Is Prevention the Future of SGLT2s? Inzucchi Offers Data That Suggest "Yes"

How soon can an endocrinologist, a cardiologist—or a primary care physician—prescribe a sodium glucose co-transporter 2 (SGLT2) inhibitor and see benefits that make the drug cost effective?

The answer could be when patients reach prediabetes, based on data that Silvio Inzucchi, MD, professor of medicine at Yale and a leader in major trials involving the drug class, presented late Saturday during a symposium, “DAPA-HF Update: Have We Lost SGLT2 inhibitors to the Cardiologists?”

The symposium attracted leaders from across endocrinology and cardiology to the second day of the 80^th American Diabetes Association Scientific Session, being held virtually due to coronavirus disease 2019.

Inzucchi, who has been involved in groundbreaking trials with SGLT2 inhibitors for the past decade, shared data that show patients who did not have type 2 diabetes (T2D) when they started the recent heart failure trial were 32% less likely to develop the disease if they took dapagliflozin (Farxiga) instead of placebo.

While Inzucchi cautioned that DAPA-HF was an “event-driven trial,” with only 18 months of follow-up, he said, “I would remind you, this is the first SGLT2 inhibitor trial to show a potential diabetes prevention effect—the effect was principally driven by our participants who have prediabetes.”

SGLT2 inhibitors were developed to treat T2D by targeting a key protein, causing the body to filter excess glucose out through the urine. Early on, the drugs were shown to lower glycated hemoglobin (A1C) and help patients lose a modest amount of weight; a diuretic effect was apparent as well. But only when results came in for FDA-mandated cardiovascular outcomes trials did their potential to prevent heart failure or renal decline become evident. This has opened new opportunities for collaboration among endocrinologists and cardiologists, who may treat the same patients—among the sickest and costliest to the health system. The total cost of diabetes to the United States was $327 billion in 2017; a separate study found the mean per-patient cost of a heart failure hospitalization was $14,631, and readmissions are common.

Inzucchi, an endocrinologist, was the lead investigator on the groundbreaking EMPA-REG OUTCOME trial in 2015, which first found a cardiovascular benefit in an SGLT2 inhibitor, empagliflozin (Jardiance). He was a co-author on last year’s DAPA-HF study, which found that dapagliflozin could reduce heart failure hospitalization and cardiovascular death equally well in patients regardless of diabetes status.

And on Saturday, Inzucchi dug into the DAPA-HF data to examine what happened to those who developed T2D during the trial’s follow-up period—meaning, they had a A1C of 6.5% recorded on 2 consecutive visits. Inzucchi said that among the 2605 trial participants without diabetes when the trial began, 157 patients (6%) developed T2D during the trial.

Among these patients, 93 were among the 1307 taking placebo (7.1%), while 64 were among the 1298 taking dapagliflozin (4.9%). That means patients taking the study drug were 32% less likely to develop T2D over the 18 months (HR = 0.68, 95% CI: 0.50-0.95; P = .019).

According to Inzucchi, 150 of the 157 patients who developed diabetes already had prediabetes, based on the A1C range described by ADA of 5.7% to 6.4%. The patients who did develop diabetes, he said, tended to be older and much sicker—and also accounted for a larger share of the cardiovascular deaths in the trial.

He noted that in the past, the idea of preventing T2D with a drug has been controversial. “Previous studies have shown that lifestyle changes and certain medications, specifically glucose-lowering drugs, as well as anti-obesity agents, prevent type 2 diabetes. I put that in quotes because there’s always been a concern about masking hyperglycemia as opposed to true disease prevention, but this remains controversial whether this will impact future complications or morality,” Inzucchi said.

Unlike earlier classes of T2D drugs that were shown to increase heart failure risk, SGLT2 inhibitors have been shown to produce cardiovascular benefits. “The SGLT2 inhibitors obviously reduce glucose without the risk of hypoglycemia, and they also have been shown to improve both insulin action as well as insulin secretion so they may be considered good candidates for diabetes prevention,” he said.

For Cardiologists, from Caution to Collaboration

DAPA-HF lead investigator John J.V. McMurray, MD, of the University of Glasgow, reviewed the DAPA-HF results, which he said were more dramatic than expected, including for the prevention of renal decline. He noted that the FDA has now approved dapagliflozin as a treatment for heart failure with reduced ejection fraction—the first time an SGLT2 inhibitor has received this indication. (Trials are ongoing to see what results dapagliflozin produces in heart failure with preserved ejection fraction; the EMPEROR trial results for empagliflozin in both types of heart failure are anticipated shortly.)

McMurray said cardiologists and endocrinologists have much to learn from each other; for example, he said the diuretic effect of dapagliflozin caused caution among investigators when DAPA-HF began. “I’m sure you remember we built in that 14-day follow up visit—and that’s unusual to see patients just 2 weeks after randomization, but because we are cardiologists, we’re not familiar with these drugs.”

In DAPA-HF, investigators used this first touch point to assess fluid volume and adjust other background therapy if necessary.

Mikhail Kosiborod, MD, vice president of research at Saint Luke's Health System, in Kansas City, Missouri, reviewed the quality of life findings from DAPA-HF, which showed another benefit comparable to other choices for treating heart failure—patients feel better, and they feel better fairly quickly.

“I think it's an important clinical point that not all treatments that we use for heart failure and reduced ejection fraction improve patient symptoms,” Kosiborod said. “In fact, some do and some don't, and definitely, there are treatments that improve or reduce the risk of death from hospitalization, but do not improve symptoms and may even have, at least in some patients, even a negative impact on symptoms.

For example, he said beta blockers don’t offer patients an immediate improvement in symptoms.

The quality of life concern is important, said commentator Jeffrey M. Testani, MD, MTR, of Yale School of Medicine, whose area of research includes the effect of diuretics. He projected more uptake of SGLT2 inhibitors among cardiologists, even though the drug may be added to several other therapies and may cost more than other options.

“So, why would I say that? The reason is the SGLT2 inhibitors are actually really easy to use,” Testani said. Other choices can cause renal dysfunction or electrolyte abnormalities, require more bloodwork and other monitoring, and can contribute to falls among the elderly.

“As long as the cardiologists don't feel like they have to own the A1C in diabetic patients, if they were to add an SGLT2 inhibitor, which does in fact terrify all of us, I do think that cardiologists are eventually going to have quite a bit of an uptick here.”

Inzucchi said it is important for cardiologists to understand the potential of SGTL2 inhibitors because they are more likely to see patients who will benefit. He and Kosiborod have collaborated on a research project to find out which specialty is more likely to see the patients who have diabetes and heart failure—it turns out the cardiologist is 4 times more likely to “touch” the patient. “And, if you actually have heart failure, the number increases to be 7 and 8,” Inzucchi said.

“So, if we’re going to get patients with diabetes and cardiovascular disease on these [medications], in cases that have a significant clinical impact, in both morbidity and mortality, it's going to have to be through cardiology, not necessarily endocrinology,” he said. “Certainly, in those patients that have cardiovascular disease or heart failure, and don't have diabetes, obviously, this becomes a cardiovascular therapy.”

As collaboration continues, Inzucchi said, “Any opportunity we have, whether it's an endocrinologist, cardiologist or a primary care physician, to assess the diabetes management in our patients, to see if we can transition them to more evidence based therapies, I think will have an enormous impact on the lives of our patients.”