Physicians' Academy for Cardiovascular Education

SGLT2 inhibitor may promote early reverse cardiac remodeling in T2DM with stable CAD

AHA 2018 – Chicago, IL, USA

News - Nov. 19, 2018

EMPA-HEART Cardiolink-6 Trial: A Randomized Trial Evaluating the Effect of Empagliflozin on Left Ventricular Structure, Function and Biomarkers in People With Type 2 Diabetes (T2D) and Coronary Heart Disease

Presented at the AHA congress 2018 by: Subodh Verma (Toronto, ON, Canada)

Introduction and methods

The EMPA-REG OUTCOME trial, which randomized over 7000 adults with type 2 diabetes (T2DM) and established CVD to treatment with the SGLT2 inhibitor empagliflozin or placebo, demonstrated that empagliflozin was associated with 14% lower risk for 3-point MACE, 38% lower risk of CV death, 32% lower risk of all-cause mortality and 35% lower risk of hospitalization for heart failure. The mechanisms responsible for these SGLT2 inhibitor-associated CV benefits remain unclear, but may involve natriuresis, reduction in interstitial edema, reduced preload and afterload and reduction in LV wall stress, improved renal function and cardiorenal physiology, inhibition of cardiac sodium-hydrogen exchange, and improved cardiac bioenergetics.

Left ventricular mass (LVM) is a strong and independent predictor of major CV outcomes, among which CV and all-cause mortality, myocardial infarction and heart failure. The magnitude of LVM regression correlates with the extent of clinical outcome benefit seen with pharmacological and device therapies. This study aimed to evaluate the impact of SGLT2 inhibition with empagliflozin on LV remodeling, by cardiac MRI, the gold-standard to evaluate LVM. A secondary objective was to identify the pathophysiological mechanisms of empagliflozin-associated LV remodeling.

423 eligible patients with a history of T2DM (HbA1c ≥6.5 and ≤10% within 3 months of the screening visit) and established CAD on stable (≥2 months) background antihyperglycemic therapy were assessed, of whom 97 were randomized. Cardiac MRI and biomarkers were determined at baseline and at 6 months. LV volumes, function and mass were calculated using CVi42 (circle imaging) and LV epicardium and endocardium were manually contoured by two blinded level 3 readers.

Main results

Conclusion

Empagliflozin 10 mg QD for 6 months significantly reduced LV mass compared with placebo, in individuals with T2DM and a history of stable CAD. These benefits were seen in a normotensive population, with preserved EF, without known heart failure, and on top of standard of care therapies, and were greater in patients with higher baseline LVMI. Empagliflozin treatment was associated with a significant reduction in ambulatory systolic BP and elevation in hematocrit levels. Thus, these data suggest that empagliflozin promotes early, statistically and clinically significant reverse remodeling, which may contribute to the CV and HF benefits observed in the EMPA-REG OUTCOME trial and other SGLT2 inhibitor trials.

Limitations of this trial that should be acknowledged are its small sample size and the short follow-up and that the stable and well-treated CAD population did not have marked LV hypertrophy at baseline, had low BNP and no HF. A strength of the trial is that both physiologic and biologic examinations were performed.

Discussion

The discussant Elliott Antman also noted the observed benefits of SGLT2 inhibition as seen in the outcome trials: improved glycemia and weight loss, a delayed decline in eGFR and delayed albuminuria, and reduced hospitalization for heart failure. He viewed the EMPA-HEART results in the context of effects of aliskiren in LV hypertrophy in the ALLAY trial, in which a similar mean change in LVMI was seen with aliskiren 300 mg in comparison to losartan 100 mg. This is when comparing the overall effect seen of empagliflozin in EMPA-HEART, but he pointed out that a much larger reduction in LVMI was seen in those with baseline LVMI >60 g/m^2.7. Thus, in addition to the mentioned benefits of empagliflozin treatment, he noted that preload and afterload are lowered, and that possibly myocardial bioenergetics are improved and that NHE may be affected. Moreover, he postulated an effect on epicardial adipose tissue.

- Our reporting is based on the information provided at the AHA Scientific Sessions -

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