SGLT-2 inhibitors that were initially released as a diabetes treatment have expanded their scope and risen as a representative heart drug. In addition to Heart Failure with reduced EF (HFrEF) and Heart Failure with mildly reduced EF (HFmrEF), SGLT-2 inhibitors have also demonstrated an effect in Heart Failure with Preserved Ejection Fraction (HFpEF), transforming heart failure guidelines in Korea and abroad.

The heart failure treatment effect of SGLT-2 inhibitors, which was first demonstrated with Jardiance (empagliflozin), was confirmed with Forxiga (dapagliflozin). In the EMPEROR-Preserved clinical trial on HFpEF patients, Jardiance succeeded in reaching the primary efficacy endpoint. Then, Forxiga demonstrated its effect in HFrEF and HFpEF patients in the DELIVER trial.

Based on such grounds, the Korean Society of Heart Failure (KSHF) published a newly revised Heart Failure Clinical Practice Guidelines and recommended SGLT-2 inhibitors as a main treatment regardless of the patient’s diabetic status in all areas of heart failure including HFrEF, HFmrEF, and HFpEF.

The US has also recommended SGLT-2 inhibitors as the main drug in the guidelines for the treatment of heart failure. Some have compared the SGLT-2 inhibitor to a '21st-century statin' and predicted that it will become a standard of care in heart failure.

Dailypharm met with professor Javed Butler from the University of Mississippi Medical Center in Jackson and Professor Seok-Min Kang from the Yonsei University College of Medicine (Chair of KSHF) to highlight the changes SGLT-2 inhibitors brought to the heart failure treatment paradigm.

-Among SGLT-2 inhibitors, Jardiance was the first to present data demonstrating an effect on all heart failures including HFpEF. What significance does this hold and how was Jardiance able to become the first SGLT-2 inhibitor to demonstrate such data? ?

Prof. Butler: Jardiance marked two milestones in the history of heart failure treatments. First, the drug was the first to demonstrate a reduction in cardiovascular deaths in diabetes patients in 2015 through the EMPA-REG OUTCOME trial. Also, the drug holds significance for being the first to demonstrate clinical efficacy in HFpEF, an area where no treatment option exists, through the EMPEROR-Preserved trial. In patients with HFpEF, Jardiance reduced the relative risk of hospitalization from HF or cardiovascular deaths by 21% and reduced the relative risk of all hospitalization from HF by 27%. This is significant because it can be felt in the field while treating patients, beyond being simply statistical figures.

Although the cardiac ejection fraction rate will continue to serve as a key indicator in determining the type of heart failure and the according treatment method, it will not hold much meaning in determining the use of SGLT-2 inhibitors.

Furthermore, when discussing treating heart failures, we usually discuss treatment in the spectrum of HFrEF to HFpEF. However, as SGLT-2 inhibitors have also demonstrated a relative risk reduction in the development of new heart failure events in patients with Type 2 diabetes, I would like to expand the spectrum and discuss extending its use to prevention as well. For patients with diabetes or chronic kidney disease (CKD), the best time for them to start treatment with SGLT-2 inhibitors is at the ‘pre-heart failure’ stage.

-When comparing the two representative SGLT-2 inhibitors Jardiance and Forxiga, Jardiance showed a slight reduction in effect in the patient group with an ejection fraction rate of 65% or higher, but recent data on Forxiga showed that its effect remained constant in these patients. How should we interpret this difference?

Prof. Butler: It would be difficult to say that the results signify any difference between the two drugs. Based on the primary efficacy endpoint, it is difficult to say that the drugs show different efficacy in different ranges of ejection fraction rate. Only in the secondary efficacy endpoint does Jardiance show a slight reduction in effect in the group with an ejection fraction between 65-70%. However, as the drug’s efficacy rises again in the group with an ejection fraction rate of 70% or higher, the measure in the EF of 65-70% group has to be considered a noise that arose in the process of conducting the subgroup analysis. Even when taking into account the biological mechanism and principle of action of SGLT-2 inhibitors, it is difficult to provide a reasonable explanation on why its effect decreases in the EF of 65-70% group and rises again in the EF of 70% or higher group.

When looking at the trend lines of clinical trials conducted on Forxiga and Jardiance, although the two may seem contrasting, it is difficult to see the difference as a clear signal indicating a significant difference when comprehensively analyzing the overall data. Also, a comprehensive meta-analysis of these data shows a fairly consistent effect across the entire cardiac ejection fraction rate spectrum.

-Then, rather than discuss which drug is better, should we understand that SLGT-2 inhibitors have a class effect?

Prof. Butler: It is too soon to consider it a class effect. Of course, the clinical trials of the two drugs that were conducted on patients with HFrEF and HFpEF showed consistent results. However, as we saw in various cases where the results were different after expecting such a class effect in the past, it is hard to prescribe SGLT-2 inhibitors while expecting a class effect. In other words, it would be difficult to put other SGLT-2 inhibitors on the same line other than the two drugs that have proven their treatment effect in heart failure.

-The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure gave a Class 2A recommendation for SGLT-2 inhibitors to treat HFpeF. How was the recommendation for the guideline determined at that level?

Prof. Butler: There had been no other treatment option recommended in HFpEF before then. We used diuretics to treat congestion or were at the level of dealing with comorbidities. The US was the first to revise the major practice guidelines for heart failure in HFpEF after the Jardiance trial results were presented. The recommendations were changed based on the convincing trial results.

However, the US guidelines require at least 2 related studies to recommend a treatment as Class 1 when revising guidelines. At the time of the revision, only one study - EMPEROR-Preserved – existed for SGLT-2 inhibitors, which was why it was not given a Class 1 recommendation.

In Korea, SGLT-2 inhibitors have a Class 1 recommendation in HFpEF. I believe this is a more reasonable and advanced decision than the one made in the Us guidelines. With more relevant data being presented, I believe the US and European guidelines will also be revised to follow Korea’s guidelines.

-Until now, the Korean practice guidelines mostly followed those in Europe and the US. What enabled your society to make such a bold decision this time?

Prof. Kang: Korea lacks the conditions to conduct large-scale randomized clinical studies like Europe or the United States. This is why Korea commonly sets guidelines by adopting or accepting results from foreign clinical studies. We underwent various voting and debates to determine the level of evidence for several drugs before releasing our heart failure guidelines on July 22nd. Also, the DELIVER trial on Forxiga was scheduled to be presented at the European Society of Cardiology (ESC) Congress 2022 in August. We already knew the top-line results and were able to analyze the results to some extent. Considering how the prevalence of heart failure in Korea will continue to increase rapidly, the prevailing opinion was that it is reasonable to defiantly recommend a good treatment option as soon as possible.


-You also mentioned SGLT-2 inhibitors should be used for prevention as well. At what scope are SGLT-2 inhibitors being prescribed in the US?

Prof. Butler: As SGLT-2 inhibitors were first introduced to treat diabetes, it was mainly used by primary care doctors or endocrinologists that commonly treat diabetes. In cardiology, there is still a perception that SGLT-2 inhibitors are used to treat diabetes. Therefore, several heart failure-related societies are making efforts to raise awareness of SGLT-2 inhibitors as a treatment that can reduce cardiovascular risk, regardless of the patient’s diabetic status

SGLT-2 inhibitors are being moderately used as a treatment for heart failure. However, compared to ARNis, its usage is increasing relatively quickly.

-In Korea, the drugs would need to also receive reimbursement in the indication, but setting the reimbursement standards for SGLT-2 inhibitors may also be a difficult task. Even when basing the standards on the cardiac ejection fraction rate, it would be difficult to apply for reimbursement benefits according to the specific ejection rate.

Prof. Kang: I cannot say what would be the clear standard for reimbursement, and this area would need to be considered further. When using the level of ejection fraction as a standard, we could set an arbitrary level and reimburse all substandard drugs for other class drugs, but for SGLT-2 inhibitors, we would need to contemplate what should be considered a normal ejection fraction rate.

- So SGLT-2 inhibitors are now set in the forefront of heart failure treatment. Are there any tasks we need to solve to select patients that will benefit more from the use of SGLT-2 inhibitors or any precautions that need to be taken?

Prof. Butler: SGLT-2 inhibitors are more of a supplement than a replacement of existing drugs. We need to first focus on starting drug treatment as soon as possible, and take into consideration the patient's condition, including blood pressure, cardiac and kidney condition, to start administration of drugs in the appropriate order so that patients can receive all 4 drugs within 3-4 weeks of initial administration.

In most cases, we can add SGLT-2 inhibitors without regulating the use of the existing drugs, however, patients who are old, have hypotension, or dehydration may need to reduce their diuretic dose, etc.

Prof. Kang: As there are many phenotypes of HFpEF, more follow-up studies on the use of SGLT-2 inhibitors in these various patients would be needed. Some may oppose the prospect that SGLT-2 inhibitors may be beneficial across the entire cardiac ejection fraction rate spectrum. Therefore, data supporting how effective SGLT-2 inhibitors are for the various characteristics of heart failure is needed.