• Trajenta® demonstrates no increased cardiovascular risk compared to glimepiride in adults with type 2 diabetes and cardiovascular risk
  • With a median follow-up of more than 6 years, CAROLINA® adds evidence to the long-term safety profile of Trajenta® in a broad range of adults with type 2 diabetes

Ingelheim, Germany and Indianapolis, US, 14 February 2019 – Boehringer Ingelheim and Eli Lilly and Company (NYSE:LLY) announced CAROLINA® (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) met its primary endpoint, defined as non-inferiority of Trajenta® (linagliptin) vs glimepiride in time to first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (3P-MACE).1,2

CAROLINA® is the only active-comparator cardiovascular outcome trial for a dipeptidyl peptidase-4 (DPP-4) inhibitor.1,2 The trial evaluated the cardiovascular safety of linagliptin (5 mg once daily) compared to the sulphonylurea glimepiride, on top of standard of care in 6,033 adults with type 2 diabetes and increased cardiovascular risk or established cardiovascular disease.1,2 The trial 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.1,2 The overall safety profile of linagliptin in CAROLINA® was consistent with previous data and no new safety signals were observed.3

People who have type 2 diabetes are at an increased risk of cardiovascular disease and, despite recent advancements in treatment options, cardiovascular disease remains the leading cause of death for this population.4 Together with CARMELINA®, the placebo-controlled cardiovascular outcome trial, which demonstrated long-term cardiovascular safety in adults with type 2 diabetes at high risk for heart and kidney disease,5 CAROLINA® confirms linagliptin’s long-term overall safety profile in a broad range of adults with type 2 diabetes.

“Many guidelines recommend early use of a diabetes treatment with cardiovascular benefit,” said Waheed Jamal, MD, Corporate Vice President and Head of Cardiovascular & Metabolic Medicine, Boehringer Ingelheim. “When other therapies such as DPP-4 inhibitors are considered for people with type 2 diabetes, physicians need a treatment with an established long-term safety profile. With these results, CAROLINA® expands our understanding of the long-term cardiovascular safety of linagliptin, which now has one of the most comprehensive datasets on the cardiovascular safety of a DPP-4 inhibitor.”

“These data provide further confidence in the well-established safety and tolerability profile of linagliptin for the treatment of adults with type 2 diabetes,” added Jeff Emmick, MD, PhD, Vice President, Product Development, Lilly Diabetes. “Linagliptin is an important option for physicians considering a DPP-4 inhibitor for their patients with type 2 diabetes. Boehringer Ingelheim and Lilly look forward to sharing the full results later this year.”

The full results of CAROLINA® will be presented on 10 June at the American Diabetes Association’s 79th Scientific Sessions in San Francisco, United States.

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.1,2 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).2 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.1,2 These people reflect patients that doctors typically see in their daily clinical practice.6

CAROLINA® was led by an academic trial steering committee and Boehringer Ingelheim and Eli Lilly and Company. CAROLINA® is the first 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.3 Trajenta® has the lowest kidney excretion rate of all DPP-4 inhibitors.7,8,9,10

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.4 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.* † 11,12,13 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.1,2 CAROLINA® and the CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with type 2 diabetes at high vascular risk trial (CARMELINA®)5,14 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.5,14 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.5,14 The trial met its primary endpoint, with linagliptin demonstrating a similar cardiovascular safety profile compared to placebo when added to standard of care.5 CARMELINA® also included a key secondary composite endpoint,§ showing a similar kidney safety profile compared to placebo.5 The overall safety profile of linagliptin in CARMELINA® was consistent with previous data and no new safety signals were observed.3,5 CARMELINA® also showed a similar rate of hospitalisation for heart failure for linagliptin compared to placebo.5

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

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 each contributed to the alliance.

Boehringer Ingelheim

Improving the health and quality of life of patients 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.


* 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

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 2017, Boehringer Ingelheim achieved net sales of nearly 18.1 billion euros. R&D expenditure, exceeding three billion euros, corresponded to 17.0 per cent of net sales.

As a family-owned company, Boehringer Ingelheim plans in generations and focuses on long-term success, rather than short-term profit. 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.com 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.

Boehringer Ingelheim and Lilly’s CAROLINA® cardiovascular outcome trial for Trajenta® meets primary endpoint of non-inferiority compared to glimepiride.

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

REFERENCES

1 ClinicalTrials.Gov. CARdiovascular Outcome study of LINAgliptin versus Glimepiride in patients with Type 2 diabetes. Available at: https://clinicaltrials.gov/ct2/show/NCT01243424. Accessed: February 2019.

2 Marx N, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diabetes & Vascular Disease Research 2015;12(3):164-74.

3 European Medicines Agency. Trajenta® (linagliptin) tablets. EMA Summary of Product Characteristics. Last updated July 2018. Available at: https://www.ema.europa.eu/documents/product-information/trajenta-epar-product-information_en.pdf Accessed: February 2019.

4 World Heart Federation. Cardiovascular Disease Risk Factors. Available at: https://www.world-heart- federation.org/resources/risk-factors/. Accessed: February 2019.

5 Rosenstock J, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA® Randomized Clinical Trial. JAMA. 2018 Nov 9. doi: 10.1001/jama.2018.18269.

6 Boehringer Ingelheim and Eli Lilly and Company. Data on file.

7 European Medicines Agency. Onglyza® (saxagliptin) tablets. EMA Summary of Product Characteristics. Available from: https://www.ema.europa.eu/documents/product-information/onglyza-epar-product-information_en.pdf Last updated: July 2016. Accessed: February 2019.

8 European Medicines Agency. Vipidia® (alogliptin) tablets. EMA Summary of Product Characteristics. Available from: http://ec.europa.eu/health/documents/community-register/2015/20150115130399/anx_130399_en.pdf Last updated: January 2015. Accessed: February 2019.

9 European Medicines Agency. Januvia® (sitagliptin) tablets. EMA Summary of Product Characteristics. Available from: https://ec.europa.eu/health/documents/community-register/2018/20180516140764/anx_140764_en.pdf Last updated: August 2017. Accessed: February 2019.

10 European Medicines Agency. Galvus® (vildagliptin) tablets. EMA Summary of Product Characteristics. Available from: https://www.ema.europa.eu/documents/product-information/galvus-epar-product-information_en.pdf Last updated: June 2017. Accessed: February 2019.

11 Jardiance® (empagliflozin) tablets U.S. Prescribing Information. FDA. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s008lbl.pdf. Accessed February 2019.

12 Jardiance® (empagliflozin) Summary of Product Characteristics. EMA. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf. Accessed: February 2019.

13 Zinman B, et al. EMPA-REG OUTCOME® Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.

14 ClinicalTrials.Gov. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes ascular risk. Available at: https://clinicaltrials.gov/ct2/show/NCT01897532?term=NCT01897532&rank=1. Accessed: February 2019.

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