Diabetes: Mulling Jardiance Heart Benefit

Last week, researchers released the full results for a trial of empagliflozin (Jardiance), a sodium glucose cotransporter 2 (SGLT2) for treating type 2 diabetes.

The drug was found to significantly cut risk of cardiovascular death and death by all causes without significantly increasing risk of side effects, except for genital infections. The results drew both gasps and cheers from researchers who heard the results at the European Association for the Study of Diabetes (EASD) meeting in Stockholm.

In the days following that presentation, MedPage Today reached out to clinicians and researchers to determine the likely impact of those findings.

Reactions

"It's an amazing result, and totally unexpected," Naveed Sattar, PhD, of the University of Glasgow, told MedPage Today. "The most dramatic changes, particularly in CV death and mortality, are astounding. Plus those results were achieved in the context of what looks like safety -- no increase in events -- with a modest increase in infections."

Clare Lee, MD, of Johns Hopkins Hospital in Baltimore, wrote in an email that the risk of cardiovascular disease remains the one of the biggest threats to the well-being of patients with diabetes, and called the results welcome. "We are currently limited in the number of pharmacotherapy options that deliver glycemic control and cardiovascular risk reduction: metformin and pioglitazone have been associated with reduced cardiovascular risk while DPP-4 inhibitor and GLP-1 agonist have not clearly demonstrated to reduce cardiovascular risk thus far."

"This is huge," added Michael McDermott, MD, of the University of Colorado School of Medicine.

Will Guidelines Change?

At the EASD there was some suggestion by the authors that societies should examine the new evidence to determine how it fits -- or doesn't fit -- with current guidelines. But others cautioned that talk of changing the guidelines was premature.

The American Diabetes Association recommends metformin as the first pharmacotherapy choice together with a healthy lifestyle, said Lee.

"While the recent findings on empagliflozin in its association with cardiovascular risk reduction is encouraging, empagliflozin lags behind metformin in terms of glycemic reduction capacity and cost," she wrote. "Over the 48 months of study period, empagliflozin maintained only 0.36% reduction in hemoglobin A1C compared to placebo, which suggests this drug may not be the best choice as a first line or stand-alone therapy to obtain glycemic control in individuals with T2DM."

And Yunsheng Ma, MD, PhD, MPH, at the University of Massachusetts Medical School, wrote in an email that it is simply too early to consider a change to the guidelines. "I think this is a very new anti-diabetic medication, and I would like to see longer follow-up studies, and studies in older diabetic adults," he wrote.

Taking a different tack, McDermott argued that the guidelines should be changed to reflect the new results. "No diabetes medication has ever been superior to other medications in terms of reducing CV outcomes and so this place the SGLT2 inhibitors in a more prominent position in guidelines with earlier use recommended," he wrote. "High cost is still an issue but reducing CV outcomes will partly compensate for the long term medication cost."

Karl Nadolsky, DO, at the Walter Reed National Military Medical Center, wrote that the results "actually support the currently favorable position of SGLT2 inhibitors, especially the AACE diabetes treatment algorithm and also the ADA standards of care."

He added: "I favor those who have proposed early combination therapy via different mechanisms and I feel SGLT2 inhibitors fit a nice role in that philosophy including treating the underlying disease of obesity."

The Mechanism

Researchers at the meeting admitted that they did not yet know the mechanism by which the drug lowered the risk of premature all-cause mortality as well as cardiovascular death, but theorized that the cause was likely multi-factorial and not likely due to a blood pressure effect alone.

"Given the well-documented blood pressure lowering effect of SGLT2 inhibitors, lower blood pressure may be one of the mechanisms through which this class of drugs exert cardioprotective effect," wrote Lee. "Therefore, similar cardioprotective findings may be associated with canagliflozin and dapagliflozin, although the results are not available yet."

It will be 3 to 4 years before the cardiovascular trials of the two other SGLT2 inhibitors -- canagliflozin (Invokana) and dapagliflozin (Farxiga) -- are finished. In the meantime, the suggestion that the lowering of cardiovascular risk is a class effect will remain mostly speculation.

"I think and hope it is a class effect," wrote Nadolsky. "The authors propose some mechanisms in the article which are class effects including the benefits on blood pressure, visceral adiposity, etc. The separation of outcomes benefit was seen very early so while glucose control was obviously better, it was not the early driving force and is intriguing.

"As many patients did not reach the target of HbA1c <7%, the authors speculated that the benefits of empagliflozin possibly involved changes in arterial stiffness, cardiac function, cardiac oxygen demand, as well as cardio renal effects, reduction in albuminuria, etc," wrote Ma.

McDermott added that it's possible that higher glucagon levels have a positive cardiovascular benefit.

Whatever the case, there remains more research to be done.

"I think we all are looking forward to more studies with similar benefits with other treatments in the near future," wrote Nadolsky.

"Long-term studies, as well as studies in older diabetic adults are needed," added Ma. In addition, Lee urged caution. "While SGLT2 inhibitor represents an exciting newest addition to the pharmacotherapy options for individuals with T2DM, its use should be practiced with prudence especially given the recent case reports of euglycemic diabetic ketoacidosis in those with insulin-dependent diabetes and, increased genital infection risk and relatively high cost," she wrote.

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