Chapter V: News Digest

EMPEROR-POOLED analysis | ESC 2021 | August 27 2021

Recently results from EMPEROR-Pooled analysis were presented at the 2021 European Society of Cardiology (ESC) meeting. Pooled analysis from EMPEROR-Preserved and EMPEROR-Reduced, on an individual patient level, demonstrated that the heart failure benefit with empagliflozin was consistent across two trials, with essential differences in renal outcomes.

It was observed that empagliflozin significantly reduced the risk of major renal outcomes in the EMPEROR-REDUCED, but not in the EMPEROR-PRESERVED trial.

For a more detailed analysis of this study, click here: https://www.nejm.org/doi/full/10.1056/NEJMc2112411

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EMPEROR-PRESERVED DEMONSTRATES EMPAGLIFLOZIN SIGNIFICANTLY REDUCES THE RISK OF HF HOSPITALIZATION IN PATIENTS WITH HFpEF | ESC 2021 | AUGUST 27 2021

Results from EMPEROR-PRESERVED were presented at the 2021 European Society of Cardiology (ESC) meeting. This was a double-blind, placebo-controlled trial, in which 5988 patients with an ejection fraction of more than 40% received 10mg empagliflozin or placebo.

The trial demonstrated that empagliflozin reduced the combined risk HF death or hospitalization in patients with HFpEF, irrespective of diabetes status, showing for the first time that a therapeutic intervention can improve outcomes in HFpEF.

For more information : https://www.nejm.org/doi/full/10.1056/NEJMoa2107038

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The SGLT2 inhibitors dapagliflozin and empagliflozin are now class I recommended therapy in the 2021 ESC/HFA Heart failure guidelines | ESC 2021 | August 27 2021

Several evidence-based treatments are part of foundational therapy for patients with heart failure with reduced ejection fraction (HFrEF), including angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs).

In recent years, sodium glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin and dapagliflozin, have demonstrated significant efficacy in the treatment of HFrEF patients, particularly in reducing the risk of HF hospitalizations, and have gotten FDA approvals for this indication. As such, the 2021 ESC/HFA HF guidelines, presented at the 2021 ESC meeting, now include these SGLT-2is as part of foundational therapy, in addition to the agents above, for the treatment of chronic HFrEF.

For more information: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Acute-and-Chronic-Heart-Failure | European Society of Cardiology

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DAPA CKD sub-analysis explored the role of dapagliflozin in patient with or without heart failure and CKD | ESC 2021

Recently a study presented at ESC 2021 conference showed that dapagliflozin reduced the risk of kidney failure, heart failure hospitalizations, and cardiovascular death in patients with CKD, with or without type 2 diabetes, irrespective of their history of heart failure.

In this study, a total of 4,305 participants were randomized to either 10mg dapagliflozin or placebo. The primary endpoint constituted of ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. It was observed that dapagliflozin reduced the risk of the primary outcome equally in patients with HF and without HF.
For more information: https://www.jacc.org/doi/10.1016/j.jchf.2021.06.017

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Study sheds light into potential mechanisms of benefit of SGLT-2 is in heart failure

July 26, 2021 – Additional results from the EMPA-TROPISM trial, which tested the hypothesis that the beneficial heart failure benefits with empagliflozin were due to glucose-independent mechanisms, were published.

In a prior publication, authors had highlighted that empagliflozin ameliorates cardiac remodeling, reduces LV volumes and mass, increases LV systolic function, and enhance functional capacity. New results showed that empagliflozin reduced epicardial fat and subcutaneous adipose tissue, as well as improved myocardial fibrosis and arterial stiffness. In addition to these imaging findings, empagliflozin also significantly reduced the levels of inflammatory biomarkers in HFrEF patients without type 2 diabetes. Taken together, the results of this study suggest that glucose-independent mechanisms are responsible (or at-least partially responsible) for the benefits seen with empagliflozin in heart failure.

The full results of this study can be accessed here

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EMPEROR-PRESERVED, A PHASE III TRIAL WITH SGLT2 INHIBITOR EMPAGLIFLOZIN MEETS ITS PRIMARY ENDPOINT IN HFpEF.

July 7, 2021 – After several neutral trials for heart failure with preserved ejection fraction (HFpEF), an effective therapy that can improve outcomes might be on the horizon, a first for this subset of heart failure.

Topline results from EMPEROR-Preserved trial, which evaluated the efficacy and safety of empagliflozin in HFpEF, met its primary endpoint, showing that treatment with this SGLT-2 inhibitor significantly reduced the risk of hospitalization and cardiovascular death for HFpEF patients, with or without T2DM. The full results of the study will be presented as a late breaker at the upcoming European Society of Cardiology meeting, which will take place virtually from August 27-30, 2021.

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Global Use of SGLT2 Inhibitors and GLP-1 Receptor Agonists in Type 2 Diabetes: Results from DISCOVER

June 28, 2021 – Findings from DISCOVER study presented at the ADA 2021 Scientific Sessions indicated that the global usage of SGLT2 inhibitors and GLP-1 agonists has increased over time among individuals with type 2 diabetes.

However, despite strong evidence of benefits, this observational study found that the use of these agents remains suboptimal, especially in high-risk patients that could benefit from these therapies.

For more information: https://diabetes.diabetesjournals.org/content/70/Supplement_1/324-OR

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SCORED and SOLOIST Trials- Effect of sotagliflozin on CV outcomes among patients with type 2 diabetes and moderate renal impairment.

May 17, 2021 – Pooled data from SCORED and SOLOIST trials, presented at the American College of Cardiology (ACC) 2021, showed that sotagliflozin significantly reduced the risk of CV death, HF hospitalizations, and urgent HF visits compared to placebo.

Benefits were also preserved for both men and women and were consistent regardless of baseline ejection fraction (including HFpEF patients) or history of heart failure. A reduction in renal events was not observed, which could be related to the fact that the trial was stopped early due to a loss of funding.
For more information:
https://www.acc.org/latest-in-cardiology/clinical-trials/2020/11/11/22/02/scored

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FDA Approves Dapagliflozin for the Treatment of Chronic Kidney Disease

April 30, 2021 – U.S. Food and Drug Administration approved oral tablets of dapagliflozin to reduce the risk for kidney function decline, kidney failure, cardiovascular death, and hospitalization associated with heart failure in adult patients with chronic kidney disease who are at increased risk of disease progression, regardless of the presence of absence of diabetes.

This approval was based on the results from the DAPA-CKD trial, which showed a significant reduction in the risk of a composite endpoint (sustained decline in the estimated glomerular filtration rate of at least 50%, end-stage kidney disease, kidney transplant, renal death, or cardiovascular death) in patients who were administered dapagliflozin compared to those who received placebo.

For more information:

https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-chronic-kidney-disease

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Newer Analysis Show that Dapagliflozin May Work for Preventing Cardio-Renal Adverse Events in Patients Without ASCVD, and Reduce the Risk of CV Events Equally in Men and Women

March 31, 2021 – Analyses from the DECLARE-TIMI 58 and the DAPA-HF trials provided some more information about the efficacy of dapagliflozin across specific subgroups.

A secondary analysis of the DECLARE-TIMI 58 showed that the reduction of cardiovascular death or hospitalization for heart failure observed with dapagliflozin in the main trial results, as well as renal outcomes, were applicable regardless of the presence or absence of existing atherosclerotic cardiovascular disease (ASCVD).

This is important because 59.4% of the enrolled study population did not have established ASCVD in this trial, suggesting that the benefits of dapagliflozin can extend to a broader primary prevention population.

The analysis from the DAPA-HF trial showed that dapagliflozin reduced the risk of worsening heart failure, cardiovascular death, and all-cause death, as well as improved symptoms, physical function, and health-related quality of life similarly in men and women with HFrEF. The conclusions from this analysis can be important, particularly since women may respond differently to certain HFrEF treatments compared to men.

The full results of these studies can be accessed here and here.

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Effects of Ertugliflozin on Renal Outcomes – Prespecified Analysis from the VERTIS CV

March 4, 2021 – A prespecified analysis of the VERTIS CV trial showed that ertugliflozin led to significant reductions in the incidence of kidney disease endpoints in patients with type 2 diabetes and established cardiovascular disease, as part of a secondary analysis. The analysis included more than 8200 patients, with mean baseline eGFR (estimated glomerular filtration rate) of 75.7-76.1 mg/min/1.73m2 and median UACR (urine albumin-to-creatinine ration) of 18-19 mg/g across groups.

The incidence of the composite renal outcome (40% reduction from baseline in eGFR, time to renal dialysis, transplant, or death) was 34% with ertugliflozin compared to placebo, as well as greater UACR decreases and less eGFR decline with ertugliflozin. These benefits were stable across groups, however, were more pronounced in patients with macroalbuminuria and existing chronic kidney disease. With these results, authors suggest that ertugliflozin is now part of the class effects observed with other SGLT-2 inhibitors as it pertains to renal outcomes, however, it has yet to be studied in a dedicated CKD or DKD trial.

The full study results can be accessed here

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Dapagliflozin Quickly Reduces HF Events in HFrEF patients

February 17, 2021 – A recent secondary analysis from the DAPA-HF trial, published in JAMA Cardiology, showed that there was a relatively rapid reduction in the risk of cardiovascular death or worsening heart failure with dapagliflozin in HFrEF patients compared to placebo.

These benefits were apparent as soon as 28 days in the dapagliflozin-treated group, and patients with a more recent HF hospitalization experienced a greater relative and absolute risk reductions with dapagliflozin after 2 years.

The full study results can be accessed here

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The Effects of Canagliflozin on Blood Pressure

February 8, 2021 – A secondary analysis of the CREDENCE trial, showed that canagliflozin lowered systolic blood pressure across all BP-defined subgroups, as well as reduced the need for additional BP-lowering pharmacotherapy in patients with type 2 diabetes and chronic kidney disease. Canagliflozin reduced systolic BP by 3.50mmHg by week 3,

an effect which was maintained throughout the duration of the trial. Furthermore, the effect of canagliflozin on the primary outcome of the CREDENCE trial (kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease), as well as on other key secondary and safety endpoints, was consistent across BP and BP-lowering therapy subgroups.

The full study results can be accessed here

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Benefits of Dapagliflozin in DAPA-HF According to Baseline MRA Use

February 8, 2021 – A prespecified safety analysis from the DAPA-HF study examined the effect of baseline mineralocorticoid receptor antagonist (MRA) use on the primary composite outcome of CV death or worsening

heart failure with dapagliflozin. The analysis showed that effect of dapagliflozin on the primary outcome compared to placebo was similar in patients taking or not taking an MRA, supporting the use of these two drug classes together.

The full study results can be accessed here

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Benefits of Empagliflozin in HF According to Baseline ARNI Use

February 3, 2021 – A prespecified analysis from the EMPEROR-Reduced trial in HFrEF patients, showed that the benefits of empagliflozin on heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. In prior trials of SGLT-2 inhibitors in patients with

diabetes, no patients were receiving sacubitril/valsartan, and on the same token, in large ARNI trials, no patients were receiving background therapy with an SGLT-2 inhibitor. The EMPEROR-Reduced trial itself only had 10.7% of enrolled HFrEF patients who were receiving an ARNI at baseline. The study seems to suggest that combined treatment with both an SGLT-2i and ARNI could be beneficial in these patients.

The full study results can be accessed here

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ACC Updates HF Decision Pathway To Incorporate SGLT-2 Inhibitors

January 11, 2021 – The American College of Cardiology (ACC) released an update to their 2017 Expert Decision Pathway on 10 pivotal issues about heart failure with reduced ejection fraction (HFrEF). The guidance, originally created to provide clinicians with practical ways to make treatment decisions in HF

and implement guideline-directed medical therapy (GDMT), now includes SGLT-2 inhibitors and angiotensin receptor neprilysin inhibitor (ARNi) sacubitril/valsartan. Two SGLT-2 inhibitors, dapagliflozin and empagliflozin, are included based on their results in the DAPA-FH and EMPEROR-Reduced, respectively. According to the pathway, they are recommended for HFrEF patients (EF ≤40%), NYHA class II-IV HF, and should be administered in conjunction with a background GDMT for HF.
The full document can be accessed here

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Canagliflozin effective in CKD patients with eGFR<30

December 4, 2020 – A recent post hoc analysis of the CREDENCE trial, which analyzed the subset of participants with eGFR <30/ml/min/1.73m2, showed that canagliflozin slowed kidney disease progression compared to placebo without increasing acute kidney injury (AKI).

The effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent in those with eGFR <30 and ≥30 30/ml/min/1.73m2, with the occurrence of kidney failure also being similar between groups. This is an important study, considering that not much is known about the efficacy of SGLT-2 inhibitors in patients with advanced CKD and particularly with an eGFR <30.
The full results of this sub-analysis can be accessed here

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Empagliflozin reduces first and recurrent adverse CVD events

December 1, 2020 – In a recently published secondary analysis of the EMPA-REG OUTCOME trial, empagliflozin was shown to reduce total (first plus recurrent) adverse CVD events in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD).

Compared to placebo, empagliflozin reduced the risk of total major adverse cardiovascular events (MACE, a composite of CV death, non-fatal stroke, or non-fatal MI), fatal or non-fatal MI (and their composite), admissions to hospital for heart failure, as well as all-case hospital admissions. In this study, risk reduction were larger for total events than for first events.

The full results of this analysis can be accessed here

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Dual SGLT-1/2 Inhibitor Sotagliflozin Shows Benefit in Diabetes Patients with HF or CKD

November 16, 2020 – During the 2020 American Heart Association virtual Scientific Sessions, two important studies on sotagliflozin in diabetes patients

were presented. The SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) demonstrated that sotagliflozin decreased the risk of the composite primary endpoint (deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure) compared to placebo in patients with diabetes and chronic kidney disease, with our without albuminuria. In this trial, diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common in patients treated with sotagliflozin compared to placebo.

On the other hand, the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) showed that this agent decreased the risk for the composite primary endpoint (same components as the ones in the SCORED trial) in patients with diabetes and recent worsening heart failure.

The full results of the SCORED trial can be accessed here

The full results of the SOLOIST-WHF trial can be accessed here

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Study Might Shed Light on the Mechanisms of Empagliflozin in HF

November 13, 2020 – In a small trial of non-diabetic patients with HFrEF (EMPATROPISM trial), empagliflozin, added to guideline-directed medical therapy, was shown to ameliorate cardiac

remodeling, reduce LV volumes, decrease LV mass, increase LV systolic function, and enhance functional capacity compared to placebo. The study seems to support the use of empagliflozin in HFrEF patients regardless of diabetes status (similar to what was observed in the larger EMPEROR-Reduced trial), and suggests some potential mechanisms by which this agent improves HF outcomes.

The full results of the EMPATROPISM trial can be accessed here

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EMPEROR-Reduced Results by Baseline Diabetes Status

November 11, 2020 – A recent sub-analysis of the EMPEROR-Reduced study showed that the beneficial effects of empagliflozin on cardiac and renal outcomes in HFrEF patients,

initially observed in the main study results announced earlier this year, are independent of baseline diabetes status and occur throughout the spectrum of glycated hemoglobin (HbA1c) levels.

The full results of this trial can be accessed here

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Cardiorenal Benefits of Canagliflozin Could Be Greater in Higher-Risk Patients

September 21, 2020 – A recent sub-analysis of the CREDENCE trial demonstrated that the cardio-renal benefits of canagliflozin are more pronounced in very high-risk chronic kidney disease (CKD) patients,

as classified by the Kidney Disease Improving Global Outcomes (KDIGO) system:

Low Risk – eGFR ≥60 mL/min/1.73 m²and UACR <30 mg/g
Moderate Risk – eGFR 45-<60 mL/min/1.73 m²and UACR <30 mg/g, or eGFR ≥60 mL/min/1.73 m² and UACR 30-300 mg/g
High Risk – eGFR 30-<45 mL/min/1.73 m²and UACR <30 mg/g, eGFR 45-<60 mL/min/1.73 m² and UACR 30-300 mg/g, or eGFR ≥60 mL/min/1.73 m² and UACR >300 mg/g
Very High Risk – eGFR <30 mL/min/1.73 m²with any UACR, eGFR 30-<45 mL/min/1.73 m² and UACR ≥30 mg/g, or eGFR 45-<60 mL/min/1.73 m² and UACR >300 mg/g

Although the relative cardio-renal benefits of canagliflozin were consistent across these risk categories, the absolute risk reduction was greater in higher risk categories and particularly for very high-risk patients. Similar patterns were observed across endpoints, including major adverse cardiovascular events (MACE) composite, CV death or hospitalization for heart failure, CV death, fatal/nonfatal MI, fatal/nonfatal stroke, fatal/nonfatal HF, 40% reduction in eGFR/ESKD/kidney related death, and all-cause mortality.

Click here to access the full results of the sub-analysis.

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Pre-specific Analysis of VERTIS-CV Trial Shows that Ertugliflozin Reduces HF Hospitalizations

August 31, 2020 – The main results of the VERTIS-CV trial, initially published in June 2020, demonstrated cardiovascular safety of the SGLT-2 inhibitor ertugliflozin compared to placebo,

however, no benefit was demonstrated with ertugliflozin compared to placebo for the occurrence of the primary endpoint (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). A recent sub-analysis of this trial, presented at the 2020 European Society of Cardiology (ESC) meeting, showed that ertugliflozin lowered the time to first heart failure hospitalization (HHF) event compared to placebo, with this effect being significantly greater in patients with baseline estimated glomerular filtration rate (eGFR) = <60 mL/min/1.73m², in patients with albuminuria and in those taking diuretics. Additionally, ertugliflozin significantly reduced total HHF and total HHF/CV deaths compared to placebo.

Click here to read clinical summaries of the VERTIS-CV trial

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DAPA-CKD meets primary endpoint

August 30, 2020 – During the 2020 European Society of Cardiology (ESC) virtual meeting, held from 8/29 – 9/1, the main results of the DAPA-CKD trial were announced.

This trial, designed to evaluate the effects of dapagliflozin on renal outcomes, enrolled CKD patients with or without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) = ≥25 and ≤75 mL/min/1.73m²and urine albumin-to-creatinine ratio (UACR) = ≥200 and ≤5000 mg/g. The primary endpoint was time to the first occurrence of any of the components of the composite: ≥50% sustained decline in eGFR or reaching ESRD or CV death or renal death. The late-breaking trial presented as ESC, showed:

A 58% relative risk reduction for the occurrence of primary endpoint events with dapagliflozin compared to placebo over a median follow-up of 2.4 years (197 events in dapagliflozin group vs. 312 events in the placebo group, HR = 0.61, p = 0.000000028)
This benefit was consistent regardless of the presence or absence of type 2 diabetes at baseline

The full results of the DAPA-CKD trial are expected to become available later this year.

Click here for more info on the late-breaking trial presented at ESC

Click here to access the full publication of these results

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Results of the EMPEROR-Reduced Study Announced

August 29, 2020 – The full results of the EMPEROR-Reduced study, which evaluated the effects of empagliflozin for the treatment of patients with heart failure and reduced ejection fraction (HFrEF) were announced at the European Society of Cardiology (ESC) meeting and subsequently published in the New England Journal Of Medicine.

The study showed that patients treated with empagliflozin had a lower risk of cardiovascular death or hospitalization for heart failure compared to placebo, regardless of the presence or absence of diabetes. Additionally, the annual rate of decline in estimated glomerular filtration rate (eGFR) was slower in the empagliflozin group compared to placebo, and patients treated with empagliflozin had a lower risk of serious adverse renal outcomes.

The full results of this trial can be accessed here.

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FDA Removes Canagliflozin’s Black Box Warning for Lower Limb Amputations

August 26, 2020 – Based on a review of new data from three recent clinical trials, the FDA decided to remove the black box warning about amputation risk from the canagliflozin label.

Additionally, the contraindication for patients with severe renal impairment being treated for glycemic control, as well as a warning on potentially increases in low-density lipoprotein were also removed from the label.

More info on the full FDA press release and updated canagliflozin label can be found here.

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Updates in SGLT-2 Inhibitors and Cardiorenal Risk Reduction – Call for Articles and Perspectives

Do you have unique insights and perspectives about the application of SGLT-2 inhibitors in clinical practice? If so, we encourage you to submit short articles about the evolving landscape of SGLT-2 inhibitors in T2DM and beyond. The articles may include original thought pieces, editorials, clinical pearls, case reports and more. Upon review, articles will be indexed here and in our official publication, Cardiometabolic Chronicle.

Click Here to Submit An Article

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