Mixed results for PRIORITY diabetic nephropathy trial
medwireNews: The CKD273 proteomic biomarker panel can predict which people with type 2 diabetes will develop detectable diabetic nephropathy, but early intervention with spironolactone does not mitigate this risk, report the PRIORITY investigators.
The team had chosen the medication based on previous evidence supporting use of an aldosterone antagonist to reduce albuminuria in patients already receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), and also because it is inexpensive and readily available.
They tested the medication in 216 people with type 2 diabetes who had normoalbuminuria but were at high risk according to a proteomic biomarker panel – CKD273 – of 273 urinary peptides that have been shown to differentiate between CKD and controls in retrospective studies.
Gemma Currie (University of Glasgow, UK), who presented the results at the 55th EASD Annual Meeting in Barcelona, Spain, noted that CKD273 can offer earlier detection of diabetic nephropathy because it can “capture changes in multiple disease processes at once.”
She added that PRIORITY is the first prospective study of CKD273.
Using CKD273, the researchers divided 1775 people with type 2 diabetes and normoalbuminuria into a group (of 216 people) who were at high risk for diabetic nephropathy and a low-risk group.
During an average follow-up of 2.57 years, 28.2% of people in the high-risk group developed microalbuminuria, defined as a urinary albumin-to-creatinine ratio (UACR) greater than 30 mg/g in at least two of three morning voids, and at least a 30% rise from baseline, or of greater than 40 mg/g.
By contrast, just 8.9% of those categorized as low risk developed microalbuminuria. When incorporated into a base model of age, sex, glycated hemoglobin, systolic blood pressure, retinopathy status, estimated glomerular filtration rate (eGFR), and UACR, CKD273 significantly increased the area under the receiver operating characteristic curve from 0.7589 to 0.7810. The model had a sensitivity of 30.5% and a specificity of 90.2%.
In the high-risk group, eGFR declined significantly during follow-up, and 25.5% and 3.2% developed stage 3 and 4 chronic kidney disease (CKD), respectively, versus 8.1% and 0.2% of the low-risk group.
In a bid to test if very early intervention could slow the progression of diabetic nephropathy, the researchers also randomly assigned the high-risk participants to receive spironolactone or placebo, stratifying them according to whether they were taking an ACE inhibitor or ARB (around 88% were).
Luigi Gnudi discusses the findings of the PRIORITY trial and addresses whether diabetologists should consider intervening earlier in diabetic nephropathy (4:08)
Presenting these results, Morten Lindhardt (Steno Diabetes Center, Gentofte, Denmark) reported that patients on active treatment had an average 7.2 mmHg fall in systolic blood pressure, relative to placebo, during the first few weeks of treatment, but the difference disappeared over time.
They did not have a significant reduction in the rate of microalbuminuria, although there was some suggestion of a difference emerging after around 3 years of treatment. However, only a small proportion of patients were followed up for this long. Principal investigator Peter Rossing (University of Copenhagen, Denmark) suggested that the team might have achieved a positive result had they been able to follow up more patients for longer, pointing to the scale and duration of cardiovascular outcomes trials for modern diabetes medications.
There was an increased rate of stage 3 CKD among patients given active versus placebo treatment, but Lindhardt attributed this to the acute effects of spironolactone on eGFR; the rate of decline after the first few weeks of treatment was the same in both groups.
More patients taking spironolactone than placebo had hyperkalemia, at 13 versus four events (>5.5 mmol), with nine participants in the spironolactone group discontinuing treatment because of this adverse effect.
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