Ongoing clinical trials will uncover the potential benefit of SGLT2 inhibitors in patients with prevalent heart failure with or without diabetes mellitus.
In this article we have used consensus expert opinion alongside the available evidence, product indication and most recent clinical guidance to provide support for the diabetes healthcare community regarding the appropriate use of SGLT2 inhibitors, focussing on specific considerations for appropriate prescribing of dapagliflozin within the T1DM management pathway.
Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.<sup>1</sup> Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).<sup>2-3</sup> Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.<sup>1</sup> We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.
Whilst we have little direct evidence for the antiplatelet effects of SGLT2 inhibitors, some studies have shown that these agents may inhibit platelet aggregation and reduce the risk of thrombotic events in diabetes.
The consistent observation of an increase in hematocrit, even in those without diabetes, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin (EPO) secretion by the kidney.<sup>4</sup> This SGLT2 inhibitor mediated increase in EPO production (and resultant rise in hematocrit) could lead to systemic organ protection by virtue of its capacity as a circulating pleiotropic cytokine, known to favorably influence cardiomyocyte mitochondrial function, angiogenesis, cell proliferation and inflammation.
Recently SGLT2 inhibitors showed the promising result to treat diabetes and therefore several molecules are approved by US FDA Objective: SGLT2 inhibitors were designed based on the dioxabicyclo[3.2.1] octane with the aim to search new lead molecule.
Furthermore, the benefit of SGLT-2 inhibitors in a population of patients with HF yet without diabetes remains to be demonstrated across multiple trials.
These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes.
This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM.
The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease.
Sodium/glucose cotransporter 2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with decreased kidney function.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed significant effects in patients with diabetes or metabolic syndrome (MetS) with high cardiovascular risk.
These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.
Type 2 diabetes mellitus (Otsuka Long-Evans Tokushima Fatty rats [OLETF]) and control (Long-Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors and almost all glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown, beyond their effect on glucose control, to lead to a significant decrease in the cardiovascular burden of diabetes.
Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown.
While dipeptidyl peptidase-4 (DPP-4) inhibitors exhibited increased heart failure hospitalization in the SAVOR-TIMI 53 trial evaluating saxagliptin and in the secondary analysis of the EXAMINE trial for alogliptin, the effects of glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose co-transporter-2 (SGLT2) inhibitors on CV outcomes in diabetes have largely been positive.
Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus.