How Is Empagliflozin Working in Type 2 Diabetes in EMPA-REG?

June 28, 2016

NEW ORLEANS — The potential mechanisms by which the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Lilly/Boehringer Ingelheim) may have reduced cardiovascular death in the landmark EMPA-REG OUTCOME trial in type 2 diabetes patients with cardiovascular disease, reported last September, was the subject of much discussion by experts at the recent American Diabetes Association (ADA) 2016 Scientific Sessions.

In EMPA-REG, empagliflozin lowered CV mortality by a significant 38%, primarily driven by a reduction in heart-failure hospitalization rather than any effects on classic traditional CV end points, such as myocardial infarction and stroke.

And in the latest analysis, also reported earlier this month at the ADA meeting, empagliflozin was shown to be renoprotective too, significantly reducing the incidence of worsening nephropathy, by 39%.

But it is puzzling that the curves for heart-failure hospitalization, renal outcomes, and cardiovascular mortality began to separate widely within 3 months of the start of EMPA-REG, and these differences were maintained for more than 3 years, said lead investigator Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut.

Indeed, "all the things we thought were important going into the trial appear to have little effect," he observed.

New Mediation Analysis: Is It Volume Changes?

Dr Inzucchi said a number of theories have been proposed in the 10 months since the trial was first reported, including the fact that the effects of empagliflozin "are mainly mediated through effects on plasma volume and off-loading of the heart." While he said this is an "attractive explanation," he noted that "only 10% of patients in EMPA-REG had overt heart failure, at least at baseline."

At the other end of the spectrum, there are suggestions "the outcome is linked to fuel energetics, alterations in fat oxidation, and increases in ketones circulating that somehow may be more efficient for the ventricles to utilize."

Reporting on a new post hoc mediation analysis of EMPA-REG, Dr Inzucchi explained that he and his coauthors focused on several areas.

Modest improvements in glycemic parameters, lipids, or blood-pressure control are unlikely to have contributed significantly to these beneficial cardiorenal outcomes within 3 months, he said. While most of these covariates changed significantly and favorably, the magnitude of change was not sufficient to fully explain the results.

Therefore, other "biological underpinnings of the reduction in CV mortality have been the topic of much speculation" over the past 9 months or so, he observed.

"The most striking observation you can make is that none of these covariates seem to be important, with one exception, and that is volume mechanism represented by change in hematocrit," he pointed out.

The hazard ratio for volume (hematocrit) was 0.791 for empagliflozin vs placebo in EMPA-REG, representing a 51.8% change, "which is a potentially significant mediator" of empagliflozin on the outcome of CV mortality, he told conference attendees.

Dr Inzucchi explained that a rise in hematocrit of around 3% correlates with a change in plasma volume of around 7%.

"This effect, which appears sustained, may be advantageous when left ventricular [cardiac] function is impaired," he observed.

Also, a rise in hematocrit when cardiac output is maintained may increase the oxygen-carrying capacity of the blood, enhancing tissue oxygenation: "This may be beneficial in the setting of ischemic heart disease and/or when left ventricular function is impaired."

But Dr Inzucchi cautioned that these findings "are post hoc and therefore should only be considered hypothesis-generating."

Could Ketonemia Be Playing a Role?

Dr Inzucchi also noted that cardiovascular death has a broad definition, "with multiple subcategories and etiologies," but only covariates that were actually measured in EMPA-REG could be included in the post hoc mediation analysis.

In other talks at the ADA meeting, and in two papers published in Diabetes Care to coincide with the conference, researchers discussed some alternative theories.

Ele Ferrannini, MD, of CNR Institute of Clinical Physiology, Pisa, Italy, along with colleagues from Boehringer Ingelheim, propose that a "thrifty-substrate paradigm" may be at play (Diabetes Care. 2016:39:1108-1114).

"We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT-2 inhibitors, beta-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids," they say.

Dr Inzucchi noted that this is indeed a viable theory but that "we did not measure ketones" in EMPA-REG.

Dr Ferrannini and colleagues note that any hypothesis "should be not just plausible but verifiable.

"To this end, the presence, amount, and time course of SGLT2 [inhibitor]–induced ketonemia could be measured and related to cardiac outcomes in adequately powered clinical studies in patients with type 2 diabetes."

Functional studies (3D echocardiography and magnetic resonance spectroscopy) and imaging studies (MRI, positron-emission tomography) in patients with diabetes who have a high CV load "could be performed before and after an SGLT-2 [inhibitor] treatment course," they suggest.

And finally, "if the thrifty-substrate paradigm held up in high-risk patients, studies in patients with lower CV risk would generate clinically useful data to inform therapeutic strategies," they add.

And in the second paper in Diabetes Care, Sunder Mudaliar MD, of Veterans Affairs Medical Center and University of California, San Diego, and colleagues continue the theme (Diabetes Care. 2016:39:1115-1122.)

They postulate that the cardiorenal benefits of empagliflozin "are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation — which are energy inefficient in the setting of the type 2 diabetic heart and kidney — toward an energy-efficient superfuel like ketone bodies, which improve myocardial/renal work efficiency and function."

This theory could at least be a partial explanation for the effects seen in EMPA-REG, they note.

"Even small beneficial changes in energetics minute to minute can translate into large differences in efficiency over weeks to months." And "furthermore, myocardial changes would benefit the kidney and vice versa.

"Well-planned physiologic and imaging studies need to be done to characterize fuel energetics-based mechanisms for the cardiovascular/renal benefits," they conclude.

Dr Ferannini has been a speaker and consultant for Merck, Sharpe & Dohme, Sanofi, Eli Lilly, Boehringer Ingelheim, Johnson & Johnson, and AstraZeneca. The other authors are employees of Boehringer Ingelheim Germany. Dr Mudaliar is a consultant to and serves on the advisory board and speaker's bureau of AstraZeneca and received research support paid to the Veterans Medical Research Foundation from Janssen Pharmaceuticals. Disclosures for the coauthors are listed in the article.

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