BOEHRINGER-INGELHEIM

Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced full data from the CAROLINA^® trial demonstrating that Trajenta^® (linagliptin) did not increase cardiovascular risk compared to glimepiride in adults with type 2 diabetes and cardiovascular risk.¹ The findings were reported today at the American Diabetes Association’s 79th Scientific Sessions in San Francisco.

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The trial met its primary endpoint, defined as non-inferiority for linagliptin versus glimepiride in time to first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (3P-MACE), which occurred in 11.8 percent (356 people) of the linagliptin group compared to 12.0 percent (362 people) of the glimepiride group.¹ The overall safety profile of linagliptin in CAROLINA^® was consistent with previous data, and no new safety signals were observed.^1,2

The study assessed linagliptin safety over the longest period ever studied in a DPP-4 inhibitor cardiovascular outcome trial, with a median follow-up of more than 6 years.¹ Linagliptin was similar to glimepiride in the secondary endpoint of 3P-MACE plus hospitalisation for unstable angina (4P-MACE - 13.2 percent for linagliptin versus 13.3 percent for glimepiride).¹

In CAROLINA^® , a higher proportion of patients within the linagliptin group (16.0 percent) achieved the secondary composite efficacy endpoint of treatment sustainability versus the glimepiride group (10.2 percent).^*1 Compared with glimepiride, linagliptin demonstrated similar overall effects on HbA1c, but significantly reduced the relative risk for hypoglycaemia (low blood sugar) by 77 percent (10.6 percent of patients treated with linagliptin experienced any hypoglycaemic incident versus 37.7 percent for glimepiride).¹ This risk reduction was consistent and significant across all hypoglycaemia categories, including severe hypoglycaemia and those requiring hospitalisation. Linagliptin was also associated with a modest weight reduction of 1.5 kg versus glimepiride.¹

“CAROLINA^® is unique in that it is the only DPP-4 inhibitor cardiovascular outcome trial with an active comparator,” said Waheed Jamal, MD, Corporate Vice President and Head of Cardiovascular & Metabolic Medicine, Boehringer Ingelheim. “When additional glucose-lowering is needed, DPP-4 inhibitors and sulfonylureas continue to be frequently used as add-on therapies to metformin. These data can further support physicians in choosing the most appropriate glucose-lowering treatment for each individual patient.”

“The American Diabetes Association and European Association for the Study of Diabetes recommend type 2 diabetes treatments with proven cardiovascular benefits for patients with established cardiovascular disease,” said Jeff Emmick, M.D., Ph.D., Vice President, Product Development, Lilly Diabetes. “But, physicians considering additional therapies to lower blood glucose for their patients need a DPP-4 inhibitor with an established long-term safety profile. These new data from CAROLINA^® , along with data from the placebo-controlled cardiovascular outcome trial CARMELINA^® , expand the evidence and experience with linagliptin, to provide healthcare professionals with confidence in the long-term safety profile across a broad range of patients with type 2 diabetes.”

About CAROLINA ^®
CAROLINA^® (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) is a multi-national, randomised, double-blind, active-controlled clinical trial that involved 6,033 adults with type 2 diabetes from 43 countries at more than 600 sites observed for a median duration of more than 6 years.^3,4 The trial included adults with early type 2 diabetes: adults with a median disease duration of 6.2 years, who either received no treatment at all, or received 1-2 glucose lowering agents (e.g. metformin).⁴ It was designed to assess the effect of Trajenta^® (linagliptin) (5 mg once daily) compared to the sulphonylurea glimepiride (both added to stable background glucose-lowering medication and cardiovascular standard of care) on cardiovascular safety in adults with type 2 diabetes and increased cardiovascular risk or established cardiovascular disease.^3,4 These people reflect patients that doctors typically see in their daily clinical practice.⁵

CAROLINA^® was led by an academic trial steering committee and Boehringer Ingelheim and Eli Lilly and Company. CAROLINA^® is the only DPP-4 inhibitor, active-comparator cardiovascular outcome trial.

About Trajenta ^® (linagliptin)
Trajenta^® is a one dose, once daily DPP-4 inhibitor that provides significant efficacy in the reduction of blood sugar levels for adults with type 2 diabetes. It can be prescribed for adults with type 2 diabetes regardless of age, disease duration, ethnicity, body mass index (BMI), liver and kidney function.² Trajenta^® has the lowest kidney excretion rate of all DPP-4 inhibitors.^6-9

About our cardiovascular outcome trials
Cardiovascular outcome trials are highly relevant, as cardiovascular disease is a major complication and the leading cause of death in type 2 diabetes. Worldwide, most people with type 2 diabetes die of a cardiovascular event.¹⁰ In 2015, Boehringer Ingelheim and Eli Lilly and Company announced results from the landmark cardiovascular outcome trial EMPA-REG OUTCOME^® with the SGLT2 inhibitor, empagliflozin, which reduced the relative risk of cardiovascular death by 38 percent in adults with type 2 diabetes and established cardiovascular disease, on top of standard of care.^†‡11-13 As a result, empagliflozin was the first oral type 2 diabetes medicine to have either a cardiovascular indication or data on the reduction of the risk of cardiovascular death included in the label in many countries.^11,12

CAROLINA^® is one of two cardiovascular outcome trials with the DPP-4 inhibitor, linagliptin.^3,4 CAROLINA^® and the CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with type 2 diabetes at high vascular risk trial (CARMELINA^® )^14,15 provide one of the most comprehensive datasets on the long-term safety of a DPP-4-inhibitor.

CARMELINA^® is a multi-national, randomised, double-blind, placebo-controlled clinical trial that involved 6,979 adults with type 2 diabetes from 27 countries at more than 600 sites observed for a median duration of 2.2 years.^14,15 CARMELINA^® studied the impact of Trajenta^® (linagliptin) on cardiovascular and kidney safety in adults with type 2 diabetes at high risk for heart and/or kidney disease.^14,15 The trial met its primary endpoint,^§ with linagliptin demonstrating a similar cardiovascular safety profile compared to placebo when added to standard of care.¹⁴ CARMELINA^® also included a key secondary composite endpoint,^** showing a similar kidney safety profile compared to placebo.¹⁴ The overall safety profile of linagliptin in CARMELINA^® was consistent with previous data and no new safety signals were observed.^2,14 CARMELINA^® also showed a similar rate of hospitalisation for heart failure for linagliptin compared to placebo.¹⁴

To learn more about CAROLINA^® and CARMELINA^® , please visit: https://www.carmelinatrial.com/

Please click on the following link for ‘Notes to Editors’ and ‘References’:

http://www.boehringer-ingelheim.com/press-release/CAROLINA-full-data

^* Secondary composite efficacy outcome defined as HbA1c at or below 7 percent at the final visit without rescue medication, moderate or severe hypoglycaemia or a 2 percent or greater weight gain.
^† Adult patients with type 2 diabetes and coronary artery disease, peripheral artery disease, or a history of MI or stroke
^‡ Standard of care included cardiovascular medications and blood sugar lowering agents given at the discretion of physicians
^§ Primary endpoint defined as time to first occurrence of the 3P-MACE (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke)
^** Key secondary endpoint defined as time to first occurrence of sustained end stage kidney disease (ESKD), death due to kidney disease, or a sustained decrease in eGFR from baseline of ≥40 percent compared to placebo

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Contact:

Tetsu Owari Media & PR Boehringer Ingelheim Email: press@boehringer-ingelheim.com Phone: +49 (6132) 77 184867

Stephan Thalen Global Business Communications Lilly Diabetes Email: stephan.thalen@lilly.com Phone: +1 317 903 5640

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