Boehringer Ingelheim and Eli Lilly and Company announced phase III study results for linagliptin (proposed trade name Trajenta in Europe), demonstrating improved glycaemic control in adults with type 2 diabetes (T2D) whose blood glucose is not adequately maintained. In one long-term study over two years evaluating linagliptin or glimepiride when added to metformin, linagliptin was as effective at lowering blood glucose as glimepiride, as measured by haemoglobin A1C (HbA1c) but with relative weight loss (-1.4 kg vs. +1.5 kg; adjusted mean difference, -2.9 kg; p<0.0001), reduced incidence of hypoglycaemia (7.5 per cent vs. 36.1 per cent; p<0.0001) and fewer cardiovascular (CV) events (1.5 per cent vs. 3.4 per cent; Relative Risk 0.46 [0.23-0.91] p=0.02). Results will be presented at the 71st Annual American Diabetes Association (ADA) Scientific Sessions in San Diego, 24 – 28 June.

"The combination of linagliptin plus metformin provides meaningful glucose control comparable to that of a combination of a sulphonylurea plus metformin. The added benefit is that, unlike a sulphonylurea, linagliptin is not associated with weight gain and does not per se increase the occurrence of hypoglycaemia" said Prof. Klaus Dugi, corporate senior vice president medicine, Boehringer Ingelheim. "In addition, compared to the sulphonylurea glimepiride, linagliptin was associated with a 54 per cent relative risk reduction for cardiovascular events in this study. This highlights the promising cardiovascular safety data seen with linagliptin to date which we are currently further exploring in the CAROLINA study."

Another study of 24-weeks evaluating linagliptin demonstrated mean placebo-corrected HbA1c reductions of up to 1.7 per cent from baseline when linagliptin 2.5 mg twice daily (bid) was used in combination with metformin 1,000 mg bid in T2D patients with insufficient glycaemic control. 2 The combination of linagliptin plus metformin was well tolerated and improved glycaemic control more than either medication when used alone. In the trial, there was no weight gain with the linagliptin plus metformin combination, and a very low risk of hypoglycaemia (five cases, or 1.8 per cent of patients). 2 In an open label arm including patients with poor glycaemic control (HbA1c at baseline >11 per cent) linagliptin 2.5 mg twice daily (bid) in combination with metformin 1,000 mg bid achieved a reduction from baseline of HbA1c of 3.7 per cent. 2

Linagliptin was also evaluated in T2D patients with different degrees of renal function. 3 A large pooled analysis of three randomised, placebo-controlled Phase III trials (n=2,141) showed that patients who received linagliptin had HbA1c reductions independent of renal function, with placebo corrected mean -0.63 per cent (p<0.0001) for those with normal renal function and -0.69 per cent for those with mildly or moderately impaired renal function (p<0.0001, p=0.0174, respectively). 3 In an additional study evaluating T2D patients with severe renal impairment (RI) whose blood glucose was insufficiently controlled, linagliptin provided a clinically meaningful placebo-corrected HbA1c reduction of -0.6 per cent (p<0.0001) after 12 weeks of treatment.  Renal function remained stable over time and CV deaths in this high-risk population were low with one patient per arm.

Similar Efficacy to Glimepiride but Improved CV Safety over Two Years (39-LB).

The aim of this two-year study was to assess the long-term efficacy and safety profile of adding linagliptin or glimepiride to ongoing stable metformin (greater than or equal to 1,500 mg/d for greater than or equal to 10 weeks) to treat T2D in those who have not achieved glycaemic control.
T2DM patients on stable metformin (1,500mg/d) for 10 weeks were randomised to linagliptin 5mg/d (N=764) or glimepiride 1-4 mg/d (N=755) over two years.

The efficacy endpoint was the change in HbA1c from baseline. Key secondary endpoints assessed the frequency of hypoglycaemic events and changes in body weight over time. Another safety endpoint evaluated pre-specified, prospective and adjudicated capture of CV events. For the primary endpoint linagliptin showed similar efficacy as compared to glimepiride (difference in mean HbA1c change from baseline between groups -0.20 percent; 95 per cent –CI, 0.11-0.29 percent on a pre-specified non-inferiority margin of 0.35 per cent).

Fewer patients experienced investigator-defined, drug-related hypoglycaemia with linagliptin than glimepiride. Body weight was also decreased with linagliptin and increased with glimepiride (-1.4 kg vs +1.5 kg; adjusted mean difference, -2.9 kg; p<0.0001).

Twice as many patients taking glimepiride (26 patients) experienced CV events as compared to those taking linagliptin (12 patients), demonstrating a 54 percent reduction in relative risk for the combined CV endpoint (RR, 0.46; 95 percent CI, 0.23-0.91; p=0.02).

The six treatment groups were randomised into combinations of linagliptin 2.5 mg bid plus either low- or high-dose (500 or 1000 mg) metformin bid, linagliptin 5 mg once daily (qd), metformin 500 or 1,000 mg bid, and placebo. Patients with a baseline HbA1c greater than or equal to 11 percent received open-label combination therapy with linagliptin 2.5 mg plus metformin 1,000 mg bid (n=66). Mean baseline HbA1c was between 8.5 per cent and 8.7 per cent, and 11.8 per cent in the open-label arm.

For the combination of linagliptin 2.5 mg bid plus metformin 500 or 1,000 mg, the placebo-corrected reduction in HbA1c was -1.3 per cent and -1.7 per cent, respectively. Both combination regimens were superior to the monotherapy arms. In patients with poor glycaemic control, who were studied in an open label arm of the study, mean change in HbA1c from baseline was -3.7 percent with linagliptin 2.5 mg bid plus metformin 1,000 mg.

The combination of linagliptin plus metformin was well tolerated and improved glycaemic control more than either monotherapy. Adverse event (AE) rates were similar across treatment arms. The total number of hypoglycaemic events during combination treatment was low (in total, five [1.8 percent] randomised patients receiving linagliptin 2.5 mg plus metformin 500 or 1,000 mg). The difference in body weight after treatment with linagliptin 2.5 mg plus metformin 1,000 mg compared with metformin 1,000 mg alone was -0.23 kg.

In January 2011, Boehringer Ingelheim and Eli Lilly and Company announced an alliance in the field of diabetes that centres on four pipeline compounds representing several of the largest treatment classes. This alliance leverages the companies’ strengths as two of the world’s leading pharmaceutical companies, combining Boehringer Ingelheim’s solid track record of research-driven innovation and Lilly’s innovative research, experience, and pioneering history in diabetes. By joining forces, the companies demonstrate commitment in the care of patients with diabetes and stand together to focus on patient needs.