Boehringer Ingelheim announces results of phase III data showing that
linagliptin significantly lowered blood glucose with an excellent safety and
tolerability profile

New phase III data demonstrate clinically meaningful improvements in blood glucose control with linagliptin mono- and combination therapy

INGELHEIM, GERMANY, June 28 /CNW/ - Linagliptin phase III data were presented for the first time this week at the 70th Scientific Sessions of the American Diabetes Association (ADA), showing that this investigational compound, a dipeptidyl peptidase (DPP)-4 inhibitor, achieved significant, sustained and clinically meaningful reductions in blood glucose as measured by haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and postprandial glucose (PPG) concentrations.(1-6) Linagliptin is being investigated by Boehringer Ingelheim as a once-daily oral treatment in type 2 diabetes.

In the pivotal phase III studies, linagliptin was shown to have a very favourable safety profile, with an overall rate of adverse events similar to placebo. In addition, linagliptin showed an excellent tolerability, was weight neutral, showed no increased risk of drug-drug interactions and, importantly, there was no increased risk of hypoglycaemia attributed to linagliptin use in monotherapy, or combination therapy with metformin or pioglitazone.(1-6)

Notably, in diabetes patients with mild and moderate renal impairment, linagliptin blood plasma levels were comparable to those seen in diabetes patients with normal renal function,(1) suggesting that linagliptin, which has a primarily non-renal route of excretion, may have distinct pharmacological features not yet seen in this novel class of drugs.(8) The data suggest that linagliptin would not need dose adjustment in patients with type 2 diabetes regardless of the stage of renal impairment.

In four multi-centre, 24 weeks, randomised, double-blind, controlled trials, statistically significant reductions in blood glucose were observed with linagliptin monotherapy versus placebo(1) and when used in combination with other commonly used oral anti-diabetes drugs.(2-4) This was accompanied by significant improvements in beta-cell function.(1),(3) Declining beta-cell function is a key factor driving the progression of type 2 diabetes.(7)

In a further study, linagliptin monotherapy showed superiority in glucose lowering versus placebo and versus voglibose, the most commonly used alpha glucosidase inhibitor in Japan.(5-6)

"Many type 2 diabetes patients treated with traditional anti-diabetes agents fail to achieve their glycaemic targets or maintain them over time, which can leave them at a higher likelihood of developing diabetic complications, including renal disease. Although renal impairment is very common in patients with type 2 diabetes, early stage renal dysfunction often goes undiagnosed. It is important to identify those patients as they will require effective and safer drugs with low risk of hypoglycaemia", commented Julio Rosenstock, M.D., Director of Dallas Diabetes and Endocrine Center at Medical City and also a Clinical Professor of Medicine, University of Texas Southwestern Medical School, Dallas, Texas, USA. "For linagliptin, we see from studies that only approximately five percent of the orally administered drug is excreted via the kidneys. Data to date appear to indicate that linagliptin would not require dose adjustment, which could translate into an important benefit for physicians when choosing a treatment, not only for the type 2 diabetes patient population with diagnosed renal impairment, but also for those patients at risk of developing renal complications", he added.

Notes to Editor:

Please be advised: This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the U.S.A.

About Diabetes and Type 2 Diabetes

There are approximately 285 million people with diabetes in the adult population worldwide.(9) The International Diabetes Federation estimates that the number of people with diabetes will increase to 438 million people worldwide by 2030. Nearly four million people within the 20-79 age group are predicted to die from diabetes and its complications in 2010.(9) Approximately 50% of people with diabetes die of cardiovascular disease,(9) and more than 8% die of renal causes.(10)

    
    For more information about type 2 diabetes, please also visit:
    -   Media webcast hosted by Boehringer Ingelheim at
        http://www.boehringer-ingelheim-webcast.com/diabetes
    -   Diabetes Health Lounge website at http://www.DiabetesHealthLounge.com
    -   DPP-4 mode of action video at
        http://www.youtube.com/user/diabetesmatters
    

Boehringer Ingelheim Diabetes Pipeline

Metabolism is one of Boehringer Ingelheim's core R&D areas and diabetes one of the indications at the centre 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 and increase overall quality of life. These include:

    
    -   The DPP-4 inhibitor linagliptin is the most advanced compound in the
        Boehringer Ingelheim diabetes portfolio. Linagliptin is being
        investigated as an oral once-daily tablet for the treatment of type 2
        diabetes, as monotherapy and as combination therapy. Linagliptin has
        a primarily non-renal route of excretion (only approx. 5% excreted
        via the kidneys).
    -   The compound BI10773 is a sodium-dependent glucose transporter-2
        (SGLT-2) inhibitor. The Phase II clinical trials have concluded.
        BI10773 blocks renal glucose absorption in the kidneys, thereby
        improving glycaemic control. The inhibition of SGLT-2 has been seen
        to have a positive effect on body weight loss and reduction in blood
        pressure.
    -   An 11B-HSD1 inhibitor: Inhibition of 11B-HSD1 offers a novel
        potential therapy for the management of diabetes by lowering
        intracellular cortisol concentrations resulting in improved insulin
        sensitivity, blood lipid levels and vascular function. The 11B-HSD1
        inhibitor compound currently being studied by Boehringer Ingelheim is
        in early stage of clinical development.
    

Linagliptin phase III pivotal trials description:(1-6)

Four multi-centre, randomised, placebo-controlled, double-blind, phase III studies were conducted to investigate the efficacy, safety and tolerability of linagliptin (5 mg once daily) versus placebo, administered over 24 weeks in type 2 diabetes mellitus patients with insufficient glycaemic control. The overall HbA1c range for these studies was (greater than or equal to)6.5% and (less than or equal to)11%, with the following background therapy: linagliptin monotherapy(1) (exercise and diet alone), as add-on to metformin(2), as add-on to metformin plus a sulfonylurea(3), and as initial combination with pioglitazone.(4) A multi-centre, 12 and 26 weeks, randomised, double-blind, controlled study comparing the efficacy and safety and tolerability of linagliptin versus placebo and the alpha glucosidase inhibitor voglibose in drug-naïve or previously treated Japanese patients with type 2 diabetes (baseline HbA1c 7 -10% if drug-naïve, 7.0-9.0% if previously treated with an oral hypoglycaemic agent).(5-6)

    
    Summary of key efficacy results from these trials:
    -   Linagliptin as monotherapy provided significant, clinically
        meaningful and sustained improvements in glycaemic control
        accompanied by improvements in beta-cell function.(1) Among other
        results, data from this trial showed that:
        -  Linagliptin showed a mean placebo-adjusted change in HbA1c from
           baseline of -0.69% (p(less than)0.0001).
        -  Linagliptin patients were significantly more likely to achieve a
           reduction in HbA1c (greater than or equal to)0.5% at 24 weeks than
           placebo (47.1% versus 19.0%, p(less than)0.0001).
        -  Greatest mean placebo-adjusted HbA1c reductions (-1,01%) were seen
           in patients with elevated blood glucose levels at baseline, HbA1c
           (greater than or equal to)9.0%.
        -  Linagliptin showed a highly significant placebo-adjusted change in
           postprandial glucose (PPG) levels of -58.4 mg/dl (p(less than)
           0.0001).
        -  Conclusion: Linagliptin monotherapy showed a significant,
           clinically meaningful and sustained improvement in glycaemic
           control reflected in changes in FPG, PPG, and HbA1c. This is
           accompanied by beta-cell function improvements and a safety
           profile comparable to placebo.

    -   Linagliptin as an add-on to metformin resulted in a significant
        change in HbA1c.(2) Among other results, data from this trial showed
        that:
        -  Linagliptin showed a significant placebo-adjusted mean change in
           HbA1c from baseline of -0.64% (p(less than)0.0001) after 24 weeks
           of treatment.
        -  Linagliptin showed a highly significant placebo-adjusted change in
           postprandial glucose (PPG) levels of -67.1 mg/dl (p(less than)
           0.0001).
        -  Conclusion: Linagliptin 5 mg as add-on therapy for type 2 diabetes
           patients inadequately controlled on metformin was well tolerated
           and produced significant and clinically meaningful improvements in
           glycaemic control.

    -   Linagliptin as an add-on to metformin plus a sulfonylurea was
        efficacious and safe in producing significant and clinically
        meaningful improvements in glycaemic control.(3) Among other results,
        data from this trial showed that:
        -  After 24 weeks of treatment, mean placebo-adjusted HbA1c was -
           0.62% lower (p(less than)0.0001) with the addition of linagliptin
           versus placebo.
        -  Patients with baseline HbA1c (greater than or equal to)7.0% were
           significantly more likely to achieve a target HbA1c (less than)
           7.0% when treated with linagliptin (29.2%) compared to placebo
           (8.1%, p(less than)0.0001).
        -  Conclusion: Therapy with linagliptin added to the combination of
           metformin and sulfonylurea was shown to be efficacious and safe in
           producing significant and clinically meaningful improvements in
           glycaemic control in type 2 diabetes patients. Thus, linagliptin
           may provide an additional option prior to insulin therapy in many
           patients failing on oral anti-diabetic combination therapy.

    -   Linagliptin in combination with pioglitazone showed significant and
        clinically meaningful improvements in FPG and HbA1c levels.(4)
        -  Linagliptin in combination with pioglitazone resulted in a mean
           placebo-adjusted HbA1c change of -1.06% from baseline and a
           difference of -0.51% in comparison with the pioglitazone and
           placebo group.
        -  Conclusion: Initial combination therapy with linagliptin and
           pioglitazone showed significant and clinically meaningful
           improvements in FPG and HbA1c levels and was well tolerated.
           Combining these two drugs may be an important initial dual therapy
           for type 2 diabetes, targeting both, B-cell dysfunction and
           peripheral insulin resistance, known as the pathophysiological key
           factors of this disease. Initial combination therapy with
           linagliptin and pioglitazone may provide an important synergistic
           initial treatment option for type 2 diabetes patients with
           inadequate glycaemic control or those with renal impairment for
           whom metformin is contraindicated.

    -   Japanese study (week 12 and week 26): Linagliptin as monotherapy
        demonstrated greater efficacy than placebo and voglibose,
        respectively, for improving glycaemic control in Japanese patients
        with type 2 diabetes and was well tolerated in this population.(5-6)

           At week 12:(5)
           -  The differences of placebo-adjusted mean changes from baseline
              in HbA1c were -0.87% for linagliptin 5 mg vs. placebo
              (p(less than)0.0001) and -0.88% for linagliptin 10 mg versus
              placebo (p(less than)0.0001)
           -  The proportions of patients achieving HbA1c (less than)7.0%
              after 12 wks were 26.4% for linagliptin 5 mg and 35.7% for
              linagliptin 10 mg versus 10.0% for placebo
           -  Conclusion: Linagliptin demonstrated a significant and
              clinically meaningful improvement in glycaemic control,
              reflected in changes in HbA1c and FPG in Japanese patients with
              type 2 diabetes.

           At week 26:(6)
           -  The differences of placebo-adjusted mean changes from baseline
              in HbA1c were -0.32% for linagliptin 5mg versus voglibose
              (p=0.003) and -0.39% for linagliptin 10mg versus
              voglibose (p(less than)0.0001)
           -  Drug-related gastrointestinal disorders were less frequently
              observed in the linagliptin groups than in the voglibose group
              (8.2% and 8.1% for linagliptin 5mg and 10mg, respectively;
              14.2% for voglibose).
           -  Conclusion: Linagliptin monotherapy demonstrated greater
              efficacy than voglibose for improving glycaemic control in
              Japanese patients with type 2 diabetes and was well tolerated
              in this population.
    

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 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 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.

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

    
    References
    ----------
    1.  Owens D.R. et al. Linagliptin monotherapy improves glycaemic control
        and measures of beta-cell function in Type 2 diabetes. Poster No 548-
        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. Poster No
        579-P from the 70th American Diabetes Association Scientific
        Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.
    3.  Del Prato S, et al. Linagliptin monotherapy improves glycaemic
        control and measures of beta-cell function in Type 2 diabetes. Poster
        No 695-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. Poster No 551-P from the 70th American
        Diabetes Association Scientific Sessions, 25-29 June 2010, Orlando,
        Florida, U.S.A.
    5.  Kawamori R. et al. Linagliptin Provides Superior Glycemic Control
        Compared to Voglibose as Monotherapy in Japanese Patients with Type 2
        Diabetes. Poster No 632-P from the 70th American Diabetes Association
        Scientific Sessions, 25-29 June 2010, Orlando, Florida, U.S.A.
    6.  Kawamori R. et al. Linagliptin Monotherapy Improves Glycemic Control
        in Japanese Patients with T2DM over 12 Weeks. Poster number 696-P
        from the 70th American Diabetes Association Scientific Sessions, 25-
        29 June 2010, Orlando, Florida, U.S.A.
    7.  Kahn S. The Importance of ss-Cell Failure in the Development and
        Progression of Type 2 Diabetes. The Journal of Clinical Endocrinology
        & Metabolism. 2010;86(9):4047-4058.
    8.  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.
    9.  International Diabetes Federation. Available at www.idf.org accessed
        on: 1 March 2010.
    10. Morrish, N.J. et al. Mortality and causes of death in the WHO
        Multinational Study of Vascular Disease in Diabetes.
        Diabetologia.2001;44 Suppl 2: S14-S21.
    

SOURCE Boehringer Ingelheim

For further information: For further information: Derek O'Toole, Director, Corporate Affairs and Communications, Boehringer Ingelheim (Canada) Ltd., Phone: (905) 631-4739, Fax: (905) 639-9369, E-mail: derek.otoole@boehringer-ingelheim.com

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