Why were the results of EMPA-REG so surprising?

Risk factors

13 Jul 2016

Diuresis with associated glucose and sodium excretion might help explain the “highly impressive and unexpected” reductions in heart failure hospitalisation, all-cause death and cardiovascular death in the EMPA-REG Outcomes study of empagliflozin, a recent review has suggested.

As one of a large number of FDA-mandated studies to establish the cardiovascular safety of newer treatments for type 2 diabetes, EMPA-REG Outcomes compared the SGLT2 inhibitor with placebo, when added to standard care, in more than 7,000 patients with type 2 diabetes and existing cardiovascular disease.

Treatment was associated with modest reductions in HbA1c, weight and blood pressure, and slight increases in both LDL and HDL cholesterol.

These changes were thought to be insufficient to explain a 14% reduction in the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

“The pattern of results from other pre-specified outcomes revealed something rather different,” the reviewers wrote in Diabetologia.

“Empagliflozin significantly lowered death from cardiovascular causes (by 38%), heart failure hospitalisation (by 35%) and death from any cause (by 32%).

“Although one must be cautious in interpreting these results on the basis that they were secondary outcomes and while further trial evidence is crucial, such a substantial reduction in all-cause death in particular gives confidence in their validity.”

The reduction in cardiovascular death was also the main driver of the reduction in the primary endpoint: in fact, there was the reduction in non-fatal MI was non-significant and there was a non-significant increase in stroke.

Reductions in mortality and heart failure emerged almost immediately, strongly suggesting that the effect was mediated by a mechanism other than reduced atherothrombosis.

“We consider that the cardiovascular benefit of empagliflozin is related to the manner in which it induces diuresis (both glucose and sodium losses), notably with a reduction in the progression to renal failure and with a slowing in the deterioration of renal function,” they said.

“In essence, improving renal sodium and glucose handling, with subsequent reductions in fluid burden especially in individuals with or susceptible to cardiac dysfunction, may have been the key driver.”

If the theory was correct, then other SGLT2 inhibitors were likely to have broadly similar effects, although they differed in their specificities for SGLT1 and SGLT2 receptors.

The CANVAS study of cardiovascular outcomes with canagliflozin, due to be completed in 2017, and the DECLARE-TIMI 58 study of dapagliflozin, due for completion in 2019, would help provide the answer, they said.

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