Linagliptin recommended for approval in the treatment of type 2 diabetes

Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) today received a positive opinion from the European Medicines Agency’s (EMA) medicinal committee recommending approval of linagliptin 5 mg film-coated tablets (to be marketed under the trade name Trajenta®) for the treatment of adults with type 2 diabetes. If adopted by the European Commission, linagliptin will be the only DPP-4 inhibitor approved at one dosage strength for type 2 diabetes patients in Europe.

The Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of linagliptin 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 Linagliptin is also recommended for approval in combination with metformin and metformin + sulphonylurea. 1 Data shows that linagliptin reduces 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. It is used as a marker to determine the efficacy of glucose-lowering therapies.

“This will be an important step forward in the management of type 2 diabetes in Europe” said Prof. Anthony Barnett, Clinical Director, Department of Diabetes and Endocrinology, University of Birmingham and Heart of England NHS, UK. “Studies show that linagliptin is efficacious with a favourable safety and tolerability profile. It is also primarily excreted unmetabolised via bile and gut, meaning no dose adjustment is needed in patients with declining kidney or liver function. Therefore, this will be the first DPP-4 inhibitor available at one dose for all patients”.

Linagliptin 5 mg received a positive opinion 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

In a 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 reductions in HbA1c were -0.16% with linagliptin (mean baseline HbA1c 7.69%) and -0.36% with glimepiride (mean baseline HbA1c 7.69%) with a mean 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%). Patients treated with linagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glimepiride (-1.39 vs +1.29 kg).

“Type 2 diabetes is increasing at an alarming rate worldwide. We are proud that we may soon have the opportunity to offer a new treatment option from our own Boehringer Ingelheim research labs to the millions of European patients with type 2 diabetes whose blood glucose is not adequately controlled,” said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim.

The CHMP positive opinion for linagliptin marks another regulatory milestone for the Boehringer Ingelheim and Eli Lilly and Company worldwide diabetes alliance which was formed in January 2011. Linagliptin received approval for use in the US in May 2011.

“We are extremely pleased by the CHMP positive recommendation for approval of linagliptin in Europe,” said Enrique Conterno, President of Lilly Diabetes. “Based on our comprehensive studies and the CHMP’s positive recommendation, we believe linagliptin can be an important new treatment option for patients with type 2 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 metformin2 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. 8 Diabetes is a chronic disease that occurs when the body either does not properly produce, or use, the hormone insulin. 9

References

1. Trajenta™ (linagliptin) tablets. EMA Summary of Product Characteristics.
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: Diabetes prevalence, 2009.
8. International Diabetes Federation: www.idf.org, 2010.
9. World Health Organization: Fact Sheet No. 312 What is Diabetes?, 2010.