Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study

Abstract

Objective: This placebo-controlled study assessed long-term efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes and severe renal impairment (RI).

Research design and methods: In this 1-year, double-blind study, 133 patients with type 2 diabetes (HbA(1c) 7.0-10.0%) and severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m(2)) at screening were randomized to linagliptin 5 mg (n = 68) or placebo (n = 65) once daily, added to existing background therapy. The primary efficacy end point was HbA(1c) change from baseline to week 12. Efficacy and safety end points were assessed after 1 year.

Results: At week 12, adjusted mean HbA(1c) decreased by -0.76% with linagliptin and -0.15% with placebo (treatment difference, -0.60%; 95% CI -0.89 to -0.31; P < 0.0001). HbA(1c) improvements were sustained with linagliptin (-0.71%) over placebo (0.01%) at 1 year (treatment difference -0.72%, -1.03 to -0.41; P < 0.0001). Mean insulin doses decreased by -6.2 units with linagliptin and -0.3 units with placebo. Overall adverse event incidence was similar over 1 year (94.1 vs. 92.3%). Incidence of severe hypoglycemia with linagliptin and placebo was comparably low (three patients per group). Linagliptin and placebo had little effect on renal function (median change in eGFR, -0.8 vs. -2.2 mL/min/1.73 m(2)), and no drug-related renal failure occurred.

Conclusions: In patients with type 2 diabetes and severe RI, linagliptin provided clinically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, stable body weight, and no cases of drug-related renal failure. The potential for linagliptin to spare insulin and provide long-term renal safety warrants further investigations.

Figure 1

Flow chart of participants. The first participant was enrolled on 11 December 2008, and the last participant completed assessments on 5 January 2011. qd, once daily.

Figure 2

Time course of adjusted mean ± SE change from baseline in HbA_1c over 52 weeks (A) in the FAS (LOCF). Change from baseline to week 12 and to week 52 in adjusted mean ± SE HbA_1c in all patients (B) and in patients with baseline HbA_1c ≤8% and baseline HbA_1c >8% (C) in the FAS (LOCF). Time course of mean ± SE eGFR over 1 year in the TS (D). *P < 0.01, **P < 0.001, ***P < 0.0001 vs. placebo. White bars/circles, linagliptin; black bars/circles, placebo. MDRD, modification of diet in renal disease.