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SGLT-2 Inhibitor Reduces Risk of Cardiovascular Death: Should Current Guidelines be Impacted?

New study generates lively discussion among experts at EASD on how to consider the results in prescribing, exploration of possible mechanism and potential class effect

As decision makers, we need to examine all the pros and cons of using a particular drug. All drugs have side effects, but research can also identify new benefits. On the brighter side for SGLT-2 Inhibitors, last September 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.

Many of the doctors and PHDs at EASD had positive comments about the new findings, calling them amazing and even astounding, as cardiovascular disease remains one of the biggest threats to the well-being of patients with diabetes.

At the EASD meeting, 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.

Clare Lee, MD, of Johns Hopkins Hospital in Baltimore, commented that, “While the recent findings on empagliflozin in its association with cardiovascular risk reduction is encouraging, it lags behind metformin in terms of glycemic reduction capacity and cost. 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.”

Many of those attending EASD agreed that it is simply too early to consider a change to the guidelines and we should have longer follow-up studies, especially in older adults with diabetes.

And others like Dr. Mcdermott, of the University of Colorado School of Medicine, differed in his opinion and 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 places the SGLT2 inhibitors in a more prominent position in guidelines with earlier use.” He added that, “High cost is still an issue but reducing CV outcomes will partly compensate for the long term medication cost.”

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 SGLT-2 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.

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.

Dr. McDermott added that, “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.”

Dr. Lee urged caution. “While SGLT-2 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 and serious urinary infections in those with insulin-dependent diabetes, and increased genital infection risk and at relatively high cost,” she wrote.

Practice Pearls:

  • Empagliflozine¬†was found to significantly cut risk of cardiovascular death and death by all causes.
  • The mechanism by which the drug lowered the risk of premature all-cause mortality and cardiovascular death has not yet been identified; future studies will help determine whether there is a class effect.
  • While some doctors urge a change to guidelines, this may be premature; more study is needed.
  • Looking at both pros and cons of any drug and discussing with your patient is recommended for every drug decision we make.

Presented empagliflozine study results at the EASD, Sept 10, 2015