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Tirzepatide and prevention of chronic kidney disease

Bosch, Catalina, Carriazo, Sol, Soler, María José, Ortiz, Alberto, Fernandez-Fernandez, Beatriz·2023·Clinical Kidney Journal
DOI 10.1093/ckj/sfac274PMC PMC10157759
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Abstract

Tirzepatide is a twincretin recently approved to improve glycemic control in type 2 diabetes mellitus (T2DM). More specifically, tirzepatide is an agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP1) receptors. In recent clinical trials in persons with obesity or overweight with associated conditions, tirzepatide decreased body weight and other cardiorenal risk factors (blood pressure, low-density lipoprotein cholesterol, glycated hemoglobin and albuminuria). Moreover, in a post hoc analysis of the SURPASS-4 randomized clinical trial, tirzepatide decreased albuminuria and total estimated glomerular filtration rate (eGFR) slopes and nearly halved the risk of a pre-specified composite kidney endpoint (eGFR decline ≥40%, renal death, kidney failure or new-onset macroalbuminuria) in participants with T2DM and high cardiovascular risk when compared with insulin glargine. Similar to other kidney-protective drugs, tirzepatide, alone or combined with sodium-glucose co-transporter 2 inhibitors, caused an early dip in eGFR. Moreover, tirzepatide also decreased eGFR slopes in participants with eGFR >60 mL/min/1.73 m2 or with normoalbuminuria. We now review the potential kidney health implications of tirzepatide, addressing its structure and function, relationship to current GLP1 receptor agonists, impact of recent results for the treatment and prevention of kidney disease, and expectations for the future.

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Graphical Abstract
Graphical Abstract CC BY-NC · PubMed Central
Figure 1: Structure of GLP1, the GLP1 receptor agonist semaglutide, GIP and the dual GLP1 and GIP receptor agonist tirzepatide. Amino acids are color-coded reflecting shared or unique amino acids. Arrows identify amino acids that are unique for the synthetic agonists. The thick arrow indicates aminoisobutyric acid (Aib) residues in positions 2 and 13 which is shared by semaglutide and tirzepatide. Tirzepatide has a C-terminal amide, and a lysine residue at position 20 attached to 1,20-eicosanedioic acid via a linker. The GLP1 receptor and GIP receptors are also shown (adapted from [4]).
Figure 1: Structure of GLP1, the GLP1 receptor agonist semaglutide, GIP and the dual GLP1 and GIP receptor agonist tirzepatide. Amino acids are color-coded reflecting shared or unique amino acids. Arrows identify amino acids that are unique for the synthetic agonists. The thick arrow indicates aminoisobutyric acid (Aib) residues in positions 2 and 13 which is shared by semaglutide and tirzepatide. Tirzepatide has a C-terminal amide, and a lysine residue at position 20 attached to 1,20-eicosanedioic acid via a linker. The GLP1 receptor and GIP receptors are also shown (adapted from [4]).CC BY-NC · PubMed Central
Figure 2: Physiology of GIP and GLP1. Food ingestion triggers the release of incretins from gut neuroepithelial cells. GIP is encoded by the GIP gene and is generated by proteolysis of a precursor peptide (PreproGIP) by K cells in the duodenum. GLP1 is encoded by the GCG gene that also encodes glucagon and GLP-2. GLP1 is generated by proteolysis of a precursor peptide (proglucagon) by L cells from the distal small intestine. Both GIP and GLP1 have incretin effects (i.e. promote insulin release from pancreatic beta cells) and have additional shared and unique actions as reflected in Fig. 3. Both have short half-life (approximately 5 and 2 min for GIP and GLP1, respectively) and are metabolized by DPP-4 into inactive peptides that are filtered by glomeruli and reabsorbed and further degraded by kidney proximal tubular cells. DPP-4 inhibitors are also antidiabetic drugs, but they degrade other peptides beyond the incretins and the clinical impact of DPP-4 inhibitors may thus differ from that of GLP1R agonists or dual GLP1R/GIPR agonists. Adapted from [8].
Figure 2: Physiology of GIP and GLP1. Food ingestion triggers the release of incretins from gut neuroepithelial cells. GIP is encoded by the GIP gene and is generated by proteolysis of a precursor peptide (PreproGIP) by K cells in the duodenum. GLP1 is encoded by the GCG gene that also encodes glucagon and GLP-2. GLP1 is generated by proteolysis of a precursor peptide (proglucagon) by L cells from the distal small intestine. Both GIP and GLP1 have incretin effects (i.e. promote insulin release from pancreatic beta cells) and have additional shared and unique actions as reflected in Fig. 3. Both have short half-life (approximately 5 and 2 min for GIP and GLP1, respectively) and are metabolized by DPP-4 into inactive peptides that are filtered by glomeruli and reabsorbed and further degraded by kidney proximal tubular cells. DPP-4 inhibitors are also antidiabetic drugs, but they degrade other peptides beyond the incretins and the clinical impact of DPP-4 inhibitors may thus differ from that of GLP1R agonists or dual GLP1R/GIPR agonists. Adapted from [8].CC BY-NC · PubMed Central
Figure 3: Shared and unique actions by GIP and GLP1 in key target organs that may be reproduced by tirzepatide.
Figure 3: Shared and unique actions by GIP and GLP1 in key target organs that may be reproduced by tirzepatide.CC BY-NC · PubMed Central
Figure 4: Key pre-specified kidney endpoints reported for SURPASS-4. SURPASS-4 compared tirzepatide 5, 10 or 15 mg/week and insulin glargine during a median follow-up of 85–104 weeks in people with T2DM, BMI ≥25 kg/m2 and high cardiovascular risk with a primary endpoint of non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. Kidney outcomes were secondary endpoints and for this analysis, tirzepatide groups were combined [3]. (A) Full population (n = 1995). (B) CKD defined by UACR ≥30 mg/g (n = 707/1995, 35% of the full population). (C) CKD defined by eGFR <60 mL/min/1.73 m2 (n = 342/1992, 17% of the full population). Endpoint 1: eGFR decline ≥40% from baseline, renal death, progression to kidney failure or new-onset macroalbuminuria. Endpoint 2: eGFR decline ≥40% from baseline, renal death, progression to kidney failure. New-onset macroalbuminuria: UACR >300 mg/g. There were no exclusion criteria based on albuminuria or eGFR but patients who had had a transplanted organ or were awaiting an organ transplant were excluded. Horizontal line indicates HR of 1.0. Figure designed using data reported in reference [3].
Figure 4: Key pre-specified kidney endpoints reported for SURPASS-4. SURPASS-4 compared tirzepatide 5, 10 or 15 mg/week and insulin glargine during a median follow-up of 85–104 weeks in people with T2DM, BMI ≥25 kg/m2 and high cardiovascular risk with a primary endpoint of non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. Kidney outcomes were secondary endpoints and for this analysis, tirzepatide groups were combined [3]. (A) Full population (n = 1995). (B) CKD defined by UACR ≥30 mg/g (n = 707/1995, 35% of the full population). (C) CKD defined by eGFR <60 mL/min/1.73 m2 (n = 342/1992, 17% of the full population). Endpoint 1: eGFR decline ≥40% from baseline, renal death, progression to kidney failure or new-onset macroalbuminuria. Endpoint 2: eGFR decline ≥40% from baseline, renal death, progression to kidney failure. New-onset macroalbuminuria: UACR >300 mg/g. There were no exclusion criteria based on albuminuria or eGFR but patients who had had a transplanted organ or were awaiting an organ transplant were excluded. Horizontal line indicates HR of 1.0. Figure designed using data reported in reference [3].CC BY-NC · PubMed Central
Figure 5: Changes in eGFR between baseline and end of treatment in SURPASS-4. SURPASS-4 compared tirzepatide and insulin glargine during a median follow-up of 85–104 weeks in people with T2DM, BMI ≥25 kg/m2 and high cardiovascular risk [3]. The primary endpoint was non-inferiority of tirzepatide 10 mg or 15 mg per week, or both, versus glargine in HbA1c change from baseline to 52 weeks. For the analysis of change in eGFR, tirzepatide groups were combined. Between-group differences in mean eGFR slope decline and 95% CI are shown. (A) According to baseline eGFR. (B) According to baseline UACR. (C) Information was not provided for the subgroup of patients without CKD (i.e. eGFR 60 mL/min/1.73 m2and UACR <30 mg/g) which represents the largest subgroup of participants. G and A categories are defined according to KDIGO 2012. Horizontal line at zero indicates no difference and values above zero favor tirzepatide. Figure designed using data reported in reference [3].
Figure 5: Changes in eGFR between baseline and end of treatment in SURPASS-4. SURPASS-4 compared tirzepatide and insulin glargine during a median follow-up of 85–104 weeks in people with T2DM, BMI ≥25 kg/m2 and high cardiovascular risk [3]. The primary endpoint was non-inferiority of tirzepatide 10 mg or 15 mg per week, or both, versus glargine in HbA1c change from baseline to 52 weeks. For the analysis of change in eGFR, tirzepatide groups were combined. Between-group differences in mean eGFR slope decline and 95% CI are shown. (A) According to baseline eGFR. (B) According to baseline UACR. (C) Information was not provided for the subgroup of patients without CKD (i.e. eGFR 60 mL/min/1.73 m2and UACR <30 mg/g) which represents the largest subgroup of participants. G and A categories are defined according to KDIGO 2012. Horizontal line at zero indicates no difference and values above zero favor tirzepatide. Figure designed using data reported in reference [3].CC BY-NC · PubMed Central

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Cites

Show all 11 references

Research works printed but not linked: 18

  1. Novikoff, 2021, Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists, Mol Metab, 49, 101181, 10.1016/j.molmet.2021.101181 · DOI
  2. Sun, 2022, Structural determinants of dual incretin receptor agonism by tirzepatide, Proc Natl Acad Sci USA, 119, e2116506119, 10.1073/pnas.2116506119 · DOI
  3. Nauck, 2021, The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update, Diabetes Obes Metab, 23, 5, 10.1111/dom.14496 · DOI · Paper page
  4. Zhao, 2022, Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors, Nat Commun, 13, 1057, 10.1038/s41467-022-28683-0 · DOI · Paper page
  5. Wilson, 2020, The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes, Diabetes Obes Metab, 22, 2451, 10.1111/dom.14174 · DOI
  6. Bailey, 2021, Tirzepatide: a new low for bodyweight and blood glucose, Lancet Diabetes Endocrinol, 9, 646, 10.1016/S2213-8587(21)00217-5 · DOI
  7. Heise, 2022, Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial, Lancet Diabetes Endocrinol, 10, 418, 10.1016/S2213-8587(22)00085-7 · DOI · Paper page
  8. Zhenyukh, 2018, Branched-chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation, J Cell Mol Med, 22, 4948, 10.1111/jcmm.13759 · DOI
  9. Kadowaki, 2022, Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial, Lancet Diabetes Endocrinol, 10, 634, 10.1016/S2213-8587(22)00187-5 · DOI · Paper page
  10. Inagaki, 2022, Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial, Lancet Diabetes Endocrinol, 10, 623, 10.1016/S2213-8587(22)00188-7 · DOI · Paper page
  11. Rosenstock, 2021, Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial, Lancet North Am Ed, 398, 143, 10.1016/S0140-6736(21)01324-6 · DOI · Paper page
  12. Del Prato, 2021, 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 North Am Ed, 398, 1811, 10.1016/S0140-6736(21)02188-7 · DOI · Paper page
  13. Ludvik, 2021, Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial, Lancet North Am Ed, 398, 583, 10.1016/S0140-6736(21)01443-4 · DOI · Paper page
  14. Gerstein, 2019, Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial, Lancet North Am Ed, 394, 121, 10.1016/S0140-6736(19)31149-3 · DOI · Paper page
  15. Wanner, 2016, Empagliflozin and progression of kidney disease in type 2 diabetes, N Engl J Med, 375, 323, 10.1056/NEJMoa1515920 · DOI · Paper page
  16. Fernandez-Fernandez, 2020, SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia, Clin Kidney J, 13, 728, 10.1093/ckj/sfaa198 · DOI
  17. Levin, 2020, Empagliflozin and cardiovascular and kidney outcomes across KDIGO risk categories: post hoc analysis of a randomized, double-blind, placebo-controlled, multinational trial, Clin J Am Soc Nephrol, 15, 1433, 10.2215/CJN.14901219 · DOI
  18. Mosenzon, 2022, Dapagliflozin and prevention of kidney disease among patients with type 2 diabetes: post hoc analyses from the DECLARE-TIMI 58 trial, Diabetes Care, 45, 2350, 10.2337/dc22-0382 · DOI

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Metadata

Authors
Bosch, C., Carriazo, S., Soler, M. J., Ortiz, A., & Fernandez-Fernandez, B.
Affiliations
  • Instituto Universitario CEMIC, Buenos Aires , Argentina
  • Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM , Madrid , Spain
  • RICORS2040 , Madrid , Spain
ORCID
Venue
Clinical Kidney Journal
Publisher
Oxford University Press (OUP)
Published
2022-12-23
Volume
16
Issue
5
Pages
797-808
ISSN
  • 2048-8505
  • 2048-8513
DOI
10.1093/ckj/sfac274
PMC
PMC10157759
Cited by
60
References
11
Language
en
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor, 1 d)
Funders
  • FEDER (PI18/01366, PI19/00588, PI19/00815, PI20/00744, DTS18/00032)
  • PERSTIGAN (AC18/00071)
  • ISCIII-RETIC (RD016/0009)
  • Sociedad Española de Nefrología
  • Sociedad Madrileña de Nefrología
  • FRIAT (B2017/BMD-3686)
  • Comunidad de Madrid en Biomedicina (CIFRA2-CM)
  • Instituto de Salud Carlos III (RICORS2040-395, RD21/0005/0001, PMP21/00109)
  • European Union (RD16/0009)

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