Marcel H. A. Muskiet

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), together with newer multi-hormone receptor modulators that target glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin, have emerged as promising therapies for chronic kidney disease. This review examines the mechanisms through which these agents may protect the kidney and summarizes the emerging clinical evidence in populations without diabetes. Kidney protection appears to arise through complementary direct and indirect routes. Direct effects include natriuresis through inhibition of the sodium-hydrogen exchanger (NHE)-3, modulation of glomerular hemodynamics through effects on afferent arteriolar tone and vasoconstrictor pathways, and attenuation of renal inflammation; mechanisms that are largely independent of glucose lowering. Indirect mechanisms include reductions in the metabolic, hemodynamic and cardiac burden on the kidney through weight loss, blood pressure lowering, and improvement of heart failure. Beyond selective GLP-1R-agonism, the added hormonal components of multi-hormone receptor modulators engage distinct physiological pathways whose interactions may be additive, synergistic or counteracting, but remain incompletely understood. The efficacy of GLP-1 RAs and multi-hormone receptor modulators in people without diabetes is currently supported by results from secondary kidney endpoints in phase-3 obesity and cardiovascular outcome trials, including reductions in albuminuria and preservation of estimated glomerular filtration rate. Several dedicated outcome studies of GLP-1 RAs and multi-hormone receptor modulators are now underway and will determine whether these therapies become a new pillar of care in nondiabetic kidney disease.

Aims: Sotagliflozin, an inhibitor of sodium‐glucose co‐transporter (SGLT)‐1 and 2, reduces albuminuria, slows GFR decline, and may have diuretic and osmoregulatory effects. The effect of sotagliflozin added to insulin was assessed on markers of neurohormone activation and volume homeostasis in patients with type 1 diabetes (T1D). Materials and Methods: This is a post‐hoc analysis of the randomised, double‐blinded, placebo‐controlled inTandem3 trial, which assessed efficacy of sotagliflozin 400 mg/d versus placebo as an adjunct to insulin. The present biomarker analysis included 362 participants (26%) who had biological samples collected at baseline and week 24. Plasma renin, copeptin, serum N‐terminal pro b‐type natriuretic peptide (NT‐proBNP), and markers of tubular injury, inflammation, haematopoiesis, and iron homeostasis were measured at baseline and following week 24 treatment; fractional excretion of lithium (FE _Li ) and glucose (FE _Glucose ) were calculated. Results: Participants were 46 years of age (60% female) with a mean eGFR and median UACR of 88.4 mL/min/1.73 m ² and 7.5 mg/g, respectively. Sotagliflozin increased copeptin, FE _Li , and FE _Glucose by 33%, 14%, and 60‐fold, respectively (all p < 0.01), but did not change renin or NT‐proBNP (both p ≥ 0.11) compared to placebo. Further, urinary kidney injury molecule‐1 decreased by 19% ( p = 0.03). Haemoglobin and haematocrit increased (both p < 0.01), without altering inflammatory, erythropoietic, or iron biomarkers (all p ≥ 0.11). Conclusions: In this T1D population, sotagliflozin increased copeptin levels, FE _Li , and FE _Glucose without altering renin, reflecting adaptive mechanisms that preserve sodium and fluid balance and protect against volume depletion. Sotagliflozin also decreased markers of kidney injury and increased haematocrit.

The “Warburg effect”, a metabolic adaptation observed in dividing cells, involves a shift from mitochondrial oxidative phosphorylation to cytoplasmic glucose metabolism. This metabolic process is characterized by increased cellular uptake of glucose and glutamine, elevated intracellular pH and sodium levels, enhanced protection against oxidative stress, altered autophagy, and increased lactate production. Initially identified by Otto Warburg in cancer cells, the Warburg effect is now recognized as a common feature of all dividing cells, prioritizing biomass production for cell proliferation over energy generation for specialized cellular functions. Indeed, the Warburg effect is emerging as an important feature not only in cancer but also in a range of metabolic, endocrine, and neurological chronic disorders, including type 2 diabetes, heart and kidney failure, therapy-refractory epilepsy, Alzheimer's and Parkinson's diseases, chronic fatigue syndrome, and post-viral syndromes. The prevailing notion that “dysfunctional mitochondria” are the primary cause of the “energy deficit” observed in these conditions may be misleading. Instead, this “energy deficit” can result from cells reprogramming their metabolism to support cell division. Additionally, in these disorders, senescent cells are abundant, exhibiting a Warburg-like metabolism with cell cycle arrest and enhanced anabolic activity. This review explores the multifaceted role of the Warburg effect in type 2 diabetes and other metabolic and endocrine chronic disorders and examines the therapeutic potential of different interventions such as intermittent fasting, ketogenic diets, ketone supplements, and sodium/glucose co-transporter 2 inhibitors. Through a comprehensive analysis of existing literature, we aim to shed light on the mechanisms underlying these interventions and their potential impact on disease progression and patient outcomes. Graphical Abstract

Over the last decade, significant progress has been made in cardiorenal protection for metabolic diseases such as type 2 diabetes (T2D) and obesity. With an expanding range of pharmacological options and continuously evolving guidelines, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have garnered substantial clinical and societal attention for their role in T2D and weight management. GLP-1RAs have consistently demonstrated robust HbA1c- and body weight–reducing efficacy in clinical and real-world studies. In addition, mounting data established their cardiorenal benefits beyond glycaemic control in select high-risk populations. In T2D, GLP-1RAs have been shown to improve both hard cardiovascular and, more recently, relevant kidney outcomes. Meanwhile, in individuals with obesity but without T2D, semaglutide (at a higher dose than in T2D) reduces body weight by up to 15% and lowers the risk of major adverse cardiovascular events by 20%. The success of GLP-1-based therapy fuelled the development of new single molecules that combine GLP-1R agonism with activation of other entero-pancreatic hormone receptors [e.g. glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin] aiming to achieve complementary and potentially synergistic effects. These next-generation GLP-1-based therapeutics for metabolic diseases, either already available or approaching clinical approval, appear to enhance metabolic and weight-reducing efficacy compared with existing GLP-1RAs. An example is tirzepatide, a dual GLP-1/GIP receptor agonist, which has been approved for both T2D and obesity management, demonstrating up to 22.5% weight loss in phase 3 trials. This review explores the landscape of current and emerging GLP-1-based therapies, their efficacy in managing hyperglycaemia and body weight, recent evidence supporting their cardiorenal benefits and clinical implications of these advancements.