Summary | Why could patients with HF and T2DM benefit from SGLT2i?
Prof. Verma showed a graph of the relationship between risk of CV death and HF hospitalization and net benefit of SGLT2i: with a higher event rate for CV death and HF hospitalization, SGLT2i gives greater reduction in CV outcomes. Unknown at this time is whether patients with established HF with or without diabetes will benefit from SGLT2i. A recent analysis of the DECLARE-TIMI 58 trial examining efficacy of SGLT2i across the range of ejection fraction (EF) showed that in the placebo group, patients with reduced EF tended to have higher event rates compared to those without reduced EF. In patients with reduced EF, substantial reduction in CV death and HF hospitalization was observed with dapagliflozin, and also all-cause mortality was greatly reduced . In patients without reduced EF, dapagliflozin resulted in similar reduction of HF hospitalization, but there was no reduction in CV death or all-cause mortality. This raises the question whether the effect of SGLT2i depends on HF type.
The rationale to use SGLT2i in HF patients without diabetes is underpinned by three observations: 1) Patients with HF have similar pathophysiological features as diabetes patients [7,8]. 2) Glucosuria and natriuresis benefits of SGLT2i are seen in patients with and without diabetes [9-11]. 3) The CV benefits observed in the SGLT2i trials were largely independent of glucose levels .
The benefits of SGLT2i appear to be independent of baseline eGFR, which was demonstrated in the EMPA-REG OUTCOME trial: a consistent reduction in CV outcomes with SGLT2i was observed irrespective of renal function [13,14].
Several mechanisms have been suggested to mediate the benefits of SGLT2i . SGLT2 inhibition results in afferent arterial vasoconstriction and thereby reduces intraglomerular hypertension and improves renal function. Natriuretic benefits as well as glucosuria caused by SLGT2 inhibition are associated with reductions in BP and afterload, which is suggested to improve filling conditions of the ventricle. Emerging data show that SGLT2i have beneficial effects on myocardial metabolism, more specifically; effects on ketone utilization or branched-chain amino acid (BCAA) utilization. Other potential factors or mechanisms may involve cardiac sodium hydrogen exchange, adipokines, epicardial tissue and fibrosis.
Verma then asked how SGLT2i compare to diuretics and showed data of a study comparing the effect of dapagliflozin with that of the loop diuretic bumetanide . Dapagliflozin resulted in an increase in sodium excretion and a reduction in interstitial fluid volume and no change in blood volume, suggesting differential regulation of interstitial and intravascular compartments. Consistent with these results, in response to dapagliflozin there was no rise in plasma renin activity, neurohormonal activation, and sympathetic activation. In contrast, bumetanide resulted in a rapid increase in sodium excretion, a reduction in interstitial fluid volume and reduction in intravascular fluid volume. This may be the reason that sympathetic activity and neurohormonal activation increase with loop diuretics.
SGLT2i may lower expression of the cardiac sodium hydrogen exchanger and thereby reduce intracellular sodium, which regulates cardiac structure and function . More recently, SGLT2i have been demonstrated to inhibit Ca²+/calmodulin-dependent protein kinase II (CaM kinase II), which is involved in intracellular Ca2+ trafficking and cardiac myocyte apoptosis. Thus, SGLT2i may improve myocyte function by inhibition of cardiac myocyte apoptosis.
What about the role of energetics and ketones in the effects of SGLT2i? Diabetic animals treated with empagliflozin showed improvement in cardiac ATP generation, which was secondary to improved cardiac glucose oxidation and there was no increase in utilization of ketones . Although it is not known whether ketones play a role in the energetic effects of SGLT2i, there are other mechanisms by which ketones can have beneficial effects. An increase in beta hydroxybutyrate inhibits histone deacetylase, which can result in higher antihypertrophic transcription and may facilitate a reduction in fibrosis .
Integration of beneficial effects on BP, afterload and metabolism by SGLT2i will likely facilitate reverse remodeling of the heart. A hypothesis-generating study of 10 diabetes patients with established CVD receiving empagliflozin showed a reduction in left ventricular (LV) mass at 6 months and an increase in lateral E’ velocity, which suggests that diastolic function was improved . In the EMPA-Heart CardioLink-6 trial, the effect of empagliflozin vs. placebo on LV mass was examined in T2DM patients with a history of coronary artery disease (CAD) using cardiac MRI . The primary outcome of LV mass indexed to body surface area was reduced after 6 months of treatment with empagliflozin. These results suggests that empagliflozin promotes reverse remodeling in an early phase of treatment.
Verma then raised the question whether SGLT2i can protect the heart in the absence of diabetes. In two mice models of HFrEF, treatment with empagliflozin prevented the decrease in EF [22,23]. Data from a porcine HFrEF model demonstrated that empagliflozin was associated with improved cardiac structure and function due to a shift in myocardial utilization of ketones and BCAA , suggesting that the myocardial metabolism hypothesis may be important in conditions of HFrEF without diabetes. An in vitro study with human fibroblasts demonstrated that empagliflozin reduced expression of profibrotic markers and markers of extracellular matrix turnover. Ongoing studies examining the effect of SGLT2i in experimental models of HF with preserved EF (HFpEF) without diabetes, suggest that empagliflozin prevents decline in EF and reduces fibrosis (unpublished, Dyck and Verma). Other studies showed that canagliflozin reduces NT-proBNP, high-sensitivity troponin and IL-6 levels and favorably affects the levels of the adipokines leptin, adiponectin and leptin/adiponectin ratio [25,26].
A recent perspective by Sano and Goto proposed that erythropoietin (EPO) secretion by the kidney is involved in beneficial effects of SGLT2i . In their hypothesis, increased activity of the Na+/K+ pump to reduce glucose levels in those with diabetes leads to renal hypoxia and stress, which transforms EPO secreting fibroblasts into myofibroblasts that can no longer secrete EPO. Theoretically, treatment with SGLT2i reduces intrarenal stress and hypoxia and prevents the aberrant transformation of fibroblasts resulting in normal EPO secretion.
A recent study suggested that empagliflozin not only improves prognosis, but also cardiorespiratory fitness in diabetes patients . Ongoing studies like IMPERIAL and DETERMINE will add more data in the near future.
In summary, SGLT2i have shown remarkable benefits on several pathways, including effects on LV hypertrophy, cytokines, inflammation, extracellular remodeling, cardiac metabolism, and cardiac myocyte apoptosis. These factors may play an accumulative role in the remodeling of the myocardium and thereby affect CV outcomes.
This is a summary of the presentation given by prof. Subodh Verma, during the PACE symposium entitled 'Heart Failure, diabetes and SGLT2i: Time to change practice?', held during ESC HF in Athens, Greece on May 25, 2019.