GLP-1 Receptor Agonists in Chronic Kidney Disease: History
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Contributor:
Joshua J. Neumiller
,
Radica Z. Alicic
,
Katherine R. Tuttle

Diabetic kidney disease (DKD) represents an important diabetes (DM) complication associated with significant impacts on morbidity, mortality, and quality of life. The evidence from cardiovascular and kidney outcome trials has dramatically impacted the standard of care for patients with DKD. While agents from the glucagon-like peptide-1 (GLP-1) receptor agonist class are known for their atherosclerotic cardiovascular disease (ASCVD) benefits, growing mechanistic and clinical evidence supports the benefit of GLP-1 receptor agonist therapy on progression of DKD. GLP-1 receptor activation is associated with anti-inflammatory and antifibrotic effects in the kidney, providing a plausible mechanism for kidney protection. Based on currently available clinical trial evidence, guidelines recommend the use of GLP-1 receptor agonists to mitigate ASCVD risk in patients with type 2 diabetes (T2D). 

  • diabetes
  • GLP-1 receptor
  • agents

1. Introduction

The number of people living with diabetes (DM) continues to increase steadily worldwide [1]. An estimated 537 million adults had DM in 2021, equating to approximately 10.5% of all adults worldwide [1]. The number of people living worldwide with DM is projected to increase to 783 million cases by the year 2045 [1]. Incredibly, while the world population is projected to increase by 20% by 2045, the number of people living with DM is anticipated to increase by 46% [1]. Of the total number of people living with DM, the large majority (~95%) have type 2 diabetes (T2D) [2]. A major goal of T2D management is optimization of glycemic control to prevent or delay vascular complications that markedly increase risk for morbidity and mortality [3][4]. Chronic kidney disease (CKD) in DM, also known as diabetic kidney disease (DKD), is a particularly challenging complication given the impact of DKD on health outcomes, quality of life, and day-to-day medication management [5]. In terms of health-related outcomes, DKD increases the risk of all-cause and cardiovascular (CV) death by five- to six-fold [6][7]. Additionally, when compared to people without DM, patients with DKD have a greater likelihood of developing coronary heart disease and heart failure (HF) [5]. Fortunately, findings from recent large cardiovascular outcome trials (CVOTs) and dedicated kidney outcome trials with agents from the sodium-glucose cotransporter-2 (SGLT2) inhibitor, non-steroidal mineralocorticoid receptor antagonist (MRA), and glucagon-like peptide-1 (GLP-1) receptor agonist classes have identified important CV and kidney benefits that have changed the standard of care for treating people with DKD [5][8].

2. Proposed Mechanisms for Kidney Benefit with GLP-1 Receptor Agonists

GLP-1 receptor agonists were initially developed as glucose-lowering therapies, which have demonstrated significant efficacy for glycemia lowering with low risk of hypoglycemia [8][9]. Although glucose lowering per se may mitigate kidney injury from diabetes, the beneficial effects on atherosclerotic cardiovascular disease (ASCVD) and DKD have mostly been attributed to non-glycemic actions. [10][11][12][13][14][15][16][17]. GLP-1 receptor agonist therapy also results in improvements for other shared CV and DKD risk factors such as reductions in body weight and blood pressure [8]. A systematic review and meta-analysis reported a mean weight loss with GLP-1 receptor agonist therapy of approximately three kilograms [18]. Newer agents within the class, however, are associated with the potential for considerably greater weight loss [19][20][21], with injectable semaglutide recently joining liraglutide as GLP-1 receptor agonists that carry an obesity indication [22][23]. GLP-1 receptor agonist treatment was additionally associated with mean systolic blood pressure reductions in the range of 3–4 mmHg in large CVOTs [24]. Figure 1 provides a summary of putative mechanisms of GLP-1 receptor agonist benefit on DKD and ASCVD outcomes [14][25][26][27][28][29].
Kidneydial 02 00034 g001 550
Figure 1. Putative mechanisms of GLP-1 receptor agonist therapies on DKD and ACVD. Legend: Systemic effects of glucagon-like peptide-1 (GLP-1) receptor agonist treatment include reduction in hyperglycemia, insulin resistance, body weight, blood pressure, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) activity, resulting in modulation of the inflammatory response. Proposed effects in the kidney are principally related to suppression of inflammation and specifically include suppression of oxidative stress, reduced fibrosis, and blockade of immune cell infiltration. In the heart, GLP-1 receptor agonist therapy also reduces inflammation, and appears to benefit both endothelial dysfunction and dyslipidemia. In the carotid body, GLP-1 signaling is associated with suppressed sympathetic and arterial blood pressure responses, offering a plausible hypothesis for blood pressure reduction. Tachycardia may be mediated by direct agonism of GLP-1 receptors expressed by cells within the autonomic nervous system. Reprinted with permission from Ref. [29].
The pathogenesis of DKD involves damage to the kidney via multiple metabolic and hemodynamic mechanisms, including inflammation and fibrosis, that lead to a progressive decline in estimated glomerular filtration rate (eGFR) [28]. The production of advanced glycation end-products in conjunction with increases in oxidative stress, insulin resistance and resultant hyperglycemia promotes immune system activation early in the course of DM [15][25][26]. Immune system activation subsequently exacerbates inflammation within the kidney over time and possibly activates resident kidney T cell populations [30]. Inflammatory cell invasion subsequently promotes growth factors and pro-fibrotic cytokine upregulation, contributing to fibrosis and damage to the kidney [26][31][32].
GLP-1 receptor agonists have demonstrated anti-inflammatory, antioxidant, and antifibrotic effects, which may explain their beneficial effects on the kidney in T2D [28]. Treatment with native GLP-1 and exenatide reduced levels of multiple markers of inflammation and oxidative stress in adults with T2D (e.g., interleukin-6, interleukin-1β, monocyte chemoattractant protein-1, prostaglandins, serum amyloid A, tumor necrosis factor-α, Toll-like receptors and circulating mononuclear cells) [33]. Furthermore, GLP-1 receptor agonist treatment has demonstrated anti-inflammatory and antioxidative effects in experimental models of DKD, leading to reductions in proteinuria and indicators of endothelial cell injury [34][35]. The anti-inflammatory and antifibrotic effects of GLP-1 receptor agonists in the kidney are believed to be largely mediated by GLP-1 receptor activation (Figure 2) [28]. Current studies demonstrate a variable expression of GLP-1 receptors in different structures of kidney including within the arterial vasculature, glomerular capillaries, endothelial cells, macrophages, juxtaglomerular cells and possibly proximal tubules [36][37][38][39].
Kidneydial 02 00034 g002 550
Figure 2. Proposed incretin signaling pathways in kidney cells. Legend: The glucagon-like peptide 1 receptor (GLP-1R) is a G protein-coupled receptor that can be activated by endogenously produced GLP-1 and synthetic GLP-1 receptor agonists. Dipeptidyl peptidase 4 (DPP4) inhibitors indirectly facilitate GLP-1R activation by preventing the rapid degradation of endogenous GLP-1 in circulation. (a,b) GLP-1 receptor agonists may reduce the production of reactive oxygen species (ROS) through receptor-mediated and non-receptor-mediated mechanisms. Haem oxygenase 1 (HO1) is upregulated by GLP-1 receptor agonists and protects against oxidative stress in ischemia-reperfusion injury. (c) GLP-1R activation inhibits the binding of nuclear factor-κB (NF-κB) p65 to its target genes, which may reduce the downstream expression of chemokines, cytokines (such as tumor necrosis factor, IL-1β, IL-6 and transforming growth factor-β), and pro-fibrotic factors and adhesion molecules (such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin). (d) Administering a DPP-4 inhibitor to mice reduced the ratio of the apoptosis regulator BAX to the apoptosis regulator BCL-2, and the ratio of BCL-2-like protein 11 to BCL-2; this effect suggests a decrease in apoptosis. Whether this anti-apoptotic effect is directly medicated by DPP4 inhibitors or by GLP-1R activation is uncertain. Reprinted with permission from Ref. [28].
It has been hypothesized that GLP-1 receptor agonists may also convey benefits in the setting of DKD through promotion of natriuresis and urine alkalization (Figure 1) [40]. Acute infusion of GLP-1 agonists in rodents induces natriuresis and diuresis [41][42]. Some human studies demonstrate similar effect on natriuresis and diuresis [43][44]. For example, studies in overweight adults with and without T2D have reported increased natriuresis resulting from infusion of exenatide when compared to placebo [43][45]. These effects do not appear to be sustained long term, however, with a 12-week liraglutide treatment trial not finding sustained changes in sodium and fluid balance, with kidney sodium excretion matching sodium intake at the end of the 12-week trial period [46]. A proposed mechanism for natriuresis and diuresis is via the inhibition of the sodium hydrogen exchanger (NHE3) [47].

This entry is adapted from the peer-reviewed paper 10.3390/kidneydial2030034

References

  1. International Diabetes Foundation. IDF Diabetes Atlas: Tenth Edition 2021, 10th ed.; International Diabetes Federation: Brussels, Belgium, 2021.
  2. American Diabetes Association Professional Practice Committee. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022, 45 (Suppl. S1), S17–S38.
  3. American Diabetes Association Professional Practice Committee. 6. Glycemic targets: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022, 45 (Suppl. S1), S83–S96.
  4. Buse, J.B.; Wexler, D.J.; Tsapas, A.; Rossing, P.; Mingrone, G.; Mathieu, C.; D’Alessio, D.A.; Davies, M.J. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2020, 43, 487–493.
  5. American Diabetes Association Professional Practice Committee. 11. Chronic kidney disease and risk management: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022, 45 (Suppl. S1), S175–S184.
  6. Rao Kondapally Seshasai, S.; Kaptoge, S.; Thompson, A.; Di Angelantonio, E.; Gao, P.; Sarwar, N.; Whincup, P.H.; Mukamal, K.J.; Gillum, R.F.; Holme, I.; et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 2011, 364, 829–841.
  7. Afkarian, M.; Sachs, M.C.; Kestenbaum, B.; Hirsch, I.B.; Tuttle, K.R.; Himmelfarb, J.; De Boer, I.H. Kidney disease and increased mortality risk in type 2 diabetes. J. Am. Soc. Nephrol. 2013, 24, 302–308.
  8. American Diabetes Association Professional Practice Committee. 9. Pharmacological approaches to glycemic treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022, 45 (Suppl. S1), S125–S143.
  9. Trujillo, J.M.; Nuffer, W.; Smith, B.A. GLP-1 receptor agonists: An updated review of head-to-head clinical studies. Ther. Adv. Endocrinol. Metab. 2021, 12, 2042018821997320.
  10. ADVANCE Collaborative Group; Patel, A.; MacMahon, S.; Chalmers, J.; Neal, B.; Billot, L.; Woodward, M.; Marre, M.; Cooper, M.; Glasziou, P.; et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 2008, 358, 2560–2572.
  11. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein, H.C.; Miller, M.E.; Byington, R.P.; Goff, D.C., Jr.; Bigger, J.T.; Buse, J.B.; Cushman, W.C.; Genuth, S.; Ismail-Beigi, F.; et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 2008, 358, 2545–2559.
  12. Duckworth, W.; Abraira, C.; Moritz, T.; Reda, D.; Emanuele, N.; Reaven, P.D.; Zieve, F.J.; Marks, J.; Davis, S.N.; Hayward, R.; et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 2009, 360, 129–139.
  13. Pickup, J.C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004, 27, 813–823.
  14. Lopez-Candales, A.; Hernandez Burgos, P.M.; Hernandez-Suarez, D.F.; Harris, D. Linking Chronic Inflammation with Cardiovascular Disease: From Normal Aging to the Metabolic Syndrome. J. Nat. Sci. 2017, 3, e341.
  15. Tuttle, K.R. Linking metabolism and immunology: Diabetic nephropathy is an inflammatory disease. J. Am. Soc. Nephrol. 2005, 16, 1537–1538.
  16. Pichler, R.; Afkarian, M.; Dieter, B.P.; Tuttle, K.R. Immunity and inflammation in diabetic kidney disease: Translating mechanisms to biomarkers and treatment targets. Am. J. Physiol. Renal. Physiol. 2017, 312, F716–F731.
  17. Matoba, K.; Takeda, Y.; Nagai, Y.; Kawanami, D.; Utsunomiya, K.; Nishimura, R. Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease. Int. J. Mol. Sci. 2019, 20, 3393.
  18. Vilsboll, T.; Christensen, M.; Junker, A.E.; Knop, F.K.; Gluud, L.L. Effects of glucagon-like peptide-1 receptor agonists on weight loss: Systematic review and meta-analyses of randomised controlled trials. BMJ 2012, 344, d7771.
  19. Davies, M.; Færch, L.; Jeppesen, O.K.; Pakseresht, A.; Pedersen, S.D.; Perreault, L.; Rosenstock, J.; Shimomura, I.; Viljoen, A.; Wadden, T.A.; et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021, 397, 971–984.
  20. Wadden, T.A.; Bailey, T.S.; Billings, L.K.; Davies, M.; Frias, J.P.; Koroleva, A.; Lingvay, I.; O’Neil, P.M.; Rubino, D.M.; Skovgaard, D.; et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 randomized clinical trial. JAMA 2021, 325, 1403–1413.
  21. Rubino, D.; Abrahamsson, N.; Davies, M.; Hesse, D.; Greenway, F.L.; Jensen, C.; Lingvay, I.; Mosenzon, O.; Rosenstock, J.; Rubio, M.A.; et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 randomized clinical trial. JAMA 2021, 325, 1414–1425.
  22. Wegovy (Semaglutide) Injection ; Novo Nordisk Inc.: Plansboro, NJ, USA, 2021.
  23. Saxenda (Liraglutide) Injection ; Novo Nordisk Inc.: Plansboro, NJ, USA, 2021.
  24. Htike, Z.Z.; Zaccardi, F.; Papamargaritis, D.; Webb, D.R.; Khunti, K.; Davies, M.J. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis. Diabetes Obes. Metab. 2017, 19, 524–536.
  25. Alicic, R.Z.; Johnson, E.J.; Tuttle, K.R. Inflammatory Mechanisms as New Biomarkers and Therapeutic Targets for Diabetic Kidney Disease. Adv. Chronic Kidney Dis. 2018, 25, 181–191.
  26. Alicic, R.Z.; Rooney, M.T.; Tuttle, K.R. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin. J. Am. Soc. Nephrol. 2017, 12, 2032–2045.
  27. Yaribeygi, H.; Maleki, M.; Sathyapalan, T.; Jamialahmadi, T.; Sahebkar, A. Anti-inflammatory potentials of incretin-based therapies used in the management of diabetes. Life Sci. 2019, 241, 117152.
  28. Alicic, R.Z.; Cox, E.J.; Neumiller, J.J.; Tuttle, K.R. Incretin drugs in diabetic kidney disease: Biological mechanisms and clinical evidence. Nat. Rev. Nephrol. 2021, 17, 227–244.
  29. Cox, E.J.; Alicic, R.; Neumiller, J.J.; Tuttle, K. Clinical evidence and proposed mechanisms for cardiovascular and kidney benefits from glucagon-like peptide-1 receptor agonists. US Endocrinol. 2020, 16, 80–87.
  30. Turner, J.E.; Becker, M.; Mittrucker, H.W.; Panzer, U. Tissue-Resident Lymphocytes in the Kidney. J. Am. Soc. Nephrol. 2018, 29, 389–399.
  31. Lee, S.B.; Kalluri, R. Mechanistic connection between inflammation and fibrosis. Kidney Int. 2010, 78 (Suppl. S119), S22–S26.
  32. Meng, X.M.; Nikolic-Paterson, D.J.; Lan, H.Y. Inflammatory processes in renal fibrosis. Nat. Rev. Nephrol. 2014, 10, 493–503.
  33. Hogan, A.E.; Gaoatswe, G.; Lynch, L.; Corrigan, M.A.; Woods, C.; O’Connell, J.; O’Shea, D. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia 2014, 57, 781–784.
  34. Park, C.W.; Kim, H.W.; Ko, S.H.; Lim, J.H.; Ryu, G.R.; Chung, H.W.; Han, S.W.; Shin, S.J.; Bang, B.K.; Breyer, M.D.; 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.
  35. Kodera, R.; Shikata, K.; Kataoka, H.U.; Takatsuka, T.; Miyamoto, S.; Sasaki, M.; Kajitani, N.; Nishishita, S.; Sarai, K.; Hirota, D.; 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.
  36. Pyke, C.; Heller, R.S.; Kirk, R.K.; Ørskov, C.; Reedtz-Runge, S.; Kaastrup, P.; Hvelplund, A.; Bardram, L.; Calatayud, D. GLP-1 receptor localization in monkey and human tissue: Novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 2014, 155, 1280–1290.
  37. Bullock, B.P.; Heller, R.S.; Habener, J.F. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996, 137, 2968–2978.
  38. Erdogdu, Ö.; Nathanson, D.; Sjöholm, Å.; Nyström, T.; Zhang, Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol. Cell. Endocrinol. 2010, 325, 26–35.
  39. Schlatter, P.; Beglinger, C.; Drewe, J.; Gutmann, H. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul. Pept. 2017, 141, 120–128.
  40. Crajoinas, R.O.; Oricchio, F.T.; Pessoa, T.D.; Pacheco, B.P.; Lessa, L.M.; Malnic, G.; Girardi, A.C. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am. J. Physiol.-Ren. Physiol. 2011, 301, F355–F363.
  41. Moreno, C.; Mistry, M.; Roman, R.J. Renal effects of glucagon-like peptide in rats. Eur. J. Pharmacol. 2002, 434, 163–167.
  42. Jensen, E.P.; Poulsen, S.S.; Kissow, H.; Holstein-Rathlou, N.H.; Deacon, C.F.; Jensen, B.L.; Holst, J.J.; Sorensen, C.M. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. Am. J. Physiol.-Ren. Physiol. 2015, 308, F867–F877.
  43. Muskiet, M.H.; Tonneijck, L.; Smits, M.M.; Kramer, M.H.H.; Diamant, M.; Joles, J.A.; van Raalte, D.H. Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men. Diabetes Obes. Metab. 2016, 18, 178–185.
  44. Gutzwiller, J.P.; Tschopp, S.; Bock, A.; Zehnder, C.E.; Huber, A.R.; Kreyenbuehl, M.; Gutmann, H.; Drewe, J.; Henzen, C.; Goeke, B.; 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.
  45. Tonneijck, L.; Smits, M.M.; Muskiet, M.H.; Hoekstra, T.; Kramer, M.H.; Danser, A.H.; Diamant, M.; Joles, J.A.; van Raalte, D.H. 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.
  46. Tonneijck, L.; Smits, M.M.; Muskiet, M.H.; Hoekstra, T.; Kramer, M.H.; Danser, A.J.; Ter Wee, P.M.; Diamant, M.; Joles, J.A.; Van Raalte, D.H. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2016, 39, 2042–2050.
  47. Tonneijck, L.; Muskiet, M.H.; Blijdorp, C.J.; Smits, M.M.; Twisk, J.W.; Kramer, M.H.; Danser, A.J.; Diamant, M.; Joles, J.A.; Hoorn, E.J.; 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.-Ren. Physiol. 2019, 316, F231–F240.
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