Anti-inflammatory effects of sodium-glucose co-transporter 2 inhibitors on atherosclerosis.
TL;DR: Large-scale clinical trials have confirmed the cardiovascular protective effects of SGLT inhibitors in patients with diabetes diagnosed with or at a higher risk of atherosclerotic cardiovascular disease.
About: This article is published in Vascular Pharmacology.The article was published on 2020-08-16. It has received 22 citations till now. The article focuses on the topics: Foam cell & Type 2 Diabetes Mellitus.
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TL;DR: In this article, the authors summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.
Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.
42 citations
TL;DR: The role of SGLT2 inhibitors in mediating the vascular actions of these drugs remains to be established as important off-target effects have been identified as discussed by the authors, and future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLTs in patients with distinct cardiovascular pathologies.
Abstract: Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.
32 citations
TL;DR: In this paper, the authors explored the inherent immune diversity in atheromatous plaques and suggest that the dysfunction of different immune cells plays an important role in atherosclerosis.
Abstract: Atherosclerosis is a chronic inflammatory disease that affects multiple arteries. Numerous studies have shown the inherent immune diversity in atheromatous plaques and suggest that the dysfunction of different immune cells plays an important role in atherosclerosis. However, few comprehensive bioinformatics analyses have investigated the potential coordinators that might orchestrate different immune cells to exacerbate atherosclerosis. Immune infiltration of 69 atheromatous plaques from different arterial beds in GSE100927 were explored by single-sample-gene-set enrichment analysis (presented as ssGSEA scores), ESTIMATE algorithm (presented as immune scores) and CIBERSORT algorithm (presented as relative fractions of 22 types of immune cells) to divide these plaques into ImmuneScoreL cluster (of low immune infiltration) and ImmuneScoreH cluster (of high immune infiltration). Subsequently, comprehensive bioinformatics analyses including differentially-expressed-genes (DEGs) analysis, protein–protein interaction networks analysis, hub genes analysis, Gene-Ontology-terms and KEGG pathway enrichment analysis, gene set enrichment analysis, analysis of expression profiles of immune-related genes, correlation analysis between DEGs and hub genes and immune cells were conducted. GSE28829 was analysed to cross-validate the results in GSE100927. Immune-related pathways, including interferon-related pathways and PD-1 signalling, were highly enriched in the ImmuneScoreH cluster. HLA-related (except for HLA-DRB6) and immune checkpoint genes (IDO1, PDCD-1, CD274(PD-L1), CD47), RORC, IFNGR1, STAT1 and JAK2 were upregulated in the ImmuneScoreH cluster, whereas FTO, CRY1, RORB, and PER1 were downregulated. Atheromatous plaques in the ImmuneScoreH cluster had higher proportions of M0 macrophages and gamma delta T cells but lower proportions of plasma cells and monocytes (p < 0.05). CAPG, CECR1, IL18, IGSF6, FBP1, HLA-DPA1 and MMP7 were commonly related to these immune cells. In addition, the advanced-stage carotid plaques in GSE28829 exhibited higher immune infiltration than early-stage carotid plaques. Atheromatous plaques with higher immune scores were likely at a more clinically advanced stage. The progression of atherosclerosis might be related to CAPG, IGSF6, IL18, CECR1, FBP1, MMP7, FTO, CRY1, RORB, RORC, PER1, HLA-DPA1 and immune-related pathways (IFN-γ pathway and PD-1 signalling pathway). These genes and pathways might play important roles in regulating immune cells such as M0 macrophages, gamma delta T cells, plasma cells and monocytes and might serve as potential therapeutic targets for atherosclerosis.
19 citations
TL;DR: In this article, a mini review of the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical to ASCVD, is presented.
Abstract: Objective: Sodium glucose cotransporter 2 inhibitors (SGLT2-is) are antidiabetic drugs that improve glycemic control by limiting urinary glucose reuptake in the proximal tubule. SGLT2-is might suppress atherosclerotic processes and ameliorate the prognosis of patients with diabetes mellitus diagnosed with or at high risk of atherosclerotic cardiovascular disease (ASCVD). In this mini review, we examine the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical atherosclerosis to ASCVD. Data Sources-PubMed and Google Scholar were searched for publications related to SGLT2-is and atherosclerosis. All types of articles were considered, including clinical trials, animal studies, in vitro observations, and reviews and meta-analyses. Data were examined according to their impact and clinical relevance. Synopsis of Content-We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2-is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds. Additionally, we propose future directions that can improve our understanding of SGLT2-is and atherosclerosis.
12 citations
TL;DR: Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medication with broad cardiovascular benefits in those with type 2 diabetes, chronic kidney disease, and heart failure as mentioned in this paper.
Abstract: Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medication with broad cardiovascular benefits in those with type 2 diabetes, chronic kidney disease, and heart failure. These include reductions in major adverse cardiac events and cardiovascular death. The mechanisms that underlie their benefits in atherosclerotic cardiovascular disease (ASCVD) are not well understood, but they extend beyond glucose lowering. This narrative review summarises the ASCVD benefits of SGLT2 inhibitors seen in large human outcome trials, as well as the mechanisms of action explored in rodent and small human studies. Potential pathways include favourable alterations in lipid metabolism, inflammation, and endothelial function. These all require further investigation in large human clinical trials with mechanistic endpoints, to further elucidate the disease modifying benefits of this drug class and those who will benefit most from it.
5 citations
References
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TL;DR: This integrating paradigm provides a new conceptual framework for future research and drug discovery in diabetes-specific microvascular disease and seems to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain.
Abstract: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.
8,289 citations
TL;DR: The evidence in favour of alternative macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 is assessed, and its limits and relevance to a range of immune and inflammatory conditions are defined.
Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
5,930 citations
TL;DR: Patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.
Abstract: BackgroundCanagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. MethodsThe CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. ResultsThe mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% c...
4,842 citations
University of Texas Southwestern Medical Center1, Harvard University2, Novo Nordisk3, University of Erlangen-Nuremberg4, Ruhr University Bochum5, Cleveland Clinic6, University of London7, Imperial College London8, George Washington University9, University of Toronto10, University of North Carolina at Chapel Hill11
TL;DR: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, orNonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.
Abstract: BackgroundThe cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. MethodsIn this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. ResultsA total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo ...
4,409 citations
TL;DR: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, orNonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semag lutide.
Abstract: BackgroundRegulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. MethodsWe randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. ResultsAt baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 10...
3,551 citations