Full data from CAROLINA® outcome trial support long-term cardiovascular safety profile of Trajenta®

June 2019

• CAROLINA® demonstrated no increased cardiovascular risk for Trajenta® (linagliptin) versus glimepiride in the only active-comparator cardiovascular outcome trial for a dipeptidyl peptidase-4 (DPP-4) inhibitor
• Adults with diabetes treated with Trajenta® experienced significantly fewer events of hypoglycaemia and a modest weight reduction compared to patients treated with glimepiride
• Detailed results from CAROLINA® were presented at the American Diabetes Association’s 79th Scientific Sessions

Ingelheim, Germany and Indianapolis, US, 10 June 2019 – 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.

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 HbA_1c, 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.”

* Secondary composite efficacy outcome defined as HbA_1c at or below 7 percent at the final visit without rescue medication, moderate or severe hypoglycaemia or a 2 percent or greater weight gain.

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/^🡥

† 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

Boehringer Ingelheim and Eli Lilly and Company

In January 2011, Boehringer Ingelheim and Eli Lilly and Company announced an alliance in diabetes that centres on compounds representing several of the largest diabetes treatment classes. The alliance leverages the strengths of two of the world’s leading pharmaceutical companies. By joining forces, the companies demonstrate commitment in the care of people with diabetes and stand together to focus on patient needs. Depending on geographies, the companies either co-promote or separately promote the respective molecules that each contributed to the alliance.

Boehringer Ingelheim

Improving the health of humans and animals is the goal of the research-driven pharmaceutical company Boehringer Ingelheim. The focus in doing so is on diseases for which no satisfactory treatment option exists to date. The company therefore concentrates on developing innovative therapies that can extend patients’ lives. In animal health, Boehringer Ingelheim stands for advanced prevention.

Family-owned since it was established in 1885, Boehringer Ingelheim is one of the pharmaceutical industry’s top 20 companies. Some 50,000 employees create value through innovation daily for the three business areas human pharmaceuticals, animal health and biopharmaceuticals. In 2018, Boehringer Ingelheim achieved net sales of around 17.5 billion euros. R&D expenditure of almost 3.2 billion euros, corresponded to 18.1 per cent of net sales.

As a family-owned company, Boehringer Ingelheim plans in generations and focuses on long-term success. The company therefore aims at organic growth from its own resources with simultaneous openness to partnerships and strategic alliances in research. In everything it does, Boehringer Ingelheim naturally adopts responsibility towards mankind and the environment.

More information about Boehringer Ingelheim can be found on www.boehringer-ingelheim.in^🡥
or in our annual report: http://annualreport.boehringer-ingelheim.com^🡥

About Lilly Diabetes

Lilly has been a global leader in diabetes care since 1923, when we introduced the world's first commercial insulin. Today we are building upon this heritage by working to meet the diverse needs of people with diabetes and those who care for them. Through research and collaboration, a wide range of therapies and a continued determination to provide real solutions—from medicines to support programs and more—we strive to make life better for all those affected by diabetes around the world. For more information, visit www.lillydiabetes.com^🡥

About Eli Lilly and Company

Lilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com ^🡥and newsroom.lilly.com/social-channels.^🡥

Intended audiences

This press release is issued from Boehringer Ingelheim Corporate Headquarters in Ingelheim, Germany and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where Boehringer Ingelheim and Eli Lilly and Company do business.

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Trajenta® and its safety profile, and reflects Lilly's current belief. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there can be no guarantee that future study results will be consistent with the results to date or that Trajenta® will receive additional regulatory approvals. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission.

Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

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