Treatment with the dipeptidyl peptidase-4 inhibitor linagliptin or placebo followed by glimepiride in patients with type 2 diabetes with moderate to severe renal impairment: a 52-week, randomized, double-blind clinical trial

Laakso M, Rosenstock J, Groop PH et al.,
Diabetes Care. 2015 Feb;38(2):e15-7. doi: 10.2337/dc14-1684
 Glucose-lowering treatment options are limited in patients with type  2 diabetes (T2DM) with comorbid chronic kidney disease (CKD). The prevalence of this patient group is increasing [1]. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor.
This randomised, double-blind study evaluated the efficacy and safety of linagliptin (5 mg/day) in T2DM patients with insufficient glycaemic control, with moderate to severe renal impairment. The study started with a 12-week placebo-controlled phase, followed by a 40-week active-controlled extension, in which placebo-treated patients were switched to glimepiride 1-4 mg/day. 235 patients were randomised to linagliptin (n=113) or placebo (n=122). The primary endpoint was change in HbA1c from baseline to week 12.

Main results

• Mean change (+SE) from baseline in HbA1c at 12 weeks was -0.53 + 0.11% (-5.8 +1.2 mmol/mol) with linagliptin and -0.11 + 0.11% (-1.3 +1.2 mmol/mol) with placebo.
• After 52 weeks, adjusted mean change from baseline in HbA1c was -0.64% (-7.0 mmol/mol) in the linagliptin group and -0.50% (-5.5 mmol/mol) in the placebo/glimepiride group.
• eGFR remained stable throughout the whole study period in both treatment groups.
• The occurrence of adverse events in the placebo-controlled 12 weeks was similar in both groups (76.1% with linagliptin vs. 73.8% with placebo). Drug-related events occurred in respectively 23.9% and 24.6% in both groups. 7.1% and 8.2% of patients respectively reported serious adverse events.
• In the extension period, 90.7% patients on linagliptin reported any adverse events, as compared to 96.5% in the glimepiride group. Serious adverse events were reported in 22.4% and 26.3% respectively.
• Adjudicated CV events occurred in fewer patients treated with linagliptin (n=3) than with glimepiride (n=8), and hospitalisation for heart failure occurred in 7 and 6 patients respectively.
• Hypoglycaemia occurred in fewer linagliptin patients than in control patients in both the first 12 weeks and the extension period. Severe hypoglycaemia occurred in 6 patients in both groups.

Conclusion

This study shows that linagliptin was well tolerated and efficacious in T2DM patients with moderate or severe renal impairment, while renal function remained stable. The incidence of hypoglycaemia was relatively high, which is not unexpected given the high rate of insulin use, albeit lower in patients treated with linagliptin as compared with placebo/glimepiride-treated patients.
Considering that this vulnerable population has limited treatment options, linagliptide may provide beneficial changes in glycaemic control with an acceptable side-effect profile in T2DM patients with renal failure.

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Reference

1. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850–886