Sex differences in risk of cardiovascular events and mortality with sodium glucose co-transporter-2 inhibitors versus glucagon-like peptide 1 receptor agonists in Australians with type 2 diabetes: a population-based cohort study.

Background: Sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D). Despite known sex differences in diabetes-induced cardiovascular disease (CVD), pharmacological treatment recommendations are independent of sex. Our objective was to investigate possible sex differences in rates of MACE with SGLT2i vs. GLP-1RA use. Methods: This population-based cohort study included men and women with T2D (≥30 years), discharged from a Victorian hospital between 1st July 2013 and 1st July 2017, and dispensed an SGLT2i or GLP-1RA within 60 days of discharge. Using Cox proportional hazards regression with competing risks, subdistribution hazard ratios (sHR) with 95% confidence intervals (CI) were estimated for MACE in a follow-up to 30th June 2018. Analyses were conducted for men and women, and subgroups based on age, baseline heart failure (HF), and atherosclerotic CVD (ASCVD) status. Findings: From a total of 8026 people (44.3% women, median follow-up time = 756 days), SGLT2i (n = 4231), compared to GLP-1RAs (n = 3795), reduced MACE rates in men (sHR 0.78; 95%CI 0.66-0.93), but not women. SGLT2i reduced MACE rates in men (sHR 0.72; 95%CI 0.54-0.98) and women (sHR 0.52; 95%CI 0.31-0.86) ≥65 years; in men with baseline HF (sHR 0.45; 95%CI 0.28-0.73); and in women with ASCVD (sHR 0.36; 95%CI 0.18-0.71). Interpretations: SGLT2i, relative to GLP-1RAs, demonstrate favourable effects for MACE reductions among older Australian men and women with T2D. Analogous benefits were also observed in men with HF and women with ASCVD. Funding: Dementia Australia Yulgilbar Innovation Award.

Current challenges in the treatment of cardiac fibrosis: Recent insights into the sex-specific differences of glucose-lowering therapies on the diabetic heart: IUPHAR Review 33.

A significant cardiac complication of diabetes is cardiomyopathy, a form of ventricular dysfunction that develops independently of coronary artery disease, hypertension and valvular diseases, which may subsequently lead to heart failure. Several structural features underlie the development of diabetic cardiomyopathy and eventual diabetes-induced heart failure. Pathological cardiac fibrosis (interstitial and perivascular), in addition to capillary rarefaction and myocardial apoptosis, are particularly noteworthy. Sex differences in the incidence, development and presentation of diabetes, heart failure and interstitial myocardial fibrosis have been identified. Nevertheless, therapeutics specifically targeting diabetes-associated cardiac fibrosis remain lacking and treatment approaches remain the same regardless of patient sex or the co-morbidities that patients may present. This review addresses the observed anti-fibrotic effects of newer glucose-lowering therapies and traditional cardiovascular disease treatments, in the diabetic myocardium (from both preclinical and clinical contexts). Furthermore, any known sex differences in these treatment effects are also explored. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.

The adiponectin signalling pathway - A therapeutic target for the cardiac complications of type 2 diabetes?

Diabetes is associated with an increased risk of heart failure (HF). This is commonly termed diabetic cardiomyopathy and is often characterised by increased cardiac fibrosis, pathological hypertrophy, increased oxidative and endoplasmic reticulum stress as well as diastolic dysfunction. Adiponectin is a cardioprotective adipokine that is downregulated in settings of type 2 diabetes (T2D) and obesity. Furthermore, both adiponectin receptors (AdipoR1 and R2) are also downregulated in these settings which further results in impaired cardiac adiponectin signalling and reduced cardioprotection. In many cardiac pathologies, adiponectin signalling has been shown to protect against cardiac remodelling and lipotoxicity, however its cardioprotective actions in T2D-induced cardiomyopathy remain unresolved. Diabetic cardiomyopathy has historically lacked effective treatment options. In this review, we summarise the current evidence for links between the suppressed adiponectin signalling pathway and cardiac dysfunction, in diabetes. We describe adiponectin receptor-mediated signalling pathways that are normally associated with cardioprotection, as well as current and potential future therapeutic approaches that could target this pathway as possible interventions for diabetic cardiomyopathy.