SGLT2 Inhibitor Lowers Serum Uric Acid

The SGLT2 inhibitor canagliflozin is approved to treat hyperglycemia, but it may have other uses, according to a new study published in Diabetes, Obesity & Metabolism.¹

“In addition to improvement in glycemic control observed in clinical trials with canagliflozin, this post-hoc analysis describes an additional potential benefit of reductions in serum uric acid levels for patients with type 2 diabetes,” commented first author Michael Davies, PhD, Scientific Director at Janssen Pharmaceuticals in Raritan New Jersey.   

The study found that canagliflozin could decrease serum uric acid levels by as much as 13%, compared to placebo.  The study also found that up to 30% of patients with baseline hyperuricemia were able to normalize their uric acid levels after 26 weeks of taking canagliflozin.

“Hyperuricaemia is associated with an increased risk of gout, kidney stones, and cardiovascular disease,” Dr Davies added. “Given the various disorders associated with hyperuricaemia, lowering serum uric acid may be beneficial for patients with type 2 diabetes, who may have a higher risk of microvascular and cardiovascular disease.” 

Studies have suggested that hyperuricemia could predate the development of prediabetes and diabetes.² Hyperuricemia has also been linked to increased vascular complications and increased mortality in type 2 diabetes (T2DM).³

Dr Davies and colleagues pooled data from four phase III randomized clinical trials. Each trial lasted 26 weeks and looked at canagliflozin 100 mg or 300 mg vs placebo, either as monotherapy or as add-on to metformin alone, metformin plus a sulfonylurea, or metformin plus pioglitazone.  The researchers looked at changes in serum uric acid levels in the total population of patients with T2DM (n=2313), and a subpopulation with both T2DM and baseline hyperuricemia, defined as serum uric acid level ≥8 mg/dL (n=115).  They also looked at whether this subgroup could achieve serum uric acid levels below 6 mg/dL (the usual treatment target).

The characteristics of the overall population and hyperuricemia subgroup were similar, except that the hyperuricemia group had a higher proportion of men, higher BMI, and lower eGFR than the overall group.  

Key results at 26 weeks included:

Overall group: Canagliflozin 100 mg and 300 mg linked to ~13% decrease in serum uric acid, compared to placebo (least square mean percent change: -13.4% [95% CI -15.2, -11.5] and -13.6 [95% CI -15.4, -11.7], respectively).

Hyperuricemia subgroup: Similar reductions (least square mean percent change for canagliflozin 100 mg -13.7 [95% CI -20.5, -7.0] and canagliflozin 300 mg -10.7 [95% CI -17.5, -4.0]).

More patients with baseline hyperuricemia normalized their serum acid levels with canagliflozin 100 mg (23.5%) and canaglflozin 300 mg (32.4%), vs placebo (3.1%)

All groups had low incidence of gout and kidney stones (ranging between 0 and 0.5%)
 

Table. Baseline Characteristics and Percent Change in Uric Acid

Placebo

(Overall)

n=646

Canagliflozin 100 mg

(Overall)

n=833

Canagliflozin 300 mg

(Overall)

n=834

Placebo

(hyperuricemia)

n=37

Canagliflozin 100 mg

(hyperuricemia

n=40

Canagliflozin 300 mg

(hyperuricemia

n=38

Sex, n (%)

Female

Male

312 (48.3)

334 (51.7)

425 (51.0%)

408 (49.0%)

430 (51.6)

404 (48.4)

16 (43.2)

21 (56.8)

14 (35.0)

26 (65.0)

11 (28.9)

27 (71.1)

Mean BMI (kg/m²) n (%)

31.9 (6.4)

32.3 (6.4)

32.0 (6.5)

35.0 (7.8)

36.4 (6.8)

36.1 (9.1)

Mean eGFR, n (%)

87.0 (19.8)

88.3 (19.0)

88.8 (18.9)

71.3 (18.5)

80.9 (13.6)

75.0 (14.7)

    % change uric acid (mg/dL) from baseline

+2.8

-10.6

-10.8

-9.5

-23.3

-20.3

“Whether [lowering serum uric acid] will have other beneficial effects on renal and/or cardiovascular complications will require evaluation in longer-term studies,” Dr Davies concluded.

Ongoing studies are currently evaluating the cardiovascular (CANVAS) and renal (CANVAS-R) safety of canagliflozin. 

Take-Home Points:

  ►►Hyperuricemia is associated with increased risk of gout, kidney stones, cardiovascular disease, and death in patients with T2DM

  ►►26 weeks of treatment with canagliflozin 100 mg and 300 mg was linked to an approximately 13% reduction in serum uric acid levels, compared to placebo.

  ►►Up to 30% of patients with baseline hyperuricemia were able to normalize their uric acid levels after 26 weeks on canagliflozin.

  ►►Longer term studies are needed to evaluate whether lowering serum uric acid levels has an effect on renal and cardiovascular comorbidities in T2DM.

Disclosures:

1. Davies MJ, Trujillo A, Vijapurkar U, Damaraju CV, Meininger G.  Effect of canagliflozin on serum uric acid ain patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015 Jan 20. doi: 10.1111/dom.12439. [Epub ahead of print]

2. Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: a 15-year follow-up study. Am J Epidemiol. 2012;176:108-116.

3. Xu Y, Zhu J, Gao L et al. Hyperuricemia as an independent predictor of vascular complications and mortality in type 2 diabetes patients: a meta-analysis. PLoS One. 2013; 8: e78206.