Trajenta® (linagliptin) receives approval for the treatment of type 2 diabetes in Europe

Boehringer IngelheimBoehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) received Marketing Authorisation from the European Commission ) for Trajenta® (linagliptin) 5 mg film-coated tablets for the treatment of adults with type 2 diabetes. The European Commission has approved linagliptin in combination with metformin and metformin plus sulphonylurea.(1) Linagliptin is also approved for use as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.(1)

"The phase III clinical trial programme has demonstrated the meaningful efficacy provided by linagliptin in the treatment of type 2 diabetes. We are delighted that linagliptin will soon be available to patients across Europe" said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "Observed improvements in glycaemic control have proved to be durable up to 52 weeks and effective for a wide range of adult patients making linagliptin a reliable and efficacious treatment for type 2 diabetes."

Studies show that linagliptin is efficacious with a favourable safety and tolerability profile, reducing haemoglobin A1c (HbA1c) levels by a mean of -0.6 to -0.7 percent (2,3) (compared to placebo). HbA1c is measured in people with diabetes to provide an index of blood glucose control for the previous two to three months and is used as a marker to determine the efficacy of glucose-lowering therapies.

"Unlike other DPP-4 inhibitors, linagliptin is primarily excreted unmetabolised via bile and gut, meaning no dose adjustment is needed in adult patients with declining kidney or liver function." said Prof. Anthony Barnett, Consultant Physician, Heart of England NHS Foundation Trust and Emeritus Professor of Medicine, University of Birmingham, UK. "This means that linagliptin is available at only one dose. This is convenient for physicians, because one dose is the right dose for all adult patients."

The approval of linagliptin 5 mg was based on a clinical trial programme which involved approximately 6,000 adults with type 2 diabetes. Included in the programme were placebo-controlled studies evaluating linagliptin as monotherapy 4 and in combination with the commonly prescribed oral antihyperglycaemic medications metformin and / or sulphonylurea. (2,5-6) In two monotherapy studies, linagliptin showed a statistically significant mean difference in HbA1c from placebo of -0.6 to -0.7 percent.(3-4) In patients who were not adequately controlled on metformin or metformin plus sulphonylurea, the addition of linagliptin also resulted in a statistically significant mean difference in HbA1c from placebo of -0.6 percent.(2,5) Hypoglycaemia was rare and weight did not change significantly from baseline.(2,5)

In a 2-year study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (mean dose 3 mg) in patients with inadequate glycaemic control on metformin monotherapy (mean baseline HbA1c 7.69%), linagliptin was similar to glimepiride in reducing HbA1c, with a treatment difference of 0.20% (97.5% CI: 0.09, 0.299).

The incidence of hypoglycaemia in the linagliptin group (7.5%) was significantly lower than that in the glimepiride group (36.1%).(1) Patients treated with linagliptin exhibited a significant relative weight loss of -2.7 kg (Linagliptin: -1.39 vs. Glimepiride: +1.29 kg).(1)

In the pooled analysis of the placebo.controlled trials, the overall incidence of adverse events in patients treated with placebo was similar to that seen with linagliptin 5 mg (53.8% versus 55.0%). The most frequently reported adverse reaction was hypoglycaemia observed with the triple combination of linagliptin plus metformin plus sulphonylurea (14.7% with linagliptin versus 7.6% with placebo). None of the hypoglycaemias were classified as severe.

"The EU approval of linagliptin marks another major regulatory milestone for the Boehringer Ingelheim and Lilly alliance in diabetes. Linagliptin can be an important treatment option for people living with type 2 diabetes." said Enrique Conterno, President of Lilly Diabetes.

About Linagliptin
Linagliptin is an inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase-4) an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homoeostasis.(1)

Treatment with linagliptin produced significant reductions in fasting plasma glucose (FPG) compared to placebo, when used as monotherapy (4) and in combination with metformin and/or sulphonylurea.(2,5) Treatment with linagliptin produced significant reductions in two-hour post-prandial glucose (PPG) levels compared with placebo when used in combination with metformin. FPG is used to determine glucose levels in a fasting state (usually upon wakening in the morning), and PPG is used to determine glucose levels after meals (usually two hours after eating).

No dose adjustment for linagliptin is required even for patients with renal impairment.(1) In controlled studies, change from baseline in body weight did not differ significantly between groups when linagliptin was administered as monotherapy (4), in combination with metformin (2) or in combination with metformin plus sulphonylurea.(5) Patients treated with linagliptin exhibited a significant mean decrease from baseline body weight compared to a significant weight gain in patients administered sulphonylurea (-1.39 kg vs. +1.29 kg. p<0.0001).

About Diabetes
An estimated 285 million people worldwide have diabetes.(7) Type 2 diabetes is the most common type, accounting for an estimated 90 percent of all diabetes cases.(7) Diabetes is a chronic disease that occurs when the body either does not properly produce, or use, the hormone insulin.(8)

Boehringer Ingelheim and Eli Lilly and Company
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.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24 percent of net sales in its largest business segment Prescription Medicines on research and development.

About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, IN, Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs.

About Lilly Diabetes
For more than 85 years, Lilly has been a worldwide leader in pioneering industry-leading solutions to support people living with and treating diabetes. Lilly introduced the world's first commercial insulin in 1923, and remains at the forefront of medical and delivery device innovation to manage diabetes. Lilly is also committed to providing solutions beyond therapy - practical tools, education, and support programmes to help overcome barriers to success along the diabetes journey. At Lilly, the journeys of each person living with or treating diabetes inspire ours.

1. Trajenta™ (linagliptin) tablets. EMA Summary of Product Characteristics. 2011
2. Taskinen MR, Rosenstock J, Tamminen I, et al: Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:65-74.
3. Del Prato S, Barnett AH, Huisman H, et al: Effect of linagliptin monotherapy on glycaemic control and markers of B-cell function in patients with inadequately controlled type 2 diabetes: a randomised controlled trial. Diabetes Obes Metab 2011;13:193-287.
4. Barnett AH, Harper R, Toorawa R, et al: Linagliptin monotherapy improves glycaemic control in type 2 diabetes patients for whom metformin therapy is inappropriate, 46th Annual Meeting of the European Association for the Study of Diabetes. Stockholm, Sweden, 2010, pp Poster 823.
5. Owens DR, Swallow R, Woerle HJ, et al: Linagliptin improves glycemic control in type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain and low risk of hypoglycemia, 70th American Diabetes Association Scientific Sessions. Orlando, Florida, U.S.A., 2010, pp Poster 548-P.
6. Lewin AJ, Arvay L, Liu D, et al: Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes, 46th Annual Meeting of the European Association for the Study of Diabetes. Stockholm, Sweden, 2010, pp Poster 821-P
7. International Diabetes Federation:, 2010.
8. World Health Organization: Fact Sheet No. 312 What is Diabetes?, 2010.