Layout 1 The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 Familial Hypercholesterolemia (FH), an autosomal dominant genetic disorder, causes high levels of Low- Density Lipoprotein Cholesterol (LDL-C) due to mutations in genes controlling cholesterol regulation. The most common mutation affects the LDLR gene, responsible for building LDL receptors that remove LDL cholesterol from the blood.1 These mutations hinder LDL receptor function or production. While LDLR mutations are most frequent, abnormalities in APOB, LDLRAP1, and PCSK9 genes can also contribute to FH. PCSK9, a liver-secreted serine protease, plays a crucial role by regulating LDL cholesterol levels. Its binding to LDL Abstract Despite the availability of statins and lifestyle modifications, many patients with Dyslipidemia struggle to achieve optimal low-density lipoprotein cholesterol (LDL-C) control. PCSK9 inhibitors offer a promising new therapeutic option with superior LDL-C lowering efficacy compared to statins. However, data on their real-world use, particularly in Iran, is limited. This study aims to address this gap by investigating the one-year effects of evolocumab on lipid profiles and potential cardiovascular outcomes in Iranian patients with Familial Hypercholesterolemia (FH).This single- center, prospective study evaluated evolocumab effectiveness in lowering LDL-C in 50 Iranian adults with FH. Participants with a documented LDL-C >190 mg/dL on existing cholesterol medications (excluding PCSK9 inhibitors) and a clinical FH diagnosis was included. After baseline assessments (medical history, demographics, lipid profile), evolocumab was administered subcutaneously every two weeks for one year. Follow-up assessments at year one measured changes in LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. The study enrolled 50 participants with an average age of 55 years old (range 35-80 years). Treatment with evolocumab led to significant improvements in lipid profiles at all follow-up points compared to baseline. On average, LDL-C levels decreased by 105.24 mg/dL, triglycerides decreased by 59.20 mg/dL, and HDL-C levels increased by a modest but significant 4.5 mg/dL after one year(p<0.001). Subgroup analysis revealed no statistically significant interactions between baseline demographics (age, sex, BMI) or lifestyle habits (smoking, alcohol) and changes in lipid levels(p>0.05). However, a significant interaction emerged between baseline lipid levels and their corresponding reductions, suggesting greater improvement in patients with higher baseline values(p<0.05). It is noteworthy that no new cardiovascular events were reported during the study period. This study demonstrates the effectiveness of evolocumab in improving lipid profiles in Iranian patients with FH. The observed reductions in LDL-C and triglycerides, along with a modest increase in HDL-C, suggest potential benefits for cardiovascular risk reduction. The absence of new cardiovascular events during the study is encouraging, but further research with larger and longer-term follow-up is needed to confirm these findings and assess the long-term safety and impact on quality of life. Key Words: dyslipidemia; hypercholesterolemia; PCSK9 inhibitors; lipid profile; cardiovascular disease. Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Maryam Moshkani Farahani,1 Alireza Nasiri,1 Mahdi Salari,2 Ali Shamsedini1 1Atherosclerosis Research Center, Baqiayatallah University of Medical Sciences, Tehran, Iran; 2Shafa Cardiovascular Medical and Research Center, Kerman University of Medical Sciences, Kemran, Iran. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 113 - Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 receptors triggers their degradation, reducing LDL-C clearance from the bloodstream.2,3 Not all cases will have a clear genetic cause, and some may involve a combination of factors.4,6 Early diagnosis and treatment of FH are crucial to sig- nificantly reduce the risk of developing CHD and other cardiovascular problems. Despite the well-established benefits, screening rates for FH remain low, leading to suboptimal management in this patient population. Due to the high prevalence of FH, widespread screening is essential to identify affected individuals and their rel- atives. This allows for appropriate genetic evaluation and management to be initiated promptly. Screening can be done simply by measuring LDL-C levels, making it a cost-effective approach. Effective FH screening programs require healthcare pro- viders’ familiarity with FH diagnostic criteria, particularly the widely accepted Simon Broome criteria. These criteria consider factors like LDL-C levels, family history of pre- mature coronary heart disease, and physical signs like ten- don xanthomas and corneal arcus.7 Genetic testing complements this approach by enabling the identification of disease-causing mutations in the LDL receptor, APOB, and PCSK9 genes. This method is considered the gold standard for definitive FH diagnosis and is particularly useful when clinical criteria are inconclusive or when there is a strong family history of FH.8,12,13 PCSK9 inhibitors, such as evolocumab and alirocumab, are monoclonal antibodies that lower LDL-C levels by blocking the PCSK9 protein. PCSK9 normally binds to LDL receptors on liver cells, promoting their degradation and hindering LDL-C clearance from the bloodstream. Blocking this interaction leads to an increase in func- tional LDLRs on the liver surface, enhancing LDL-C up- take and removal, ultimately resulting in lower LDL-C levels.9,10 Approved for FH management in various coun- tries, including the United States,11 PCSK9 inhibitors offer a valuable therapeutic option for patients who struggle to achieve optimal LDL-C control with tradi- tional therapies. Studies have shown significant reduc- tions (50-60%) in LDL-C levels for patients with HeFH.6,12,13 However, the effectiveness is less pro- nounced in patients with HoFH, especially those with minimal residual LDLR activity.14 Despite promising evidence for PCSK9 inhibitors, data on their real-world use, particularly at the national level and for long-term effects in Iranian patients with dyslipidemia, remains limited. This knowledge gap hinders understand- ing of how effectively these medications reach high-risk patients and their long-term impact in countries like Iran. This study aims to address these limitations by investigat- ing the one-year effects of PCSK9 inhibitor therapy on lipid levels, cardiovascular events, and quality of life in Iranian patients with FH. By examining both the national- level implications of PCSK9 inhibitor recommendations and the long-term effects in Iranian patients, this research has the potential to significantly contribute to improving dyslipidemiamanagement in Iran. This comprehensive ap- proach can provide valuable insights for physicians, ulti- mately ensuring these therapies reach those who can benefit most and improve clinical practice and patient care for dyslipidemia management in Iran. Materials and Methods Study design and participants This was a single-center, prospective, one-year follow-up study evaluating the efficacy of Evolocumab in lowering LDL-C levels in patients with dyslipidemia diagnosed with FH. Fifty participants over 18 years of age were selected. Inclusion criteria consisted of documented LDL-C levels exceeding 190 mg/dL on a stable regimen of cholesterol- lowering medications (excluding PCSK9 inhibitors) and a clinical diagnosis of FH based on established criteria (Based on physical examination, previous history of FH and as- sessment of LDL-C level in blood). Patients with underly- ing medical conditions that could confound the study results were excluded. Additionally, participants with incomplete medical records were not included. Informed consent was obtained from all participants, and the study adhered to eth- ical guidelines for patient confidentiality. Baseline assessment and intervention Prior to initiating Evolocumab therapy, all participants un- derwent a comprehensive clinical examination. Demo- graphic data, medical history, including cardiovascular events (Myocardial Infarction (MI), Percutaneous Coro- nary Intervention (PCI), Coronary Artery Bypass Grafting (CABG), Peripheral Artery Disease(PAD), vascular in- volvement), history of angiography, diabetes, and prior hospitalization in the coronary care unit (CCU), were doc- umented. Blood samples were collected to measure base- line levels of LDL-C, HDL-C, and triglycerides. Evolocumab was administered subcutaneously at a stan- dard dose (140 mg/ml) with a two-week interval for one year. After one year of treatment, participants returned for a follow-up clinical examination. Blood samples were again collected to assess changes in LDL-C, HDL-C, and triglyceride levels. Statistical analysis At the inferential level to control the presumption of data normality the Shapiro-Wilk test was used; if this assump- tion was established, the test One-way ANOVA along with Bonferroni’s post hoc test and otherwise Kruskal-Wallis and Mann-Whitney test were performed. To compare the qualitative variables between patients with different sev- erity of the disease chi-square or Fisher’s exact test was used. Analyzes was performed at the 5% error level using SPSS software version 24. Results Baseline demographics and lifestyle habits The study enrolled 50 participants with an average age of 55 years old (range 35-80 years). The group was predom- inantly male, with 35 males (70%), 15 females (30%), and with an average body mass index (BMI) of 25.5 (range - 114 - Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 19.8-30.8). In terms of lifestyle habits, 8 participants (16%) reported smoking and 5 participants (10%) reported occasional alcohol consumption (Table 1). Cardiovascular history The study population had a moderate average Left Ven- tricular Ejection Fraction (LVEF) of 51.32%. However, there was heterogeneity within the group, with 24 patients (48%) having a low LVEF (mean: 47.29%) and 26 pa- tients (52%) having a normal LVEF (mean: 55.04%). In terms of prior cardiovascular events (CVD), 13 patients (26%) had a history of MI, 10 patients (20%) had under- gone PCI, 3 patients (6%) had received CABG, and 4 pa- tients (8%) had PAD. The average vessel involvement in patients with PAD was 1.8. Importantly, none of these pa- tients experienced new cardiovascular events during the one-year follow-up period. Additionally, 16 patients (32%) within the study population were diagnosed with diabetes mellitus (Table 2). Baseline medication Baseline medication use revealed that statins were the most common cholesterol-lowering therapy, with 42 pa- tients (84%) receiving medications like atorvastatin and rosuvastatin. Among these statin users, 7 patients (17%) also received ezetimibe for additional LDL-C reduction. Fibrates (fenofibrate and gemfibrozil) were used by a smaller proportion of patients (5 out of 50, 10%), with 2 of them (40%) also taking ezetimibe. Only 1 patient (2%) received both statins and fibrates concurrently. No- tably, 2 patients (4%) did not receive medication specif- ically for LDL-C control but were taking anti-platelet drugs and beta-blockers, likely for other cardiovascular conditions. Regarding prior procedures, 25 patients (50%) had undergone angiography before entering the study, and 23 patients (46%) had a prior admission to the CCU. Importantly, no new occurrences of these proce- dures were observed during the one-year follow-up period. - 115 - Table 1. Baseline Demographics and Lifestyle Habits of Study Participants with Familial Hypercholesterolemia (n=50). Variables N % Mean Range SD Gender Male 35 70.0 Female 15 30.0 Smoker 8 16.0 Alcohol use 5 10.0 Age 55.38 35-80 11.62 BMI index 25.52 19.8-30.8 2.37 Table 2. Baseline cardiovascular parameters (n=50). Count Mean SD Count Column N % Ejection fraction Low 24 47.29 3.61 Normal 26 55.04 0.20 Vascular involvement None 29 58.0 1 8 16.0 2 9 18.0 3 4 8.0 Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 Evolocumab significantly improved lipid profile At baseline, participants exhibited average triglyceride and LDL-C levels of 270.2±38.94 mg/dL and 227.7±28.84 mg/dL, respectively. Following one year of evolocumab treatment, these values demonstrated statistically significant reductions (p-values <0.001). Follow-up measurements re- vealed a decrease in triglycerides to an average of 210.8±34.75 mg/dL and a notable reduction in LDL-C to 122.5±22.80 mg/dL. Conversely, HDL-C levels displayed a statistically significant increase (p-value <0.001) from a baseline of 44.34±6.23 mg/dL to 48.84±5.81 mg/dL after one year. These findings provide strong evidence that evo- locumab therapy effectively improved the overall lipid pro- file of study participants, potentially reducing their risk of cardiovascular events. (Tables 3 and 4). Subgroup analysis and evolocumab efficacy We investigated whether evolocumab’s effectiveness var- ied based on patient characteristics by performing sub- group analysis and linear regression. These analyses explored potential influences of age, gender, smoking status, occasional alcohol consumption, and BMI. While evolocumab demonstrably improved lipid profiles overall, we did not observe any statistically significant interactions between these factors and changes in triglyceride, LDL- C, or HDL-C levels (p>0.05). In simpler terms, Evolocu- mab appeared to be equally effective in lowering LDL-C, increasing HDL-C, and reducing triglycerides regardless of a patient’s age, gender, smoking status, occasional al- cohol consumption, or BMI (Table 5). We further investigated the influence of baseline lipid levels (LDL-C, triglycerides, and HDL-C) on evolocumab’s effi- cacy. Interestingly, we observed statistically significant in- teractions. Patients with higher baseline lipid levels experienced a greater reduction in those specific lipids com- pared to those with lower baseline values. This suggests evolocumab may be particularly beneficial for individuals with more severe dyslipidemia (p<0.05) (Table 6). Our analysis did not reveal any significant relationships be- tween evolocumab efficacy and prior cardiovascular events (history of MI, PCI, CABG, PAD), presence of diabetes mellitus, or baseline medications (ezetimibe, fibrates, statins, anti-platelet drugs, and beta-blockers) (p>0.05). - 116 - Table 3. Lipid profile at baseline and after evolocumab treatment (mg/dL; Mean±SE, Range). Baseline lipid profile (mg/dL) Lipid profile after treatment (mg/dL) TG LDL HDL TG LDL HDL Mean 270.20 227.74 44.34 210.80 122.50 48.84 SE of mean 5.507 4.078 .881 4.914 3.224 .822 Median 270.00 230.00 46.00 200.00 120.00 50.00 SD 38.940 28.838 6.232 34.749 22.796 5.815 Range 200 110 25 180 110 22 200-400 190-300 30-55 140-320 80-190 38-60 Table 4. Paired Samples T-test results: changes in triglycerides, LDL-C, and HDL-C after one-year evolocumab therapy (mg/dL) Mean SD SE 95% CI of the t df Sig. mean difference (2- tailed) Lower Upper Pair 1 TG before and after treatment 59.400 25.747 3.641 52.083 66.717 16.314 49 .000 Pair 2 LDL before and after treatment 105.240 23.153 3.274 98.660 111.820 32.141 49 .000 Pair 3 HDL before and after treatment -4.500 2.816 .398 -5.300 -3.700 -11.301 49 .000 Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 - 117 - Table 5. Impact of demographics on changes in triglycerides, LDL-C, and HDL-C after evolocumab treatment: tests of between-subjects effects. Dependent Source Type III sum df Mean square F Sig. variable of squares TG Change Corrected model 14773.667a 27 547.173 0.680 0.831 Intercept 95333.285 1 95333.285 118.438 0.000 Gender 61.227 1 61.227 0.076 0.785 Age 9834.108 22 447.005 0.555 0.912 Gender * Age 3150.883 4 787.721 0.979 0.439 Error 17708.333 22 804.924 Total 208900.000 50 Corrected total 32482.000 49 a, R Squared = 0.455 (Adjusted R Squared = -0.214). LDL Change Corrected model 17438.037a 27 645.853 1.609 0.129 Intercept 346988.435 1 346988.435 864.614 0.000 Gender 4.890 1 4.890 0.012 0.913 Age 16862.070 22 766.458 1.910 0.068 Gender * Age 683.629 4 170.907 0.426 0.788 Error 8829.083 22 401.322 Total 580040.000 50 Corrected total 26267.120 49 a, R Squared = 0.455 (Adjusted R Squared = -0.214). HDL Change Corrected model 237.500a 27 8.796 1.282 0.278 Intercept 665.027 1 665.027 96.891 0.000 Gender 0.260 1 0.260 0.038 0.847 Age 211.242 22 9.602 1.399 0.219 Gender * Age 14.477 4 3.619 0.527 0.717 Error 151.000 22 6.864 Total 1401.000 50 Corrected total 388.500 49 a, R Squared = 0.611 (Adjusted R Squared = 0.134). Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 However, it is important to consider the limitations of a small sample size in this analysis as well. Future studies with larger and more diverse patient populations are needed to definitively assess the potential interactions be- tween these factors and evolocumab’s effectiveness. Discussion Our study aimed to assess the effectiveness of evolocumab in lowering LDL-C levels for patients with dyslipidemia. The findings demonstrated a significant improvement in the lipid profiles of participants following one year of evolo- cumab therapy. Treatment resulted in a substantial decrease in LDL-C by an average of 105.24±2315 mg/dL, bringing LDL-C levels closer to the recommended range of 50 to 100 mg/dL. Additionally, evolocumab treatment led to a no- table reduction in triglycerides (average decrease of 59.40±25.74 mg/dL) and a modest, yet statistically signif- icant, decreased in HDL-C (average of -4.5±2.81 mg/dL). These findings align with previous research highlighting evolocumab’s efficacy in improving overall lipid profiles for patients with similar conditions. Our findings regarding EVOLOCUMAB’S effectiveness in lowering LDL-C and improving overall lipid profiles are consistent with prior research on PCSK9 inhibitors for dys- lipidemia management. The network meta-analysis by Toth et al. (2017) strengthens these findings by positioning evo- locumab among the most effective non-statin therapies for LDL-C reduction.15 These observations are further sup- ported by Rosenson et al. (2016), whose research indicates evolocumab’s effectiveness in lowering LDL-C for patients with mixed hyperlipidemia.16 Furthermore, Zhang et al. (2022) provide compelling data from a large-scale meta- analysis, demonstrating significant reductions in LDL-C, triglycerides, and ApoB with PCSK9 inhibitor use, particu- larly in high-risk cardiovascular patients.17 Interestingly, their analysis also revealed an average increase in HDL-C of 6.27 mg/dL, aligning closely with the 4.5 mg/dL increase observed in our study. Taken together, these findings high- light evolocumab’s potential as a valuable therapeutic tool for managing a broad spectrum of dyslipidemia, especially for those with high cardiovascular risk. It’s important to note that some studies have reported slightly higher or lower average reductions in LDL-C de- pending on factors like baseline LDL-C levels, treatment duration, and patient characteristics.18 However, the overall consensus from prior research strongly supports the effec- tiveness of evolocumab and similar PCSK9 inhibitors in significantly improving lipid profiles. Our investigation explored potential factors influencing evolocumab’s efficacy. While we did not observe statisti- cally significant interactions between demographics (age, sex, BMI) or occasional lifestyle habits (smoking, alcohol consumption) and changes in lipid levels, a different pattern - 118 - Table 6. Linear regression analysis: predictors of changes in lipid profile after evolocumab treatment. Coefficients Dependent Unstandardized Standardized t Sig. variable coefficients coefficients B Std. error Beta TG Change (Constant) 24.134 46.024 0.524 0.603 Baseline TG -0.322 0.085 -0.487 -3.799 0.000* Age 0.238 0.283 0.107 0.839 0.406 BMI index -0.383 1.393 -0.035 -0.275 0.785 LDL Change (Constant) 34.651 43.904 0.789 0.434 Baseline LDL -.521 0.099 -0.648 -5.251 0.000* Age -0.020 0.244 -0.010 -0.084 0.934 BMI index -0.792 1.116 -0.081 -0.710 0.482 HDL Change (Constant) 10.556 5.093 2.073 0.044 Baseline HDL -0.173 0.062 -0.384 -2.781 0.008* Age 0.023 0.033 0.094 0.681 0.500 BMI index 0.015 0.162 0.012 0.090 0.929 *significant. Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 emerged when considering baseline lipid levels. There was a statistically significant interaction between baseline levels (LDL-C, triglycerides, HDL-C) and their corresponding changes after evolocumab treatment. This suggests that pa- tients with higher baseline lipid levels experienced a greater reduction in those specific lipids compared to those with lower baseline values. This finding aligns with observations in some prior research.19 Evolocumab’s mechanism of action, by inhibiting PCSK9 and promoting LDL-C clearance, likely contributes to the significant improvements in lipid profiles observed in our study.20 This aligns with the growing recognition of PCSK9 inhibitors as a valuable therapeutic approach, particularly for high-risk patients like those with FH. As highlighted by Mohamed et al. (2023), statin monotherapy often falls short in achieving optimal LDL-C reduction for such patients.21 PCSK9 inhibitors, as discussed in their review, offer a promising alternative with the potential to improve cardio- vascular outcomes. Our findings on evolocumab’s efficacy are further bolstered by research on other PCSK9 inhibitors. The Ginsberg et al. (2016) study with Alirocumab demon- strates positive outcomes in patients with FH despite maxi- mized statin therapy.22 This reinforces the effectiveness of this drug class in a population highly similar to our own, strengthening the generalizability of our observations to a broader range of high-risk FH patients. Together, these studies support the rationale behind our investigation – to explore alternative options for effectively managing LDL- C in high-risk individuals. Our study findings, combined with the existing body of research, provide compelling ev- idence for evolocumab’s efficacy in improving lipid profiles in patients with FH, offering a valuable tool for managing dyslipidemia in this high-risk population. Furthermore, evolocumab’s impact may extend beyond simply lowering LDL-C. Although the exact mechanisms remain under investigation, some studies suggest evolocu- mab may indirectly influence HDL-C levels.23 This poten- tial influence could involve stimulating HDL production or reducing its breakdown within the body, leading to the mod- est increase in HDL-C observed in our study (4.5 mg/dL). These combined effects of evolocumab on both LDL-C and HDL-C have the potential to translate into significant clin- ical benefits. A lower LDL-C level and a more favorable LDL-C to HDL-C ratio are well-established risk factors for atherosclerosis, the hardening and narrowing of arteries due to plaque buildup. Atherosclerosis is a major precursor to various cardiovascular events, including myocardial infarc- tion and stroke. Therefore, evolocumab’s capacity to im- prove both LDL-C and HDL-C holds promise for mitigating cardiovascular risk in patients with familial hy- percholesterolemia. Based on our results, it is noteworthy that a considerable proportion of the study population had a high cardiovascu- lar risk burden, with approximately half (50%, n = 25) of the participants had undergone coronary angiography be- fore study enrollment, and nearly half (46%, n = 23) had a documented prior admission to the Coronary Care Unit (CCU). These findings underscore the pre-existing cardio- vascular risk burden faced by many patients with familial hypercholesterolemia. Encouragingly, none of the partici- pants experienced new cardiovascular events during the one-year follow-up, including those with a history of MI, PCI, CABG, or PAD. While our study design precludes de- finitive conclusions about evolocumab’s long-term impact on cardiovascular events, these initial observations are promising and warrant further investigation in larger trials. These observations align with findings from recent meta- analyses, such as the one by Ma et al. (2021), which dem- onstrated that PCSK9 inhibitors, compared to placebo, significantly reduce LDL-C levels and show promise for reducing Major Adverse Cardiac Events (MACE) including stroke and myocardial infarction.24 Notably, their study found no significant difference in cardiovascular event pre- vention between PCSK9 inhibitors and ezetimibe, high- lighting the potential advantages of Evolocumab for high-risk patients who may not respond adequately to other therapies.Furthermore, as highlighted by Berman and Blankstein (2019), PCSK9 inhibitors represent a significant recent advancement in dyslipidemia treatment.25 Their re- view emphasizes the effectiveness of this drug class in low- ering LDL-C and reducing cardiovascular events in high-risk patients – precisely the population we targeted in our study. This aligns with the growing recognition of the importance of risk assessment and targeted therapies, as emphasized by Karantas et al. (2021) in their review of up- dated dyslipidemia management guidelines.26 Our study adds to the growing evidence supporting evo- locumab’s effectiveness in managing dyslipidemia, par- ticularly in high-risk patients with FH. The observed significant reduction in LDL-C aligns with findings from other PCSK9 inhibitor trials, such as the one by Blom et al. (2020) demonstrating similar reductions in HoFH pa- tients using Alirocumab.14 This strengthens the case for evolocumab’s ability to address the core challenge of el- evated LDL-C in FH. Furthermore, our study comple- ments the existing research on evolocumab’s role in overcoming limitations of statin therapy. The BERSON trial design by Lorenzatti et al. (2018) targets patients with type 2 diabetes and dyslipidemia, reflecting a similar ra- tionale for evolocumab in FH patients where statins may be insufficient.27 However, it’s important to acknowledge that our study did not differentiate between HeFH and HoFH subtypes, which might require tailored treatment approaches. Further investigation is warranted to explore this aspect. Also, while our analysis did not identify sta- tistically significant associations between evolocumab ef- ficacy and factors like prior cardiovascular history or baseline medications, the limited sample size necessitates further exploration in more comprehensive studies. Systematic reviews like the one by AlHajri et al. (2017) an- alyzing data from multiple evolocumab trials offer a broader perspective on its effectiveness and highlight its po- tential for overcoming statin limitations.28 Looking beyond LDL-C reduction, the review by Lazarte and Hegele (2020) emphasizes the multifaceted nature of dyslipidemia man- agement, highlighting the importance of diet, lifestyle changes, and potentially targeting other lipids like triglyc- erides.29 Evolocumab can be a valuable tool within a broader treatment plan, potentially alongside statins as the cornerstone therapy30 or combined with ezetimibe for high- risk patients with uncontrolled LDL-C.29 Future research can definitively assess how factors like prior cardiovascular history and baseline medications influence evolocumab’s effectiveness in reducing cardiovascular risk. Additionally, - 119 - Non -co mmerc ial us e o nly The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up Eur J Transl Myol 34 (3) 12937, 2024 doi: 10.4081/ejtm.2024.12937 exploring the potential benefits of evolocumab in combi- nation with other lipid-lowering strategies is warranted. However, a key limitation lies in the relatively small sample size (50 participants). This limitation restricts the general- izability of our findings to the broader population with FH. Larger, multicenter trials with more diverse participants are necessary to confirm our observations with greater certainty and enhance the generalizability of the results. Future re- search could also explore the efficacy of evolocumab in dif- ferent patient populations, such as those with other types of dyslipidemia or additional cardiovascular risk factors. Fur- thermore, investigating evolocumab’s effectiveness in var- ious treatment settings, including longer treatment durations or combination therapies with other lipid-lowering medi- cations, would provide valuable information for optimizing patient care. By addressing these limitations and expanding the scope of future research, we can gain a more compre- hensive understanding of evolocumab’s role in managing dyslipidemia and reducing cardiovascular risk across a wider range of patients. It is important to acknowledge the limitations of our study, particularly the relatively small sample size. Future research with larger and more diverse populations is needed to con- firm our observations and enhance generalizability. Further- more, investigating the impact of baseline lipid levels on treatment response and exploring evolocumab’s efficacy in broader treatment settings are important areas for future ex- ploration. Despite these limitations, our findings contribute valuable insights into evolocumab’s potential for managing dyslipidemia and reducing cardiovascular risk in patients with familial hypercholesterolemia. Conclusions In conclusion, our study demonstrated that evolocumab treatment significantly improved lipid profiles in patients with familial hypercholesterolemia. Following one year of therapy, participants experienced a substantial reduction in LDL-C, with average levels approaching the recommended target range. Additionally, evolocumab treatment led to a decrease in triglycerides and a modest increase in HDL-C. These findings are consistent with prior research on evolo- cumab’s efficacy in improving overall lipid profiles. En- couragingly, none of the participants with a history of prior cardiovascular events experienced new occurrences during the follow-up period, suggesting a potential association with reduced cardiovascular risk. List of acronyms LDL-C: low-density lipoprotein cholesterol. HDL-C: high-density lipoprotein cholesterol. FH: Familial hypercholesterolemia. MI: Myocardial Infarction. PCI: Percutaneous Coronary Intervention. CABG: Coronary Artery Bypass Grafting. PAD: Peripheral Artery Disease. CCU: coronary care unit. CVD: cardiovascular events. Conflict of interest The authors declare no potential conflict of interest, and all authors confirm accuracy. Funding Atherosclerosis Research Center, Baqiayatallah University of Medical Sciences, Tehran, IR Iran. Ethics approval The Ethics Committee of Baqiayatallah University of Med- ical Sciencesapproved this study (IR.BMSU.BAQ. REC.1402.052). The study is conformed with the Helsinki Declaration of 1964, as revised in 2013, concerning human and animal rights. Informed consent All patients participating in this study signed a written in- formed consent form for participating in this study. Patient consent for publication Written informed consent was obtained from a legally au- thorized representative(s) for anonymized patient infor- mation to be published in this article. Availability of data and materials All data generated or analyzed during this study are in- cluded in this published article. Corresponding Author Ali Shamsedini, Atherosclerosis Research Center, Baqiaya- tallah University of Medical Sciences, Tehran, IR Iran. ORICD ID: 0000-0002-0000-1236 E-mail: ali_shamsadini2000@yahoo.com Maryam Moshkani Farahani ORCID ID: 0000-0003-4902-273X E-mail:Moshkani_farahani@yahoo.com Alireza Nasiri ORCID ID: 0000-0003-2608-3660 E-mail:alirezanasiri6592@yahoo.com Mahdi Salari ORCID ID: 0000-0001-8568-658X E-mail:salaricardiologist@yahoo.com References 1. Hovingh GK, Raal FJ, Dent R, et al. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol 2017;11:1448-57. 2. 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Current options and future perspectives in the treatment of dyslipide- mia. J Clin Med 2022;11:4716. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their af- filiated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 18 August 2024. Accepted: 2 September 2024. Early access: 13 September 2024. - 121 - Non -co mmerc ial us e o nly