
==== Front
J Nephrol
J Nephrol
Journal of Nephrology
1121-8428
1724-6059
Springer International Publishing Cham

38512373
1906
10.1007/s40620-024-01906-x
Research Letter
A secondary analysis of concurrent use of metformin and tolvaptan in ADPKD tolvaptan trials
Stanley I. Kitty i.stanley@uq.edu.au

1
Palma Anton M. 2
Viecelli Andrea K. 134
Johnson David W. 134
Hawley Carmel M. 134
Staatz Christine E. 5
http://orcid.org/0000-0002-8752-2551
Mallett Andrew J. andrew.mallett@health.qld.gov.au

4678
1 https://ror.org/00rqy9422 grid.1003.2 0000 0000 9320 7537 Centre for Health Services Research, The University of Queensland, Brisbane, QLD Australia
2 grid.419943.2 0000 0004 0459 5953 Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ USA
3 https://ror.org/04mqb0968 grid.412744.0 0000 0004 0380 2017 Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Australia
4 https://ror.org/00rqy9422 grid.1003.2 0000 0000 9320 7537 Centre for Kidney Disease Research, The University of Queensland, Brisbane, Australia
5 https://ror.org/00rqy9422 grid.1003.2 0000 0000 9320 7537 School of Pharmacy, The University of Queensland, Brisbane, Australia
6 grid.417216.7 0000 0000 9237 0383 Department of Renal Medicine, Townsville University Hospital, Townsville, Australia
7 https://ror.org/04gsp2c11 grid.1011.1 0000 0004 0474 1797 College of Medicine and Dentistry, James Cook University, Townsville, Australia
8 https://ror.org/00rqy9422 grid.1003.2 0000 0000 9320 7537 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
21 3 2024
21 3 2024
2024
37 5 14171419
14 12 2023
15 1 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
issue-copyright-statement© Italian Society of Nephrology 2024
==== Body
pmcAutosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of kidney disease [1]. Tolvaptan, a vasopressin V2-receptor antagonist, is the only disease-modifying therapy available with proven efficacy in slowing disease progression. The anti-diabetic medication, metformin, has been theorised to be of potential benefit in ADPKD. Metformin activates 5 AMP-activated protein kinase, which negatively regulates the cystic fibrosis transmembrane conductance regulator and the mammalian target of rapamycin, both of which are implicated in the growth of cysts in ADPKD [2]. Two phase II trials [3, 4] have found metformin to be safe and tolerable in patients with ADPKD, with a non-significant slowing of estimated glomerular filtration rate (eGFR) decline and total kidney volume expansion. A phase III trial is currently underway to further define metformin’s role in ADPKD [5]. Given the established role of tolvaptan and the potential role of metformin in the management of ADPKD, the safety and efficacy of combined therapy are also of interest.

Two phase III trials, Tolvaptan Efficacy and safety in Management of autosomal dominant Polycystic kidney disease and its Outcomes (TEMPO) 3:4 [6] and Replicating Evidence of Preserved Renal function: an Investigation of tolvaptan Safety and Efficacy in ADPKD (REPRISE) [7], established tolvaptan’s efficacy. The datasets of all subjects from these trials were pooled in this analysis and participants were assessed for eligibility for analysis on primary efficacy endpoints. Patients’ use of metformin and allocated treatment groups were used to create 4 groups for analysis: tolvaptan only, placebo only, tolvaptan with metformin and placebo with metformin. Baseline characteristics were described using frequencies (n/%) for categorical variables and descriptive statistics (mean/SE) for continuous variables. Chi-squared tests and t-tests for association assessed whether distributions differed by treatment group. Subject-level incidence of adverse events (n/%) were also compared.

Linear mixed models for repeated measures were conducted to evaluate change in total kidney volume (%) from baseline to 12 and 36 months in the TEMPO 3:4 trial and annualized eGFR slope (mL/min/1.73m2 per year) from baseline to 4, 8 and 12 months in both trials. Due to varying eligibility criteria in each trial, analyses for eGFR slope were restricted to participants with stage 2 chronic kidney disease (CKD) or higher at baseline. Both models included fixed effects for visit (categorical), treatment group and a visit*treatment interaction term and random effects for repeated measures within subjects. Model-estimated least square means and 95% confidence intervals for each endpoint were calculated at each visit and compared between each pair of treatment groups, adjusted for multiple comparisons using Tukey’s Honest Significant Difference test. Analyses were repeated with baseline CKD stage. R statistical software v4.2.1 (R Core Team, Vienna, Austria, 2020) was used for the analyses.

The pooled dataset included 2488 subjects from the TEMPO 3:4 (n = 1157) and REPRISE (n = 1331) trials. Metformin use was observed in 28 participants and used to create 4 treatment groups for analysis: tolvaptan only (n = 1390), placebo only (n = 1070), tolvaptan with metformin (n = 18), placebo with metformin (n = 10). Baseline characteristics by treatment group are shown in Supplementary Table S1. At baseline, metformin users were older (47 vs. 43.5 years), heavier (96 vs. 81 kg), had lower eGFR (49.6 vs. 58 mL/min/1.73m2) and higher prevalence of cardiovascular-related comorbidities, including diabetes mellitus (79 vs. 1.5%) (p < 0.001).

Results from models of the change in eGFR are displayed in Fig. 1a. Baseline kidney function was measured at the end of the titration phase and excluded any observations after end of treatment to minimize the potential acute haemodynamic effects of tolvaptan. Participants receiving tolvaptan had a slightly slower decline in kidney function vs. placebo only (annualized eGFR slope – 3.2% [95%CI, – 4.1 to – 2.4%] vs. – 4.0%, [95%CI, – 5 to – 3.1%] p = 0.584). Participants receiving both tolvaptan and metformin did not experience a statistically significant difference in eGFR decline compared with the other groups (Supplemental Table S2). Results also did not differ by CKD stage at baseline (Fig. 1b, Supplemental Table S3).Fig. 1 Change in estimated glomerular filtration rate and total kidney volume by treatment group and CKD stage

Total kidney volume increased significantly from baseline to 36 months in all treatment groups in the TEMPO 3:4 trial, tolvaptan alone (3.2%, 95%CI, 2.7–3.7%), placebo (6.3%, 95%CI, 5.7–7.0%), metformin with tolvaptan (7.5%, 95%CI, 1.7% to 13.4%) and metformin with placebo (15.7%, 95%CI, 2.6–28.8%). The only statistically significant difference was between tolvaptan only and placebo only, p =  < 0.001; (Fig. 1c). Results stratified by CKD stage showed no clear differences (Fig. 1d, Supplemental Table S3).

The most common adverse events experienced during the trials were polyuria (25.8% of overall participants), thirst (20.1%) and headache (14.5%). Adverse events and safety outcomes were comparable between metformin users and non-users (Supplemental Table S4). There were higher rates of urinary tract infection (20%) and lower rates of nausea (0%) in the metformin with placebo group (p-value 0.04), although this was the smallest participant group.

This preliminary report analysed outcomes from the TEMPO3:4 and REPRISE trials in participants using metformin at baseline. Efficacy estimates showed no meaningful difference between participants treated with metformin. Concomitant therapy showed no signal of harm and further investigation of metformin combined with tolvaptan is warranted. The upcoming phase III trial of metformin for ADPKD will permit the inclusion of patients being treated with tolvaptan [5], and an active comparator trial comparing metformin to tolvaptan in ADPKD has been proposed [8].

Limitations of this study include the small sample size of metformin-treated participants, which restricts statistical power. Neither TEMPO3:4 nor REPRISE excluded participants with type 2 diabetes mellitus. Unsurprisingly, diabetes was identified as a comorbidity in 80% of metformin-treated participants, compared to just 1.5% of participants not on metformin, and may have confounded these results (Supplementary Table S1). To create a unified data set in the models for eGFR slope, participants from the REPRISE population with stage 1 CKD were excluded, and TEMPO 3:4 results were restricted to 12 months. This may explain why we observed non-significant differences in eGFR decline between tolvaptan- and placebo-treated participants, whereas statistically significant benefits were reported in the primary publications of these trials [6, 7].

Overall, these data suggest that metformin may be safe to use in conjunction with tolvaptan. Due to the low number of participants taking metformin, there are currently insufficient data to determine the impact of co-therapy on clinical outcomes. Upcoming trials may provide more insight.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 40 kb)

Acknowledgements

The authors wish to acknowledge the participants, clinicians and investigators who contributed to the TEMPO3:4 and REPRISE clinical trials.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Anton M. Palma. The first draft of the manuscript was written by I. Kitty Stanley and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability

Data may be made available upon request and application to Otsuka Pharmaceutical Development & Commercialization, Inc.

Declarations

Conflict of interest

AMP is an employee of Otsuka Pharmaceutical Development & Commercialization. AJM is supported by a Queensland Health Advancing Clinical Research Fellowship.

Ethical approval

The institutional review board or ethics committee at each site for the TEMPO 3:4 [NCT00428948] and REPRISE [NCT02160145] clinical trials provided ethical approval for each trial.

Human and animal rights

The TEMPO 3:4 [NCT00428948] and REPRISE [NCT02160145] clinical trials were carried out in accordance with and adhered to all relevant human rights and research guidelines and regulations.

Informed consent

All participants in both the TEMPO 3:4 [NCT00428948] and REPRISE [NCT02160145] clinical trials provided written informed consent for participation, data collection and analysis.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Chapman AB Devuyst O Eckardt K Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a kidney disease: improving global outcomes (KDIGO) controversies conference Kidney Int 2015 88 1 17 27 10.1038/ki.2015.59 25786098
Chapman AB, Devuyst O, Eckardt K et al (2015) Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int 88(1):17–27. 10.1038/ki.2015.5925786098 10.1038/ki.2015.59
2. Capuano I Riccio E Caccavallo S ADPKD and metformin: from bench to bedside Clin Exp Nephrol 2019 23 11 1341 1342 10.1007/s10157-019-01770-1 31346894
Capuano I, Riccio E, Caccavallo S et al (2019) ADPKD and metformin: from bench to bedside. Clin Exp Nephrol 23(11):1341–1342. 10.1007/s10157-019-01770-131346894 10.1007/s10157-019-01770-1
3. Perrone RD Abebe KZ Watnick TJ Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD) Kidney Int 2021 100 3 684 696 10.1016/j.kint.2021.06.013 34186056
Perrone RD, Abebe KZ, Watnick TJ et al (2021) Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD). Kidney Int 100(3):684–696. 10.1016/j.kint.2021.06.01334186056 10.1016/j.kint.2021.06.013
4. Brosnahan GM Wang W Gitomer B Metformin therapy in autosomal dominant polycystic kidney disease: a feasibility study Am J Kidney Dis 2022 79 4 518 526 10.1053/j.ajkd.2021.06.026 34391872
Brosnahan GM, Wang W, Gitomer B et al (2022) Metformin therapy in autosomal dominant polycystic kidney disease: a feasibility study. Am J Kidney Dis 79(4):518–526. 10.1053/j.ajkd.2021.06.02634391872 10.1053/j.ajkd.2021.06.026
5. ClinicalTrials.gov. Identifier: NCT04939935, Implementation of metformin therapy to ease decline of kidney function in polycystic kidney disease (IMPEDE-PKD). 2022 [28/11/2022]; Available from: https://clinicaltrials.gov/ct2/show/NCT04939935.
6. Torres VE Chapman AB Devuyst O Tolvaptan in patients with autosomal dominant polycystic kidney disease N Engl J Med 2012 367 25 2407 2418 10.1056/NEJMoa1205511 23121377
Torres VE, Chapman AB, Devuyst O et al (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367(25):2407–2418. 10.1056/NEJMoa120551123121377 10.1056/NEJMoa1205511
7. Torres VE Chapman AB Devuyst O Tolvaptan in later-stage autosomal dominant polycystic kidney disease N Engl J Med 2017 377 20 1930 1942 10.1056/NEJMoa1710030 29105594
Torres VE, Chapman AB, Devuyst O et al (2017) Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med 377(20):1930–1942. 10.1056/NEJMoa171003029105594 10.1056/NEJMoa1710030
8. ClinicalTrials.gov. Identifier: NCT03764605. Metformin vs Tolvaptan for treatment of autosomal dominant polycystic kidney disease (METROPOLIS). 2018 [29/11/2022]; Available from: https://clinicaltrials.gov/ct2/show/NCT03764605.
