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Top 5 Takeaways on SGLT2 Inhibitors From AHA 2020

  • Authors: David Cherney, MD, PhD
  • CME / ABIM MOC / CE Released: 12/22/2020
  • Valid for credit through: 12/22/2021
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Target Audience and Goal Statement

This activity is intended for cardiologists, pharmacists, diabetologists, endocrinologists, and primary care physicians.

The goal of this activity is to educate clinicians about updates and new data in cardiovascular (CV) protection in type 2 diabetes (T2D) presented at the 2020 American Heart Association (AHA) Scientific Sessions.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with T2D and heart failure (HF)
    • New data presented at AHA 2020 on the use of SGLT2 inhibitors in patients with T2D and HF


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  • David Cherney, MD, PhD

    Professor of Medicine
    Senior Scientist
    Division of Nephrology
    University Health Network
    University of Toronto


    Disclosure: David Cherney, MD, PhD, has disclosed the following relevant financial relationships
    Served as an advisor or consultant for: AbbVie; AstraZeneca; Bayer; Boehringer Ingelheim-Lilly; Bristol Myers Squibb; Janssen; Maze; Merck; Mitsubishi-Tanabe; Novo Nordisk; Prometic; Sanofi
    Received grants for clinical research from: AstraZeneca; Boehringer Ingelheim-Lilly; Janssen; Merck; Novo Nordisk; Sanofi


  • Anne G. Le, PharmD

    Senior Medical Education Director, Medscape, LLC


    Disclosure: Anne G. Le, PharmD, has disclosed no relevant financial relationships.

  • Kim Storck, PharmD, RPh

    Senior Medical Writer, Medscape, LLC


    Disclosure: Kim Storck, PharmD, RPh, has disclosed no relevant financial relationships.

CME, CE Reviewer

  • Robert Morris, PharmD

    Associate Director, Accreditation and Compliance, Medscape, LLC 


    Disclosure: Robert Morris, PharmD, has disclosed the following relevant financial relationships: 
    Served as an advisor or consultant for: ViiV Healthcare 
    Owns stock, stock options, or bonds from: GlaxoSmithKline  

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Top 5 Takeaways on SGLT2 Inhibitors From AHA 2020

Authors: David Cherney, MD, PhDFaculty and Disclosures

CME / ABIM MOC / CE Released: 12/22/2020

Valid for credit through: 12/22/2021


Sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel class of recently approved glucose‐lowering medications. While initially developed for the treatment of type 2 diabetes (T2D), their use has expanded into multiple cardiovascular (CV) settings -- such as heart failure (HF), coronary heart disease, and cerebrovascular disease, among others – supported by the evidence and recommended by multiple specialty guidelines.[1-3]

The American Heart Association (AHA) held its Scientific Sessions in November 2020 to disseminate the latest in CV science and innovation. Amidst the excitement, Medscape sat with acclaimed scientist, professor, and AHA presenter, David Cherney, MD, and asked, “what are 5 things to know about SGLT2 inhibition, heart failure, and the ground-breaking work presented at AHA’s 2020 Scientific Sessions?” Here are his answers.

This data analysis from the Get With The Guidelines (GWTG)-HF registry provides rich context for the evidence on SGLT2 inhibition presented at AHA 2020.[4] By now, most clinical guidelines have recognized SGLT2 inhibitors for their ability to reduce mortality, hospitalization for heart failure (HHF), and HF symptoms.[1-3] Yet, it still seems only a small number of patients with HF receive an SGLT2 inhibitor.[5,6] With an interest in the generalizability of trial outcomes to the real-world HF population, investigators quantified the proportion of patients with HFrEF who would be considered guideline-eligible for an SGLT2 inhibitor – the answer was 81%.[7]

This study, now published in JAMA Cardiology, [7] evaluated the records of 154,714 patients with HFrEF (ejection fraction [EF] ≤ 40%) collectively admitted to more than 400 US hospital sites between January 2014 and September 2019. The outcome measure was the proportion of patients who would be eligible for SGLT2 inhibitor treatment -- specifically with dapagliflozin -- based on its FDA labeling and the eligibility criteria used in the DAPA-HF trial. Four out of 5 patients with HFrEF (with or without T2D) were found to be treatment candidates.[8] Patient outcomes will improve when healthcare providers (HCPs) apply the most up-to-date, evidence-based treatment guidelines for HF. It is time to rapidly translate the evidence for SGLT2 inhibition into HF clinical practice.

A prespecified analysis of VERTIS CV data[9] struck 2 important chords at AHA 2020: i) the consistent CV benefit observed with SGLT2 inhibition in high-risk patients with T2D; and ii) the value of measuring urine albumin to creatinine ratio (UACR) to predict both CV risk and response to SGLT2 inhibition. In the VERTIS CV trial, 8246 patients with T2D and atherosclerotic CV disease (ASCVD) on guideline-directed medical therapy (GDMT) were randomized to treatment with the SGLT2 inhibitor, ertugliflozin 5 mg or 15 mg, or to placebo.[10] Ertugliflozin was noninferior to placebo for the primary endpoint of time to first major adverse cardiovascular event (MACE) and was shown to significantly reduce HHF by 30% (HR 0.70, 95% CI: 0.54, 0.90, P = .006) during 3.5 years of follow up.[10,11]

In an exploratory analysis of VERTIS CV, patients in moderate and high/very high Kidney Disease Improving Global Outcomes (KDIGO) chronic kidney disease (CKD) risk categories or with albuminuria at baseline derived the greatest HF benefit from ertugliflozin.[12] Relative risk reduction and absolute event rate reduction in HHF and composite HHF/CV death were the largest in these subgroups. (Table 1.)

Table 1. Cardiovascular Outcomes by Baseline Kidney Function Categories [12]

The VERTIS CV subanalysis reinforces the value of stratifying kidney disease risk by both UACR and measures of kidney function in patients with T2D.[9] Measuring albuminuria is not only for nephrologists; all HCPs should use UACR to identify patients with increased CV risk, as well as those who would benefit most from SGLT2 inhibition.

In the pivotal DAPA-HF trial, dapagliflozin 10 mg daily in addition to GDMT significantly lowered the risk of worsening HF or CV death in HF patients with a left ventricular ejection fraction (LVEF) of ≤ 40% (HR 0.74; 95% CI: 0.65, 0.85; P < .001).[13] A subanalysis of the DAPA-HF trial presented at AHA 2020 categorized all study participants (N = 4474) by their duration of HF.[14] Patients' HF durations at baseline ranged from less than 1 year to longer than 5 years (ie, 0 to 1, > 1 to 2, > 2 to 5, and > 5 years). Patients with longer-duration HF had higher rates of worsening HF and death, as would be expected. Still, the benefit of dapagliflozin on the primary endpoint of worsening HF and CV death was consistent irrespective of baseline HF duration.

An analysis of the impact of HF symptom burden and quality of life on SGLT2 inhibitor benefit was also presented at the 2020 AHA Scientific Sessions.[15] In the pivotal EMPEROR-Reduced trial, treatment with empagliflozin 10 mg daily in addition to GDMT significantly improved CV outcomes in patients with HF and an LVEF of ≤ 40%.[16] Specifically, empagliflozin reduced the risk of CV death or HHF (HR 0.75; 95% CI: 0.65, 0.86; P < .001). A prespecified analysis of study participants (n = 2458; 66% of enrolled) showed that treatment with empagliflozin resulted in significant improvement in HF symptoms and physical limitation irrespective of the patient's health status at baseline.[15] In short, patients with HFrEF treated with empagliflozin felt better and were able to exercise more by week 52 of the study regardless of the extent of their symptom burden and physical limitations at the study's start.

DAPA-HF and EMPEROR-Reduced enrolled HF patients with, or without T2D and an LVEF ≤ 40%, and both showed that treatment with an SGLT2 inhibitor reduced the risk of CV death or HHF by about 25%.[13,16] With consideration of the findings from their 2 subanalyses, it would seem that the benefits of SGLT2 inhibitors have expanded squarely into the HFrEF realm, independent of diabetes status, and perhaps even independent of HF duration and symptom burden at baseline.

Presented as a late-breaker at AHA 2020[17] and simultaneously published in the New England Journal of Medicine,[18] the SOLOIST-WHF trial is the first large, randomized controlled trial to evaluate SGLT2 inhibition in patients with T2D and a recent episode of acute HF. Study participants were randomized to receive a first dose of the dual SGLT1/SGLT2 inhibitor, sotagliflozin, or placebo while still in the hospital or shortly after hospital discharge (median = 2 days). The trial ended early because of the loss of supporter funding due to COVID-19. However, 1222 patients with acute HF were enrolled and followed for a median of 9 months; 79% of patients had an EF < 50%, and 21% had an EF > 50%.

Sotagliflozin, currently under clinical investigation, reduced the primary composite outcome of CV death, HHF, or urgent visits for HF by 33% (HR 0.67; 95% CI: 0.52, 0.85; P < .001).[18] Sotagliflozin's CV benefit occurred early in the study and was statistically significant within 28 days (P = .035).[17] Patients who received sotagliflozin had higher rates of diarrhea (6% vs 3%) and severe hypoglycemia (1.5% vs 0.3%) than placebo, but the SGLT1/SGLT2 inhibitor was generally well-tolerated and safe.[18] SOLOIST-WHF builds on the results from DAPA-HF and EMPEROR-Reduced, and demonstrates benefits with SGLT2 inhibition closer to the index hospitalization, a setting where SGLT2 inhibitors typically aren't used. This body of work seems to suggest that SGLT2 inhibitors, as a class, improve CV outcomes in patients with HF, irrespective of when HF occurs, and that closely monitored SGLT2 inhibition can be considered for patients admitted with acute decompensated HFrEF or HF with preserved EF (HFpEF).

Approximately 50% of patients with HF have a preserved EF, yet evidence-based treatments are scarce for HFpEF.[19] Alongside the SOLOIST-WHF trial, data from sotagliflozin's SCORED trial were presented at AHA 2020 and simultaneously published in the New England Journal of Medicine.[20] The SCORED trial evaluated sotagliflozin's ability to prevent CV events in patients with T2D and CKD with or without albuminuria. Like SOLOIST-WHF, SCORED was stopped early due to loss of funding during the COVID-19 pandemic. Together, SOLOIST-WHF and SCORED included 739 patients with HFpEF. In a pooled analysis, sotagliflozin reduced the relative risk of CV death, HHF, or urgent outpatient visit by 37% (HR 0.63; 95% CI: 0.45, 0.89; P < .009) for patients with HFpEF.[21] While clinicians should apply caution in interpreting the HFpEF signal, these studies add to an already fueled interest in SGLT2 inhibition for HFpEF. Results are anticipated in 2021 from the DELIVER (dapagliflozin) and EMPEROR-Preserved (empagliflozin) trials, examining these drugs in patients with HFpEF, with or without T2D.[22,23]

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