scholarly journals Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Heart ◽  
2021 ◽  
pp. heartjnl-2020-318060
Author(s):  
Shruti S Joshi ◽  
Trisha Singh ◽  
David E Newby ◽  
Jagdeep Singh
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Health ◽  
Blood Glucose Control ◽  
Sglt2 Inhibitor ◽  
Mechanisms Of Action ◽  
Calcium Handling ◽  
Healthy Population ◽  
Clinical Benefits

Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor–mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.

scholarly journals Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF

2020 ◽  
Author(s):  
Silvio E Inzucchi ◽  
Kieran F Docherty ◽  
Lars Køber ◽  
Mikhail N Kosiborod ◽  
Felipe A Martinez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Sglt2 Inhibitor ◽  
Adverse Outcomes ◽  
Exploratory Analysis ◽  
Diabetes Incidence ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure

<b>Objective </b> <p>The SGLT2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the <a>Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure </a>trial (DAPA-HF). This report explores the effect of dapagliflozin on incident type 2 diabetes in the non-diabetic cohort enrolled in the trial.</p> <p><b> </b></p> <p><b>Research Design/Methods</b></p> <p>The subgroup of 2605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and a HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model.</p> <p><b> </b></p> <p><b>Results</b></p> <p>At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93/1307 patients (7.1%) in the placebo group and 64/1298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (HR 0.68, 95% CI, 0.50-0.94; p=0.019.) More than 95% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5.7-6.4%.) Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not.</p> <p><b>Conclusions</b></p> <p>In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.</p>

scholarly journals Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF

2020 ◽  
Author(s):  
Silvio E Inzucchi ◽  
Kieran F Docherty ◽  
Lars Køber ◽  
Mikhail N Kosiborod ◽  
Felipe A Martinez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Sglt2 Inhibitor ◽  
Adverse Outcomes ◽  
Exploratory Analysis ◽  
Diabetes Incidence ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure

<b>Objective </b> <p>The SGLT2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the <a>Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure </a>trial (DAPA-HF). This report explores the effect of dapagliflozin on incident type 2 diabetes in the non-diabetic cohort enrolled in the trial.</p> <p><b> </b></p> <p><b>Research Design/Methods</b></p> <p>The subgroup of 2605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and a HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model.</p> <p><b> </b></p> <p><b>Results</b></p> <p>At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93/1307 patients (7.1%) in the placebo group and 64/1298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (HR 0.68, 95% CI, 0.50-0.94; p=0.019.) More than 95% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5.7-6.4%.) Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not.</p> <p><b>Conclusions</b></p> <p>In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.</p>

Effect of Canagliflozin on Estimated Fluid Volumes in Patients with Heart Failure and type 2 Diabetes: A Post-hoc Analysis of the CANDLE Trial

2021 ◽  
Author(s):  
Shinya Fujiki ◽  
Takumi Imai ◽  
Atsushi Tanaka ◽  
Michio Shimabukuro ◽  
Hiroki Uehara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Extracellular Volume ◽  
Sglt2 Inhibitor ◽  
The Body ◽  
Open Label ◽  
Post Hoc Analysis ◽  
The Difference ◽  
Post Hoc

Abstract Background:In patients with chronic heart failure (CHF) and type 2 diabetes (T2D), inhibition of the sodium-glucose cotransporter-2 (SGLT2) improves cardiorenal outcomes, but the effects of the SGLT2 inhibitor canagliflozin on body fluid volume and renal function remain to be clarified.Methods:This was a post-hoc analysis of 233 patients with CHF and T2D in the CANDLE Trial (UMIN000017669), an investigator-initiated, multi-center, randomized open-label trial that compared the effect of canagliflozin (100 mg, n=113) with glimepiride (starting dose: 0.5 mg, n=120) on changes in N-terminal pro-brain natriuretic peptide. The time courses of estimated plasma volume (ePV, calculated with the Straus formula), estimated extracellular volume (eEV, determined by the body surface area), and estimated glomerular filtration rate (eGFR, calculated with the modified Cockcroft formula) were compared between the canagliflozin and glimepiride groups at weeks 4, 12, and 24. Results:Reductions in ePV and eEV were observed only in the canagliflozin group until week 12 (change from baseline at week 12, ePV; -7.63%; 95% confidence interval [CI], -10.71 to -4.55%, p<0.001, eEV; -123.15 mL; 95% CI, -190.38 to -55.92 mL, p<0.001). Whilst ePV stopped falling after week 12, eEV continued to fall until week 24 ([change from baseline at week 24] – [change from baseline at week 12], ePV; 1.01%; 95%CI, -2.30 to 4.32%, p=0549, eEV; -125.15 mL; 95% CI, -184.35 to -65.95 mL, p<0.001). An initial significant reduction in eGFR was observed in the canagliflozin group (change from baseline at week 4, -4.18 mL/min/1.73 m2; 95% CI, -5.99 to -2.37 mL/min/1.73 m2, p<0.001), but after 4 weeks, eGFR stopped falling, and the difference between groups became insignificant (change from baseline at week 24, -1.27 mL/min/1.73 m2; 95% CI, -3.05 to 0.51 mL/min/1.73 m2, p=0.162, [change from baseline at week 24] – [change from baseline at week 12], 0.89 mL/min/1.73 m2; 95% CI, -0.74 to 2.51 mL/min/1.73 m2, p=0.284).Conclusions:Canagliflozin reduced ePV and eEV gradually, whilst glimepiride did not. Maintenance of a modest reduction in ePV by canagliflozin suggests appropriate intravascular volume reduction contributing to cardiorenal benefits in patients with CHF and T2D.Trial Registration: UMIN000017669

Clinical benefits of empagliflozin in very old patients with type 2 diabetes hospitalized for acute heart failure

2021 ◽  
Author(s):  
Luis M. Pérez‐Belmonte ◽  
Jaime Sanz‐Cánovas ◽  
Mercedes Millán‐Gómez ◽  
Julio Osuna‐Sánchez ◽  
Almudena López‐Sampalo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Acute Heart Failure ◽  
Old Patients ◽  
Very Old ◽  
Clinical Benefits ◽  
Very Old Patients

Abstract 13625: Effect of Empagliflozin versus Placebo on Plasma Volume Status in Patients With Acute Myocardial Infarction and Type 2 Diabetes Mellitus: Subgroup Analysis of the Embody Trial

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yu Hoshika ◽  
Yoshiaki Kubota ◽  
Kosuke Mozawa ◽  
Shuhei Tara ◽  
Yukichi Tokita ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Body Weight ◽  
Placebo Group ◽  
Plasma Volume ◽  
Subgroup Analysis ◽  
Sglt2 Inhibitor

Background: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been evaluated recently as a prognostic marker of patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor affect the improvement of heart failure and PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF). Methods: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of the SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. A total of one hundred and five patients were randomized (1:1) to receive once-daily 10 mg empagliflozin or placebo 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS on baseline, weeks 4, 12 and 24. Results: Overall, 96 patients were included in the subgroup analysis set (64.3±10.9 years, male 80.2%, and 46 in the empagliflozin group and 50 in the placebo group). The empagliflozin group showed significant decreases in body weight, systolic blood pressure, and PVS compared with the placebo group at 24 weeks (-2.2 vs. +0.1 kg, P=0.0007; -6.6 vs. +3.5 mmHg, P=0.003; and -5.1 vs. -0.3%, P=0.0006; respectively). Decreased of PVS, defined as change of PVS < -4.5 % was associated with received empagliflozin (odds ratio, 2.61; 95% confidence interval, 1.11 - 6.15; P=0.028). On the other hand, NT-Pro BNP levels significantly decreased in the empagliflozin group and placebo group (1028.7 to 370.3 pg/ml, P=0.0001 and 1270.6 to 673.7 pg/ml, P=0.006, respectively). Conclusion: Empagliflozin reduced not only body weight but also PVS. These results suggested that early SGLT2 inhibitor administration in patients with AMI, CHF and T2DM could be effective to reduce body weight and PVS.

Dapagliflozin for heart failure – is it a class effect?

2020 ◽  
Author(s):  
Gerard Marshall Raj ◽  
Mukta Wyawahare
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Sglt2 Inhibitor ◽  
Therapeutic Application ◽  
Glucose Lowering ◽  
Reduced Ejection Fraction ◽  
Beneficial Effects

Dapagliflozin, an SGLT2 inhibitor used in the management of Type 2 diabetes mellitus, has been recently approved for the control of worsening cardiovascular events, including deaths and hospitalizations, in adults with heart failure with reduced ejection fraction. Previously, canagliflozin had a label change with regards to its additional usage in the reduction of risk of hospitalization for heart failure in patients with both Type 2 diabetes mellitus and diabetic nephropathy with albuminuria. On the other hand, the therapeutic application of empagliflozin and ertugliflozin in heart failure is yet to be delineated comprehensively. The beneficial effects of these SGLT2 inhibitors, dapagliflozin in particular, in heart failure are found to be independent of neither the glucose-lowering nor the SGLT2 inhibiting effects.

scholarly journals Canagliflozin Treatment in Patients with Type 2 Diabetes Mellitus

2015 ◽  
Vol 8 ◽  
pp. CMED.S31526 ◽  
Author(s):  
Curtis Triplitt ◽  
Susan Cornell
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Sglt2 Inhibitor ◽  
Multidisciplinary Teams ◽  
Patient Centered ◽  
Clinical Pharmacists ◽  
Increased Risk ◽  
Clinical Benefits

Current guidelines for treatment of type 2 diabetes mellitus (T2DM) indicate a patient-centered approach that should go beyond glycemic control. Of the many antihyperglycemic agents available for treatment of T2DM, sodium-glucose cotransporter 2 (SGLT2) inhibitors offer the advantages of reduced glycated hemoglobin (A1C), body weight (BW), and systolic blood pressure (SBP) and are associated with a low risk of hypoglycemia when used either as monotherapy or with other agents not typically associated with increased risk of hypoglycemia. Collaborative, multidisciplinary teams are best suited to provide care to patients with diabetes, and clinical pharmacists can enhance the care provided by these teams. This review aims to provide insight into the mode of action, pharmacology, potential drug–drug interactions, clinical benefits, and safety considerations associated with use of the SGLT2 inhibitor canagliflozin in patients with T2DM and to provide information to enhance clinical pharmacists' understanding of canagliflozin.

P2629Early benefits of empagliflozin in patients with type 2 diabetes with heart failure are not offset by increased adverse events: results from the EMPA-REG OUTCOME trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Pellicori ◽  
A Pernille Ofstad ◽  
D Fitchett ◽  
C Zeller ◽  
C Wanner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Adverse Events ◽  
Repeated Measures ◽  
Cox Regression ◽  
Sglt2 Inhibitor ◽  
Safety Data ◽  
Increased Risk ◽  
Outcome Trial

Abstract Background The cardiovascular (CV) benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) have been demonstrated in long-term clinical trials. In the EMPA-REG OUTCOME trial, the SGLT2 inhibitor empagliflozin (EMPA), compared with placebo (PBO), significantly reduced the risk of CV death and hospitalisation for heart failure (HHF) in patients with T2D and established CV disease, with a median follow-up time of 3.1 years. Purpose To investigate the early benefits and safety associated with use of EMPA in patients enrolled in the EMPA-REG OUTCOME trial according to heart failure (HF) status at baseline. Methods We evaluated the effects of treatments on glycated haemoglobin (HbA1c) levels and on the clinical endpoints of HHF, HHF or CV death, and HHF or all-cause mortality (ACM), as well as the occurrence of adverse events (AEs), at 12 weeks, 6 months, and 1 year after randomisation. Outcomes data were explored descriptively at 12 weeks, and assessed by Cox regression models adjusting for baseline risk factors at 6 months, and 1 year, whereas safety data were explored descriptively. Effects on HbA1c were evaluated using a Mixed Model Repeated Measures (MMRM) model. Results A total of 7020 participants, 706 (10%) with investigator-reported HF at baseline, were randomised to PBO, or two different doses of EMPA (10 mg or 25 mg once daily). In patients with HF at baseline, the adjusted mean differences in HbA1c between pooled EMPA and PBO at 12 weeks, 6 months, and 1 year after randomisation were −0.55, −0.54 and −0.53%-point, respectively, p<0.001 vs PBO for all, with similar results in those without HF (p for interactions 0.822, 0.939 and 0.539 at 12 weeks, 6 months and 1 year, respectively). Already at 12 weeks, patients assigned to EMPA had a lower frequency of all evaluated clinical outcome events (HHF, HHF or CV death, HHF or ACM) compared with PBO, regardless of HF status. This effect was sustained and significant at 6 months and 1 year in those with and without HF (see Figure). During the same time frame, the rates of AEs were generally higher in those with HF than without HF, but were not increased by the use of EMPA. At 1 year, any AE occurred in 206 (84.4%) and 1694 (81.1%) patients with and without HF, respectively, on PBO vs 363 (78.6%) and 3246 (76.8%) patients with and without HF on EMPA; any serious AE at 1 year occurred in 79 (32.4%) and 447 (21.4%) patients with and without HF on PBO vs 105 (22.7%) and 764 (18.1%) of those with and without HF on EMPA. Conclusions In the EMPA-REG OUTCOME trial, EMPA led to early beneficial effects on morbidity and mortality outcomes in patients with T2D with or without HF, which were not offset by an increased risk of AEs.

scholarly journals Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)

Circulation ◽  
2020 ◽  
Author(s):  
Matthew M. Y. Lee ◽  
Katriona J. M. Brooksbank ◽  
Kirsty Wetherall ◽  
Kenneth Mangion ◽  
Giles Roditi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Global Longitudinal Strain ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Reduced Ejection Fraction ◽  
B Lines

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP). Results: From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m 2 (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m 2 (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines. Conclusions: The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.

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