CHICAGO – Empagliflozin significantly reduced left ventricular mass compared with placebo over the course of 6 months in patients with type 2 diabetes and stable coronary artery disease in the randomized EMPA-HEART CardioLink-6 trial.
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Dr. Subodh Verma
Use of empagliflozin (Jardiance), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), also was associated with a clinically meaningful reduction in ambulatory systolic blood pressure and a boost in hematocrit in this population of normotensive patients with preserved left ventricular ejection fraction and high utilization of background guideline-directed medical therapy, Subodh Verma, MD, reported at the American Heart Association scientific sessions.
“Taken together, these data suggest that empagliflozin promotes early statistically and clinically significant reverse remodeling, which may contribute to the cardiovascular and heart failure benefits observed in the EMPA-REG OUTCOME trial and other SGLT2i studies,” added Dr. Verma, professor of surgery, pharmacology, and toxicology at the University of Toronto.
EMPA-REG OUTCOME was a landmark randomized trial that included 7,020 patients with type 2 diabetes and established ischemic cardiovascular disease in which the SGLT2i reduced all-cause mortality by 32%, compared with placebo over a median 3.1 years of follow-up, cardiovascular mortality by 38%, and hospitalizations for heart failure by 35% (N Engl J Med. 2015 Nov 26;373[22]:2117-28).
The mechanism responsible for these impressive clinical benefits has been unclear. The EMPA-HEART CardioLink-6 trial was a small study – 97 randomized patients – designed to shed light on this issue. The hypothesis was that SGLT2i therapy facilitates cardiac reverse remodeling. This indeed turned out to be the case when cardiac MRI findings at baseline and after 6 months were compared by blinded evaluators.
From a baseline mean left ventricular mass indexed to body surface area of 60 g/m2, which is within normal range, left ventricular mass decreased by a mean of 4.71 g in the empagliflozin group, compared with a mere 0.39-g reduction in placebo-treated controls.
Dr. Verma underscored the importance of this result: “Left ventricular mass is a strong and independent predictor of major cardiovascular events, including cardiovascular and all-cause mortality, myocardial infarction, and heart failure. Furthermore, the magnitude of left ventricular mass regression correlates with the extent of clinical outcome benefit seen with pharmacological and device therapies.”
In a prespecified subgroup analysis stratified by baseline LV mass index, patients with a baseline value greater than 60 g/m2 experienced a much greater benefit from empagliflozin, with a mean between-group difference in LV mass index reduction of 7.26 g/m2, compared with a 0.46-g/m2 difference between the SGLT2i and placebo among those with a baseline LV mass index of 60 g/m2 or less.
Ambulatory systolic blood pressure fell from a baseline of 139 mm Hg by a mean of 7.9 mm Hg in the empagliflozin group and 0.7 mm Hg with placebo. From a baseline hematocrit of 42%, hematocrit improved by an absolute 1.91% more with empagliflozin than placebo. However, there were no significant between-group differences in the secondary cardiac MRI outcomes of change in LV end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction.
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Dr. Elliott M. Antman
Discussant Elliott M. Antman, MD, hailed EMPA-HEART CardioLink-6 as “a very important mechanistic study.”
“As I leave Chicago for home, I plan to further increase the use of SGLT2 inhibitors in my patients with type 2 diabetes, especially if they have a history of heart failure, and especially if they have coronary artery disease. I would encourage you to think about doing the same, and I would also recommend that we urge our colleagues in general medicine, endocrinology, and nephrology to consider this information as well,” said Dr. Antman, professor of medicine and associate dean for clinical and translational research at Harvard Medical School, Boston, as well as an AHA past president.
He noted that EMPA-HEART CardioLink-6 provides “biologically plausible data” to explain the mechanism for the major clinical benefits of empagliflozin earlier documented in EMPA-REG OUTCOME. The likely driver of the reduction in left ventricular mass seen in EMPA-HEART CardioLink-6 was the combination of lower systolic blood pressure and higher hematocrit.
“These surrogates suggest that our traditional concepts of afterload and preload appear to be favorably affected by SGLT2 inhibition,” according to the cardiologist.
The EMPA-HEART CardioLink-6 study was funded by Boehringer Ingelheim. Dr. Verma reported receiving research support and/or speaker payments from that pharmaceutical company and roughly a dozen others. Dr. Antman had no disclosures.
SOURCE: Verma S. AHA 2018, Abstract 19332.