SGLT2 Inhibitors for Cardio, Not Just Diabetes

Medscape

a day ago

When canagliflozin (Invokana) was approved in 2013, the SGLT2 inhibitor was touted as a first in a new medication class that was, at the time, the only oral, once-daily medication to reduce blood glucose as well as body weight and systolic blood pressure.
Since then, additional SGLT2 inhibitors have been approved (dapagliflozin, empagliflozin, bexagliflozin, and ertugliflozin), and the indications for prescribing the medications have expanded.
The medications have gone from targeting glucose-lowering to also providing cardiac protection, including for diabetes-free patients with heart failure.
Next, experts said, discussions will focus on other decisions, such as when and whether to prescribe the SGLT2 inhibitors with GLP-1 receptor agonists for the best outcomes.
The Path From Glucose-Lowering to Heart Benefits
From the start, it was clear the medications — which work by binding to the SGLT2 protein expressed in the proximal tubules and preventing the reabsorption of filtered glucose — could help those with diabetes.
What took some time to prove was their benefit for cardiac outcomes, said Paul Heidenreich, MD, MS, professor of medicine and vice chair for Quality in the Department of Medicine, Stanford University School of Medicine, Stanford, California.
Paul Heidenreich, MD, MS
He chaired the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guideline on heart failure management, which added a strong recommendation for SGLT2 inhibitors for some patients with heart failure.
In a recent interview, he highlighted some noteworthy findings and research on SGLT2 inhibitors in heart disease and diabetes, and other researchers tracked the rising use of the medications as studies proved their benefits.
Research Timeline
After the SGLT2 inhibitors were shown to benefit patients with type 2 diabetes, reducing cardiovascular events, including hospitalization for heart failure, the next natural research question, Heidenreich said, was to determine if the medications could also help those with heart failure who are diabetes-free.
'And that was shown to be true,' Heidenreich said.
'It starts as, let's control blood sugar, but then there are all these other benefits.'
In the 2022 update of the guidelines, a strong recommendation is given for SGLT2 inhibitors to treat patients with chronic, symptomatic heart failure with reduced ejection fraction (HFrEF) to reduce hospitalization and cardiovascular mortality, regardless of diabetes status. Heidenreich terms HFrEF as the worst form.
It was after those studies on HRrEF that the guidelines were published, he said, recommending the medication for those patients.
Next, after the guidelines had been updated and issued, other research found the SGLT2 inhibitors also helped treat those with heart failure with preserved ejection fraction (HFpEF). The 2022 guidelines give the medications less than the strongest recommendation for HFpEF. With the next updating of the guidelines, Heidenreich said, he expects the SGLT2 inhibitors will also receive a strong recommendation for patients with preserved ejection fraction.
As the research accumulates, there is growing use of the medication, he said. 'All the studies have shown a dramatic increase in the use [of the SGLT2 medications] in the last few years,' he said. And the guidelines are probably just one small reason, he said, with other published data on the drugs' effectiveness playing a role.
He cites two major studies useful for pointing out the value of the SGLT2 inhibitors in heart health:
The EMPEROR trial — The SGLT2 inhibitor empagliflozin (Jardiance) reduced the combined outcome of cardiovascular disease and hospitalization for heart failure in those with HFpEF, regardless of diabetes status.
The DELIVER trial — The SGLT2 inhibitor dapagliflozin (Farxiga) reduced the combined outcome of worsening heart failure or cardiovascular death in those with heart failure with mildly reduced ejection fraction or HFpEF. Worsening heart failure included unplanned hospitalization or an urgent visit for heart failure.
Moving on, another question, he said, will focus on how the SGLT2 inhibitors will be prescribed and combined or not with other medications. Will physicians tend to prescribe a GLP-1, SGLT2, or both? Heidenreich hopes ongoing research will make the answers clearer in the next few years.
Rising Acceptance, Use
Within 2 years of publication of clinical trial evidence documenting benefit in reducing the risk for heart failure outcomes in those with preserved ejection fraction, discharge prescription rates of SGLT2 inhibitors increased substantially for these patients, researchers from the Saint Luke's Mid America Heart Institute in Kansas City, Missouri, and elsewhere reported.
They set out to ask: Has the adoption rate and variation in the use of SGLT2 inhibitors changed for US patients with heart failure and left ventricular ejection fraction greater than 40% since that trial in 2021 finding benefit?
Study leader Mohammad Abdel Jawad, MD, a cardiology research fellow at Saint Luke's Mid America Heart Institute, and colleagues evaluated 158,849 patients across 557 US hospitals, finding the SGLT2 inhibitor prescription rates increased from approximately 4% in July to September 2021 to approximately 24% in July to September 2023. However, they did find substantial variation in rates across hospitals.
Mohammad Abdel Jawad, MD
Until that trial proving benefit, Jawad told Medscape Medical News, there was no treatment this effective.
'Before the EMPEROR-Preserved trial was published in 2021, we had no proven therapies with such a consistent and clinically meaningful treatment effect in patients with heart failure with preserved or mildly reduced ejection fraction,' he said.
He calls the trial a turning point, one that demonstrated a clear and reproducible benefit of the medication in this population. The updated guidelines from the American College of Cardiology for the medication recommending the SGLT2 inhibitors are the strongest given to any medication for this group of patients, he said.
It is well-known, he said, that getting effective treatments into clinical practice can take a very long time. He cites the often-quoted finding of a 17-year time lag between research that has found treatments effective and the treatment becoming commonly prescribed.
'I think there are always delays in adopting new evidence,' agreed study co-researcher John A. Spertus, MD, MPH, clinical director of Outcomes Research at Saint Luke's Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City. 'My sense is that these medications are increasingly being recognized as beneficial and relatively easy to prescribe.'
Costs, Complications
When the SGLT2 inhibitors were first introduced, Jawad said, 'There were case reports of diabetic ketoacidosis (DKA), especially in patients with type 1 diabetes or those using the drugs off-label.'
John A. Spertus, MD, MPH
After that, the FDA revised the labels, warning about symptoms of DKA such as nausea, vomiting, abdominal pain, and trouble breathing.
The complication is rare but can be serious and life-threatening. Estimates vary, but one report estimated that the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1000 person-years.
'For the vast majority of patients with type 2 diabetes, heart failure, or chronic kidney disease, the risk is minimal and manageable with proper patient selection and education,' Jawad said.
Costs are another consideration if insurance doesn't cover them. In one recent report, the out-of-pocket costs for GLP-1 receptor agonists were $166.50 compared to $81 for SGLT2 inhibitors. Without insurance, monthly costs can be $600 or more for SGLT2 inhibitors and $1300 or more for GLP-1 receptor agonists. If cost is not a barrier for the SGLT2 inhibitors, Jawad added, 'I believe there's no good reason not to prescribe them.'