Boehringer Ingelheim Announces Pivotal Phase III Data Showing Linagliptin Reduced Blood Sugar Compared to Placebo in People With Type 2 Diabetes

ORLANDO, Fla., June 26 /PRNewswire/ -- Data from four pivotal Phase III clinical trials demonstrate that linagliptin achieved statistically significant and sustained reductions in blood sugar as measured by hemoglobin A1c (HbA1c),(1-4) fasting plasma glucose (FPG)(1-4) and postprandial glucose (PPG).(1,2)  Boehringer Ingelheim Pharmaceuticals, Inc. is investigating the dipeptidyl peptidase 4 (DPP-4) inhibitor as an oral once-daily tablet, as monotherapy and combination therapy, to treat type 2 diabetes. The linagliptin data are being presented this week at the 70th Annual American Diabetes Association (ADA) Scientific Sessions in Orlando, Fla.

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In the Phase III studies, statistically significant placebo-adjusted changes in HbA1c were observed with linagliptin (5 mg) monotherapy versus placebo (-0.69 percent, p<0.0001)(1) and when used in combination with other commonly-used oral anti-diabetic drugs, including metformin (-0.64 percent, p<0.0001),(2) metformin plus a sulfonylurea (-0.62 percent, p<0.0001),(3) and as initial combination with pioglitazone (-0.51 percent, p<0.0001).(4) Linagliptin therapy also resulted in improvements in beta-cell function.(1) Declining beta-cell function is believed to be a key factor driving the progression of type 2 diabetes.(5)

"It is imperative that blood sugar levels in people with type 2 diabetes are adequately controlled," said Dr. Giora Davidai, executive director & medical leader, medical affairs, cardiovascular & metabolic medicine, Boehringer Ingelheim Pharmaceuticals, Inc. "Uncontrolled blood sugar puts type 2 diabetes patients at a higher risk of developing serious complications like renal impairment and cardiovascular disease, which are very common in patients with type 2 diabetes."

Notably, in these trials in type 2 diabetes patients with mild and moderate renal impairment, linagliptin blood plasma levels were comparable to those seen in type 2 diabetes patients with normal renal function,(1) which is consistent with existing data showing that linagliptin may have a primarily non-renal route of excretion.(6)

Two additional linagliptin studies conducted in Japanese patients also were presented at ADA. (7,8)

About the linagliptin pivotal Phase III trials(1-4)

The aim of the four, 24-week, international, randomized, double-blind, placebo-controlled studies was to assess the efficacy and safety profile of linagliptin (5 mg once-daily) versus placebo, administered over 24 weeks in patients with type 2 diabetes who were failing to achieve glycemic control (defined as HbA1c greater than or equal to 7.0 percent and less than or equal to 10.0 percent).  The primary endpoint was the change in HbA1c from baseline to week 24.  The studies assessed linagliptin as monotherapy (exercise and diet alone) (n=336 linagliptin, n=167 placebo), as add-on to metformin (n=523 linagliptin + metformin, n=177 placebo + metformin), as add-on to metformin plus a sulfonylurea (n=792 linagliptin + metformin + sulfonylurea, n=263 placebo + metformin + sulfonylurea), and as initial combination with pioglitazone (n=259 linagliptin +pioglitazone, n=130 placebo + pioglitazone).

Safety data and additional results from the pivotal trials

• Patients who received linagliptin monotherapy were significantly more likely to achieve a reduction in HbA1c greater than or equal to 0.5 percent at 24 weeks than placebo (47.1 percent versus 19.0 percent).  The greatest placebo-adjusted changes in HbA1c  (-1.01 percent, p< 0.001) were seen in patients with elevated blood sugar levels at baseline (HbA1c greater than or equal to 9.0 percent).(1)
  • The proportion of patients reporting at least one adverse event (AE) was similar for both groups (52.4 percent linagliptin; 58.7 percent placebo).  Hypoglycemia occurred in one patient in each of the groups (0.3 percent linagliptin; 0.6 percent placebo).  Serious AEs were reported in both groups (3.0 percent linagliptin; 4.2 percent placebo) but were not determined by the investigators to be drug related.(1)
• Patients who received linagliptin as an add-on to metformin with baseline HbA1c greater than or equal to 7.0 percent were more likely to achieve an HbA1c <7.0 percent than those receiving metformin + placebo (26.2 percent versus 9.2 percent, p=0.0001).(2)
  • Linagliptin + metformin showed a statistically significant change in placebo-adjusted postprandial glucose (PPG) levels of -67.1 mg/dl compared to placebo + metformin (p<0.0001).
  • The proportion of patients reporting at least one AE was similar for both groups (52.8 percent linagliptin; 55.4 percent placebo).  Hypoglycemia occurred in five placebo patients (2.8 percent) and three linagliptin patients (0.6 percent), two of which were considered drug-related by the investigator.(2)
• Patients who received linagliptin as add-on to metformin and sulfonylurea with baseline HbA1c greater than or equal to 7.0 percent were significantly more likely to achieve a target HbA1c  less than or equal to 7.0 percent when treated with linagliptin (29.2 percent) compared to placebo (8.1 percent, p<0.0001).(3)
  • The proportion of patients reporting a severe AE in the linagliptin and placebo groups was 2.4 percent and 1.5 percent, respectively.  Drug-related hypoglycemia was reported in the placebo + metformin + sulfonylurea group (7.6 percent) at about half the frequency reported in the linagliptin + metformin+ sulfonylurea group (14.5 percent).  No significant changes in weight were noted for either treatment group.(3)
• Patients in the linagliptin and pioglitazone group were more likely to achieve a target HbA1c <7.0 percent versus those on placebo and pioglitazone (42.9 percent versus 30.5 percent, respectively, p=0.0051).4
  • The proportion of patients who experienced at least one AE was similar for both linagliptin and placebo (52.5 percent versus 53.1 percent, respectively).  Hypoglycemia occurred in 3 patients (1.2 percent) in the linagliptin + pioglitazone group and none in the placebo + pioglitazone group. All hypoglycemic events were of mild intensity.(4)

About diabetes

Approximately 27 million Americans and 285 million people worldwide have diabetes.(9) Type 2 diabetes is the most common type, accounting for more than 90 percent of all diabetes cases in the developed world.(10) Each year, more than 231,000 people in North America and more than 3.96 million people worldwide die from diabetes and its complications(9) – a number which is expected to increase by more than 50 percent over the next decade.(10) Diabetes is a chronic disease that occurs when the body either does not properly produce, or use the hormone, insulin.(11)

About Boehringer Ingelheim and diabetes

Metabolism is one of Boehringer Ingelheim's core R&D areas and diabetes is one of the indications at the center of interest within the company's global research network. Boehringer Ingelheim is committed to researching and developing new diabetes compounds with novel modes of action to improve patients' health.

In addition to linagliptin, Boehringer Ingelheim is also investigating the sodium-dependent glucose co-transporter-2 (SGLT-2) inhibitor, BI-10773, which belongs to a new, emerging class of antidiabetic compounds that block tubular reabsorption of glucose in the kidney.  Phase II clinical trials for this innovative approach to diabetes treatment have concluded.  Currently, there are no SGLT-2 inhibitors approved for use in the U.S.

Boehringer Ingelheim is also developing an 11 beta-HSD1 inhibitor. Inhibition of 11 beta-HSD1 offers a novel potential therapy for the management of diabetes by lowering intracellular cortisol concentrations, which are believed to result in improved insulin sensitivity, blood lipid levels and vascular function.

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 142 affiliates in 50 countries and more than 41,500 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.

In 2009, Boehringer Ingelheim posted net sales of US $17.7 billion (12.7 billion euro) while spending 21 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.

(1) Del Prato S. et al. Linagliptin monotherapy improves glycaemic control and measures of beta-cell function in Type 2 diabetes. Abstract No 695-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.

(2) Taskinen M-R. et al. Efficacy and safety of linagliptin in Type 2 diabetes inadequately controlled on metformin monotherapy. Abstract No 579-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.

(3) Owens D.R. et al. Linagliptin Improves Glycemic Control in Type 2 Diabetes Patients Inadequately Controlled by Metformin and Sulfonylurea without Weight Gain or Hypoglycemia. Abstract No 548-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.

(4) Gomis R. et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled Type 2 diabetes. Abstract No 551-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.

(5) Kahn S. The Importance of beta-Cell Failure in the Development and Progression of Type 2 Diabetes. The Journal of Clinical Endocrinology & Metabolism. 2010;86(9):4047-4058.

(6) Blech S. et al. The Metabolism and Disposition of the Oral Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, in Humans. Drug Metabolism and Disposition: 2010;38:667–678.

(7) Kawamori R. et al. Linagliptin Monotherapy Improves Glycemic Control in Japanese Patients with T2DM over 12 Weeks. Abstract No 696-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.

(8) Kawamori R. et al. Linagliptin Provides Superior Glycemic Control Compared to Voglibose as Monotherapy in Japanese Patients with Type 2 Diabetes. Abstract No 632-P from the 70th American Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.

(9) International Diabetes Federation. Diabetes Atlas. 4th edn.  Brussels: International Diabetes Federation, 2009.

(10) World Health Organization. Fact Sheet No. 312: What is Diabetes? Available at:

http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed on: February 4, 2009.

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

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.

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