P5997GLP-1(28-36) prevents progression of ischemic heart failure in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M A Siraj ◽  
A Momen ◽  
D Zarrin Khat ◽  
M Husain
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Weight Ratio ◽  
Neutral Endopeptidase ◽  
Major Adverse Cardiovascular Events ◽  
Lv Function ◽  
Triphenyltetrazolium Chloride ◽  
Heart Research ◽  
Cardiovascular Outcome Trials ◽  
Beneficial Effects

Abstract Background Glucagon-like peptide-1 (GLP-1), its metabolites and related drugs have demonstrated cardioprotective benefits in several animal models of cardiovascular disease (CVD) and select clinical trials. Indeed, large cardiovascular outcome trials (CVOT) of GLP-1 analogs showed significant reductions in major adverse cardiovascular events (MACE). However, smaller studies in patients with heart failure (HF) (e.g. FIGHT), and secondary analyses of some CVOT (e.g. LEADER), have suggested that the cardiovascular benefits of GLP-1 analogs may be muted in select patients. Speculating on how this may be due to undesirable increases in heart rate caused by activation of sinoatrial GLP-1 receptors (Glp1r), we have explored the Glp1r-independent cardioprotective actions of GLP-1(28–36), a neutral endopeptidase (NEP)-derived metabolite of GLP-1. We have shown that the cardioprotective effects of GLP-1(28–36) are mediated by mitochondrial trifunctional protein-α (MTPα)-dependent metabolic shift from fatty acid- to glucose oxidation in coronary vascular cells. As metabolic perturbations are believed to contribute to the pathophysiology of HF, we hypothesized that treatment with GLP-1(28–36) may have beneficial effects on this condition. Purpose To evaluate if treatment with GLP-1(28–36) can prevent onset of HF and/or reverse established HF in a post-MI mouse model. Methods and results Permanent LAD ligation was performed in 10–12wk old male C57BL/6J wild-type mice (wt). Immediately post-MI, mice were assigned to receive either GLP-1(28–36) or scrambled peptide [Scram(28–36)] at 18.5nmol/kg/d (N=30/group) subcutaneously (s.c.) via osmotic mini-pumps for 4wk. Although, treatment with GLP-1(28–36) did not improve post-MI survival, triphenyltetrazolium chloride (TTC)-stained hearts 28d post-MI reveal smaller infarct size in GLP-1(28–36)- vs. Scram(28–36)-treated mice (35.3±1.9% vs. 41.2±1.7%, N=12–15/group, P<0.05). Echocardiography at 28d post-MI showed improved LVEF in mice treated with GLP-1(2–36) (30.1±2.3% vs. 24.2±3.7%, N=12–15/group, P<0.05). Similarly, treatment with GLP-1(28–36) reduced heart/body weight ratio (7.9±0.3 vs. 8.8±0.4 mg/g, N=12–15/group, P<0.05). Next, we tested if GLP-1(28–36) might reverse ischemic HF in this model. After permanent LAD ligation of 10–12wk old male wt mice, only those with echocardiography-defined LVEF between 20–35% at 28d post-MI were randomized to treatment with GLP-1(28–36) or Scram(28–36) [18.5nmol/kg/d (N=15/group)] via s.c. mini-pumps for 4wk. Echocardiography at 56d post-MI (i.e. 28d post-treatment start) revealed that GLP-1(28–36) preserved LV function with no deterioration in LVEF vs. Scram(28–36)-treated controls [−3.1±4.9% vs. −22.8±4%, relative change, N=15/group, P<0.001]. Conclusion In a post-MI mouse model of HF, treatment with GLP-1(28–36) prevents progression to HF, and preserves LV function after the development of established HF. Acknowledgement/Funding This study was funded by a Fellowship from Ted Rogers Centre for Heart Research and a Project Grant from Heart and Stroke Foundation, Canada

scholarly journals Comparison of Repeated Doses of C-kit-Positive Cardiac Cells versus a Single Equivalent Combined Dose in a Murine Model of Chronic Ischemic Cardiomyopathy

2021 ◽  
Vol 22 (6) ◽  
pp. 3145
Author(s):  
Qianhong Li ◽  
Yiru Guo ◽  
Yibing Nong ◽  
Alex Tomlin ◽  
Anna Gumpert ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Ischemic Cardiomyopathy ◽  
Dose Group ◽  
Weight Ratio ◽  
Cardiac Cells ◽  
Vehicle Group ◽  
Lv Function ◽  
Body Weight Ratio ◽  
Beneficial Effects ◽  
The Difference

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (−32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and −28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.

Abstract 1876: Functional Effect of Chronic Urotensin II Receptor Antagonist on L-Type Ca 2+ Current in Mouse Model of Progressive Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Peng Zhou ◽  
Heng-Jie Cheng ◽  
Michael Cross ◽  
Michael F Callahan ◽  
Bridget Brosnihan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Receptor Antagonist ◽  
Weight Ratio ◽  
Heart Association ◽  
Cell Voltage ◽  
Fold Increase ◽  
Left Ventricular ◽  
Lv Function ◽  
List Type ◽  
Urotensin Ii

Voltage-gated Ca 2+ channels play fundamental roles in the regulation of cardiac function by various neurotransmitters. Recently, we have shown that urotensin II (UII), a potent vasoconstrictor, inhibits L-type Ca 2+ current (I Ca,L ) and produces negative inotropic action. In heart failure (HF), the UII-mediated pathway is upregulated, suggesting a therapeutic value of UII receptor antagonist (UII-ANT) for HF. However, the role and mechanism of chronic UII-ANT in HF is unclear. We tested the hypothesis that chronic UII-ANT may improve cardiac I Ca,L , preventing β-adrenergic deregulation on I Ca,L and limit HF progression. We examined plasma levels of norepinephrine (NE), left ventricular (LV) function, and myocyte I Ca,L responses to isoproterenol (ISO) in 3 age-matched groups of mice: HF (n = 7), 2 months after ISO (150 mg/kg sq for 2 days); HF/UII-ANT (n = 11), 1 month after receiving ISO, then urantide, a potent UII-ANT (10 −5 M/kg/day, sq via implanted osmotic mini pump), given for 1 month; and Controls (n = 7). I Ca,L was measured using whole-cell voltage clamp technique. Compared with controls, ISO-treated mice progressed to HF with 4.7-fold increase in plasma NE (18975 vs 4066 pg/ml) and LV dilatation associated with increased myocyte length (ML, 155 vs120 μm) and heart-to-body weight ratio (H/BW, 7.6 vs 5.5 g/kg). Stroke volume (SV, 30.3 vs 61.4 μl) and ejection fraction (EF, 39% vs 60%) were decreased. Compared with normal myocytes, in HF myocytes, I Ca,L was reduced (50%, 3.7 ± 0.2 vs 7.4 ± 0.2 pA/pF), and I Ca,L response to β-AR stimulation (ISO, 10 −8 M) was attenuated (11% vs 35%) (p < 0.01). In HF/UII-ANT mice, plasma NE (5148 pg/ml), SV (57.9 μl), and EF (57%) returned close to control levels with retained normal ML (124 μm) and H/BW (5.9 g/kg). Moreover, compared with controls, in HF/UII-ANT mice, ISO caused similar increases in the peak I Ca,L (32% vs 35%). Chronic UII-ANT treatment normalizes LV L-type Ca 2+ channel basal function and β-adrenergic regulation, leading to regression of LV and myocyte dysfunction and remodeling in mice with ISO-induced HF. This research has received full or partial funding support from the American Heart Association, AHA National Center.

4113Glucose lowering drugs or strategies, major adverse cardiovascular events and heart failure outcomes, and association with weight loss - meta-analysis of large cardiovascular outcome trials

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O R Ghosh-Swaby ◽  
S G Goodman ◽  
L A Leiter ◽  
A Cheng ◽  
K Connelly ◽  
...  
Keyword(s):  
Heart Failure ◽  
Weight Loss ◽  
Risk Reduction ◽  
Cardiovascular Events ◽  
Cardiovascular Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Cardiovascular Risk Reduction ◽  
Cardiovascular Outcome Trials ◽  
Lower Weight ◽  
Meta Regression

Abstract Background Glucose lowering drugs or strategies (GLDS) have varied effects on major adverse cardiovascular events (MACE) and heart failure (HF) in cardiovascular outcomes trials. Mechanisms driving cardiovascular risk reduction remain elusive. Methods We searched MEDLINE, PubMed, and meeting abstracts up to 11/21/2018 for large GLDS cardiovascular outcome trials (CVOTs) in patients with or at risk for type 2 diabetes. Primary endpoints of MACE and HF were evaluated with random effects risk ratios (RR) and explored by baseline CVD subgroups and meta-regression by weight change across treatment arms. Results In 27 GLDS CVOTs, a total 207,820 patients, median age 63 years, 64% male, 64% CVD and 11% with prior HF were studied over a mean 3.8 years with 20,118 (10%) patients having MACE and 7,212 (4%) a HF event. Compared with standard care, GLDS overall lowered MACE (RR 0.92, P<0.ehz745.01171) but not HF (RR 1.01, P=0.91). Across GLDS, the magnitude and directionality varied modestly for MACE RR (P-int=0.07) but markedly for HF (P-int<0.ehz745.01171). Meta-regression showed a change in HF RR by 6% (95% CI 3%-9%) per 1 kg weight gain/loss between treatment arms (P=0.0006; Figure). In 9 trials of GLDS that achieved marked weight loss (lifestyle, GLP1 agonists, SGLT2 inhibitors), MACE benefit was confined to patients with baseline CVD (RR 0.89 [0.84–0.95] versus without (RR 1.02 [0.91–1.15]; P-int=0.01) with consistent HF effect (RR 0.80 [0.72–0.88] vs RR 0.76 [0.56–1.03]; P-int=0.74). Heart Failure Risk and Changes in Weight Conclusion HF outcomes were improved with GLDS that lower weight. Among diabetes GLDS that lower weight, there was a robust risk reduction in atherothrombotic and heart failure events, with the MACE benefit confined to patients with established CVD. Acknowledgement/Funding Heart and Stroke Foundation

scholarly journals Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure

2008 ◽  
Vol 295 (5) ◽  
pp. H2149-H2155 ◽  
Author(s):  
Sharad Rastogi ◽  
Victor G. Sharov ◽  
Sudhish Mishra ◽  
Ramesh C. Gupta ◽  
Brent Blackburn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Oral Treatment ◽  
Capillary Density ◽  
Cellular Level ◽  
Left Ventricular ◽  
Lv Function ◽  
Systolic Volume ◽  
Moderate Heart Failure ◽  
Beneficial Effects ◽  
Lv Dysfunction

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs ( n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 ± 1% to 37 ± 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 ± 1% to 40 ± 1% with Ran + Ena and from 34 ± 1% to 41 ± 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.

scholarly journals Darbepoetin-α prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure

2008 ◽  
Vol 295 (6) ◽  
pp. H2475-H2482 ◽  
Author(s):  
Sharad Rastogi ◽  
Makoto Imai ◽  
Victor G. Sharov ◽  
Sudhish Mishra ◽  
Hani N. Sabbah
Keyword(s):  
Heart Failure ◽  
Caspase 3 ◽  
Hypoxia Inducible Factor ◽  
Left Ventricular ◽  
Stem Cell Marker ◽  
Lv Function ◽  
Systolic Volume ◽  
Beneficial Effects ◽  
End Diastolic Volume ◽  
End Systolic Volume

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-α (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) ∼25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 μg/kg, n = 7) or to no therapy (HF, n = 7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1α, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1α and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.

scholarly journals Series: Cardiovascular outcome trials for diabetes drugs Liraglutide and LEADER

2020 ◽  
Vol 20 (2) ◽  
pp. 142-144
Author(s):  
Miles Fisher
Keyword(s):  
Heart Failure ◽  
Cardiovascular Events ◽  
Cardiovascular Death ◽  
Cardiovascular Outcome ◽  
Secondary Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Cardiovascular Outcome Trials ◽  
Major Cardiovascular Events ◽  
Cardiovascular Outcome Trial ◽  
Outcome Trial

LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was an FDA-mandated cardiovascular outcome trial with liraglutide and was the first trial with a glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate a significant reduction in cardiovascular events. It compared liraglutide and placebo in 9,340 people with type 2 diabetes and either existing cardiovascular disease or age >60 years with at least one cardiovascular risk factor. LEADER demonstrated superiority for major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was not significantly reduced. Compared with the EMPA-REG OUTCOME trial, the curves for major adverse cardiovascular events in LEADER separated later, and the absence of a clear effect on hospitalisation for heart failure or on estimated glomerular filtration rate suggests that the mechanism of cardiovascular benefit for liraglutide was different from that for empagliflozin

Abstract 17087: VNS Induced Early Suppression of the Excessive Inflammatory Response May Contribute to its Beneficial Effects on Chronic Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Akiko Nishizaki ◽  
Keita Saku ◽  
Takuya Kishi ◽  
Tomomi Ide ◽  
Kenji Sunagawa
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Inflammatory Response ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Heart Weight ◽  
Lv Function ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Excessive Inflammatory Response

Background: The inflammatory response plays a pivotal role in the pathogenesis of chronic heart failure (CHF). Although vagal nerve stimulation (VNS) improves CHF, the central mechanism remains unclear. Since VNS exerts powerful anti-inflammatory effects, we investigated how VNS impacts on the inflammatory regulation and the development of CHF. Methods: In 8 weeks old Sprague-Dawley rats, we created large myocardial infarction (MI) and started VNS 2 weeks after MI. We adjusted the intensity of VNS below the threshold of bradycardia (20 Hz, 1.5±0.9 volts, 10 sec on, 50 sec off). In the first group (EARLY) (CHF: n=8, VNS: n=13), we continued VNS for 3 days and evaluated the early impact of VNS on inflammation on the 3rd day. In the second group (LATE) (CHF: n=13, VNS: n=13), we continued VNS for 4 weeks and evaluated cardiac remodeling and function on the last day. Results: In EARLY, hemodynamic parameters or plasma BNP as an index of CHF did not change significantly. In contrast, VNS halved the invasion of CD 68 positive cells in the left ventricle (LV) (CHF: 295.1±142.1, VNS: 110.7±59.6 counts/mm2, p<0.01), and markedly reduced interleukin-1β (IL-1β) not only in plasma (CHF: 75.7±27.6, VNS: 32.9±6.8 pg/mL, p<0.01) but also in the heart (CHF: 13.2±4.6, VNS: 9.3±2.4 pg/mg, p<0.05) and spleen (CHF: 170.2±65, VNS: 115.4±58.8 pg/mg, p<0.05). TNF-α, IL-6, HMGB-1 and CRP remained unchanged. In addition, VNS significantly reduced the expression of TGF-β in LV which is a key mediator of fibroblast activation (CHF: 31±4.0, VNS: 16.6±2.0 %, p<0.01). In LATE, VNS significantly decreased cardiac fibrosis (Masson’s trichrome stain) (CHF: 4.4±0.7, VNS: 2.9±1.1 %, p<0.01), heart weight (CHF: 3.7±0.5, VNS: 3.2±0.5 g/kg, p<0.01) and LVEDP (CHF: 24.2±5.0, VNS: 17.5±7.1 mmHg, p<0.01), suggesting that VNS prevented cardiac remodeling and preserved LV function. Conclusion: VNS significantly decreased the invasion of macrophage, IL-1β and TGF-β production from the beginning of VNS initiation, and resulted in the decrease of cardiac fibrosis and the improvement of cardiac remodeling as well as cardiac function. VNS induced early suppression of the excessive inflammatory response may lead to its late beneficial effects on CHF.

Therapeutic Progress and Knowledge Basis on the Natriuretic Peptide System in Heart Failure

2019 ◽  
Vol 19 (20) ◽  
pp. 1850-1866 ◽  
Author(s):  
Shihui Fu ◽  
Zhenyu Chang ◽  
Leiming Luo ◽  
Juelin Deng
Keyword(s):  
Heart Failure ◽  
Disease Burden ◽  
Neutral Endopeptidase ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Current Review ◽  
High Prevalence ◽  
Peptide System ◽  
Poor Outcomes ◽  
The One

Notwithstanding substantial improvements in diagnosis and treatment, Heart Failure (HF) remains a major disease burden with high prevalence and poor outcomes worldwide. Natriuretic Peptides (NPs) modulate whole cardiovascular system and exhibit multiple cardio-protective effects, including the counteraction of the Renin–Angiotensin–Aldosterone System (RAAS) and Sympathetic Nervous System (SNS), promotion of vasodilatation and natriuresis, and inhibition of hypertrophy and fibrosis. Novel pharmacological therapies based on NPs may achieve a valuable shift in managing patients with HF from inhibiting RAAS and SNS to a reversal of neurohormonal imbalance. Enhancing NP bioavailability through exogenous NP administration and inhibiting Neutral Endopeptidase (NEP) denotes valuable therapeutic strategies for HF. On the one hand, NEP-resistant NPs may be more specific as therapeutic choices in patients with HF. On the other hand, NEP Inhibitors (NEPIs) combined with RAAS inhibitors have proved to exert beneficial effects and reduce adverse events in patients with HF. Highly effective and potentially safe Angiotensin Receptor Blocker Neprilysin Inhibitors (ARNIs) have been developed after the failure of NEPIs and Vasopeptidase Inhibitors (VPIs) due to lacking efficacy and safety. Therapeutic progress and knowledge basis on the NP system in HF are summarized in the current review.

scholarly journals Important Considerations for the Treatment of Patients with Diabetes Mellitus and Heart Failure from a Diabetologist’s Perspective: Lessons Learned from Cardiovascular Outcome Trials

2019 ◽  
Vol 17 (1) ◽  
pp. 155 ◽  
Author(s):  
Chrysi Koliaki ◽  
Nicholas Katsilambros
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
High Risk ◽  
Scientific Evidence ◽  
Lessons Learned ◽  
Cardiovascular Outcome ◽  
First Line ◽  
Cardiovascular Outcome Trials ◽  
Beneficial Effects ◽  
First Line Therapy

Heart failure (HF) represents an important cardiovascular complication of type 2 diabetes mellitus (T2DM) associated with substantial morbidity and mortality, and is emphasized in recent cardiovascular outcome trials (CVOTs) as a critical outcome for patients with T2DM. Treatment of T2DM in patients with HF can be challenging, considering that these patients are usually elderly, frail and have extensive comorbidities, most importantly chronic kidney disease. The complexity of medical regimens, the high risk clinical characteristics of patients and the potential of HF therapies to interfere with glucose metabolism, and conversely the emerging potential of some antidiabetic agents to modulate HF outcomes, are only some of the challenges that need to be addressed in the framework of a team-based personalized approach. The presence of established HF or the high risk of developing HF in the future has influenced recent guideline recommendations and can guide therapeutic decision making. Metformin remains first-line treatment for overweight T2DM patients at moderate cardiovascular risk. Although not contraindicated, metformin is no longer considered as first-line therapy for patients with established HF or at risk for HF, since there is robust scientific evidence that treatment with other glucose-lowering agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) should be prioritized in this population due to their strong and remarkably consistent beneficial effects on HF outcomes.

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