Beyond the myocardium: Sodium‐glucose co‐transporter‐2 inhibitors in heart failure

This letter considers how recently postulated mechanisms of action of sodium-glucose co-transporter-2 (SGLT2) inhibitors might contribute to the observed risk reduction in cardiovascular (CV) mortality and hospitalization for heart failure (HF), as reported in CV outcomes trials in patients with and without type 2 diabetes mellitus (T2DM); namely, stimulation of haematocrit/erythropoietin (EPO) and sympatho-inhibition. The issue of HF in T2DM has become a rapidly evolving concern, and several reviews have been published recently. This is of increasing importance, given that HF prevalence in the United States is projected to increase by 46% by 2030, resulting in more than eight million adults living with HF and incurring medical costs of $69.8 bn. The increase in HF is driven to a large extent by projected increases in the prevalence of both diabetes and obesity in the United States over the next decade. By 2030, half of all adults are projected to be obese (with approximately a quarter of adults being classed as severely obese), and cases of diabetes will rise from 35.6 million to 54.9 million. Currently, HF contributes to one in eight deaths in the United States (2017 data). Cardiorespiratory fitness (CRF), defined as peak oxygen uptake during exercise (VO2 max), is considered to be the best predictor of CV mortality and all-cause mortality. The American Heart Association proposed that CRF should be regarded as a vital sign. Exercise capacity (ie, VO2 max) is diminished in HF, 26–30 and functional impairment is quantified by the degree of reduction in VO2. 31 Contributory mechanisms include changes in oxygen transport and utilization, and skeletal muscle abnormalities. Furthermore, each patient appears to have a unique profile of defects in the oxygen pathway. Decreased myocardial oxygen delivery results in cell hibernation, with severe hypoxia leading to eventual cell death. It is well documented that exercise capacity is also impaired and CRF is decreased in prediabetes, diabetes, and metabolic syndrome. The VO2 maximum in people with diabetes is approximately 20% lower than in those without diabetes. The suggested causes are multifactorial (reviewed in Wahl et al), and include reductions in oxygen delivery and oxygen extraction. One of the class effects of SGLT2 inhibitors is an increase in haematocrit (by approximately 2% to 4% relative to placebo) that is independent of their diuretic effect. Laboratory data showed simultaneous increases in reticulocyte count, haematocrit, and serum EPO concentration in patients with T2DM following SGLT2 inhibitor treatment (Figure 1). Patients with T2DM may have low levels of EPO regardless of the presence of anaemia or renal dysfunction. Renal cell damage from metabolic stress caused by hyperglycaemia contributes to diminished EPO production in patients with T2DM. Conversely, mitigation of such metabolic stress could be expected to increase EPO release, raise haematocrit, and increase oxygen delivery to the tissues. An exploratory analysis from an SGLT2 inhibitor CV outcome trial suggested changes in markers of plasma volume status were the most important mediators of the observed risk reduction in CV death for the SGLT2 inhibitor versus placebo, and changes in haematocrit and haemoglobin mediated 51.8% and 48.9% of this effect, respectively. This is supported by data from a trial investigating SGLT2 inhibitor effects on cardiac structure, in which SGLT2 inhibitor treatment was associated with an early increase in plasma EPO accompanied by increased haematocrit in patients with T2DM and stable coronary artery disease. Observed changes in iron stores and red blood cell morphology confirmed this was attributable to enhanced erythropoiesis rather than haemoconcentration. Further reports of SGLT2 inhibitor treatment leading to improvements in erythropoiesis have been published. The mechanisms for increased EPO and haematocrit may include SGLT2 inhibitorassociated suppression of hepcidin and modulation of iron regulatory proteins, and reduction in metabolic stress and hypoxia-induced injury in proximal kidney tubules and renal interstitium, enabling local fibroblasts to regain their EPO-producing ability. SGLT2 inhibitormediated increases in EPO may also facilitate systemic pleiotropic effects of EPO as a tissue-protective cytokine, including cardiac protection from increased oxygen delivery and reduction of left ventricular mass.