INTRODUCTION
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.
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PUTATIVE MECHANISMS FOR KIDNEY PROTECTION BY INCRETINS
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].
FIGURE 1: 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].
FIGURE 2: 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.
KIDNEY AND HEART PROTECTION WITH INCRETIN THERAPIES
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 (ClinicalTrials.gov 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; ClinicalTrials.gov 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; ClinicalTrials.gov 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.
CURRENT GUIDANCE FOR INCRETIN THERAPIES IN TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE
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.
INCRETIN THERAPIES IN COMBINATION WITH OTHER THERAPIES FOR CHRONIC KIDNEY DISEASE IN 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].
CONCLUSIONS
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.
Acknowledgements
None.
Financial support and sponsorship
None.
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.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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