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Meta-Analysis
. 2025 Feb 18;2(2):CD015849.
doi: 10.1002/14651858.CD015849.pub2.

Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes

Patrizia Natale  1   2 , Suetonia C Green  3 , David J Tunnicliffe  1 , Giovanni Pellegrino  2 , Tadashi Toyama  4   5 , Giovanni Fm Strippoli  2   6   7
Affiliations
Meta-Analysis

Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes

Patrizia Natale et al. Cochrane Database Syst Rev. .

Abstract

Background: Approximately 40% of people with diabetes develop kidney failure and experience an accelerated risk of cardiovascular complications. Glucagon-like peptide 1 (GLP-1) receptor agonists are glucose-lowering agents that manage glucose and weight control.

Objectives: We assessed the benefits and harms of GLP-1 receptor agonists in people with chronic kidney disease (CKD) and diabetes.

Search methods: The Cochrane Kidney and Transplant Register of Studies was searched to 10 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria: Randomised controlled studies were eligible if participants with diabetes and CKD were randomly allocated to a GLP-1 receptor agonist, placebo, standard care or a second glucose-lowering agent. CKD included all stages (from 1 to 5).

Data collection and analysis: Three authors independently extracted data and assessed the risk of bias using the risk of bias assessment tool 2. Pooled analyses using summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and/or hazard ratio (HR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. The primary outcomes included death (all-cause and cardiovascular), 3- and 4-point major adverse cardiovascular events (MACE), kidney failure, composite kidney outcome, and severe hypoglycaemia. The secondary outcomes included non-fatal or fatal myocardial infarction (MI) or stroke, non-fatal peripheral arterial events, heart failure, hospitalisation due to heart failure, estimated glomerular filtration rate or creatinine clearance, doubling of serum creatinine, urine albumin-to-creatinine ratio, albuminuria progression, vascular access outcomes, body weight, body mass index, fatigue, life participation, peritoneal dialysis infection, peritoneal dialysis failure, adverse events, serious adverse events, withdrawal due to adverse events, HbA1c, sudden death, acute MI, ischaemic stroke, and coronary revascularisation. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: Forty-two studies involving 48,148 participants were included. All studies were conducted on people with type 2 diabetes, and no studies were carried out on children. The median study age was 66 years. The median study follow-up was 26 weeks. Six studies were conducted in people with CKD stages 1-2, 11 studies in people with CKD stages 3-5, one study in people on dialysis, and the remaining studies included people with both CKD stages 1-2 and 3-5. Risks of bias in the included studies for all the primary outcomes in studies that compared GLP-1 receptor agonists to placebo were low in most methodological domains, except one study that was assessed at high risk of bias due to missing outcome data for death (all-cause and cardiovascular). The overall risk of bias for all-cause and cardiovascular death in studies that reported the treatment effects of GLP-1 receptor agonists compared to standard care, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors were assessed as unclear or at high risk of bias due to deviations from intended interventions or missing data. For GLP-1 receptor agonists compared to insulin or another GLP-1 receptor agonist, the risk of bias for all-cause and cardiovascular death was low or unclear. Compared to placebo, GLP-1 receptor agonists probably reduced the risk of all-cause death (RR 0.85, 95% CI 0.74 to 0.98; I2 = 23%; 8 studies, 17,861 participants; moderate-certainty evidence), but may have little or no effect on cardiovascular death (RR 0.84, 95% CI 0.68 to 1.05; I2 = 42%; 7 studies, 17,801 participants; low-certainty evidence). Compared to placebo, GLP-1 receptor agonists probably decreased 3-point MACE (RR 0.84, 95% CI 0.73 to 0.98; I² = 65%; 4 studies, 19,825 participants; moderate-certainty evidence), and 4-point MACE compared to placebo (RR 0.77, 95% CI 0.67 to 0.89; 1 study, 2,158 participants; moderate-certainty evidence). Based on absolute risks of clinical outcomes, it is likely that GLP-1 receptor agonists prevent all-cause death in 52 people with CKD stages 1-2 and 116 in CKD stages 3-5, cardiovascular death in 34 people with CKD stages 1-2 and 71 in CKD stages 3-5, while 95 CKD stages 1-2 and 153 in CKD stages 3-5 might experience a major cardiovascular event for every 1000 people treated over 1 year. Compared to placebo, GLP-1 receptor agonists probably had little or no effect on kidney failure, defined as starting dialysis or kidney transplant (RR 0.86, 95% CI 0.66 to 1.13; I2 = 0%; 3 studies, 4,134 participants; moderate-certainty evidence), or on composite kidney outcomes (RR 0.89, 95% CI 0.78 to 1.02; I2 = 0%; 2 studies, 16,849 participants; moderate-certainty evidence). Compared to placebo, GLP-1 receptor agonists may have little or no effect on the risk of severe hypoglycaemia (RR 0.82, 95% CI 0.54 to 1.25; I2 = 44%; 4 studies, 6,292 participants; low-certainty evidence). The effects of GLP-1 receptor agonists compared to standard care or other hypoglycaemic agents were uncertain. No studies evaluated treatment on risks of fatigue, life participation, amputation or fracture.

Authors' conclusions: GLP-1 receptor agonists probably reduced all-cause death but may have little or no effect on cardiovascular death in people with CKD and diabetes. GLP-1 receptor agonists probably lower major cardiovascular events, probably have little or no effect on kidney failure and composite kidney outcomes, and may have little or no effect on the risk of severe hypoglycaemia in people with CKD and diabetes.

Trial registration: ClinicalTrials.gov NCT03496298 NCT01621178 NCT02963766 NCT01761318 NCT02660047 NCT01336023 NCT01392573 NCT01676116 NCT01618162 NCT01952145 NCT01147250 NCT01144338 NCT03819153 NCT01798706 NCT01794143 NCT02465515 NCT01394341 NCT01179048 NCT01098539 NCT02730377 NCT01620489 NCT00097500 NCT01847313 NCT03550378 NCT02827708 NCT02692716 NCT01394952 NCT04515849 NCT04061200 NCT03914326 NCT01720446 NCT03136484 NCT03824002 NCT02545738 NCT02690883 NCT00712673 NCT00763451 NCT00707031 NCT05536804 NCT06182891 NCT06555146 NCT04865770.

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Conflict of interest statement

  1. Patrizia Natale: has declared that they have no conflict of interest.

  2. Suetonia Green: has declared that they have no conflict of interest.

  3. David Tunnicliffe: has declared that they have no conflict of interest.

  4. Giovanni Pellegrino: has declared that they have no conflict of interest.

  5. Tadashi Toyama: Mitsubishi Tanabe Pharma Corporation (Independent Contractor ‐ Other); Mitsubishi Tanabe Pharma Corporation (Independent Contractor ‐ Consultant).

  6. Giovanni FM Strippoli: has declared that they have no conflict of interest.

Update of

  • doi: 10.1002/14651858.CD015849

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References

References to studies included in this review

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    1. Mann JF, Fonseca V, Mosenzon O, Raz I, Goldman B, Idorn T, et al. Response by Mann et al to Letter regarding article, "Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease: results from the LEADER trial. Circulation 2019;139(22):e1017-8. [PMID: ] - PubMed
Leiter 2014 {published data only}
    1. Leiter L, Carr MC, Stewart M, Jones-Leone A, Yang F, Handelsman Y. HARMONY 8: once-weekly glucagon-like peptide 1 receptor agonist albiglutide vs sitagliptin for patients with type 2 diabetes with renal impairment: week 26 results [abstract no: 906]. Diabetologia 2013;56(Suppl 1):S361-2. [EMBASE: 71439328]
    1. Leiter LA, Carr MC, Stewart M, Jones-Leone A, Scott R, Yang F, 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 2014;37(10):2723-30. [MEDLINE: ] - PubMed
LIRA‐PRIME 2019 {published data only}
    1. Unger J, Allison DC, Carlton M, Lakkole K, Lowe D, Murphy G, et al. Trial design and baseline data for LIRA-PRIME: A randomized trial investigating the efficacy of liraglutide in controlling glycaemia in type 2 diabetes in a primary care setting. Diabetes, Obesity & Metabolism 2019;21(7):1543-50. [PMID: ] - PMC - PubMed
LIRA‐RENAL 2016 {published data only}
    1. Davies MJ, Bain SC, Atkin SL, Rossing P, Scott D, Shamkhalova MS, 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 2016;39(2):222-30. [MEDLINE: ] - PubMed
    1. Mathieu C, Umpierrez G, Atkin S, Bain S, Rossing P, Scott D, et al. Efficacy and safety of liraglutide versus placebo in subjects with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomised trial [abstract no: OP60]. Diabetes Research & Clinical Practice 2014;106(Suppl 1):S31. [EMBASE: 71824748]
    1. Ngo P, Davies M, Atkin S, Bain S, Rossing P, Scott D, et al. Efficacy and safety of liraglutide vs. placebo as add-on to existing diabetes medication in subjects with type 2 diabetes and moderate renal impairment (LIRA-RENAL) [abstract no: 18]. Canadian Journal of Diabetes 2014;38(5 Suppl):S9-10. [EMBASE: 72003971]
    1. Scott D, Umpierrez G, Atkin S, Bain S, Rossing P, Shamkhalova M, et al. Efficacy and safety of liraglutide versus placebo by age subgroup in subject with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized trial [abstract no: FR-PO791]. Journal of the American Society of Nephrology 2014;25(Abstract Suppl):550A.
    1. Scott D, Umpierrez G, Atkin S, Bain S, Rossing P, Shamkhalova M, et al. Efficacy and safety of liraglutide versus placebo by eGFR subgroup in subjects with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized trial [abstract no: FR-OR122]. Journal of the American Society of Nephrology 2014;25(Abstract Suppl):75A.
Liu 2022 {published data only}
    1. Liu J, Guo S, Li H, Liu XY. Effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on podocytes, inflammation, and oxidative stress in patients with diabetic nephropathy (DN). Pakistan Journal of Medical Sciences 2022;38(5):1170-4. [DOI: 10.12669/pjms.38.5.4719] [PMID: ] - DOI - PMC - PubMed
Ma 2024 {published data only}
    1. Ma J, Fu J, Guo N, Liu Z. Clinical efficacy and safety of liraglutide and dapagliflozin on glucose and lipid metabolism and insulin function in patients with type 2 diabetes mellitus. Alternative Therapies in Health & Medicine 2024;30(8):144-51. [PMID: ] - PubMed
Muskiet 2019 {published data only}
    1. Muskiet MH, Bunck MC, Heine RJ, Corner A, Yki-Jarvinen H, Eliasson B, et al. Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: a post-hoc analysis of a 52-week randomised trial. Diabetes Research & Clinical Practice 2019;153:14-22. [PMID: ] - PubMed
Neff 2016 {published data only}
    1. Neff KJ, Tobin LM, Hogan AE, Docherty NG, Le Roux CW, O'Shea D. The effect of low dose liraglutide on renal inflammation in type 2 diabetic kidney disease: a randomised controlled study [abstract no: 101]. Diabetic Medicine 2016;33(Suppl 1):64. [EMBASE: 72230717]
Parker 2022 {published data only}
    1. Parker VE, Hoang T, Schlichthaar H, Chang YT, Petrone M, Hansen L, et al. Efficacy and safety of cotadutide, a dual GLP-1 and glucagon receptor agonist, for patients with type 2 diabetes mellitus and CKD [abstract no: PO1018]. Journal of the American Society of Nephrology 2020;31(Abstract Suppl):348. [EMBASE: 633702902]
    1. Parker VE, Hoang T, Schlichthaar H, Gibb FW, Wenzel B, Posch MG, et al. Efficacy and safety of cotadutide, a dual GLP-1 and glucagon receptor agonist in patients with T2DM and DKD [abstract no: 675-P]. Diabetes 2021;70(Suppl 1):674. [DOI: 10.2337/db21-674-P] [PMID: ] - DOI
    1. Parker VE, Hoang T, Schlichthaar H, Gibb FW, Wenzel B, Posch MG, et al. Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease. Diabetes, Obesity & Metabolism 2022;24(7):1360-9. [DOI: 10.1111/dom.14712] [PMID: ] - DOI - PMC - PubMed
PIONEER 5 2019 {published data only}2015‐005326‐19
    1. Mosenzon O, Blicher TM, Rosenlund S, Eriksson JW, Heller S, Hels OH, 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 & Endocrinology 2019;7(7):515-27. [PMID: ] - PubMed
    1. Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J. Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovascular Diabetology 2022;21(1):172. [DOI: 10.1186/s12933-022-01585-7] [PMID: ] - DOI - PMC - PubMed
PIONEER 6 2019 {published data only}
    1. Bain SC, Mosenzon O, Arechavaleta R, Bogdanski P, Comlekci A, Consoli A, et al. Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes, Obesity & Metabolism 2019;21(3):499-508. [PMID: ] - PMC - PubMed
    1. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine 2019;381(9):841-51. [MEDLINE: ] - PubMed
    1. Tuttle KR, Bosch-Traberg H, Cherney DZ, Hadjadj S, Lawson J, Mosenzon O, 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 International 2023;103(4):772-81. [DOI: 10.1016/j.kint.2022.12.028] [PMID: ] - DOI - PubMed
REWIND 2019 {published data only}
    1. Botros FT, Gerstein HC, Malik R, Nicolay C, Hoover A, Turfanda I, et al. Dulaglutide and kidney function-related outcomes in Type 2 diabetes: a REWIND post hoc analysis. Diabetes Care 2023;46(8):1524-30. [DOI: 10.2337/dc23-0231] [PMID: ] - DOI - PubMed
    1. Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, Garcia-Perez LE, Lakshmanan M, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurology 2020;19(7):582-90. [PMID: ] - PubMed
    1. Dagenais GR, Ryden L, Leiter LA, Lakshmanan M, Dyal L, Probstfield JL, et al. Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis. Cardiovascular Diabetology 2020;19(1):199. [PMID: ] - PMC - PubMed
    1. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes, Obesity & Metabolism 2018;20(1):42-9. [PMID: ] - PubMed
    1. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121-30. [MEDLINE: ] - PubMed
Selvarajah 2024a {published data only}2020‐000255‐12
    1. Robertson D, Selverajah V, Hansen L, Jermutus L, Smith K, Frickleton C, et al. Efficacy of cotadutide dual GLP1-glucagon receptor agonist on albuminuria and glycaemic control in patients with diabetic kidney disease [abstract no: 58]. Diabetologia 2023;66(Suppl 1):S32. [DOI: 10.1007/s00125-023-05969-6] [PMID: ] - DOI
    1. Selvarajah V, Robertson D, Hansen L, Jermutus L, Smith K, Coggi A, et al. A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease. Kidney International 2024;106(6):1170-80. [DOI: 10.1016/j.kint.2024.08.023] [PMID: ] - DOI - PubMed
    1. Selvarajah V, Robertson D, Hansen L, Jermutus L, Smith K, Frickleton C, et al. Efficacy and safety of cotadutide, a dual GLP1-glucagon receptor agonist, in patients with chronic kidney disease and T2DM [abstract no: 3000]. Nephrology Dialysis Transplantation 2023;38(Suppl 1):i87. [DOI: 10.1093/ndt/gfad063a_3000] [EMBASE: 641942408] - DOI
Selvarajah 2024b {published data only}2020‐000255‐12
    1. Robertson D, Selverajah V, Hansen L, Jermutus L, Smith K, Frickleton C, et al. Efficacy of cotadutide dual GLP1-glucagon receptor agonist on albuminuria and glycaemic control in patients with diabetic kidney disease [abstract no: 58]. Diabetologia 2023;66(Suppl 1):S32. [EMBASE: 642618046]
    1. Selvarajah V, Robertson D, Hansen L, Jermutus L, Smith K, Coggi A, et al. A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease. Kidney International 2024;106(6):1170-80. [PMID: ] - PubMed
    1. Selvarajah V, Robertson D, Hansen L, Jermutus L, Smith K, Frickleton C, et al. Efficacy and safety of cotadutide, a dual GLP1-glucagon receptor agonist, in patients with chronic kidney disease and T2DM [abstract no: 3000]. Nephrology Dialysis Transplantation 2023;38(Supp 1):i87. [EMBASE: 641942408]
SEMPA 2023 {published data only}2019‐000781‐38
    1. Gullaksen S, Vernstrom L, Sorensen SS, Ringgaard S, Laustsen C, Birn H, et al. The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: a prespecified, secondary analysis from a randomized, clinical trial. Journal of Diabetes & its Complications 2024;38(2):108673. [DOI: 10.1016/j.jdiacomp.2023.108673] [PMID: ] - DOI - PubMed
    1. Gullaksen S, Vernstrom L, Sorensen SS, Ringgaard S, Laustsen C, Funck KL, et al. Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial. Diabetologia 2023;66(5):813-25. [DOI: 10.1007/s00125-023-05876-w] [PMID: ] - DOI - PubMed
    1. Vernstrom L, Gullaksen S, Sorensen SS, Ringgaard S, Laustsen C, Birn H, et al. Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial. Diabetologia 2024;67(10):2175-87. [DOI: 10.1007/s00125-024-06228-y] [PMID: ] - DOI - PMC - PubMed
Sivalingam 2024 {published data only}2019‐003175‐19
    1. Sivalingam S, Soendergaard Wasehuus V, Rotbain Curovic V, Willum Hansen T, Persson F, Rossing P. Renal effects of empagliflozin alone or in combination with semaglutide in albuminuric type 2 diabetes: a randomised, placebo-controlled trial [abstract no: 235]. Diabetologia 2023;66(Suppl 1):S125. [DOI: 10.1007/s00125-023-05969-6] [EMBASE: 642618603] - DOI
    1. Sivalingam S, Wasehuus VS, Rotbain Curovic V, Blond MB, Hansen TW, Persson F, et al. Albuminuria-lowering effect of adding semaglutide on top of empagliflozin in individuals with type 2 diabetes: a randomized and placebo-controlled study. Diabetes, Obesity & Metabolism 2024;26(1):54-64. [DOI: 10.1111/dom.15287] [PMID: ] - DOI - PubMed
SOUL 2023 {published data only}
    1. McGuire DK, Busui RP, Deanfield J, Inzucchi SE, Mann JF, Marx N, 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, Obesity & Metabolism 2023;25(7):1932-41. [PMID: ] - PubMed
SUSTAIN‐6 2016 {published data only}2012‐002839‐28
    1. Apperloo EM, Cherney DZ, Kuhlman AB, Mann JF, Rasmussen S, Rossing P, et al. Effect of semaglutide on kidney function across different levels of baseline HbA1c, blood pressure, body weight and albuminuria in SUSTAIN 6 and PIONEER 6. Nephrology Dialysis Transplantation 2024;pre-publication:[in press]. [DOI: 10.1093/ndt/gfae150] [PMID: ] - DOI - PMC - PubMed
    1. Consoli A, Bain SC, Davies M, Lingvay I, Bergan EQ, Hansen O, et al. Semaglutide provides sustained reductions in body weight over 2 years in subjects with type 2 diabetes (SUSTAIN 6) [abstract no: 4]. Diabetologia 2017;60(1 Suppl 1):S4. [EMBASE: 618051943]
    1. Jacob S, Silver R, Gumprecht J, Vilsboll T, Hansen T, Petterson J, et al. Semaglutide treatment and renal function in the SUSTAIN 6 trial [abstract]. Diabetologie und Stoffwechsel 2019;14(Suppl 1):S80. [EMBASE: 629494313]
    1. Leiter LA, Bain SC, Hramiak I, Jodar E, Madsbad S, Gondolf T, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovascular Diabetology 2019;18(1):73. [PMID: ] - PMC - PubMed
    1. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine 2016;375(19):1834-44. [MEDLINE: ] - PubMed
SUSTAIN 8 2019 {published data only}
    1. Lingvay I, Catarig AM, Frias JP, Kumar H, Lausvig NL, le Roux CW, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes & Endocrinology 2019;7(11):834-44. [PMID: ] - PubMed
Tuttolomondo 2021 {published data only}
    1. Tuttolomondo A, Cirrincione A, Casuccio A, Del Cuore A, Daidone M, Di Chiara T, et al. Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial. Cardiovascular Diabetology 2021;20(1):1. [PMID: ] - PMC - PubMed
van der Aart‐van 2023 {published data only}2017‐004709‐42‐NL
    1. Aart-van der Beek AB, Apperloo E, Jongs N, Rouw DB, Sjostrom CD, Friedli I, et al. Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: a randomized cross-over clinical study. Diabetes, Obesity & Metabolism 2023;25(6):1758-68. [DOI: 10.1111/dom.15033] [PMID: ] - DOI - PubMed
    1. Aart-van der Beek AB, Apperloo E, Jongs N, Rouw DB, Sjostrom D, Van Raalte DH, et al. Albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes: a randomised crossover clinical trial [abstract no: 750]. Diabetologia 2022;65(Suppl 1):S387. [DOI: 10.1007/s00125-022-05755-w] [EMBASE: 639058218] - DOI
von Scholten 2017 {published data only}2014‐004502‐15
    1. Von Scholten BJ, Persson F, Rosenlund S, Eugen-Olsen J, Pielak T, Faber J, et al. Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub-analysis of a randomized, placebo-controlled, double-blind, crossover trial. Diabetes, Obesity & Metabolism 2017;19(6):901-5. [MEDLINE: ] - PubMed
    1. Scholten BJ, Persson F, Rosenlund S, Hovind P, Faber J, Hansen TW, et al. The effect of liraglutide on renal function: a randomized clinical trial. Diabetes, Obesity & Metabolism 2017;19(2):239-47. [MEDLINE: ] - PubMed
    1. Scholten BJ, Persson FI, Rosenlund S, Hansen T, Rossing P. Renal effects of liraglutide in type 2 diabetic patients with albuminuria: a randomized clinical trial [abstract no: FR-PO815]. Journal of the American Society of Nephrology 2016;27(Abstract Suppl):555A. [EMBASE: 641130951]
Wajdlich 2024 {published data only}
    1. Wajdlich M, Nowicki M. Short term hemodynamic effect of the GLP 1 analogue-liraglutide in patients with diabetic nephropathy [abstract no: SP081]. Nephrology Dialysis Transplantation 2018;33(Suppl 1):i372-3. [EMBASE: 622606435]
    1. Wajdlich M, Nowicki M. The impact of GLP-1 receptor agonist liraglutide on blood pressure profile, hydration, natriuresis in diabetic patients with severely impaired kidney function. Scientific Reports 2024;14(1):5002. [DOI: 10.1038/s41598-024-55724-z] [PMID: ] - DOI - PMC - PubMed
Wang 2020a {published data only}
    1. Jimin L, Xiangyu W, Qian Z, Cuihua X, Xiangrong L, Ya J, et al. Renal efficacy of exenatide in diabetic kidney disease patients with different baseline renal function. Chinese Journal of Diabetes Mellitus 2022;14(7):690-5. [DOI: 10.3760/cma.j.cn115791-20210922-00507] [EMBASE: 2023672952] - DOI
    1. Wang X, Zhang H, Zhang Q, Guan M, Sheng S, Mo W, et al. Exenatide and renal outcomes in patients with type 2 diabetes and diabetic kidney disease. American Journal of Nephrology 2020;51(10):806-14. [PMID: ] - PMC - PubMed
Zhang 2012a {published data only}
    1. Zhang H, Zhang X, Hu C, Lu W. Exenatide reduces urinary transforming growth factor-beta1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria. Kidney & Blood Pressure Research 2012;35(6):483-8. [MEDLINE: ] - PubMed
Zhou 2019a {published data only}
    1. Zhou LJ, Lu GY, Shen YP. Renal protection of exenatide in patients with diabetic kidney disease in early stage. Journal of Xi'an Jiaotong University (Medical Sciences) 2019;40(6):967-72. [EMBASE: 2003972952]

References to studies excluded from this review

Ahren 2013 {published data only}2007‐005880‐80
    1. Ahren B, Leguizamo DA, Miossec P, Saubadu S, Aronson R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care 2013;36(9):2543-50. [MEDLINE: ] - PMC - PubMed
Bolli 2014 {published data only}2008‐001002‐16
    1. Bolli GB, Munteanu M, Dotsenko S, Niemoeller E, Boka G, Wu Y, et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabetic Medicine 2014;31(2):176-84. [MEDLINE: ] - PubMed
Rosenstock 2014 {published data only}
    1. Rosenstock J, Raccah D, Koranyi L, Maffei L, Boka G, Miossec P, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013;36(10):2945-51. [MEDLINE: ] - PMC - PubMed

References to ongoing studies

ChiCTR2200059717 {published data only}2200059717
    1. ChiCTR2200059717. Effect of ultra-short-term insulin therapy combined with once-weekly semaglutide in clinical remission in middle-aged and elderly patients with type 2 diabetes mellitus: an open-label, randomised controlled trial. trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR2200059717 (date of registration: 9 May 2022).
ChiCTR2400080751 {published data only}2400080751
    1. ChiCTR2400080751. A randomized, controlled trial to evaluate the improvement of oxidative stress levels and renal function in patients with diabetic kidney disease treated with semaglutide for 28 weeks. trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR2400080751 (date of registration: 6 February 2024).
NCT05536804 {published data only}
    1. NCT05536804. A study of tirzepatide (LY3298176) in participants with overweight or obesity and chronic kidney disease with or without type 2 diabetes (TREASURE-CKD) [Tirzepatide study of renal function in people with overweight or obesity and chronic kidney disease with or without type 2 diabetes: focus on kidney hypoxia in relation to fatty kidney disease using multiparametric magnetic resonance imaging]. https://clinicaltrials.gov/study/NCT05536804 (first received 22 September 2022).
NCT06182891 {published data only}
    1. NCT06182891. Renoprotective effects of dulaglutide in patients with type 2 diabetic nephropathy. https://clinicaltrials.gov/study/NCT06182891 (date first received 7 November 2023).
NCT06555146 {published data only}
    1. NCT06555146. Semaglutide's effect on renal hemodynamics and function in patients with type 2 diabetes mellitus and nephropathy (SEMA-RMA) [Glucagon-like peptide-1's effect on renal regional blood flow and the renal function in patients with type 2 diabetes mellitus]. https://clinicaltrials.gov/study/NCT06555146 (date first received: 7 August 2024).
NL‐OMON46820 {published data only}2017‐004709‐42‐NL46820
    1. NL‐OMON46820. An open-label randomised cross-over study to evaluate the albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes [An open-label randomised cross-over study to evaluate the albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes - DECADE]. https://trialsearch.who.int/Trial2.aspx?TrialID=NL-OMON46820 (date registered: 28 March 2018).
OTID 2024 {published data only}
    1. Al-Ozairi E, Narula K, Miras AD, Taghadom E, Samad AE, Al Kandari J, et al. Obesity Treatments to Improve Type 1 Diabetes (OTID): a randomized controlled trial of the combination of glucagon-like peptide 1 analogues and sodium-glucose cotransporter 2 inhibitors-protocol for Obesity Treatments to Improve Type 1 Diabetes (the OTID trial). Trials [electronic Resource] 2024;25(1):129. [DOI: 10.1186/s13063-024-07930-3] [PMID: ] - DOI - PMC - PubMed
REMODEL 2022 {published data only}
    1. Bjornstad P, Cherney D, Lawson J, Montegaard C, Pruijm M, Tuttle K, et al. REMODEL: A mechanistic trial evaluating the effects of semaglutide on the kidneys in people with type 2 diabetes and chronic kidney disease. Nephrology Dialysis Transplantation 2022;37(Suppl 3):i290-1. [DOI: 10.1093/ndt/gfac070.013] [EMBASE: 638264104] - DOI
RESET1 2024 {published data only}12623001277639
    1. Frampton R, Snaith JR, Hocking S, Holmes-Walker J, Olsen N, Greenfield JR. Reducing cardiometabolic risk with semaglutide in type 1 diabetes (RESET1): study protocol of a phase 2 double-blinded randomised placebo-controlled trial. Diabetic Medicine 2024;41(10):e15377. [DOI: 10.1111/dme.15377] [PMID: ] - DOI - PubMed

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ADA 2022
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Cao 2022
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Chatterjee 2017
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Chen 2022
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Collins 2008
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de Boer 2022
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Drucker 2018a
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Filippatos 2014
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References to other published versions of this review

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