#1790 Metformin versus standard of care in slowing progression of autosomal dominant polycystic kidney disease and correlation with total kidney volume

Abstract

Abstract Background and Aims Autosomal dominant kidney disease (ADPKD) is the most common monogenic disorder leading to renal failure with very limited therapeutic options. Apart from lifestyle modifications and control of hypertension, tolvaptan is the only Food and Drug Administration (FDA) approved disease modifying drug. Although, it has proven therapeutic benefit in slowing disease progression in high risk Mayo Class (Mayo Class 1C-E), the aquaretic potential, potential hepatotoxicity and the cost limits its widespread use especially in resource constrained country. Metformin has been shown to be effective in ADPKD in preclinical studies and is also well tolerated by the general population. We planned this study to assess the efficacy and safety of metformin in non diabetic ADPKD patients. Method Our study is a prospective, randomized controlled, open labelled clinical trial of 52 non diabetic adults 18 to 60 years of age with typical ADPKD, estimated glomerular filtration rate (eGFR) > 45 ml/min/m2 and no risk factors of rapid progression. Participants were randomized in a 1:1 ratio by a computer-generated random number table into Metformin + standard of care group (Metformin arm) and standard of care group (Placebo arm). Primary outcome of the study was to evaluate the effects of metformin versus placebo arm on the percentage and absolute change in eGFR over 6-month period. Secondary outcomes were to study the effect of metformin versus placebo arm on the percentage and absolute change in height adjusted total kidney volume (htTKV ml/m) at 6 months, to evaluate the effect of baseline plasma copeptin levels with percentage change in htTKV and eGFR over 6 months, to evaluate metformin tolerability, to evaluate the effects of metformin versus placebo on the changes in body weight, BMI, blood pressure and urine protein excretion at 6 months period. Results Mean (SD) age of the cohort was 37.15 (10.16) years with half of them being females. The mean (SD) baseline htTKV and eGFR was 335.67 (153.3) ml/m and 100.23 (25.95) ml/min/m2. Clinical exome sequencing was available in 9 (17.3%) patients of which two third had PKD1 mutation. Baseline characteristics were distributed equally across randomized groups. Baseline proteinuria was significantly higher in the Metformin arm (p = 0.014). The eGFR difference and percentage change in eGFR was not different between the groups at 6 months (p = 0.535, 0.483). There was no statistically significant difference in htTKV difference and percentage change in htTKV at 6 months between the groups although increase in htTKV was numerically smaller in the metformin group (p = 0.769, 0.805). Blood pressure, weight, body mass index (BMI) and proteinuria also did not differ between two groups. Half of the cohort tolerated the maximum dose of metformin. Around 2/3rd patients reported adverse effects most commonly asthenia. There was no lactic acidosis or significant gastrointestinal side effects as assessed by gastrointestinal rating scale (GSRS) scale. Baseline copeptin levels did not correlate with eGFR or htTKV difference at 6 months. Conclusion Metformin appears to be safe and tolerable in non diabetic ADPKD patients over 6 months. However larger clinical trials are needed to conclude regarding the efficacy in terms of eGFR decline or htTKV progression.