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Diabetes & Metabolism Journal Nov 2023To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic... (Randomized Controlled Trial)
Randomized Controlled Trial
The Efficacy and Safety of Moderate-Intensity Rosuvastatin with Ezetimibe versus High-Intensity Rosuvastatin in High Atherosclerotic Cardiovascular Disease Risk Patients with Type 2 Diabetes Mellitus: A Randomized, Multicenter, Open, Parallel, Phase 4 Study.
BACKGRUOUND
To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic cardiovascular disease (ASCVD) risk patients with type 2 diabetes mellitus (T2DM).
METHODS
This study was a randomized, multicenter, open, parallel phase 4 study, and enrolled T2DM subjects with an estimated 10-year ASCVD risk ≥7.5%. The primary endpoint was the low-density lipoprotein cholesterol (LDL-C) change rate after 24-week rosuvastatin 10 mg/ezetimibe 10 mg treatment was non-inferior to that of rosuvastatin 20 mg. The achievement proportion of 10-year ASCVD risk <7.5% or comprehensive lipid target (LDL-C <70 mg/dL, non-high-density lipoprotein cholesterol <100 mg/dL, and apolipoprotein B <80 mg/dL) without discontinuation, and several metabolic parameters were explored as secondary endpoints.
RESULTS
A hundred and six participants were assigned to each group. Both groups showed significant reduction in % change of LDL-C from baseline at week 24 (-63.90±6.89 vs. -55.44±6.85, combination vs. monotherapy, p=0.0378; respectively), but the combination treatment was superior to high-intensity monotherapy in LDL-C change (%) from baseline (least square [LS] mean difference, -8.47; 95% confidence interval, -16.44 to -0.49; p=0.0378). The combination treatment showed a higher proportion of achieved comprehensive lipid targets rather than monotherapy (85.36% vs. 62.22% in monotherapy, p=0.015). The ezetimibe combination significantly improved homeostasis model assessment of β-cell function even without A1c changes (LS mean difference, 17.13; p=0.0185).
CONCLUSION
In high ASCVD risk patients with T2DM, the combination of moderate-intensity rosuvastatin and ezetimibe was not only non-inferior but also superior to improving dyslipidemia with additional benefits compared to high-intensity rosuvastatin monotherapy.
Topics: Humans; Rosuvastatin Calcium; Ezetimibe; Cholesterol, LDL; Anticholesteremic Agents; Hypercholesterolemia; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Drug Therapy, Combination; Atherosclerosis
PubMed: 38043782
DOI: 10.4093/dmj.2023.0171 -
Indian Heart Journal Mar 2024Diabetes mellitus is a metabolic disorder that often predisposes to cardiovascular diseases (CVD). CVD is an important cause of morbidity and mortality in diabetes. The... (Review)
Review
Diabetes mellitus is a metabolic disorder that often predisposes to cardiovascular diseases (CVD). CVD is an important cause of morbidity and mortality in diabetes. The typical diabetic dyslipidaemia is characterized by low HDL cholesterol, high triglycerides with mildly increased or even normal LDL. This attenuated rise in LDL is due to the more atherogenic small dense LDL particles. Genetic factors, obesity, lack of physical activity, alcohol abuse, poorly controlled glucose levels are some of the common risk factors for dyslipidaemia. Non-pharmacological management of dyslipidaemia is important and includes modification in the diet, increase in physical activity and efforts to reduce weight. Statins remain the mainstay of pharmacotherapy for dyslipidaemia in diabetes. Due to the small dense LDL, even patients with diabetes who have normal LDL cholesterol, achieve reduction in cardiovascular risk with statin therapy. Those patients who do not achieve acceptable LDL reductions with statin alone can be treated with combination therapy of ezetimibe with statins. Many novel therapies have also emerged such as bempedoic acid and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors. The targets for LDL cholesterol depend upon the patients underlying cardiovascular risk category. The use of pharmacotherapy for lowering triglycerides in patients with mild to moderate hypertriglyceridemia and diabetes is still a matter of debate. Proper management of dyslipidaemia is critical component of treatment of diabetes mellitus.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Diabetes Mellitus, Type 2; Cholesterol, LDL; Dyslipidemias; Cardiovascular Diseases; Triglycerides; Anticholesteremic Agents
PubMed: 37956957
DOI: 10.1016/j.ihj.2023.11.002 -
Circulation Jan 2024Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein...
BACKGROUND
Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP.
METHODS
The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment.
RESULTS
Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC.
CONCLUSIONS
Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; C-Reactive Protein; Inflammation; Cholesterol; Myocardial Infarction; Treatment Outcome
PubMed: 37929602
DOI: 10.1161/CIRCULATIONAHA.123.066213 -
Current Atherosclerosis Reports Aug 2023To review recent international and domestic definitions, considerations, and treatment algorithms for statin intolerance, and specifically, statin-associated muscle... (Review)
Review
PURPOSE OF REVIEW
To review recent international and domestic definitions, considerations, and treatment algorithms for statin intolerance, and specifically, statin-associated muscle symptoms (SAMS).
RECENT FINDINGS
Multiple organizations around the world have produced guidance documents to aid clinicians on managing statin intolerance. A common theme resides among all the guidance documents that most patients can tolerate statins. For those patients who cannot, healthcare teams need to evaluate, rechallenge, educate, and ensure adequate reduction of atherogenic lipoproteins. Statin therapy remains the cornerstone of lipid-lowering therapies to reduce atherosclerotic cardiovascular disease (ASCVD) and reduce mortality and morbidity. The common theme throughout all these guidance documents is the importance of statin therapy to reduce ASCVD and continual adherence to treatment. Because adverse events occur and inhibit patients from achieving adequate lowering of their atherogenic lipoproteins, trial and rechallenge of statin therapy, as well as addition of non-statin therapies, especially in high-risk patients, is also undisputed. The main differences stem from laboratory monitoring and the classification of the severity of the adverse effect. Future research should focus on consistently diagnosing SAMS so that these patients can be easily identified in the electronic health records.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins; Atherosclerosis; Cardiovascular Diseases
PubMed: 37410332
DOI: 10.1007/s11883-023-01124-z -
Current Atherosclerosis Reports Mar 2024Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide... (Review)
Review
PURPOSE OF REVIEW
Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications.
RECENT FINDINGS
Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Fatty Acids; Dicarboxylic Acids
PubMed: 38294660
DOI: 10.1007/s11883-024-01188-5 -
Cells Nov 2023Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used... (Review)
Review
Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used in patients with or at risk of cardiovascular disease. Available data on thromboembolic disease include primary and secondary prevention as well as bleeding and mortality rates in statin users during anticoagulation for VTE. Experimental studies indicate that statins alter blood clotting at various levels. Statins produce anticoagulant effects via downregulation of tissue factor expression and enhanced endothelial thrombomodulin expression resulting in reduced thrombin generation. Statins impair fibrinogen cleavage and reduce thrombin generation. A reduction of factor V and factor XIII activation has been observed in patients treated with statins. It is postulated that the mechanisms involved are downregulation of factor V and activated factor V, modulation of the protein C pathway and alteration of the tissue factor pathway inhibitor. Clinical and experimental studies have shown that statins exert antiplatelet effects through early and delayed inhibition of platelet activation, adhesion and aggregation. It has been postulated that statin-induced anticoagulant effects can explain, at least partially, a reduction in primary and secondary VTE and death. Evidence supporting the use of statins for prevention of arterial thrombosis-related cardiovascular events is robust, but their role in VTE remains to be further elucidated. In this review, we present biological evidence and experimental data supporting the ability of statins to directly interfere with the clotting system.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Thrombin; Venous Thromboembolism; Factor V; Blood Coagulation; Thrombosis; Anticoagulants
PubMed: 38067146
DOI: 10.3390/cells12232719 -
American Heart Journal Dec 2023Atherosclerotic cardiovascular disease (ASCVD) is a prevalent chronic condition managed through pharmacotherapy targeting modifiable risk factors. However, ASCVD... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) is a prevalent chronic condition managed through pharmacotherapy targeting modifiable risk factors. However, ASCVD patients often face poor medication adherence due to a high pill burden from multiple oral drugs, contributing to cardiovascular events. Recent evidence indicates that polypills combining antihypertensive and statin medications effectively control risk factors and improve adherence in various ASCVD risk patients. Randomized clinical trials demonstrate polypill efficacy in reducing major cardiovascular events, making them a convenient strategy for both established ASCVD patients and those without ASCVD. These positive results encourage the incorporation of polypills into comprehensive cardiovascular prevention programs, particularly for socio-economically vulnerable populations. Nevertheless, barriers remain, such as unclear regulatory approval pathways and physician hesitancy. Despite challenges, the benefits of fixed-dose combinations are evident and should be encouraged for secondary and primary prevention, especially in high-risk categories. Technological advancements could further support the successful integration of polypills in clinical practice. This review discusses the evidence, challenges, and perspectives of polypills, emphasizing their potential impact on cardiovascular disease management.
Topics: Humans; Cardiovascular Diseases; Drug Combinations; Antihypertensive Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk Factors; Secondary Prevention; Primary Prevention
PubMed: 37634656
DOI: 10.1016/j.ahj.2023.08.012 -
Clinica Chimica Acta; International... Jul 2023Diabetes mellitus (DM) is strongly associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin type 9... (Review)
Review
Diabetes mellitus (DM) is strongly associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) was recently identified as an important regulator of circulating low-density lipoprotein-cholesterol (LDL-C) levels via degradation of the LDL receptor, proving to be a valid target to improve lipoprotein profiles and cardiovascular outcomes in patients with ASCVD. Beyond LDL receptor processing and cholesterol homeostasis, the PCSK9 protein has recently been verified to be associated with glucose metabolism. Importantly, clinical trials suggest that treatment with PCSK9 inhibitors for patients with DM is more effective. Hence, in this review, we summarize the current findings derived from experimental, preclinical, and clinical studies regarding the association between PCSK9 and glucose metabolism, including the relationship of PCSK9 genetic mutations to glucose metabolism and diabetes, the link between plasma PCSK9 concentrations and glucose metabolic parameters, the effects of glucose-lowering drugs on plasma PCSK9 levels and the impacts of PCSK9 inhibitors on cardiovascular outcomes of patients with DM. Clinically, exploring this field may improve our understanding regarding the roles of PCSK9 in glucose metabolism and may offer an in-depth interpretation of how PCSK9 inhibitors exert effects on the treatment of patients with DM.
Topics: Humans; Proprotein Convertase 9; PCSK9 Inhibitors; Cholesterol, LDL; Receptors, LDL; Atherosclerosis; Glucose
PubMed: 37315725
DOI: 10.1016/j.cca.2023.117444 -
Pharmacological Research Oct 2023With changing lifestyles, non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. A substantial increase in the incidence,... (Review)
Review
With changing lifestyles, non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. A substantial increase in the incidence, mortality, and associated burden of NAFLD-related advanced liver disease is expected. Currently, the initial diagnosis of NAFLD is still based on ultrasound and there is no approved treatment method. Lipid-lowering drugs, vitamin supplementation, and lifestyle improvement treatments are commonly used in clinical practice. However, most lipid-lowering drugs can produce poor patient compliance and specific adverse effects. Therefore, the exploration of bio-diagnostic markers and active lead compounds for the development of innovative drugs is urgently needed. More and more studies have reported the anti-NAFLD effects and mechanisms of natural products (NPs), which have become an important source for new drug development to treat NAFLD due to their high activity and low side effects. At present, berberine and silymarin have been approved by the US FDA to enter clinical phase IV studies, demonstrating the potential of NPs against NAFLD. Studies have found that the regulation of lipid metabolism, insulin resistance, oxidative stress, and inflammation-related pathways may play important roles in the process. With the continuous updating of technical means and scientific theories, in-depth research on the targets and mechanisms of NPs against NAFLD can provide new possibilities to find bio-diagnostic markers and innovative drugs. As we know, FXR agonists, PPARα agonists, and dual CCR2/5 inhibitors are gradually coming on stage for the treatment of NAFLD. Whether NPs can exert anti-NAFLD effects by regulating these targets or some unknown targets remains to be further studied. Therefore, the study reviewed the potential anti-NAFLD NPs and their targets. Some works on the discovery of new targets and the docking of active lead compounds were also discussed. It is hoped that this review can provide some reference values for the development of non-invasive diagnostic markers and new drugs against NAFLD in the clinic.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Biological Products; Liver; Hypolipidemic Agents; Drug Development; Lipids
PubMed: 37714392
DOI: 10.1016/j.phrs.2023.106925 -
Clinics in Orthopedic Surgery Dec 2023Rotator cuff tears are a condition characterized by damage to the muscles and tendons that connect the scapula and humerus, which are responsible for shoulder rotation... (Review)
Review
Rotator cuff tears are a condition characterized by damage to the muscles and tendons that connect the scapula and humerus, which are responsible for shoulder rotation and arm lifting. Metabolic factors such as diabetes, thyroid disease, high cholesterol, vitamin D deficiency, obesity, and smoking have been associated with an increased risk of rotator cuff tears. Interestingly, patients with hyperlipidemia, a condition characterized by high levels of cholesterol and other fats in the blood, have been found to have a higher incidence of rotator cuff tears and breakdown of tendon matrix. As a result, statin therapy, which is commonly used to lower cholesterol levels in hyperlipidemia, has been explored as a potential treatment to improve clinical outcomes in rotator cuff tears. However, the results of preclinical and clinical studies on the effects of statins on tendon healing in rotator cuff tears are limited and not well-defined. Moreover, since hyperlipidemia and rotator cuff tears are more prevalent in older individuals, a literature review on the efficacy and safety of statin therapy in this population is needed.
Topics: Humans; Aged; Rotator Cuff; Rotator Cuff Injuries; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Treatment Outcome; Cholesterol; Hyperlipidemias
PubMed: 38045588
DOI: 10.4055/cios23131