Response by Kato et al to Letter Regarding Article, “Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus”
Authors: Eri T. Kato, Marc S. Sabatine, Stephen D. Wiviott
Journal: Circulation (2019)

In Response:We thank Dr Elghazaly and colleagues for their letter.We agree that the mechanisms of action of sodium-glucose cotransporter-2 (SGLT2) inhibitors for reducing hospitalization for heart failure (HF) are of interest and are not fully understood.SGLT2 inhibitors block the SGLT2 transporter in the proximal renal tubule, reducing intraglomerular pressure and increasing urinary excretion of glucose and sodium. 1 These effects result not only in a reduction in circulating glucose, but also in body weight and blood pressure. 1To that end, in the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) trial, treatment with dapagliflozin as compared with placebo led to modest reductions in hemoglobin A1c (0.42%), systolic blood pressure (2.7 mm Hg), diastolic blood pressure (0.7 mm Hg), and body weight (1.8 kg). 2 Whether these reductions translated directly to a 27% reduction in hospitalization for HF cannot be fully determined from a randomized trial designed to look at cardiovascular outcomes.Certainly hypertension is one of the major risk factors for the development and progression of HF.In a previous meta-analysis, each 10-mm-Hg reduction in systolic blood pressure was associated with a significant 38% reduction of HF. 3 In addition, a 5% to 7% increase in the risk of developing HF per 1 unit body mass index increase has been reported.Extrapolating from these data suggests that the individual component effects may not be enough to explain the robust reduction of HF risk observed in DECLARE-TIMI 58 with the use of the SGLT2 inhibitor, dapagliflozin.Moreover, dapagliflozin decreased the risk of hospitalization for HF to similar amounts regardless of diuretic use, 4 suggesting the presence of additional mechanisms beyond simple diuresis that likely have contributed to the benefit.Some additional proposed mechanisms include improvement in arterial stiffness, plasma uric acid levels, inflammatory epicardial adipose tissue, renal protection, renally-mediated attenuation of the renin-angiotension-aldosterone system, stimulation and sympathetic nervous system activity, red blood cell mass expansion augmenting oxygen delivery capacity to tissue, and potential inhibition of cardiac sodium-hydrogen exchanger 1. 1 More recently, there has been a growing attention to a ketone hypothesis and Na + /H + exchanger inhibition hypothesis.SGLT2 inhibitors have been demonstrated to increase ketone synthesis, which could result in an improved mitochondrial function presenting more energy-efficient fuel for the heart compared with glucose. 1 Also, SGLT2 inhibitors inhibit Na + / H + exchanger, presenting direct cardiac effects by reducing cytosolic Na + , cytosolic Ca + and reducing mitochondorial Ca 2+ concentration, which is believed to be one of the drivers for HF. 5 HF, particularly with diabetes, can represent a complex interplay between the heart and kidney, and quantifying the role of effects on individual components in the multifactorial disease is beyond the scope of a clinical outcomes trial.How-