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BMJ (Clinical Research Ed.) Oct 2023To compare the long term efficacy and safety of rosuvastatin with atorvastatin treatment in adults with coronary artery disease. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the long term efficacy and safety of rosuvastatin with atorvastatin treatment in adults with coronary artery disease.
DESIGN
Randomised, open label, multicentre trial.
SETTING
12 hospitals in South Korea, September 2016 to November 2019.
PARTICIPANTS
4400 adults (age ≥19 years) with coronary artery disease.
INTERVENTIONS
Participants were assigned to receive either rosuvastatin (n=2204) or atorvastatin (n=2196) using 2×2 factorial randomisation.
MAIN OUTCOME MEASURES
The primary outcome was a three year composite of all cause death, myocardial infarction, stroke, or any coronary revascularisation. Secondary outcomes were safety endpoints: new onset diabetes mellitus; hospital admissions due to heart failure; deep vein thrombosis or pulmonary thromboembolism; endovascular revascularisation for peripheral artery disease; aortic intervention or surgery; end stage kidney disease; discontinuation of study drugs owing to intolerance; cataract surgery; and a composite of laboratory detected abnormalities.
RESULTS
4341 of the 4400 participants (98.7%) completed the trial. Mean daily dose of study drugs was 17.1 mg (standard deviation (SD) 5.2 mg) in the rosuvastatin group and 36.0 (12.8) mg in the atorvastatin group at three years (P<0.001). The primary outcome occurred in 189 participants (8.7%) in the rosuvastatin group and 178 (8.2%) in the atorvastatin group (hazard ratio 1.06, 95% confidence interval 0.86 to 1.30; P=0.58). The mean low density lipoprotein (LDL) cholesterol level during treatment was 1.8 mmol/L (SD 0.5 mmol/L) in the rosuvastatin group and 1.9 (0.5) mmol/L in the atorvastatin group (P<0.001). The rosuvastatin group had a higher incidence of new onset diabetes mellitus requiring initiation of antidiabetics (7.2% 5.3%; hazard ratio 1.39, 95% confidence interval 1.03 to 1.87; P=0.03) and cataract surgery (2.5% 1.5%; 1.66, 1.07 to 2.58; P=0.02). Other safety endpoints did not differ between the two groups.
CONCLUSIONS
In adults with coronary artery disease, rosuvastatin and atorvastatin showed comparable efficacy for the composite outcome of all cause death, myocardial infarction, stroke, or any coronary revascularisation at three years. Rosuvastatin was associated with lower LDL cholesterol levels but a higher risk of new onset diabetes mellitus requiring antidiabetics and cataract surgery compared with atorvastatin.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02579499.
Topics: Adult; Humans; Young Adult; Atorvastatin; Cataract; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction; Rosuvastatin Calcium; Stroke; Treatment Outcome
PubMed: 37852649
DOI: 10.1136/bmj-2023-075837 -
JAMA Jul 2023The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully...
IMPORTANCE
The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.
OBJECTIVE
To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients.
DESIGN, SETTING, AND PARTICIPANTS
This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients.
INTERVENTIONS
Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106).
MAIN OUTCOME MEASURES
The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.
RESULTS
Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
CONCLUSIONS
In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02993406.
Topics: Humans; Female; Aged; Male; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases; Myocardial Infarction; Stroke; Primary Prevention
PubMed: 37354546
DOI: 10.1001/jama.2023.9696 -
American Journal of Cardiovascular... Sep 2023Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular... (Review)
Review
Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Secondary Prevention; Hypolipidemic Agents; Ezetimibe; Cardiovascular Diseases; Hypertriglyceridemia; Pharmaceutical Preparations; Angiopoietin-Like Protein 3
PubMed: 37486464
DOI: 10.1007/s40256-023-00594-5 -
JAMA Sep 2023Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.
OBJECTIVE
To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.
DESIGN, SETTING, AND PARTICIPANTS
This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.
INTERVENTIONS
The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.
MAIN OUTCOMES AND MEASURES
Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.
RESULTS
Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.
CONCLUSION
Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04472676.
Topics: Adult; Female; Humans; American Indian or Alaska Native; Apoprotein(a); Lipoprotein(a); Administration, Oral; Cardiovascular Agents; Hypolipidemic Agents; Double-Blind Method; Male; Adolescent; Young Adult; Middle Aged; Dose-Response Relationship, Drug; White; Black or African American; Racial Groups
PubMed: 37638695
DOI: 10.1001/jama.2023.16503 -
Arthritis Research & Therapy Aug 2023In addition to decreasing the level of cholesterol, proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has pleiotropic effects, including immune regulation....
BACKGROUND
In addition to decreasing the level of cholesterol, proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has pleiotropic effects, including immune regulation. However, the impact of PCSK9 on autoimmune diseases is controversial. Therefore, we used drug target Mendelian randomization (MR) analysis to investigate the effect of PCSK9 inhibitor on different autoimmune diseases.
METHODS
We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published genome-wide association studies statistics and conducted drug target MR analysis to detect the causal relationship between PCSK9 inhibitor and the risk of autoimmune diseases. 3-Hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, the drug target of statin, was used to compare the effect with that of PCSK9 inhibitor. With the risk of coronary heart disease as a positive control, primary outcomes included the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis (MG), multiple sclerosis (MS), asthma, Crohn's disease (CD), ulcerative colitis (UC), and type 1 diabetes (T1D).
RESULTS
PCSK9 inhibitor significantly reduced the risk of SLE (OR [95%CI] = 0.47 [0.30 to 0.76], p = 1.74 × 10) but increased the risk of asthma (OR [95%CI] = 1.15 [1.03 to 1.29], p = 1.68 × 10) and CD (OR [95%CI] = 1.38 [1.05 to 1.83], p = 2.28 × 10). In contrast, HMGCR inhibitor increased the risk of RA (OR [95%CI] = 1.58 [1.19 to 2.11], p = 1.67 × 10), asthma (OR [95%CI] = 1.21 [1.04 to 1.40], p = 1.17 × 10), and CD (OR [95%CI] = 1.60 [1.08 to 2.39], p = 2.04 × 10).
CONCLUSIONS
PCSK9 inhibitor significantly reduced the risk of SLE but increased the risk of asthma and CD. In contrast, HMGCR inhibitor may be a risk factor for RA, asthma, and CD.
Topics: Humans; Arthritis, Rheumatoid; Genome-Wide Association Study; Lupus Erythematosus, Systemic; Mendelian Randomization Analysis; Proprotein Convertase 9; PCSK9 Inhibitors; Asthma
PubMed: 37580807
DOI: 10.1186/s13075-023-03122-7 -
Autoimmunity Reviews Dec 2023The discovery of autoantibodies directed against the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme has defined a sub-set of immune-mediated necrotising... (Review)
Review
The discovery of autoantibodies directed against the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme has defined a sub-set of immune-mediated necrotising myopathy (IMNM) which is strongly associated with exposure to statin medications. Although understanding of anti-HMGCR IMNM has grown considerably with the reporting of multiple cohorts in North America, Europe, Asia and Oceania, there remain many unanswered questions. The true incidence of anti-HMGCR IMNM is not known and heterogeneity of phenotype and treatment response within this autoantibody sub-group is being increasingly recognised. Statin-naïve adults and juvenile patients with anti-HMGCR potentially share characteristics distinct from statin-exposed patients, alluding to unique pathogenesis. Conflicting data exists on whether malignancies are associated with anti-HMGCR and further clarification is required to determine the degree of cancer screening required. Treatment approaches to anti-HMGCR IMNM are heterogeneous but generally highlight the efficacy of intravenous immunoglobulin. Even with multimodal immunosuppression, patients with anti-HMGCR remain prone to relapse, with younger patients generally manifesting more refractory disease. In this Review, we aim to summarise the current literature on anti-HMGCR and discuss the remaining issues.
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oxidoreductases; Necrosis; Myositis; Autoimmune Diseases; Autoantibodies; Hydroxymethylglutaryl CoA Reductases; Muscular Diseases; Muscle, Skeletal
PubMed: 37884200
DOI: 10.1016/j.autrev.2023.103468 -
International Journal of Molecular... Sep 2023Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease,... (Review)
Review
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Apoprotein(a); Lipoprotein(a); Apolipoproteins A; Hyperlipoproteinemias; Aortic Valve Stenosis
PubMed: 37686428
DOI: 10.3390/ijms241713622 -
Frontiers in Endocrinology 2023Statins are widely used to prevent cardiovascular disease events. Cardiovascular diseases and type 2 diabetes are tightly connected since type 2 diabetes is a major risk... (Review)
Review
Statins are widely used to prevent cardiovascular disease events. Cardiovascular diseases and type 2 diabetes are tightly connected since type 2 diabetes is a major risk factor for cardiovascular diseases. Additionally, cardiovascular diseases often precede the development of type 2 diabetes. These two diseases have common genetic and environmental antecedents. Statins are effective in the lowering of cardiovascular disease events. However, they have also important side effects, including an increased risk of type 2 diabetes. The first study reporting an association of statin treatment with the risk of type 2 diabetes was the WOSCOPS trial (West of Scotland Coronary Prevention Study) in 2001. Other primary and secondary cardiovascular disease prevention studies as well as population-based studies have confirmed original findings. The purpose of our review is to examine and summarize the most important findings of these studies as well as to describe the mechanisms how statins increase the risk of type 2 diabetes.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Risk Factors
PubMed: 37795366
DOI: 10.3389/fendo.2023.1239335 -
Indian Heart Journal Mar 2024Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals... (Review)
Review
Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals in general population roughly estimated to be 5 million in India. The prevalence of FH is higher in young CAD patients (<55 years in men; <60 years in women). FH is underdiagnosed and undertreated. Screening during childhood and Cascade screening of family members of known FH patients is of utmost importance in order to prevent the burden of CAD. Early identification of FH patients and early initiation of the lifelong lipid lowering therapy is the most effective strategy for managing FH. FH management includes pharmaceutical agents (statins and non statin drugs) and lifestyle modification. Inspite of maximum dose of statin with or without Ezetimibe, if target levels of LDL-C are not achieved, Bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors/Inclisiran can be added.
Topics: Male; Humans; Female; Proprotein Convertase 9; Anticholesteremic Agents; Cholesterol, LDL; Hyperlipoproteinemia Type II; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 38599725
DOI: 10.1016/j.ihj.2023.12.002 -
The New England Journal of Medicine Dec 2023The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.
METHODS
In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).
RESULTS
Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.
CONCLUSIONS
Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
Topics: Humans; Bayes Theorem; COVID-19; COVID-19 Drug Treatment; Critical Illness; Hospital Mortality; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Treatment Outcome
PubMed: 37888913
DOI: 10.1056/NEJMoa2309995