The Benefit of Intensive Albuminuria Lowering In Patients With Type 2 Diabetes

Hyperuricemia has been implicated in the development and progression of chronic kidney disease, and the effects of intensive albuminuria lowering may be beneficial.  

Lowering albuminuria in patients with type 2 diabetes mellitus is an important goal to prevent chronic kidney disease progression and its consequences. Albuminuria is an emerging biomarker for chronic kidney disease progression and is a surrogate endpoint for longer-term kidney disease outcomes. Hyperuricemia is associated with the development of chronic kidney disease. It is an independent predictor for the development of moderately increased albuminuria, with the risk most significant for those with the highest serum urate concentrations.  

Previous clinical trial evidence has shown that lowering serum urate levels through xanthine oxidase inhibition may slow kidney disease progression and reduce major renal and CV events. In addition, extreme lowering of serum urate levels may improve kidney protection above and beyond existing renal protection strategies by reducing albuminuria and risk for chronic kidney disease progression.  

Verinurad is a urate transporter 1 (URAT1) inhibitor that reduces serum urate levels in patients with gout, and Febuxostat is a competitive xanthine oxidase inhibitor commonly used to treat hyperuricemia in patients with gout. Stack et al. hypothesized that an intensive urate-lowering strategy with a combination of verinurad plus febuxostat would reduce serum urate concentration and lead to measurable benefits on kidney function.  

The purpose of this study was to evaluate the impact of this combination on albuminuria in hyperuricemic patients with type 2 diabetes mellitus, assess any additional effects on kidney function, and examine the safety profile of this novel combination. This study was a multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial in hyperuricemic patients with type 2 diabetes mellitus and albuminuria receiving standard-of-care treatment. The primary objective was to assess the effect of verinurad plus febuxostat on albuminuria. Secondary objectives included the evaluation of kidney function, cardiovascular health, and assessment of metabolic effects. Participants were randomly assigned 1:1 to once-daily oral verinurad (9 mg) and febuxostat (80 mg) or matched placebo. Treatment duration was for 24 weeks, and patients were followed up for four weeks after treatment had ended to assess the effects of treatment discontinuation.  

Inclusion criteria included adults ≥ 18 years or older with type 2 diabetes mellitus, serum urate concentration ≥ 6.0 mg/dL, eGFR ≥ 30 mL/min/1.73m2, and urinary albumin-creatinine ratio (UACR) of 30 to 3,500 mg/g. Participants were required to be receiving a stable dose of a RAS inhibitor for one month or longer before randomization, unless contraindicated, not tolerated, unavailable, or considered unsuitable by the investigator. Exclusion criteria were prior treatment with any urate-lowering agents six months before randomization, uncontrolled hypertension (SBP > 180mmHG), history of gout requiring prophylaxis NSAIDs or colchicine, diagnosis of heart failure, known hypersensitivity to either study drug, etc.  

Sixty patients were enrolled, with 32 randomly assigned to the verinurad plus febuxostat group and 28 to the placebo group. The study met the primary objective with a reduction in UACR from baseline at 12 weeks for verinurad plus febuxostat versus placebo. At week 12, mean percentage change from baseline in UACR was -48.7% (95% CI, -64.8% to -25.1%) for verinurad plus febuxostat and -15.3% (95% CI, -43.2% to 26.4%) for placebo. At 24 weeks, mean percent change from baseline in UACR was -38.4% (95% CI, -58.1% to -9.5%) for verinurad plus febuxostat and 21.4% (95% CI, -18.9% to 81.1%) for placebo. The effect of verinurad plus febuxostat combination was consistent with a true pharmacologic effect, as shown by an increase from baseline in UACR at four weeks after the end of treatment. Mean change in UACR from baseline at follow-up, 184.28 mg/g for verinurad plus febuxostat and 71.94 mg/g for placebo.  

The reduction in serum urate levels from baseline was notably greater with verinurad plus febuxostat compared with placebo at both week 12 and week 24. Mean percentage changes from baseline were -56.8% (95% CI, -63.9% to -48.4%) and -61.9% (95% CI, -68.3% to -54.3%) for the verinurad plus febuxostat combination and 6.9% (95% CI, -11.8% to 29.5%) and 4.7% (95% CI, -13.8% to 27.2%) for placebo at each time point, respectively. Verinurad plus febuxostat had no apparent effect on eGFR versus placebo in patients at the end of treatment. And there were no pronounced differences between the verinurad plus febuxostat, and placebo arms were noted for serum creatinine or cystatin C levels at weeks 12 and 24.  

In conclusion, an intensive urate-lowering strategy with a combination of verinurad 9 mg plus febuxostat 80 mg once daily reduced albuminuria among patients with type 2 diabetes mellitus and hyperuricemia receiving standard-of-care RAS inhibition.  

Practice Pearls:  

• Hyperuricemia has been implicated in the development and progression of chronic kidney disease.  
• Verinurad plus febuxostat lowered albuminuria and serum urate concentrations in patients with type 2 diabetes mellitus.  
• No clinically meaningful changes were observed in eGFR, serum creatinine, or serum cystatin C concentrations.  

Stack A et al. “Effect of intensive urate-lowering with combined verinurad and febuxostat on albuminuria in patients with type 2 diabetes: a randomized trial” Am J Kidney Dis. 77(4):481-489. doi:10.1053/j.ajkd.2020.09.009 

Azeezat Rasaki, PharmD Candidate, Florida A&M University