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The Lancet. Diabetes & Endocrinology May 2024Previous meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size... (Meta-Analysis)
Meta-Analysis
Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis.
BACKGROUND
Previous meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size or timing of this effect, or who is at greatest risk. We aimed to address these gaps in knowledge through analysis of individual participant data from large, long-term, randomised, double-blind trials of statin therapy.
METHODS
We conducted a meta-analysis of individual participant data from randomised controlled trials of statin therapy that participated in the CTT Collaboration. All double-blind randomised controlled trials of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants were eligible for inclusion in this meta-analysis. All recorded diabetes-related adverse events, treatments, and measures of glycaemia were sought from eligible trials. Meta-analyses assessed the effects of allocation to statin therapy on new-onset diabetes (defined by diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA values) and on worsening glycaemia in people with diabetes (defined by complications of glucose control, increased use of glucose-lowering medication, or HbA increase of ≥0·5%). Standard inverse-variance-weighted meta-analyses of the effects on these outcomes were conducted according to a prespecified protocol.
FINDINGS
Of the trials participating in the CTT Collaboration, 19 trials compared statin versus placebo (123 940 participants, 25 701 [21%] with diabetes; median follow-up of 4·3 years), and four trials compared more versus less intensive statin therapy (30 724 participants, 5340 [17%] with diabetes, median follow-up of 4·9 years). Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48). For each trial, the rate of new-onset diabetes among participants allocated to receive placebo depended mostly on the proportion of participants who had at least one follow-up HbA measurement; this proportion was much higher in the high-intensity than the low-intensity or moderate-intensity trials. Consequently, the main determinant of the magnitude of the absolute excesses in the two types of trial was the extent of HbA measurement rather than the proportional increase in risk associated with statin therapy. In participants without baseline diabetes, mean glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity (95% CI 0·03-0·05) and high-intensity statins (0·02-0·06), and mean HbA increased by 0·06% (0·00-0·12) with low-intensity or moderate-intensity statins and 0·08% (0·07-0·09) with high-intensity statins. Among those with a baseline measure of glycaemia, approximately 62% of new-onset diabetes cases were among participants who were already in the top quarter of the baseline distribution. The relative effects of statin therapy on new-onset diabetes were similar among different types of participants and over time. Among participants with baseline diabetes, the RRs for worsening glycaemia were 1·10 (1·06-1·14) for low-intensity or moderate-intensity statin therapy and 1·24 (1·06-1·44) for high-intensity statin therapy compared with placebo.
INTERPRETATION
Statins cause a moderate dose-dependent increase in new diagnoses of diabetes that is consistent with a small upwards shift in glycaemia, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes. Importantly, however, any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia (or, indeed, from any other mechanism) are already accounted for in the overall reduction in cardiovascular risk that is seen with statin therapy in these trials. These findings should further inform clinical guidelines regarding clinical management of people taking statin therapy.
FUNDING
British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.
Topics: Aged; Female; Humans; Male; Middle Aged; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 38554713
DOI: 10.1016/S2213-8587(24)00040-8 -
Cell Reports Sep 2023Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using...
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.
Topics: Humans; Decitabine; Azacitidine; Antimetabolites, Antineoplastic; Leukemia, Myeloid, Acute; DNA Methylation; DNA; Adaptor Proteins, Signal Transducing
PubMed: 37714156
DOI: 10.1016/j.celrep.2023.113098 -
Kardiologia Polska 2024Statin therapy is a cornerstone in the management of dyslipidemia, both in primary and secondary prevention of cardiovascular events. Despite strong guidelines... (Review)
Review
Statin therapy is a cornerstone in the management of dyslipidemia, both in primary and secondary prevention of cardiovascular events. Despite strong guidelines supporting statin use, concerns regarding side effects, particularly musculoskeletal symptoms, contribute to statin intolerance and patient reluctance. While statin intolerance is reported in 5% to 30% of patients, its true prevalence may be overestimated due to the influence of the nocebo effect. Factors associated with higher incidence of statin intolerance include older age, female sex, comorbidities such as diabetes and chronic kidney disease, and concurrent use of medications such as antiarrhythmic agents or calcium channel blockers. Clinical characterization of statin intolerance requires thorough evaluation and exclusion of alternative causes of musculoskeletal symptoms. Strategies to address statin intolerance include reassessing cardiovascular risk, engaging in shared decision-making, statin rechallenge after appropriate washout periods, dosage titration for tolerability, and consideration of alternative therapies when low-density lipoprotein goals cannot be achieved with statins. This review provides an overview of the spectrum of statin intolerance, its clinical assessment, and a systematic approach to caring for a patient with statin intolerance.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Female; Male; Dyslipidemias; Cardiovascular Diseases; Middle Aged; Aged
PubMed: 38712783
DOI: 10.33963/v.phj.100526 -
Indian Heart Journal Mar 2024Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density... (Review)
Review
Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Cholesterol, LDL; Anticholesteremic Agents; Acute Disease; Pancreatitis; Hypolipidemic Agents; Oligonucleotides, Antisense; Dyslipidemias; Chemical and Drug Induced Liver Injury
PubMed: 37979722
DOI: 10.1016/j.ihj.2023.11.003 -
Journal of Neuroinflammation Sep 2023Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the...
BACKGROUND
Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID.
METHODS
Wild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods.
RESULTS
Atorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task.
CONCLUSIONS
These data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.
Topics: Animals; Mice; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperhomocysteinemia; Cognitive Dysfunction; Cognition; Alzheimer Disease; Dementia, Vascular; Homocysteine
PubMed: 37658433
DOI: 10.1186/s12974-023-02883-x -
Cardiovascular Diabetology Nov 2023Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia.
METHODS
PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867).
RESULTS
Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79-0.95), myocardial infarction (OR 0.76, 95% CI 0.64-0.88) and unstable angina (OR 0.69, 95% CI 0.54-0.88) compared to control, over a median follow up of 87 (15-162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]-22.42,95% CI - 24.02% to - 20.82%), total cholesterol (- 16.50%,95% - 19.21% to - 13.79%), Apo-B lipoprotein (- 19.55%, - 22.68% to - 16.42%) and high-sensitivity CRP (- 27.83%, - 31.71% to - 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27-1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy.
CONCLUSIONS
The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Cholesterol; Myocardial Infarction; Gout; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 38017541
DOI: 10.1186/s12933-023-02022-z -
BMC Medicine Oct 2023With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have...
BACKGROUND
With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics.
METHODS
A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong's "Children of 1997" birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the "Children of 1997" birth cohort and coronary artery disease from Biobank Japan.
RESULTS
Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], - 1.06 [- 1.52 to - 0.60]; PCSK9: - 0.93 [- 1.56 to - 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid - 0.79 [- 1.25 to - 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed.
CONCLUSIONS
Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.
Topics: Child; Humans; Adolescent; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; PCSK9 Inhibitors; Mendelian Randomization Analysis; East Asian People; Cholesterol, LDL
PubMed: 37904165
DOI: 10.1186/s12916-023-03115-y -
Indian Heart Journal Mar 2024Indians have early onset atherosclerotic cardiovascular disease and acquire the risk factors at a younger age, and hence we need to aggressively address the management... (Review)
Review
Indians have early onset atherosclerotic cardiovascular disease and acquire the risk factors at a younger age, and hence we need to aggressively address the management of dyslipidemia in the young. Cholesterol levels early in life will influence the development of atherosclerosis. Young atherosclerotic cardiovascular disease (ASCVD) patients (18-40 yrs) should receive lipid-lowering drugs to reduce LDL-C<55 mg. Due to the asymptomatic nature of dyslipidemia, early screening will enable the implementation of management strategies which will decrease future cardiovascular events. In this review, we will provide insights into identifying and managing dyslipidemia in the 18-40 years age group (young adults). It is suggested that early detection and more aggressive management of dyslipidemia in young adults with or without risk factors like diabetes, hypertension, tobacco and central obesity, might reduce the risk of CV events occurring later in life. Although lifestyle modification is the mainstay of treatment (dietary recommendations, exercise, tobacco cessation, weight reduction, etc.) but in certain young adults we suggest use of statins in low dose or non-statin drugs if they have associated risk factors, LDL-C >160 mg or a high coronary calcium score. Young adults who are carriers of FH gene should receive aggressive lifestyle modification and appropriate antilipidemic therapy.
Topics: Humans; Young Adult; Cholesterol, LDL; Cardiovascular Diseases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dyslipidemias; Hypolipidemic Agents; Atherosclerosis; Risk Factors
PubMed: 38360458
DOI: 10.1016/j.ihj.2023.11.265 -
Alzheimer's Research & Therapy Dec 2023Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer's disease (AD). Lipid-lowering medications could interfere with...
BACKGROUND
Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer's disease (AD). Lipid-lowering medications could interfere with neurodegenerative processes in AD through cholesterol metabolism or other mechanisms.
OBJECTIVE
To explore the association between the use of lipid-lowering medications and cognitive decline over time in a cohort of patients with AD or mixed dementia with indication for lipid-lowering treatment.
METHODS
A longitudinal cohort study using the Swedish Registry for Cognitive/Dementia Disorders, linked with other Swedish national registries. Cognitive trajectories evaluated with mini-mental state examination (MMSE) were compared between statin users and non-users, individual statin users, groups of statins and non-statin lipid-lowering medications using mixed-effect regression models with inverse probability of drop out weighting. A dose-response analysis included statin users compared to non-users.
RESULTS
Our cohort consisted of 15,586 patients with mean age of 79.5 years at diagnosis and a majority of women (59.2 %). A dose-response effect was demonstrated: taking one defined daily dose of statins on average was associated with 0.63 more MMSE points after 3 years compared to no use of statins (95% CI: 0.33;0.94). Simvastatin users showed 1.01 more MMSE points (95% CI: 0.06;1.97) after 3 years compared to atorvastatin users. Younger (< 79.5 years at index date) simvastatin users had 0.80 more MMSE points compared to younger atorvastatin users (95% CI: 0.05;1.55) after 3 years. Simvastatin users had 1.03 more MMSE points (95% CI: 0.26;1.80) compared to rosuvastatin users after 3 years. No differences regarding statin lipophilicity were observed. The results of sensitivity analysis restricted to incident users were not consistent.
CONCLUSIONS
Some patients with AD or mixed dementia with indication for lipid-lowering medication may benefit cognitively from statin treatment; however, further research is needed to clarify the findings of sensitivity analyses.
Topics: Humans; Female; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Alzheimer Disease; Cohort Studies; Longitudinal Studies; Mixed Dementias; Simvastatin; Cognitive Dysfunction; Cholesterol
PubMed: 38115091
DOI: 10.1186/s13195-023-01360-0 -
International Journal of Molecular... Dec 2023Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic... (Review)
Review
Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.
Topics: Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metformin; Ascites; Ovarian Neoplasms; Insulin; Immunotherapy; Cholesterol; Tumor Microenvironment
PubMed: 38203494
DOI: 10.3390/ijms25010323