Type 2 Diabetes: Investigational empagliflozin/linagliptin combination tablet shows sustained reduction in blood glucose in Phase III study

Ingelheim, Germany and Indianapolis, U.S., 16 September, 2014 – Boehringer Ingelheim and Eli Lilly and Company today presented results from a 52-week Phase III study that demonstrated sustained efficacy of the investigational empagliflozin/linagliptin combination tablet in adults with type 2 diabetes (T2D) already taking metformin and in those who were previously untreated. Results from the study, presented during the 50th Annual Meeting of the European Association for the Study of Diabetes (EASD), also confirmed the safety profile of the combination tablet.^1,2

"We are encouraged by the results of this study because it showed clinically meaningful reductions in blood glucose levels with the empagliflozin/linagliptin combination when used with or without metformin," said Prof Hans-J. Woerle, Vice President, Head of medicine, Therapeutic Area Metabolism, Boehringer Ingelheim. "As Type 2 Diabetes is a complex and progressive condition, new treatment approaches may be required to help control blood glucose and the single tablet combination of empagliflozin/linagliptin may provide an important option for these patients."

About the study
In the parallel group study, 1,363 adults with T2D were randomised to five groups to investigate the efficacy and safety of two doses of the empagliflozin/linagliptin combination tablet compared to two doses of empagliflozin and one dose of linagliptin with or without metformin. Overall, empagliflozin/linagliptin combination therapy was well tolerated, with safety profiles similar to those known for the individual components. Patients were randomised to one the following treatments:

• Empagliflozin 25mg/linagliptin 5mg, combination tablet
• Empagliflozin 10mg/linagliptin 5mg, combination tablet
• Empagliflozin 25mg
• Empagliflozin 10mg
• Linagliptin 5mg

Empagliflozin/linagliptin combination therapy as add-on to stable dose metformin 

• At 52 weeks, both empagliflozin 25mg/linagliptin 5mg and empagliflozin 10mg/linagliptin 5mg led to significant reductions in blood glucose (HbA1c) of -1.21 and -1.04 percent, respectively, compared to baseline. The glucose lowering effects of the other treatments were as follows: linagliptin 5mg (-0.45 percent), empagliflozin 25mg (-0.69 percent) and empagliflozin 10mg (-0.70 percent).
• Confirmed hypoglycaemic adverse events (AEs) were reported in 3.6 percent, 2.2 percent, 3.5 percent, 1.4 percent and 2.3 percent of subjects on empagliflozin 25mg/linagliptin 5mg, empagliflozin 10mg/linagliptin 5mg, empagliflozin 25 mg, empagliflozin 10mg and linagliptin 5mg respectively; no subject required assistance.
• Genital infection was reported in 2.2 percent, 5.9 percent, 8.5 percent, 7.9 percent and 2.3 percent, on the same regimens respectively. Urinary tract infections were reported in 10.2 percent, 9.6 percent, 13.5 percent, 11.4 percent and 15.2 percent, on the same regimens respectively.

Empagliflozin/linagliptin combination therapy in previously untreated adults with T2D

• At 52 weeks, both empagliflozin 25mg/linagliptin 5mg and empagliflozin 10mg/linagliptin 5mg led to reductions in blood glucose (HbA1c) compared to baseline of -1.18 and -1.25 percent, respectively, as did linagliptin 5mg (-0.51 percent), empagliflozin 25mg (-1.02 percent) and empagliflozin 10mg (-0.87 percent).
• The reduction in blood glucose for empagliflozin 10mg/linagliptin 5mg combination tablet was statistically significant compared with empagliflozin 10mg or linagliptin 5mg; however, reductions seen with empagliflozin 25mg/linagliptin 5mg did not reach statistical significance compared with empagliflozin 25mg.
• Confirmed hypoglycaemic AEs were reported in 1 patient each in both the empagliflozin 25mg and linagliptin 5mg groups and 4 patients on empagliflozin 10mg; no subject required assistance.
• Genital infection was reported in 5.9 percent, 2.9 percent, 4.4 percent, 5.2 percent and 3.0 percent in empagliflozin 25mg/linagliptin 5mg, empagliflozin 10mg/linagliptin 5mg, empagliflozin 25mg, empagliflozin 10mg and linagliptin 5mg. Urinary tract infections were reported in 12.5 percent, 15.4 percent, 10.4 percent, 16.3 percent and 10.4 percent, on the same regimens respectively.

In April this year, Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly announced the U.S. Food and Drug Administration (FDA) accepted the filing of the New Drug Application for the investigational oral combination of empagliflozin/linagliptin in a single tablet for the treatment of T2D. If granted approval by the FDA, this combination will bring together, for the first time into one tablet, the distinct mechanisms of action of a sodium glucose co-transporter-2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP-4) inhibitor.

About empagliflozin
Empagliflozin, marketed as Jardiance^® in Europe and in the U.S., is an oral, once-daily tablet for the treatment of adults with Type 2 Diabetes to improve glycemic control. It is approved for use when diet and exercise alone do not provide adequate glycaemic control:³

• alone when metformin is not considered appropriate due to intolerance
• alongside other glucose-lowering medicines including insulin when glucose control is inadequate
  Empagliflozin should not be used in patients with Type 1 Diabetes or for the treatment of diabetic ketoacidosis (increased ketones in the blood or urine).

SGLT2 is a protein responsible for about 90 percent of the reabsorption of glucose back into the bloodstream.⁴ Empagliflozin reduces the kidneys’ ability to reabsorb glucose into the bloodstream, leading to urinary glucose excretion. Unlike most classes of existing oral T2D treatments, SGLT2 inhibitors like empagliflozin work independently of β-cell function and insulin pathway.

About linagliptin
Linagliptin (5 mg) is marketed in Europe as Trajenta^® and in the U.S. as Tradjenta^®, as a once-daily tablet that is used along with diet and exercise to improve glycaemic control in adults with T2D. Linagliptin should not be used in patients with Type 1 Diabetes or for the treatment of diabetic ketoacidosis (increased ketones in the blood or urine).^5,6

Boehringer Ingelheim and Eli Lilly and Company
In January 2011, Boehringer Ingelheim and Eli Lilly and Company entered into an alliance in diabetes that centres on compounds representing several of the largest diabetes treatment classes. The alliance leverages the strengths of two of the world’s leading pharmaceutical companies. By joining forces, the companies demonstrate commitment in the care of patients with diabetes and stand together to focus on patient needs. Find out more about the alliance at www.boehringer-ingelheim.com or www.lilly.com.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2013, Boehringer Ingelheim achieved net sales of about €14.1 billion. R&D expenditure corresponds to 19.5 percent of its net sales.

For more information please visit www.boehringer-ingelheim.com

About Lilly Diabetes
Lilly has been a global leader in diabetes care since 1923, when we introduced the world’s first commercial insulin. Today we are building upon this heritage by working to meet the diverse needs of people with diabetes and those who care for them. Through research and collaboration, a broad and growing product portfolio and a continued determination to provide real solutions—from medicines to support programs and more - we strive to make life better for all those affected by diabetes around the world. For more information, visit www.lillydiabetes.com.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and newsroom.lilly.com/social-channels.

This press release contains forward looking statements about the investigational empagliflozin/ linagliptin combination tablet; empagliflozin, an SGLT2 inhibitor approved for the treatment of Type 2 Diabetes along with diet and exercise; and linagliptin, a DPP-4 inhibitor approved for the treatment of Type 2 Diabetes along with diet and exercise. It reflects Lilly's current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in the process of drug development and commercialization. There is no guarantee that future study results and patient experience will be consistent with study findings to date, or that the investigational combination therapy of empagliflozin and linagliptin, will be commercially successful, or that these compounds will receive regulatory approvals. For further discussion of these and other risks and uncertainties, please see Lilly's latest Forms 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.