Nephrology Xagena

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Linagliptin, a dipeptidyl peptidase 4 inhibitor, is not associated with increased kidney disease risk in patients with type 2 diabetes mellitus

Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes mellitus, evaluation of their renal safety has been relatively neglected.

An individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor Linagliptin ( Trajenta ) was performed.

Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion / exclusion criteria, such as being drug-naive ( hemoglobin A1c, 7.0-11.0% [ 53-97 mmol/mol ] ) or being on background glucose-lowering therapy ( hemoglobin A1c, 6.5-10.5% [ 48-91 mmol/mol ] ).

Of 5,466 consenting individuals with inadequately controlled type 2 diabetes mellitus, 3,505 received Linagliptin, 5mg/d, and 1,961 received placebo.

The primary kidney disease outcome was defined as first occurrence during the study of 6 predefined safety end points: new onset of moderate elevation of albuminuria ( urinary albumin-creatinine ratio [ ACR ] more than 30 mg/g with baseline values less than or equal to 30 mg/g ), new onset of severe elevation of albuminuria ( ACR more than 300 mg/g with baseline values less than 300 mg/g ), reduction in kidney function ( serum creatinine increase to greater than or equal to 250 micromol/L from a baseline value less than 250 micromol/L ), halving of estimated glomerular filtration rate ( loss of baseline eGFR more than 50% ), acute renal failure ( ascertained from diagnostic codes ), or death from any cause.

Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI ( Chronic Kidney Disease Epidemiology Collaboration ) equation.

Cumulative exposure ( person-years ) was 1,751 for Linagliptin and 1,055 for placebo.

The primary composite outcome occurred in 448 ( 12.8% ) and 306 ( 15.6% ) participants in the Linagliptin and placebo groups, respectively.

Linagliptin treatment significantly reduced the hazard of kidney disease events by 16% compared with placebo ( hazard ratio, HR=0.84; 95% CI, 0.72-0.97; P=0.02 ).

The study presents limitations: retrospective and hypothesis-generating study involving short- to midterm clinical trials.

In conclusion, Linagliptin was not associated with increased kidney disease risk in patients with type 2 diabetes mellitus.
The potential of this drug to improve kidney disease outcomes warrants further investigation. ( Xagena )

Cooper ME et al, Am J Kidney Dis 2015;66:441-449