BI Press Release

June 2019

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

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

  • 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 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.”



* 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.

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.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.

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. Rosenstock J, et al. CAROLINA®: Cardiovascular safety and renal microvascular outcome with linagliptin in patients with T2D at high vascular risk. Oral presentation at the 79th Scientific Sessions of the American Diabetes Association (ADA), Monday, 10 June 2019, 16:30-18:30, San Francisco, CA, USA.
2. European Medicines Agency. Trajenta® (linagliptin) tablets. EMA Summary of Product Characteristics. Updated August 2017. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002110/WC500115745.pdf. Accessed: June 2019.
3. ClinicalTrials.Gov. CARdiovascular Outcome study of LINAgliptin versus Glimepiride in patients with Type 2 diabetes. Available from: https://clinicaltrials.gov/ct2/show/NCT01243424. Accessed: June 2019.
4. Marx N, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015;12(3):164-74.
5. Boehringer Ingelheim and Eli Lilly and Company. Patients and clinical practice. Data on file.
6. European Medicines Agency. Onglyza® (saxagliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001039/WC500044316.pdf. Last updated: July 2016. Accessed: June 2019.
7. European Medicines Agency. Vipidia® (alogliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/WC500152271.pdf. Last updated: January 2015. Accessed: June 2019.
8. European Medicines Agency. Januvia® (sitagliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/WC500039054.pdf. Last updated: August 2017. Accessed: June 2019.
9. European Medicines Agency. Galvus® (vildagliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf. Last updated: June 2017. Accessed: June 2019.
10. World Heart Federation. Cardiovascular Disease Risk Factors. Available from: https://www.world-heart-federation.org/resources/risk-factors/. Accessed: June 2019.
11. Jardiance® (empagliflozin) tablets U.S. Prescribing Information. FDA. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s008lbl.pdf. Accessed: June 2019.
12. Jardiance® (empagliflozin) EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf. Accessed: June 2019.
13. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28.
14. 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. 2019;321(1):69-79.
15. ClinicalTrials.Gov. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. Available from: https://clinicaltrials.gov/ct2/show/NCT01897532?term=NCT01897532&rank=1. Accessed: June 2019.
February 2019

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

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

  • 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.

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.

October 2018

Boehringer Ingelheim and Lilly present full results of Trajenta®’s CARMELINA® cardiovascular outcome trial.

Boehringer Ingelheim and Lilly present full results of Trajenta®’s CARMELINA® cardiovascular outcome trial.

Boehringer Ingelheim and Lilly present full results of Trajenta®’s CARMELINA® cardiovascular outcome trial

  • Trajenta® demonstrated a similar long-term cardiovascular and kidney safety profile compared to placebo in adults with type 2 diabetes1
  • The results of CARMELINA® were presented at the 54th EASD Annual Meeting today

Ingelheim, Germany and Indianapolis, US, 4 October 2018 – Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) today presented the full results of the long-term cardiovascular outcome trial, CARMELINA®, which 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.1,2 The study met its primary endpoint,* with linagliptin demonstrating a similar cardiovascular safety profile compared to placebo when added to standard of care.1 CARMELINA® also included a key secondary composite endpoint,† showing a similar kidney safety profile compared to placebo.1

The overall safety profile of linagliptin in CARMELINA® was consistent with previous data and no new safety signals were observed.1 CARMELINA® also showed a similar rate of hospitalisation for heart failure for linagliptin compared to placebo.1

The full results were presented at the 54th European Association for the Study of Diabetes (EASD) Annual Meeting in Berlin, Germany.

“Heart disease is a major complication and the leading cause of death for people living with type 2 diabetes. CARMELINA® adds important new evidence for type 2 diabetes patients at high risk of heart and/or kidney disease, a population that has been underrepresented in other cardiovascular outcome trials, but whom we see in our daily practice. The trial confirmed that linagliptin can be used with confidence in this patient population,” commented Bernard Zinman, M.D., Professor in the Department of Medicine, University of Toronto and Senior Scientist at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.

In CARMELINA®, cardiovascular events that contributed to the primary endpoint* occurred in 12.4 percent (434 people) of the linagliptin group compared to 12.1 percent (420 people) in the placebo group, demonstrating a similar long-term cardiovascular safety profile in adults with type 2 diabetes.1 Linagliptin also showed a similar long-term kidney safety profile compared to placebo. This was demonstrated on the composite endpoint reflecting declining kidney function† occurring in 9.4 percent (327 people) of the linagliptin group compared to 8.8 percent (306 people) of the placebo group.1

An increase in the risk of hospitalisation for heart failure has been observed in some other cardiovascular outcome trials in diabetes.3,4 In CARMELINA®, this endpoint was pre-specified and assessed thoroughly via adjudication. Hospitalisation for heart failure occurred in 6 percent (209 people) of the linagliptin group compared to 6.5 percent (226) of the placebo group.1 “These results are particularly meaningful given the patient population in CARMELINA, including those most vulnerable to developing heart failure,” said Waheed Jamal, MD, Corporate Vice President and Head of CardioMetabolic Medicine, Boehringer Ingelheim.

* Primary endpoint defined as time to first occurrence of the 3-P 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 Assessed by an independent clinical event committee in a blinded way

“While many guidelines5,6 now recognise the importance of choosing a diabetes treatment with a proven benefit on reducing cardiovascular risk and mortality in people with type 2 diabetes and heart disease, there remains a need for additional glucose-lowering options,” Waheed Jamal pointed out. “CARMELINA® reinforces confidence in linagliptin as an effective and well-tolerated treatment, with a simple dosing regimen for adults with type 2 diabetes.”

“We have created a unique cardiovascular outcome trial programme for linagliptin with two trials — CARMELINA®, whose results are released today, as well as CAROLINA®, which will report initial results in the near future,” added Jeff Emmick, MD, PhD, Vice President, Product Development, Lilly Diabetes. “This programme will provide clinical data on the long-term safety profile of linagliptin in a broad range of adults with type 2 diabetes, which reflects patients that doctors see in their daily practice.7

About CARMELINA®
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.2,8 The study was designed to assess the effect of linagliptin (5mg once daily) compared to placebo (both added to standard of care) on cardiovascular outcomes in adults with type 2 diabetes and high cardiovascular risk, the majority of whom also had kidney disease.2,8 This population of people with high risk of cardiovascular and/or kidney disease reflects patients that doctors see in their daily practice.7 Standard of care included both glucose lowering agents and cardiovascular drugs (including antihypertensive and lipid lowering agents).

CARMELINA® was led by an academic trial steering committee and the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Compared to other recently reported outcome trials of dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes, CARMELINA® included the highest number of patients with impaired kidney function.§

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

§ Glomerular filtration rate below 30 mL/min/m2

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 adult patients with type 2 diabetes regardless of age, disease duration, ethnicity, body mass index (BMI), liver and kidney function.9 Trajenta® has the lowest kidney excretion rate of all DPP-4 inhibitors.9-13

About our cardiovascular outcome trials
As cardiovascular disease is a major complication and the leading cause of death in type 2 diabetes,14 cardiovascular safety of all type 2 diabetes treatments is important. Worldwide, most people with type 2 diabetes die of a cardiovascular event.15 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.16,17

CARMELINA® is one of two cardiovascular outcome trials with the DPP-4 inhibitor linagliptin. CAROLINA®,18 will be the first DPP-4 inhibitor cardiovascular outcome trial to compare commonly used second line treatments — linagliptin and the sulphonylurea glimepiride. This trial includes adults with relatively early type 2 diabetes and increased cardiovascular risk or established complications, with less than optimised blood sugar control. The majority did not yet have heart and kidney disease. The study will report initial results in the near future. CARMELINA® and CAROLINA® will provide clinical data on the long-term safety profile of linagliptin in a broad range of adults with type 2 diabetes, which reflects patients that doctors see in their daily practice.7

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.

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.

CONTACT:
Katharina Opitz
Product Communication
Boehringer Ingelheim
Email: press@boehringer-ingelheim.com
Phone: +49 (6132) 77 2012
Gregory Andrew Kueterman
Director of Communications
Lilly Diabetes and Lilly USA
Email: kueterman_gregory_andrew@lilly.com
Phone: +1 (317) 432-5195

REFERENCES
1. Rosenstock J, et al. Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®). Oral presentation at the 54thAnnual Meeting of the European Association for the Study of Diabetes (EASD), Thursday, 4 October 2018, 17:15 - 18:15, Langerhans Hall, Berlin Germany.
2. ClinicalTrials.Gov. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. Available from: https://clinicaltrials.gov/ct2/show/NCT01897532?term=NCT01897532&rank=1. Accessed: September 2018.
3. Green JB, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-42.
4. Scirica BM, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.
5. Piepoli MF, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315-81.
6. Introduction: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S1-S2.
7. Boehringer Ingelheim and Eli Lilly and Company. Data on file.
8. Rosenstock J, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018;17(1):39.
9. European Medicines Agency. Trajenta® (linagliptin) tablets. EMA Summary of Product Characteristics. Updated August 2017. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002110/WC500115745.pdf. Accessed: September 2018.
10. European Medicines Agency. Onglyza® (saxagliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001039/WC500044316.pdf. Last updated: July 2016. Accessed: September 2018.
11. European Medicines Agency. Vipidia® (alogliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/WC500152271.pdf. Last updated: Janaury 2015. Accessed: September 2018.
12. European Medicines Agency. Januvia® (sitagliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/WC500039054.pdf. Last updated: August 2017. Accessed: September 2018.
13. European Medicines Agency. Galvus® (vildagliptin) tablets. EMA Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf. Last updated: June 2017. Accessed: September 2018.
14. World Heart Federation. Cardiovascular Disease Risk Factors. Available from: https://www.world-heart-federation.org/resources/risk-factors/. Accessed: September 2018.
15. Morrish NJ, et al. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44 Suppl 2:S14-21.
16. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28.
17. Jardiance® (Full Prescribing Information). U.S.; Boehringer Ingelheim Pharmaceuticals, Inc; 2017.
18. ClinicalTrials.Gov. CARdiovascular Outcome study of LINAgliptin versus Glimepiride in patients with Type 2 diabetes. Available from: https://clinicaltrials.gov/ct2/show/NCT01243424. Accessed: September 2018.
July 2018

Boehringer Ingelheim and Lilly announce Trajenta®’s CARMELINA® cardiovascular outcome trial met its primary endpoint.

Boehringer Ingelheim and Lilly announce Trajenta®’s CARMELINA® cardiovascular outcome trial met its primary endpoint.

  • Trajenta® demonstrates long-term cardiovascular safety in adults with type 2 diabetes

Ingelheim, Germany and Indianapolis, US, 19 July, 2018 – CARMELINA® (CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with type 2 diabetes at high vascular risk) met its primary endpoint, defined as time to first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (3-point MACE), with Trajenta® (linagliptin) demonstrating similar cardiovascular safety compared to placebo. Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced today positive top-line results, which evaluated the impact of treatment with linagliptin vs. placebo on cardiovascular safety on top of standard of care.

The study included 6,979 adults with type 2 diabetes and high cardiovascular risk.1 The majority of patients also had kidney disease, an important risk factor for cardiovascular disease. The overall safety profile of linagliptin in CARMELINA®, including adults with kidney disease, was consistent with previous data and no new safety signal was observed.

People who have diabetes are at an increased risk of cardiovascular disease and chronic kidney disease.2,3 Despite recent advancements in treatment options, cardiovascular disease remains the leading cause of death for people living with diabetes,4 and about two thirds of chronic kidney disease cases are attributable to metabolic conditions, such as diabetes, obesity and hypertension.5,6,7

“CARMELINA® reinforces the long-term clinical safety profile of linagliptin in adults with type 2 diabetes, even in those most vulnerable for vascular complications,” said Waheed Jamal, MD, Corporate Vice President and Head of Cardiometabolic Medicine, Boehringer Ingelheim. “The trial adds important new evidence for patients at high risk for heart and kidney disease, a population that has previously been underrepresented in other cardiovascular outcome trials in diabetes.”

“Linagliptin demonstrated cardiovascular safety in adults with type 2 diabetes and high vascular risk, with no need for dose adjustments regardless of kidney function,” added Jeff Emmick, MD, PhD, Vice President, Product Development, Lilly Diabetes. “CARMELINA® provides confidence in linagliptin as an effective and well-tolerated treatment, with a simple dosing regimen, for adults with type 2 diabetes.”

The full results of CARMELINA® will be presented on 4 October at the 54th European Association for the Study of Diabetes Annual Meeting in Berlin, Germany.

About the Study
CARMELINA® (CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with type 2 diabetes at high vascular risk) is a multi-national, randomised, double-blind, placebocontrolled 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.1 The study was designed to assess the effect of Trajenta® (linagliptin) (5mg once daily) compared to placebo (both added to standard of care) on cardiovascular outcome in adults with type 2 diabetes and high cardiovascular risk, the majority of whom also had kidney disease. This population reflects patients that doctors see in their daily practice. CARMELINA® was led by an academic trial steering committee and the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Compared to other recently reported outcome trials of dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes, CARMELINA® included the highest number of patients with impaired kidney function.*

Standard of care included both glucose lowering agents and cardiovascular drugs (including antihypertensive and lipid lowering agents).

About Trajenta® (linagliptin)
Trajenta® is a one dose, once daily DPP-4-inihibitor that provides significant efficacy in the reduction of blood sugar levels for adults with type 2 diabetes. It can be prescribed for people with type 2 diabetes regardless of age, disease duration, ethnicity, body mass index (BMI), liver and kidney function.8
Trajenta® has the lowest kidney excretion rate of all DPP-4 inhibitors.8,9,10,11,12 It is prescribed at the same dose and has demonstrated proven efficacy regardless of kidney function,8,13,14 making it simple to administer and use.

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.15 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 demonstrated a 38% relative risk reduction in cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.†16,17

CARMELINA® is one of two cardiovascular outcome trials with the DPP-4 inhibitor linagliptin.
CAROLINA®,18 will be the first DPP-4 inhibitor cardiovascular outcome trial to compare commonly used second line treatments - linagliptin and the sulphonylurea glimepiride. This trial includes adults with type 2 diabetes at increased cardiovascular risk, however, the majority did not yet have heart and kidney disease. The study is expected to complete in 2018. CARMELINA® and CAROLINA® will provide the most comprehensive clinical database on the long-term safety profile of a DPP-4-inhibitor in a broad range of adults with type 2 diabetes.

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.

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 http://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 Jardiance 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 Jardiance 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.

* glomerular filtration rate below 30 mL/min/m2
Adult patients with type 2 diabetes and coronary artery disease, peripheral artery disease, or a history of myocardial infarction or stroke

CONTACT:
Katharina Opitz
Product Communication
Boehringer Ingelheim
Email: press@boehringer-ingelheim.com
Phone: +49 (6132) 77 2012
Grant Smith
Manager, Global Business Communications
Lilly Diabetes
Email: grant.smith@lilly.com
Phone: +1 (317) 954 9907

REFERENCES
1 CARMELINA®: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. Available at https://clinicaltrials.gov/ct2/show/NCT01897532?term=NCT01897532&rank=1. Accessed: July 2018
2 National Institute of Diabetes and Digestive Kidney Diseases. Diabetic Kidney Disease. (https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/diabetic-kidney-disease). Accessed: July 2018
3 World Heart Federation. Cardiovascular Disease Risk Factors. (https://www.world-heart-federation.org/resources/risk-factors/). Accessed: July 2018
4 National Diabetes Education Program. Snapshot of Diabetes. (http://www.nkfm.org/sites/default/files/documents/ndep_diabetes_snapshot.pdf). Accessed: July 2018 5 Levin A, et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 2017;390:1888-917
6 United States Renal Data System, USRDS 2012 Annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2012. Available at: http://www.usrds.org/reference.htm. Accessed: July 2018
7 Liyanage T, et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet 2015; 385(9981):1975-82
8 Trajenta® (linagliptin) tablets. EMA Summary of Product Characteristics. Updated August 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002110/WC500115745.pdf. Accessed: July 2018
9 Galvus® (vildagliptin) tablets. EMA Summary of Product Characteristics. Updated June 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf. Accessed: July 2018
10 Januvia® (sitagliptin) tablets. EMA Summary of Product Characteristics. Updated August 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/WC500039054.pdf. Accessed: July 2018
11 Vipidia® (alogliptin) tablets. EMA Summary of Product Characteristics. Updated January 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/WC500152271.pdf. Accessed: June 2018
12 Onglyza® (saxagliptin) tablets. EMA Summary of Product Characteristics. Updated July 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001039/WC500044316.pdf. Accessed: June 2018
13 Groop P, et al Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment. Diabetes Obes Metab. 2014;16(8):560-68
14 McGill J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care. 2013;36:237-244
15 Morrish NJ, et al. The WHO Multinational Study Group. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001;44:S14-S21
16 Jardiance® (Full Prescribing Information). U.S.; Boehringer Ingelheim Pharmaceuticals, Inc; 2017
17 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
18 CAROLINA®: Cardiovascular safety and renal microvascular outcome with linagliptin in patients with type 2 diabetes at high vascular risk. Available at: https://clinicaltrials.gov/ct2/show/NCT01243424?term=NCT01243424&rank=1. Accessed: July 2018