The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status.

Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors.

Comparing and Contrasting the Effects of the SGLT Inhibitors Canagliflozin and Empagliflozin on the Progression of Retinopathy.

Background: Diabetic retinopathy (DR) is a leading cause of end-stage blindness globally and is arguably one of the most disabling complications of both Type 1 and Type 2 diabetes. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have now been successfully introduced to clinical medicine and exert multiple beneficial effects in diabetic patients. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may alleviate the progression of DR.

The Sympathetic Nervous System Regulates Sodium Glucose Co-Transporter 1 Expression in the Kidney.

Hyperactivation of the sympathetic nervous system (SNS) has been demonstrated in various conditions including obesity, hypertension and type 2 diabetes. Elevated levels of the major neurotransmitter of the SNS, norepinephrine (NE), is a cardinal feature of these conditions. Increased levels of the sodium glucose cotransporter 1 (SGLT1) protein have been shown to occur in the parotid and submandibular glands of hypertensive rodents compared to normotensive controls.

Retinal Capillary Damage Is Already Evident in Patients With Hypertension and Prediabetes and Associated With HbA1c Levels in the Nondiabetic Range.

Objective: We analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage.

Research Design And Methods: In a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes.

Results: The CDF was lower in patients with prediabetes than in those with normal glucose metabolism.

The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy.

Diabetic kidney disease (DKD) is a chronic disorder characterized by elevated urine albumin excretion, reduced glomerular filtration rate, or both. At present, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the standard care for the treatment of DKD, resulting in improved outcomes. However, alternative treatments may be required because although the standard treatments have been found to slow the progression of DKD, they have not been found to halt the disease.

Targeting Features of the Metabolic Syndrome Through Sympatholytic Effects of SGLT2 Inhibition.

Purpose Of Review: The moderate glucose-lowering effect of sodium glucose co-transporter 2 (SGLT2) inhibitors is unlikely to explain SGLT2 inhibitor-mediated beneficial outcomes, and unravelling the underlying mechanisms is a high priority in the research community. Given the dominant pathophysiologic role of the sympathetic nervous system activation in conditions such as hypertension and perturbed glucose homeostasis, it is pertinent to postulate that SGLT2 inhibitors may exert their beneficial effects at least in part via sympathetic inhibition.

Recent Findings: SGLT2 inhibitors have shown enormous potential to improve cardiovascular outcomes in patients with type 2 diabetes, and their therapeutic potential is currently being investigated in a range of associated comorbidities such as heart failure and chronic kidney disease.

Determining the role of SGLT2 inhibition with Empagliflozin in the development of diabetic retinopathy.

Diabetes mellitus is a chronic metabolic disease that occurs when the pancreas is not producing enough insulin or when the insulin that it does produce is not able to be used effectively in the body. This results in hyperglycemia and if the blood sugars are not controlled, then it can lead to serious damage of various body systems, especially the nerves and the blood vessels. Uncontrolled diabetes is a major cause of kidney failure, heart attacks, stroke and amputation.

TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes.

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 Diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents.

Role of Microparticles in Cardiovascular Disease: Implications for Endothelial Dysfunction, Thrombosis, and Inflammation.

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Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)-A Condition Associated with Heightened Sympathetic Activation.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood.

Implications of ADAM17 activation for hyperglycaemia, obesity and type 2 diabetes.

In this review, we focus specifically on the role that the metalloproteinase, A Disintegrin and Metalloproteinase 17 [ADAM17] plays in the development and progression of the metabolic syndrome. There is a well-recognised link between the ADAM17 substrate tumour necrosis factor α (TNF-α) and obesity, inflammation and diabetes. In addition, knocking out ADAM17 in mice leads to an extremely lean phenotype.

Combined renal and common hepatic artery denervation as a novel approach to reduce cardiometabolic risk: technical approach, feasibility and safety in a pre-clinical model.

Background: Cardiovascular and metabolic regulation is governed by neurohumoral signalling in relevant organs such as kidney, liver, pancreas, duodenum, adipose tissue, and skeletal muscle. Combined targeting of relevant neural outflows may provide a unique therapeutic opportunity for cardiometabolic disease.

Objectives: We aimed to investigate the feasibility, safety, and performance of a novel device-based approach for multi-organ denervation in a swine model over 30 and 90 days of follow-up.

Retinal capillary rarefaction is associated with arterial and kidney damage in hypertension.

Microvascular disease and rarefaction are key pathological hallmarks of hypertension. The retina uniquely allows direct, non-invasive investigation of the microvasculature. Recently developed optical coherence tomography angiography now allows investigation of the fine retinal capillaries, which may provide a superior marker of overall vascular damage.

Microvascular changes at different stages of chronic kidney disease.

Patients with progressing chronic kidney disease (CKD) are more likely to experience cardio- and cerebrovascular events than progressing to end-stage renal disease. The authors explored whether retinal microvascular calibers differed with the degree of renal impairment and between the standard and extended optic disk and may serve as a simple additional tool for risk stratification in this highly vulnerable patient cohort. The authors analyzed central retinal arteriolar and venular equivalent calibers (CRAE, CRVE) at different retinal zones (zone B&C) using digital retinal imaging in hypertensive patients with stage 2 (n = 66) or stage 3 CKD (n = 30).

Supine blood pressure-A clinically relevant determinant of vascular target organ damage in hypertensive patients.

Night-time blood pressure (BP) is an important predictor of cardiovascular outcomes. Its assessment, however, remains challenging due to limited accessibility to ambulatory BP devices in many settings, costs, and other factors. We hypothesized that BP measured in a supine position during daytime may perform similarly to night-time BP when modeling their association with vascular hypertension-mediated organ damage (HMOD).

SGLT2 Inhibitor-Induced Sympathoexcitation in White Adipose Tissue: A Novel Mechanism for Beiging.

Recent preclinical data show that sodium glucose cotransporter 2 (SGLT2) inhibitors are able to reduce weight gain and induce beiging in white adipose tissue (WAT). We have previously shown that in neurogenic hypertensive Schlager (BPH/2J) mice, treatment with the SGLT2 inhibitor, Dapagliflozin, reduced blood pressure and prevented weight gain. Here we show that chemical sympathetic denervation achieved by systemic administration of 6-hydroxy-dopamine (6-OHDA) reduces body weight and the heightened sympathetic nervous system (SNS) innervation in WAT.

Nocturnal hypertension: a common phenotype in a tertiary clinical setting associated with increased arterial stiffness and central blood pressure.

Objective: Although the detrimental effect of increased mean blood pressure (BP) is well established, the role of the dynamic and circadian features of BP is less well defined but may be similarly important. In this prospective analysis of hypertensive patients from a tertiary hospital hypertension clinic, we investigated whether the presence of night-time systolic hypertension is associated with more pronounced end-organ damage as assessed by measures of pulse wave analysis (PWA) and pulse wave velocity (PWV).

Methods: A cohort of 222 consecutive hypertensive patients underwent ambulatory blood pressure measurements, PWA, PWV testing and collection of routine clinical data.

The Influence of Hypertensive Therapies on Circulating Factors: Clinical Implications for SCFAs, FGF21, TNFSF14 and TNF-α.

Studying the role of circulatory factors in the pathogenesis of diseases has been key to the development of effective therapies. We sought to examine the effect of antihypertensive therapies on numerous circulatory factors including short chain fatty acids and growth factors in a human cohort. A subset of participants from an earlier study was characterized by their hypertensive and/or treatment status and separated into three groups: (i) normotensives; (ii) untreated hypertensive and (iii) treated hypertensive subjects.

Sodium glucose co-transporter 2 inhibition reduces succinate levels in diabetic mice.

Background: Type 1 diabetes (T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity. The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2 (SGLT2). Presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications.

An evaluation of empagliflozin and it's applicability to hypertension as a therapeutic option.

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits.

Areas Covered: This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of Empagliflozin and discusses its role in diabetes-associated hypertension.

SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection.

Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction.

The Schlager mouse as a model of altered retinal phenotype.

Hypertension is a risk factor for a large number of vision-threatening eye disorders. In this study, we investigated for the first time the retinal neural structure of the hypertensive BPH/2J mouse (Schlager mouse) and compared it to its control counterpart, the normotensive BPN/3J strain. The BPH/2J mouse is a selectively inbred mouse strain that develops chronic hypertension due to elevated sympathetic nervous system activity.