Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease : Current Opinion in Nephrology and Hypertension

Secondary Logo

Journal Logo

RENAL PATHOPHYSIOLOGY: Edited by Orson W. Moe and Susan Quaggin

Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease

Alicic, Radica Z.a,b; Neumiller, Joshua J.a,c; Tuttle, Katherine R.a,b,d

Author Information
Current Opinion in Nephrology and Hypertension 32(4):p 377-385, July 2023. | DOI: 10.1097/MNH.0000000000000894
  • Open


Purpose of review 

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials.

Recent finding 

GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects.


An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.


Chronic kidney disease (CKD) develops in approximately 40% of patients with type 2 diabetes (T2D) and 30% of those with type 1 diabetes. If CKD is attributed to diabetes without other recognizable causes, then it is described as diabetic kidney disease (DKD) [1–3]. In the period spanning 1990 to 2016, the global burden of CKD grew by approximately 90%, with an estimated global prevalence of 9.1% [4]. This increase was primarily driven by an increased number of patients developing DKD, reflecting the global pandemic of diabetes and obesity [4–6]. Development of albuminuria and decreased glomerular filtration rate are independently and additively associated with heightened risks of progression to kidney failure, cardiovascular events, and death [7–9]. The risk of dying is particularly high in adults aged 65 years and older, who are 13-times more likely to die than to progress to kidney failure [10]. For close to two decades, guideline directed medical therapy (GDMT) for patients with DKD was primarily based on optimization of glycemia, blood pressure, and use of renin-angiotensin system inhibitors. This therapeutic approach left patients with notable residual risk for progression to kidney failure and premature mortality [11–13]. Recent clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and specific incretin-based therapies (glucagon-like peptide-1 [GLP-1] and emerging dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] receptor agonists) have demonstrated treatment benefits on multiple cardiovascular and kidney disease risks and risk factors, thus transforming the standard of care for DKD and prompting frequent updates of clinical practice guidelines. This review will provide a concise update on the biology of GLP-1 and GIP, proposed putative mechanisms for their kidney protective effects, and provide a summary of current GDMT recommendations and clinical considerations for their use. 

Box 1:
no caption available


The incretin (INtestine seCRETion of Insulin) effect, describing the observation that postprandial insulin secretion is augmented following oral intake of glucose, was first described in 1930 [14]. GLP-1 is an incretin hormone produced by enteroendocrine L cells in the terminal ileum and colon and by neurons in the solitary nucleus of the brainstem [15–17]. Besides nutrients, GLP-1 release is also stimulated by neuroendocrine modulators (e.g., acetylcholine), microbiomic products (e.g., lipopolysaccharide), and immune cell-derived cytokines (e.g., interleukin-6) [18–23]. GLP-1 lowers blood glucose and induces weight loss by stimulating insulin secretion from pancreatic β-cells, suppressing glucagon secretion from pancreatic α-cells, slowing upper gastrointestinal secretion and motility, and triggering satiety through central nervous system actions [24]. Another incretin, GIP, is released in the duodenum and jejunum by enteroendocrine K cells in response to glucose, fat, and protein intake [16,25,26▪]. GIP stimulates insulin secretion and induces pancreatic secretion of glucagon. Additionally, GIP increases blood flow, insulin sensitivity and lipoprotein lipase activity in adipose tissue [27,28]. Emerging evidence from rodent studies highlight the role of GIP in suppression of appetite and food intake, in parallel with increasing energy expenditure. This “antiobesity” role is mediated largely through central nervous system mechanisms [29]. The postprandial effects of both peptides are short lived (4–7 min) because they are rapidly metabolized by dipeptidyl peptidase-4 [30].

GLP-1 and GIP act via distinct, but structurally related G-protein-coupled receptors. Both types of receptors are expressed in the endocrine pancreas where they have additive effects on insulin secretion with opposing actions on glucagon secretion [26▪]. Interestingly, while the incretin action of GLP-1 is preserved in T2D, the insulinotropic effect of GIP is largely lost, likely as a result of downregulation of GIP receptors on pancreatic beta-cells in response to chronic hyperglycemia. However, the GIP insulinotropic effect may be partially restored by improving glycemic control [27,31–33]. Beyond the pancreas, GIP and GLP-1 receptors are expressed in multiple organs, including within the central nervous and cardiovascular systems (Fig. 1) [26▪,27].

Tissue distribution of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors and proposed biological actions. VSCM, vascular smooth muscle cells [26▪,27].

Characterization of GLP-1 receptors in the kidney has been technically challenging, so exact localization remains under investigation. To-date, GLP-1 receptor mRNA and protein have been detected in vascular smooth muscle cells of afferent arterioles, efferent arterioles, hilar interlobular and arcuate arteries, juxtaglomerular cells, and proximal tubular epithelial cells in human kidneys with variations observed in different studies [34–37]. GLP-1 receptor agonists increase natriuresis and diuresis, as shown in experimental models of healthy human volunteers, and persons with obesity or diabetes [38–43]. A proposed mechanism behind this effect is inhibition of sodium-hydrogen exchanger 3-mediated transport in the proximal tubule. Binding of GLP-1 or GLP-1 receptor agonists activates the cAMP/Protein kinase A signaling pathway with phosphorylation of sodium-hydrogen exchanger 3 resulting in reduction in sodium, bicarbonate, and fluid reabsorption in the proximal tubule [37,40]. As such, diuresis and resultant blood pressure lowering could contribute to benefits of these agents on the kidney and cardiovascular system [24]. However, in a mediation analysis of kidney disease outcomes (macroalbuminuria, doubling of serum creatinine, estimated glomerular filtration rate [eGFR] <45 mL/min/1.73m2, kidney failure) from cardiovascular outcome trials (CVOTs) of liraglutide and semaglutide, lower glycemia or blood pressure only moderately mediated (10–25%) these effects, pointing to direct actions on the kidney as a predominant mechanism [44]. Other GLP-1 effects may include endothelial-derived nitric oxide-mediated vasodilation in the kidney and decreased circulating renin and angiotensin II concentrations [40,45–47]. In contrast, GIP receptors have not been detected in the kidney, suggesting that the kidney protective effects of GIP agonism are indirectly mediated [48,49▪▪,50▪▪].

Furthermore, incretins may modulate innate immunity operating as an interface between metabolic and inflammatory functions [24,51,52]. In the hematopoietic and immune systems, GIP receptors are expressed in myeloid lineages (e.g., monocytes and macrophages) and bone marrow T-cells, thus influencing immunoregulatory activities within bone marrow and macrophage-dependent inflammation in tissues [51,53]. A major site of immune cell GLP-1 receptor expression is within the intestinal intraepithelial lymphocyte signaling network [54]. Anti-inflammatory effects of GLP-1 receptor agonist therapy have been reported in several studies. For example, administration of the GLP-1 receptor agonists dulaglutide and exenatide reduced systemic C-reactive protein levels in humans, with a meta-analysis reporting an approximate 2 mg/L mean reduction in serum C-reactive protein in clinical trial participants with T2D [55]. In vitro studies additionally demonstrated that GLP-1 and exenatide induce macrophage polarization to an anti-inflammatory M2 subtype [56], while exenatide treatment suppressed plasma concentrations of chemokine ligand 2, matrix metalloproteinase 9, serum amyloid A, and interleukin-6 [57]. The mechanism(s) responsible for the anti-inflammatory actions of GLP-1 are incompletely understood, but it appears that GLP-1 down-regulates several pro-inflammatory signaling pathways, including protein kinase A/activator of transcription 3, phosphoinositide 3-kinases/protein kinase B, and mitogen-activated protein kinase/nuclear factor-κB pathways [56,58–62].

In rodent models and in cultured human mesangial cells, treatment with liraglutide, exedin-4, and GLP-1 reduced oxidative stress and had anti-inflammatory effects in the kidney [24]. Treatment with liraglutide and GLP-1 suppress activity of nicotinamide adenine dinucleotide phosphate oxidase, nicotinamide adenine dinucleotide phosphate oxidase 4, and nuclear factor-κB pathways [35,63,63]. GLP-1 receptor agonists block activation of the mononuclear phagocyte system and decrease inflammatory cell infiltration of the kidney [63,64]. They also reduce the production of proinflammatory cytokines (e.g., monocyte chemoattractant protein-1), cellular adhesion factors (e.g., intracellular adhesion molecule-1), and profibrotic factors (e.g., transforming growth factor-beta) [63–67]. The net effect of these actions is less inflammatory and fibrotic structural changes characteristic of DKD (Fig. 2) [24].

Incretin effects on structural changes observed in diabetic kidney disease. A. Histological manifestations of diabetic kidney disease include glomerular hypertrophy with expansion of the mesangium by matrix and mesangial cells; mesangial matrix accumulation with the formation of nodules (Kimmelstiel–Wilson nodules) and focal to global glomerulosclerosis; thickening of the glomerular basement membrane (GBM); podocyte foot process fusion, effacement and loss; tubular basement membrane thickening with interstitial inflammation, fibrosis and immune cell infiltration (including macrophages, lymphocytes and polymorphonuclear leukocytes); and arteriolar hyalinosis. B. Treatment with incretin-based therapies can ameliorate the structural changes in the kidney that are induced by diabetes, at least in part, through anti-inflammatory and antifibrotic effects. ECM, extracellular matrix. Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol 2021; 17(4):227-244.


Owing to the 2008 U.S. Food and Drug Administration guidance to industry requiring new glucose-lowering medications to demonstrate cardiovascular safety [68], the atherosclerotic cardiovascular disease (ASCVD) benefits of agents within the GLP-1 receptor agonist class are now widely recognized [69–71]. Several large clinical CVOTs included kidney disease as key secondary outcome measures. Most analyses have reported benefit of GLP-1 and dual GLP-1/GIP receptor agonist therapy on reducing albuminuria and slowing the rate of eGFR decline in participants with T2D [72–75,76▪▪,77▪▪]. Notably, the observed kidney benefits in the GLP-1 receptor agonist trials were greater in studies that enrolled participants with eGFR <60 mL/min/1.73m2, suggesting meaningful clinical benefits for moderate-to-severe CKD. A recent meta-analysis of GLP-1 receptor agonist CVOTs showed a reduced risk of a composite outcome inclusive of development of macroalbuminuria, doubling of serum creatinine, ≥40% decline in eGFR, progression to kidney replacement therapy, or death due to kidney disease (hazard ratio: 0.79; 95% confidence interval: 0.73–0.87; p<0.0001) [78▪▪]. Importantly, the meta-analysis found no heterogeneity for the ASCVD benefit of GLP-1 receptor agonist therapy when stratified by eGFR (eGFR <60 mL/min/1.73m2 vs. eGFR ≥60 mL/min/1.73m2; Pinteraction = 0.52) [78▪▪]. In addition, the robust glucose-lowering effects of GLP-1 receptor agonists are preserved as eGFR declines [72].

Based on the signals of kidney benefit from preclinical studies, clinical trials, CVOTs, and meta-analysis, several clinical and mechanistic studies are underway to further evaluate and define the role of GLP-1 and dual GLP-1/GIP receptor agonists in patients with CKD. The “Effect of Semaglutide versus placebo on the progression of renal impaiment in subjects wiht typw 2 diabetes” (FLOW) is a phase 3 trial enrolling participants with T2D, an eGFR of 25–75 mL/min/1.73m2 and a urine albumin-to-creatinine ratio of 100–5000 mg/g ( Identifier: NCT03819153). FLOW will assess the impact of once weekly injectable semaglutide therapy on the primary outcome of progression to kidney failure (persistent eGFR <15 mL/min/1.73m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR, or death from kidney or cardiovascular causes [79▪]. FLOW is expected to complete in the year 2024 [79▪]. In addition to FLOW, several important mechanistic studies are underway. The “Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease” (REMODEL; Identifier: NCT04865770) and the “Study of Tirzepatide (LY3298176) in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes” (TREASURE; Identifier: NCT05536804) trials are utilizing kidney biopsies and magnetic resonance imaging to elucidate the kidney mechanisms of GLP-1 and dual GIP/GLP-1 receptor agonists in patients with CKD and T2D and/or overweight and obesity.


GLP-1 receptor agonists are recommended as part of GDMT by guideline forming organizations to improve glycemic control, promote weight loss, and reduce ASCVD-related risks in patients with T2D [80–84,85▪▪]. Indeed, the American Diabetes Association (ADA) recommends GLP-1 receptor agonists with evidence of ASCVD benefit as a first-line treatment option in patients with T2D at high risk or with established ASCVD [80]. Use of a GLP-1 receptor agonist is further recommended in patients with T2D and CKD unable to use metformin or an SGLT2 inhibitor [86]. Streamlining for ease of use in patients with T2D and CKD, several GLP-1 receptor agonists and the dual GLP-1/GIP receptor agonist tirzepatide do not require dose adjustment by eGFR level for glycemic control or weight loss (Table 1) [86–93].

Table 1 - Key administration and dosing information for currently available GLP-1 and dual GLP-1/GIP receptor agonists [86–93]
Agent Route of administration Administration frequency Indication(s) Recommended Adult Dosing Recommended kidney dose adjustment
GLP-1 Receptor Agonists
Exenatide SubQ Injection Twice daily • Adjunct to diet and exercise to improve glycemic control in adults with T2D • Starting dose: 5 mcg twice daily
• Maintenance dose: 5 to 10 mcg twice daily
• Not recommended with CrCl <30 mL/min
• Caution recommended with initiating or escalating the dose with CrCl 30-50 mL/min
Lixisenatide SubQ Injection Once daily • Adjunct to diet and exercise to improve glycemic control in adults with T2D • Starting dose: 10 mcg once daily
• Maintenance dose: 20 mcg once daily
• Not recommended with eGFR <15 mL/min/1.73m2
Liraglutide SubQ Injection Once daily • Adjunct to diet and exercise to improve glycemic control in patients ≥10 years with T2D
• To reduce the risk of MACE in adults with T2D and established CVD
• Starting dose: 0.6 mg once daily
• Maintenance dose: 1.2 to 1.8 mg once daily
• No dosage adjustments recommended
Exenatide XR SubQ Injection Once weekly • Adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years old with T2D • Starting dose: 2 mg once weekly
• Maintenance dose: 2 mg once weekly
• Not recommended with eGFR <45 mL/min/1.73 m2 or ESKD
Dulaglutide SubQ Injection Once weekly • Adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years old with T2D
• To reduce the risk of MACE in adults with T2D and established CVD or multiple CV risk factors
• Starting dose: 0.75 mg once weekly
• Maintenance dose: 0.75 to 4.5 mg once weekly
• No dosage adjustments recommended
Semaglutide SubQ Injection Once weekly • Adjunct to diet and exercise to improve glycemic control in adults with T2D
• To reduce the risk of MACE in adults with T2D and established CVD
• Starting dose: 0.25 mg once weekly
• Maintenance dose: 0.5 to 2 mg once weekly
• No dosage adjustments recommended
Oral Once daily • Adjunct to diet and exercise to improve glycemic control in adults with T2D • Starting dose: 3 mg once daily
• Maintenance dose: 7 to 14 mg once daily
Dual GLP-1/GIP Receptor Agonist
Tirzepatide SubQ Injection Once weekly • Adjunct to diet and exercise to improve glycemic control in adults with T2D • Starting dose: 2.5 mg once weekly
• Maintenance dose: 5 to 15 mg once weekly
• No dosage adjustments recommended
CrCl, creatinine clearance; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; MACE, major adverse cardiovascular events; SubQ, subcutaneous; T2D, type 2 diabetes; XR, extended-release.

The most common dose-limiting side effect with GLP-1 and dual GLP-1/GIP receptor agonists are nausea, vomiting, and diarrhea which typically resolve over time with continued use. To minimize gastrointestinal side effects it is recommended to start medications at low dose, with gradual increase every 2–4 weeks as tolerated [80]. In the AWARD-7 trial which enrolled participants with moderate-to-severe CKD, these gastrointestinal side effects were reported in approximately 15–20% of patients [72]. Use of long-acting GLP-1 receptor agonists and tirzepatide is not recommended in patients with a personal or family history of medullary thyroid carcinoma, or in patients with Multiple Endocrine Neoplasia syndrome type 2 [80]. Caution is additionally recommended in patients with history or risk factors for pancreatitis, pancreatic cancer, and/or gallbladder disease [80]. While GLP-1 and dual GLP-1/GIP receptor agonists are not associated with hypoglycemia when used alone or as add-on to metformin, dose reduction or discontinuation of background sulfonylurea and/or insulin therapy may be needed to avoid hypoglycemia (Table 2) [94▪▪,95].

Table 2 - Recommended monitoring and risk mitigation strategies when using GLP-1 and dual GLP-1/GIP receptor agonists in patients with T2D and CKD [94▪▪,95].
Adverse Event Monitoring and/or Risk Mitigation Strategies
Gastrointestinal Intolerance (e.g., nausea, vomiting, diarrhea) • Educate on tolerability and symptom recognition
• Start at the lowest recommended dose and titrate upward slowly to meet individualized management goals
Hypoglycemia • Educate on hypoglycemia prevention, recognition, and treatment
• Adjust background glucose-lowering agents (e.g., insulin and/or sulfonylureas) as appropriate to reduce risk
• Monitor glycemia via blood glucose monitoring (BGM) and/or continuous glucose monitoring (CGM)
CKD, chronic kidney disease; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; T2D, type 2 diabetes.


A “four pillar” approach to managing CKD in T2D has been proposed with a renin angiotensin system inhibitor, long-acting GLP-1 receptor agonist, SGLT2 inhibitor, and finerenone, layered on a foundation of healthy lifestyle and control of conventional risk factors including hypertension, hyperglycemia, and dyslipidemia [96]. Even though randomized controlled trials testing use of combination therapies for heart and kidney protection are lacking, it is already recommended by kidney disease improving global outcomes (KDIGO) and the ADA to layer these therapies sequentially based on ongoing risk assessments [94▪▪,95]. Within the Effect of efpeglenatide on cardiovascular outcomes (AMPLITUDE-O) trail of the investigational GLP-1 receptor agonist efpeglenatide, more than 15% of participants received concomitant SGLT2 inhibitor therapy, with no heterogeneity of cardiovascular benefit observed between SGLT2 inhibitor users and nonusers [97]. These findings prompted the 2023 ADA Standards of Care to recommend that combination therapy with GLP-1 receptor agonists and SGLT2 inhibitors may be considered for potential additive benefits [80]. KDIGO also recommends adding a GLP-1 receptor agonist to background SGLT2 inhibitor or the nonsteroidal mineralocorticoid receptor agonist finerenone as needed for glucose lowering, weight loss, and ASCVD risk reduction [98].


Recent therapeutic advancements have dramatically changed the standard-of-care for patients with T2D and CKD. In addition to the established benefits of SGLT2 inhibitors and a nonsteroidal mineralocorticoid receptor agonist now codified in GDMT, evidence continues to build supporting the role of incretin-based therapies in this population. Current guidelines highlight the established role of GLP-1 receptor agonists in reducing ASCVD risk and assisting patients meet glycemic and weight goals. Ongoing kidney disease outcome trials and mechanistic studies will further define the potential role of GLP-1 and dual GLP-1/GIP receptor agonists in slowing progression of CKD and reducing risks of kidney failure and other adverse events for patients with T2D and/or overweight and obesity.



Financial support and sponsorship


Conflicts of interest

RZA reports support from NIH research grants 3U24TR001608-05S4, 1OT2OD032581, OT2HL161847, CDC project number 75D301-21-P-12254, grants from Bayer AG, and personal fees and other support from Boehringer Ingelheim outside the submitted work. JJN reports personal fees and other support from Bayer AG, Sanofi, Novo Nordisk, and Dexcom outside the submitted work. KRT is supported by NIH research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568 and CDC project number 75D301-21-P-12254; and reports other support from Eli Lilly; personal fees and other support from Boehringer Ingelheim; personal fees and other support from AstraZeneca; grants, personal fees and other support from Bayer AG; grants, personal fees and other support from Novo Nordisk; grants and other support from Goldfinch Bio; other support from Gilead; and grants from Travere outside the submitted work.


Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest


1. Chu L, Fuller M, Jervis K, et al. Prevalence of chronic kidney disease in type 2 diabetes: the Canadian Registry of Chronic Kidney Disease in Diabetes Outcomes (CREDO) study. Clin Ther 2021; 43:1558–1573.
2. US Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2022. Available at: Accessed February 3, 2023.
3. United States Renal Data System. 2022 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2022. Available from: [Accessed 27 Apr 2023]
4. Xie Y, Bowe B, Mokdad AH, et al. Analysis of the global burden of disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int 2018; 94:567–581.
5. International Diabetes Federation. IDF Diabetes Atlas. 9th ed. International Diabetes Federation; 2019. Available at: Accessed January 15, 2023.
6. Di Angelantonio E, Bhupathiraju S, Wormser D, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 2016; 388:776–786.
7. van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 2011; 79:1341–1352.
8. Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int 2011; 79:1331–1340.
9. Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011; 80:93–104.
10. Dalrymple LS, Katz R, Kestenbaum B, et al. Chronic kidney disease and the risk of end-stage renal disease versus death. J Gen Intern Med 2011; 26:379–385.
11. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869.
12. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.
13. Parving HH, Brenner BM, Cooper ME, et al. [Effect of losartan on renal and cardiovascular complications of patients with type 2 diabetes and nephropathy]. Ugeskr Laeger 2001; 163:5514–5519.
14. Nauck MA, Heimesaat MM, Ørskov C, et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993; 91:301–307.
15. Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab 2019; 30:72–130.
16. Holst JJ, Albrechtsen NJW, Rosenkilde MM, et al. Physiology of the incretin hormones, GIP and GLP-1-regulation of release and posttranslational modifications. Compr Physiol 2019; 9:1339–1381.
17. Holt MK, Richards JE, Cook DR, et al. Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food. Diabetes 2019; 68:21–33.
18. Lim GE, Brubaker PL. Glucagon-like peptide 1 secretion by the L-cell. Diabetes 2006; 55:S70–S77.
19. Adam TC, Westerterp-Plantenga MS. Nutrient-stimulated GLP-1 release in normal-weight men and women. Horm Metab Res 2005; 37:111–117.
20. Ellingsgaard H, Seelig E, Timper K, et al. GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study. Diabetologia 2020; 63:362–373.
21. Kahles F, Meyer C, Mollmann J, et al. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 2014; 63:3221–3229.
22. Balks HJ, Holst JJ, von zur Muhlen A, et al. Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J Clin Endocrinol Metab 1997; 82:786–790.
23. Lebrun LJ, Lenaerts K, Kiers D, et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep 2017; 21:1160–1168.
24. Alicic RZ, Cox EJ, Neumiller JJ, et al. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol 2021; 17:227–244.
25. Reimann F, Diakogiannaki E, Moss CE, et al. Cellular mechanisms governing glucose-dependent insulinotropic polypeptide secretion. Peptides 2020; 125:170206.
26▪. Nauck MA, Quast DR, Wefers J, et al. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab 2021; 23:5–29.
27. Holst JJ, Rosenkilde MM. Recent advances of GIP and future horizons. Peptides 2020; 125:170230.
28. Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat Rev Endocrinol 2023; 19:201–216.
29. Fukuda M. The role of GIP Receptor in the CNS for the pathogenesis of obesity. Diabetes 2021; 70:1929–1937.
30. Deacon CF. What do we know about the secretion and degradation of incretin hormones? Regul Pept 2005; 128:117–124.
31. Calanna S, Christensen M, Holst JJ, et al. Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. Diabetes Care 2013; 36:3346–3352.
32. Holst JJ, Windelov JA, Boer GA, et al. Searching for the physiological role of glucose-dependent insulinotropic polypeptide. J Diabetes Investig 2016; 7:8–12.
33. Hojberg PV, Vilsboll T, Rabol R, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 2009; 52:199–207.
34. Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 2014; 155:1280–1290.
35. Schlatter P, Beglinger C, Drewe J, et al. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept 2007; 141:120–128.
36. Körner M, Stöckli M, Waser B, et al. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007; 48:736–743.
37. Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol 2011; 301:F355–F363.
38. Ronn J, Jensen EP, Wewer Albrechtsen NJ, et al. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors. Physiol Rep 2017; 5:e13503.
39. Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004; 89:3055–3061.
40. Skov J, Dejgaard A, Frokiaer J, et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J Clin Endocrinol Metab 2013; 98:E664–E671.
41. Gutzwiller JP, Hruz P, Huber AR, et al. Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion 2006; 73:142–150.
42. Tonneijck L, Smits MM, Muskiet MH, et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia 2016; 59:1412–1421.
43. Tonneijck L, Muskiet MHA, Blijdorp CJ, et al. Renal tubular effects of prolonged therapy with the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes mellitus. Am J Physiol Renal Physiol 2019; 316:F231–F240.
44. Mann JFE, Buse JB, Idorn T, et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes Metab 2021; 23:2058–2066.
45. Thomson SC, Kashkouli A, Liu ZZ, et al. Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin. Am J Physiol Renal Physiol 2017; 313:F854–F858.
46. Muskiet MH, Tonneijck L, Smits MM, et al. Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men. Diabetes Obes Metab 2016; 18:178–185.
47. Asmar A, Cramon PK, Simonsen L, et al. Extracellular fluid volume expansion uncovers a natriuretic action of GLP-1: a functional GLP-1-renal axis in man. J Clin Endocrinol Metab 2019; 104:2509–2519.
48. Seino Y, Yabe D. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: Incretin actions beyond the pancreas. J Diabetes Investig 2013; 4:108–130.
49▪▪. Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021; 398:1811–1824.
50▪▪. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021; 385:503–515.
51. Mantelmacher FD, Zvibel I, Cohen K, et al. GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nat Metab 2019; 1:58–69.
52. Yaribeygi H, Maleki M, Sathyapalan T, et al. Anti-inflammatory potentials of incretin-based therapies used in the management of diabetes. Life Sci 2019; 241:117152.
53. Pujadas G, Varin EM, Baggio LL, et al. The gut hormone receptor GIPR links energy availability to the control of hematopoiesis. Mol Metab 2020; 39:101008.
54. Yusta B, Baggio LL, Koehler J, et al. GLP-1 receptor (GLP-1R) agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte (IEL) GLP-1R. Diabetes 2015; 64:2537–2549.
55. Mazidi M, Karimi E, Rezaie P, et al. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J Diabetes Compl 2017; 31:1237–1242.
56. Shiraishi D, Fujiwara Y, Komohara Y, et al. Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation. Biochem Biophys Res Commun 2012; 425:304–308.
57. Chaudhuri A, Ghanim H, Vora M, et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab 2012; 97:198–207.
58. Vinué Á, Navarro J, Herrero-Cervera A, et al. The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype. Diabetologia 2017; 60:1801–1812.
59. Shi L, Ji Y, Jiang X, et al. Liraglutide attenuates high glucose-induced abnormal cell migration, proliferation, and apoptosis of vascular smooth muscle cells by activating the GLP-1 receptor, and inhibiting ERK1/2 and PI3K/Akt signaling pathways. Cardiovasc Diabetol 2015; 14:18.
60. Wang X, Chen J, Rong C, et al. GLP-1RA promotes brown adipogenesis of C3H10T1/2 mesenchymal stem cells via the PI3K-AKT-mTOR signaling pathway. Biochem Biophys Res Commun 2018; 506:976–982.
61. Zhao YY, Chen LH, Huang L, et al. Cardiovascular protective effects of GLP-1: a focus on the MAPK signaling pathway. Biochem Cell Biol 2021; 100:9–16.
62. Chen J, Mei A, Wei Y, et al. GLP-1 receptor agonist as a modulator of innate immunity. Front Immunol 2022; 13:997578.
63. Hendarto H, Inoguchi T, Maeda Y, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism 2012; 61:1422–1434.
64. Sancar-Bas S, Gezginci-Oktayoglu S, Bolkent S. Exendin-4 attenuates renal tubular injury by decreasing oxidative stress and inflammation in streptozotocin-induced diabetic mice. Growth Factors 2015; 33:419–429.
65. Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 2011; 54:965–978.
66. Park CW, Kim HW, Ko SH, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol 2007; 18:1227–1238.
67. Ishibashi Y, Nishino Y, Matsui T, et al. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism 2011; 60:1271–1277.
68. U.S. Food and Drug Administration. Guidance for Industry: Diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008. Available from: [Accessed 27 Apr 2023]
69. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–322.
70. Marso SP, Bain SC, Consoli A, et al. SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375:1834–1844.
71. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394:121–130.
72. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6:605–617.
73. Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377:839–848.
74. Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2018; 6:859–869.
75. Shaman AM, Bain SC, Bakris GL, et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER. Circulation 2022; 145:575–585.
76▪▪. Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: posthoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol 2022; 10:774–785.
77▪▪. Tuttle KR, Bosch-Traberg H, Cherney DZI, et al. Changes in estimated glomerular filtration rate in people with type 2 diabetes at high cardiovascular risk treated with semaglutide versus placebo: post hoc analysis of SUSTAIN 6 and PIONEER 6. Kidney Int 2023; S0085-2538:00056–X.
78▪▪. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021; 9:653–662.
79▪. Rossing P, Baereas FMM, Bakris G, et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 2023; [Epub ahead of print].
80. ElSayed NA, Aleppo G, Aroda VR, et al. American diabetes association standards of care in diabetes - 2023. Diabetes Care 2023; 46:S1–S291.
81. Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2022; 65:1925–1966.
82. Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan - 2022 update. Endocr Pract 2022; 28:923–1049.
83. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, prediabetes, and cardiovascular disease developed in collaboration with the EASD. Eur Heart J 2020; 41:255–323.
84. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020; 76:1117–1145.
85▪▪. Handelsman Y, Anderson JE, Bakris GL, et al. DCRM multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complications 2022; 36:108101.
86. Exenatide (Byetta) injection. Prescribing information. AstraZeneca Pharmaceuticals LP; Wilmington, DE. December 2022. Available from: [Accessed 27 Apr 2023]
87. Lixisenatide (Adlyxin) injection. Prescribing information. Sanofi-aventis U.S., LLC; Bridgewater, NJ. June 2022. Available from: [Accessed 27 Apr 2023]
88. Liraglutide (Victoza) injection. Prescribing information. Novo Nordisk Inc.; Plainsboro, NJ. June 2022. Available from: [Accessed 27 Apr 2023]
89. Exenatide extended-release (Bydureon) injection. Prescribing information. AstraZeneca Pharmaceuticals LP; Wilmington, DE. December 2022. Available from: [Accessed 27 Apr 2023]
90. Dulaglutide (Trulicity) injection. Prescribing information. Eli Lilly and Company; Indianapolis, IN. November 2022. Available from: [Accessed 27 Apr 2023]
91. Semaglutide (Ozempic) injection. Prescribing information. Novo Nordisk Inc.; Plainsboro, NJ. October 2022. Available from: [Accessed 27 Apr 2023]
92. Semaglutide (Rybelsus) tablets. Prescribing information. Novo Nordisk Inc.; Plainsboro, NJ. January 2023. Available from: [Accessed 27 Apr 2023]
93. Tirzepatide (Mounjaro) injection. Prescribing information. Eli Lilly and Company; Indianapolis, IN. September 2022. Available from: [Accessed 27 Apr 2023]
94▪▪. de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2022; 102:974–989.
95. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2022; 102:S1–S127.
96. Agarwal R, Fouque D. The foundation and the four pillars of treatment for cardiorenal protection in people with chronic kidney disease and type 2 diabetes. Nephrol Dial Transplant 2023; 38:253–257.
97. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021; 385:896–907.
98. Rossing P, Caramori ML, Chan JCN, et al. Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence. Kidney Int 2022; 102:990–999.

diabetic kidney disease; GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists; glucagon-like peptide receptor agonist; kidney protection; weight loss

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.