SGLT-2 inhibitors came to the forefront as one of the most controversial topics in the field of cardiology and endocrinology. Although developed as an antidiabetic drug, SGLT-2 inhibitors opened up a new era in diabetes treatment by demonstrating cardiovascular benefits while proving its potential as a treatment for heart failure, creating a paradigm shift.

Cardiac and diabetes experts are now engaged in a fierce debate over whether SGLT-2 inhibitors are heart or diabetes drugs. Cardiac experts say that SGLT-2 inhibitors should be seen as heart drugs, not antidiabetics, while diabetes experts say that SGLT-2 inhibitors shouldn't be considered as such.

The Medical Observer took a look at the history behind SGLT-2 inhibitors' rise as a possible heart drug and met with a cardiac and diabetes expert to discuss whether the drug should be considered a heart or diabetes drug.

SGLT-2 inhibitors prove CVD prevention effect

The Cardiovascular Outcome Trial (CVOT) for SGLT-2 inhibitors gave rise to the drugs' potential as a cardiac drug. Results showed that rosiglitazone, which are thiazolidinediones (TZD), increased the risk of cardiovascular diseases such as myocardial infarction. This prompted the U.S. Food and Drug Administration to request a verification of the cardiovascular safety of all marketed antidiabetic drugs.

CVOT's goal was to demonstrate the non-inferiority of antidiabetic agents to the cardiovascular system concerning cardiovascular safety.

Unlike DPP-4 inhibitors, which proved non-inferiority and safety for cardiovascular disease, SGLT-2 inhibitors significantly lowered the primary endpoint risk for cardiovascular disease.

In the EMPA-REG study, SGLT-2 inhibitor empagliflozin reduced the risk of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke for type 2 diabetes patients who are at high risk of cardiovascular disease.

The CANVAS study also showed that SGLT-2 inhibitor canagliflozin reduced the risk of cardiovascular death, myocardial infarction, and stroke by 14 percent. The study included type 2 diabetes patients at high risk for cardiovascular disease.

Finally, the DECLARE-TIMI 58 study showed that dapagliflozin lowered the risk of the primary endpoint risk regarding the cardiovascular system by 7 percent compared to the placebo, although there was no statistical significance. However, the risk of death from cardiovascular disease or hospitalization from heart failure was significantly lower by 17 percent.

P3 trial aimed at patients with heart failure underway

SGLT-2 inhibitors are particularly emerging as next-generation therapeutic agents for heart failure. CVOT succeeded in improving evaluation indicators related to heart failure and is currently poised to become a drug for heart failure.

Unlike CVOT, which included diabetic patients who were at high risk for cardiovascular disease, the phase 3 trial on heart failure patients test whether SGLT-2 inhibitors are effective in treating heart failure patients regardless of diabetes.

The leading SGLT-2 inhibitor as a treatment for heart failure is dapagliflozin. The DAPA-HF study is the first SGLT-2 inhibitor to demonstrate its potential as a therapeutic agent for heart failure, proving that it can expand its therapeutic area.

According to the study results, dapagliflozin lowered the risk of death by cardiovascular disease or worsening of heart failure in patients with heart failure with reduced ejection fraction (HFrEF) by 26 percent. 

Also, the DELIVER study is underway to evaluate the effects of dapagliflozin as a treatment for patients with heart failure with preserved ejection fraction (HFpEF).

Experts are now closely watching dapagliflozin's effect on heart failure patients, especially considering there are no approved HFpEF therapies and the disappointing P3 results of valsartan/sacubitril.

Empagliflozin is getting geared up in two trials that recruited local patients. The EMPEROR-Reduced study on HFrEF patients and the EMPEROR-Preserved study on HFpEF patients are in full swing.

"We completed enrolling patients for both studies and we expect the EMPEROR-Reduced results to be positive based on our experience so far," said Professor Choi Jin Oh Korean of Samsung Medical Center, Division of Cardiology, who also serves as the Academic Director of the Korean Society of Heart Failure.

"The results will be announced later this year and will help clarify whether SGLT-2 inhibitors are effective in treating heart failure," Choi added.

Meanwhile, sotagliflozin, which is both an SGLT-1 and SGLT-2 inhibitor, is also undergoing testing in the SOLOIST-WHF study that includes diabetic patients with HFrEF to secure indications for heart failure.

SGLT-2 inhibitors as 1st-line therapy for diabetes patients with CVD?

Expectations are rising regarding whether these drugs can be first-line therapy considering the advances of SGLT-2 inhibitors for cardiovascular disease.

Experts in the industry are suggesting that SGLT-2 inhibitors should be used as first-line therapy for diabetes patients with atherosclerotic cardiovascular disease (ASCVD) as a cardiac drug with blood glucose control effect.

Domestic and international diabetes guidelines recommend metformin as the first-line treatment for diabetes. Diabetic patients with ASCVD are advised to take SGLT-2 inhibitors or GLP-1 receptor agonists if metformin fails to control blood glucose.

Experts are calling for SGLT-2 inhibitors to be used before metformin for diabetes patients with ASVCD because there is not enough evidence that demonstrates metformin's cardiovascular benefits. Although the UKPDS34 study found metformin lowered the risk of death from all causes, including diabetes-related deaths, there was little evidence that metformin prevented cardiovascular disease.

Adverse events and cost act as Achilles heel of SGLT-2 inhibitors

Despite the benefits of efficacy, safety concerns stand in the way of SGLT-2 inhibitors becoming a drug that can act as a first-line therapy that demonstrates both glycemic control and cardiovascular benefits

Metformin has been used in a clinical setting for more than 50 years, being prescribed safely to patients. In contrast, SGLT-2 inhibitors, which have developed relatively recently, lack long-term safety data. Also, risks of genital infections, dehydration, diabetic ketoacidosis, and fractures, among others, are hard to ignore.

Also, researchers state there aren't enough funds to conduct a large-scale study to verify the preventive effect of metformin against cardiovascular disease.

"Pharmaceutical firms that develop new drugs invest research funds to broadening a drug's indications. In the case of metformin, which has been around for 50 years, no pharmaceuticals are going to sponsor research to test its cardiovascular benefits," said Yonsei University College of Medicine Professor Cha Bong-soo, Department of Endocrine Medicine. He also previously served as the Academic Director of the Korean Diabetes Association.

Meanwhile, experts also point out that metformin is cheaper than SGLT-2 inhibitors, making it challenging to make SGLT-2 inhibitors first-line therapy.

"If you can't explain the mechanics, it's not a heart drug"

Although SGLT-2 inhibitors have demonstrated cardiovascular benefits with CVOT, it is not clear how the cardioprotective effect occurs. Experts cite this as one of the problems SGLT-2 inhibitors have to solve to become a heart drug.

In the past, SGLT-2 inhibitors were thought to hold cardiovascular benefits because of the glycemic effect. However, SGLT-2 inhibitors proved to prevent cardiovascular disease at the beginning of treatment. Considering cardiovascular disease prevention effect through robust blood sugar control is seen after about 10 years of follow-up, experts say it is difficult to explain the cardioprotective effect of SGLT-2s.

It was hypothesized that the diuretic action of SGLT-2 inhibitors would remove excess water and salt in the body, thereby reducing the burden on the heart. However, in the DEFINE-HF study of dapagliflozin, the change in NT-proBNP, a heart failure biomarker that decreases as heart burden decreases, was not different from placebo. No data is indicating that left ventricular function improved after taking SGLT-2 inhibitors, and the mechanism of cardioprotective effects of SGLT-2 inhibitors is still unknown.

"Currently, SGLT-2 inhibitors are thought to produce a cardioprotective effect because they reduce the volume overload of the heart. Unlike diuretics, which rapidly remove body fluids, SGLT-2 inhibitors continue to remove fluids," Professor Choi said. "However, the exact mechanism of action of SGLT-2 inhibitors is unknown."

Diabetes experts, who say that SGLT-2 inhibitors are hardly heart drugs, point out that being unable to explain the mechanisms shows that they are not heart drugs.

"The mechanism of cardioprotective effect of SGLT-2 inhibitors is not clear, and not knowing how it works on the heart means that it is not a heart medicine after all," said Professor Cha. "Controlled blood sugar means better insulin function. Insulin manages the energy required by the cell or tissue. In other words, the control of blood sugar means that energy use is facilitated, which leads to better heart function."