Trial Reference
EMPA-HEART CardioLink-6 randomized clinical trial
Expert Comment
Professor Thomas Kahan, MD, PhD, FAHA, FESC
Karolinska Institutet; Danderyd University Hospital – Stockholm, Sweden
Sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed to control blood glucose levels in patients with type 2 diabetes. However, their ability to reduce cardiovascular morbidity and mortality in patients with type 2 diabetes and atherosclerotic disease may be more important; and this may be the case also in the absence of diabetes (at least among patients with heart failure and a reduced ejection fraction). There are several proposed mechanisms by which SGLT2 inhibitors may exert their effects to reduce cardiovascular events, including improved glucose control, diuresis, vasodilatation with reductions in blood pressure, preload and afterload, and alterations in cardiomyocyte function.1,2
Verma and collaborators recently reported on the effects of the SGLT2 inhibitor empaglifozin on blood pressure and left ventricular mass in patients with type 2 diabetes and coronary artery disease.3 The EMPA-HEART Cardiolink-6 trial randomized 90 patients (mostly men) randomized to double blind empaglifozin od or placebo for six months. Mean age was of 63 years, duration of type 2 diabetes 11 years, glycated haemoglobin 8.0%, estimated glomerular filtration rate 88 mL/min/1.73 m2. Mean 24 h ambulatory blood pressure was 139/80 and 138/88 mm Hg, and left ventricular mass index (by cardiac magnetic resonance) 59 and 62 g/m2 in the empaglifozin and the placebo group, respectively.
Compared to placebo, empaglifozin reduced ambulatory systolic and diastolic blood pressure by (mean between group difference and 95% CI) –6.8 [–11.2; –2.3] mm Hg (P=0.003) and –3.2 [–5.8; –0.6] mm Hg (P=0.016) at six months. Also left ventricular mass index was reduced more by empaglifozin than by placebo, –3.4 [–5.9; –0.8] g/m2 (primary outcome, P=0.01). The changes in glycated haemoglobin by empaglifozin and placebo were small (–0.4 and –0.3%, respectively).
This is the first randomized clinical trail to show that empaglifozin reduces LV mass. Furthermore, the study confirms a non trivial reduction in ambulatory blood pressure by SGLT2 inhibitors.4 The reduction in left ventricular mass did not relate to changes in blood pressure, suggesting an effect beyond that of blood pressure reduction alone. A similar dissociation between effects on blood pressure and on myocardial geometry and function has also been observed when antihypertensive drug classes have been compared. Hypertensive heart disease is a strong cardiovascular risk factor, and regression of left ventricular mass reduces future cardiovascular disease.5 Thus, the results of by Verma et al may help us to understand how patients treated with SGLT2 inhibitors will reduce future cardiovascular events.
References
- Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018; 61:2108–2117. doi: 10.1007/s00125-018-4670-7
- Chin KL, Ofori-Asenso R, Hopper I, et al. Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies. Cardiovasc Res 2019;115:266–276. doi: 10.1093/cvr/cvy295
- Verma S, Mazer CD, Yan AT, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: The EMPA-HEART CardioLink-6 randomized clinical trial. Circulation 2019;140:1693-1702. doi: 10.1161/CIRCULATIONAHA.119.042375
- Kario K, Okada K, Kato M, et al. 24-hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study. Circulation 2019;139:2089–2097. doi: 10.1161/CIRCULATIONAHA.118.037076
- Jekell A, Nilsson PM, Kahan T. Treatment of hypertensive left ventricular hypertrophy. Curr Pharm Des 2018;24:4391-4396. doi: 10.2174/1381612825666181203092918.