Gout Drug Disappoints as Renoprotective Agent in T1D

Reduction of serum urate with allopurinol didn’t have much clinical benefit for those with type 1 diabetes and kidney disease, according to the Preventing Early Renal Loss in Diabetes (PERL) trial.

In the double-blind trial, those with established type 1 diabetes and early-to-moderate diabetic kidney disease were able to effectively lower their average serum urate levels with allopurinol — from 6.1 down to 3.9 mg/dL — while those on placebo remained stagnant at 6.1 mg/dL, reported Alessandro Doria, MD, PhD, MPH, of Joslin Diabetes Center in Boston, and colleagues.

During the 3-year intervention period, those on allopurinol saw an average annual drop in iohexol-based GFR of -3.0 mL/min/1.73 m2 versus an annual drop of -2.5 mL/min/1.73 m2 for those on placebo (between-group difference, -0.6 mL/min/1.73 m2 per year, 95% CI -1.5 to 0.4), they stated in the New England Journal of Medicine (NEJM).

However, after allopurinol was stopped during a 2-month wash-out period, serum urate levels bounced back nearly to baseline levels with an average level of 5.9 mg/dL. And after this wash-out period, there wasn’t any significant sustained renal benefit, with an average between-group iohexol-based GFR difference of 0.001 mL/min/1.73 m2 (95% CI -1.9 to 1.9, P=0.99).

Also after wash-out, the average urinary albumin excretion rate was about 40% higher among those that received allopurinol compared with those who received placebo.

Previous data have shown that people with type 1 diabetes and higher serum uric acid levels also have an increased risk of faster diabetic kidney disease progression and end-stage kidney disease. Doria and colleagues assessed if allopurinol — a generic drug commonly used to lower serum uric acid in gout — could hold promise as a potential treatment option.

“Our results show quite clearly that there is no point in giving allopurinol to subjects with type 1 diabetes and early diabetic kidney disease, unless this is indicated for other reasons, such as symptomatic hyperuricemia,” Doria explained to MedPage Today. “However, as with any trial, one should be careful in generalizing findings.”

“We cannot exclude that allopurinol has beneficial effects on kidney function in people with different clinical characteristics,” he said, listing several benefits for those with higher serum uric acid, more advanced stages of kidney disease, or for those with type 2 diabetes instead of type 1 diabetes.

However, Doria also referenced another recent NEJM study, from Sunil Badve, MBBS, MD, PhD, of St. George Hospital in Sydney, and colleagues, that found similar results with allopurinol — failing to significantly slow the decline in eGFR versus placebo — in people with stage 3 or 4 chronic kidney disease.

“We were, of course, hoping that allopurinol would work in slowing down kidney function loss, but we were cognizant that other promising therapies had previously failed to achieve this goal,” he added. “We were disappointed by the neutral results because we were hoping to be able to offer something new to people with type 1 diabetes at high risk of end-stage kidney disease. The current interventions to prevent diabetic kidney disease progression and end-stage kidney disease in people with type 1 diabetes were developed more than 20 years ago and are only partially effective.”

Nevertheless, Doria said that “from a scientific point of view,” his group was happy to provide “a clear, unambiguous answer to this question.”

“During the trial, serum uric acid declined on average by 36% in people randomized to allopurinol as compared to those randomized to placebo. Yet, kidney function at the end of the trial was virtually identical in the two treatment groups,” he pointed out.

The 16-site trial included 267 participants who were randomized to receive allopurinol and 263 who received placebo. All individuals had established type 1 diabetes, with an average HbA1c of 8.2% and average duration of diabetes of nearly 35 years. All participants also had diabetic kidney disease with a serum urate level of at least 4.5 mg/dL and an eGFR of 40.0 to 99.9 mL/min/1.73 m2 of body-surface area.

Doria noted that this study specifically focused on those in relatively early stages of diabetic kidney disease, unlike many prior studies in this area, in order to yield a potentially longer delay of end-stage kidney disease.

Participants first entered a 9-week run-in phase, during which renin-angiotensin system inhibitors were either initially administered or adjusted for a target blood pressure of 104/90 mmHg. Those randomized to receive allopurinol were give a starting dose of 100 mg/day for 4 weeks, which was later adjusted to 400 mg/day if the eGFR was 50 mL/min/1.73 m2 or higher, to 300 mg/day if the eGFR was between 25-49 mL/min/1.73 m2, or to 200 mg/day if the eGFR was between 15-24 ml mL/min/1.73 m2.

Treatment with allopurinol was also generally safe, as there was a total of 171 serious adverse events in the allopurinol group and 183 in the placebo group during the 3-year treatment period.

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    Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years.


The trial was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the JDRF, the National Center for Advancing Translational Sciences, and the National Institute on Aging.

The iohexol used to assess iohexol-based GFR was provided by GE Healthcare.

Doria disclosed support from Sanofi-Aventis US to the Joslin Diabetes Center. Co-authors disclosed multiple relevant relationships with industry.