Heart failure poses significant challenges in both diagnosis and treatment. However, in recent times, the landscape of managing this condition has undergone a transformative shift with the introduction of numerous new drugs. A notable example is the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors.

SGLT-2 inhibitors, which were indicated initially only for treating type 2 diabetes, have expanded their indications to chronic heart failure recently, thanks to large-scale studies related to Boehringer Ingelheim’s Jardiance (empagliflozin).

The EMPA-REG OUTCOME study, an extensive study on patients with type 2 diabetes, provided clues that SGLT-2 inhibitors could benefit type 2 diabetes, chronic cardiac failure, and kidney disease. The subsequent EMPEROR-Reduced study confirmed a 25 percent reduction in the relative risk of hospitalization for heart failure or death from cardiovascular causes compared to placebo in chronic heart failure patients with reduced ejection fraction. In the EMPEROR-Preserved study, Jardiance reduced the risk of cardiovascular death or hospitalization for heart failure by 21 percent compared to placebo and the risk of first hospitalization and readmission for heart failure by 27 percent.

These findings have been incorporated into national and international heart failure guidelines. Last year, the Korean heart failure guidelines recommended SGLT-2 inhibitors as Class 1 for the first time in ejection fraction-preserving heart failure.

In the U.S., treatment guidelines have not yet been revised.

Still, the 2023 ACC Expert Consensus Decision-making Guidelines for the Management of Ejection Fraction-Preserving HF (ECDP), released this year, recommended SGL-T2 inhibitors as the preferred choice for ejection fraction-preserving HF.

The guideline stated that the recommendation level for SGL-T2 inhibitors might be increased to Class 1 in the following guideline revision based on the results of the Jardiance and other SGLT-2 inhibitor studies.

Based on the results of two studies (EMPEROR-Reduced and EMPEROR-Preserved), Jardiance is recommended for use in chronic HF patients across the ejection fraction spectrum: those with ejection fraction reduction rate of below 40 percent, with mild ejection fraction reduction rate of 40 to 50 percent, and with preserved ejection fraction rate of 50 percent or more.

Despite its proven effectiveness in heart failure and recommendation by leading guidelines, Jardiance is not widely available to heart transplant recipients in Korea. One reason is it has yet to get insurance coverage.

“Since Jardiance has proven its efficacy not just in ejection fraction-reduced heart failure but also in ejection fraction-preserved heart failure, for which there had been no treatment options, it must get reimbursement,” said Yoon Jong-chan, a professor of cardiology at the Catholic University of Korea Seoul St. Mary’s Hospital. He added that an ongoing financial impact study has shown that the earlier Jardiance is used, the greater the financial savings get.

Korea Biomedical Review spoke with Professor Yoon about using SGLT-2 inhibitors in heart failure and the need for improving its reimbursement.

Question: In diabetes, some say that we should view benefits demonstrated by SGLT-2 inhibitors, including Jardiance, as the drug class effect. What about that in heart failure?

Answer: Among SGLT inhibitors, only Jardiance and dapagliflozin have proven improvement effects in chronic heart failure. So is difficult to say that all SGLT2 inhibitors are effective in these two conditions.

Q: We are also curious about the mechanism of SGLT-2 inhibitors in chronic heart failure.

A: Although it has not been identified, several studies are underway to determine the mechanism. When SGLT-2 inhibitors first emerged in treating type 2 diabetes, some were skeptical about how they improved blood glucose levels through urinary excretion of sugar. However, as studies have shown benefits not only in type 2 diabetes but also in cardiac and renal protection, SGLT-2 inhibitor mechanisms across the cardiovascular-renal-metabolism (CRM) spectrum are being explored actively, and their effects are slowly emerging. If the mechanisms are further elucidated, we may see another drug like Jardiance that can effectively manage the heart, kidneys, and metabolism together.

Q: Were any side effects identified in the EMPEROR-Reduced and EMPEROR-Preserved studies?

A: There were some side effects, such as urinary tract infections and genital infections, due to the excretion of sugar in the urine. However, these were not significantly different from placebo and are generally considered safe. There were no cases of complicated urinary tract infections that required hospitalization or antibiotic treatment.

Urinary tract infections and genital infections are not problems if patients can care for themselves by, for instance, drinking water frequently. However, patients less capable of managing their infections, such as those with limited mobility or extended stays in nursing homes, may have difficulty recognizing and managing side effects. For these patients, restricting SGLT-2 inhibitors is recommended to minimize the risk of infection. Except for those patients, they can be used safely.

Besides, current treatment options for heart failure, such as ARNIs and beta-blockers, are challenging to use for patients at high risk for hypotension due to the potential for lowered blood pressure. Jardiance is less likely to pose this risk and could be used in more heart transplant patients.

Q: Can Jardiance be used from the start for treating chronic heart failure?

A: That’s what's happening. In the past, they used a gradual approach to treatment by trying a conventional agent first. If that didn’t work, they tried another agent. However, there’s been a shift in recent years to considering SGLT-2 inhibitors like Jardiance first, as data showed that using, even in small doses, a combination of agents with proven benefits for heart failure is more likely to improve outcomes.

Additionally, while existing heart failure medications require a gradual titration from a lower dose to ensure tolerability, Jardiance is a single-dose therapy without titration. This makes Jardiance an appropriate option for treatment patterns requiring multiple agents simultaneously as treatment goals change to more accessible and faster outcomes.

Q: Are there any restrictions on prescribing Jardiance?

A: It is not hard to prescribe it for patients with type 2 diabetes because it is reimbursed. However, it requires explanations before prescription for patients without type 2 diabetes because they are not covered. Patients with severe symptoms who experienced hospitalizations are more likely to accept prescriptions even if they are off-label. Still, outpatients with milder symptoms are likelier to question the prescription of off-label medications and are reluctant to accept them. That exposes patients with a high risk of heart failure to the danger of worsening symptoms and hospitalization. I think it is a public health crisis that so many patients with heart failure go untreated because of the reimbursement hurdles.

Q: Older adults often have type 2 diabetes, heart failure, and chronic kidney disease simultaneously. So, can we see SGLT-2 inhibitors becoming a standard treatment for them?

A: Many experts see high chances. As the risk of obesity and metabolic disease continues to rise in infants, children, and adolescents, more people are expected to develop these diseases in the future. It is likely to be widely used in the three diseases, if not in all people.

Q: The ongoing commercial viability study of Jardiance will likely be helpful for its reimbursement discussion. When will it come out?

A: The study is nearing completion, and the results will be finalized and published soon. However, even without this data, we already know there has been an economic evaluation of Jardiance. Jardiance appears to be deprioritized in favor of more expensive drugs, such as cancer drugs. Since Jardiance is not an expensive drug with a proven therapeutic effect, hastening its reimbursement will be more beneficial to health insurance finances.

Q: Is there anything you would like to improve in the heart failure treatment environment?

A: People are less aware of heart failure than other cardiovascular diseases, such as hypertension and myocardial infarction. Some healthcare professionals who do not deal with heart failure also think it is a disease that kills people because there were no treatments for it in the past. However, the treatment landscape for heart failure has improved dramatically with new medications, including SGLT-2 inhibitors such as Jardiance. I hope that awareness will increase.

In the U.S. and Europe, there is a shift toward proactive treatment to prevent morbidity from heart failure, not only in patients with heart failure but also in patients with risk factors for heart failure. Heart failure is a disease like a slippery slope. Once it starts, heart function continues to decline, and the goal is to slow it down as much as possible. It is necessary to consider proactive management strategies for patients at risk of heart failure in Korea to safely maintain their heart function in an outpatient setting without hospitalization.

Q: Does this mean that heart failure needs to be managed like the diabetes community categorizes patients at risk for diabetes as pre-diabetics?

A: Yes. As mentioned, the U.S. and Europe categorize people with heart failure risk factors as converters and emphasize aggressive treatment. The pre-stage patients also need to be managed, which still needs to be improved in Korea.