Association of Statin Use with Dementia Risk Among Older Adults in Japan: A Nested Case-Control Study Using the LIFE Study.

Background: Previous studies have shown a possible association between statin use and a decreased risk of dementia, but the association has not been sufficiently established, especially in the super-aging society of Japan. Objective: This study aimed to determine the association between statin use and the risk of dementia among Japanese participants aged> =65 years old. Methods: Data from the Longevity Improvement and Fair Evidence (LIFE) Study were utilized, including medical and long-term care (LTC) claim data from 17 municipalities between April 2014 and December 2020. A nested case-control study was conducted with one case matched to five controls based on age, sex, municipality, and year of cohort entry. We used a conditional logistic regression model to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: This study included 57,302 cases and 283,525 controls, with 59.7% of the participants being woman. After adjusting for potential confounders, statin use was associated with a lower risk of dementia (OR, 0.70; 95% CI: 0.68-0.73) and Alzheimer's disease (OR: 0.66; 95% CI: 0.63-0.69). Compared with non-users, the ORs of dementia were as follows: 1.42 (1.34-1.50) for 1-30 total standardized daily dose (TSDD), 0.91 (0.85-0.98) for 31-90 TSDD, 0.63 (0.58-0.69) for 91-180 TSDD, and 0.33 (0.31-0.36) for >180 TSDD in dose-analysis. Conclusions: Statin use is associated with a reduced risk of dementia and Alzheimer's disease among older Japanese adults. A low cumulative statin dose is associated with an increased risk of dementia, whereas a high cumulative statin dose is a protective factor against dementia.

A Systematic Review and Meta-Analysis on the Role of Bempedoic Acid in Cardiovascular Outcomes for Patients With Statin Intolerance.

Atherosclerosis, a multifaceted pathogenic process affecting the arteries and aorta, poses a significant threat because of its potential to impede or entirely obstruct blood flow by narrowing blood vessels. This intricate progression involves various factors such as dyslipidemia, immunological responses, inflammation, and endothelial dysfunction. The initial phase manifests as the formation of fatty streaks, considered a pivotal hallmark in the inception of atherosclerotic plaques, a process that can commence as early as childhood. Over time, this process evolves, characterized by the thickening of the arterial inner layer (intima) and accumulation of lipid-laden macrophages, commonly known as foam cells, along with the buildup of the extracellular matrix. Subsequent stages witness the proliferation and aggregation of smooth muscle cells, culminating in the formation of atheroma plaques. As these lesions progress, apoptosis can occur in the deeper layers, further recruiting macrophages, which may undergo calcification and transform into atherosclerotic plaques. Notably, mechanisms such as arterial remodeling and intraplaque hemorrhage also contribute significantly to the progression of atherosclerotic cardiovascular disease, although these facets fall beyond the scope of this article. This study aimed to systematically review and conduct a meta-analysis of randomized controlled trials investigating the efficacy and safety of bempedoic acid in statin-intolerant patients with hyperlipidemia and to provide conclusions and recommendations accordingly. A systematic search of databases, such as PubMed, Web of Science, and Embase, will be performed. Only randomized trials will be included comparing bempedoic acid with placebo in statin-intolerant patients. This study aimed to provide a comprehensive understanding of the role of bempedoic acid in managing hyperlipidemia in statin-intolerant patients. In primary prevention, for patients unable to tolerate recommended statins, bempedoic acid was associated with a significant reduction in major adverse cardiovascular events (MACE) as the primary endpoint.

Treat-to-target or high-intensity statin treatment in older adults with coronary artery disease: a post hoc analysis of the LODESTAR trial.

BACKGROUND: The optimal statin treatment strategy that is balanced for both efficacy and safety has not been clearly determined in older adults with coronary artery disease (CAD). METHODS: In the post hoc analysis of the LODESTAR (low-density lipoprotein cholesterol-targeting statin therapy versus intensity-based statin therapy in patients with coronary artery disease) trial, the impact between a treat-to-target strategy versus a high-intensity statin therapy strategy was compared in older adults (aged 75 years or older). The goal of treat-to-target low-density lipoprotein cholesterol (LDL-C) level was 50-70 mg/dl. The primary endpoint comprised the three-year composite of all-cause death, myocardial infarction, stroke or coronary revascularisation. RESULTS: Among 4,400 patients with CAD enrolled in the LODESTAR trial, 822 (18.7%) were aged 75 years or older. Poor clinical outcomes and risk factors for atherosclerosis were more frequently observed in older adults than in younger population (<75 years old). Among these older adults with CAD, the prescription rate of high-intensity statin was significantly lower in the treat-to-target strategy group throughout the study period (P < 0.001). The mean LDL-C level for three years was 65 ± 16 mg/dl in the treat-to-target strategy group and 64 ± 18 mg/dl in the high-intensity statin group (P = 0.34). The incidence of primary endpoint occurrence was 10.9% in the treat-to-target strategy group and 12.0% in the high-intensity statin group (hazard ratio 0.92, 95% confidence interval 0.61-1.38, P = 0.69). CONCLUSIONS: High-intensity statin therapy is theoretically more necessary in older adults because of worse clinical outcomes and greater number of risk factors for atherosclerosis. However, the primary endpoint occurrence with a treat-to-target strategy with an LDL-C goal of 50-70 mg/dl was comparable to that of high-intensity statin therapy and reduced utilisation of a high-intensity statin. Taking efficacy as well as safety into account, adopting a tailored approach may be considered for this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02579499.

A novel chemically engineered multifunctional statin conjugate as self-assembled nanoparticles inhibiting bile acid transporters.

Statins are widely used to treat hyperlipidemia; however, their mechanism-inhibiting cholesterol production without promoting its utilization-causes problems, such as inducing diabetes. In our research, we develop, for the first time, a chemically engineered statin conjugate that not only inhibits cholesterol production but also enhances its consumption through its multifunctional properties. The novel rosuvastatin (RO) and ursodeoxycholic acid (UDCA) conjugate (ROUA) is designed to bind to and inhibit the core of the apical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the effect of rosuvastatin. Consequently, ROUA not only preserves the cholesterol-lowering function of statins but also prevents the reabsorption of bile acids, thereby increasing cholesterol consumption. Additionally, ROUA's ability to self-assemble into nanoparticles in saline-attributable to its multiple hydroxyl groups and hydrophobic nature-suggests its potential for a prolonged presence in the body. The oral administration of ROUA nanoparticles in animal models using a high-fat or high-fat/high-fructose diet shows remarkable therapeutic efficacy in fatty liver, with low systemic toxicity. This innovative self-assembling multifunctional molecule design approach, which boosts a variety of therapeutic effects while minimizing toxicity, offers a significant contribution to the advancement of drug development.

Diffuse Large B-cell Lymphoma Complicated with Anti-3-hydroxy-3-methylglutaryl-Coenzyme A Reductase Immune-mediated Necrotizing Myopathy: A Case Report.

A 75-year-old woman presented with significant muscle weakness after statin use. A muscle biopsy revealed necrotizing myopathy, and the patient tested positive for serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, leading to a diagnosis of anti-HMGCR immune-mediated necrotizing myopathy (IMNM). Computed tomography revealed intraperitoneal lymphadenopathy, which was diagnosed as a diffuse large B-cell lymphoma. Immunostaining confirmed HMGCR expression in the lymphoma cells. The patient received chemotherapy and achieved complete remission of the lymphoma, along with nearly complete recovery from IMNM. Although the etiologies of IMNM and lymphoma remain unclear, HMGCR expression in lymphoma cells is likely to be associated with the development of IMNM.

Statin use and fall risk in adults: a cross-sectional survey and mendelian randomization analysis.

Background and Objective: The issue of falls poses a significant threat to the health of the elderly population. Although statins can cause myopathy, which implies that they may cause balance problems and increase the risk of falling, this has not been tested. Our objective was to assess whether the use of statins is linked to a higher risk of falls. Methods: A cross-sectional survey study and Mendelian randomization (MR) study were conducted to examine whether the use of statins was associated with an increased risk of falling and balance problems. The cross-sectional study included 2,656 participants from the US population (NHANES) who reported information on balance and falling problems in the past year and their use of statins. Univariate and multivariate logistic regression models were used to investigate the association between statin use and the likelihood of falling or experiencing balance problems. The MR study identified five Single Nucleotide Polymorphisms (SNPs) that predict statin use across five ancestry groups: Admixed African or African, East Asian, European, Hispanic, and South Asian. Additionally, SNPs predicting the risk of falls were acquired from the UK Biobank population. A two-sample MR analysis was performed to examine whether genetically predicted statin use increased the risk of falls. Results: The use of statins was found to be associated with an increased likelihood of balance and falling problems (balance problem, OR 1.25, 95%CI 1.02 to 1.55; falling problem, OR 1.27, 95%CI 1.03-1.27). Subgroup analysis revealed that patients under the age of 65 were more susceptible to these issues when taking statins (balance problem, OR 3.42, 95%CI 1.40 to 9.30; falling problem, OR 5.58, 95%CI 2.04-15.40). The MR analysis indicated that the use of statins, as genetically proxied, resulted in an increased risk of falling problems (OR 1.21, 95% CI 1.1-1.33). Conclusion: Our study found an association between the use of statins and an increased risk of balance problems and falls in adults over 40 years old, and the MR study result suggested statin use increased risk of falls. The risk was higher in participants under 65 years old compared to those over 65 years old.

The impact of statin therapy on the healing of diabetic foot ulcers: a case-control series.

BACKGROUND: Diabetic foot ulcers (DFU) are a costly complication of diabetes mellitus (DM), with significant implications for the patient and the healthcare professionals that treat them. The primary objective of this study was to evaluate if there were improved healing rates in patients with a DFU that were taking a statin medication compared to those patients with a DFU who were not taking a statin medication. Secondary outcomes assessed were correlations with wound healing or statin use on data obtained from retrospective chart review. METHODS: A case-control series was performed to obtain appropriate demographic information, comorbid conditions, laboratory values, and physical examination findings. From the time of presentation with DFU, these patients were followed for 12 weeks to evaluate for healing. Healing was defined as full epithelialization of the DFU with no further drainage. Wound healing and statin use correlation testing was then done for collected variables and each cohort. Chi square and Pearson correlation were then performed to identify any significant correlations. All p-values were two-sided, and findings were considered statistically significant at p < 0.05. RESULTS: Our study identified 109 patients, 75 patients with a DFU on statin medication and 34 patients with a DFU not on statin medication. The statin cohort was more likely to be older, less than 5-year duration of diabetes, have more comorbidities, decreased low-density lipoprotein (LDL) cholesterol, and decreased total cholesterol (p < 0.05). Among those patients taking a statin medication, 48.0% (36/75) healed their DFU within 12 weeks. Among those patients not taking a statin medication, 44.1% (15/34) healed their DFU within 12 weeks. No correlation was noted between wound healing and statin use (p = 0.7). For wound healing, a negative correlation was noted for prior minor amputations (p < 0.05). For statin use, correlations were noted for age, duration of DM, LDL cholesterol level, total cholesterol level, HTN, CAD, and HLD (p < 0.05). CONCLUSIONS: Statin medication use did not influence DFU healing rates between cohorts. There was a correlation noted between wound healing and prior minor amputations and between statin use and age, duration of DM, LDL cholesterol, total cholesterol, HTN, CAD and HLD. Additionally, we observed no correlation between DFU healing rates and use of a statin medication.

Long-term statin use and risk of cancers: a target trial emulation study.

BACKGROUND AND OBJECTIVES: Controversy exists regarding potential cancer risks associated with long-term statin use. This study aimed to use real-world data to investigate the association between cancer incidence and sustained statin use over a 10-year period. METHODS: Using territory-wide public electronic medical records in Hong Kong, we emulated a sequence of nested target trials on patients who met indications for statin initiation in each calendar month from January 2009 to December 2011. Statin initiators and noninitiators were matched in a 1:1 ratio to mimic the randomization of eligible person-trials at baseline. Pooled logistic regression was applied to obtain the hazard ratios for the cancer incidence of statin initiation in intention-to-treat analysis, with the adjustment of baseline confounders and the inverse probability weighting accounting for the postbaseline confounders in per-protocol analysis. RESULTS: Among 8,560,051 eligible person-trials, 119,715 noninitiators were matched to 119,715 initiators for analysis. Over the 10-year study period, the estimated hazard ratio of overall cancer incidence was 0.96 (0.87, 1.05), and the standardized 10-year risk difference was -0.4% (-1.3%, 0.4%) in the per-protocol analysis. For the cancer subtypes of interest (ie, breast cancer, colorectal cancer, hematological cancer, pancreatic cancer, prostate cancer, urothelial carcinoma, and lung cancer), the 10-year risk differences ranged from -0.3% to 0.2% in the per-protocol analysis. No observable risk change for cancer was found in all patient subgroups with regards to their sex, age (<70/≥70 years), Charlson Comorbidity Index (≤4/>4), and statin indication. CONCLUSION: Statin use has no impact on cancer incidence over a 10-year follow-up period, including all cancer subtypes of interest and patient subgroups with regards to sex, age, comorbidities, and statin indications.

Pharmacologic Treatment of Portal Hypertension.

Portal hypertension is the key mechanism driving the transition from compensated to decompensated cirrhosis. In this review, the authors described the pathophysiology of portal hypertension in cirrhosis and the rationale of pharmacologic treatment of portal hypertension. We discussed both etiologic and nonetiologic treatment of portal hypertension and the specific clinical scenarios how nonselective beta-blocker can be used in patients with cirrhosis. Finally, the authors summarized the evidence for emerging alternatives for portal hypertension in patients with cirrhosis.

Anti-HMGCR (Hydroxy-3-Methylglutaryl-CoA Reductase) Myopathy: A Rare Cause of Proximal Muscle Weakness.

Idiopathic inflammatory myopathy (IIM) represents a rare group of autoimmune conditions resulting in muscle weakness and includes polymyositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), overlap myositis, and inclusion body myositis. Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody IMNM represents a rare but increasingly recognized subtype of IIM. Here we report a case of a 65-year-old woman on rosuvastatin who presented with two months of progressive proximal muscle weakness, significant truncal weakness, and elevated creatine kinase concerning for rhabdomyolysis and inflammatory myopathy. The patient was eventually diagnosed on day 8 of her hospital stay with anti-HMGCR antibody IMNM after delayed testing for this specific myopathy. Increased awareness of this IIM subtype, as well as its risk factors and presenting features, might improve rapidity of testing and shorten hospital stays if the diagnosis is considered in the emergency department or early in the hospital course.

Effects of Statin and Annatto-extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice.

BACKGROUND/AIM: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. MATERIALS AND METHODS: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. RESULTS: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. CONCLUSION: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.

Short-Term Statin Treatment Reduces, and Long-Term Statin Treatment Abolishes, Chronic Vascular Injury by Radiation Therapy.

BACKGROUND: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long-term administration. METHODS AND RESULTS: C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X-ray head-and-neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho-nuclear factor kappa B p65] and TNF-α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca2+ activated K+ BK channel (potassium calcium-activated channel subfamily M alpha 1 and potassium calcium-activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation-induced changes. CONCLUSIONS: Short-term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation.

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

Statin use and risk of Parkinson's disease among older adults in Japan: a nested case-control study using the Longevity Improvement and Fair Evidence study.

The association between statin use and the risk of Parkinson's disease remains inconclusive, particularly in Japan's super-ageing society. This study aimed to investigate the potential association between statin use and the risk of Parkinson's disease among Japanese participants aged ≥65 years. We used data from the Longevity Improvement and Fair Evidence Study, which included medical and long-term care claim data from April 2014 to December 2020 across 17 municipalities. Using a nested case-control design, we matched one case to five controls based on age, sex, municipality and cohort entry year. A conditional logistic regression model was used to estimate the odds ratios with 95% confidence intervals. Among the 56 186 participants (9397 cases and 46 789 controls), 53.6% were women. The inverse association between statin use and Parkinson's disease risk was significant after adjusting for multiple variables (odds ratio: 0.61; 95% confidence interval: 0.56-0.66). Compared with non-users, the dose analysis revealed varying odds ratios: 1.30 (1.12-1.52) for 1-30 total standard daily doses, 0.77 (0.64-0.92) for 31-90 total standard daily doses, 0.62 (0.52-0.75) for 91-180 total standard daily doses and 0.30 (0.25-0.35) for >180 total standard daily doses. Statin use among older Japanese adults was associated with a decreased risk of Parkinson's disease. Notably, lower cumulative statin doses were associated with an elevated risk of Parkinson's disease, whereas higher cumulative doses exhibited protective effects against Parkinson's disease development.

Pregabalin-induced rhabdomyolysis: a case series and literature analysis.

Pregabalin is a prescription medicine that has recently been approved for individuals who suffer from fibromyalgia, neuropathic pain, anxiety disorder, or epilepsy. Pregabalin has the side effects of dizziness, sleepiness, and angioedema. Pregabalin-induced rhabdomyolysis has been rarely reported, with only four reports to date. We report two cases of rhabdomyolysis after pregabalin treatment. A man aged older than 90 years presented with exhaustion, muscle aches, and a high serum creatine kinase concentration after taking 75 mg of pregabalin on the first day of treatment. A woman in her 90s with long-term use of pregabalin presented with considerably elevated serum creatine kinase concentrations. Both patients had a long history of taking statins. Pregabalin therapy was stopped, high-volume intravenous fluids were administered, and serum electrolytes were frequently checked. Alkalinisation was performed with excellent outcomes. The Naranjo Adverse Drug Reaction scale and previous research suggest an association between pregabalin and rhabdomyolysis. Clinicians should be alert to the possibility of rhabdomyolysis occurring with the use of pregabalin, especially when taking statins.

Pharmaceutical Modulation of Intracranial Aneurysm Development and Rupture.

Management of intracranial aneurysms (IAs) is determined by patient age, risk of rupture, and comorbid conditions. While endovascular and microsurgical interventions offer solutions to mitigate the risk of rupture, pharmacological management strategies may complement these approaches or serve as alternatives in appropriate cases. The pathophysiology of IAs allows for the targeting of inflammation to prevent the development and rupture of IAs. The aim of this review is to provide an updated summary of different pharmaceutical management strategies for IAs. Acetylsalicylic acid and renin-angiotensin-aldosterone system (RAAS) inhibitor antihypertensives have some evidence supporting their protective effect. Studies of selective cyclooxygenase-2 (COX-2) inhibitors, statins, ADP inhibitors, and other metabolism-affecting drugs have demonstrated inconclusive findings regarding their association with aneurysm growth or rupture. In this manuscript, we highlight the evidence supporting each drug's effectiveness.