Statin Medication: Systematic Review with ☸️SAIMSARA.

DOI: 10.62487/saimsarad97359b1

• Generated: 2026-02-16 22:03:25 CET
• Plan: Pro (expanded craft tokens; source: Europe PMC)
• Source: Europe PMC
• Scope: Titles/Abstracts (tiab)
• Keyword Gate: Fuzzy (≥60% of required terms, minimum 2 terms matched in title/abstract)
• Total Abstracts/Papers: 2695
• Downloaded Abstracts/Papers: 2695
• Included original Abstracts/Papers: 1928
• Total study participants (naïve ΣN): 26142367

• Bias: Qualitatively inferred from study design fields. Randomized controlled trials (RCTs) generally offer the lowest risk of bias for intervention effects, while cohort and mixed-design studies may be susceptible to confounding and selection biases. Cross-sectional studies are limited in establishing causality. Studies with unspecified designs or directionality carry the highest uncertainty regarding potential biases.

• Adherence and Persistence: Statin adherence is frequently suboptimal, with a median reported rate of 63.9% [551] and a range from 4% [442] to 100% [1720]. Factors influencing adherence include age (lower in younger adults, higher in older adults) [18, 25, 26, 442], sex (lower in females) [25, 26, 455], cost/copayments [129, 323, 421], pill burden [416], and social needs like loneliness or lack of transportation [639]. Interventions such as pharmacist-led programs [247, 265, 608, 660, 884, 1111], daily alarms with feedback [391, 403], appointment-based medication synchronization (ABMS) [760, 833], and physician mailings [1013] have shown improvements in adherence. However, some interventions like consumer apps [969, 976] and text messaging [604, 656] have shown mixed or no significant effects. Generic substitution may also impact persistence [1162, 1393].
• Cardiovascular Outcomes and Efficacy: Statins are effective in reducing LDL-C [168, 205, 208, 259, 430, 1049, 1610, 1745], with a 40% reduction estimated for LDL cholesterol [168]. They are associated with reduced stroke recurrence [8, 195, 232], lower cardiovascular disease (CVD) risk [3, 564], reduced restenosis after angioplasty [10, 27], and decreased mortality after acute ischemic stroke (AIS) [230] and myocardial infarction (MI) [450, 491, 1463, 1728]. Statin use is also linked to reduced aneurysm diameter and growth rate [175, 127], improved endothelial function [338, 1781], and reduced risk of new-onset atrial fibrillation (NOAF) in hypertensive adults [68, 130].
• Safety and Adverse Effects: Statin-associated muscle symptoms (SAMS) are a significant concern, reported by physicians [15] and patients [254, 284, 405, 162, 151, 206, 207, 263, 385, 568, 890, 1071, 1689], with myalgias observed in 29.2% with rosuvastatin and 26.5% with atorvastatin [15]. Rare but severe adverse effects include necrotizing autoimmune myopathy [76, 181, 207, 385, 568, 890, 1071, 1689], rhabdomyolysis [250, 1640, 1848], and liver injury [128]. Statins may increase the risk of ocular hypertension and primary open-angle glaucoma (POAG) [17, 120, 439], and potentially diabetic nephropathy (DN) with long-term use [160]. Some studies suggest an increased risk of immune-related adverse events (irAEs) [93] and postoperative pneumonia [30]. No causal relationship was found with Achilles tendinopathy [51].
• Impact on Other Conditions: Statins have shown diverse effects beyond lipid lowering. They are associated with reduced mortality in sepsis patients [9, 39, 249, 486, 1747], improved survival in head and neck cancer [32], breast cancer [38, 666], ovarian cancer [539], oral squamous cell carcinoma [349], and hepatocellular carcinoma (HCC) [161, 264, 465]. They may also reduce Graves' orbitopathy (GO) risk [33, 43] and fracture risk in older males [79]. However, statin use has been linked to increased risk of Parkinson's disease [632, 756] and potentially amyotrophic lateral sclerosis (ALS) [308].
• Implementation and Healthcare Delivery: Gaps exist in statin prescribing, especially in low-income [42, 80, 90, 481, 690, 724, 290], incarcerated [23], and minority populations [42, 282, 1355]. Coronary computed tomography angiography (CCTA) can increase statin initiation/intensification [176, 1350, 462]. Shared decision-making (SDM) is crucial for older adults regarding continuation/discontinuation [119, 64, 937]. Pharmacist interventions [245, 247, 265, 483, 500, 584, 608, 660, 661, 884, 1037, 1089, 1111] and technology-assisted tools [144, 1650] can improve adherence and goal attainment.
• Mechanistic Insights and Biomarkers: Statins can alter gut microbiota composition [4, 252], with negative correlations observed for five species and positive for one [4]. They influence inflammatory markers like IL-6 and CRP [339, 653, 1681, 1777, 1827]. Genetic variants (e.g., SLCO1B1*5, NAT2) are associated with statin response and side effects [135, 151, 206, 242, 263, 557]. Statin therapy can also increase PCSK9 levels [415].
• Co-medications and Interactions: Combined statin and antiplatelet therapy may reduce the risk of cerebral cavernous malformation hemorrhage [11]. Combination therapy with ezetimibe or PCSK9 inhibitors can achieve lower LDL-C targets, especially in statin-intolerant patients or those with suboptimal response [109, 179, 214, 215, 219, 269, 292, 430, 700, 1054, 1855]. Drug-drug interactions (DDIs) can occur, such as with Danazol [209], Tribulus terrestris [250], or HIV antiretroviral therapy [521], potentially increasing myopathy risk [1492, 1848]. Metformin use may dampen vaccine responsiveness in diabetics [2] but enhance LDL-C response to statins [122].

• Personalized Adherence Strategies: Given the wide range of adherence, individualized interventions (e.g., pharmacist-led counseling, digital reminders, addressing social needs) are crucial to improve statin uptake and persistence, particularly in vulnerable populations [247, 265, 391, 403, 639, 660, 833, 987].
• Monitoring and Management of Side Effects: Clinicians should actively inquire about and manage statin-associated muscle symptoms (SAMS) and other side effects, considering alternative statins (e.g., hydrophilic) or combination therapies (e.g., ezetimibe, PCSK9 inhibitors) for intolerant patients to maintain lipid-lowering goals [15, 109, 162, 179, 275, 292, 683].
• Optimizing Prescribing Practices: Despite clear guidelines, gaps in statin prescribing persist, especially in minority, low-income, and older adult populations, highlighting the need for enhanced clinician education, decision support tools, and health system interventions to ensure appropriate initiation and intensification of therapy [42, 80, 234, 282, 438, 455, 904, 1102, 1353, 1374, 1386].
• Beyond Lipid Lowering: The pleiotropic effects of statins extend to reduced mortality in sepsis and COVID-19, and improved outcomes in certain cancers and neurological conditions, suggesting broader therapeutic considerations beyond traditional cardiovascular risk reduction [9, 32, 33, 35, 38, 39, 43, 249, 349, 475, 486, 510, 539, 614, 666, 713, 789, 832, 870, 957, 974, 1225, 1269].
• Caution with Specific Comorbidities: Awareness of potential adverse effects in specific populations (e.g., increased glaucoma risk [17, 120, 439], diabetic nephropathy [160], or interactions with other medications [209, 250, 521, 1492, 1848]) is important for personalized care.

• Long-term Adherence Interventions: Efficacy of sustained, tailored interventions to improve statin adherence across diverse socioeconomic and cultural contexts, particularly in low-income settings [90, 247, 460, 690].
• Mechanistic Pathways in Non-CVD Benefits: Elucidating the precise molecular mechanisms underlying statins' protective effects in conditions like sepsis, COVID-19, and various cancers, to inform new therapeutic targets [9, 32, 35, 39, 249, 475, 486, 510, 529, 539, 614, 666, 713, 789, 832, 870, 957, 974, 1225, 1269].
• Pharmacogenomics and Personalized Therapy: Prospective studies integrating pharmacogenomic testing (e.g., SLCO1B1, NAT2) to predict statin response, optimize dosing, and mitigate adverse effects like SAMS in diverse populations [135, 151, 206, 242, 263, 493, 557].
• Statin Effects on Neurodegenerative Diseases: Further investigation into the complex and sometimes conflicting associations between statin use and neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, ALS), including specific statin types and long-term cognitive outcomes [121, 123, 124, 158, 201, 277, 308, 347, 444, 603, 606, 632, 635, 756].
• Impact on Specific Organ Systems: Dedicated research on the long-term effects of statins on ocular health (glaucoma, ocular hypertension) [17, 120, 439], bone density [28, 79, 216, 436, 1542], and male fertility [411], as these areas present conflicting or limited evidence.

• Heterogeneity in Adherence Measurement — Diverse methods (PDC, MPR, self-report, pill count, plasma levels) limit direct comparison and pooling of adherence rates, impacting the precision of central tendency estimates [220, 426, 495, 567, 627, 772, 913, 1434].
• Observational Study Predominance — Many findings, especially regarding non-CVD benefits and adverse events, derive from observational designs (cohort, case-control), which are susceptible to confounding and cannot establish causality [3, 9, 32, 38, 39, 160, 254, 308, 315, 485, 632, 756, 967].
• Population Specificity and Generalizability — Studies often focus on specific populations (e.g., older adults, diabetics, certain ethnicities), making it challenging to generalize findings across broader demographics or healthcare systems [18, 42, 282, 333, 455, 493, 724, 795, 840, 896, 1102, 1355, 1384, 1565].
• Reporting Inconsistencies — Variability in reporting specific statin types, dosages, and duration of use limits granular analysis of dose-response relationships or differences between individual statins [194, 208, 340, 375, 431, 1019, 1685].
• Lack of Mechanistic Detail — While associations are reported, underlying biological mechanisms for many pleiotropic effects or adverse events are often not fully elucidated, limiting a deeper understanding of statin action [4, 66, 206, 251, 252, 330, 411].

• Standardize Adherence Metrics — Implement consistent, validated adherence measures (e.g., MPR, PDC) in future clinical trials and observational studies to enable robust comparisons [220, 495, 567, 627].
• RCTs for Pleiotropic Effects — Conduct randomized controlled trials to definitively assess the causal impact of statins on non-cardiovascular outcomes (e.g., sepsis mortality, cancer survival) [9, 32, 35, 39, 249, 475, 486, 510, 539, 614, 666, 713, 789, 832, 870, 957, 974, 1225, 1269].
• Pharmacogenomic-Guided Trials — Design prospective studies to evaluate the clinical utility and cost-effectiveness of pharmacogenomic testing in guiding statin selection and dosing [135, 151, 206, 242, 263, 493, 557].
• Longitudinal Safety Studies — Establish long-term, large-scale prospective cohorts to monitor rare or delayed adverse effects, particularly on ocular health, bone, and neurological function [17, 28, 120, 160, 439, 442, 632, 756, 967].
• Real-World Implementation Research — Evaluate the effectiveness of integrated, multi-component interventions (e.g., pharmacist-led, digital health, policy changes) in improving statin prescribing, adherence, and outcomes in diverse, underserved populations [247, 265, 274, 290, 460, 500, 584, 660, 661, 884, 904, 1093].