Abstract
Aims
The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and ...patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF).
Methods and results
HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were −4.0 m (−16.0, 6.0; P = 0.42) and 4.0 m (−5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported.
Conclusion
The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.
Graphical Abstract
Peripheral arterial disease (PAD) is a global health issue associated with impaired functional capacity and elevated risk of major adverse cardiovascular events (MACEs). With changing risk factor ...profiles and an aging population, the burden of disease is expected to increase. This review considers evidence for the noninvasive management of PAD and makes clinical recommendations accordingly.
A comprehensive literature review was performed to examine the evidence for smoking cessation, exercise therapy, antiplatelet therapy, anticoagulant therapy, antihypertensive therapy, lipid-lowering therapy, and glycemic control in diabetes for patients with PAD.
Nicotine replacement, bupropion, and varenicline are safe and more effective than placebo in achieving smoking abstinence. Wherever it is practical and available, supervised exercise therapy is ideal treatment for intermittent claudication. Alternatively, step-monitored exercise can increase walking performance and the participant's compliance with less staff supervision. Clopidogrel is preferable to aspirin alone for all patients. However, small studies support the use of dual antiplatelet therapy after revascularization to improve limb outcomes. More recently, the addition of low-dose rivaroxaban to aspirin alone was proven to be more effective in reducing MACEs without a significant increase in major bleeding. However, the exact role of direct oral anticoagulant therapy in the management of PAD is still being understood. Evidence is emerging for more intensive blood pressure and lipid-lowering therapy than traditional targets. Whereas research in PAD is limited, there is clinical scope for an individualized approach to these risk factors. The management of diabetes remains challenging as glycemic control has not been demonstrated to improve macrovascular outcomes. Any potential impact of glycemic control on microvascular disease needs to be weighed against the risks of hypoglycemia. Sodium-glucose cotransporter 2 inhibitors appear to reduce MACEs, although caution is advised, given the increased incidence of lower limb amputation in clinical trials of canagliflozin.
Medical and lifestyle management of PAD should aim to improve functional outcomes and to reduce MACEs. Smoking cessation counseling or pharmacotherapy is recommended, although new strategies are needed. Whereas supervised exercise therapy is ideal, there can be barriers to clinical implementation. Other initiatives are being used as an alternative to walking-based supervised exercise therapy. More studies are required to investigate the role of intensive glycemic, blood pressure, and dyslipidemia control in patients with PAD. Overall, a multifactorial approach is recommended to alter the natural history of this condition.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) metabolism. Pharmacological PCSK9 inhibitors have been developed as a novel approach to ...treating dyslipidemia. This article reviews the spectrum of evidence implicating the role of PCSK9 in lipid metabolism and the clinical impact of PCSK9 inhibitors on lipid parameters and cardiovascular risk. Biochemical and genomic studies have established the role that PCSK9 plays in lipid metabolism and potential protection from cardiovascular disease observed in the setting of PCSK9 deficiency. This led to the development of inhibitory monoclonal antibodies (evolocumab, alirocumab) that produce dose-dependent lowering of LDL cholesterol up to 60%, with evidence of regression and stabilization of coronary atherosclerosis (GLAGOV, HUYGENS, PACMAN-AMI) and reduction in cardiovascular risk in large clinical outcomes trials (FOURIER, ODYSSEY Outcomes). More recent developments have witnessed alternative approaches to PCSK9 inhibition such as RNA interference (inclisiran), vaccines, and gene editing, which are currently undergoing clinical evaluation. PCSK9 inhibition has emerged as an important component of treatment approaches to lowering LDL cholesterol and plays an increasing role in preventive strategies.
Plaque Calcification: Do Lipoproteins Have a Role? Akers, Emma J; Nicholls, Stephen J; Di Bartolo, Belinda A
Arteriosclerosis, thrombosis, and vascular biology,
2019-October, 2019-10-00, 20191001, Letnik:
39, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Vascular calcification (VC) is strongly associated with all-cause mortality and is an independent predictor of cardiovascular events. Resulting from its complex, multifaceted nature, targeted ...treatments for VC have not yet been developed. Lipoproteins are well characterized in the pathogenesis of atherosclerotic plaques, leading to the development of plaque regressing therapeutics. Although their roles in plaque progression are well documented, their roles in VC, and calcification of a plaque, are not well understood. In this review, early in vitro data and clinical correlations suggest an inhibitory role for HDL (high-density lipoproteins) in VC, a stimulatory role for LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) and a potentially causal role for Lp(a) (lipoprotein a). Additionally, after treatment with a statin or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, plaque calcification is observed to increase. With the notion that differing morphologies of plaque calcification associate with either a more stable or unstable plaque phenotype, uncovering the mechanisms of lipoprotein-artery wall interactions could produce targeted therapeutic options for VC.
Numerous lines of evidence implicate a role for myeloperoxidase (MPO) in the pathogenesis of atherosclerosis. Enriched within vulnerable plaque, MPO serves as an enzymatic source of eicosanoids and ...bioactive lipids and generates atherogenic forms of both low- and high-density lipoproteins. These factors likely contribute to clinical studies demonstrating that increased systemic levels of MPO and its oxidation products predict increased cardiovascular risk. As a result, interest has focused on the potential to target MPO for the development of new risk markers, imaging, and therapies to prevent cardiovascular events.
IMPORTANCE: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)–containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the ...risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. OBJECTIVE: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C–lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. EXPOSURES: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. MAIN OUTCOMES AND MEASURES: Odds ratio (OR) for coronary heart disease (CHD)—defined as coronary death, myocardial infarction, or coronary revascularization—per 10-mg/dL lower concentration of ApoB-containing lipoproteins. RESULTS: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10−1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10−465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 95% CI, 0.741-0.802, P = 3.9 × 10−38 and OR, 0.773 95% CI, 0.747-0.801, P = 1.1 × 10−46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 95% CI, 0.965-1.065, P = .19; LDL-C: OR, 1.010 95% CI, 0.967-1.055, P = .19; ApoB: OR, 0.761 95% CI, 0.723-0.798, P = 7.51 × 10−20). CONCLUSIONS AND RELEVANCE: Triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
Lepodisiran for Elevated Lipoprotein(a)—Reply Nissen, Steven E; Linnebjerg, Helle; Nicholls, Stephen J
JAMA : the journal of the American Medical Association,
04/2024, Letnik:
331, Številka:
16
Journal Article
Recenzirano
Endo and Kami critiques a randomized clinical trial by Nissen and colleagues, which found that lepodisiran, an extended-duration short interfering RNA targeting lipoprotein(a), demonstrated high ...tolerability while decreasing serum lipoprotein(a) concentrations in a dose-dependent way over an extended period. These results were unexpected, necessitating a cautious approach to their interpretation. In response, Nissen and colleagues disagree with Drs Endo and Kami that the long duration of action of lepodisiran raises special safety concerns. Although they acknowledged in the article that a small phase 1 trial cannot definitively establish the safety of any new therapeutic agent, the observed incidence of minor concerns among participants shows no patterns suggestive of drug-induced adverse effects.
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