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Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community.

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Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min–1·1.73 m–2and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL·min–1·1.73 m–2). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.

Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of heart failure, particularly when blood pressure is minimally affected, are not known.

Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzyme sphingosine kinase 1 and its functional antagonist S1P phosphohydrolase-1. The intracellular localization of S1P phosphohydrolase-1 necessitates the import of extracellular S1P into the intracellular compartment before its degradation. The present investigation proposes that the cystic fibrosis transmembrane conductance regulator transports extracellular S1P and hence modulates microvascular S1P signaling in health and disease.

Background:Stem cell antigen-1 (Sca-1)-expressing progenitor cells contribute to vessel remodeling by differentiating into vascular smooth muscle cells and related myofibroblast-like progeny. However, the functional role for Sca-1 expression in vessel remodeling has not been examined. Here, we assessed the requirement for vascular Sca-1 using a mouse model of Sca-1 deficiency.Methods & Results:Male and female Sca-1-deficient mice (Sca1KO) and C57BL/6N wild-type mice (WT) controls, aged 12-14-wk, were subjected to wire denudation injury of the left common carotid artery. Sca1KO displayed larger neointima at 14d post-injury [35±3mm2vs.25±3mm2, p<0.05, n=11-12/group], and more adventitial matrix at 8d [87±3mm2vs.58±4mm2, p<0.001, n=9-11/group] and 14d post-injury [109±10mm2vs.51±11mm2, p<0.01, n=11-12/group] by Masson’s trichrome staining. Underlying these differences, cell numbers per cross-section were increased in adventitia at 8d [649±27 vs.435±30, p<0.001, n=9-11/group] and 14d post-injury [778±45 vs.485±47, p<0.001, n=11-12/group]. Non-leukocyte proliferation by CD45-Ki67+staining was increased 1.8-fold in neointima [p<0.01, n=9-11/group] and 1.4-fold in adventitia [p<0.05, n=9-11/group] at 8d post-injury in Sca1KO vs.WT. Cell-type analyses of Sca1KO vs.WT revealed increased pro-fibrotic vimentin+cell proportions at 8d [1.4-fold in neointima, p<0.05; 2.5-fold in media, p<0.001; 1.8-fold in adventitia, p<0.001; n=9-11/group] and 14d post-injury [1.5-fold in neointima, p<0.05; 1.8-fold in media, p<0.05; 1.9-fold in adventitia, p<0.001; n=11-12/group]. CD45+leukocyte proportions were increased 1.5-fold in neointima [p<0.01, n=9-11/group] and 1.4-fold in adventitia [p<0.01, n=9-11/group] at 8d post-injury, which was also increased 1.5-fold in adventitia by 14d [p<0.01, n=11-12/group].Conclusion:Taken together, our findings suggest that the loss of Sca-1 worsens remodeling by disinhibiting proliferative, pro-fibrotic, and immune responses to injury, demonstrating a critical role for vascular Sca-1 expression, which may inform novel strategies for the prevention and treatment of vessel remodeling.

Background:B-cells have been shown to serve pathogenic roles in heart failure through cardiac-specific monocyte mobilization and autoantibody deposition. Beyond this, we recently showed that mice with hypomorphic c-Myb activity (c-mybh/h) have reduced B-cells and that B-cell deficiency is associated with increased sodium- and water-excretion and reduced blood pressure. Here, we determine the relevance of these responses in an experimental model of heart failure.Methods & Results:C57BL/6J wild-type (WT) and B-cell deficient c-mybh/hmice (male and female; aged 10-12 weeks) underwent either: (i) permanent LAD ligation to induce myocardial infarction (MI); or (ii) sham surgery. Echocardiography showed that B-cell deficiency preserved ejection fraction (53±2 vs. 44±2 %; N=6-7/group; P<0.01) and limited pathologic remodeling with reduced LVID (end-diastolic: 4.9±0.1 vs. 5.5±0.1 mm; N=6-7/group; P<0.01; end-systolic: 3.8±0.2 vs. 4.5±0.1 mm; N=6-7/group; P<0.001) at 4-weeks post-MI compared to WT. Heart weight/tibia length and right lung weight/tibia length ratios (g/mm; P<0.01), as well as pleural effusion volumes (μl; P<0.05) were increased post-MI in WT, rather than c-mybh/hmice. Indeed, mice with B-cell deficiency manifest reduced right lung weight/tibia length ratio (0.005±0.000 vs. 0.009±0.001 g/mm; N=5-6/group; P<0.01) and pleural effusion volume (17±6 vs. 55±18 μl; N=6-7/group; P<0.06) post-MI compared to WT. Underlying this decongestion, metabolic cage studies revealed that B-cell deficient mice had sustained increases in 24-h urine volume/body weight and 24-h sodium excretion/body weight ratios, which correlated with ejection fraction 4-weeks post-MI (r=0.53; N=13 pairs; P<0.05; and r=0.50; N=13 pairs; P<0.05, respectively).Conclusion:Together, these data show that B-cells play a role in sodium- and water-retention, and consequently, extracellular fluid volume expansion and congestion post-MI, and suggest that B-cells may represent a therapeutic target in heart failure.

Introduction:For older patients with type 2 diabetes, treatments that minimize the risk of hypoglycemia and provide benefits in terms of comorbidities, while optimizing glycemic control, are particularly important. Semaglutide, a glucagon-like peptide-1 receptor agonist available as a once-weekly (OW) subcutaneous and once-daily oral formulation, reduces HbA1cand body weight with a low risk of hypoglycemia. In addition, major adverse cardiovascular events (MACE) were reduced in SUSTAIN 6 (OW semaglutide; significant) and PIONEER 6 (oral semaglutide; not significant) vs placebo. The aim of this post hocanalysis was to evaluate cardiovascular (CV), metabolic and safety outcomes with semaglutide according to age.Methods:Subgroup analyses for semaglutide vs placebo by age as quartiles (≤60 years; >60 years to ≤65; >65 years to ≤70 years; >70 years) were performed for pooled SUSTAIN 6 and PIONEER 6 data in relation to: CV (3-point and individual MACE components), metabolic (change in HbA1c, body weight) and safety (severe hypoglycemia, serious adverse events [SAEs]) outcomes.Results:In patients treated with semaglutide (n=3,239) vs placebo (n=3,241), the reduction in MACE and individual components of MACE was consistent across age subgroups (pinteraction>0.05 for all; Table). Minor heterogeneity for change in HbA1cfrom baseline was observed with semaglutide vs placebo across the four age subgroups (pinteraction=0.01). Weight reduction with semaglutide vs placebo did not differ across age subgroups. Semaglutide (vs placebo) did not result in an increase in severe hypoglycemia or SAEs in any of the age subgroups (Table).Conclusions:This post hoccombined analysis of SUSTAIN 6 and PIONEER 6 indicates that the CV and metabolic benefits and the safety profile of semaglutide (vs placebo) align with the drug class and were consistent across age subgroups.

Introduction:Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have individually shown cardiovascular benefits in patients with type 2 diabetes (T2D). SGLT2i also reduced events in patients with reduced ejection fraction heart failure, with or without T2D. However, it is not known whether the cardiovascular effects of SGLT2i and GLP-1RA are through shared or distinct mechanisms, and whether combining these agents would confer additive cardioprotection against ischemia-reperfusion injury (IRI) in the absence of diabetes.Methods & Results:Non-diabetic male C56BL/6-J mice randomized to 7-d treatment with SGLT2i dapagliflozin (Dapa) and/or GLP-1RA exenatide (Ex-4) or vehicle-controls underwent IRI via 30-min left anterior descending (LAD) artery ligation. Analysis of late cardiac remodeling at d-28 post-IRI revealed preserved ejection fraction (EF) in mice treated with Dapa+Ex4 (50±2%; n=12, P<0.05) vs.vehicle-treated controls (36±3; n=11, P<0.05), whereas treatment with Dapa- and Ex-4-alone showed no such benefit. These improvements in LV function were associated with reduced infarct size (%LV) in mice treated with Dapa+Ex4 (17±3; n=8, P<0.001) and Ex-4-alone (29±3; n=10, P<0.05) vs.vehicle-control (44±5; n=10). Metabolome and merged proteome+phosphoproteome analyses revealed systemic and myocardial metabolic modulation following 7-d Dapa+Ex-4 treatment, with distinct enrichment of mitochondrial electron transport chain pathways. Cardiomyocytes isolated from mice treated in vivofor 7-d also showed enhanced aerobic respiration as measured by oxygen consumption rate (OCR;17.6±1.7 pmol/min/μg protein; n=4 mice) compared Dapa- (8.9±0.8; n=3, P<0.001), Ex-4-alone (11.4±0.9; n=3, P<0.01) and vehicle-treated controls (9.5±0.6; n=5, P<0.001).Conclusions:Combined therapy with SGLT2i+GLP-1RA in non-diabetic mice better prevented late cardiac remodeling after IRI compared to either agent alone or vehicle controls. These findings provide rationale for the combined use of these agents in a condition (IRI) for which there remains no approved therapy, and implicate metabolic modulation as a cardioprotective strategy in the absence of diabetes.

Background:Arginine vasopressin, through vasopressin receptor 2 (AVP-V2R), regulates water reabsorption via aquaporin-2 and sodium reabsorption via several mechanisms. We recently implicated V2R, and its transcriptional downregulation, in a model of B-cell deficiency with increased sodium- and water-excretion and reduced blood pressure (BP). Here, we identify mechanisms underlying the immunoregulation of V2R transcription and evaluate the importance of V2R in BP regulation.Methods & Results:Using an Avpr2promoter-luciferase reporter in an immortalized mouse inner medullary collecting duct cell line [mIMCD-3], we found that IL-6 (100ng/mL), a stimulator of NF-κβ signaling, increased promoter-reporter activity (10.4±3.2 vs4.0±0.5 RLU; N=2-3/group); while PDTC (60μM), an inhibitor of NF-κβ signaling, reduced promoter-reporter activity (2.2 vs4.0±0.5 RLU; N=1-3/group). Importantly, single point mutations in two putative NF-κβ binding sites in the proximal Avpr2promoter also reduced promoter activity (2.3±0.6 vs4.0±0.5 RLU; N=2-3/group), and blocked the stimulatory effect of IL-6 (2.4 vs2.3±0.6 RLU; N=1-2/group). An anti-IL-6 receptor antibody (10μg/mL vsisotype, 10μg/mL) also abolished the stimulatory effect of IL-6 on promoter activity (3.2 vs9.1 RLU; N=1/group). To determine the role of V2R in BP regulation, wild-type C57BL/6J mice (male and female; aged 10-wk) were randomized to (i) Tolvaptan (TOL), a selective V2R-antagonist or (ii) DMSO/glycerol control (50/50) via osmotic mini-pump (0.0375mg/d). Invasive hemodynamics 12-d post-implant revealed reduced mean arterial pressure (MAP) in TOL-treated mice (76±3 vs86±3 mmHg; N=4-5/group; P<0.05), while metabolic cage studies 8-11-d post-implant showed higher 24-h urine volume/body weight (UV/BW; 0.07±0.00 vs0.05±0.00 mL/g; N=4-5/group; P<0.05) and 24-h sodium excretion/BW (0.25±0.01 vs0.17±0.01 mg/d/g; N=4-5/group; P<0.01). Correlation analyses revealed inverse relationships between MAP and 24-h UV/BW (r=-0.65; N=9 pairs; P<0.05) and 24-h sodium excretion/BW (r=-0.64; N=9 pairs; P<0.05).Conclusion:These studies suggest that the V2R promoter is responsive to NF-κβ signaling, and that V2R serves a role in BP homeostasis through sodium- and water-handling.