SGLT2 Inhibitors In Heart Failure, Diabetes Prevention Take Center Stage at American Diabetes Association Annual Meeting

Silvio Inzucchi, M.D.

Christopher P. Cannon, M.D.

Nearly five years after results about the drug Jardiance stunned the diabetes world, the class called SGLT2 inhibitors continued to dominate discussion at the annual meeting of the American Diabetes Association (ADA), which wrapped up its five-day virtual meeting today.

Today, however, the endocrinologists are sharing the ADA stage with collaborators from cardiology, as the sodium glucose co-transporter 2 (SGLT2) inhibitors are proving to produce more profound results in preventing heart failure and renal decline than they did in controlling blood sugar in diabetes.

Results from a pair of SGLT2 trials - involving a mainstay, Farxiga (dapagliflozin, AstraZeneca) and a relative newcomer, Steglatro (ertugliflozin, Merck/Pfizer) - were the big news of the ADA meeting, but for different reasons. 

Merck had already announced that topline results from the VERTIS CV trial showing that Steglatro had not matched its SGLT2 rivals in meeting certain key targets, notably a measure that included whether the drug helps lower the risk of cardiovascular death.
 
But today offered better news about the relatively late entrant to the SGLT2 market - it was approved in December 2017,  more than four years after the FDA approved the first SGLT2 inhibitor, Janssen’s Invokana (canagliflozin). According to results from the VERTIS CV trial, Steglatro cut the risk of heart failure hospitalization by 30% among patients with diabetes and cardiovascular disease, which is similar to the results for its SGLT2 inhibitors rivals. Steglatro did not match the 2015 EMPA-REG OUTCOME results of Jardiance (empagliflozin, Eli Lilly/Boehringer Ingelheim) in reducing cardiovascular death.

But today’s presenters and a commentator did not focus on that shortcoming. Instead, they emphasized that the SGLT2 class is on firm footing in the treatment guidelines for patients with type 2 diabetes with cardiovascular or renal risk. 

Sam Engel, M.D., associate vice president of clinical research for Merck, said in an interview that the heart failure results from the VERTIS CV trial were “consistent with the class” and support other data that show SGLT2 inhibitors can benefit patients at risk for heart failure. 

“We’ve been very excited in the medical community, because these are new opportunities for patients with diabetes who are at risk for hospitalization for heart failure,” he said. “We are looking forward to sharing these results with regulatory agencies around the world.”

Farxiga Shows Potential in Preventing Diabetes
Results presented over the weekend from the DAPA-HF study of Farxiga point to the next wave of inquiry for the SGLT2 inhibitors - and a return to the roots as diabetes drugs. This time, though, the drug class might be taken to prevent the disease rather than treat it.

Results from DAPA-HF that were presented last year in Paris, broke new ground by showing that Farxiga, a drug developed for diabetes, could reduce risk of heart failure in patients regardless of their diabetes status.

The American College of Cardiology and the American Heart Association have already endorsed the class for prevention in patients with diabetes who have tried lifestyle changes and metformin.

But are there new populations who might benefit from the drugs?

During a Saturday session titled, “Have we lost SGLT2 inhibitors to the cardiologists?” Silvio Inzucchi, M.D., a Yale endocrinologist, shared data that show that patients in the Farxiga trial  who did not have diabetes were 32% less likely to progress to diabetes during the course of the study, which in this analysis had a follow-up period of  18 months. All the patients in DAPA-HF had chronic heart failure with reduced ejection fraction; of this group, 58% already had diabetes. Among the rest, nearly all who developed diabetes started the trial with prediabetes, meaning their A1C was between 5.7% and 6.4%.

“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,” Inzucchi said.

The challenge now, experts say, is getting cardiologists on board with the idea of prescribing SGLT2 inhibitors in their patients, even if they do not have diabetes. As Jeffrey M. Testani, M.D., MTR, of Yale School of Medicine, said during Saturday’s panel discussion, the roadblock has been that cardiologists don’t want to “own” responsibility for a patient’s A1C level-which may be tied to quality ratings and reimbursement. 

But Inzucchi said sheer numbers mean that for the right patients to get the care they need; cardiologists must be educated. He and Mikhail Kosiborod, M.D., a cardiologist at St. Luke’s Mid-America in Kansas City, Missouri, calculated that patients with diabetes and cardiovascular risk are four times more likely to see a cardiologist than an endocrinologist, and if the patient has heart failure, the likelihood of seeing the cardiologist first goes even  higher.

“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,” Inzucchi said. “Certainly, in those patients that have cardiovascular disease or heart failure, and don't have diabetes, obviously, this becomes a cardiovascular therapy.”

Inzucchi added, “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.”