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A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease.

ABSTRACT: BACKGROUND:Metformin has shown promising results regarding cystogenesis inhibition in preclinical studies with autosomal dominant polycystic kidney disease (ADPKD) models. We designed a prospective, preliminary, single-arm study to evaluate the tolerability, safety and the effect of Metformin on kidney function and body mass index (BMI) in Romanian patients with ADPKD. METHODS:We enrolled 34 adult patients with ADPKD, chronic kidney disease (CKD) stages 1-5 not on dialysis and without diabetes mellitus. The primary endpoint was to assess the tolerability and safety of Metformin. The secondary endpoints evaluated changes in estimated glomerular filtration rate (eGFR), body mass index (BMI) and renal replacement therapy (RRT) necessity. Patients received an initial dose of Metformin of 500?mg/day within the first month that was increased to 1000?mg/day thereafter according to tolerability. Change in eGFR and BMI was expressed as mean difference with the corresponding 95% confidence intervals and as a percentage. For the primary endpoint, we included all 34 enrolled patients. To assess the secondary endpoint, intention-to-treat (ITT) and per-protocol (PP) analysis was performed. RESULTS:Sixteen patients out of 34 completed the follow-up period at 24?months. Eighteen patients developed adverse events and 63.6% of these events were gastrointestinal related. Nausea was the most common adverse event (17.6%). Two patients (5.8%) permanently discontinued medication due to adverse events. We recorded no case of hypoglycemia, lactic acidosis or death. Mean eGFR changed by -?1.57?ml/min/1.73m2 (95%CI:-22.28 to 19.14, P =?0.87) in ITT and by -?4.57?ml/min/1.73m2 (95%CI:-28.03 to 18.89, P =?0.69) in PP population. Mean BMI change was -?1.10?kg/m2 (95%CI:-3.22 to 1.02, P =?0.30) in ITT population and?-?0.80?kg/m2 (95%CI:-3.27 to 1.67, P =?0.51) in PP analysis. Three patients (8.8%) needed RRT. CONCLUSIONS:Metformin was well tolerated, had a good safety profile even in ADPKD patients with advanced CKD and it was not associated with change in eGFR or BMI across the follow-up period. TRIAL REGISTRATION:The study was retrospectively registered on https://www.isrctn.com (number ISRCTN 93749377); date registered: 02/25/2019.

SUBMITTER: Sorohan BM

PROVIDER: S-EPMC6651959 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease.

Sorohan Bogdan Marian BM Ismail Gener G Andronesi Andreea A Micu Georgia G Obrișcă Bogdan B Jurubiță Roxana R Sinescu Ioanel I Baston Cătălin C

BMC nephrology 20190723 1

<h4>Background</h4>Metformin has shown promising results regarding cystogenesis inhibition in preclinical studies with autosomal dominant polycystic kidney disease (ADPKD) models. We designed a prospective, preliminary, single-arm study to evaluate the tolerability, safety and the effect of Metformin on kidney function and body mass index (BMI) in Romanian patients with ADPKD.<h4>Methods</h4>We enrolled 34 adult patients with ADPKD, chronic kidney disease (CKD) stages 1-5 not on dialysis and wit ...[more]

PMID: 31337351

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Project description:BackgroundThe course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.MethodsIn this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.ResultsOver a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).ConclusionsTolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).

Dataset Information

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease.

Publications

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease.

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