SGLT2 inhibition and heart failure-current concepts.

Type 2 diabetes mellitus (T2DM) is a major risk factor for several cardiovascular (CV) conditions, including heart failure (HF). However, until recently, no therapy to treat patients with diabetes could also reduce CV risks related to HF. The EMPA-REG OUTCOME trial with empagliflozin was the first to demonstrate significant cardioprotective benefits in this population. Its impressive 35% reduction in hospitalizations for HF drew the attention of the scientific community to the possibility that pharmacologic sodium-glucose cotransporter 2 (SGLT2) inhibition could be part of the armamentarium for treating patients with HF, with and without diabetes. The recently published CANVAS Program (with canagliflozin) and real-life data from the CVD-Real Study (using dapagliflozin, empagliflozin, and canagliflozin) further strengthened this hypothesis, suggesting that the observed benefit is not restricted to a particular drug, but is rather a class effect. This review explores the effects of pharmacologic SGLT2 inhibitors' use in cardiac function and discusses the potential role of this class of medication as a treatment for HF.

Should Metformin Remain First-Line Medical Therapy for Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease? An Alternative Approach.

PURPOSE OF REVIEW: With recent cardiovascular outcome trial (CVOT) results for antihyperglycemic medications, the treatment algorithm for patients with type 2 diabetes (T2DM) and atherosclerotic vascular disease (ASCVD) requires revision. RECENT FINDINGS: All completed CVOTs have demonstrated CV safety of the tested medications, with some trials demonstrating CV efficacy. While metformin remains the first-line recommended medication for T2DM, 18-37% of the patients enrolled in the completed CVOTs were not treated with metformin, providing substantial power to assess CV outcomes independent of metformin. The safety and tolerability of metformin are indisputable, but there are no robust data proving its efficacy for either macro or microvascular disease outcomes. We should reconsider the primacy of metformin in the management of T2DM in patients with ASCVD. This article will review the evidence for CV effects of antihyperglycemic agents (AHAs), and propose an evidence-based treatment algorithm for patients with T2DM and ASCVD.

A randomized clinical trial evaluating the effect of empagliflozin on triglycerides in obese adults: Role of visceral fat.

BACKGROUND: Empagliflozin, a sodium glucose cotransporter 2 inhibitor, is a medication to treat type 2 diabetes. The effect of empagliflozin in persons without diabetes has received less attention. Here we conducted a randomized, double-blind placebo-controlled clinical trial to examine the effect of empagliflozin on plasma triglycerides in obese non-diabetic adults. METHODS: Participants (n = 35; BMI ≥ 30 kg/m2) underwent body composition assessments using MRI, and were randomly assigned to either placebo or empagliflozin (10 mg/d) for three months. At the baseline and post-treatment visit, after an overnight fast, blood was drawn for biochemical analysis. Participants received [U-13C3]glycerol orally followed by multiple blood draws over 3 h to examine glycerol incorporation into triglycerides using NMR spectroscopy. RESULTS: The changes in blood triglyceride concentration with empagliflozin therapy related to the mass of baseline visceral adipose tissue (VAT; r = 0.53, p = 0.04). Empagliflozin slightly lowered triglycerides in obese subjects with low VAT, but increased triglycerides in the subjects with high VAT. Consistently, empagliflozin effectively suppressed triglyceride synthesis following [U-13C3]glycerol administration in the subjects with low VAT (p < 0.05), but not in the subjects with high VAT. The subjects with high VAT lost body weight after three months of empagliflozin treatment. In all subjects, about 20% of the triglyceride backbone originated from mitochondrial metabolism of glycerol. CONCLUSIONS: The effect of empagliflozin on triglycerides in obese adults differed depending on VAT. Empagliflozin suppressed triglyceride synthesis in the subjects with low VAT, but tended to increase triglycerides in those with high VAT.

Effects of Empagliflozin Treatment on Glycerol-Derived Hepatic Gluconeogenesis in Adults with Obesity: A Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (13 C)-labeled glycerol. METHODS: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-13 C3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models. RESULTS: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss. CONCLUSIONS: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity.

Effects of sodium glucose co-transporter 2 inhibitors on the kidney.

Sodium-glucose cotransporter 2 inhibitors are antihyperglycaemic medications with an emerging evidence base for cardiovascular and kidney disease risk reduction. Sodium-glucose cotransporter 2 inhibitors medications lower plasma glucose by inhibiting glucose reabsorption in the proximal tubule of the kidney independent of insulin. Furthermore, they reduce intraglomerular pressure by restoring tubuloglomerular feedback. Large cardiovascular outcome trials of both empagliflozin and canagliflozin have consistently shown beneficial kidney effects that go beyond glycaemic control, such as reducing risk for incident nephropathy and progression of chronic kidney disease. The mechanisms by which sodium-glucose cotransporter 2 inhibitors improve kidney outcomes are not clear. Proposed hypotheses underpinning the kidney benefits include kidney-specific effects such as decreased intraglomerular pressure, activation of angiotensin-(1-7) and the Mas receptor leading to decreased inflammation, decrease in overall kidney oxygen consumption, rise in erythropoietin levels, inhibition of the renal sodium-hydrogen exchanger and secondary kidney effects related to improvements in HbA1c and blood pressure. This review will focus on describing the mechanisms of action of sodium-glucose cotransporter 2 inhibitors in the kidney, clinical efficacy data on their use in patients with chronic kidney disease, postulated physiologic underpinnings of kidney protection observed with sodium-glucose cotransporter 2 inhibitors and the promise and potential pitfalls for their use in patients with chronic kidney disease.

Diabetes medications and cardiovascular outcome trials: Lessons learned.

The US Food and Drug Administration's current standards require that new diabetes medications demonstrate cardiovascular safety in large, long-term trials. New drugs that have been assessed in such trials are changing the management of type 2 diabetes.

Impact of empagliflozin in patients with diabetes and heart failure.

Heart failure (HF) is a common disease with increased risk for mortality and morbidity among patients with type 2 diabetes mellitus (T2DM). Optimal glycemic control in this patient population is challenging as many available therapies can potentially exacerbate symptoms of HF. Empagliflozin is one in a novel class of agents, the sodium glucose co-transporter 2 (SGLT2) inhibitors, that lowers blood glucose by increasing urinary glucose excretion and improves glycemic control and lowers body weight and blood pressure. In the recent EMPA-REG OUTCOME trial, empagliflozin was shown to improve cardiovascular outcomes in patients with T2DM and established cardiovascular risk where it reduced HF hospitalizations and cardiovascular death, with a consistent benefit among patients both with and without baseline HF. Here, we review the empagliflozin data on HF outcomes and discuss potential mechanisms for its benefits in HF with a focus on the potentially significant impact that empagliflozin may have on the care of patients with T2DM and HF in the future.