New data for linagliptin* show clinically meaningful efficacy similar to glimepiride but with fewer cardiovascular events

Two-year Phase III study confirms linagliptin has significant efficacy and good tolerability in combination therapy with metformin.

Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) today 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)**¹ 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 percent vs. 36.1 percent; p<0.0001) and fewer cardiovascular (CV) events (1.5 percent vs. 3.4 percent; Relative Risk 0.46 [0.23-0.91] p=0.02).¹ Results will be presented at the 71^st 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 percent 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 percent 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 percent of patients).² In an open label arm including patients with poor glycaemic control (HbA1c at baseline >11 percent) 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 percent.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 percent (p<0.0001) for those with normal renal function and -0.69 percent 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 percent (p<0.0001) after 12 weeks of treatment.⁴ Renal function remained stable over time and CV deaths in this high-risk population were low with one patient per arm.⁴

“Renal impairment is frequently associated with type 2 diabetes, and is a major factor in limiting the choice of glucose-lowering agents,” said Mark Cooper, MD, deputy director and chief scientific officer, Baker IDI Heart and Diabetes Institute, Australia. “In this trial, linagliptin was effective at lowering A1C, even in patients with poor glycaemic control and renal impairment.”

About the Linagliptin Studies

Similar Efficacy to Glimepiride but Improved CV Safety over Two Years (39-LB) ¹

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 percent –CI, 0.11-0.29 percent on a pre-specified non-inferiority margin of 0.35 percent).
• 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).

Combination with Metformin in T2D Patients (279-OR) ²

The aim of this 24-week, study was to evaluate the combination of linagliptin plus metformin in T2D patients with inadequate glycaemic control.

• 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 percent and
  8.7 percent, and 11.8 percent 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 percent and -1.7 percent, 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.

Efficacy and Safety in Patients with T2D with or Without RI (1068-P) ³

The aim of this pooled analysis of three global studies was to evaluate the effect of renal function on the efficacy and safety of linagliptin in T2D patients with or without declining renal function.

• The primary endpoint in all trials was the change in HbA1c from baseline to week 24. The data assessed 2,141 patients with T2D who were grouped by renal function as normal GFR greater than or equal to 80 mL/min, n=1,684), mild RI (GFR, 50 to less than 80 mL/min, n=418), or moderate RI (GFR, 30 to less than 50 mL/min, n=39).
• Patients who received linagliptin showed consistent placebo-corrected adjusted mean HbA1c changes across all three groups (-0.6 percent in both the Normal and Mild RI groups and
  -0.7 percent in the Moderate RI group).
• Linagliptin was well tolerated. The proportion of patients reporting a severe AE with linagliptin in the normal/mild/moderate groups were 2.5 percent, 5.4 percent and 3.7 percent, respectively, and similar to placebo (3.4 percent, 3.8 percent, 8.3 percent, respectively).
• Renal function, as assessed by Glomerular Filtration Rate (GFR), and a surrogate for diabetic nephropathy, the urinary albumin/creatinine ratio, was unaffected in all three groups after
  24 weeks of linagliptin treatment.

Safety and Efficacy in T2D Patients with Severe RI (413-PP) ⁴

The aim of this study was to evaluate the effect of renal function on the efficacy and safety of linagliptin in T2D patients (defined as HbA1c greater than or equal to 7 percent and less than or equal to 10 percent) and severe RI (defined as GFR less than 30 mL/min/1.73 m² ).

• The primary endpoint was the change in HbA1c from baseline to week 12. The study assessed linagliptin 5 mg qd (n=68) vs. placebo (n=65) in patients whose glucose-lowering background therapy remained unchanged (insulin and/or sulphonylurea).
• The change from baseline for all patients was significantly greater with linagliptin tablets 5 qd (n=66; -0.8 percent) than with placebo (n=62; -0.2 percent) p= 0.0001. The change from baseline in the subgroup of poorly controlled patients (baseline HbA1c greater than or equal to 9 percent) was significantly more with linagliptin 5 qd (n=11; -1.5 percent) than with placebo (n=13; -0.3 percent), p= 0.0021.
• The proportion of patients reporting an AE was 85.3 percent for linagliptin and 70.8 percent for placebo, respectively. Hypoglycaemia occurred in 51.5 percent of linagliptin and 27.7 percent of placebo-treated patients. Notably, as 61 of the 66 patients receiving linagliptin were on insulin and/or sulphonylurea background therapy, their unchanged doses of background therapy may account for the hypoglycaemic event rate in this arm. Renal function remained stable throughout the study in both treatment arms and CV deaths in this high-risk population were low: one patient per arm.

About Diabetes

An estimated 285 million people worldwide have type 1 and type 2 diabetes.⁵ T2D is the most common type, accounting for an estimated 90 percent of all diabetes cases.⁶ Diabetes is a chronic disease that occurs when the body either does not properly produce, or use, the hormone insulin.⁷

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. 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, 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.

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

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. Additional information about Lilly is available at www.lilly.com .

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 programs to help overcome barriers to success along the diabetes journey. At Lilly, the journeys of each person living with or treating diabetes inspire ours. For more information, visit www.lillydiabetes.com .

This press release contains forward-looking statements about linagliptin tablets for the treatment of type 2 diabetes. 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 linagliptin will be commercially successful. 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.

* Linagliptin is an investigational compound and has not be approved in all countries

** Difference in mean HbA1c change from baseline between groups -0.20 percent; 95 percent –CI, 0.11-0.29 percent on a pre-specified non-inferiority margin of 0.35 percent

REFERENCES

1. Gallwitz B, Uhlig-Laske B, Bhattacharaya S, et al. Linagliptin has Similar Efficacy to Glimepiride but Improved Cardiovascular Safety over 2 Years in Patients with Type 2 Diabetes Inadequately Controlled on Metformin 71th Scientific Sessions of the American Diabetes Association, San Diego, California. 2011;Poster 39-LB.

2. Haak T, Meinicke T, Jones R, et al. Combination of Linagliptin and Metformin Improves Glycemic Control in Type 2 Diabetes: A Randomized Trial with an Open-Label Arm in Patients with Poor Glycemic Control. 71th Scientific Sessions of the American Diabetes Association, San Diego, California. 2011;Oral presentation 279.

3. Cooper M, von Eynatten M, Emser A, et al. Efficacy and Safety of Linagliptin in Patients With Type 2 Diabetes With or Without Renal Impairment: Results from a Global Phase 3 Program. 71th Scientific Sessions of the American Diabetes Association, San Diego, California. 2011;1068-P.

4. Sloan L, Newman J, Sauce C, et al. Safety and Efficacy of Linagliptin in Type 2 Diabetes Patients with Severe Renal Impairment. 71th Scientific Sessions of the American Diabetes Association, San Diego, California. 2011;Poster 413-PP.

5. International Diabetes Federation: Diabetes prevalence, 2009.

6. International Diabetes Federation: www.idf.org , 2010.

7. World Health Organization. Fact sheet N°312. 2011:http://www.who.int/mediacentre/factsheets/fs312/en/ .

Contact:

Boehringer Ingelheim GmbH
Ute E Schmidt, +49 (6132) 77 97296
press@boehringer-ingelheim.com
or
Lilly Diabetes
Kelley Murphy, +1-317-701-4007
Communications Director
kmurphy@lilly.com kmurphy@lilly.com