SGLT-2

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Highlights from #AHA21: Coffee and SGLT2 inhibitors!

Andi Shahu, MD, MHS

So much great work is being shared at the AHA. I’d like to put a spotlight on two studies that stood out from Day 2 of #AHA21!

The CRAVE  Trial

The Coffee and Real-Time Assessment of Atrial and Ventricular Ectopy (CRAVE) trial attempted to address an urban myth that has been around for decades: coffee could contribute to arrhythmias. But is this actually true? The objective of this study was to assess in a more structured and scientific way to study the effects of coffee on individuals in the ambulatory setting. In this randomized crossover trial, 100 participants were each given a Fitbit Flex 2 (an accelerometer that can records step counts and number of hours of sleep), a Zio Patch (a continuously recording electrocardiogram [ECG] device), and a continuous glucose monitor to measure glucose levels. Study investigators also obtained blood samples to extract DNA to determine whether participants exhibited fast or slow caffeine metabolism genetic variants.

Participants were randomly assigned using a mobile app to either consume or avoid coffee on a day-to-day basis. Coffee consumption was validated via geo-location trackers, money incentives and daily surveys. Study investigators then compared days when people were assigned to drink coffee with those in which they were assigned to avoid it. Increased coffee consumption did not lead to an increase in atrial arrhythmias (in fact, it was associated with less supraventricular tachycardias [SVT]). However, increased coffee consumption was associated with more premature ventricular contractions (PVCs). Genetic analyses of DNA samples from participants showed that faster metabolizers were more likely to have more PVCs.

In the analysis of the Fitbit data, coffee intake was associated with 1000 additional steps on those days in which coffee was consumed, but with less sleep that same evening. Slow metabolizers of caffeine were more affected and were more likely to have reduced sleep. There were no differences in serum glucose levels with regard to coffee intake.

Study investigators concluded that coffee consumption did not lead to increased atrial arrhythmias but did increase PVCs and that coffee consumption. It also led to more physical activity, may lead to less sleep, with differential effects depending on how well people can metabolize caffeine. This is further evidence that the physiologic effects of caffeine intake are complex and varied in different populations, and should be further studied.

https://www.youtube.com/watch?v=AAc0JnX90NA&ab_channel=AHAScienceNews

The EMPULSE Trial

The Empagliflozin in Patients Hospitalized for Acute Heart Failure  (EMPULSE) trial was a randomized, placebo-controlled trial that assessed the safety and efficacy of the sodium glucose transporter cotransporter-2 (SGLT2) inhibitor empagliflozin in 500 patients who were hospitalized for acute decompensated heart failure (regardless of whether or not they had diabetes, HFpEF or HFrEF). This last distinction is key as many recent studies of empagliflozin have focused specifically on diabetic patients or patients with heart failure with reduced left ventricular ejection fraction (HFrEF). Primary outcomes included death, number of heart failure events (HFE), time to first heart failure event, change in baseline Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS) after 90 days of treatment. Participants were randomized to empagliflozin 10 mg daily (and continued for at least 90 days) or to a placebo during their acute heart failure hospitalization.

After 90 days of treatment starting during their hospitalization for acute decompensated heart failure, participants who received empagliflozin were 36% more likely to see a clinical benefit (a composite of time to death, number of HFEs, time to HFE, and change from baseline KCCQ-TSS). There was a 35% percent reduction in death or first heart failure event. There was also greater weight loss, greater reduction in NT-proBNP and there were no safety concerns associated with taking the medication. Findings were similar in patients without and with diabetes, those with HFpEF and HFrEF as well as those with a new heart failure diagnosis or those with chronic heart failure.

In conclusion, this study showed that empagliflozin was both safe for patients to start taking during a hospitalization for acute decompensated heart failure and led to lower likelihood of death or new heart failure events – among other benefits – if the medication was started during that hospitalization, regardless of one’s diabetes status or ejection fraction. More work needs to be done to better understand the mechanism by which SGLT2 improve these clinical outcomes, though some speculate that their benefits have to do with the diuretic effect of the medication. In a similar vein, EMPEROR-Preserved Trial published in the New England Journal of Medicine earlier this year showed that empagliflozin reduced the risk of cardiovascular death or hospitalization in patients with heart failure with a left ventricular ejection fraction of at least 40%, regardless of whether or not they have diabetes.

Studies such as EMPULSE and EMPEROR-Preserved provide further support for utilization of empagliflozin in all patients with heart failure – not just those with a reduced ejection fraction (for which a number of studies have already shown clinical benefit, and for which SGLT2 inhibitors are already standard of care). Lively discussions in the medical community are ongoing as to whether we should be placing all patients – with reduced and preserved ejection fraction –  who are hospitalized with heart failure on an SGLT2 inhibitor, prior to discharge.

https://www.youtube.com/watch?v=Vtflg2v8m8A&ab_channel=AHAScienceNews

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”
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From evidence to practice: Insights from the GWTG-HF Registry on the Applicability of FDA Labeling for Dapagliflozin in Heart Failure with Reduced Ejection Fraction

Aaysha Cader, MD, MRCP

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors continue to amaze the world of cardiovascular pharmacotherapeutics. Initially developed as anti-diabetic agents, SGLT-2 inhibitors have demonstrated a wide range of benefits across various patient subsets, most notably those with heart failure.

The landmark Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, a phase 3, placebo-controlled trial the results of which were published in November 2019, demonstrated that the SGLT-2 inhibitor dapagliflozin reduced mortality and worsening heart failure events, and improved health-related quality of life among patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence or absence of diabetes.1

Based on these DAPA-HF trial results, in May 2020, dapagliflozin was the first SGLT-2 inhibitor approved by the US Food and Drug Administration (FDA) for HFrEF.2 However, as previous registries have shown, many novel evidence-based therapies are either delayed or not optimally utilized in practice. 3,4 Thus, in order to determine the proportion of eligible candidates for the initiation of dapagliflozin and define potential barriers to therapeutic optimization, an analysis of the American Heart Association (AHA)’s The Get With The Guidelines®–Heart Failure (GWTG-HF) registry was undertaken by Vaduganathan and colleagues. This blog is a summary of the results of this analysis, part of TRANSLATE-HF research platform, the results of which were presented at AHA Scientific Sessions 2020, with simultaneous publication in  JAMA Cardiology.5

The GWTG-HF registry: This a large contemporary hospital-based quality improvement registry including a total of 586,580 patients from 529 sites across the United States.

Population of interest: After exclusion criteria were applied, the primary study cohort for this analysis included 154,714 patients hospitalized with HFrEF at 406 sites between January 2014 – September 2019. As with DAPA-HF, the focus was on chronic HFrEF (≤40%) and treatment eligibility of patients based on discharge parameters during the transition to ambulatory care.

Treatment candidates for Dapagligflozin: The FDA label excluded patients with type 1 diabetes and chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m2 and dialysis). When this FDA label was applied to patients in the above cohort, 81.1% would be candidates for dapagliflozin, with similar proportions across all study years (range 80.4-81.7%). When analyzed for 355 sites with ≥10 hospitalizations (enrolling 154,522 patients), the median proportion of FDA label candidates was similar, at 81.1%.

Eligibility according to diabetic status: Notably, the proportion of eligible patients for dapagliflozin was higher among those withOUT a history of or new diagnosis of diabetes, as compared with those with type 2 diabetes (85.5% vs. 75.6%).

Reasons for not meeting FDA label: The predominant reason for ineligibility for dapagliflozin in this cohort was an eGFR<30 mL/min/1.73 m2 at discharge; this was more frequent among diabetics (23.9%) than non-diabetics (14.3%). Other reasons were far less frequent: 3.2% were ineligible due to chronic dialysis and only 0.02% due to type 1 diabetes.

Especially in terms of ineligibility for Dapagliflozin reported in this publication, it is important to note that this data analysis was undertaken between April 1st to June 30th, 2020. More compelling data from two other pivotal SGLT-2 trials reported after DAPA-HF are likely to further extend SGLT-2 inhibitor treatment indications to patients with more severe CKD. DAPA CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease6 evaluated patients with albuminuric chronic kidney disease with eGFR down to as low as 25mL/min/1.73 m2 and EMPEROR-Reduced7 evaluated patients with HFrEF with eGFR as low as 20mL/min/1.73 m2.

Differences between DAPA-HF Trial Participants vs. FDA Label Candidates in GWTG-HF: Participants in DAPA-HF were younger, less often women, and less often Black compared with participants in GWTG-HF, underscoring the need for greater representation of older adults, women, racial/ethnic minority groups, and those with multiple comorbidities in clinical trials relative to reference usual care (i.e. registry) populations. GWTG-HF registry participants had lower left ventricular EF and eGFR; however, a history of myocardial infarction and percutaneous coronary intervention) were more prevalent among DAPA-HF participants.  The overall prevalence of diabetes was similar between both cohorts (44.1%  in GWTG-HF registry vs 45% in DAPA-HF population). There was a lower use of evidence-based HF medical therapies among GWTG-HF participants, but higher use of implantable-cardioverter defibrillators. Most other clinical characteristics were qualitatively similar between the two groups

Conclusions & implications: A lag from clinical trial to clinical practice is not uncommon for most novel pharmacotherapeutics. However, data from this large, contemporary US hospitalized HF registry show that 4 out of 5 patients with HFrEF, irrespective of type 2 diabetes status are candidates for initiation of dapagliflozin at hospital discharge, supporting broad generalizability to practice. This represents a potential opportunity for in-hospital implementation of evidence-based medical therapies and treatment optimization of stable chronic HFrEF, pending data on safety and efficacy of SGLT2 inhibitors in acute HF (NCT04363697, NCT04298229, NCT04157751).

References

  1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
  2. US Food and Drug Administration. FDA approves new treatment for a type of heart failure. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed on December 1, 2020.
  3. Greene SJ, Fonarow GC, DeVore AD, et al. Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2019;73(19):2365-83.
  4. Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018;72(4):351-66.
  5. Vaduganathan M, Greene SJ, Zhang S, et al. Applicability of US Food and Drug Administration Labeling for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in US Clinical Practice: The Get With the Guidelines-Heart Failure (GWTG-HF) Registry. JAMA Cardiol. 2020 Nov 13:e205864. doi: 10.1001/jamacardio.2020.5864
  6. Heerspink HJL, Stefánsson BV, Correa-Rotter R. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.
  7. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. 32865377.

 
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The Story of SGLT-2 Inhibitors

Yehia Saleh, MD

There were a lot of interesting presentations at the American Heart Association 2020 Scientific Sessions today. However, I found the most interesting was “But Wait, There are More Targets: SGLT-2 inhibitor…” by Dr. Marc Pfeffer. In his presentation, he discussed how did we end up using an antihyperglycemic drug (SGLT-2 inhibitors) in treating and preventing heart failure.

In 2008, the Food and drug administration (FDA) mandated that in order to approve glucose-lowering medications, cardiovascular safety should be established. Which was defined at the time as cardiovascular death, myocardial infarction, and stroke (heart failure was not included). Subsequently, all antihyperglycemic drugs were passing the bar when it comes to cardiovascular events. Until 2015, unexpectedly the EMPA-REG OUTCOME study showed that in patients with type 2 diabetes, empagliflozin had a lower rate of cardiovascular deaths, heart failure hospitalizations, and death from any cause.(1) Following this study, the endocrinologic and metabolic drugs advisory committee vote was split in regards to the impact of SGLT-2 inhibitors on cardiovascular outcomes. The final vote was 12 “Yes” vs 11 “No”, and as a result, the FDA concluded that SGLT-2 inhibitors reduced cardiovascular death.

Afterward, EMPA-REG OUTCOME results were reproduced in several studies (CANVAS, DECLARE-TIMI). Most importantly, this effect was independent of HbA1c level. However, the population in the aforementioned studies were not predominantly heart failure patients. At this point, the cardiovascular community adopted the drug, and from 2017 to 2018 four large outcomes trials were launched (DAPA-HF, EMPEROR-Preserved, EMPEROR-Reduced and DELIVER) In 2019, DAPA showed that among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.(2) In 2020, EMPEROR-Reduced showed that among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.(3) The previous findings were confirmed in a metanalysis that included both studies.(4) Although it is not very clear how SGLT2 inhibitors decrease cardiovascular events and heart failure, currently we have robust evidence proving its efficacy.

While many discoveries in medicine are incidental. I find the story of SGLT2 inhibitors as fascinating as other landmark accidental discoveries in medicine such as penicillin and warfarin. The moral of the story is always be observant and trust the data.

References:

  1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28.
  2. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.
  3. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-24.
  4. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. The Lancet. 2020;396(10254):819-29.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”