Linagliptin Lowers Albuminuria on Top of Recommended Standard Treatment in Patients With Type 2 Diabetes and Renal Dysfunction

Abstract

OBJECTIVEPreclinical 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.RESEARCH DESIGN AND METHODSA 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 end point was the percentage change in geometric mean UACR from baseline to week 24.RESULTSUACR at week 24 was reduced by 32% (95% CI −42 to −21; P < 0.05) with linagliptin compared with 6% (95% CI −27 to +23) with placebo, with a between-group difference of 28% (95% CI −47 to −2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was −0.61% (−6.7 mmol/mol) in favor of linagliptin (95% CI −0.88 to −0.34% [−9.6 to −3.7 mmol/mol]; 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.CONCLUSIONSLinagliptin 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. Further research to prospectively investigate the renal effects of linagliptin is underway.

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

“…Urine albumin levels were elevated in STZ mice, and linagliptin treatment suppressed the trend of the urine albumin levels (Fig. 2J) as observed in human clinical trial (21). These antifibrotic effects of linagliptin in diabetic mice are associated with a suppressed trend of TGF-b1 and DPP-4, and significant suppression of TGF-b2 protein levels in the kidney (Fig.…”

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

“…SGLT2 inhibition has similar anti-albuminuric effects in animal models of type 2 diabetes [21], including recent evidence that empagliflozin reduced albuminuria, independent of effects on BP or hyperglycaemia, in BTBR ob/ob mouse models of type 2 diabetes [22]. Previous clinical studies in type 2 diabetes patients with and without CKD have shown that SGLT2 inhibition is associated with an acute but modest decline in eGFR within 3-6 weeks of treatment initiation, followed by a period of stable renal function for 52-104 weeks; this change is reversible after drug cessation for 2 weeks [17,23,24]. Notably, within this same treatment period, renal safety assessments of SGLT2 inhibitors have also reported a reduction in UACR or urinary albumin excretion in patients with type 2 diabetes and CKD [15,24].…”

“…Endpoints The primary assessment of this pooled analysis was defined as percentage change in geometric mean of the UACR from baseline to week 24 as described for other drug interventions targeting albuminuria [16,17]. Empagliflozin 10 and 25 mg doses were pooled to define the overall magnitude of the drug effect compared with placebo.…”

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

“…16 Linagliptin administered in addition to stable renin-angiotensin-aldosterone system inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. 17 Furthermore, we have recently found that linagliptin could inhibit renal damage in streptozotocin (STZ)-induced diabetic rats (STZ rats) by suppressing the AGE-RAGE axis. 18 Since linagliptin did not improve hyperglycemia in STZ rats, our findings suggest that inhibition of DPP-4 might have glucose-lowering-independent, AGE-RAGE-axis suppressive pleiotropic actions on diabetic nephropathy.…”

“…[15][16][17] Indeed, linagliptin, an inhibitor of DPP-4, ameliorated kidney fibrosis in type 1 diabetic mice by blocking the endothelial-tomesenchymal transition. 16 Linagliptin administered in addition to stable renin-angiotensin-aldosterone system inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction.…”