GLP-1 Receptor Agonists in Diabetic Kidney Disease.
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ABSTRACT:
SUBMITTER: Michos ED
PROVIDER: S-EPMC8499005 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
GLP-1 Receptor Agonists in Diabetic Kidney Disease.
Michos Erin D ED Tuttle Katherine R KR
Clinical journal of the American Society of Nephrology : CJASN 20210413 10
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Project description:With the emergence of various classes of blood glucose-lowering agents, choosing the appropriate drug for each patient is emphasized in diabetes management. Among incretin-based drugs, glucagon-like peptide 1 (GLP-1) receptor agonists are a promising therapeutic option for patients with diabetic kidney disease (DKD). Several cardiovascular outcome trials have demonstrated that GLP-1 receptor agonists have beneficial effects on cardiorenal outcomes beyond their blood glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). The renal protective effects of GLP-1 receptor agonists likely result from their direct actions on the kidney, in addition to their indirect actions that improve conventional risk factors for DKD, such as reducing blood glucose levels, blood pressure, and body weight. Inhibition of oxidative stress and inflammation and induction of natriuresis are major renoprotective mechanisms of GLP-1 analogues. Early evidence from the development of dual and triple combination agents suggests that GLP-1 receptor agonists will probably become popular treatment options for patients with T2DM.
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Project description:Diabetic kidney disease (DKD) is one of the most common complications in type 2 diabetes mellitus (T2D) and a major cause of morbidity and mortality in diabetes. Despite the widespread use of nephroprotective treatment of T2D, the incidence of DKD is increasing, and it is expected to become the fifth cause of death worldwide within 20 years. Previous studies have demonstrated that GLP-1 receptor agonists (GLP-1 RA) have improved macrovascular and microvascular outcomes independent of glycemic differences, including DKD. GLP-1Ras' improvement on kidney physiology is mediated by natriuresis, reduction in hyperfiltration and renin-angiotensin-aldosterone system (RAAS) activity and anti-inflammatory properties. These findings translate into improved clinical outcomes such as an enhanced urine albumin-to-creatinine ratio (UACR) and a reduction in renal impairment and the need for renal replacement therapies (RRT). In this article, we review the role of GLP-1RAs on the mechanisms and effect in DKD and their clinical efficacy.
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Project description:Diabetic Kidney Disease (DKD) is the leading cause of end stage renal disease (ESRD) worldwide. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are now widely used in the treatment of patients with type 2 diabetes (T2D). A series of clinical and experimental studies demonstrated that GLP-1RAs have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by natriuresis, anti-inflammatory and anti-oxidative stress properties. Furthermore, GLP-1RAs have been shown to suppress renal fibrosis. Recent clinical trials have demonstrated that GLP-1RAs have beneficial effects on renal outcomes, especially in patients with T2D who are at high risk for CVD. These findings suggest that GLP-1RAs hold great promise in preventing the onset and progression of DKD. However, GLP-1RAs have only been shown to reduce albuminuria, and their ability to reduce progression to ESRD remains to be elucidated. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying the effects of GLP-1RAs in DKD.
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Project description:Type 2 diabetes mellitus (T2DM) represents the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESKD), and diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes. Despite advances in the nephroprotective treatment of T2DM, DKD remains the most common complication, driving the need for renal replacement therapies (RRT) worldwide, and its incidence is increasing. Until recently, prevention of DKD progression was based around strict blood pressure (BP) control, using renin-angiotensin system blockers that simultaneously reduce BP and proteinuria, adequate glycemic control and control of cardiovascular risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a new class of anti-hyperglycemic drugs shown to improve cardiovascular and renal events in DKD. In this regard, GLP-1RA offer the potential for adequate glycemic control in multiple stages of DKD without an increased risk of hypoglycemia, preventing the onset of macroalbuminuria and slowing the decline of glomerular filtration rate (GFR) in diabetic patients, also bringing additional benefit in weight reduction, cardiovascular and other kidney outcomes. Results from ongoing trials are pending to assess the impact of GLP-1RA treatments on primary kidney endpoints in DKD.
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Project description:Semaglutide (Smg), a GLP-1 receptor agonist (GLP-1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β-Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK-2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). Subsequently, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP-1RAs and KLB targeting as promising therapeutic approaches for DKD management.
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Project description:Diabetic kidney disease (DKD) remains the main cause for chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Both CKD and ESKD lead to major increases in risk of cardiovascular disease and death in people with diabetes. Despite optimal management of lifestyle, glucose levels and hypertension, residual risk remains high, indicating that additional therapies to mitigate the burden of the disease are desired. In past decades, new treatment options for the management of diabetes have emerged, of which some have showed promising renoprotective potential. This review discusses current understanding of the renal effects of glucagon-like peptide receptor agonists and their potential use in prevention and treatment of DKD.
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Project description:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as game-changers across the cardiovascular-kidney-metabolic (CKM) spectrum: overweight/obesity, type 2 diabetes mellitus (T2DM) and associated chronic kidney disease (CKD) and cardiovascular disease (CVD). Liraglutide, semaglutide and tirzepatide are European Medicines Agency approved to improve metabolic control in T2DM and to decrease weight in persons with obesity [body mass index (BMI) ≥30 kg/m2] or with overweight (BMI ≥27 kg/m2) associated with weight-related comorbidities such as hypertension, dyslipidaemia, CVD and others. Additionally, liraglutide and semaglutide are approved to reduce CVD risk in patients with CVD and T2DM. Semaglutide is also approved to reduce CVD risk in patients with CVD and either obesity or overweight and in phase 3 clinical trials showed kidney and cardiovascular protection in patients with T2DM and albuminuric CKD (FLOW trial) as well as in persons without diabetes that had CVD and overweight/obesity (SELECT trial). Thus, nephrologists should consider prescribing GLP-1 RAs to improve metabolic control, reduce CVD risk or improve kidney outcomes in three scenarios: patients with overweight and a related comorbid condition such as hypertension, dyslipidaemia or CVD, patients with obesity and patients with T2DM. This review addresses the promising landscape of GLP-1 RAs to treat persons with overweight or obesity, with or without T2DM, within the context of CKD, assessing their safety and impact on weight, metabolic control, blood pressure and kidney and cardiovascular outcomes, as part of a holistic patient-centred approach to preserve CKM health.
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