New Phase III Data and Pooled Analysis for Linagliptin Show Improved Blood Sugar Control in Adults With Type 2 Diabetes When Used Alone and With Metformin

SAN DIEGO, June 24, 2011 /PRNewswire/ -- Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) today announce Phase III study results for linagliptin, demonstrating improved glycemic control in adults with type 2 diabetes (T2D) whose blood sugar is not adequately controlled. In the open-label arm (n=66) of a 24-week study in adult patients with T2D with a mean baseline hemoglobin A1c (HbA1c or A1C) of 11.8 percent receiving linagliptin 2.5 mg twice daily (bid) plus metformin 1000 mg bid, patients experienced a mean A1C reduction of 3.7 percent. The total dose of linagliptin received was 5 mg daily. Linagliptin 2.5 mg bid is an investigational dose and not approved or available. For the monotherapy arms of linagliptin 5 mg once daily (qd), metformin 500 bid or metformin 1000 mg bid, the placebo-corrected reduction in A1C was 0.6 percent, 0.8 percent or 1.2 percent, respectively, from a mean baseline A1C of 8.7 percent, 8.7 percent and 8.5 percent, respectively. The combination of linagliptin 2.5 mg bid and metformin 500 or 1000 mg bid improved glycemic control more than either therapy used alone. The difference in body weight after treatment with linagliptin 2.5 mg bid plus metformin 1000 mg bid compared with metformin 1000 mg bid was -0.23 kg. In addition, there was low incidence of investigator-defined hypoglycemia (five cases, or 1.8 percent) with the linagliptin plus metformin combination.(1) Results will be presented at the 71st American Diabetes Association (ADA) Scientific Sessions in San Diego on June 24-28.

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In May 2011, the U.S. Food and Drug Administration (FDA) approved linagliptin, 5 mg, marketed under the trade name Tradjenta™ (linagliptin) tablets, to be used along with diet and exercise to lower blood sugar in adults with T2D. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis (increased ketones in the blood or urine). It has not been studied in combination with insulin.  

In a pooled analysis, three Phase III, placebo-controlled trials (n=2258) evaluated linagliptin as monotherapy or in combination with metformin or metformin plus sulfonylurea in patients with T2D and poor glycemic control (A1C greater than or equal to 9.0 percent; n=386). Treatment with linagliptin resulted in mean A1C reduction from baseline of 1.2 percent (n=294) versus 0.4 percent for placebo (n=102) (p<0.0001). The placebo-corrected effect of linagliptin monotherapy on A1C was -1.0 percent. When added to metformin or metformin plus sulfonylurea, the placebo-corrected effect on A1C was –0.7 percent. Linagliptin had an adverse event (AE) rate comparable to placebo (61.9 percent versus 62.7 percent, respectively). Hypoglycemia with linagliptin was less than or equal to one percent, both as monotherapy and in combination with metformin. Hypoglycemic event rates were increased when linagliptin was administered in combination with sulfonylurea (linagliptin 17.9 percent versus placebo 8.3 percent).(2)

"The results demonstrated by these Phase III data support linagliptin's safety and efficacy profile as a treatment option for the millions of American adults with type 2 diabetes," said John J. Smith, MD, PhD, senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "Additionally, linagliptin, when used both as monotherapy or in combination with two commonly used diabetes medications, lowered A1C in patients with poor blood sugar control."

Linagliptin was also evaluated in patients with normal renal function and mild, moderate and severe renal impairment (RI). In a large pooled analysis of three, randomized, placebo-controlled, Phase III trials (n=2141), patients who received linagliptin showed consistent placebo-corrected mean A1C changes independent of renal function with -0.7 percent (p<0.0001) for those with normal renal function and -0.69 percent for those with mild and moderate RI (p<0.0001, p=0.0174, respectively). In an additional study evaluating patients with T2D and severe RI whose blood sugar was insufficiently controlled (including a treatment arm of patients with A1C greater than or equal to 9.0 percent), renal function remained unchanged in both treatment arms. Cardiovascular (CV) deaths in this population were the same for linagliptin and placebo (1.5 percent).(3)

"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 glycemic control and renal impairment."

About the Linagliptin Studies

Combination with Metformin in Patients with T2D and Poor Glycemic Control (279-OR)(1)

The aim of this 24-week, randomized, double-blind, placebo-controlled, Phase III study was to evaluate the combination of linagliptin and metformin in patients with T2D and poor glycemic control.

• The six treatment groups included two arms receiving combinations of linagliptin 2.5 mg bid plus either low- or high-dose (500 or 1000 mg) metformin bid, and four arms receiving linagliptin 5 mg qd, metformin 500 or 1000 mg bid, or placebo. Mean baseline A1C was between 8.5 percent and 8.7 percent. In an additional treatment group, patients with a baseline A1C greater than or equal to 11.0 percent received open-label combination therapy with linagliptin 2.5 mg bid plus metformin 1000 mg bid (n=66). Mean baseline A1C was 11.8 percent in the open-label arm.
• For the combination arms of linagliptin 2.5 mg bid plus metformin 500 or 1000 mg bid, the placebo-corrected reduction in A1C was 1.3 percent and 1.7 percent, respectively. Both combination regimens had greater A1C reductions than the monotherapy arms.
• For the open-label arm (patients with a baseline A1C greater than or equal to 11.0 percent), mean change in A1C from baseline was -3.7 percent.
• For the monotherapy arms of linagliptin 5 mg qd, metformin 500 bid or metformin 1000 mg bid, the placebo-corrected reduction in A1C was 0.6 percent, 0.8 percent or 1.2 percent, respectively.
• The combination of linagliptin 2.5 mg bid and metformin 500 or 1000 mg bid improved glycemic control more than either monotherapy. AE rates were similar across treatment arms. The total number of hypoglycemic events during combination treatment was low (in total, five [1.8 percent] randomized patients receiving linagliptin 2.5 mg bid plus metformin 500 or 1000 mg bid). The difference in body weight after treatment with linagliptin 2.5 mg bid plus metformin 1000 mg bid compared with metformin 1000 mg bid was -0.23 kg.

Efficacy and Safety of Linagliptin in Patients with T2D and Poor Glycemic Control (1067-P)(2)

The aim of this large, pooled analysis of three, randomized, placebo-controlled, Phase III clinical trials was to determine the safety and efficacy of linagliptin in patients with T2D with poor glycemic control.

• 2258 subjects treated with linagliptin or placebo in monotherapy or as add-on to metformin or metformin plus sulfonylurea were eligible for this analysis. In total, 396 patients had a baseline A1C greater than or equal to 9.0 percent. At enrollment, 59 percent were treated with two or more oral antihyperglycemic drugs (OADs), and 58 percent had diabetes for more than five years.
• After 24 weeks treatment with linagliptin, A1C showed statistically significant changes from a baseline of –1.2 percent +/- standard error [SE] 0.2 (n=294) versus –0.4 percent +/- 0.2 (n=102) for placebo (p<0.0001 for mean difference). The placebo-corrected effect of linagliptin monotherapy on A1C was –1.0 percent +/- 0.3 and –0.7 percent +/- 0.2 when added to metformin plus sulfonylurea.
• Multivariate analyses of the pooled data showed treatment and wash-out of previous OADs prior to randomization were the only independent predictors of treatment response. In patients without previous wash-out, the change in A1C from baseline was –1.5 percent for linagliptin and –0.8 percent for placebo.
• Linagliptin had an AE rate comparable to placebo (61.9 percent versus 62.7 percent, respectively). Most of these events were mild, with no specific type of serious AE being predominant.
• Hypoglycemia with linagliptin was less than or equal to one percent, both as monotherapy and as add-on therapy to metformin. Hypoglycemic event rates were increased when linagliptin was administered in combination with sulfonylurea (linagliptin 17.9 percent versus placebo 8.3 percent), with 96 percent of reported hypoglycemic events arising from the study in which this combination was used.

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

The aim of this pooled analysis of three, global, randomized, placebo-controlled studies was to evaluate the efficacy and safety of linagliptin in patients with T2D with or without RI.

• Renal function, as assessed by estimated glomerular filtration rate (eGFR) by Cockcroft-Gault equation and renal damage marker and expressed as urinary albumin/creatinine ratio, was unaffected in all three groups after 24 weeks of linagliptin treatment. Patients who received linagliptin showed consistent, placebo-corrected, adjusted mean A1C changes across all three groups: normal renal function, mild RI and moderate RI, with no significant inter-group difference (p=0.865).
• The incidence rates of severe AEs 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).
• The primary endpoint in all trials was the change in A1C from baseline to week 24. The analysis assessed 2141 patients with T2D who were grouped by renal function as normal (eGFR greater than or equal to 80 mL/min, n=1684), mild RI (eGFR 50 to less than 80 mL/min, n=418), or moderate RI (eGFR 30 to less than 50 mL/min, n=39).

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

The aim of this Phase III, randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of linagliptin in patients with T2D (A1C greater than or equal to 7.0 percent and less than or equal to 10.0 percent) and severe RI (defined as eGFR by MDRD equation less than 30 mL/min/1.73 m2).

• The change from baseline in the subgroup of patients who were poorly controlled (baseline A1C greater than or equal to 9.0 percent) was greater with linagliptin 5 mg qd (-1.5 percent) than placebo (-0.28 percent) (p=0.0001). The change from baseline in A1C for all patients was -0.8 percent for linagliptin 5 mg qd and -0.2 percent for placebo (p=0.0001).
• AEs and serious AEs were 85.3 percent and 11.8 percent for linagliptin and 70.8 percent and 6.2 percent for placebo, respectively. In patients whose antihyperglycemic background therapy remained unchanged (insulin and/or sulfonylurea), hypoglycemia occurred in 48.5 percent of linagliptin and 26.2 percent of placebo-treated patients. Renal function remained unchanged throughout the study in both treatment arms. CV deaths in this population were the same for linagliptin and placebo (1.5 percent).
• The primary efficacy endpoint was the change in A1C from baseline to week 12. The efficacy endpoints were assessed using the full analysis set – linagliptin 5 mg qd (n=66) versus placebo (n=62). The primary safety endpoint was the incidence and intensity of AEs, including hypoglycemic events, renal function and electrolytes. The safety endpoints were assessed using the treated set – linagliptin 5 mg qd (n=68) and placebo (n=65).

To learn more about TRADJENTA and for full prescribing information visit: www.TRADJENTA.com or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257.

Please report any unexpected effects or product problems to the Boehringer Ingelheim Drug Information Unit by calling 1-800-542-6257.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

About Diabetes

Approximately 25.8 million Americans(5) and an estimated 220 million people(6) worldwide have type 1 and type 2 diabetes. Type 2 diabetes is the most common type, accounting for an estimated 90 to 95 percent of all diabetes cases.(5) Diabetes is a chronic disease that occurs when the body either does not properly produce, or use, the hormone insulin.(7)

Indication and Important Limitations of Use

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

Important Safety Information

CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS

Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONS

Adverse reactions reported in greater than or equal to 5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus zero in 433 person-years for comparator).

DRUG INTERACTIONS

The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments is strongly recommended.

USE IN SPECIFIC POPULATIONS

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

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 centers 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 Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

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 approximately $16.7 billion (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 http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

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 TRADJENTA 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 TRADJENTA 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.

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(1) Haak T, 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. (279-OR)

(2) Del Prato S, et al: Efficacy and safety of linagliptin in patients with type 2 diabetes and poor glycemic control. (1067-P)

(3) Cooper M, 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. (1068-P)

(4) Sloan L, et al: Safety and efficacy of linagliptin in type 2 diabetes patients with severe renal impairment. (413-P)

(5) Centers for Disease Control and Prevention. National Diabetes Fact Sheet 2011. Available at http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed on: June 7, 2011.

(6) World Health Organization. Fact Sheet No. 312: What is Diabetes? Available at: http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed on: June 7, 2011.

(7) International Diabetes Federation. Diabetes Atlas. 3rd edn. Brussels: International Diabetes Federation, 2006.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company

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