). Out of them 38% had history of ASCVD, and 89% were on maximum LLT. Median LDL-C at the moment of starting PCSK9i was 145 mg/dL (IQR, 123–177), representing a poor 2016 &amp; 2019 ESC/EAS guidelines achievement (3% and 0.1% respectively). After a median follow-up of 3.7 years (IQR, 2.3–4.8), 669 patients (96%) remained on PCSK9i treatment during entire follow-up. Only 27 patients (4%) discontinued, 5 temporarily (0.7%) and 22 permanently (3.2%). Most common reasons for PCSK9i treatment interruption were medical decision (n=6), adverse event (AE) (n=5), patient decision not related with AE (n=5) and comorbidity (n=5). Median time to permanent discontinuation was 15 months (IQR, 4–33). Median LDL-C levels observed and % of LDL-C reduction obtained after 1 year of treatment and in the last follow-up visit were: 63 mg/dL (IQR, 43–88), 61 mg/dL (IQR, 44–82), 57.6% (IQR, 39.5–69) and 58% (IQR, 44–68), respectively. 2016 ESC/EAS guidelines LDL-C goals was achieved by 70% of patients at year 1 and 77% in the last follow-up visit after the introduction of PCSK9i (p&amp;lt;0.001). 2019 ESC/EAS goals were achieved by 44.5% and 48% (p=0.1). Conclusion Long-term persistence to PCSK9i treatment in FH patients is very high (96%) and reasons for discontinuation are diverse. This study shows that COVID-19 pandemic did not affected persistence to treatment. Effectiveness in LDL-C reduction and LDL-C goal achievement improved significantly with introduction of PCSK9i in clinical practice setting. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AMGEN

High individual variability in LDL-reductions after inclisiran administration in a “real-world setting”

Abstract Background and aims Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9) (1). Previous studies suggest that inclisiran provides sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. Patients included in the ORION program received inclisiran on top of maximally tolerated statin therapy and demonstrated a profound 50% LDL-C reduction as early as 3 months (2). The aim of this retrospective, multi-center analysis was to use individual patient data to determine the extent of the variability in LDL-C reduction in response to inclisiran administration in a real-world setting. Methods Since February 2021 the German Inclisiran Network (GIN) enrolled patients who received inclisiran due elevated LDL-cholesterol (LDL-C) levels in German lipid clinics. In contrast to patients included in the ORION program inclisiran could be administered to a broad range of patients with elevated LDL-C levels, including patients naive of lipid-lowering drugs, as well as patients on apheresis who failed to attain LDL-C goals. Results In 10 lipid clinics in Germany a total of 117 consecutive patients received inclisiran. Patients, who were not on stable lipid-lowering medication at least 3 months prior to inclisiran administration, were excluded. Thus, a total of 61 patients were analyzed. Mean LDL-C level at baseline was 151.86±64.31 mg/dl (95 percent confidence interval (CI): 135.39 to 168.33 mg/dl). After 3 months, inclisiran reduced LDL-C levels by 34.6% (95% CI: 29.3 to 39.8%), mean LDL-C levels were 103.26±60.36 mg/dl (95% CI: 87.8 to 118.72 mg/dl). At baseline 18 (30%) patients received statins, 22 (36%) ezetimibe and 13 (21%) bempedoic acid. Twenty-five (41%) patients were not on any lipid lowering therapy at baseline and 15 (25%) were on apheresis and failed to attain LDL-C target levels at baseline. Altogether there was a high inter-individual variability in LDL-C reduction 3 months after the first administration of inclisiran (Figure 1). Interestingly, patients who received statins at baseline demonstrated a trend towards a more profound LDL-C reduction (42.6±20.6 vs. 30.33±19.2%). This effect, however, was not significant. Two patients did not demonstrate any LDL-C reduction after the first administration. Inclisiran was well tolerated. Only one patient reported a minor injection-site reaction. No further side-effects were reported. Conclusion These results indicate that there is substantial individual variability in the LDL-C reduction after the first administration of inclisiran. Inclisiran was well tolerated without any serious side-effects. A longer follow-up period and further research is warranted to elucidate reasons for the high inter-individual variability in LDL-reductions in this real-world setting. Funding Acknowledgement Type of funding sources: None.

426.1: Dyslipidemia in Kidney Transplant Recipients: Is It Time for A Change in Strategy?

Introduction: Dyslipidemia is common in kidney transplant recipients (KTRs), and is associated with a more than 20-fold higher risk of major adverse cardiovascular events compared to the general population. Although KDIGO 2013 guidelines suggest that all KTRs be treated with statins, they are poorly tolerated due to myopathy, hepatotoxicity, and interaction with immunosuppression medications leading to poor compliance. The introduction of the novel lipid-lowering Proprotein convertase subtilisin/Kexin type 9 (PCSK-9) inhibitors presents an opportunity to treat a significant unmet need in KTRs. Methods: Here we report findings of 3 studies related to hyperlipidemia in KTRs. We conducted a single-center cross-sectional analysis of 250 KTRs about the prevalence of hyperlipidemia, ASCVD scores, frequency of lipid monitoring, and statin use. After our analysis, we performed a nationwide survey using a questionnaire on a lipid management strategy that was sent out to KTR providers and pharmacists. We also conducted a prospective study evaluating PCSK-9 inhibitor (Evolocumab) in the treatment of LDL-cholesterol (LDL-C) levels for KTRs. Patients included in the study were started on Evolocumab 140 mg subcutaneously every 2 weeks and their lipids were checked at 3 months. Results: Our institutional study showed suboptimal lipid control in KTRs with only about 52.3% getting optimal monitoring (Figure 2). This was also seen in the national survey involving 34 centers, where we found disparities and a lack of general consensus in lipid management (Figure 3). With regards to PCSK-9 inhibitor study, all 17 patients with 3 monthly follow-up (n=44 enrolled to date) showed a significant drop in their LDL-C levels (35% to 90%). There was also a remarkable reduction in ASCVD scores. The mean eGFR for all patients was stable (Figure 4). Overall, Evolocumab was well tolerated by all patients.Discussion: Sub-optimal lipid control found at our institution, along with the disparities in the survey responses indicate that there is no uniform strategy in lipid management in KTRs. This could be due to a lack of strong evidence on which the 2013 KDIGO guidelines are based. There is a need for long-term studies to assess the benefits of lipid management on patient and graft survival in KTRs and the development of a clearer, more standardized approach to the management of lipids. In terms of treatment, PCSK-9 inhibitors seem to be very effective for the reduction of LDL-C levels in KTRs. They have a favorable side effect profile and do not interact with immunosuppressive medications. Unlike cardiovascular benefits shown by statins in long-term studies, there is no data regarding PCSK-9 inhibitors as of yet. Given the challenges faced with statins, PCSK-9 inhibitors could be considered the therapy of choice for statin-intolerant patients, if supported by evidence of beneficial cardiovascular outcomes. “Study of safety and efficacy of PCSK-9 inhibitor (Evolocumab) in kidney transplant recipients.” is funded by AMGEN.

A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort

Background and aimsODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial. Methods and resultsThe methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol.Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6).LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH).Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively. ConclusionThe efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment. Clinicaltrials.gov identifierNCT02476006.

Importance of baseline LDL-C in the association between LDL-C lowering and cardiovascular risk: A meta-regression analysis

Background and Aims : Lipid lowering treatments (LLTs) are typically approved based on LDL-C lowering effects observed in randomized controlled trials (RCTs). In economic evaluations, effectiveness in preventing cardiovascular events is typically predicted using the relationship between LDL-C lowering and cardiovascular risk. Several studies have demonstrated that treatments which reduce LDL-C levels also reduce cardiovascular events, and this relationship is robust across diverse biological mechanisms of lipid lowering. We aimed to explore the importance of baseline LDL-C in the relationship between LDL-C reduction and cardiovascular risk.Methods: Thirty-six RCTs were identified from a systematic literature review supplemented with targeted searches. Random effects meta-regression was performed with and without the inclusion of baseline LDL-C as a covariate. Models were compared using the Akaike and Bayesian Information Criteria (AIC and BIC). Correlation (R-squared) and statistical heterogeneity (Higgins I-squared) were assessed.Conclusions: The results support the well documented association between LDL-C and cardiovascular risk reduction. Furthermore, models accounting for baseline LDL-C as well as the LDL-C reduction on treatment may provide more accurate predictions of cardiovascular risk than models based on LDL-C reduction alone. Limitations of this work include the use of aggregate trial data rather than patient-level data (which were not available to us from source studies). Background and Aims : Lipid lowering treatments (LLTs) are typically approved based on LDL-C lowering effects observed in randomized controlled trials (RCTs). In economic evaluations, effectiveness in preventing cardiovascular events is typically predicted using the relationship between LDL-C lowering and cardiovascular risk. Several studies have demonstrated that treatments which reduce LDL-C levels also reduce cardiovascular events, and this relationship is robust across diverse biological mechanisms of lipid lowering. We aimed to explore the importance of baseline LDL-C in the relationship between LDL-C reduction and cardiovascular risk. Methods: Thirty-six RCTs were identified from a systematic literature review supplemented with targeted searches. Random effects meta-regression was performed with and without the inclusion of baseline LDL-C as a covariate. Models were compared using the Akaike and Bayesian Information Criteria (AIC and BIC). Correlation (R-squared) and statistical heterogeneity (Higgins I-squared) were assessed. Conclusions: The results support the well documented association between LDL-C and cardiovascular risk reduction. Furthermore, models accounting for baseline LDL-C as well as the LDL-C reduction on treatment may provide more accurate predictions of cardiovascular risk than models based on LDL-C reduction alone. Limitations of this work include the use of aggregate trial data rather than patient-level data (which were not available to us from source studies).