New data from the linagliptin late stage clinical trial programme were presented this week at the 46th Annual Meeting of the European Association for the Study of Diabetes (EASD). The studies included two phase III trials: one investigating linagliptin monotherapy in type 2 diabetes patients for whom metformin therapy is inappropriate, and the other studying linagliptin as add-on therapy to a sulphonylurea in patients with inadequately controlled type 2 diabetes. In addition, a pharmacokinetic study was presented at the congress which investigated linagliptin in a special patient population with different degrees of renal impairment.

Linagliptin belongs to the novel class of DPP-4 inhibitors and is currently in late stage development as a once-daily, single-dose oral tablet. The new data add to the large body of clinical evidence demonstrating that linagliptin cannot only achieve significant and sustainable reductions in blood glucose, but that based on its unique pharmacokinetic profile, linagliptin may not require dose adjustment even in patients with type 2 diabetes with any degree of renal impairment. Boehringer Ingelheim is filing linagliptin for market authorisation in key countries across the globe in 2010 and is looking forward to making this novel treatment available to people with type 2 diabetes as soon as possible.

One of the unique characteristics of linagliptin among the DPP-4 inhibitors is its primarily non-renal route of excretion. The pharmacokinetic study was performed to support the assumption that linagliptin exposure would not show a clinically relevant increase when administered in patients with any degree of renal impairment. Notably, results from this study confirmed that decreases in renal function had only little effect on the elimination of linagliptin and only minor changes were observed in linagliptin exposure in patients with renal impairment (1.4-fold increase in exposure in type 2 diabetes patients with severe renal impairment compared with type 2 diabetes patients with normal renal function). This, along with the large safety window of linagliptin,4 supports the assumption that no dose adjustment of linagliptin may be required in type 2 diabetes patients with any degree of renal impairment.

“Treating type 2 diabetes demands a holistic approach if we want to be successful in helping patients not only achieve but also maintain good blood glucose levels. Kidney function is an important consideration when prescribing an anti-diabetes therapy. Many type 2 diabetes patients either have, or are at significant risk of developing kidney impairment,” said Professor Anthony Barnett, Professor of Medicine and Clinical Director of the Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK. “Currently available DPP-4 inhibitors are mainly eliminated via the kidney and therefore not recommended in patients with advanced renal impairment in many countries. Others either require dose adjustment or are contraindicated for such patients. The clinical data for linagliptin seen to date suggest an advantage in this respect due to its primarily non-renal route of excretion. The convenience of a drug not needing additional monitoring of kidney function or not needing dose adjustment as kidney function declines, could improve patient compliance as well as making life easier for the health professional.”

The phase III study assessing the efficacy, safety and tolerability of linagliptin patients with inadequately controlled type 2 diabetes for whom metformin therapy is inappropriate due to intolerability or contraindication,1 confirmed earlier efficacy and safety findings. Importantly, the incidence of hypoglycaemia was very low and the observed episodes of mild intensity (1.3% in the linagliptin group). No significant difference in change in body weight was observed between the groups. The overall incidence of reported adverse events was similar for both groups (48.7% placebo versus 40.4% linagliptin). An earlier phase III study investigating linagliptin monotherapy versus placebo had already shown that a once-daily 5 mg single dose for 24 weeks produced significant, clinically meaningful and sustained improvements in glycaemic control compared to placebo (–0.7% placebo-adjusted reduction in HbA1c). This new 18-week interim analysis in patients for whom metformin is inappropriate further supports linagliptin’s favourable efficacy profile. Linagliptin 5 mg showed a clinically relevant and statistically significant mean difference in HbA1c reduction (primary outcome) compared to placebo. Statistically significant differences between linagliptin and placebo could already be seen at week 6, and at week 18 the placebo adjusted mean difference was –0.6% (p<0.0001). Linagliptin was also superior to placebo in reducing fasting plasma glucose (FPG) levels (adjusted mean change from baseline –1.1 mmol/l (–20.5 mg/dl); p=0.0002).

Metformin is currently the standard first-line treatment for patients with type 2 diabetes. However, it is known that metformin is not tolerated at high doses in all patients6 (metformin is associated with dose-related side effects such as diarrhoea, nausea and abdominal bloating, and a potential risk for lactic acidosis), thus limiting metformin use across the range of patients with type 2 diabetes. This study suggests that linagliptin would be a valuable treatment also in this type 2 diabetes population for whom metformin therapy is inappropriate due to contraindications and intolerability, including patients with renal impairment.

In the other phase III study presented at the EASD Annual Meeting, linagliptin 5 mg was assessed in an 18-week, multi-centre, randomised, double-blind, placebo-controlled, parallel-group design to determine the efficacy, safety and tolerability of linagliptin as add-on therapy to sulphonylurea (SU) in patients with type 2 diabetes and insufficient glycaemic control.

An earlier phase III study in over 1,000 patients had demonstrated significant improvements in glycaemic control when linagliptin was added to the combination of metformin and an SU (mean placebo adjusted HbA1c reduction was –0.6%; p<0.0001).7 The new study, although conducted in a smaller patient group (n=245 randomised), shows a statistically significant and clinically relevant reduction in HbA1c from baseline (mean placebo adjusted HbA1c reduction –0.5%; p<0.0001), thus further supporting the efficacy of linagliptin as add-on therapy.

Further, the trial results showed an overall incidence of adverse events similar to placebo (42.2% versus 42.9% respectively) and, importantly, there was no significantly increased risk for hypoglycaemia when linagliptin was added to SU background therapy (5.6% in the linagliptin group versus 4.8% in the placebo group). The percentage of participants requiring rescue therapy in the linagliptin group was only half the proportion of those requiring rescue therapy in the placebo group (7.6% versus 15.9%). No significant difference in change in body weight was observed between the groups. The safety results from this study are an important finding as sulphonylureas are associated with side effects such as weight gain and risk of hypoglycaemia which could be exacerbated with uptitration of the SU agent. The study concluded that linagliptin has the potential to be used safely as add-on therapy in type 2 diabetes patients with insufficient gylcaemic control on sulphonylurea alone.