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Open Access 12-03-2024 | Diabetic Nephropathy | Review

Renal effects of GLP-1 receptor agonists and tirzepatide in individuals with type 2 diabetes: seeds of a promising future

Authors: Irene Caruso, Francesco Giorgino

Published in: Endocrine

Abstract

Purpose

Chronic kidney disease (CKD) is one of the most common complications of type 2 diabetes (T2D), and CKD-related disability and mortality are increasing despite the recent advances in diabetes management. The dual GIP/GLP-1 receptor agonist tirzepatide is among the furthest developed multi-agonists for diabetes care and has so far displayed promising nephroprotective effects. This review aims to summarize the evidence regarding the nephroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) and tirzepatide and the putative mechanisms underlying the favorable renal profile of tirzepatide.

Methods

A comprehensive literature search was performed from inception to July 31st 2023 to select research papers addressing the renal effects of GLP-1RA and tirzepatide.

Results

The pathogenesis of CKD in patients with T2D likely involves many contributors besides hyperglycemia, such as hypertension, obesity, insulin resistance and glomerular atherosclerosis, exerting kidney damage through metabolic, fibrotic, inflammatory, and hemodynamic mechanisms. Tirzepatide displayed an unprecedented glucose and body weight lowering potential, presenting also with the ability to increase insulin sensitivity, reduce systolic blood pressure and inflammation and ameliorate dyslipidemia, particularly by reducing triglycerides levels.

Conclusion

Tirzepatide is likely to counteract most of the pathogenetic factors contributing to CKD in T2D, potentially representing a step forward in incretin-based therapy towards nephroprotection. Further evidence is needed to understand its role in renal hemodynamics, fibrosis, cell damage and atherosclerosis, as well as to conclusively show reduction of hard renal outcomes.

M.C. Thomas, M.E. Cooper, P. Zimmet, Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat. Rev. Nephrol. 12, 73–81 (2016)PubMedCrossRef

H. Li, W. Lu, A. Wang, H. Jiang, J. Lyu, Changing epidemiology of chronic kidney disease as a result of type 2 diabetes mellitus from 1990 to 2017: estimates from Global Burden of Disease 2017. J. Diabetes Investig. 12, 346–356 (2021)PubMedCrossRef

J.L. Harding, M.E. Pavkov, D.J. Magliano, J.E. Shaw, E.W. Gregg, Global trends in diabetes complications: a review of current evidence. Diabetologia 62, 3–16 (2019)PubMedCrossRef

R. Retnakaran, C.A. Cull, K.I. Thorne, A.I. Adler, R.R. Holman, UKPDS Study Group: risk factors for renal dysfunction in type 2 diabetes: U.K. Prospect. Diabetes Study 74. Diabetes 55, 1832–1839 (2006)

G. Penno, A. Solini, E. Bonora, C. Fondelli, E. Orsi, G. Zerbini et al. Clinical significance of nonalbuminuric renal impairment in type 2 diabetes. J. Hypertens. 29, 1802–1809 (2011)PubMedCrossRef

R.Z. Alicic, E.J. Cox, J.J. Neumiller, K.R. Tuttle, Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat. Rev. Nephrol. 17, 227–244 (2021)PubMedCrossRef

S. Zoungas, H. Arima, H.C. Gerstein, R.R. Holman, M. Woodward, P. Reaven et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 5, 431–437 (2017)PubMedCrossRef

I. Caruso, F. Giorgino, SGLT-2 inhibitors as cardio-renal protective agents. Metabolism 127, 154937 (2022)PubMedCrossRef

I. Caruso, A. Cignarelli, F. Giorgino, Heterogeneity and similarities in GLP-1 receptor agonist cardiovascular outcomes trials. Trends Endocrinol. Metab. 30, 578–589 (2019)PubMedCrossRef

10.

I. Caruso, A. Cignarelli, L. Laviola, F. Giorgino, GLP-1 receptor agonists for cardiovascular protection: a matter of time. Diabetes Care 45, e30–e31 (2022)PubMedPubMedCentralCrossRef

11.

N. Sattar, M.M.Y. Lee, S.L. Kristensen, K.R.H. Branch, S. Del Prato, N.S. Khurmi 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. 9(10), 653–662 (2021)PubMedCrossRef

12.

M.H.A. Muskiet, L. Tonneijck, Y. Huang, M. Liu, A. Saremi, H.J.L. Heerspink 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. 6, 859–869 (2018)PubMedCrossRef

13.

J.B. Buse, S.C. Bain, J.F.E. Mann, M.A. Nauck, S.E. Nissen, S. Pocock et al. Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER Trial. Diabetes Care 43, 1546–1552 (2020)PubMedPubMedCentralCrossRef

14.

F. Persson, S.C. Bain, O. Mosenzon, H.J.L. Heerspink, J.F.E. Mann, R. Pratley et al. Changes in albuminuria predict cardiovascular and renal outcomes in type 2 diabetes: a post hoc analysis of the LEADER Trial. Diabetes Care 44, 1020–1026 (2021)PubMedPubMedCentralCrossRef

15.

S.C. Tye, S.T. de Vries, J.F.E. Mann, M. Schechter, O. Mosenzon, P. Denig et al. Prediction of the effects of liraglutide on kidney and cardiovascular outcomes based on short-term changes in multiple risk markers. Front Pharm. 13, 786767 (2022)CrossRef

16.

J.F.E. Mann, D.D. Ørsted, K. Brown-Frandsen, S.P. Marso, N.R. Poulter, S. Rasmussen et al. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 377, 839–848 (2017)PubMedCrossRef

17.

J.F.E. Mann, T. Hansen, T. Idorn, L.A. Leiter, S.P. Marso, P. Rossing et al. Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials. Lancet Diabetes Endocrinol. 8, 880–893 (2020)PubMedCrossRef

18.

K.R. Tuttle, H. Bosch-Traberg, D.Z.I. Cherney, S. Hadjadj, J. Lawson, O. Mosenzon et al. Post hoc analysis of SUSTAIN 6 and PIONEER 6 trials suggests that people with type 2 diabetes at high cardiovascular risk treated with semaglutide experience more stable kidney function compared with placebo. Kidney Int. 103, 772–781 (2023)PubMedCrossRef

19.

A.M. Shaman, S.C. Bain, G.L. Bakris, J.B. Buse, T. Idorn, K.W. Mahaffey 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 145, 575–585 (2022)PubMedCrossRef

20.

H.C. Gerstein, H.M. Colhoun, G.R. Dagenais, R. Diaz, M. Lakshmanan, P. Pais et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 394, 131–138 (2019)PubMedCrossRef

21.

O. Mosenzon, M. Schechter, G. Leibowitz, Kidney outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes. Adv. Chronic Kidney Dis. 28, 347–360 (2021)PubMedCrossRef

22.

M.A. Bethel, R.J. Mentz, P. Merrill, J.B. Buse, J.C. Chan, S.G. Goodman et al. Renal outcomes in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL). Diabetes 67, 522–P (2018)CrossRef

23.

A.B. van der Aart-van der Beek, L.E. Clegg, R.C. Penland, D.W. Boulton, C.D. Sjöström, R.J. Mentz et al. Effect of once-weekly exenatide on estimated glomerular filtration rate slope depends on baseline renal risk: a post hoc analysis of the EXSCEL trial. Diabetes Obes. Metab. 22, 2493–2498 (2020)PubMedPubMedCentralCrossRef

24.

S. Yoshiji, H. Minamino, D. Tanaka, S. Yamane, N. Harada, N. Inagaki, Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: a meta-analysis and meta-regression analysis. Diabetes Obes. Metab. 24, 1029–1037 (2022)PubMedCrossRef

25.

J.F.E. Mann, J.B. Buse, T. Idorn, L.A. Leiter, R.E. Pratley, S. Rasmussen et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes. Metab. 23, 2058–2066 (2021)PubMedPubMedCentralCrossRef

26.

D.K. McGuire, R.P. Busui, J. Deanfield, S.E. Inzucchi, J.F.E. Mann, N. Marx et al. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: design and baseline characteristics of SOUL, a randomized trial. Diabetes Obes. Metab. 25, 1932–1941 (2023)PubMedCrossRef

27.

M.J. Davies, S.C. Bain, S.L. Atkin, P. Rossing, D. Scott, M.S. Shamkhalova et al. Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. Diabetes Care 39, 222–230 (2016)PubMedCrossRef

28.

L.A. Leiter, M.C. Carr, M. Stewart, A. Jones-Leone, R. Scott, F. Yang et al. Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study. Diabetes Care 37, 2723–2730 (2014)PubMedCrossRef

29.

O. Mosenzon, T.M. Blicher, S. Rosenlund, J.W. Eriksson, S. Heller, O.H. Hels et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 7, 515–527 (2019)PubMedCrossRef

30.

K.R. Tuttle, M.C. Lakshmanan, B. Rayner, R.S. Busch, A.G. Zimmermann, D.B. Woodward 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. 6, 605–617 (2018)PubMedCrossRef

31.

P. Rossing, F.M.M. Baeres, G. Bakris, H. Bosch-Traberg, M. Gislum, S.C.L. Gough 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. Transpl. 38(9), 2041–2051 (2023)CrossRef

32.

I. Caruso, A. Cignarelli, G.P. Sorice, A. Natalicchio, S. Perrini, L. Laviola et al. Cardiovascular and renal effectiveness of GLP-1 receptor agonists vs. other glucose-lowering drugs in type 2 diabetes: a systematic review and meta-analysis of real-world studies. Metabolites 12(2), 183 (2022)PubMedPubMedCentralCrossRef

33.

M. Rondinelli, A. Rossi, A. Gandolfi, F. Saponaro, L. Bucciarelli, G. Adda et al. Use of liraglutide in the real world and impact at 36 months on metabolic control, weight, lipid profile, blood pressure, heart rate, and renal function. Clin. Ther. 39, 159–169 (2017)PubMedCrossRef

34.

B. Pasternak, V. Wintzell, B. Eliasson, A.-M. Svensson, S. Franzén, S. Gudbjörnsdottir et al. Use of glucagon-like peptide 1 receptor agonists and risk of serious renal events: Scandinavian cohort study. Diabetes Care 43, 1326–1335 (2020)PubMedCrossRef

35.

M. Lugner, N. Sattar, M. Miftaraj, J. Ekelund, S. Franzén, A.-M. Svensson et al. Cardiorenal and other diabetes related outcomes with SGLT-2 inhibitors compared to GLP-1 receptor agonists in type 2 diabetes: nationwide observational study. Cardiovasc Diabetol. 20, 67 (2021)PubMedPubMedCentralCrossRef

36.

Y. Xie, B. Bowe, A.K. Gibson, J.B. McGill, G. Maddukuri, Y. Yan et al. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: emulation of a target trial using health care databases. Diabetes Care 43, 2859–2869 (2020)PubMedCrossRef

37.

P. Ueda, V. Wintzell, E. Dahlqwist, B. Eliasson, A.-M. Svensson, S. Franzén et al. The comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a Scandinavian cohort study. Diabetes Obes. Metab. 24, 473–485 (2022)PubMedCrossRef

38.

M. Baviera, A. Foresta, P. Colacioppo, G. Macaluso, M.C. Roncaglioni, M. Tettamanti et al. Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study. Cardiovasc Diabetol. 21, 162 (2022)PubMedPubMedCentralCrossRef

39.

F.S. Willard, J.D. Douros, M.B. Gabe, A.D. Showalter, D.B. Wainscott, T.M. Suter, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 5(17) (2020)

40.

D.J. Drucker, J.J. Holst, The expanding incretin universe: from basic biology to clinical translation. Diabetologia 66(10), 1765–1779 (2023)PubMedCrossRef

41.

B. Sun, F.S. Willard, D. Feng, J. Alsina-Fernandez, Q. Chen, M. Vieth, Structural determinants of dual incretin receptor agonism by tirzepatide. Proc. Natl Acad. Sci. USA 119(13), e2116506119 (2022)PubMedPubMedCentralCrossRef

42.

A. Novikoff, S.L. O’Brien, M. Bernecker, G. Grandl, M. Kleinert, P.J. Knerr et al. Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Mol. Metab. 49, 101181 (2021)PubMedPubMedCentralCrossRef

43.

B. Jones, T. Buenaventura, N. Kanda, P. Chabosseau, B.M. Owen, R. Scott et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nat. Commun. 9, 1602 (2018)ADSPubMedPubMedCentralCrossRef

44.

M. Lucey, P. Pickford, S. Bitsi, J. Minnion, J. Ungewiss, K. Schoeneberg et al. Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists. Mol. Metab. 37, 100991 (2020)PubMedPubMedCentralCrossRef

45.

J.J. Meier, M.A. Nauck, D. Kranz, J.J. Holst, C.F. Deacon, D. Gaeckler et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53, 654–662 (2004)PubMedCrossRef

46.

T. Idorn, F.K. Knop, M.B. Jørgensen, M. Christensen, J.J. Holst, M. Hornum et al. Elimination and degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with end-stage renal disease. J. Clin. Endocrinol. Metab. 99, 2457–2466 (2014)PubMedCrossRef

47.

S. Urva, T. Quinlan, J. Landry, J. Martin, C. Loghin, Effects of renal impairment on the pharmacokinetics of the dual GIP and GLP-1 receptor agonist tirzepatide. Clin. Pharmacokinet. 60, 1049–1059 (2021)PubMedPubMedCentralCrossRef

48.

S. Del Prato, S.E. Kahn, I. Pavo, G.J. Weerakkody, Z. Yang, J. Doupis 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 398, 1811–1824 (2021)PubMedCrossRef

49.

H.J.L. Heerspink, N. Sattar, I. Pavo, A. Haupt, K.L. Duffin, Z. Yang et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 10, 774–785 (2022)PubMedCrossRef

50.

F.A. Holtkamp, D. de Zeeuw, M.C. Thomas, M.E. Cooper, P.A. de Graeff, H.J.L. Hillege et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 80, 282–287 (2011)PubMedCrossRef

51.

M. Oshima, M.J. Jardine, R. Agarwal, G. Bakris, C.P. Cannon, D.M. Charytan et al. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney Int. 99, 999–1009 (2021)PubMedCrossRef

52.

H.J.L. Heerspink, N. Sattar, I. Pavo, A. Haupt, K.L. Duffin, Z. Yang et al. Effects of tirzepatide versus insulin glargine on cystatin C-based kidney function: a SURPASS-4 post hoc analysis. Diabetes Care 46, 1501–1506 (2023)PubMedPubMedCentralCrossRef

53.

M.C. Thomas, M. Brownlee, K. Susztak, K. Sharma, K.A.M. Jandeleit-Dahm, S. Zoungas et al. Diabetic kidney disease. Nat. Rev. Dis. Prim. 1, 15018 (2015)PubMedCrossRef

54.

K.R. Tuttle, R. Agarwal, C.E. Alpers, G.L. Bakris, F.C. Brosius, P. Kolkhof et al. Molecular mechanisms and therapeutic targets for diabetic kidney disease. Kidney Int 102, 248–260 (2022)PubMedCrossRef

55.

R. Agarwal. Pathogenesis of diabetic nephropathy. Chronic kidney disease and type 2 diabetes. (American Diabetes Association, Arlington (VA)), 2021)

56.

R.Z. Alicic, J.J. Neumiller, K.R. Tuttle, Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 32, 377–385 (2023)PubMedPubMedCentralCrossRef

57.

J. Skov, A. Dejgaard, J. Frøkiær, J.J. Holst, T. Jonassen, S. Rittig et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J. Clin. Endocrinol. Metab. 98, E664–71 (2013)PubMedCrossRef

58.

A. Asmar, P.K. Cramon, L. Simonsen, M. Asmar, C.M. Sorensen, S. Madsbad 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. 104, 2509–2519 (2019)PubMedCrossRef

59.

S.C. Thomson, A. Kashkouli, Z.Z. Liu, P. Singh, Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin. Am. J. Physiol. Ren. Physiol. 313, F854–F858 (2017)CrossRef

60.

F. Moschovaki Filippidou, A.H. Kirsch, M. Thelen, M. Kétszeri, K. Artinger, I. Aringer et al. Glucagon-like peptide-1 receptor agonism improves nephrotoxic serum nephritis by inhibiting T-cell proliferation. Am. J. Pathol. 190, 400–411 (2020)PubMedCrossRef

61.

M. Mazidi, E. Karimi, P. Rezaie, G.A. Ferns, 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 Complic. 31, 1237–1242 (2017)CrossRef

62.

R. Hammoud, D.J. Drucker, Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat. Rev. Endocrinol. 19, 201–216 (2023)PubMedCrossRef

63.

X. Gao, A. Lindqvist, M. Sandberg, L. Groop, N. Wierup, L. Jansson, Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats. Physiol. Rep. 6, e13685 (2018)PubMedPubMedCentralCrossRef

64.

S.H. Hammoud, I. AlZaim, Y. Al-Dhaheri, A.H. Eid, A.F. El-Yazbi, Perirenal adipose tissue inflammation: novel insights linking metabolic dysfunction to renal diseases. Front. Endocrinol. 12, 707126 (2021)CrossRef

65.

S. Ben-Shlomo, I. Zvibel, C. Varol, L. Spektor, A. Shlomai, E.M. Santo et al. Role of glucose-dependent insulinotropic polypeptide in adipose tissue inflammation of dipeptidylpeptidase 4-deficient rats. Obesity 21, 2331–2341 (2013)PubMedCrossRef

66.

S.D. Pedersen, F. Giorgino, G. Umpierrez, V.T. Thieu, A. Rodríguez, C. Nicolay et al. Relationship between body weight change and glycaemic control with tirzepatide treatment in people with type 2 diabetes: a post hoc assessment of the SURPASS clinical trial programme. Diabetes Obes. Metab. 25, 2553–2560 (2023)PubMedCrossRef

67.

J. Rosenstock, C. Wysham, J.P. Frías, S. Kaneko, C.J. Lee, L. Fernández Landó et al. 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 398, 143–155 (2021)PubMedCrossRef

68.

J.P. Frías, M.J. Davies, J. Rosenstock, F.C. Pérez Manghi, L. Fernández Landó, B.K. Bergman et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021)PubMedCrossRef

69.

B. Ludvik, F. Giorgino, E. Jódar, J.P. Frias, L. Fernández Landó, K. Brown et al. 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 398, 583–598 (2021)PubMedCrossRef

70.

D. Dahl, Y. Onishi, P. Norwood, R. Huh, R. Bray, H. Patel et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 327, 534–545 (2022)PubMedPubMedCentralCrossRef

71.

M.J. Davies, V.R. Aroda, B.S. Collins, R.A. Gabbay, J. Green, N.M. Maruthur 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). Diabetes Care 45, 2753–2786 (2022)PubMedPubMedCentralCrossRef

72.

I. Lingvay, P. Sumithran, R.V. Cohen, C.W. le Roux, Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet 399, 394–405 (2022)PubMedCrossRef

73.

R.V. Cohen, T.V. Pereira, C.M. Aboud, T.B.Z. Petry, J.L. Lopes Correa, C.A. Schiavon et al. Effect of gastric bypass vs best medical treatment on early-stage chronic kidney disease in patients with type 2 diabetes and obesity: a randomized clinical trial. JAMA Surg. 155, e200420 (2020)PubMedPubMedCentralCrossRef

74.

M.K. Thomas, A. Nikooienejad, R. Bray, X. Cui, J. Wilson, K. Duffin et al. Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. J. Clin. Endocrinol. Metab. 106, 388–396 (2021)PubMedCrossRef

75.

T. Heise, A. Mari, J.H. DeVries, S. Urva, J. Li, E.J. Pratt et al. 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, 418–429 (2022)PubMedCrossRef

76.

C.J. Lee, H. Mao, V.T. Thieu, L.F. Landó, M.K. Thomas, Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1). J. Endocr. Soc. 7, bvad056 (2023)PubMedPubMedCentralCrossRef

77.

I. Lingvay, O. Mosenzon, K. Brown, X. Cui, C. O’Neill, L. Fernández Landó et al. Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program. Cardiovasc. Diabetol. 22, 66 (2023)PubMedPubMedCentralCrossRef

78.

B. Finan, T. Ma, N. Ottaway, T.D. Müller, K.M. Habegger, K.M. Heppner et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013)PubMedCrossRef

79.

J.P. Frias, M.A. Nauck, J. Van, M.E. Kutner, X. Cui, C. Benson et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 392, 2180–2193 (2018)PubMedCrossRef

80.

D. Yu, S. Shen, J. Zhang, Q. Wang, Effect of the dual glucose-dependent insulinotropic peptide/glucagon-like peptide 1 receptor agonist tirzepatide on lipid profile and waist circumference: a systematic review and meta-analysis. Clin. Ther. 45(8), 787–796 (2023)PubMedCrossRef

81.

M. Asmar, A. Asmar, L. Simonsen, F. Dela, J.J. Holst, J. Bülow, GIP-induced vasodilation in human adipose tissue involves capillary recruitment. Endocr. Connect. 8, 806–813 (2019)PubMedPubMedCentralCrossRef

82.

J.M. Wilson, A. Nikooienejad, D.A. Robins, W.C. Roell, J.S. Riesmeyer, A. Haupt et al. 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, 2451–2459 (2020)PubMedPubMedCentralCrossRef

83.

N. Sattar, D.K. McGuire, I. Pavo, G.J. Weerakkody, H. Nishiyama, R.J. Wiese et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat. Med. 28, 591–598 (2022)PubMedPubMedCentralCrossRef

84.

J.M. Wilson, Y. Lin, M.J. Luo, G. Considine, A.L. Cox, L.M. Bowsman et al. The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: a post hoc analysis. Diabetes Obes. Metab. 24, 148–153 (2022)PubMedCrossRef

85.

E. Gallego-Colon, W. Wojakowski, T. Francuz, Incretin drugs as modulators of atherosclerosis. Atherosclerosis 278, 29–38 (2018)PubMedCrossRef

86.

Y. Mori, T. Matsui, T. Hirano, S.-I. Yamagishi, GIP as a potential therapeutic target for atherosclerotic cardiovascular disease: a systematic review. Int. J. Mol. Sci. 21(4), 1509 (2020)PubMedPubMedCentralCrossRef

87.

P. Rossing, M.L. Caramori, J.C.N. Chan, H.J.L. Heerspink, C. Hurst, K. Khunti 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. 102, 990–999 (2022)PubMedCrossRef

88.

A. Mima, H. Gotoda, R. Lee, A. Murakami, R. Akai, S. Lee, Effects of incretin-based therapeutic agents including tirzepatide on renal outcomes in patients with type 2 Diabetes: a systematic review and meta-analysis. Metab. Open 17, 100236 (2023)CrossRef

89.

K.S. Boye, R. Mody, J. Wu, M.J. Lage, F.T. Botros, B. Woodward, Effects of dulaglutide and insulin glargine on estimated glomerular filtration rate in a real-world setting. Clin. Ther. 40, 1396–1407 (2018)PubMedCrossRef

90.

K.S. Boye, F.T. Botros, A. Haupt, B. Woodward, M.J. Lage, Glucagon-like peptide-1 receptor agonist use and renal impairment: a retrospective analysis of an electronic health records database in the U.S. population. Diabetes Ther. 9, 637–650 (2018)PubMedPubMedCentralCrossRef

Title: Renal effects of GLP-1 receptor agonists and tirzepatide in individuals with type 2 diabetes: seeds of a promising future
Authors: Irene Caruso
Francesco Giorgino
Publication date: 12-03-2024
Publisher: Springer US
Keywords: Diabetic Nephropathy
Chronic Kidney Disease
Type 2 Diabetes
Incretin Mimetics
Tirzepatide
Incretin Mimetics
Metabolic Disease and Nutrition
Published in: Endocrine
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-024-03757-9

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine