Cardiovascular and renal safety profile of linagliptin demonstrated in Asian adults with type 2 diabetes

Ingelheim, Germany, Mon, 06/29/2020 - 13:00

In a sub-analysis of the CAROLINA® cardiovascular outcome trial, linagliptin demonstrated no increased cardiovascular risk versus glimepiride in Asian adults with type 2 diabetes and high cardiovascular risk¹
In addition, a sub-analysis of the CARMELINA® cardiovascular outcome trial demonstrated a similar cardiovascular and renal safety profile for linagliptin versus placebo in Asian adults with type 2 diabetes and high cardiorenal risk²

Ingelheim, Germany, 29 June 2020 – Boehringer Ingelheim have announced the results of a sub-group analysis from the CAROLINA® cardiovascular outcome trial focusing on Asian adults with type 2 diabetes mellitus and elevated cardiovascular risk. The findings, published in Diabetology International, demonstrated that linagliptin did not increase cardiovascular risk in this population versus glimepiride,¹ and were in line with the results of the overall CAROLINA® study population.¹

The prevalence of type 2 diabetes mellitus has increased rapidly in recent years within Asia.³In 2019, the International Diabetes Federation estimated that over half (251 million) of the 463 million people globally with diabetes were in Southeast Asia and the Western Pacific.⁴ The prespecified CAROLINA® sub-group analysis comprised 933 adults from Asia, 15.5% of the overall 6,033 participants in the CAROLINA® study.¹

Amongst the Asian participants in the CAROLINA® study, treatment with linagliptin demonstrated a lower rate of hypoglycemia and lower risk for weight gain compared to treatment with glimepiride.¹Hypoglycemia of any severity occurred in 13.1% of Asian patients treated with linagliptin compared to 42.1% of those treated with glimepiride.¹Linagliptin showed modest weight reduction between the two treatment groups, with an average mean difference of –1.82 kg compared to glimepiride.¹

CAROLINA® and CARMELINA® make up the two cardiovascular outcome trials for linagliptin, providing one of the most comprehensive datasets on the long-term safety of a DPP-4-inhibitor.^5,6A sub-analysis of the CARMELINA® trial, published in Diabetology International in October 2019, demonstrated that linagliptin did not increase risk for cardiovascular or kidney events compared to placebo in Asian adults with type 2 diabetes at high risk for heart and/or kidney disease.² These results are consistent with findings in the overall CARMELINA® study population.²

“When the CARMELINA® and CAROLINA® trials were first published, they demonstrated linagliptin’s long-term safety profile across a broad range of patients with type 2 diabetes,” said Waheed Jamal, MD, Corporate Vice President and Head of CardioMetabolic Medicine, Boehringer Ingelheim. “These region-specific, sub-analyses will give clinicians confidence when choosing the most appropriate glucose-lowering treatment for their patients.”

These trials demonstrate the cardiovascular and renal safety profile of linagliptin in a broad range of Asian adults with type 2 diabetes.^1,2

About CAROLINA®
CAROLINA® (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) is a multi-national, randomized, 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.^5,7The 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).⁷It was designed to assess the effect of Trajenta® (linagliptin) (5 mg once daily) compared to the sulfonylurea 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.^5,7 These people reflect patients that doctors typically see in their daily clinical practice.⁸

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 CARMELINA®
CARMELINA® is a multi-national, randomized , 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.^6,9 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.^6,9 This population of people with high risk of cardiovascular and/or kidney disease reflects patients that doctors see in their daily practice.⁸ 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 proportion of patients with impaired kidney function.^10*

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

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.¹¹ Trajenta® has the lowest kidney excretion rate of all globally available DPP-4 inhibitors.^12–15

Linagliptin is developed and commercialized by the Boehringer Ingelheim and Eli Lilly and Company Alliance.

About our cardiovascular outcome trials
Cardiovascular outcome trials are highly clinically 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.¹⁶ 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.^{17–19†‡} 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.^17,18

CAROLINA® is one of two cardiovascular outcome trials with the DPP-4 inhibitor, linagliptin.^5,7 CAROLINA® and the CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with type 2 diabetes at high vascular risk trial (CARMELINA®)^6,9provide one of the most comprehensive datasets on the long-term safety of a DPP-4 inhibitor.

CARMELINA® is a multi-national, randomized, 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^.6,9 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.^6,9 The trial met its primary endpoint,^§ with linagliptin demonstrating a similar cardiovascular safety profile compared to placebo when added to standard of care.⁹CARMELINA® also included a key secondary composite endpoint,^** showing a similar kidney safety profile compared to placebo.⁹ The overall safety profile of linagliptin in CARMELINA® was consistent with previous data and no new safety signals were observed.⁹ CARMELINA® also showed a similar rate of hospitalization for heart failure for linagliptin compared to placebo.⁹

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

About Boehringer Ingelheim
Making new and better medicines for humans and animals is at the heart of what we do. Our mission is to create breakthrough therapies that change lives. Since its founding in 1885, Boehringer Ingelheim is independent and family-owned. We have the freedom to pursue our long-term vision, looking ahead to identify the health challenges of the future and targeting those areas of need where we can do the most good.

As a world-leading, research-driven pharmaceutical company, more than 51,000 employees create value through innovation daily for our three business areas: Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. In 2019, Boehringer Ingelheim achieved net sales of 19 billion euros. Our significant investment of almost 3.5 billion euros in R&D drives innovation, enabling the next generation of medicines that save lives and improve quality of life.

We realize more scientific opportunities by embracing the power of partnership and diversity of experts across the life-science community. By working together, we accelerate the delivery of the next medical breakthrough that will transform the lives of patients now, and in generations to come.

More information about Boehringer Ingelheim can be found at www.boehringer-ingelheim.com or in our annual report: https://annualreport.boehringer-ingelheim.com.

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.

Footnotes

* Glomerular filtration rate below 60 mL/min/1.73m²
† 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

References

1. Kadowaki T, Wang G, Rosenstock J, et al. Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial. Diabetol Int. 2020. doi.org/10.1007/s13340-020-00447-5.

2. Inagaki N, Yang W, Watada H, et al. Linagliptin and cardiorenal outcomes in Asians with type 2 diabetes mellitus and established cardiovascular and/or kidney disease: subgroup analysis of the randomized CARMELINA® trial. Diabetol Int. 2019. doi:10.1007/s13340-019-00412-x.

3. Nanditha A, Ma RC, Ramachandran A, et al. Diabetes in Asia and the Pacific: implications for the global epidemic. Diabetes Care. 2016;39(3):472–85.

4. International Diabetes Federation. IDF Diabetes Atlas. 9th ed. Brussels, Belgium: International Diabetes Federation; 2019. https://www.diabetesatlas.org/en/resources/. Accessed: June 2020.

5. ClinicalTrials.Gov. CAROLINA: Cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. Available at: https://clinicaltrials.gov/ct2/show/NCT01243424. Accessed: June 2020.

6. ClinicalTrials.Gov. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus (CARMELINA). Available at: https://clinicaltrials.gov/ct2/show/NCT01897532?term=NCT01897532&rank=1. Accessed: June 2020.

7. Rosenstock J, Kahn SE, Johansen OE, et al. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA. 2019;322(12):1155–66.

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

9. Rosenstock J, Perkovic V, Johansen O, 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.

10. Rosenstock J, Perkovic V, Alexander JH, 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.

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13. European Medicines Agency. Vipidia® (alogliptin) tablets. EMA Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/WC500152271.pdf. Last updated: December 2018. Accessed: June 2020.

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19. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–28.