Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end-stage renal failure in the majority of affected patients. Despite decades of clinical and basic research no specific treatment is available. Compounds tested in animal models have either not been effective in humans or associated with too much toxicity. Therefore there is an urgent need for a well-tolerated drug that can be given over a long period of time. Metformin has a track record of tolerability and safety in patients with type 2 diabetes as well as in non-diabetic subjects with polycystic ovary syndrome. Potential benefits of metformin in ADPKD are related to its ability to stimulate AMP-kinase, an important enzyme involved in regulation of cell metabolism. Decreased AMP-kinase activity in cystic epithelia results in increased cell proliferation and fluid secretion, prerequisites for cyst enlargement. When used in two mouse models of severe ADPKD, metformin treatment significantly reduced cyst burden and preserved renal parenchyma. Metformin also has anti-inflammatory and antioxidant properties which are important for reducing kidney fibrosis and loss of renal function, as shown in several animal models of acute kidney injury and progressive chronic kidney disease. In humans, a large retrospective cohort study among 13,238 veterans who initiated either metformin or sulfonylurea therapy for type 2 diabetes revealed that over 5 years follow-up metformin users had significantly lower risk for renal function decline, ESRD or death, even after adjustments for multiple time- varying covariates. Therefore, there is ample evidence for metformin potentially being a very useful drug for the treatment of ADPKD, by reducing cyst enlargement and preserving renal function. We propose a pilot clinical trial to determine the feasibility, in terms of safety and tolerability of metformin in non-diabetic ADPKD patients. To achieve this we will conduct a 12-month parallel-group, randomized, double-blind, placebo-controlled trial in 50 ADPKD patients with an eGFR of 50-75 mL/min/1.73m2. A secondary, exploratory goal is to determine the effect of metformin on kidney volume growth and on kidney function decline. Working Hypotheses: Hypothesis 1. Metformin is safe and well tolerated in non-diabetic ADPKD patients with estimated GFR 50-75 mL/min/1.73 m2. Hypothesis 2. Metformin will slow cyst growth and kidney function decline in non-diabetic ADPKD patients with estimated GFR 50-75 ml/min/1.73 m2. Impact on the Field: If successful, data obtained in this pilot study will be used to plan a larger interventional outcomes trial in ADPKD. Metformin has the potential to be useful for early (inhibition of cyst enlargement) and later stages (preservation of renal function) of the disease. This could be a major step forward towards alleviating the burdens of ADPKD patients.
The proposed pilot study will determine whether non-diabetic subjects with autosomal dominant polycystic kidney disease (ADPKD) and mildly decreased kidney function can tolerate treatment with metformin, an FDA- approved medication for the treatment of diabetes mellitus type 2. Metformin has been studied in other non- diabetic populations and generally is very well tolerated. It has many properties that may help to preserve kidney function, particularly in ADPKD, which will also be evaluated in the proposed study.