Estimating the Effect of Inclisiran on Dyslipidemia and Primary Prevention of Cardiovascular Disease: The NHANES 1999-2018 Study

Estimating the Effect of Inclisiran on Dyslipidemia and Primary Prevention of Cardiovascular Disease: The NHANES 1999-2018 Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Estimating the Effect of Inclisiran on Dyslipidemia and Primary Prevention of Cardiovascular Disease: The NHANES 1999-2018 Study Haonan Li, Song Zhao, Jiawen Wu, Jun Han, Yawei Xu, Yi Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4727339/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Sep, 2024 Read the published version in Lipids in Health and Disease → Version 1 posted 10 You are reading this latest preprint version Abstract Background Dyslipidemia has been delineated as independent predictors of cardiovascular disease (CVD). Inclisiran, an innovative small interfering RNA (siRNA) agent, is anticipated to engender a notable reduction of approximately 50% in low-density lipoprotein cholesterol (LDL-C) levels. Given its transformative impact, we scrutinized the eligibility of US population for inclisiran treatment and evaluated its potential effects on dyslipidemia and the primary prevention of CVD. Methods We applied eligibility criteria from the ORION 10 and 11 trials to the 1999–2018 National Health and Nutrition Examination Survey dataset to estimate the eligible population size for atherosclerotic cardiovascular disease (ASCVD) and ASCVD-risk equivalents. Utilizing lipid reduction data from the ORION 10, we predicted the impact of inclisiran on LDL-C levels and dyslipidemia prevalence among ASCVD patients. Similarly, leveraging the ORION 11's lipid reduction data, we forecasted inclisiran's effect on 10-year CVD risk change and preventable CVD events in the ASCVD-risk equivalents population, employing the Framingham CVD Risk Score. Results We identified 613 ASCVD patients (5.28 million) and 377 ASCVD-risk equivalents (2.63 million) who met the eligibility criteria of the ORION 10 and 11. Among ASCVD population, 3.71 million (70.3%) would achieve ≥ 50% LDL-C reduction post-treatment. Furthermore, 4.86 million (91.9%) with high LDL-C, 0.22 million (4.2%) with low high-density lipoprotein cholesterol, 1.19 million (22.5%) with high total cholesterol, and 0.5 million (9.5%) with high triglycerides would attain target lipid profiles. For ASCVD-risk equivalents population, the estimated 10-year CVD risk would decrease from 25.2–17.6% (7.6% absolute, 30.2% relative) post-inclisiran treatment, potentially preventing 199,878 CVD events over a decade, including 136,217 coronary heart disease cases, 37,024 strokes, and 23,619 heart failures. Conclusions Inclisiran holds the potential to substantially diminish the prevalence of dyslipidemia and mitigate the occurrence of nearly 200 thousand CVD events in eligible US adults. Inclisiran Cardiovascular disease NHANES LDL-C Dyslipidemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Over the past six decades, there has been a notable increase in mean life expectancy, coupled with a decline in the remaining lifetime risk of atherosclerotic cardiovascular disease (ASCVD), as evidenced in the predominantly White, community-based Framingham Study 1 . However, ASCVD remains the leading cause of mortality worldwide 2 . Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), stands out as a pivotal risk factor for ASCVD 3 . Despite the widespread utilization of statin therapy, either alone or in combination with other lipid-lowering agents, a significant proportion of patients continue to exhibit elevated LDL-C levels 4 . In the epoch of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), known for their profound LDL-C reduction either as standalone therapy or alongside statins 5 , inclisiran has emerged as a promising therapeutic option. This double-stranded small interfering RNA (siRNA) exerts its action by targeting and degrading the mRNA of PCSK9 6 . Inclisiran received endorsement of the European Medicines Agency (EMA) 7 in 2020 as an agent for LDL-C reduction, followed by approval from the Food and Drug Administration (FDA) 8 in 2021. Subsequently, in early 2023, the FDA extended the approved indications for inclisiran to encompass the treatment of adults with high LDL-C levels and those at heightened risk of ASCVD 9 . Numerous investigations, including the four-year open-label extension trial ORION-3, consistently demonstrate that biannual administration of inclisiran leads to a substantial reduction of approximately 50% in LDL-C levels. This effect is also observed when inclisiran is employed alongside maximally tolerated oral lipid-lowering therapy across diverse cohorts. Notably, those cohorts encompass individuals with heterozygous familial hypercholesterolemia, ASCVD, and those with equivalent risk profiles 10–14 . Regarding safety, a comprehensive analysis from seven clinical trials underscores inclisiran's favorable tolerability profile across a diverse patient population during long-term treatment with no discernible safety concerns 15 . Furthermore, a patient-level pooled analysis spanning the ORION-9, -10, and − 11 offers early insights into the potential cardiovascular advantages associated with LDL-C reduction through inclisiran therapy. This analysis suggests promising prospects for diminishing major adverse cardiovascular events (MACE), thereby highlighting inclisiran's potential role in cardiovascular risk reduction 16 . As a promising therapeutic avenue for dyslipidemia and primary prevention of ASCVD, inclisiran holds substantial potential to benefit a considerable proportion of the eligible US population. The objective of this study is: 1) to delineate the eligible US population suitable for inclisiran treatment based on the stringent eligibility criteria established in the ORION 10 and 11 trials, 2) to project the population-wide impact of inclisiran on dyslipidemia among individuals with ASCVD, and 3) to quantify the potential reduction in CVD events attributable to inclisiran therapy among individuals with ASCVD-risk equivalents. These insights have the potential to provide valuable implications for ongoing clinical trials such as the ORION 4 and the VICTORION-2 PREVENT, which aim to assess the cardiovascular outcomes associated with inclisiran treatment 17,18 . Methods Study sample Our study predominantly centered on two discrete cohorts within the United States population: individuals diagnosed with ASCVD and those deemed to be at an equivalent risk of ASCVD. To delineate these cohorts, we employed the publicly available US National Health and Nutrition Examination Survey (NHANES) database spanning the years from 1999 to 2018. It's imperative to note that prior consent for research use of their data was obtained from all NHANES participants. We identified the ASCVD sample and the ASCVD-risk equivalent sample by applying the inclusion and exclusion criteria from the ORION 10 and 11 trials to the NHANES database, respectively (Fig. 1 ). Inclusion and exclusion criteria Inclusion criteria are as follows: ( 1 ) Participants of any gender, aged 18 years or older; ( 2 ) Participants with a history of ASCVD (including coronary heart disease, angina pectoris, heart attack, or stroke) for ASCVD sample, or participants without diagnosis of ASCVD but presenting with equivalent risk factors for ASCVD (such as type 2 diabetes, or individuals whose 10-year risk of a cardiovascular event assessed by the Framingham Risk Score is ≥ 20%) for ASCVD-risk equivalent sample; ( 3 ) Serum LDL-C levels ≥ 1.8 mmol/L (≥ 70 mg/dL) for ASCVD sample, or ≥ 2.6 mmol/L (≥ 100 mg/dL) for ASCVD-risk equivalent sample; ( 4 ) Fasting triglyceride levels < 4.52 mmol/L ( 30 mL/min/1.73m^2 as determined by estimated glomerular filtration rate (eGFR) using Cockcroft-Gault methodology; ( 6 ) Currently receiving statin therapy. Exclusion criteria are as follows: ( 1 ) New York Heart Association (NYHA) Class IV heart failure or last recorded left ventricular ejection fraction 180 mmHg or diastolic blood pressure > 110 mmHg despite antihypertensive therapy; ( 3 ) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceeding three times the upper limit of normal (ULN), or total bilirubin levels surpassing two times the ULN; ( 4 ) Severe concurrent non-cardiovascular ailment posing a risk of reducing life expectancy to less than 2 years; ( 5 ) History of malignancy; ( 6 )Pregnancy or positive urine pregnancy test; ( 7 )Treatment with monoclonal antibodies targeting PCSK9. Weighting Throughout the screening process, samples meeting the rigorous criteria at each pivotal step underwent weighting. Given the necessary of fasting blood laboratory tests for every eligible participant, we amalgamated the Fasting Subsample 2 Year Mec Weight (WTSAF2YR) spanning from 1999 to 2018 to derive the definitive Fasting Subsample 20 Year Mec Weight (WTSAF20YR) 19 . These intricately calculated weights were then employed to ascertain the corresponding population estimates for the United States. Variables We meticulously curated variables to align with those utilized in the ORION trials. Age, gender, and ethnicity information were extracted from the Demographic Data within the NHANES database. Data pertaining to ASCVD, hypertension, diabetes, and smoking status were sourced from the Questionnaire Data. Lipid levels, adhering to the same statistical methodology and units of measure as employed in the ORION trials, were retrieved from the Laboratory Data. Subsequently, baseline data from NHANES samples were juxtaposed with those of participants in the ORION trials for comparative analysis. Estimate the effect of inclisiran on dyslipidemia We assessed the likelihood of achieving a reduction in LDL-C levels exceeding 50%, derived from the proportion observed in the ORION 10 trial. These estimations were stratified by both sex and ethnicity. Additionally, we projected the anticipated shift in the number of patients attaining target lipid profiles within the ASCVD population post-treatment. Target lipid profiles were defined by LDL-C < 70 mg/dl, HDL-C ≥ 40 mg/dl in women or ≥ 50 mg/dl in men, TC < 200 mg/dl, and TG < 150 mg/dl 20,21 . These projections were based on the average changes in blood lipid levels observed in the ORION 10 trial and were also stratified by sex and ethnicity for comprehensive analysis. Estimate the effect of inclisiran on CVD risk We employed the Framingham risk scores, a laboratory-based Cox regression model developed by D’Agostino and colleagues 22 , to evaluate the baseline 10-year risk of CVD events among the ASCVD-risk equivalent population. By applying NHANES sample weighting, we estimated the population size in millions for this assessment. Subsequently, we replicated this process following the incorporation of risk factor adjustments based on findings from the ORION 11 trial to estimate the "post-treatment" 10-year CVD risk. The calculated disparity in risk between individuals receiving inclisiran treatment and those without, multiplied by the eligible population size, yielded the prospective number of preventable CVD events. These analyses were further stratified by both sex and ethnicity to facilitate a comprehensive understanding of the potential impacts across demographic subgroups. Statistics and ethics Quantitative variables were presented as mean ± standard deviation for normally distributed data and median accompanied by interquartile range (within parentheses) for non-normal distributions. Qualitative variables were reported as frequencies accompanied by percentages (within parentheses). Statistical comparisons of quantitative variables were analyzed using Student’s t-test, while the Wilcoxon rank-sum test was employed for non-normal distributions. Chi-squared test was utilized for comparisons involving qualitative variables. All analyses were conducted using SAS version 9.4. It is worth noting that this study utilized publicly available de-identified data, and was therefore exempt from institutional review board review. Results Characteristics of the Participants We identified 31,083 individuals who underwent fasting blood tests from 101,316 NHANES participants. Subsequently, we applied sample weighting using the Fasting Subsample 20-Year MEC Weight, which resulted in a weighted sample size of 261 million individuals, equivalent to the entire population of the United States. Following further screening, we identified 613 ASCVD participants, who corresponded to 5.28 million US adults, meeting the eligibility criteria of the ORION 10 trial, and 377 ASCVD-risk equivalent participants, who corresponded to 2.63 million US adults, meeting the eligibility criteria of the ORION 11 trial (Figure 1). Descriptive statistics pertaining to demographic and risk factor characteristics were obtained from the NHANES database and were compared with data from the inclisiran group in the ORION trials. Although the mean age across the ORION trials and NHANES sample was comparable, notable differences emerged in the distribution of sex and ethnicity. Specifically, the ASCVD sample showed a lower proportion of males and Whites compared to the ORION 10 trial, while the ASCVD-risk equivalent sample showed a higher proportion of males and a lower proportion of Whites compared to the ORION 11 trial. With regard to cardiovascular risk factors, the ASCVD sample showed a lower prevalence of hypertension and diabetes but a higher prevalence of smoking compared to the ORION 10 trial. Similarly, the ASCVD-risk equivalent sample showed a lower prevalence of diabetes but a higher prevalence of other cardiovascular disease risk factors compared to the ORION 11 trial. The disparities observed in the aforementioned data may be attributed to variations in background, objectives, and methodologies employed during baseline data collection. With regard to blood lipid levels, no significant differences were observed between the ASCVD sample and the ORION 10 trial. However, the ASCVD-risk equivalent sample exhibited lower levels of LDL-C, non-HDL-C, TC, and TG compared to the ORION 11 trial. These differences are primarily attributed to the limited participant pool in the ORION 11 trial, as individuals with higher risk profiles tend to be more inclined to participate in clinical trials, subsequently influencing the observed lipid levels (Table 1). Table 1. Demographic and clinical characteristics of the NHANES samples and the ORION trials ASCVD sample (n=613) Control one † (n=781) ASCVD-risk equivalent sample (n=377) Control two ‡ (n=98) Age — yr 66.8±10.3 66.4±8.9 63.7±11.5 62.7±10.6 Male sex — no.(%) 379(61.8) *** 535(68.5) 214(56.8) *** 45(45.9) White race — no.(%) 355(57.9) *** 653(83.6) 141(37.4) *** 94(95.9) Cardiovascular risk factors — no.(%) ASCVD 613(100) 781(100) 0(0) 0(0) Current smoker 130(21.2) *** 123(15.7) 65(17.2) 19(19.4) Hypertension 470(76.7) *** 714(91.4) 258(68.4) 67(68.4) Diabetes 203(33.1) *** 371(47.5) 205(54.4) *** 66(67.3) 10-year predicted CVD risk ≥20% / / 284(75.3) *** 54(55.1) Lipid measures — mg/dl LDL cholesterol 103±27.5 104.5±39.6 128.9±26 *** 143.1±65.7 Total cholesterol 181.2±35.2 180.6±46.1 210.5±31.1 *** 232±69.6 Non-HDL cholesterol 130.6±33.6 ** 134±44.5 158.8±31.4 *** 177.9±69.6 HDL cholesterol 50.6±14.3 ** 46.6±14.3 51.7±13.7 * 50.3±15.5 Triglycerides 124 (87-173) 127 (92–181) 136 (96-189) *** 159 (115-204) Quantitative variables are reported as mean ± standard deviation, while TG is reported as median with the interquartile range in parentheses due to its non-normal distribution. Qualitative parameters are presented as numbers with the percentages in parentheses. The characteristics of inclisiran group in the ORION trials are shown for comparison with the NHANES eligible samples. † Control one refers to ASCVD patients received inclisiran treatment in the ORION 10 trial. ‡ Control two refers to ASCVD-risk equivalent subjects received inclisiran treatment in the ORION 11 trial. * P < 0.05, ** P < 0.05 and *** P < 0.001. Abbreviations: NHANES = National Health and Nutrition Examination Survey; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein. Changes in LDL-C levels We estimated the number of ASCVD patients achieving ≥50% reduction in LDL-C levels after inclisiran or placebo treatment. Based on the findings of the ORION 10 trial, which revealed that 72.8% of inclisiran-treated patients experienced ≥50% LDL-C reductions, we extrapolated this to ASCVD cohort of 5.28 million patients. Consequently, we estimated that approximately 3.85 million patients within this cohort would attain such reductions. Even when considering potential placebo effects, our analysis suggested that roughly 3.71 million patients would still achieve LDL-C reductions of ≥50%. This encompassed 2.23 million men, 1.48 million women, 2.9 million White subjects, 0.32 million Black subjects, 0.11 million Mexican American subjects, and 0.1 million Hispanic subjects (Figure 2, Table S1). Changes in Dyslipidemia We predicted the number of US adults within the ASCVD population expected to transition from a state of dyslipidemia to achieving target lipid profiles following inclisiran treatment. Significant improvements were observed in LDL-C levels, with 4.86 million patients (91.9%) achieving target level. This included 2.92 million men, 1.94 million women, 3.83 million White subjects, 0.4 million Black subjects, 0.14 million Mexican American subjects, and 0.12 million Hispanic subjects (Figure 3A, Table S2). For HDL-C, 0.22 million (14.7%) out of 1.5 million ASCVD patients with low level would achieve target level, including 0.1 million men, 0.12 million women, 0.15 million White subjects, 4,048 Black subjects, 3,691 Mexican American subjects, and 12,578 Hispanic subjects (Figure 3B, Table S2). For TC, 1.19 million (95%) out of 1.25 million ASCVD patients with high level would achieve target level, including 0.59 million men, 0.6 million women, 0.92 million White subjects, 0.12 million Black subjects, 51,305 Mexican American subjects, and 46,285 Hispanic subjects (Figure 3C, Table S2). Finally, 0.5 million (26.7%) out of 1.87 million ASCVD patients with high level of TG would achieve target TG profiles, including 0.36 million men, 0.13 million women, 0.44 million White subjects, 21,401 Black subjects, 9,261 Mexican American subjects, and 10,148 Hispanic subjects (Figure 3D, Table S2). Changes in 10 ‑year CVD Risk We estimated the 10-year CVD risk before and after inclisiran treatment in ASCVD-risk equivalent population using the Framingham risk scores. Prior to treatment, the average risk for the entire population was 25.2%, with a higher risk for men at 28.7%. Among all racial groups, Whites exhibited the highest average risk at 26.4%. After inclisiran treatment, an overall absolute risk reduction of 7.6% would be observed, accompanied by a relative risk reduction of 30.2%. Particularly noteworthy is the substantial risk reduction observed among men (8.4%) and Whites (7.9%). Furthermore, we predicted a total of 199,878 preventable CVD events, including 136,217 cases of CHD, 37,024 strokes, and 23,619 cases of CHF (Figure 4A-D, Table S3). Discussion Our study underscores that approximately 5.28 million adults with ASCVD and 2.63 million adults deemed to have ASCVD-risk equivalents in the US met the eligibility criteria for inclisiran treatment based on the ORION 10 and 11 trial criteria, respectively. Within the ASCVD population, an estimated 3.71 million individuals could anticipate LDL-C reductions of ≥50%, and 4.86 million individuals (91.9%) achieving target lipid profiles post-inclisiran treatment. Among the ASCVD-risk equivalent population, the estimated 10-year CVD risks decreased from 25.2% to 17.6% following inclisiran treatment, representing a 7.6% absolute (and 30.2% relative) risk reduction. Over a decade, inclisiran could potentially prevent 199,878 CVD events, including 136,217 cases of CHD, 37,024 strokes, and 23,619 cases of CHF. These findings underscore the significant potential impact of inclisiran on the broader US population (CENTRAL ILLUSTRATION). Dyslipidemia constitutes a significant component of the global health burden, with cardiovascular morbidity escalating notably with advancing age, predominantly driven by elevated (LDL-C) levels 23,24 . Statins stand as the cornerstone pharmacotherapy for mitigating the risk of future ASCVD events 25 . Pioneering work by Dubuc et al. illuminated the intricate interplay between dietary cholesterol intake and PCSK9 expression, underscoring PCSK9 as a cholesterol-regulated gene 26 . Mechanistically, statins, by impeding cholesterol biosynthesis, augment PCSK9 transcription, thereby accelerating the degradation of LDL receptors (LDLR) 27-30 .Paradoxically, this cascade can sustain or even elevate serum LDL-C levels. Complementary murine studies corroborated these observations, demonstrating that PCSK9 deficiency not only correlated with diminished plasma cholesterol levels but also enhanced sensitivity to statin therapy 31 . Notably, genetic investigations in humans unveiled that individuals harboring non-functional PCSK9 variants enjoy a markedly reduced lifetime risk of cardiovascular events 32 , emphasizing the therapeutic promise of PCSK9 inhibition for LDL-C reduction. Through substantial endeavors by pharmaceutical industries, two distinct and robust PCSK9 inhibitory therapies have emerged: PCSK9 monoclonal antibodies (PCSK9mAbs) and siRNA targeting PCSK9. While both modalities demonstrate comparable lipid-lowering effects 13,33,34 , PCSK9mAbs necessitate frequent subcutaneous administration, whereas siRNA therapies, such as inclisiran, require fewer injections, enhancing patient adherence. As the pioneer siRNA drug targeting PCSK9, inclisiran has garnered attention and undergone extensive evaluation for its efficacy and safety profile. Nevertheless, no large-scale studies encompassing over 10,000 participants have been reported to date. A fundamental inquiry arises: what proportion of eligible Americans would derive benefits from inclisiran, and to what extent could it effectively manage their blood lipid profiles? Our study reveals that approximately 5.28 million adults with ASCVD met the eligibility criteria for inclisiran treatment based on the ORION 10 trial criteria. Among them, an estimated 3.7 million individuals would likely experience LDL-C reductions of ≥50%, with the majority achieving target lipid profiles post-inclisiran therapy. We conducted a comprehensive analysis of lipid levels, stratified by sex and ethnicity, revealing that men and individuals of White ethnicity garnered the most substantial benefits. This observation can primarily be attributed to the demographic composition of eligible population, which predominantly comprised men and individuals of White ethnicity. Further scrutiny unveiled that Hispanics exhibited the highest baseline LDL-C and TC levels. Considering their reported suboptimal adherence to statin therapy 35 , this group would significantly benefit from inclisiran. To date, several studies have endeavored to estimate the impact of inclisiran on CVD prevention. One such study employed a Markov model to project the health benefits of inclisiran treatment in individuals aged 50 and above with pre-existing ASCVD in England. The analysis specifically focused on the avoidance of cardiovascular events and associated mortality. The result indicated that over a 10-year timeframe, inclisiran treatment could potentially prevent 138,647 cardiovascular events, yielding a cost-effectiveness ratio of 1.03 36 . In another study, the augmentation of statin therapy with inclisiran was assessed against statin therapy alone. The analysis projected that among 1000 subjects over their lifetimes in Australia, the addition of inclisiran was anticipated to prevent 235 non-fatal myocardial infarctions and 114 instances of coronary revascularization 37 . However, uncertainties persist regarding the assumptions inherent in the methodological approach. Deviations between predicted and actual eligible populations for drug treatment are anticipated. In our investigation, the weighting of the NHANES database serves to mitigate these limitations. Additionally, it is worth noting that all these studies have exclusively targeted patients with ASCVD. As the significance of primary prevention in ASCVD continues to gain prominence, it warrants heightened attention 38 . However, there is a paucity of studies evaluating the impact of inclisiran on the primary prevention of ASCVD. Our objective is to ascertain the number of individuals without a diagnosis of ASCVD but meeting the ASCVD equivalent risk criteria delineated in the ORION 11 trial, and to evaluate the potential efficacy of inclisiran in averting CVD development in this cohort. Employing the Framingham risk scores, our analysis suggests that as many as 199,878 (7.6%) cardiovascular events could potentially be prevented over a decade in the United States. Upon closer examination, it became evident that men (8.4%) and individuals of White ethnicity (7.9%) derived the greatest benefit. This is primarily attributed to the heightened susceptibility of men to cardiovascular disease compared to women 39 , and the alteration in the proportion of each risk factor is notably more conspicuous within the male population. Regarding race, Whites demonstrate the highest prevalence of risk factors and rates of cardiovascular disease 40,41 , thereby constituting the majority of participants in equivalent risk groups with undiagnosed ASCVD. Consequently, they stand to derive the greatest benefit from primary prevention initiatives involving inclisiran administration. This study boasts several noteworthy strengths. Firstly, it leverages the comprehensive NHANES database, encompassing diverse US adult participants. By utilizing the database's sample weighting functionality, we can effectively gauge the population-level impact of inclisiran on ORION-eligible US adults while also exploring CVD prevention across various demographic groups. While NHANES relies on self-reported measures for certain variables, including CVD status, the reliability of these self-report measures has been firmly established in prior research 42 . Secondly, by extrapolating the lipid-lowering effects observed in the ORION 10 trial to the NHANES data, this study estimates the number of ASCVD patients who could attain a target lipid profile with inclisiran. This yields crucial insights for national lipid management strategies. Thirdly, our study encompasses individuals with equivalent risk of ASCVD, a population often overlooked in previous research on inclisiran's CVD prevention effects, primarily focused on secondary prevention. The inclusion of data on a subset of ASCVD-risk equivalent individuals from the ORION 11 trial, as reported by Professor Kausik 14 , is novel and allows us to estimate inclisiran's potential primary prevention effect against CVD in the US population by integrating these data with the NHANES database. However, this study also harbors limitations. Firstly, the NHANES database lacks a crucial indicator of familial hypercholesterolemia (FH), rendering it unfeasible to predict the impact of inclisiran on FH nationally. Moreover, the absence of lipoprotein (a) (LP(a)), an independent risk factor for CVD, precludes the assessment of inclisiran's lipid-lowering effect in patients with elevated LP(a) levels. Secondly, despite employing ORION eligibility criteria to identify NHANES sample, disparities between NHANES sample and the ORION trial participants may exist. Consequently, the observed blood lipid-lowering effect in the ORION trials may not be entirely applicable to NHANES sample. For instance, NHANES sample exhibits a lower proportion of Whites compared to the ORION 10 trial, potentially leading to an overestimation of inclisiran's lipid-lowering effect nationally, as compliant Whites may have previously received lipid-lowering treatments, reducing their sensitivity to inclisiran. Finally, while the Framingham Risk Score serves as a widely used tool to estimate CVD events, its precision is limited by the inability to account for all potential factors, including family history and other risk-enhancing elements, that may influence CVD events. Conclusions Our study suggests that inclisiran treatment in eligible US adults holds the potential to significantly mitigate dyslipidemia and prevent nearly 200 thousand CVD events. These findings offer robust data support for inclisiran's role in both primary and secondary prevention of ASCVD. The ongoing ORION 4 trial will provide valuable insights into the actual cardiovascular outcomes associated with inclisiran treatment. Abbreviations ASCVD: atherosclerotic cardiovascular disease; CVD: cardiovascular disease; NHANES: National Health and Nutrition Examination Survey; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides; CHD: coronary heart disease; CHF: congestive heart failure; eGFR: estimated glomerular filtration rate; PCSK9: proprotein convertase subtilisin/kexin type 9; siRNA: small interfering RNA; MACE: major adverse cardiovascular events Declarations Ethics approval and consent to participate This study utilized de-identified publicly available data and does not qualify for institutional review board review. The National Health and Nutrition Examination Survey obtains consent to participate from all subjects. Consent for publication Not applicable. No individual data or images are used in this manuscript. Availability of data and materials Data used in this study are publicly available from the National Health and Nutrition Examination Survey: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx. Competing interests The authors declare that they have no competing interests. Funding This study was financially supported by the National Nature Science Foundation of China (82170388，82370300), Shanghai Technology Research Leader Program (21XD1434700), the Cardiac rehabilitation fund by the International Medical Exchange Foundation (Z-2019-42-1908-3) and Grant for the construction of Innovative Flagship Hospital for Integrated Traditional Chinese and Western Medicine (No., ZY(2021-2023)-0205-05). Authors' contributions YX and YZ designed the study and revised the manuscript. HL and SZ wrote the main manuscript text, HL and JW performed the statistical analysis, SZ prepared figures 1, JW and JH prepared figures 2-4, HL prepared CENTRAL ILLUSTRATION. All authors read and approved the final manuscript. Acknowledgements This study was analyzed using the data provided by the National Health and Nutrition Examination 1999–2018. The authors would like to thank the NHANES participants and the staff members for their contribution to data collection and for making the data publicly available. References Vasan RS, Enserro DM, Xanthakis V, Beiser AS, Seshadri S. Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study. Circulation. 2022;145(17):1324–38. Global regional. national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet (London England). 2016;388(10053):1603–58. Pirillo A, Casula M, Olmastroni E, Norata GD, Catapano AL. Global epidemiology of dyslipidaemias. Nat reviews Cardiol. 2021;18(10):689–700. Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc. 2012;1(6):e001800. Räber L, Ueki Y, Otsuka T, et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022;327(18):1771–81. Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017;376(1):41–51. Aguilar-Salinas CA, Gómez-Díaz RA, Corral P. New Therapies for Primary Hyperlipidemia. J Clin Endocrinol Metab. 2022;107(5):1216–24. Al Shaer D, Al Musaimi O, Albericio F, de la Torre BG. 2021 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel Switzerland) 2022;15(2). Carugo S, Sirtori CR, Gelpi G, Corsini A, Tokgozoglu L, Ruscica M. Updates in Small Interfering RNA for the Treatment of Dyslipidemias. Curr Atheroscler Rep. 2023;25(11):805–17. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430–40. Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. lancet Diabetes Endocrinol. 2023;11(2):109–19. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520–30. Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507–19. Ray KK, Kallend D, Leiter LA, et al. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial. Eur Heart J. 2022;43(48):5047–57. Wright RS, Koenig W, Landmesser U, et al. Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials. J Am Coll Cardiol. 2023;82(24):2251–61. Ray KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2023;44(2):129–38. Scicchitano P, Milo M, Mallamaci R, et al. Inclisiran in lipid management: A Literature overview and future perspectives. Biomed pharmacotherapy = Biomedecine pharmacotherapie. 2021;143:112227. Stoekenbroek RM, Kallend D, Wijngaard PL, Kastelein JJ. Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program. Future Cardiol. 2018;14(6):433–42. Heeringa S, West BT, Berglund PA. Applied survey data analysis. Second edition. ed. Boca Raton, FL: CRC Press, Taylor & Francis Group; 2017. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586–613. Grundy SM, Stone NJ, Bailey AL, NLA/PCNA Guideline on the Management of Blood Cholesterol. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–143. /ABC/ACPM/ADA/AGS/APhA/ASPC/ . 2018 AHA/ACC/AACVPR/AAPA. D'Agostino RB, Sr., Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743–53. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141–56. Zhang Y, Pletcher MJ, Vittinghoff E, et al. Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events. JAMA Cardiol. 2021;6(12):1406–13. Jin J. Statins for the Prevention of Cardiovascular Disease. JAMA. 2022;328(8):786. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24(8):1454–9. Benjannet S, Rhainds D, Essalmani R, et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem. 2004;279(47):48865–75. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA. 2004;101(18):7100–5. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102(6):2069–74. Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 2004;279(48):50630–8. Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA. 2005;102(15):5374–9. Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–22. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097–107. Vulic D, Lee BT, Dede J, Lopez VA, Wong ND. Extent of control of cardiovascular risk factors and adherence to recommended therapies in US multiethnic adults with coronary heart disease: from a 2005–2006 national survey. Am J Cardiovasc drugs: drugs devices other interventions. 2010;10(2):109–14. Ostwald DA, Schmitt M, Peristeris P, Gerritzen T, Durand A. The Societal Impact of Inclisiran in England: Evidence From a Population Health Approach. Value health: J Int Soc Pharmacoeconomics Outcomes Res. 2023;26(9):1353–62. Kam N, Perera K, Zomer E, Liew D, Ademi Z. Inclisiran as Adjunct Lipid-Lowering Therapy for Patients with Cardiovascular Disease: A Cost-Effectiveness Analysis. PharmacoEconomics. 2020;38(9):1007–20. Cai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ. 2021;374:n1537. Kanchi R, Perlman SE, Chernov C, in Cardiovascular Disease Risk Factors among New York City Adults. Gender and Race Disparities : New York City Health and Nutrition Examination Survey (NYC HANES) 2013–2014. Journal of urban health: bulletin of the New York Academy of Medicine. 2018;95(6):801–812. Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018;39(25):2401–8. Gao Y, Isakadze N, Duffy E, et al. Secular Trends in Risk Profiles Among Adults With Cardiovascular Disease in the United States. J Am Coll Cardiol. 2022;80(2):126–37. Bergmann MM, Byers T, Freedman DS, Mokdad A. Validity of self-reported diagnoses leading to hospitalization: a comparison of self-reports with hospital records in a prospective study of American adults. Am J Epidemiol. 1998;147(10):969–77. Additional Declarations No competing interests reported. Supplementary Files Additionalfile.docx Cite Share Download PDF Status: Published Journal Publication published 27 Sep, 2024 Read the published version in Lipids in Health and Disease → Version 1 posted Editorial decision: Revision requested 29 Jul, 2024 Reviews received at journal 28 Jul, 2024 Reviews received at journal 23 Jul, 2024 Reviewers agreed at journal 15 Jul, 2024 Reviewers agreed at journal 15 Jul, 2024 Reviewers agreed at journal 12 Jul, 2024 Reviewers invited by journal 12 Jul, 2024 Editor assigned by journal 12 Jul, 2024 Submission checks completed at journal 11 Jul, 2024 First submitted to journal 11 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4727339","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":333141785,"identity":"c1c6d180-4b21-4ed4-b379-f77e93ded3c9","order_by":0,"name":"Haonan Li","email":"","orcid":"","institution":"Shanghai Tenth People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Haonan","middleName":"","lastName":"Li","suffix":""},{"id":333141787,"identity":"6f7874bb-b38c-4b64-a2b0-b69ae595cee9","order_by":1,"name":"Song Zhao","email":"","orcid":"","institution":"Shanghai Tenth People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Song","middleName":"","lastName":"Zhao","suffix":""},{"id":333141789,"identity":"3b7b0b56-9171-42c3-b722-f4682f54c6bd","order_by":2,"name":"Jiawen Wu","email":"","orcid":"","institution":"Shanghai Tenth People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiawen","middleName":"","lastName":"Wu","suffix":""},{"id":333141791,"identity":"6f795776-f019-4fc9-b845-2c4b1a45f4eb","order_by":3,"name":"Jun Han","email":"","orcid":"","institution":"Shanghai Tenth People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Han","suffix":""},{"id":333141793,"identity":"f33f1cd1-589c-4091-8af2-d6ba677ee912","order_by":4,"name":"Yawei Xu","email":"","orcid":"","institution":"Shanghai Tenth People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yawei","middleName":"","lastName":"Xu","suffix":""},{"id":333141794,"identity":"c7b8a1bb-bd6c-4f5f-bd76-8097a0e85d5c","order_by":5,"name":"Yi Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYDACZjBikAOxDzwgRYsxWEsCCRYxJDaAWERpMTjO/vhzQc2d9Plhhx8CbbGT020gpOUwQ5r0jGPPcjfeTjMAakk2NjtAWMsxZt6Gw7kbZyeAtBxI3EZYC2PzZ6CWdMPZ6R+I1cLMIA3UkiAvnUOkLZKH2dikeY4dNtwgnVNwIMGACL/wnT/++DNPzWF5+dnpmz98qLCTI6hFAabAAMwwIKAcBOQb0BmjYBSMglEwCtABAKZORluAnfEnAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Tenth People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yi","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2024-07-12 02:06:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4727339/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4727339/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12944-024-02294-8","type":"published","date":"2024-09-27T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62189869,"identity":"e7692b25-e6d7-408d-a756-c4ef210f6e00","added_by":"auto","created_at":"2024-08-10 12:24:08","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":117961,"visible":true,"origin":"","legend":"\u003cp\u003eThe screening and weighting process of eligible samples from the NHANES 1999–2018 dataset following the inclusion and exclusion criteria of the ORION 10 and 11 trials.\u003c/p\u003e\n\u003cp\u003eNote: Small letter n represents the sample size, and capital letter N represents the weighted US population. *ORION 11 criteria only refer to inclusion and exclusion criteria of ASCVD-risk equivalent subjects.\u003c/p\u003e\n\u003cp\u003eAbbreviations: ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; TG = triglycerides; eGFR = estimated glomerular filtration rate.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4727339/v1/193f370b64d60ad28ef47055.jpg"},{"id":62189870,"identity":"0f3aca83-eea8-4f2b-9491-5e87504d7b50","added_by":"auto","created_at":"2024-08-10 12:24:08","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68453,"visible":true,"origin":"","legend":"\u003cp\u003eThe number of ASCVD patients experiencing ≥50% reduction in LDL-C levels post-treatment based on the placebo-adjusted effect of inclisiran in the ORION 10.\u003c/p\u003e\n\u003cp\u003eAbbreviations: LDL-C = low-density lipoprotein cholesterol.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4727339/v1/a62247e6ac0488e28c1cce0f.jpg"},{"id":62189868,"identity":"d8e0755f-8ab9-4fba-946d-12af0e30888c","added_by":"auto","created_at":"2024-08-10 12:24:08","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":100288,"visible":true,"origin":"","legend":"\u003cp\u003eThe change in the number of ASCVD patients not achieving target lipid profile pre- and post-treatment, based on the placebo-adjusted effect of inclisiran in the ORION 10 trial. (A) Change in the number of patients with abnormal LDL-C levels. (B) Change in the number of patients with abnormal HDL-C levels. (C) Change in the number of patients with abnormal TC levels. (D) Change in the number of patients with abnormal TG levels.\u003c/p\u003e\n\u003cp\u003eAbbreviations: LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4727339/v1/c9e1c5107dfba0e1419a9bb0.jpg"},{"id":62189871,"identity":"8eea90d3-d92d-4db9-b99c-dbd13a91aa25","added_by":"auto","created_at":"2024-08-10 12:24:08","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":141685,"visible":true,"origin":"","legend":"\u003cp\u003eThe change in 10-year CVD risk of ASCVD-risk equivalent population pre- and post-treatment, based on the placebo-adjusted effect of inclisiran in the ORION 11 trial. (A) Change in 10-year CVD risk. (B) Change in 10-year CHD risk. (C) Change in 10-year Stroke risk. (D) Change in 10-year CHF risk.\u003c/p\u003e\n\u003cp\u003eAbbreviations: CVD = cardiovascular disease; CHD = coronary heart disease; CHF = congestive heart failure.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4727339/v1/a5fc8616682a586072b7ee71.jpg"},{"id":65627252,"identity":"dc2de54e-c360-424d-b36c-1d1c4a9502d4","added_by":"auto","created_at":"2024-09-30 16:13:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":922228,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4727339/v1/e8e5a953-a249-4360-a467-58d7e29344b0.pdf"},{"id":62189872,"identity":"fd879e28-d9c1-4e5c-b6a7-6b3b8c785950","added_by":"auto","created_at":"2024-08-10 12:24:08","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":32541,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-4727339/v1/b57afb12862d2a919766d804.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Estimating the Effect of Inclisiran on Dyslipidemia and Primary Prevention of Cardiovascular Disease: The NHANES 1999-2018 Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOver the past six decades, there has been a notable increase in mean life expectancy, coupled with a decline in the remaining lifetime risk of atherosclerotic cardiovascular disease (ASCVD), as evidenced in the predominantly White, community-based Framingham Study\u003csup\u003e1\u003c/sup\u003e. However, ASCVD remains the leading cause of mortality worldwide\u003csup\u003e2\u003c/sup\u003e. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), stands out as a pivotal risk factor for ASCVD\u003csup\u003e3\u003c/sup\u003e. Despite the widespread utilization of statin therapy, either alone or in combination with other lipid-lowering agents, a significant proportion of patients continue to exhibit elevated LDL-C levels\u003csup\u003e4\u003c/sup\u003e. In the epoch of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), known for their profound LDL-C reduction either as standalone therapy or alongside statins\u003csup\u003e5\u003c/sup\u003e, inclisiran has emerged as a promising therapeutic option. This double-stranded small interfering RNA (siRNA) exerts its action by targeting and degrading the mRNA of PCSK9\u003csup\u003e6\u003c/sup\u003e. Inclisiran received endorsement of the European Medicines Agency (EMA)\u003csup\u003e7\u003c/sup\u003e in 2020 as an agent for LDL-C reduction, followed by approval from the Food and Drug Administration (FDA)\u003csup\u003e8\u003c/sup\u003e in 2021. Subsequently, in early 2023, the FDA extended the approved indications for inclisiran to encompass the treatment of adults with high LDL-C levels and those at heightened risk of ASCVD\u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNumerous investigations, including the four-year open-label extension trial ORION-3, consistently demonstrate that biannual administration of inclisiran leads to a substantial reduction of approximately 50% in LDL-C levels. This effect is also observed when inclisiran is employed alongside maximally tolerated oral lipid-lowering therapy across diverse cohorts. Notably, those cohorts encompass individuals with heterozygous familial hypercholesterolemia, ASCVD, and those with equivalent risk profiles\u003csup\u003e10\u0026ndash;14\u003c/sup\u003e. Regarding safety, a comprehensive analysis from seven clinical trials underscores inclisiran's favorable tolerability profile across a diverse patient population during long-term treatment with no discernible safety concerns\u003csup\u003e15\u003c/sup\u003e. Furthermore, a patient-level pooled analysis spanning the ORION-9, -10, and \u0026minus;\u0026thinsp;11 offers early insights into the potential cardiovascular advantages associated with LDL-C reduction through inclisiran therapy. This analysis suggests promising prospects for diminishing major adverse cardiovascular events (MACE), thereby highlighting inclisiran's potential role in cardiovascular risk reduction\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs a promising therapeutic avenue for dyslipidemia and primary prevention of ASCVD, inclisiran holds substantial potential to benefit a considerable proportion of the eligible US population. The objective of this study is: 1) to delineate the eligible US population suitable for inclisiran treatment based on the stringent eligibility criteria established in the ORION 10 and 11 trials, 2) to project the population-wide impact of inclisiran on dyslipidemia among individuals with ASCVD, and 3) to quantify the potential reduction in CVD events attributable to inclisiran therapy among individuals with ASCVD-risk equivalents. These insights have the potential to provide valuable implications for ongoing clinical trials such as the ORION 4 and the VICTORION-2 PREVENT, which aim to assess the cardiovascular outcomes associated with inclisiran treatment\u003csup\u003e17,18\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy sample\u003c/h2\u003e \u003cp\u003eOur study predominantly centered on two discrete cohorts within the United States population: individuals diagnosed with ASCVD and those deemed to be at an equivalent risk of ASCVD. To delineate these cohorts, we employed the publicly available US National Health and Nutrition Examination Survey (NHANES) database spanning the years from 1999 to 2018. It's imperative to note that prior consent for research use of their data was obtained from all NHANES participants. We identified the ASCVD sample and the ASCVD-risk equivalent sample by applying the inclusion and exclusion criteria from the ORION 10 and 11 trials to the NHANES database, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eInclusion criteria are as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Participants of any gender, aged 18 years or older; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Participants with a history of ASCVD (including coronary heart disease, angina pectoris, heart attack, or stroke) for ASCVD sample, or participants without diagnosis of ASCVD but presenting with equivalent risk factors for ASCVD (such as type 2 diabetes, or individuals whose 10-year risk of a cardiovascular event assessed by the Framingham Risk Score is \u0026ge;\u0026thinsp;20%) for ASCVD-risk equivalent sample; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Serum LDL-C levels\u0026thinsp;\u0026ge;\u0026thinsp;1.8 mmol/L (\u0026ge;\u0026thinsp;70 mg/dL) for ASCVD sample, or \u0026ge;\u0026thinsp;2.6 mmol/L (\u0026ge;\u0026thinsp;100 mg/dL) for ASCVD-risk equivalent sample; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Fasting triglyceride levels\u0026thinsp;\u0026lt;\u0026thinsp;4.52 mmol/L (\u0026lt;\u0026thinsp;400 mg/dL); (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Calculated glomerular filtration rate\u0026thinsp;\u0026gt;\u0026thinsp;30 mL/min/1.73m^2 as determined by estimated glomerular filtration rate (eGFR) using Cockcroft-Gault methodology; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Currently receiving statin therapy.\u003c/p\u003e \u003cp\u003eExclusion criteria are as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) New York Heart Association (NYHA) Class IV heart failure or last recorded left ventricular ejection fraction\u0026thinsp;\u0026lt;\u0026thinsp;25%; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)Uncontrolled severe hypertension: systolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;180 mmHg or diastolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;110 mmHg despite antihypertensive therapy; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceeding three times the upper limit of normal (ULN), or total bilirubin levels surpassing two times the ULN; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Severe concurrent non-cardiovascular ailment posing a risk of reducing life expectancy to less than 2 years; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) History of malignancy; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)Pregnancy or positive urine pregnancy test; (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)Treatment with monoclonal antibodies targeting PCSK9.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eWeighting\u003c/h2\u003e \u003cp\u003eThroughout the screening process, samples meeting the rigorous criteria at each pivotal step underwent weighting. Given the necessary of fasting blood laboratory tests for every eligible participant, we amalgamated the Fasting Subsample 2 Year Mec Weight (WTSAF2YR) spanning from 1999 to 2018 to derive the definitive Fasting Subsample 20 Year Mec Weight (WTSAF20YR)\u003csup\u003e19\u003c/sup\u003e. These intricately calculated weights were then employed to ascertain the corresponding population estimates for the United States.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eVariables\u003c/h2\u003e \u003cp\u003eWe meticulously curated variables to align with those utilized in the ORION trials. Age, gender, and ethnicity information were extracted from the Demographic Data within the NHANES database. Data pertaining to ASCVD, hypertension, diabetes, and smoking status were sourced from the Questionnaire Data. Lipid levels, adhering to the same statistical methodology and units of measure as employed in the ORION trials, were retrieved from the Laboratory Data. Subsequently, baseline data from NHANES samples were juxtaposed with those of participants in the ORION trials for comparative analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eEstimate the effect of inclisiran on dyslipidemia\u003c/h2\u003e \u003cp\u003eWe assessed the likelihood of achieving a reduction in LDL-C levels exceeding 50%, derived from the proportion observed in the ORION 10 trial. These estimations were stratified by both sex and ethnicity. Additionally, we projected the anticipated shift in the number of patients attaining target lipid profiles within the ASCVD population post-treatment. Target lipid profiles were defined by LDL-C\u0026thinsp;\u0026lt;\u0026thinsp;70 mg/dl, HDL-C\u0026thinsp;\u0026ge;\u0026thinsp;40 mg/dl in women or \u0026ge;\u0026thinsp;50 mg/dl in men, TC\u0026thinsp;\u0026lt;\u0026thinsp;200 mg/dl, and TG\u0026thinsp;\u0026lt;\u0026thinsp;150 mg/dl\u003csup\u003e20,21\u003c/sup\u003e. These projections were based on the average changes in blood lipid levels observed in the ORION 10 trial and were also stratified by sex and ethnicity for comprehensive analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEstimate the effect of inclisiran on CVD risk\u003c/h2\u003e \u003cp\u003eWe employed the Framingham risk scores, a laboratory-based Cox regression model developed by D\u0026rsquo;Agostino and colleagues\u003csup\u003e22\u003c/sup\u003e, to evaluate the baseline 10-year risk of CVD events among the ASCVD-risk equivalent population. By applying NHANES sample weighting, we estimated the population size in millions for this assessment. Subsequently, we replicated this process following the incorporation of risk factor adjustments based on findings from the ORION 11 trial to estimate the \"post-treatment\" 10-year CVD risk. The calculated disparity in risk between individuals receiving inclisiran treatment and those without, multiplied by the eligible population size, yielded the prospective number of preventable CVD events. These analyses were further stratified by both sex and ethnicity to facilitate a comprehensive understanding of the potential impacts across demographic subgroups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistics and ethics\u003c/h2\u003e \u003cp\u003eQuantitative variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for normally distributed data and median accompanied by interquartile range (within parentheses) for non-normal distributions. Qualitative variables were reported as frequencies accompanied by percentages (within parentheses). Statistical comparisons of quantitative variables were analyzed using Student\u0026rsquo;s t-test, while the Wilcoxon rank-sum test was employed for non-normal distributions. Chi-squared test was utilized for comparisons involving qualitative variables. All analyses were conducted using SAS version 9.4. It is worth noting that this study utilized publicly available de-identified data, and was therefore exempt from institutional review board review.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of the Participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 31,083 individuals who underwent fasting blood tests from 101,316 NHANES participants. Subsequently, we applied sample weighting using the Fasting Subsample 20-Year MEC Weight, which resulted in a weighted sample size of 261 million individuals, equivalent to the entire population of the United States. Following further screening, we identified 613 ASCVD participants, who corresponded to 5.28 million US adults, meeting the eligibility criteria of the ORION 10 trial, and 377 ASCVD-risk equivalent participants, who corresponded to 2.63 million US adults, meeting the eligibility criteria of the ORION 11 trial (Figure 1).\u003c/p\u003e\n\u003cp\u003eDescriptive statistics pertaining to demographic and risk factor characteristics were obtained from the NHANES database and were compared with data from the inclisiran group in the ORION trials. Although the mean age across the ORION trials and NHANES sample was comparable, notable differences emerged in the distribution of sex and ethnicity. Specifically, the ASCVD sample showed a lower proportion of males and Whites compared to the ORION 10 trial, while the ASCVD-risk equivalent sample showed a higher proportion of males and a lower proportion of Whites compared to the ORION 11 trial. With regard to cardiovascular risk factors, the ASCVD sample showed a lower prevalence of hypertension and diabetes but a higher prevalence of smoking compared to the ORION 10 trial. Similarly, the ASCVD-risk equivalent sample showed a lower prevalence of diabetes but a higher prevalence of other cardiovascular disease risk factors compared to the ORION 11 trial. The disparities observed in the aforementioned data may be attributed to variations in background, objectives, and methodologies employed during baseline data collection. With regard to blood lipid levels, no significant differences were observed between the ASCVD sample and the ORION 10 trial. However, the ASCVD-risk equivalent sample exhibited lower levels of LDL-C, non-HDL-C, TC, and TG compared to the ORION 11 trial. These differences are primarily attributed to the limited participant pool in the ORION 11 trial, as individuals with higher risk profiles tend to be more inclined to participate in clinical trials, subsequently influencing the observed lipid levels (Table 1).\u003c/p\u003e\n\u003cp\u003eTable 1. Demographic and clinical characteristics of the NHANES samples and the ORION trials\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003eASCVD sample\u003c/p\u003e\n \u003cp\u003e(n=613)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003eControl one\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=781)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003eASCVD-risk equivalent sample\u003c/p\u003e\n \u003cp\u003e(n=377)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003eControl two\u003cstrong\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=98)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003eAge \u0026mdash; yr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e66.8\u0026plusmn;10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e66.4\u0026plusmn;8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e63.7\u0026plusmn;11.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e62.7\u0026plusmn;10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003eMale sex \u0026mdash; no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e379(61.8)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e535(68.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e214(56.8)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e45(45.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003eWhite race \u0026mdash; no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e355(57.9)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e653(83.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e141(37.4)\u003csup\u003e\u0026nbsp;***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e94(95.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003eCardiovascular risk factors \u0026mdash; no.(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ASCVD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e613(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e781(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Current smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e130(21.2)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e123(15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e65(17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e19(19.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e470(76.7)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e714(91.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e258(68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e67(68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e203(33.1)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e371(47.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e205(54.4)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e66(67.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e10-year predicted\u003c/p\u003e\n \u003cp\u003eCVD risk \u0026ge;20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e284(75.3)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e54(55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003eLipid measures \u0026mdash; mg/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003eLDL cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e103\u0026plusmn;27.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e104.5\u0026plusmn;39.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e128.9\u0026plusmn;26\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e143.1\u0026plusmn;65.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003eTotal cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e181.2\u0026plusmn;35.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e180.6\u0026plusmn;46.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e210.5\u0026plusmn;31.1\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e232\u0026plusmn;69.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Non-HDL cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e130.6\u0026plusmn;33.6\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e134\u0026plusmn;44.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e158.8\u0026plusmn;31.4\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e177.9\u0026plusmn;69.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;HDL cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e50.6\u0026plusmn;14.3\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e46.6\u0026plusmn;14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e51.7\u0026plusmn;13.7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e50.3\u0026plusmn;15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.61005199306759%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Triglycerides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.81109185441941%\"\u003e\n \u003cp\u003e124 (87-173)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e127 (92\u0026ndash;181)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.902946273830157%\"\u003e\n \u003cp\u003e136 (96-189)\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.291161178509533%\"\u003e\n \u003cp\u003e159 (115-204)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eQuantitative variables are reported as mean \u0026plusmn; standard deviation, while TG is reported as median with the interquartile range\u0026nbsp;in parentheses due to its non-normal distribution. Qualitative parameters are presented as numbers with the percentages in parentheses. The characteristics of inclisiran group in the ORION trials are shown for comparison with the NHANES eligible samples.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026dagger;\u003c/strong\u003e Control one refers to ASCVD patients received inclisiran treatment in the ORION 10 trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026Dagger;\u003c/strong\u003e Control two\u0026nbsp;refers to ASCVD-risk equivalent subjects received inclisiran treatment in the ORION 11 trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, **\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 and ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: NHANES = National Health and Nutrition Examination Survey; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChanges in LDL-C levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe estimated the number of ASCVD patients achieving \u0026ge;50% reduction in LDL-C levels after inclisiran or placebo treatment. Based on the findings of the ORION 10 trial, which revealed that 72.8% of inclisiran-treated patients experienced \u0026ge;50% LDL-C reductions, we extrapolated this to ASCVD cohort of 5.28 million patients. Consequently, we estimated that approximately 3.85 million patients within this cohort would attain such reductions. Even when considering potential placebo effects, our analysis suggested that roughly 3.71 million patients would still achieve LDL-C reductions of \u0026ge;50%. This encompassed 2.23 million men, 1.48 million women, 2.9 million White subjects, 0.32 million Black subjects, 0.11 million Mexican American subjects, and 0.1 million Hispanic subjects (Figure 2, Table S1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChanges in Dyslipidemia\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe predicted the number of US adults within the ASCVD population expected to transition from a state of dyslipidemia to achieving target lipid profiles following inclisiran treatment. Significant improvements were observed in LDL-C levels, with 4.86 million patients (91.9%) achieving target level. This included 2.92 million men, 1.94 million women, 3.83 million White subjects, 0.4 million Black subjects, 0.14 million Mexican American subjects, and 0.12 million Hispanic subjects (Figure 3A, Table S2). For HDL-C, 0.22 million (14.7%) out of 1.5 million ASCVD patients with low level would achieve target level, including 0.1 million men, 0.12 million women, 0.15 million White subjects, 4,048 Black subjects, 3,691 Mexican American subjects, and 12,578 Hispanic subjects (Figure 3B, Table S2). For TC, 1.19 million (95%) out of 1.25 million ASCVD patients with high level would achieve target level, including 0.59 million men, 0.6 million women, 0.92 million White subjects, 0.12 million Black subjects, 51,305 Mexican American subjects, and 46,285 Hispanic subjects (Figure 3C, Table S2). Finally, 0.5 million (26.7%) out of 1.87 million ASCVD patients with high level of TG would achieve target TG profiles, including 0.36 million men, 0.13 million women, 0.44 million White subjects, 21,401 Black subjects, 9,261 Mexican American subjects, and 10,148 Hispanic subjects (Figure 3D, Table S2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChanges in 10\u003c/strong\u003e\u003cstrong\u003e‑year CVD Risk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe estimated the 10-year CVD risk before and after inclisiran treatment in ASCVD-risk equivalent population using the Framingham risk scores. Prior to treatment, the average risk for the entire population was 25.2%, with a higher risk for men at 28.7%. Among all racial groups, Whites exhibited the highest average risk at 26.4%. After inclisiran treatment, an overall absolute risk reduction of 7.6% would be observed, accompanied by a relative risk reduction of 30.2%. Particularly noteworthy is the substantial risk reduction observed among men (8.4%) and Whites (7.9%). Furthermore, we predicted a total of 199,878 preventable CVD events, including 136,217 cases of CHD, 37,024 strokes, and 23,619 cases of CHF (Figure 4A-D, Table S3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study underscores that approximately 5.28 million adults with ASCVD and 2.63 million adults deemed to have ASCVD-risk equivalents in the US met the eligibility criteria for inclisiran treatment based on the ORION 10 and 11 trial criteria, respectively. Within the ASCVD population, an estimated 3.71 million individuals could anticipate LDL-C reductions of \u0026ge;50%, and 4.86 million individuals (91.9%) achieving target lipid profiles post-inclisiran treatment. Among the ASCVD-risk equivalent population, the estimated 10-year CVD risks decreased from 25.2% to 17.6% following inclisiran treatment, representing a 7.6% absolute (and 30.2% relative) risk reduction. Over a decade, inclisiran could potentially prevent 199,878 CVD events, including 136,217 cases of CHD, 37,024 strokes, and 23,619 cases of CHF. These findings underscore the significant potential impact of inclisiran on the broader US population (CENTRAL ILLUSTRATION).\u003c/p\u003e\n\u003cp\u003eDyslipidemia constitutes a significant component of the global health burden, with cardiovascular morbidity escalating notably with advancing age, predominantly driven by elevated (LDL-C) levels\u003csup\u003e23,24\u003c/sup\u003e. Statins stand as the cornerstone pharmacotherapy for mitigating the risk of future ASCVD events\u003csup\u003e25\u003c/sup\u003e.\u0026nbsp;Pioneering work by Dubuc et al. illuminated the intricate interplay between dietary cholesterol intake and PCSK9 expression, underscoring PCSK9 as a cholesterol-regulated gene\u003csup\u003e26\u003c/sup\u003e. Mechanistically, statins, by impeding cholesterol biosynthesis, augment PCSK9 transcription, thereby accelerating the degradation of LDL receptors (LDLR)\u003csup\u003e27-30\u003c/sup\u003e.Paradoxically, this cascade can sustain or even elevate serum LDL-C levels.\u0026nbsp;Complementary murine studies corroborated these observations, demonstrating that PCSK9 deficiency not only correlated with diminished plasma cholesterol levels but also enhanced sensitivity to statin therapy\u003csup\u003e31\u003c/sup\u003e. Notably, genetic investigations in humans unveiled that individuals harboring non-functional PCSK9 variants enjoy a markedly reduced lifetime risk of cardiovascular events\u003csup\u003e32\u003c/sup\u003e, emphasizing the therapeutic promise of PCSK9 inhibition for LDL-C reduction.\u003c/p\u003e\n\u003cp\u003eThrough substantial endeavors by pharmaceutical industries, two distinct and robust PCSK9 inhibitory therapies have emerged: PCSK9 monoclonal antibodies (PCSK9mAbs) and siRNA targeting PCSK9. While both modalities demonstrate comparable lipid-lowering effects\u003csup\u003e13,33,34\u003c/sup\u003e, PCSK9mAbs necessitate frequent subcutaneous administration, whereas siRNA therapies, such as inclisiran, require fewer injections, enhancing patient adherence. As the pioneer siRNA drug targeting PCSK9, inclisiran has garnered attention and undergone extensive evaluation for its efficacy and safety profile. Nevertheless, no large-scale studies encompassing over 10,000 participants have been reported to date.\u003c/p\u003e\n\u003cp\u003eA fundamental inquiry arises: what proportion of eligible Americans would derive benefits from inclisiran, and to what extent could it effectively manage their blood lipid profiles? Our study reveals that approximately 5.28 million adults with ASCVD met the eligibility criteria for inclisiran treatment based on the ORION 10 trial criteria. Among them, an estimated 3.7 million individuals would likely experience LDL-C reductions of \u0026ge;50%, with the majority achieving target lipid profiles post-inclisiran therapy.\u003c/p\u003e\n\u003cp\u003eWe conducted a comprehensive analysis of lipid levels, stratified by sex and ethnicity, revealing that men and individuals of White ethnicity garnered the most substantial benefits. This observation can primarily be attributed to the demographic composition of eligible population, which predominantly comprised men and individuals of White ethnicity. Further scrutiny unveiled that Hispanics exhibited the highest baseline LDL-C and TC levels. Considering their reported suboptimal adherence to statin therapy\u003csup\u003e35\u003c/sup\u003e, this group would significantly benefit from inclisiran.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo date, several studies have endeavored to estimate the impact of inclisiran on CVD prevention. One such study employed a Markov model to project the health benefits of inclisiran treatment in individuals aged 50 and above with pre-existing ASCVD in England. The analysis specifically focused on the avoidance of cardiovascular events and associated mortality. The result indicated that over a 10-year timeframe, inclisiran treatment could potentially prevent 138,647 cardiovascular events, yielding a cost-effectiveness ratio of 1.03\u003csup\u003e36\u003c/sup\u003e. In another study, the augmentation of statin therapy with inclisiran was assessed against statin therapy alone. The analysis projected that among 1000 subjects over their lifetimes in Australia, the addition of inclisiran was anticipated to prevent 235 non-fatal myocardial infarctions and 114 instances of coronary revascularization\u003csup\u003e37\u003c/sup\u003e. However, uncertainties persist regarding the assumptions inherent in the methodological approach. Deviations between predicted and actual eligible populations for drug treatment are anticipated. In our investigation, the weighting of the NHANES database serves to mitigate these limitations. Additionally, it is worth noting that all these studies have exclusively targeted patients with ASCVD. As the significance of primary prevention in ASCVD continues to gain prominence, it warrants heightened attention\u003csup\u003e38\u003c/sup\u003e. However, there is a paucity of studies evaluating the impact of inclisiran on the primary prevention of ASCVD. Our objective is to ascertain the number of individuals without a diagnosis of ASCVD but meeting the ASCVD equivalent risk criteria delineated in the ORION 11 trial, and to evaluate the potential efficacy of inclisiran in averting CVD development in this cohort. Employing the Framingham risk scores, our analysis suggests that as many as 199,878 (7.6%) cardiovascular events could potentially be prevented over a decade in the United States. Upon closer examination, it became evident that men (8.4%) and individuals of White ethnicity (7.9%) derived the greatest benefit. This is primarily attributed to the heightened susceptibility of men to cardiovascular disease compared to women\u003csup\u003e39\u003c/sup\u003e, and the alteration in the proportion of each risk factor is notably more conspicuous within the male population. Regarding race, Whites demonstrate the highest prevalence of risk factors and rates of cardiovascular disease\u003csup\u003e40,41\u003c/sup\u003e, thereby constituting the majority of participants in equivalent risk groups with undiagnosed ASCVD. Consequently, they stand to derive the greatest benefit from primary prevention initiatives involving inclisiran administration.\u003c/p\u003e\n\u003cp\u003eThis study boasts several noteworthy strengths. Firstly, it leverages the comprehensive NHANES database, encompassing diverse US adult participants. By utilizing the database\u0026apos;s sample weighting functionality, we can effectively gauge the population-level impact of inclisiran on ORION-eligible US adults while also exploring CVD prevention across various demographic groups. While NHANES relies on self-reported measures for certain variables, including CVD status, the reliability of these self-report measures has been firmly established in prior research\u003csup\u003e42\u003c/sup\u003e.\u0026nbsp;Secondly, by extrapolating the lipid-lowering effects observed in the ORION 10 trial to the NHANES data, this study estimates the number of ASCVD patients who could attain a target lipid profile with inclisiran. This yields crucial insights for national lipid management strategies. Thirdly, our study encompasses individuals with equivalent risk of ASCVD, a population often overlooked in previous research on inclisiran\u0026apos;s CVD prevention effects, primarily focused on secondary prevention. The inclusion of data on a subset of ASCVD-risk equivalent individuals from the ORION 11 trial, as reported by Professor Kausik\u003csup\u003e14\u003c/sup\u003e, is novel and allows us to estimate inclisiran\u0026apos;s potential primary prevention effect against CVD in the US population by integrating these data with the NHANES database.\u003c/p\u003e\n\u003cp\u003eHowever, this study also harbors limitations. Firstly, the NHANES database lacks a crucial indicator of familial hypercholesterolemia (FH), rendering it unfeasible to predict the impact of inclisiran on FH nationally. Moreover, the absence of lipoprotein (a) (LP(a)), an independent risk factor for CVD, precludes the assessment of inclisiran\u0026apos;s lipid-lowering effect in patients with elevated LP(a) levels. Secondly, despite employing ORION eligibility criteria to identify NHANES sample, disparities between NHANES sample and the ORION trial participants may exist. Consequently, the observed blood lipid-lowering effect in the ORION trials may not be entirely applicable to NHANES sample. For instance, NHANES sample exhibits a lower proportion of Whites compared to the ORION 10 trial, potentially leading to an overestimation of inclisiran\u0026apos;s lipid-lowering effect nationally, as compliant Whites may have previously received lipid-lowering treatments, reducing their sensitivity to inclisiran. Finally, while the Framingham Risk Score serves as a widely used tool to estimate CVD events, its precision is limited by the inability to account for all potential factors, including family history and other risk-enhancing elements, that may influence CVD events.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study suggests that inclisiran treatment in eligible US adults holds the potential to significantly mitigate dyslipidemia and prevent nearly 200 thousand CVD events. These findings offer robust data support for inclisiran\u0026apos;s role in both primary and secondary prevention of ASCVD. The ongoing ORION 4 trial will provide valuable insights into the actual cardiovascular outcomes associated with inclisiran treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eASCVD: atherosclerotic cardiovascular disease; CVD: cardiovascular disease; NHANES: National Health and Nutrition Examination Survey; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides; CHD: coronary heart disease; CHF: congestive heart failure; eGFR: estimated glomerular filtration rate; PCSK9: proprotein convertase subtilisin/kexin type 9; siRNA: small interfering RNA; MACE: major adverse cardiovascular events\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study utilized de-identified publicly available data and does not qualify for institutional review board review. The National Health and Nutrition Examination Survey obtains consent to participate from all subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No individual data or images are used in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData used in this study are publicly available from the National Health and Nutrition Examination Survey: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was financially supported by the National Nature Science Foundation of China (82170388，82370300), Shanghai Technology Research Leader Program (21XD1434700), the Cardiac rehabilitation fund by the International Medical Exchange Foundation (Z-2019-42-1908-3) and Grant for the construction of Innovative Flagship Hospital for Integrated Traditional Chinese and Western Medicine (No., ZY(2021-2023)-0205-05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYX and YZ designed the study and revised the manuscript. HL and SZ wrote the main manuscript text, HL and JW performed the statistical analysis, SZ prepared figures 1, JW and JH prepared figures 2-4, HL prepared CENTRAL ILLUSTRATION. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was analyzed using the data provided by the National Health and Nutrition Examination 1999\u0026ndash;2018. The authors would like to thank the NHANES participants and the staff members for their contribution to data collection and for making the data publicly available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVasan RS, Enserro DM, Xanthakis V, Beiser AS, Seshadri S. Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study. Circulation. 2022;145(17):1324\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlobal regional. national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990\u0026ndash;2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet (London England). 2016;388(10053):1603\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePirillo A, Casula M, Olmastroni E, Norata GD, Catapano AL. Global epidemiology of dyslipidaemias. Nat reviews Cardiol. 2021;18(10):689\u0026ndash;700.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc. 2012;1(6):e001800.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026auml;ber L, Ueki Y, Otsuka T, et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022;327(18):1771\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017;376(1):41\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAguilar-Salinas CA, G\u0026oacute;mez-D\u0026iacute;az RA, Corral P. New Therapies for Primary Hyperlipidemia. J Clin Endocrinol Metab. 2022;107(5):1216\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl Shaer D, Al Musaimi O, Albericio F, de la Torre BG. 2021 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel Switzerland) 2022;15(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarugo S, Sirtori CR, Gelpi G, Corsini A, Tokgozoglu L, Ruscica M. Updates in Small Interfering RNA for the Treatment of Dyslipidemias. Curr Atheroscler Rep. 2023;25(11):805\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. lancet Diabetes Endocrinol. 2023;11(2):109\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaal FJ, Kallend D, Ray KK, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay KK, Kallend D, Leiter LA, et al. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial. Eur Heart J. 2022;43(48):5047\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright RS, Koenig W, Landmesser U, et al. Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials. J Am Coll Cardiol. 2023;82(24):2251\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2023;44(2):129\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScicchitano P, Milo M, Mallamaci R, et al. Inclisiran in lipid management: A Literature overview and future perspectives. Biomed pharmacotherapy = Biomedecine pharmacotherapie. 2021;143:112227.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStoekenbroek RM, Kallend D, Wijngaard PL, Kastelein JJ. Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program. Future Cardiol. 2018;14(6):433\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeeringa S, West BT, Berglund PA. Applied survey data analysis. Second edition. ed. Boca Raton, FL: CRC Press, Taylor \u0026amp; Francis Group; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586\u0026ndash;613.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrundy SM, Stone NJ, Bailey AL, NLA/PCNA Guideline on the Management of Blood Cholesterol. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082\u0026ndash;143. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/ABC/ACPM/ADA/AGS/APhA/ASPC/\u003c/span\u003e\u003cspan address=\"http:///ABC/ACPM/ADA/AGS/APhA/ASPC/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 2018 AHA/ACC/AACVPR/AAPA.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD'Agostino RB, Sr., Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerence BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Pletcher MJ, Vittinghoff E, et al. Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events. JAMA Cardiol. 2021;6(12):1406\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJin J. Statins for the Prevention of Cardiovascular Disease. JAMA. 2022;328(8):786.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24(8):1454\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenjannet S, Rhainds D, Essalmani R, et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem. 2004;279(47):48865\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA. 2004;101(18):7100\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102(6):2069\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 2004;279(48):50630\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA. 2005;102(15):5374\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097\u0026ndash;107.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVulic D, Lee BT, Dede J, Lopez VA, Wong ND. Extent of control of cardiovascular risk factors and adherence to recommended therapies in US multiethnic adults with coronary heart disease: from a 2005\u0026ndash;2006 national survey. Am J Cardiovasc drugs: drugs devices other interventions. 2010;10(2):109\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstwald DA, Schmitt M, Peristeris P, Gerritzen T, Durand A. The Societal Impact of Inclisiran in England: Evidence From a Population Health Approach. Value health: J Int Soc Pharmacoeconomics Outcomes Res. 2023;26(9):1353\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKam N, Perera K, Zomer E, Liew D, Ademi Z. Inclisiran as Adjunct Lipid-Lowering Therapy for Patients with Cardiovascular Disease: A Cost-Effectiveness Analysis. PharmacoEconomics. 2020;38(9):1007\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ. 2021;374:n1537.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanchi R, Perlman SE, Chernov C, in Cardiovascular Disease Risk Factors among New York City Adults. Gender and Race Disparities : New York City Health and Nutrition Examination Survey (NYC HANES) 2013\u0026ndash;2014. \u003cem\u003eJournal of urban health: bulletin of the New York Academy of Medicine.\u003c/em\u003e 2018;95(6):801\u0026ndash;812.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBudoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018;39(25):2401\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao Y, Isakadze N, Duffy E, et al. Secular Trends in Risk Profiles Among Adults With Cardiovascular Disease in the United States. J Am Coll Cardiol. 2022;80(2):126\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergmann MM, Byers T, Freedman DS, Mokdad A. Validity of self-reported diagnoses leading to hospitalization: a comparison of self-reports with hospital records in a prospective study of American adults. Am J Epidemiol. 1998;147(10):969\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"lipids-in-health-and-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"lhad","sideBox":"Learn more about [Lipids in Health and Disease](http://lipidworld.biomedcentral.com/)","snPcode":"12944","submissionUrl":"https://submission.nature.com/new-submission/12944/3","title":"Lipids in Health and Disease","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Inclisiran, Cardiovascular disease, NHANES, LDL-C, Dyslipidemia","lastPublishedDoi":"10.21203/rs.3.rs-4727339/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4727339/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDyslipidemia has been delineated as independent predictors of cardiovascular disease (CVD). Inclisiran, an innovative small interfering RNA (siRNA) agent, is anticipated to engender a notable reduction of approximately 50% in low-density lipoprotein cholesterol (LDL-C) levels. Given its transformative impact, we scrutinized the eligibility of US population for inclisiran treatment and evaluated its potential effects on dyslipidemia and the primary prevention of CVD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe applied eligibility criteria from the ORION 10 and 11 trials to the 1999\u0026ndash;2018 National Health and Nutrition Examination Survey dataset to estimate the eligible population size for atherosclerotic cardiovascular disease (ASCVD) and ASCVD-risk equivalents. Utilizing lipid reduction data from the ORION 10, we predicted the impact of inclisiran on LDL-C levels and dyslipidemia prevalence among ASCVD patients. Similarly, leveraging the ORION 11's lipid reduction data, we forecasted inclisiran's effect on 10-year CVD risk change and preventable CVD events in the ASCVD-risk equivalents population, employing the Framingham CVD Risk Score.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe identified 613 ASCVD patients (5.28\u0026nbsp;million) and 377 ASCVD-risk equivalents (2.63\u0026nbsp;million) who met the eligibility criteria of the ORION 10 and 11. Among ASCVD population, 3.71\u0026nbsp;million (70.3%) would achieve\u0026thinsp;\u0026ge;\u0026thinsp;50% LDL-C reduction post-treatment. Furthermore, 4.86\u0026nbsp;million (91.9%) with high LDL-C, 0.22\u0026nbsp;million (4.2%) with low high-density lipoprotein cholesterol, 1.19\u0026nbsp;million (22.5%) with high total cholesterol, and 0.5\u0026nbsp;million (9.5%) with high triglycerides would attain target lipid profiles. For ASCVD-risk equivalents population, the estimated 10-year CVD risk would decrease from 25.2\u0026ndash;17.6% (7.6% absolute, 30.2% relative) post-inclisiran treatment, potentially preventing 199,878 CVD events over a decade, including 136,217 coronary heart disease cases, 37,024 strokes, and 23,619 heart failures.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eInclisiran holds the potential to substantially diminish the prevalence of dyslipidemia and mitigate the occurrence of nearly 200 thousand CVD events in eligible US adults.\u003c/p\u003e","manuscriptTitle":"Estimating the Effect of Inclisiran on Dyslipidemia and Primary Prevention of Cardiovascular Disease: The NHANES 1999-2018 Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-10 12:24:03","doi":"10.21203/rs.3.rs-4727339/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-29T11:04:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-28T15:43:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-23T10:08:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102363999570099840566198594409621955524","date":"2024-07-15T13:38:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40397661790186775420756006283560635577","date":"2024-07-15T05:56:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"212482225900869194536765387579311745629","date":"2024-07-12T13:28:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-12T11:58:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-12T07:55:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-12T03:15:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Lipids in Health and Disease","date":"2024-07-12T02:05:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"lipids-in-health-and-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"lhad","sideBox":"Learn more about [Lipids in Health and Disease](http://lipidworld.biomedcentral.com/)","snPcode":"12944","submissionUrl":"https://submission.nature.com/new-submission/12944/3","title":"Lipids in Health and Disease","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ca56d1f-79bf-4c04-9bfa-b528c500af26","owner":[],"postedDate":"August 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-30T16:04:28+00:00","versionOfRecord":{"articleIdentity":"rs-4727339","link":"https://doi.org/10.1186/s12944-024-02294-8","journal":{"identity":"lipids-in-health-and-disease","isVorOnly":false,"title":"Lipids in Health and Disease"},"publishedOn":"2024-09-27 15:57:44","publishedOnDateReadable":"September 27th, 2024"},"versionCreatedAt":"2024-08-10 12:24:03","video":"","vorDoi":"10.1186/s12944-024-02294-8","vorDoiUrl":"https://doi.org/10.1186/s12944-024-02294-8","workflowStages":[]},"version":"v1","identity":"rs-4727339","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4727339","identity":"rs-4727339","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}