-
Atherosclerosis Jan 2024Statins reduce cardiovascular events and may improve bone mineral density. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Statins reduce cardiovascular events and may improve bone mineral density.
METHODS
We conducted a sub-analysis of a randomized clinical trial that investigated the differential effect of moderate vs intensive low-density lipoprotein cholesterol (LDL-C) lowering therapies on coronary artery calcium (CAC) scores, and used the acquired images to assess the change in radiological attenuation of selected thoracic vertebrae. Baseline and 12-month unenhanced chest CT scans were performed in 420 hyperlipidemic, postmenopausal women randomized to atorvastatin (ATV) 80 mg/day or pravastatin (PRV) 40 mg/day in the Beyond Endorsed Lipid Lowering with Electron Beam Tomography Scanning (BELLES) trial. Bone attenuation was measured in three contiguous thoracic vertebrae at baseline and 12 months.
RESULTS
There were no differences in baseline demographic and clinical characteristics between treatment arms. The median percent lowering (interquartile range) in LDL-C was significantly greater with ATV than PRV [-53 (-69 to 20)% vs -28 (-55 to 74)%, p < 0.001], although the CAC score change was similar [12 (-63 to 208)% vs 13 (-75 to 358)%; p = 0.44]. At follow-up, the median bone attenuation loss was significantly greater with PRV than with ATV [-2.6 (-27 to 11)% vs 0 (-11 to 25)%; p < 0.001]. The attenuation loss in the PRV group was comparable to that of a historical untreated general population sample. In the entire cohort, the changes in LDL-C and total cholesterol were inversely correlated with bone attenuation change (p < 0.01). In adjusted multivariable linear regression analyses, race and percent change in LDL-C were independent predictors of bone attenuation change. Age, body mass index, history of smoking, diabetes mellitus, hypertension, peripheral vascular disease, or hormone replacement therapy did not affect percent change in BMD.
CONCLUSIONS
These findings support the hypothesis that there is an interaction between bone and cardiometabolic health and that intensive lipid lowering has a beneficial effect on bone health.
Topics: Humans; Female; Atorvastatin; Pravastatin; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Pyrroles; Anticholesteremic Agents
PubMed: 38109819
DOI: 10.1016/j.atherosclerosis.2023.117425 -
European Journal of Preventive... Jun 2024Clinical guidelines often recommend treating individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
The potential benefit of statin prescription based on prediction of treatment responsiveness in older individuals: an application to the PROSPER randomized controlled trial.
AIMS
Clinical guidelines often recommend treating individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment strategies: (i) overall prescription, i.e. treatment to all individuals sharing the eligibility criteria of a trial; (ii) risk-stratified prescription, i.e. treatment only to those at an elevated outcome risk; and (iii) prescription based on predicted treatment responsiveness.
METHODS AND RESULTS
We reanalysed the PROSPER randomized controlled trial, which included individuals aged 70-82 years with a history of, or risk factors for, vascular diseases. We conducted the derivation and internal-external validation of a model predicting treatment responsiveness. We compared with placebo (n = 2913): (i) pravastatin (n = 2891); (ii) pravastatin in the presence of previous vascular diseases and placebo in the absence thereof (n = 2925); and (iii) pravastatin in the presence of a favourable prediction of treatment response and placebo in the absence thereof (n = 2890). We found an absolute difference in primary outcome events composed of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke, per 10 000 person-years equal to: -78 events (95% CI, -144 to -12) when prescribing pravastatin to all participants; -66 events (95% CI, -114 to -18) when treating only individuals with an elevated vascular risk; and -103 events (95% CI, -162 to -44) when restricting pravastatin to individuals with a favourable prediction of treatment response.
CONCLUSION
Pravastatin prescription based on predicted responsiveness may have an encouraging potential for cardiovascular prevention. Further external validation of our results and clinical experiments are needed.
TRIAL REGISTRATION
ISRCTN40976937.
Topics: Humans; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Female; Aged, 80 and over; Cardiovascular Diseases; Risk Assessment; Pravastatin; Treatment Outcome; Age Factors; Drug Prescriptions; Heart Disease Risk Factors; Time Factors; Decision Support Techniques
PubMed: 38085032
DOI: 10.1093/eurjpc/zwad383 -
Journal of Drugs in Dermatology : JDD Dec 2023Porokeratosis is a group of disorders characterized by aberrant skin keratinization secondary to genetic alterations in the mevalonate pathway, which participates in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Porokeratosis is a group of disorders characterized by aberrant skin keratinization secondary to genetic alterations in the mevalonate pathway, which participates in cholesterol synthesis. While a rare disorder, malignant transformation to squamous cell carcinoma is seen in up to 11% of cases. Recently, topical cholesterol and topical statin therapy have been suggested as a pathogenesis-directed treatment for porokeratosis.
METHODS
A PubMed/MEDLINE and Embase literature search was performed using the search terms: "porokeratosis" AND "cholesterol" OR "lovastatin" OR "simvastatin" OR "atorvastatin" OR "fluvastatin" OR "pitavastatin" OR "pravastatin" OR "rosuvastatin" OR "statin." Peer-reviewed clinical trials, case series, and case reports of all porokeratosis subtypes were included.
RESULTS
Eleven articles were included in the systematic review and 9 articles in the meta-analysis. The systematic review consisted of an aggregate of 33 patients, most of whom (n=31, 93.9%) applied the treatment twice daily for an average of 9.4 weeks (median=8 weeks), with 93.9% (n=31) experiencing improvement or resolution of porokeratosis. Sixteen patients (48.5%) used lovastatin and 16 (48.5%) used simvastatin with concurrent cholesterol therapy. Mild adverse events including erythema and contact dermatitis were experienced by 12.1% of patients. Our meta-analysis yielded a random effects model supporting a robust reduction in porokeratosis severity (OR = .076, 95% CI [0.022, 0.262]).
CONCLUSION
This underpowered meta-analysis provides limited, preliminary evidence supporting the efficacy of topical cholesterol/statin therapy. Overall, quality studies and aggregated sample size are limited; future large clinical trials are needed to further elucidate the role of topical cholesterol/statin therapy in the treatment of porokeratosis. J Drugs Dermatol. 2023;22(12):1160-1165. doi:10.36849/JDD.7775.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Porokeratosis; Lovastatin; Simvastatin; Cholesterol
PubMed: 38051843
DOI: 10.36849/JDD.7775 -
Journal of Ovarian Research Nov 2023High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating...
High-grade serous carcinoma (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by gain-of-function TP53 mutations originating in the fallopian tube epithelium. Therapeutic intervention occurs at advanced metastatic disease, due to challenges in early-stage diagnosis, with common disease recurrence and therapy resistance despite initial therapy success. The mevalonate pathway is exploited by many cancers and is potently inhibited by statin drugs. Statins have shown anti-cancer activity in many, but not all cancers. Here, we investigated the role of p53 status in relation to mevalonate pathway signaling in murine oviductal epithelial (OVE) cells and identified OVE cell sensitivity to statin inhibition. We found that p53 mutant and Trp53 knockout OVE cells have increased mevalonate pathway signaling compared to p53 wild-type OVE cells. Through orthotopic implantation to replicate the fallopian tube origin of HGSC, p53 mutant cells upregulated the mevalonate pathway to drive progression to advanced-stage ovarian cancer, and simvastatin treatment abrogated this effect. Additionally, simvastatin was more efficacious at inhibiting cell metabolic activity in OVE cells than atorvastatin, rosuvastatin and pravastatin. In vitro, simvastatin demonstrated potent effects on cell proliferation, apoptosis, invasion and migration in OVE cells regardless of p53 status. In vivo, simvastatin induced ovarian cancer disease regression through decreased primary ovarian tumor weight and increased apoptosis. Simvastatin also significantly increased cytoplasmic localization of HMG-CoA reductase in ovarian tumors. Downstream of the mevalonate pathway, simvastatin had no effect on YAP or small GTPase activity. This study suggests that simvastatin can induce anti-tumor effects and could be an important inhibitor of ovarian cancer progression.
Topics: Female; Mice; Animals; Humans; Fallopian Tubes; Simvastatin; Tumor Suppressor Protein p53; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Epithelial Cells; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
PubMed: 37986175
DOI: 10.1186/s13048-023-01307-x -
Advanced Healthcare Materials Mar 2024Immunogenic cell death (ICD) shows promising therapeutic potential for tumor regression. However, the low sensitivity and immunosuppressive state of current cell death...
Immunogenic cell death (ICD) shows promising therapeutic potential for tumor regression. However, the low sensitivity and immunosuppressive state of current cell death manners seriously impede tumor immunogenicity. Ferroptosis characterized by excessive lipid peroxidation, has emerged as a potential strategy to induce ICD and activate antitumor immune responses. However, the effectiveness of ferroptosis is limited by antioxidant regulatory networks, including the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) pathways, presenting challenges for its induction. Herein, they propose a novel approach that involves utilizing functionalized chitosan-ferrocene-sodium alginate (CFA) crosslinked nanogels, which are modified to pravastatin (PRV) and M1 macrophage membrane (MM) (designing as CFA/PRV@MM). Specifically, ferrocene boots intracellular reactive oxygen species levels for efficient glutathione (GSH) depletion through Fenton reaction, thus disrupting the GPX4/GSH axis, while PRV intervenes in the mevalonate pathway to inhibit the FSP1/CoQ10 antioxidant axis, thereby synergistically causing pronounced ferroptotic damage and promoting ICD. The CFA/PRV@MM nanogels demonstrate superior therapeutic efficacy in a mouse breast model, resulting in effective tumor ablation and immune response with minimal side effects. RNA transcription analysis reveals that nanogels can significantly affect metabolic progress, as well as immune activation. This research provides valuable insights into the design of ferroptosis induction for cancer immunotherapy.
Topics: Animals; Mice; Chitosan; Metallocenes; Nanogels; Antioxidants; Biomimetics; Ferroptosis; Neoplasms; Alginates; Disease Models, Animal; Glutathione; Ferrous Compounds
PubMed: 37975280
DOI: 10.1002/adhm.202302752 -
Value in Health Regional Issues Mar 2024The high cardiovascular disease burden globally and in Australia necessitates attention on statin expenditure, the primary pharmacological intervention for...
OBJECTIVES
The high cardiovascular disease burden globally and in Australia necessitates attention on statin expenditure, the primary pharmacological intervention for cardiovascular disease risk factors. The Pharmaceutical Benefits Scheme (PBS) subsidies approved statins for Australians. Managing PBS government expenditure occurs through price control strategies of statutory price decreases upon first generic entry and price disclosure. This study investigates the impact price control measures had on statin price evolution and government expenditure between 2010 and 2022.
METHODS
Prescription and pricing data were obtained from Services Australia Medicare Statistics, and price reduction strategies from the PBS. Summary statistics compared and described statin price, prescription, number of brands, market share, and government expenditure to atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin price control timelines.
RESULTS
Statin prices exposed to price control measures decreased irrespective of dosage and correlated with reductions in government expenditure, with a comparison of 2010 and 2022 showing annual statin expenditure declined by AU$833.5 million (83.25%) whereas prescriptions reduced by 3.0 million (15.7%). Effects of price disclosure on atorvastatin and rosuvastatin market share suggest industry-prompted price reductions may arise from market share loss, whereas reasons external to pricing prompted rosuvastatin to gain market share.
CONCLUSIONS
Limited publications on contemporary effects of statin price control measures exist. This investigation found these measures reduced government expenditure for statins by AU$949.1 million, with the price reduction correlating with price control measures. In addition to affirming price control mechanisms remain effective in contemporary times, this investigation provides data for key insights into the Australian statin industry.
Topics: Aged; Humans; Atorvastatin; Australasian People; Australia; Cardiovascular Diseases; Disclosure; Drug Costs; Health Expenditures; Hydroxymethylglutaryl-CoA Reductase Inhibitors; National Health Programs; Rosuvastatin Calcium
PubMed: 37972431
DOI: 10.1016/j.vhri.2023.10.004 -
Current Hypertension Reports Feb 2024To review recent data describing the challenges and innovations in therapeutic research focused on the prevention and treatment of preeclampsia. (Review)
Review
PURPOSE OF REVIEW
To review recent data describing the challenges and innovations in therapeutic research focused on the prevention and treatment of preeclampsia.
RECENT FINDINGS
Pregnant individuals have traditionally been excluded from therapeutic research, resulting in a paucity of innovation in therapeutics for pregnancy-specific medical conditions, especially preeclampsia. With the increased awareness of maternal morbidity and mortality, there is significant interest among researchers to expand therapeutic research in pregnancy. Several medications, including aspirin, pravastatin, metformin, and esomeprazole, which are commonly used in non-pregnant populations, are now being investigated for preeclampsia prevention. However, given the historic precedent of exclusion, along with the regulatory, ethical, and feasibility concerns that accompany this population, the study of these and novel medications has been complicated by numerous challenges. While complex, and laden with challenges, there is great ongoing need for therapeutic research to address preeclampsia. Aspirin, pravastatin, metformin, and esomeprazole have all shown promise as potential therapeutic agents; however, their use remains to be optimized, and innovative therapeutics need to be developed.
Topics: Female; Humans; Pregnancy; Aspirin; Esomeprazole; Hypertension; Metformin; Pravastatin; Pre-Eclampsia; Pregnancy Complications; Clinical Trials as Topic
PubMed: 37971596
DOI: 10.1007/s11906-023-01276-y -
JCI Insight Nov 2023Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery...
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. The increased cholesterol biosynthesis in PcntSMC-/- SMCs augmented PERK signaling and phenotypic modulation compared with control SMCs. Treatment with the HMGCR inhibitor, pravastatin, blocked the augmented SMC modulation and reduced plaque burden in hyperlipidemic PcntSMC-/- mice to that of control mice. These data support the notion that Pcnt deficiency activates cellular stress to increase SMC modulation and plaque burden, and targeting this pathway with statins in patients with MOPDII has the potential to reduce CAD in these individuals. The molecular mechanism uncovered further emphasizes SMC cytosolic stress and HSF1 activation as a pathway driving atherosclerotic plaque formation independently of cholesterol levels.
Topics: Animals; Humans; Mice; Atherosclerosis; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocytes, Smooth Muscle; Plaque, Atherosclerotic
PubMed: 37937642
DOI: 10.1172/jci.insight.173247 -
Diabetes & Vascular Disease Research 2023To investigate the impact of statin use on primary prevention of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) in a dose-, class-, and...
PURPOSE
To investigate the impact of statin use on primary prevention of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) in a dose-, class-, and use intensity-dependent manner.
METHODS
We used an inverse probability treatment-weighted Cox hazards model, with statin use status as a time-dependent variable.
RESULTS
Our results showed that statin use was associated with a significant reduction in CVD risk with an adjusted hazard ratio of 0.39. Pitavastatin was found to have the lowest CVD risk among the different classes of statins, followed by rosuvastatin, pravastatin, atorvastatin, simvastatin, fluvastatin, and lovastatin. Our analysis also revealed that a higher cumulative defined daily dose per year of statin was associated with a lower CVD risk. Additionally, a higher intensity of daily statin dose was associated with a lower CVD risk in patients with T2DM.
CONCLUSION
This study highlights the importance of statin use in reducing the risk of CVD in patients with T2DM, and the significance of dose, class, and intensity of statin use, in particular, pitavastatin class of statins was found to be the most effective in primary prevention of CVD in T2DM.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Rosuvastatin Calcium; Primary Prevention
PubMed: 37933122
DOI: 10.1177/14791641231214507 -
Biomedicines Sep 2023Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin....
Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin. Since the rabbit hemodichorial placenta more closely resembles the human condition, we investigated the effects of prenatal maternal pravastatin administration in the rabbit FGR model. At a gestational age of 25 days (term 31d), pregnant dams underwent partial uteroplacental vessel ligation (UPVL) in one uterine horn to induce FGR, leaving the other horn as a control. Dams were randomized to either receive 5 mg/kg/d pravastatin dissolved in their drinking water or normal drinking water until delivery. At GA 30d, the rabbits were delivered and were divided into four groups: control without pravastatin (C/NoPrav), FGR without pravastatin (FGR/NoPrav), FGR with pravastatin (FGR/Prav), and controls with pravastatin (C/Prav). The newborn rabbits underwent pulmonary functional assessment and neurobehavioral assessment, and they were harvested for alveolar morphometry or neuropathology. The placentas underwent histology examination and RNA expression. Birth weight was lower in the FGR groups (FGR/Prav, FGR/NoPrav), but there was no difference between FGR/Prav and C/NoPrav. No differences were noted in placental zone proportions, but eNOS in FGR/Prav placentas and VEGFR-2 in FGR/Prav and C/Prav were upregulated. There were no differences in pulmonary function assessment and alveolar morphometry. FGR/Prav kittens had increased neurosensory scores, but there were no differences in neuromotor tests, neuron density, apoptosis, and astrogliosis. In conclusion, in the rabbit FGR model, pravastatin upregulated the expression of VEGFR-2 and eNOS in FGR placentas and was associated with higher neurosensory scores, without measurable effects on birthweight, pulmonary function and morphology, and neuron density.
PubMed: 37893059
DOI: 10.3390/biomedicines11102685