bims-hafaim 2021-12-26 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–12–26
thirteen papers selected by
Kyle McCommis, Saint Louis University

Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport.
Thymoquinone ameliorates pressure overload-induced cardiac hypertrophy by activating the AMPK signalling pathway.
Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice.
Cardiac Metabolism in Sepsis.
GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway.
Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.
Mitochondrial dysfunction and mitochondrial therapies in heart failure.
The Evolution of Sodium-Glucose Co-Transporter-2 Inhibitors in Heart Failure.
Efficacy of new medical therapies in patients with heart failure, reduced ejection fraction and chronic kidney disease already receiving neurohormonal inhibitors: a network meta-analysis.
Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A protocol for meta-analysis.
Ketone Body Metabolism in the Ischemic Heart.
Inhibition of mTOR or MAPK ameliorates vmhcl/myh7 cardiomyopathy in zebrafish.
Three new categories of hypoglycaemic agents and various cardiovascular diseases: A meta-analysis.

Metabolites. 2021 Dec 19. pii: 889. [Epub ahead of print]11(12):

Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport.

Tatsuya Iso, Masahiko Kurabayashi.

  The heart is a metabolic omnivore that combusts a considerable amount of energy substrates, mainly long-chain fatty acids (FAs) and others such as glucose, lactate, ketone bodies, and amino acids. There is emerging evidence that muscle-type continuous capillaries comprise the rate-limiting barrier that regulates FA uptake into cardiomyocytes. The transport of FAs across the capillary endothelium is composed of three major steps-the lipolysis of triglyceride on the luminal side of the endothelium, FA uptake by the plasma membrane, and intracellular FA transport by cytosolic proteins. In the heart, impaired trans-endothelial FA (TEFA) transport causes reduced FA uptake, with a compensatory increase in glucose use. In most cases, mice with reduced FA uptake exhibit preserved cardiac function under unstressed conditions. When the workload is increased, however, the total energy supply relative to its demand (estimated with pool size in the tricarboxylic acid (TCA) cycle) is significantly diminished, resulting in contractile dysfunction. The supplementation of alternative fuels, such as medium-chain FAs and ketone bodies, at least partially restores contractile dysfunction, indicating that energy insufficiency due to reduced FA supply is the predominant cause of cardiac dysfunction. Based on recent in vivo findings, this review provides the following information related to TEFA transport: (1) the mechanisms of FA uptake by the heart, including TEFA transport; (2) the molecular mechanisms underlying the induction of genes associated with TEFA transport; (3) in vivo cardiac metabolism and contractile function in mice with reduced TEFA transport under unstressed conditions; and (4) in vivo contractile dysfunction in mice with reduced TEFA transport under diseased conditions, including an increased afterload and streptozotocin-induced diabetes.

Keywords:  TCA cycle; capillary endothelium; cardiac metabolism; contractile function; fatty acid; glucose; pool size; trans-endothelial fatty acid transport

DOI:  https://doi.org/10.3390/metabo11120889
J Cell Mol Med. 2021 Dec 24.

Thymoquinone ameliorates pressure overload-induced cardiac hypertrophy by activating the AMPK signalling pathway.

Heng Chen, Chengui Zhuo, Aohan Zu, Shuai Yuan, Han Zhang, Jianqiang Zhao, Liangrong Zheng.

  Prolonged pathological myocardial hypertrophy leads to end-stage heart failure. Thymoquinone (TQ), a bioactive component extracted from Nigella sativa seeds, is extensively used in ethnomedicine to treat a broad spectrum of disorders. However, it remains unclear whether TQ protects the heart from pathological hypertrophy. This study was conducted to examine the potential utility of TQ for treatment of pathological cardiac hypertrophy and if so, to elucidate the underlying mechanisms. Male C57BL/6J mice underwent either transverse aortic constriction (TAC) or sham operation, followed by TQ treatment for six consecutive weeks. In vitro experiments consisted of neonatal rat cardiomyocytes (NRCMs) that were exposed to phenylephrine (PE) stimulation to induce cardiomyocyte hypertrophy. In this study, we observed that systemic administration of TQ preserved cardiac contractile function, and alleviated cardiac hypertrophy, fibrosis and oxidative stress in TAC-challenged mice. The in vitro experiments showed that TQ treatment attenuated the PE-induced hypertrophic response in NRCMs. Mechanistical experiments showed that supplementation of TQ induced reactivation of the AMP-activated protein kinase (AMPK) with concomitant inhibition of ERK 1/2, p38 and JNK1/2 MAPK cascades. Furthermore, we demonstrated that compound C, an AMPK inhibitor, abolished the protective effects of TQ in in vivo and in vitro experiments. Altogether, our study disclosed that TQ provides protection against myocardial hypertrophy in an AMPK-dependent manner and identified it as a promising agent for the treatment of myocardial hypertrophy.

Keywords:  AMPK; cardiac hypertrophy; fibrosis; heart failure; oxidative stress; thymoquinone

DOI:  https://doi.org/10.1111/jcmm.17138
Metabolites. 2021 Dec 17. pii: 881. [Epub ahead of print]11(12):

Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice.

Yogi Umbarawan, Ryo Kawakami, Mas Rizky A A Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hirofumi Hanaoka, Takako Hishiki, Noriyo Hayakawa, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi, Tatsuya Iso.

  Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport with marked enhancement of glucose use. In this study, we explore whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. We found that cardiac contractile dysfunction had deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake was not reduced in CD36KO-STZ hearts, the total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. The isotopomer analysis with 13C6-glucose revealed that accelerated glycolysis, estimated by enrichment of 13C2-citrate and 13C2-malate, was markedly suppressed in CD36KO-STZ hearts. Levels of ceramides, which are cardiotoxic lipids, were not elevated in CD36KO-STZ hearts compared to wild-type-STZ ones. Furthermore, increased energy demand by transverse aortic constriction resulted in synergistic exacerbation of contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis; therefore, the limitation of FA utilization is detrimental to cardiac energetics in this model of diabetic cardiomyopathy.

Keywords:  CD36; ceramide; diabetic cardiomyopathy; fatty acid; glucose; metabolomics; streptozotocin

DOI:  https://doi.org/10.3390/metabo11120881
Metabolites. 2021 Dec 06. pii: 846. [Epub ahead of print]11(12):

Cardiac Metabolism in Sepsis.

Satoshi Kawaguchi, Motoi Okada.

  The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis.

Keywords:  ATP; SICM; metabolic switch; sepsis; β-adrenergic receptor

DOI:  https://doi.org/10.3390/metabo11120846
iScience. 2021 Dec 17. 24(12): 103517

GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway.

Akihito Ishikita, Shouji Matsushima, Soichiro Ikeda, Kosuke Okabe, Ryohei Nishimura, Tomonori Tadokoro, Nobuyuki Enzan, Taishi Yamamoto, Masashi Sada, Yoshitomo Tsutsui, Ryo Miyake, Masataka Ikeda, Tomomi Ide, Shintaro Kinugawa, Hiroyuki Tsutsui.

  Molecular mechanisms mediating cardiac hypertrophy by glucose metabolism are incompletely understood. Hexosamine biosynthesis pathway (HBP), an accessory pathway of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. We here demonstrate that glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical HBP enzyme, is a major isoform of GFAT in the heart and is increased in response to several hypertrophic stimuli, including isoproterenol (ISO). Knockdown of GFAT2 suppresses ISO-induced cardiomyocyte hypertrophy, accompanied by suppression of Akt O-GlcNAcylation and activation. Knockdown of GFAT2 does not affect anti-hypertrophic effect by Akt inhibition. Administration of glucosamine, a substrate of HBP, induces protein O-GlcNAcylation, Akt activation, and cardiomyocyte hypertrophy. In mice, 6-diazo-5-oxo-L-norleucine, an inhibitor of GFAT, attenuates ISO-induced protein O-GlcNAcylation, Akt activation, and cardiac hypertrophy. Our results demonstrate that GFAT2 mediates cardiomyocyte hypertrophy by HBP-O-GlcNAcylation-Akt pathway and could be a critical therapeutic target of cardiac hypertrophy.

Keywords:  Cell biology; Classification Description: Cellular physiology; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2021.103517
Elife. 2021 Dec 23. pii: e60311. [Epub ahead of print]10

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.

Ienglam Lei, Shuo Tian, Wenbin Gao, Liu Liu, Yijing Guo, Paul Tang, Eugene Chen, Zhong Wang.

  Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.60311
Pharmacol Res. 2021 Dec 17. pii: S1043-6618(21)00622-8. [Epub ahead of print]175 106038

Mitochondrial dysfunction and mitochondrial therapies in heart failure.

Chennan Wu, Zhen Zhang, Weidong Zhang, Xia Liu.

  Cardiovascular diseases remain the leading cause of death worldwide in the last decade, accompanied by immense health and economic burdens. Heart failure (HF), as the terminal stage of many cardiovascular diseases, is a common, intractable, and costly medical condition. Despite significant improvements in pharmacologic and device therapies over the years, life expectancy for this disease remains poor. Current therapies have not reversed the trends in morbidity and mortality as expected. Thus, there is an urgent need for novel potential therapeutic agents. Although the pathophysiology of the failing heart is extraordinarily complex, targeting mitochondrial dysfunction can be an effective approach for potential treatment. Increasing evidence has shown that mitochondrial abnormalities, including altered metabolic substrate utilization, impaired mitochondrial oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) formation, and aberrant mitochondrial dynamics, are closely related to HF. Here, we reviewed the findings on the role of mitochondrial dysfunction in HF, along with novel mitochondrial therapeutics and their pharmacological effects.

Keywords:  Energy metabolism; Heart failure; Mitochondrial dynamics; Mitochondrial dysfunction; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.phrs.2021.106038
Cureus. 2021 Nov;13(11): e19379

The Evolution of Sodium-Glucose Co-Transporter-2 Inhibitors in Heart Failure.

Olusayo Fadiran, Chike Nwabuo.

  Sodium-glucose co-transporter-2 (SGLT2) inhibitors have evolved over the years, based on data from several randomized, double-blinded, placebo-controlled clinical trials. Formerly used primarily for blood sugar control in patients with diabetes, they are now used to decrease the risk of hospitalization for heart failure (HF), or of death from cardiovascular (CV) causes, in patients with heart failure with reduced ejection fraction (HFrEF). They have also been shown to slow the progression of renal disease and prevent death related to renal causes in patients with chronic kidney disease (CKD). They are currently being studied to decrease the risk of HF hospitalization in patients with preserved ejection fraction subtype and have shown positive results. The transition of SGLT2 from a medication used in diabetes to an established HF medication was a result of the hypothesis generated from the analysis of earlier trials in diabetic patients and further testing of this hypothesis in an HF population. By way of this review, we aim to highlight the rationale for the paradigm shift of SGLT2 inhibitors from their use in diabetic patients to their use in all patients with HF, regardless of the presence of diabetes. To support our recommendation, we'll present detailed results of several major clinical trials and a meta-analysis study that led to this discovery, along with clinical indication for the same.

Keywords:  diabetes type 2; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; review of clinical trials; sodium-glucose cotransporter-2 (sglt-2) inhibitors

DOI:  https://doi.org/10.7759/cureus.19379
Eur Heart J Cardiovasc Pharmacother. 2021 Dec 20. pii: pvab088. [Epub ahead of print]

Efficacy of new medical therapies in patients with heart failure, reduced ejection fraction and chronic kidney disease already receiving neurohormonal inhibitors: a network meta-analysis.

Pietro Ameri, Vincenzo De Marzo, Giuseppe Biondi Zoccai, Lucia Tricarico, Michele Correale, Natale Daniele Brunetti, Marco Canepa, Gaetano Maria De Ferrari, Davide Castagno, Italo Porto.

   AIMS: We assessed the efficacy of the drugs developed after neurohormonal inhibitors (NEUi) in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant chronic kidney disease (CKD).
METHODS AND RESULTS: The literature was systematically searched for phase 3 randomized controlled trials (RCTs) involving ≥90% patients with left ventricular ejection fraction <45%, of whom <30% were acutely decompensated, and with published information about the subgroup of estimated glomerular filtration rate <60 mL/min/1.73m2. Six RCTs were included in a study-level network meta-analysis evaluating the effect of NEUi, ivabradine, angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv mecarbil (OM) on a composite outcome of cardiovascular death or hospitalization for heart failure. In a fixed-effects model, SGLT2i (HR 0.78, 95%CrI 0.69-0.89), ARNI (HR 0.79, 95%CrI 0.69-0.90), and ivabradine (HR 0.82, 95%CrI 0.69-0.98) decreased the risk of the composite outcome vs. NEUi, whereas OM did not (HR 0.98, 95%CrI 0.89-1.10). A trend for improved outcome was also found for vericiguat (HR 0.90, 95%CrI 0.80-1.00). In indirect comparisons, both SLGT2i (HR 0.80, 95%CrI 0.68-0.94) and ARNI (HR 0.80, 95%CrI 0.68-0.95) reduced the risk vs. OM; furthermore, there was a trend for a greater benefit of SGLT2i vs. vericiguat (HR 0.88, 95%CrI 0.73-1.00) and ivabradine vs. OM (HR 0.84, 95%CrI 0.68-1.00). Results were comparable in a random-effects model and in sensitivity analyses. SUCRA scores were 81.8%, 80.8%, 68.9%, 44.2%, 16.6%, and 7.8% for SGLT2i, ARNI, ivabradine, vericiguat, OM, and NEUi, respectively.
CONCLUSION: Expanding pharmacotherapy beyond NEUi improves outcomes in HFrEF with CKD.

Keywords:  ARNI; Chronic kidney disease; SGLT2; ivabradine; omecamtiv; vericiguat

DOI:  https://doi.org/10.1093/ehjcvp/pvab088
Medicine (Baltimore). 2021 Dec 23. 100(51): e28448

Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A protocol for meta-analysis.

Hidekatsu Fukuta, Hiromi Hagiwara, Takeshi Kamiya.

BACKGROUND: Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium-glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, the results are inconsistent due partly to limited power. The purpose of this meta-analysis is to evaluate the efficacy and safety of SGLT-2 inhibitors in HFpEF patients.
METHODS: This meta-analysis will include RCTs examining the effects of SGLT-2 inhibitors on HF severity and health-related quality of life in HFpEF patients. Information of studies will be collected from electronic databases. The primary outcome will be HF severity (plasma B-type natriuretic peptide levels and exercise capacity assessed as 6-minute walk distance). The secondary outcome will be health-related quality of life. The safety outcomes will be all-cause death, HF hospitalization, hypotension, acute renal failure, diabetic ketoacidosis, and urinary tract infection.
DISCUSSION: This meta-analysis will evaluate the efficacy and safety of SGLT-2 inhibitors in HFpEF patients, providing evidence to the clinical use of SGLT-2 inhibitors in these patients.
SYSTEMATIC REVIEW REGISTRATION: INPLASY2021120033.

DOI: https://doi.org/10.1097/MD.0000000000028448
Front Cardiovasc Med. 2021 ;8 789458

Ketone Body Metabolism in the Ischemic Heart.

Stephen C Kolwicz.

  Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

Keywords:  beta-hydroxybutyrate; hypoxia; ischemia; ketosis; reperfusion

DOI:  https://doi.org/10.3389/fcvm.2021.789458
JCI Insight. 2021 Dec 22. pii: e154215. [Epub ahead of print]6(24):

Inhibition of mTOR or MAPK ameliorates vmhcl/myh7 cardiomyopathy in zebrafish.

Haisong Bu, Yonghe Ding, Jiarong Li, Ping Zhu, Yu-Huan Shih, Mingmin Wang, Yuji Zhang, Xueying Lin, Xiaolei Xu.

  Myosin heavy chain 7 (MYH7) is a major causative gene for hypertrophic cardiomyopathy, but the affected signaling pathways and therapeutics remain elusive. In this research, we identified ventricle myosin heavy chain like (vmhcl) as a zebrafish homolog of human MYH7, and we generated vmhcl frameshift mutants. We noted vmhcl-based embryonic cardiac dysfunction (VEC) in the vmhcl homozygous mutants and vmhcl-based adult cardiomyopathy (VAC) phenotypes in the vmhcl heterozygous mutants. Using the VEC model, we assessed 7 known cardiomyopathy signaling pathways pharmacologically and 11 candidate genes genetically via CRISPR/Cas9 genome editing technology based on microhomology-mediated end joining (MMEJ). Both studies converged on therapeutic benefits of mTOR or mitogen-activated protein kinase (MAPK) inhibition of VEC. While mTOR inhibition rescued the enlarged nuclear size of cardiomyocytes, MAPK inhibition restored the prolonged cell shape in the VEC model. The therapeutic effects of mTOR and MAPK inhibition were later validated in the VAC model. Together, vmhcl/myh7 loss of function is sufficient to induce cardiomyopathy in zebrafish. The VEC and VAC models in zebrafish are amenable to both efficient genetic and chemical genetic tools, offering a rapid in vivo platform for discovering candidate signaling pathways of MYH7 cardiomyopathy.

Keywords:  Cardiology; Cardiovascular disease; Genetic diseases; Genetics

DOI:  https://doi.org/10.1172/jci.insight.154215
J Clin Pharm Ther. 2021 Dec 23.

Three new categories of hypoglycaemic agents and various cardiovascular diseases: A meta-analysis.

Xiao-Xian Liao, Wen-Qiang Li, Zhi-Ke Peng, Hong-Bin Yu, Jie Tan.

   WHAT IS KNOWN AND OBJECTIVE: New hypoglycaemic agents consist of dipeptidyl peptidase four inhibitors (DPP4is), glucagon-like peptide one receptor agonists (GLP1RAs) and sodium-glucose cotransporter two inhibitors (SGLT2is). We aimed to define the association between each category of these new hypoglycaemic drugs and various cardiovascular diseases.
METHODS: Large randomized trials comparing DPP4is, GLP1RAs or SGLT2is with placebo were included. Outcomes of interest were 95 kinds of cardiovascular diseases. Meta-analysis was conducted to generate pooled risk ratio (RR) and 95% confidence interval (CI).
RESULTS AND DISCUSSION: Twenty-one large randomized trials were included in this meta-analysis. Compared with placebo, SGLT2is were associated with the lower risks of hypertension (RR 0.67, 95% CI 0.49-0.93), atrial fibrillation (RR 0.78, 95% CI 0.67-0.91), bradycardia (RR 0.60, 95% CI 0.40-0.89) and heart failure (RR 0.74, 95% CI 0.68-0.80); GLP1RAs were associated with the lower risk of peripheral arterial occlusive disease (RR 0.73, 95% CI 0.56-0.97) and with the higher risk of deep vein thrombosis (RR 2.12, 95% CI 1.32-3.4), while DPP4is were associated with the lower risk of peripheral ischaemia (RR 0.57, 95% CI 0.37-0.89).
WHAT IS NEW AND CONCLUSIONS: Our meta-analysis revealed that SGLT2is were associated with the lower risks of hypertension, atrial fibrillation, bradycardia and heart failure; GLP1RAs were associated with the lower risk of peripheral arterial occlusive disease and with the higher risk of deep vein thrombosis, while DPP4is were associated with the lower risk of peripheral ischaemia. These findings propose that each category of these new hypoglycaemic agents should be avoided or preferred in patients at high risks of specific cardiovascular diseases.

Keywords:  DPP4is; GLP1RAs; SGLT2is; atrial fibrillation; cardiovascular diseases; deep vein thrombosis; hypertension

DOI:  https://doi.org/10.1111/jcpt.13588