Empagliflozin Survival Benefit in Diabetes: Is it Plasma Volume Drop?

Miriam E Tucker

February 01, 2018

The strong effect of empagliflozin (Jardiance, Lilly/Boehringer Ingelheim) in reducing cardiovascular mortality in patients with type 2 diabetes at high risk of vascular events appears to result in large part from the drug's effect on plasma volume, new research indicates.

These latest data, from a post-hoc analysis of the landmark EMPA-REG OUTCOME study, originally presented in part at the American Diabetes Association (ADA) 2016 Scientific Sessions, are published in the February issue of Diabetes Care (2018;41:356-363) by Silvio E Inzucchi, MD, of Yale University School of Medicine, New Haven, Connecticut, and colleagues. 

EMPA-REG OUTCOME, which involved 7020 patients with type 2 diabetes and cardiovascular disease, was designed primarily to satisfy the US Food and Drug Administration's requirement for new diabetes drugs to prove cardiovascular safety, not to show superiority or elucidate mechanisms. Indeed, the 2015 report of a 38% reduction in cardiovascular death compared with placebo at 3 years with empagliflozin was initially greeted with astonishment by investigators and the medical community.

Since then, experts in diabetes and cardiology have debated the mechanism behind the unexpected survival benefit.

In this new analysis, Dr Inzucchi and colleagues found that about half of the mortality benefit of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, could be explained by changes in hematocrit and hemoglobin (51.8% and 48.9%, respectively), with smaller contributions from changes in uric acid, plasma glucose, and HbA1c (maximum 29.3%).

In contrast, changes in some traditional cardiovascular risk factors, including obesity, blood pressure, lipids, and renal function, played only minor roles.

Notably, the change in hematocrit was about +3% in the empagliflozin arm, likely a reflection of a decrease in plasma volume.

Because the mortality benefit with empagliflozin was seen so early in the trial — event curves began to separate around 3 months — the lack of effect of the drug on traditional risk factors associated with atherosclerosis was not completely surprising. However, the effect size on hematocrit was, Dr Inzucchi told Medscape Medical News.

"I don't think the lack of impact of the covariates surprised us, because the cardiovascular mortality effect was so early and so large it would be difficult to conceptualize how small changes in HbA1c or blood pressure could do that. But we were surprised by the hematocrit . . . 50% of the treatment effect is a big contribution."

Empagliflozin Over Liraglutide for Heart Failure Patients?

Clinically, the new findings might push the needle in favor of empagliflozin as a metformin add-on for patients with diabetes and established cardiovascular disease, especially in those with coexisting heart failure, Dr Inzucchi said.    

"I think about it this way: If a patient has atherosclerotic heart disease with a good ventricle, I could use empagliflozin or liraglutide."

"If the patient wants to lose more weight and doesn't mind injections, I might use liraglutide. But if they have cardiovascular disease with heart failure, based on what we know, empagliflozin would be a better choice than liraglutide."

However, he noted, only 10% of EMPA-REG patients actually had heart failure, so most of the benefit appeared to occur in those with no prior history of the condition.

More definitive conclusions in that population await results from ongoing studies in patients with heart failure, both with and without type 2 diabetes.

These include EMPEROR-Reduced, EMPEROR-Preserved, and Dapa-HF.

What's Glucose-Lowering Got to do With It?

In a separate related article also published in Diabetes Care (2018;41:219-223), Samy Suissa, PhD, of McGill University, Montreal, Quebec, explores the extent to which glucose-lowering accounted for all-cause (rather than cardiovascular disease) mortality outcomes in both EMPA-REG and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results — A Long Term Evaluation (LEADER), another landmark trial.

His analysis showed that although nearly all of liraglutide's (Victoza, Novo Nordisk) reduction in all-cause death of 3.7 per 1000/year was attributable to "antidiabetes effects" based on change in HbA1c and need for additional diabetes medications, at most, 4.5 of the 9.2/1000 person-year reduction in all-cause death with empagliflozin could be explained by glucose-related changes.

"My analysis suggests that there possibly remains an important cardiovascular benefit of empagliflozin, which is likely multidimensional, involving several cardiovascular mechanisms," Dr Suissa writes.

Commenting on those findings, Dr Inzucchi noted that Dr Suissa's analysis didn't account for possible effects of hypoglycemia, and that the difference in HbA1c between drug and placebo in LEADER wasn't large, similar to other studies examining the effects of HbA1c on cardiovascular outcomes.

Rather, Dr Inzucchi suggests that perhaps liraglutide's effect was a result of lowering HbA1c without weight gain or hypoglycemia, or some direct effect on the heart.

However, he also pointed out that Dr Suissa's findings were consistent with those from his group's new analysis.

"When you examine the changes in multiple factors together in a multivariate model, we could account for more than 90% of the effect of empagliflozin on cardiovascular mortality. So, it could be a combination of factors that are involved in this benefit — a lot attributable to decreases in plasma volume, but also some effect on reducing glucose without concurrent risks of hypoglycemia and weight gain."

"We also should remember that reducing glucose, irrespective of effects on cardiovascular disease, is still important to prevent microvascular complications," Dr Inzucchi concluded.  

The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Inzucchi has served on clinical trial steering committees, data monitoring committees, or as a consultant for Alere, Boehringer Ingelheim, AstraZeneca, Intarcia Therapeutics, Sanofi/Lexicon Pharmaceuticals, Janssen, Novo Nordisk, Eisai, and vTv Therapeutics. Dr Suissa has received research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis and participated in advisory boards or as speaker for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis.

Diabetes Care 2018;41:356-363. Abstract

Diabetes Care 2018;41:219-223. Abstract

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