Data show empagliflozin-associated LV remodeling
CHICAGO -- Changes in left ventricular structure and function may help explain how SGLT-2 inhibitors improve cardiovascular health, according to the small EMPA-HEART Cardiolink-6 trial presented here.
In a population of type 2 diabetes patients with well-treated coronary artery disease and no known heart failure, empagliflozin (Jardiance) reduced the left ventricular (LV) mass index to a greater extent at 6 months than did placebo (-2.6 g/m2 vs -0.01 g/m2, P=0.01) and led to more LV mass regression on cardiac MRI (-4.71 vs -0.39 g), reported Subodh Verma, MD, PhD, of the University of Toronto, and colleagues.
The difference remained robust no matter how the researchers indexed LV mass to height or weight, Verma reported in a late-breaker trial presentation at American Heart Association
(AHA) annual meeting.
"These data suggest that the SGLT-2 inhibitor, 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 SGLT-2 inhibitor studies," Verma stated.
In 2015, EMPA-REG investigators showed that empagliflozin cut the risk of cardiovascular events, particularly cardiovascular mortality and heart failure hospitalization. Yet the unanswered question of the mechanism by which SGLT-2 inhibition can lead to cardiovascular benefits remains today.
Reverse remodeling is just one of several proposed mechanisms; diuresis another important one, commented Donald Lloyd-Jones, MD, of Northwestern Medicine in Chicago.
Others possible mechanisms include reduced interstitial edema; a decrease in preload and afterload accompanied by lower LV wall stress; and inhibition of cardiac sodium-hydrogen exchange, Verma noted.
In EMPA-HEART, hematocrit levels went up more with SGLT-2 inhibition (+2.4% vs +0.4%, P=0.006). Ambulatory blood pressure monitoring also showed better reduction of systolic blood pressure with empagliflozin (-7.9 vs -0.7 mmHg, P=0.003); the difference in diastolic blood-pressure lowering was not different between the drug and placebo (-2.0 vs -0.8 mmHg, P=0.22), however.
Neither arm showed an advantage in the secondary cardiac MRI outcomes of LV end-systolic volume index and LV end-diastolic volume index. LV ejection fraction (LVEF) trended toward improvement with empagliflozin (+2.2% vs -0.01, P=0.07).
NT-proBNP, troponin I, and soluble ST2 levels were not affected by SGLT-2 inhibition, though Verma noted that biomarker levels were low to begin with and stayed unaffected over treatment.
Empagliflozin also failed to make a dent in adverse events.
EMPA-HEART included patients, ages 40-80, with a history of type 2 diabetes who had A1C levels in the 6.5-10% range. Study participants had to have had a prior coronary revascularization or MI. All were on a stable background of antihyperglycemic therapy.
Of 423 individuals screened for the trial, just 97 ended up randomized between the lack of patient interest in participation and the reasons for exclusion.
Groups were well-matched at baseline and the cohort averaged age 63 with a BMI of 27, and LV mass index around 60 g/m2. Almost all trial participants were on metformin, statins, and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers.
Subgroup analysis suggested that those with LV mass index >60 g/m2 at baseline had especially large reductions in this metric after 6 months of empagliflozin use (P=0.007 for interaction).
Nevertheless, Verma acknowledged the small sample and short follow-up in EMPA-HEART.
"This is a very important mechanistic study," stated AHA discussant Elliott Antman, MD, of Brigham and Women's Hospital in Boston. "This reduction in LV mass is also an important observation since LV mass is an independent predictor of cardiovascular events including incident heart failure."
The reduction in systolic blood pressure and increase in hematocrit associated with empagliflozin use in EMPA-HEART presumably put patients "in a more favorable position" in preload and afterload, Antman suggested.
Overall, the study jibes with other recent studies including DECLARE-TIMI 58 -- a dapagliflozin (Farxiga) trial showing reduced heart failure and renal outcomes in diabetes with that SGLT-2 inhibitor, Antman said.
The study was supported by Boehringer Ingelheim.
Verma disclosed relevant relationships with Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Valeant, and Sanofi.
Antman disclosed no relevant relationships with industry.
American Heart Association
Source Reference: Verma S, et al "EMPA-HEART CardioLink-6 trial: a randomized trial of empagliflozin on left ventricular structure, function and biomarkers in people with type 2 diabetes and coronary heart disease" AHA 2018.
American Heart Association
Source Reference: Antman E "EMPA-HEART CardioLink-6 trial" AHA 2018.
Read the original article on Medpage Today: AHA: Reverse Remodeling Plays Role in Jardiance CV Benefit