Victoria Socha

DocwireNews

Autosomal dominant polycystic kidney disease (ADPKD) is a common familial disorder that leads to kidney failure in a majority of patients. ADPKD is caused primarily by mutation in either PKD1 or PKD2 (encoding polycystin 1 and 2, respectively). The disorder occurs in all races and ethnicities worldwide; the estimated prevalence is 3.3 to 4.6 per 10,000 population.Mean age at initiation of kidney replacement therapy for patients with the more common PKD1 mutation (80%-85%) is 53 to 58 years, resulting in substantial morbidity and mortality. According to Godela M. Brosnahan, MD, and colleagues, despite progress in research in ADPKD, there has been little change over the past 20 years in patient prognosis, and treatment options are limited.To date, the only approved intervention to slow progression of kidney disease in patients with ADPKD is tolvaptan. Metformin is well tolerated and safe in other patient populations. Dr. Brosnahan et al conducted a prospective randomized controlled double-blind clinical trial to assess the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. Results of the trial were reported in the American Journal of Kidney Diseases [2022;79(4):518-526], and as this is a prestigious source of information they use a <a href="https://ground.news/media-bias">media news bias</a> to check their sources.The primary end points were the percentage of patients in each group at the end of the 12-month study period who were prescribed (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary end points included the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in estimated glomerular filtration rate (eGFR) over a 12-month period.A total of 139 patients were prescreened for participation in the trial. Of those, 51 adults 30 to 60 years of age with a diagnosis of <a href="https://www.docwirenews.com/docwire-pick/nephrology-picks/adpkd-three-studies-provide-new-insights/">ADPKD</a> and an eGFR of 50 to 80 mL/min/1.73 m2 were randomized over a period of 35 months to either metformin (n=26) or placebo (n=25). Prior to the onset of the study period, one participant in the metformin group withdrew, and three participants in the metformin group and one in the placebo group were lost to follow-up evaluation before the final study visit at 12 months.Mean age of the total cohort was 48 years, 37% were male, 98% were White, 84% had hypertension, and 65% were taking a renin-angiotensin-aldosterone system blocking drug. Mean eGFR was 70 min/mL/1.73 m2. Sixty-nine percent of participants were in the higher risk Mayo Imaging Classes of 1C, 1D, or 1E. The two randomized groups were similar in demographic characteristics. With the exception of a higher prevalence of hypertension and larger TKV in the metformin group, the groups were similar in clinical characteristics.Of the 22 patients in the metformin group who completed the study, 50% (n=11/22) completed the treatment phase on the full dose, including two participants who required per protocol dose reduction to 1000 mg daily for safety following a drop in eGFR to below 45 mL/min/1.73 m2 (they did not report any significant side effects). Seven other participants completed the treatment phase on at least 50% of the full metformin dose.More adverse symptoms were reported by participants in the metformin group. The symptoms were primarily related to the gastrointestinal tract and resolved wither spontaneously or after metformin dose reduction. Some participants in the placebo group also reported gastrointestinal symptoms, but none required dose reduction because the patients described the symptoms as tolerable.Two participants in the metformin group had safety events that required hospitalization. However, both events were unrelated to the study drug: one participant was hospitalized for acute pyelonephritis, which was successfully treated with antibiotics, and the other was hospitalized for observation for multiple symptoms with no pathologic findings on laboratory and imaging studies and was ultimately diagnosed as a viral infection.One patient in each study group reported mild hypoglycemia episodes. Both of those patients reported lightheadedness. In the patient in the metformin group, blood glucose was 49 mg/dL; in the placebo group patient, blood glucose was 54 mg/dL. The patient in the metformin group had been fasting and was advised to eat prior to exercising and taking the study drug, and no further hypoglycemic symptoms were reported.In analysis of the prespecified exploratory secondary end points (percentage increase in htTKV and absolute eGFR decline over 12 months) for one patient in each group it was difficult to accurately determine htTKV on the follow-up images, so those two were excluded from the secondary analyses. Of the 43 participants eligible for analyses for the secondary end points, 21 were in the metformin group and 22 in the placebo group.The changes in htTKV and eGFR were not significantly different between the two groups. The decline in eGFR was numerically smaller in the metformin group (&ndash;0.41 vs &ndash;3.35 mL/min/1.73 m2), although those patients had larger kidneys and more hypertension (more severe disease) than those in the placebo group; the larger decline in eGFR was therefore expected.The short study duration, small sample size, and imbalance in baseline htTKV between treatment groups were cited by the authors as limitations to the study findings.In conclusion, the researchers said, &ldquo;Metformin at 500-1000 mg twice daily had a favorable adherence and safety profile over 12 months in participants with ADPKD with a mean eGFR of 70 &plusmn; 13 mL/min/1.73 m2. Because of the therapeutic potential of metformin for ADPKD, further large-scale trials are warranted, using extended-release formulations and randomizing patients after a run-in period to exclude intolerant participants.&rdquo;Takeaway Points<ol>
<li>Treatments for ADPKD are limited. Researchers conducted a study to examine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus.</li>
<li>There were no cases of lactic acidosis in the metformin group and one patient in each group (metformin/placebo) experienced one episode of hypoglycemia.</li>
<li>Over the 12 months of the study, 50% or more of the maximal metformin dose was safe and well tolerated in patients with ADPKD.</li>
</ol>

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Safety and Tolerability of Metformin in Patients With ADPKD

ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is a common familial disorder that leads to kidney failure in a majority of patients. ADPKD is caused primarily by ...

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