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PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗

PubMed2022

Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

Cerebral Hemorrhage↗

PubMed2026

Cardioprotective glucose-lowering drugs, statins, and secondary major adverse cardiovascular events: a nationwide cohort study of individuals with type 2 diabetes and cardiovascular disease.

BACKGROUND: In type 2 diabetes, cardioprotective glucose-lowering drugs, including sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, and statins reduce the risk of secondary major adverse cardiovascular events. No trials examined the combination of these drugs as withholding statins in high-risk individuals would be unethical. We tested the hypothesis that cardioprotective glucose-lowering drug and statin combined is associated with lower risk of secondary major adverse cardiovascular events than either drug alone. METHODS: Individuals with type 2 diabetes and established cardiovascular disease from December 2012 through 2021 were identified via national Danish health registers. They were analyzed in an active comparator cohort including 15,404 individuals followed from treatment intensification with cardioprotective glucose-lowering drug or dipeptidyl peptidase-4 inhibitor and additionally in a time-varying cohort including 76,853 individuals with yearly updated treatment and covariate status. The treatment groups were: (i) no cardioprotective drug (no use of cardioprotective glucose-lowering drug or statin), (ii) cardioprotective glucose-lowering drug, (iii) statin, and (iv) cardioprotective glucose-lowering drug and statin. The primary outcome was a new major adverse cardiovascular event (myocardial infarction, stroke, or cardiovascular death). RESULTS: During mean 2.7 and 4.7 years of follow-up, 1,843 and 23,051 had major adverse cardiovascular events in the active comparator and time-varying cohorts. In the active comparator cohort, when compared to nonusers of cardioprotective glucose-lowering drug or statin, multivariable adjusted hazard ratios of major adverse cardiovascular events were 0.82 (95% confidence interval: 0.67 to 1.02) for cardioprotective glucose-lowering drug, 0.85 (0.74 to 0.97) for statin, and 0.71 (0.60 to 0.84) for cardioprotective glucose-lowering drug and statin combined. Corresponding hazard ratios in the time-varying cohort were 0.77 (0.69 to 0.86), 0.73 (0.70 to 0.75), and 0.57 (0.54 to 0.60), respectively. When restricting the active comparator cohort to individuals entering observation between 2019 and 2021 with reduced statistical power, the corresponding hazard ratios were 0.86 (0.57 to 1.31), 0.89 (0.60 to 1.30), and 0.79 (0.54 to 1.14), respectively. In both cohorts p for interaction between cardioprotective glucose-lowering drug and statin was > 0.05. CONCLUSIONS AND RELEVANCE: In individuals with type 2 diabetes and established cardiovascular disease, treatment with a cardioprotective glucose-lowering drug and statin in combination was associated with lower risk of secondary major adverse cardiovascular events than using either drug alone. This is important given the persistently suboptimal uptake of both drug classes in real-world practice. Some biases can never be completely excluded in real-world pharmacotherapy use studies such as this one, including confounding by indication, time-related or immortal time biases, and shifting standards of care, rendering causal interpretation unattainable; however, our results seemed consistent across numerous sensitivity analyses and designs.

Humans↗

PubMed2026

Association Between Statin Use and Dry Eye Disease: A Systematic Review and Meta-Analysis.

TOPIC: This systematic review and meta-analysis evaluated the literature-pooled association between statins and dry eye disease (DED). CLINICAL RELEVANCE: Statins, a common treatment modality for dyslipidemia, have been proposed as a potential contributor to DED via their activity in meibomian gland epithelial cells. However, single studies show mixed evidence, and there remains an unmet clinical need to clarify whether statin exposure is associated with DED. METHODS: This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews of Interventions (PRISMA) 2020 statement and was registered a priori on PROSPERO (CRD420251238004). Ovid MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and the reference lists of relevant reviews were searched from inception to November 2025 for studies reporting the association between statin use and DED. Random-effects meta-analysis using inverse-variance weighting was conducted to pool effect estimates as odds ratios with 95% confidence intervals (CIs). Study risk of bias was appraised using the ROBINS-E tool, and the certainty of the evidence was reported using the GRADE framework. RESULTS: Six observational studies were included in the meta-analysis (n = 560,821; 356,012/559,141 [63.7%] statin users). The pooled analysis revealed a significant positive association between statins and DED (odds ratio 1.09, 95% CI 1.05-1.13, P < .001), with an absolute risk difference of 10.2 more DED cases per 1000 (95% CI 5.5 more to 15.2 more). This result was derived from very low-certainty evidence given limitations in study design and serious inconsistency. Subgroup and sensitivity analyses for risk of bias (P = .123), method of outcome ascertainment (P = .737), type of effect estimate (P = .496), and leave-one-out analyses showed no evidence of effect modification and demonstrated consistent direction of association across studies. CONCLUSION: Statin use was associated with a small but statistically significant increase in DED, limited by very low-certainty evidence. Physicians should monitor for and educate patients on ocular surface symptoms in patients using statins with pre-existing DED risk factors. Future studies should use standardized DED diagnostic criteria to investigate the impact of statin dose, type, and duration to better characterize this potential association.

Humans↗

PubMed2026

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury.

BACKGROUND: Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS: HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS: HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27×10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5×10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14×10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97×10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68×10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION: We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

Humans↗

PubMed2025

A genome-wide association study of stroke risk in Asian statin users: evidence from KoGES and UK Biobank.

BACKGROUND: Despite proven efficacy of statins in stroke prevention, genetic factors may influence individual stroke risk among statin users. With increasing precision medicine approaches and growing evidence of population-specific genetic variations, identifying genetic markers that predict stroke risk in statin-treated Asian populations has become critically important for personalized cardiovascular prevention strategies. METHODS: We conducted a genome-wide association study of 1,678 participants using lipid-lowering agents in the Korean Genome and Epidemiology Study (KoGES) cohort. Significant findings were replicated in 2,170 Asian participants on statins from the UK Biobank using an additive genetic model adjusted for relevant covariates. RESULTS: In the discovery analysis, 83 single nucleotide polymorphisms were suggestively associated with stroke (p <1.0 × 10-5). Among these, 21 SNPs in the CDH13 gene were associated with increased stroke risk. The lead SNP, rs7201829, was significantly replicated in the UK Biobank (odds ratio: 2.29, p = 2.39 × 10-5). CONCLUSIONS: This study identified CDH13 as a significant genetic marker associated with stroke risk among Asian statin users. These findings provide the first genome-wide evidence for genetic determinants of stroke susceptibility during statin therapy, supporting the development of personalized prevention strategies in Asian populations.

Aged↗

PubMed2026

Integrative Cross-platform Analysis of Kinase Inhibitor Effects on Statin-relevant Cardioprotective Pathways in Human Cardiomyocytes.

BACKGROUND/AIM: Kinase inhibitors (KIs) can cause cardiotoxicity through mechanisms overlapping with statin cardioprotective pathways, yet their effects on these pathways in cardiomyocytes remain uncertain. We evaluated six literature-defined statin-relevant gene sets using transcriptomic and proteomic data. MATERIALS AND METHODS: Pre-ranked gene set enrichment analysis was performed for 23 KIs in primary cardiac cells (GSE146096; n=319) and iPSC-derived cardiomyocytes (GSE217421; n=541), with cross-platform analysis of 21 KIs by shotgun proteomics (PXD014791; n=300). Pathway-specific concordance was assessed by Spearman correlation with Benjamini-Hochberg correction; protein scores were estimated after adjustment for cell line. RESULTS: KI effects were heterogeneous. The anti-fibrotic pathway showed nominal concordance across the two transcriptomic datasets (ρ=0.495, p=0.016, q=0.098; 91% direction concordance) and significant cell-line-adjusted transcriptomic-proteomic concordance (ρ=0.644, p=0.0016, q=0.0081). Nilotinib reproducibly upregulated NF-κB pathway genes [normalized enrichment score (NES)=+2.29 and +2.18 in discovery and validation], with targeted inter-gene-correlation-adjusted testing supporting higher NF-κB expression than under rosuvastatin (CAMERA p=3.54×10-8). No global cross-omics summary remained significant after harmonizing pathway universes and accounting for repeated pathways. CONCLUSION: KI effects on statin-relevant pathways were pathway-specific. Anti-fibrotic concordance and nilotinib-associated NF-κB upregulation are hypothesis-generating candidates for experimental validation.

Humans↗

PubMed2025

A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy.

Chemotherapy remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), but most patients ultimately develop resistance. Here, we established 260 pancreatic cancer organoid lines, followed by extensive multi-omics profiling and therapeutic sensitivity assessments. Integrated analyses uncovered 6 novel coding and 35 noncoding driver candidates. We discovered 2,794 multi-omics features associated with drug sensitivity and 322 features linked to radiation sensitivity. Pharmacogenomic analyses revealed that chemoresistant organoids exhibited enrichment in protein glycosylation and cholesterol metabolism pathways. Notably, statins effectively targeted chemoresistant PDAC organoids. Statin treatment attenuated protein glycosylation, cholesterol levels, and the epithelial-to-mesenchymal transition (EMT) signature in PDAC organoids. We conducted a single-center, single-arm, phase 2 clinical trial (NCT06241352) combining atorvastatin with chemotherapy in patients with advanced pancreatic cancer. Among 37 patients, 26 (70.3%) demonstrated a response, with tumor markers decreasing by more than 20%, suggesting durable responses and potential clinical benefits in this challenging patient population.

Humans↗

PubMed2026

Letter to the Editor regarding: "Attainment of Low-Density Lipoprotein Cholesterol Goals and Statin Use in Patients With Atherosclerotic Cardiovascular Disease in Australian General Practice: Are We Doing Enough?".

Explore the source record for details and available documents.

Adverse events↗

PubMed2026

Bempedoic Acid and First and Recurrent Limb Outcomes in Statin-Intolerant Patients With Peripheral Artery Disease: Insights From the CLEAR Outcomes Trial.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). Recently, bempedoic acid was shown to reduce MACE in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE in patients with PAD is unknown. METHODS: CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL-Inhibiting Regimen) randomized 13 970 patients to bempedoic acid 180 mg or placebo from December 22, 2016, to August 14, 2019. The trial primary end point was MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated MALE, including adverse events indicating worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Outcomes were assessed as time to first event and total (including recurrent) events with a negative binomial approach. RESULTS: A total of 1624 of the enrolled patients (mean±SD age, 63.9±9.9 years; 915 [56.3%] female) had PAD at baseline. In patients with PAD in the placebo group, 69 (8.3%) had MALE over a median of 40.6 months, with rate of recurrent events of 4.0%/y. Bempedoic acid reduced the risk of MALE by 36% (hazard ratio, 0.64 [95% CI, 0.44-0.93]; P=0.018). Bempedoic acid reduced total MALE by 45% (relative risk, 0.55 [95% CI, 0.35-0.85]; P=0.007). First MACE-4 or MALE was reduced overall by 13% (hazard ratio, 0.87 [95% CI, 0.80-0.95]) with consistent effects with PAD (hazard ratio, 0.82 [95% CI, 0.64-1.04]) and without PAD (hazard ratio, 0.87 [95% CI, 0.79-0.86]; Pinteraction=NS) but not statistically significant within the PAD subgroup alone. Total MACE-4 or MALE was reduced (relative risk, 0.81 [95% CI, 0.73-0.90]) overall with consistent effects in PAD (relative risk, 0.71 [95% CI, 0.54-0.95]) and without PAD (relative risk, 0.82 [95% CI, 0.73-0.92]; Pinteraction=NS). CONCLUSIONS: Patients with PAD are at high risk of MALE and MACE. Bempedoic acid reduces both MACE and MALE in patients with atherosclerotic vascular disease, with notable absolute benefits in patients with PAD. These findings support (1) the importance of lowering low-density lipoprotein cholesterol in patients with PAD to reduce overall vascular risk and (2) the benefits of bempedoic acid in this population.

Humans↗

PubMed2025

Ezetimibe and the risk of new-onset type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Statins reduce cardiovascular risk but may increase new-onset type 2 diabetes mellitus (NO-T2DM). Ezetimibe, a cholesterol absorption inhibitor, is often added to statins to improve lipid control, yet its impact on NO-T2DM remains uncertain. OBJECTIVE: This systematic review evaluated moderate-intensity statin plus ezetimibe dual therapy versus high-intensity statin monotherapy for NO-T2DM risk. METHODS: Five databases were searched to identify eligible studies. Random-effects meta-analyses generated pooled relative risks (RR) quantifying the effect of ezetimibe plus moderate-intensity statins on NO-T2DM. The Attributable Risk Fraction (ARF) was quantified utilizing the pooled estimate. RESULTS: Ten observational studies and four clinical trials were included. In four cohort studies, ezetimibe plus moderate-intensity statin compared to high-intensity statin monotherapy was significantly linked to 18% reduced risk of NO-T2DM (pooled RR: 0.82; 95% CI: 0.77-0.87; I2 = 0.0%; p < 0.001). In three methodologically similar studies, compared to moderate-intensity statin monotherapy, adding ezetimibe to moderate-intensity statin dual therapy showed non-statistically (p > 0.05) significant 4% increased risk of NO-T2DM development (pooled RR: 1.04; 95% CI: 0.94-1.14, I2= 0.0%). Compared with patients receiving high-intensity statin therapy, 22% of NO-T2DM cases could potentially be averted with dual therapy (moderate-intensity statin plus ezetimibe). In four studies involving 5,072 patients on high-intensity statins who developed NO-T2DM, 1,115 patients (812-1,420) could have been prevented with ezetimibe plus moderate-intensity statin dual therapy. CONCLUSION: Incorporating ezetimibe with moderate-intensity statins, rather than relying solely on high-intensity statins, may reduce the risk of NO-T2DM in patients with dyslipidemia and elevated cardiovascular disease risk. PROSPERO REGISTRATION NUMBER: CRD42024518630.

Humans↗

PubMed2026

Current and Future Perspectives of LDL-C Lowering Therapies 2026.

LDL cholesterol (LDL-C) is the central causal factor for atherosclerotic cardiovascular disease (ASCVD), and its reduction is a cornerstone of both primary and secondary prevention. Since the introduction of statins more than three decades ago, LDL-C-lowering therapy has expanded substantially, now encompassing ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeting agents, bempedoic acid, and other emerging modalities. This expanding therapeutic landscape has improved the feasibility of achieving guideline-recommended LDL-C targets, but it has also increased the complexity of clinical decision making. This review provides a contemporary and practical overview of the LDL-C-lowering strategies, beginning with the initial evaluation of patients with elevated LDL-C, including differentiation between primary and secondary causes and the identification of familial hypercholesterolemia (FH). We summarize the current treatment targets for primary and secondary prevention, highlight the optimal selection and use of statins, and discuss the assessment and management of statin intolerance, including the role of the nocebo effect. Non-statin therapies, including ezetimibe, bile acid sequestrants, PCSK9 inhibitors, inclisiran, and bempedoic acid, are reviewed with an emphasis on their mechanisms, efficacy, and clinical positioning. Advanced therapies for severe dyslipidemia, such as lipoprotein apheresis, lomitapide, and evinacumab, are also discussed in this review. Finally, we outline the future directions, including oral PCSK9 inhibitors, next-generation cholesteryl ester transfer protein (CETP) inhibitors, lipoprotein(a)-lowering agents, and genome-editing approaches. Collectively, these developments offer new opportunities to address unmet clinical needs, particularly in patients with FH, statin intolerance, and residual cardiovascular risk. A comprehensive understanding of these therapies is essential for further reducing the burden of ASCVD in the coming decades.

Humans↗

PubMed2026

Cross-Ancestry Proteogenomic Analyses Identified New Therapeutic Insights for Ischemic Heart Disease.

BACKGROUND: Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy. OBJECTIVES: The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD. METHODS: We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies. RESULTS: In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets. CONCLUSIONS: The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.

Aged↗

PubMed2026

Comparative safety of lipid-lowering drugs alone or in combination: insights from a systematic review and network meta-analysis.

BACKGROUND AND AIMS: Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. METHODS AND RESULTS: Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of ≥200 subjects, and had ≥1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated. A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. CONCLUSIONS: PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Humans↗

PubMed2025

Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial.

IMPORTANCE: In a mechanistic substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) randomized clinical trial, pitavastatin reduced noncalcified plaque (NCP) volume, but specific protein and gene pathways contributing to changes in coronary plaque remain unknown. OBJECTIVE: To use targeted discovery proteomics and transcriptomics approaches to interrogate biological pathways beyond low-density lipoprotein cholesterol (LDL-C), relating statin outcomes to reduce NCP volume and promote plaque stabilization among people with HIV (PWH). DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of the double-blind, placebo-controlled, REPRIEVE randomized clinical trial. Participants underwent coronary computed tomography angiography (CTA), plasma protein analysis, and transcriptomic analysis at baseline and 2-year follow-up. The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites. PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible. Data analyses were conducted from October 2023 to February 2024. INTERVENTION: Oral pitavastatin calcium, 4 mg per day. MAIN OUTCOMES AND MEASURES: Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo. RESULTS: Among 558 individuals (mean [SD] age, 51 [6] years; 455 male [82%]) included in the proteomics assessment, 272 (48.7%) received pitavastatin and 286 (51.3%) received placebo. After adjusting for false discovery rates, pitavastatin increased abundance of procollagen C-endopeptidase enhancer 1 (PCOLCE), neuropilin 1 (NRP-1), major histocompatibility complex class I polypeptide-related sequence A (MIC-A) and B (MIC-B), and decreased abundance of tissue factor pathway inhibitor (TFPI), tumor necrosis factor ligand superfamily member 10 (TRAIL), angiopoietin-related protein 3 (ANGPTL3), and mannose-binding protein C (MBL2). Among these proteins, the association of pitavastatin with PCOLCE (a rate-limiting enzyme of collagen deposition) was greatest, with an effect size of 24.3% (95% CI, 18.0%-30.8%; P < .001). In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression. Among the 195 individuals with plaque at baseline (88 [45.1%] taking pitavastatin, 107 [54.9%] taking placebo), changes in NCP volume were most strongly associated with changes in PCOLCE (%change NCP volume/log2-fold change = -31.9%; 95% CI, -42.9% to -18.7%; P < .001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (<130 Hounsfield units) component of NCP (%change fibro-fatty volume/log2-fold change = -38.5%; 95% CI, -58.1% to -9.7%; P = .01) with a directionally opposite, although nonsignificant, increase in calcified plaque (%change calcified volume/log2-fold change = 34.4%; 95% CI, -7.9% to 96.2%; P = .12). CONCLUSIONS AND RELEVANCE: Results of this secondary analysis of the REPRIEVE randomized clinical trial suggest that PCOLCE may be associated with the atherosclerotic plaque stabilization effects of statins by promoting collagen deposition in the extracellular matrix transforming vulnerable plaque phenotypes to more stable coronary lesions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02344290.

Humans↗

PubMed2025

Cardiac Troponins and Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis.

BACKGROUND: The extent to which high-sensitivity cardiac troponin can predict cardiovascular disease (CVD) is uncertain. OBJECTIVES: We aimed to quantify the potential advantage of adding information on cardiac troponins to conventional risk factors in the prevention of CVD. METHODS: We meta-analyzed individual-participant data from 15 cohorts, comprising 62,150 participants without prior CVD. We calculated HRs, measures of risk discrimination, and reclassification after adding cardiac troponin T (cTnT) or I (cTnI) to conventional risk factors. The primary outcome was first-onset CVD (ie, coronary heart disease or stroke). We then modeled the implications of initiating statin therapy using incidence rates from 2.1 million individuals from the United Kingdom. RESULTS: Among participants with cTnT or cTnI measurements, 8,133 and 3,749 incident CVD events occurred during a median follow-up of 11.8 and 9.8 years, respectively. HRs for CVD per 1-SD higher concentration were 1.31 (95% CI: 1.25-1.37) for cTnT and 1.26 (95% CI: 1.19-1.33) for cTnI. Addition of cTnT or cTnI to conventional risk factors was associated with C-index increases of 0.015 (95% CI: 0.012-0.018) and 0.012 (95% CI: 0.009-0.015) and continuous net reclassification improvements of 6% and 5% in cases and 22% and 17% in noncases. One additional CVD event would be prevented for every 408 and 473 individuals screened based on statin therapy in those whose CVD risk is reclassified from intermediate to high risk after cTnT or cTnI measurement, respectively. CONCLUSIONS: Measurement of cardiac troponin results in a modest improvement in the prediction of first-onset CVD that may translate into population health benefits if used at scale.

Humans↗

PubMed2026

Management and Consequences of Genotype-Positive Familial Hypercholesterolemia.

IMPORTANCE: Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. OBJECTIVE: To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. DESIGN, SETTING, AND PARTICIPANTS: In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. EXPOSURE: FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. MAIN OUTCOMES AND MEASURES: The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. RESULTS: A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers. CONCLUSIONS AND RELEVANCE: This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.

Humans↗

PubMed2026

Prevalence of pharmacogenomically implicated prescriptions in multi-ethnic populations in Singapore.

AIM: To assess the potential impact of implementing pre-emptive pharmacogenomic (PGx) testing in Singapore, focusing on prevalence and genetic actionability of PGx prescriptions. METHODS: Electronic Health Records from 2014 to 2021 were obtained from the National University Hospital (NUH), a tertiary medical centre serving approximately 6% of Singapore's population, which were filtered for pharmacogenomically implicated medicines (CPIC Level A or A/B), defined as PGx medications. Coupling this with published data of whole-genome sequencing of 9051 Singaporeans, we estimated the proportion of patients whose prescriptions might have been modified based on pre-emptive PGx at population level. RESULTS: From 2014 to 2021, a total of 1 157 359 unique patients were seen at NUH, with 38.1% to 43.0% of patients with prescriptions receiving at least one PGx medication annually, exhibiting minimal variance over year of prescription, sex or race/ethnicity. The most frequently prescribed PGx medications were omeprazole, statins and tramadol, while the most implicated pharmacogenes were CYP2C19, CYP2D6 and SLCO1B1. The age-dependent increase in PGx medication exposure varied significantly by sex, with males prescribed these medications earlier in life than females. Similarly, Indians and Malays were more likely to be prescribed these medicines at a younger age than Chinese. Based on frequency of PGx variants in Singaporeans, we estimate that 18.4% of patients could have their prescriptions modified from pre-emptive PGx testing. DISCUSSION: Pharmacogenomically implicated medication prescriptions are common in Singapore and are particularly prevalent in elderly populations. Strategic investments in infrastructure and policy development will be pivotal to the successful integration of pre-emptive PGx into clinical practice.

Asian genomes↗