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Treatment to Possibly Prevent Kidney Failure

Liraglutide, on top of stable renin angiotensin system (RAS)-inhibition, is associated with significant reduction in albuminuria among patients with type 2 diabetes and persistent microalbuminuria.

Bernt Johan Illum von Scholten, MD, of the Steno Diabetes Center in Gentofte, Denmark, and colleagues on November 18 presented the results of a study at Kidney Week 2016 at the annual meeting of the American Society of Nephrology (ASN).

Patients with type 2 diabetes and albuminuria have high cardio-renal morbidity and mortality despite multifactorial treatment. “Short-term reduction in albuminuria suggests long-term reno-protective effects.”

The increasing prevalence of chronic kidney disease (CKD), defined as the presence of increased urinary albumin excretion and/or decreased glomerular filtration rate (GFR), is a major public health issue affecting ∼13% of the U.S. population. Diabetic kidney disease is the leading cause of end-stage renal disease (ESRD) in developed countries, and both the incidence and prevalence are increasing dramatically worldwide. The development of albuminuria is a key step in the progression of diabetic kidney disease, and worsening of albuminuria is a significant predictor of progressive renal disease. Epidemiological data indicate that 39 and 10% of subjects with type 2 diabetes have micro- or macroalbuminuria, respectively. In addition, albuminuria (both in low and high ranges) predicts cardiovascular (CV) risk in patients with type 2 diabetes and in the general population. Guidelines recommend the annual assessment of albuminuria in all patients with type 2 diabetes starting at diagnosis, and current recommendations for the treatment of kidney disease in patients with type 2 diabetes are directed toward a multifactorial intervention, including lowering blood pressure, improving glycemic and lipid control, and reducing albuminuria.

Inhibitors of the renin-angiotensin-aldosterone system (RAAS) provide renal and CV protection beyond their ability to lower blood pressure, and the beneficial effects of these agents have been linked to concomitant changes in albuminuria. Thus, reductions in albuminuria in patients with type 2 diabetes were associated with a significant reduction in the risk of progression to ESRD. These findings suggest that albuminuria may be an important therapeutic target for preventing the progression of diabetic kidney disease and might also offer CV protection. However, despite treatment with current recommended standard therapy for CKD, including RAAS inhibitors, many patients with type 2 diabetes have significant residual albuminuria and continue to progress toward ESRD. Additional treatment options that would complement the benefit of existing therapies remain an important unmet medical need.

Preclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials.

The study included 32 patients with type 2 diabetes and persistent microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.732. Patients were randomized to receive liraglutide 1.8 mg/day or placebo for 12 weeks. After a 4-week washout, patients were then crossed-over and received liraglutide or placebo for another 4 weeks. A total of 27 patients completed the study. The primary endpoint was change in 24-hour urinary albumin excretion rate (UAER).

Also, a pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30−3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n= 55). The primary endpoint was the percentage change in geometric mean UACR from baseline to week 24.

The results showed that UACR at week 24 was reduced by 32% with linagliptin compared with 6% with placebo, with a between-group difference of 28%. The between-group difference in the change in HbA1c from baseline to week 24 was −0.61% in favor of linagliptin (P < 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment.

From the results it was concluded that linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP.

Other recent experimental studies have suggested beneficial renal effects of incretin-based therapies. In a murine model of renal vascular damage (endothelial nitric oxide synthase knockout mice), coadministration of linagliptin, an oral and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, and the angiotensin receptor blocker (ARB) telmisartan synergistically decreased albuminuria and reduced glomerulosclerosis. These results occurred independent of any changes in glucose metabolism because the β-cell response to linagliptin was alleviated as a result of previous administration of streptozotocin, a β-cell toxin, to these mice.

Compared with placebo, liraglutide treatment reduced UAER by 26% (from 183 to 135; P = .022).

Liraglutide also reduced hemoglobin A1C by 9 mmol/mol and weight by 1.8 kg. Change in UAER was associated with change in 24-hour systolic blood pressure, but not with change in A1C, weight or GFR.  From the study outcomes it suggests that liraglutide treatment has reno-protective effects on top of multifactorial treatment, the authors concluded.

Practice Pearls:

  • Liraglutide has renoprotective effects on top of multifactorial treatment, the authors concluded.
  • Liraglutide lowered 24-hour urinary albumin excretion rate by 32%.
  • Compared with placebo, liraglutide treatment reduced UAER by 26%

Presentation title: Renal Effects of Liraglutide in Type 2 Diabetic Patients With Albuminuria: a Randomized Clinical Trial. Abstract FR-PO815 American Society of Nephrology (ASN) meeting, 2016.: Diabetes Care 2013 Nov; 36(11): 3460-3468. http://dx.doi.org/10.2337/dc13-0323