• Hyperglycemia/Hypoglycemia
• Diabetes & Endocrinology Clinical Trials
• Insulin Diabetes Mellitus

Linagliptin may be a treatment option in patients with type 2 diabetes mellitus (T2DM) taking basal insulin, especially in those prone to hypoglycemia and/or declining renal function, according to Hannele Yki-Järvinen, MD, PhD, University of Helsinki, Helsinki, Finland, who presented results from a 52-week, multicenter, randomized, placebo-controlled, Phase 3 clinical trial.

The objective of the Efficacy and Safety of Linagliptin in Combination with Insulin in Patients with Type 2 Diabetes study was to determine the efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin after 24 weeks, and long-term safety after 52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone in patients with T2DM [NCT00996658]. The primary endpoint was change in HbA1C from baseline to Week 24. Secondary endpoints were changes from baseline in fasting plasma glucose, basal insulin dose, and body weight after 24 and 52 weeks, ie, sustained glucose control and long-term safety data with an emphasis on hypoglycemia.

A total of 1261 patients inadequately controlled on insulin glargine, insulin detemir, or neutral protamine Hagedorn insulin were randomized 1:1 to receive either linagliptin 5 mg QD or placebo QD for at least 52 weeks. The background dose of basal insulin was kept stable up to 24 weeks but could then be freely adjusted. Inclusion criteria were male and female subjects at least 18 years of age with T2DM, body mass index (BMI) ≤45 kg/m², detectable C-peptide, pretreatment with basal insulin and/or metformin and/or pioglitazone, and HbA1C of 7% to 10% [Yki-Järvinen H et al. EASD 2012 Abstract 6].

Mean ± standard deviation (SD) baseline characteristics were similar in the linagliptin versus placebo groups: age, 59.7±9.9 versus 60.4±10.0 years; BMI, 30.8±5.4 versus 31.2±4.9 kg/m²; HbA1C, 8.3%±0.9% in both groups; and basal insulin dose, 41.5±31.9 versus 40.1±27.3 IU/day. Mean exposure to study medication was comparable in both groups: 435 days for linagliptin versus 422 days for placebo.

Overall safety and tolerability of linagliptin was similar to placebo. The proportion of patients with ≥1 adverse event (AE) was slightly lower with linagliptin (78.4%) compared with placebo (81.4%); most AEs were of mild or moderate intensity. Despite better glycemic control with linagliptin, the incidence of hypoglycemia was similar in both groups (linagliptin 31.4%; placebo 32.9%), and the number of severe hypoglycemic events was low (linagliptin 1.7%; placebo 1.1%; Table 1). Mean ± SD change in body weight was minimal and comparable between the treatment groups (linagliptin −0.30±3.70 kg; placebo −0.04±3.10 kg).

The placebo-adjusted mean ± standard error (SE) change in HbA1C from baseline to Week 52 was −0.53%±0.05% (p<0.0001). This was accompanied by a mean ± SE change in basal insulin dose up to Week 52 of +2.6±0.8 IU/day for linagliptin versus +4.2±0.8 IU/day for placebo (p<0.003).

This trial demonstrated that linagliptin as add-on therapy to basal insulin significantly improved glycemic control after 24 weeks and did so independently of renal function and type of basal insulin. It was not associated with an increased risk of hypoglycemia or weight gain. Adding a DPP-4 inhibitor instead of a sulfonylurea to further improve glucose control might avoid hypoglycemia and weight gain.

• © 2012 MD Conference Express®