A cheap, decades-old diabetes drug is being tested against a genetic kidney disease that destroys kidney function in roughly half of those affected. Autosomal Dominant Polycystic Kidney Disease (ADPKD) causes fluid-filled cysts to grow relentlessly inside the kidneys, eventually crushing healthy tissue. It accounts for 11% of UK patients on dialysis or with a kidney transplant. The only licensed drug, tolvaptan, works only in people whose disease is already rapidly progressing and often causes side effects so severe that many patients stop taking it. Metformin targets two of the signalling pathways that drive cyst growth, and animal studies show it reduces cyst burden and blood pressure. The trial will recruit 300 UK patients whose kidney function is still reasonably preserved (eGFR of 45 or above) but who are at high risk of progression. Participants will take metformin or a placebo for two years. The primary measure is the change in estimated glomerular filtration rate (eGFR), a standard blood test for kidney function. If metformin slows the decline, it could become a cheap, well-tolerated early intervention—something that could be prescribed years before tolvaptan is even considered, potentially delaying or preventing kidney failure for many patients.
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Research Question: Does metformin reduce the rate of kidney function decline in ADPKD patients with an eGFR = 45mls/min/1.73m2, who are at risk of disease progression Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading cause of kidney failure and accounts for 11% of prevalent UK kidney replacement therapy (KRT) patients. Rapidly expanding cysts damage the kidney parenchyma causing kidney failure, debilitating chronic pain and reduced quality of life. Currently tolvaptan is the only licensed treatment. However, its use is limited to those with rapid disease progression (often a late sign) and its side effect profile leads to high discontinuation rates. Metformin has been used in diabetics for decades and is a low cost, safe and well-established therapy that may also slow kidney function decline in ADPKD. It targets two key cystogenic signalling pathways providing a potentially valuable therapy that can be repurposed for the treatment of ADPKD. Pre-clinical studies have confirmed that it reduces kidney cyst burden and blood pressure in murine PKD models. Furthermore human feasibility studies have strengthened the evidence for safety and feasibility of metformin evaluation in ADPKD. Aims: i) Primary Outcome: change in eGFR (CKD-EPI) from randomisation to 24 months, ii) Secondary outcomes: blood pressure, albuminuria, QoL, adverse events, iii) UK-Specific Outcome: change in pain severity and analgesic burden from randomisation to 24 months Methods: IMPEDE-PKD is a multi-centre, double-blind, parallel group randomised controlled trial of metformin versus placebo in adult ADPKD patients with an eGFR = 45mL/min/1.73m2, who either have active disease progression or are deemed high risk based on standardised risk stratification tools. A total of 1174 participants (300 from the UK) will be recruited globally. This grant application is for the UK arm of the trial. Eligible participants will undergo a 12-week metformin run-in, commencing 1000mg daily. This will be titrated up every 4 weeks to the maximum tolerated dose. All participants will undergo 3 face-to-face clinic visits (Week 0, 4, 8) and 3 telephone consultations (week 2,6, 10) during run in. Those that successfully tolerate a minimum of 1000mg daily will then be randomised at week 12 in a 1:1 ratio to either metformin or placebo. Subjects will undergo six clinical visits during the 2 year follow up period which will include 1 telephone consultations (month 1) and five face-to-face visits (month 3, 6, 12, 18, 24). During this time evaluations will include physical examination, concomitant medication check, safety, blood and urine tests, as well as completing questionnaires on pain and QoL. Timeline: The overall study will take 5 years, and will start in January 2024 with a 6 month period for UK set-up and ethics/regulatory approvals. Site initiation and recruitment will commence in July 2024. Following a 24 month recruitment period, all patients will be followed up for 2 years with the last participant visit and study end anticipated in June 2028. Impact and dissemination: Findings will be presented at conferences and submitted to peer-reviewed journals. They will also be shared with participants and patient groups via social media and information days. If effective, we anticipate that metformin will be incorporated into evidence based guidelines as a key early intervention in those with preserved kidney function and risk factors for progression.
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