Nephroprotective effects of GLP-1 receptor agonists: where do we stand?
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REVIEW
Nephroprotective effects of GLP‑1 receptor agonists: where do we stand? Charlotte M. Mosterd1 · Petter Bjornstad2 · Daniël H. van Raalte1 Received: 5 December 2019 / Accepted: 11 April 2020 © The Author(s) 2020
Abstract Glucagon-like peptide (GLP)-1 receptor agonists are the cornerstone in the treatment of hyperglycemia in many people suffering from type 2 diabetes (T2D). These drugs have potent glucose-lowering actions and, additionally, lower body weight through satiety induction while reducing blood pressure and dyslipidemia. Partly through these actions, GLP-1 receptor agonism was shown to reduce cardiovascular disease (CVD) in people with T2D with previous CVD or at high-risk thereof. In these cardiovascular safety trials, in secondary or exploratory analyses, GLP-1 receptor agonists were also shown to reduce macro-albuminuria, an accepted surrogate marker for diabetic kidney disease (DKD), a condition that still represents a major unmet medical need. In this review we will discuss the evidence which suggests renoprotection induced by GLP-1 receptor agonists and the potential mechanisms that may be involved. These include mitigation of hyperglycemia, overweight and insulin resistance, systemic and glomerular hypertension, dyslipidemia, sodium retention, inflammation and renal hypoxia. The recently initiated large-sized FLOW trial investigating the effects of semaglutide on hard renal outcomes in patients with DKD will provide clarity whether GLP-1 receptor agonists may reduce the burden of DKD in addition to their other beneficial metabolic and cardiovascular effects. Keywords GLP-1 receptor agonists · Diabetic kidney disease · Albuminuria · Blood pressure · Incretin-based therapies
Introduction The prevalence of people living with type 2 diabetes (T2D) has increased to over 450 million worldwide and is expected to increase further in the next decades [1]. The life expectancy of people with T2D is reduced due to increased mortality from cardiovascular disease (CVD). The strongest risk factor for CVD and mortality in T2D is diabetic kidney disease (DKD) and DKD has been proposed to account for the majority of CVD risk observed in people with diabetes. In fact, although diabetes is the main cause for end-stage kidney disease (ESKD) worldwide, many people with T2D die * Daniël H. van Raalte [email protected] 1
Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Location VUMC, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Section of Endocrinology, Department of Pediatrics and Division of Nephrology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
2
from CVD before reaching ESKD [2]. DKD afflicts 20–40% of people with T2D, and manifest as increased urinary albumin excretion, impaired GFR or a combination of both [3]. It is therefore clear that DKD represent a major unmet medical need. Prevention and slowing down of DKD currently focuses on risk factor mitigation, including dietary modification (e.g. low pro
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