Explore. Safety Profile

 

Explore. Safety Profile.

Linagliptin (Trajenta®) Safety Overview

Safety Profile
Overview

This infographic is a comprehensive interactive application that allows you to explore the extensive cardiovascular and renal safety data of Linagliptin (Trajenta®) across a broad range of patients with type 2 diabetes*1.

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* Indicated for use in adult T2D patients. Linagliptin (Trajenta®) is contraindicated in those with hypersensitivity to any of the active substances or excipients, is not licensed for paediatric use and should not be used in pregnant women.

  1. Linagliptin (TRAJENTA®) PH Prescribing Information. April 2019.
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Footnotes

* Indicated for use in adult T2D patients. Linagliptin (Trajenta®) is contraindicated in those with hypersensitivity to any of the active substances or excipients, is not licensed for paediatric use and should not be used in pregnant women.

  1. Linagliptin (TRAJENTA®) PH Prescribing Information. April 2019.

Unique CVOT Program1-4

Linagliptin (Trajenta®) has an impressive CVOT program (CARMELINA and CAROLINA), which demonstrated the long-term CV and kidney safety profile of Linagliptin (Trajenta®) in more than 13,000 T2D patients*. In fact, Linagliptin (Trajenta®) is backed by a unique and robust CVOT program, which included patients with relatively early T2D as well as more severe patients at high risk for CV and/or kidney disease*.

References Open Icon References Close Icon Watch CVOT video

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities. CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  4. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities. CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  4. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.

Over 13,000 T2D patients in 2 CVOTs*1,4

CARMELINA CAROLINA

CARMELINA1-2

CARMELINA was a 2+ year study in nearly 7,000 T2D patients with established CV and/or kidney disease*1-2. To learn more about the key outcomes for CARMELINA, click on the icons below.

References Open Icon References Close Icon Heart icon Kidney Icon HHF Icon Watch CARMELINA video
Heart Icon Kidney Icon HHF Icon

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR: 1.02 (95% CI, 0.89, 1.17)). Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74).

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: Death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR: 1.04 (95% CI, 0.89, 1.22) p=0.62). Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR: 0.90 (95% CI, 0.74, 1.08) p=0.26). HR based on Cox regression analyses in patients treated with at least one dose of study drug. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Scirica B, et al. N Engl J Med. 2013;369:1317-26.
  4. White W, et al. N Engl J Med. 2013;369:1327-35.
  5. Nesina® US Prescribing Information. June 2019.
  6. Green J, et al. N Engl J Med. 2015;373:232-42.
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR: 1.02 (95% CI, 0.89, 1.17)). Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74).

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: Death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR: 1.04 (95% CI, 0.89, 1.22) p=0.62). Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR: 0.90 (95% CI, 0.74, 1.08) p=0.26). HR based on Cox regression analyses in patients treated with at least one dose of study drug. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Scirica B, et al. N Engl J Med. 2013;369:1317-26.
  4. White W, et al. N Engl J Med. 2013;369:1327-35.
  5. Nesina® US Prescribing Information. June 2019.
  6. Green J, et al. N Engl J Med. 2015;373:232-42.
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CARMELINA1-2

Heart Icon

Primary Endpoint:
3P-MACE†

CARMELINA Primary Endpoint

Linagliptin (Trajenta®) did not increase the risk of CV events vs. placebo.

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR: 1.02 (95% CI, 0.89, 1.17)). Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74).

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
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CARMELINA1-2

Kidney Icon

Key Seconday Endpoint:
Kidney Outcome‡

CARMELINA Secondary Endpoint

Linagliptin (Trajenta®) did not increase the risk of kidney events vs. placebo.

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: Death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR: 1.04 (95% CI, 0.89, 1.22) p=0.62). Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
Close modal

CARMELINA1-2

Kidney Icon

Exploraty
Endpoint: HHF§

CARMELINA HHF Endpoint

Linagliptin (Trajenta®) was not associated with increased risk of HHF vs. placebo.

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR: 0.90 (95% CI, 0.74, 1.08) p=0.26). HR based on Cox regression analyses in patients treated with at least one dose of study drug. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Scirica B, et al. N Engl J Med. 2013;369:1317-26.
  4. White W, et al. N Engl J Med. 2013;369:1327-35.
  5. Nesina® US Prescribing Information. June 2019.
  6. Green J, et al. N Engl J Med. 2015;373:232-42.

CAROLINA1-2

CAROLINA was a 6+ year study in more than 6,000 patients with relatively early T2D*1-2. With CAROLINA, Linagliptin (Trajenta®) is the only DPP4i with a CVOT that includes an active comparator. Furthermore, Linagliptin (Trajenta®) is the only DPP4i with more than one CVOT. To learn more about the key outcomes for CAROLINA, click on the icons below.

References Open Icon References Close Icon Heart Icon Hypoglycaemia Icon Weight Icon Watch CAROLINA Video
Heart Icon Hypoglycaemia Icon Weight Icon

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipidlowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). Overall median observation time and treatment duration were 6.3 and 5.9 years, respectively, in the linagliptin and glimepiride groups. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by a confirmatory superiority test (not statistically significant; p = 0.76).

‡ Percentage of patients experiencing a hypoglycaemic event was 10.6% for linagliptin and 37.7% for glimepiride (HR 0.23 (95% CI, 0.21, 0.26) p<0.001). Kaplan-Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

§ Based on MMRM including treatment, week repeated within patients, week by treatment interaction, continuous baseline weight and baseline weight by week interaction. Weighted mean between-group difference of - 1.54 kg (95% CI -1.80, -1.28) for Linagliptin (Trajenta®) vs. placebo. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
References Close Icon

Footnotes

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipidlowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). Overall median observation time and treatment duration were 6.3 and 5.9 years, respectively, in the linagliptin and glimepiride groups. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by a confirmatory superiority test (not statistically significant; p = 0.76).

‡ Percentage of patients experiencing a hypoglycaemic event was 10.6% for linagliptin and 37.7% for glimepiride (HR 0.23 (95% CI, 0.21, 0.26) p<0.001). Kaplan-Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

§ Based on MMRM including treatment, week repeated within patients, week by treatment interaction, continuous baseline weight and baseline weight by week interaction. Weighted mean between-group difference of - 1.54 kg (95% CI -1.80, -1.28) for Linagliptin (Trajenta®) vs. placebo. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
Close modal

CAROLINA1-2

Heart Icon

Primary Endpoint:
3P-MACE†

CAROLINA Primary Endpoint

Linagliptin (Trajenta®) did not increase the risk of CV events vs. glimepiride.

References Open Icon
References Close Icon

Footnotes

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). Overall median observation time and treatment duration were 6.3 and 5.9 years, respectively, in the linagliptin and glimepiride groups. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by a confirmatory superiority test (not statistically significant; p = 0.76).

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
Close modal

CAROLINA1-2

Hypoglycaemia Icon

Exploratory Endpoint:
Hypoglycaemia‡

CAROLINA Hypoglycaemia Endpoint

A lower risk of hypoglycaemia for patients on Linagliptin (Trajenta®) compared to glimepiride.

References Open Icon
References Close Icon

Footnotes

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

‡ Percentage of patients experiencing a hypoglycaemic event was 10.6% for linagliptin and 37.7% for glimepiride (HR 0.23 (95% CI, 0.21, 0.26) p<0.001). Kaplan-Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
Close modal

CAROLINA1-2

Weight Icon

Exploratory Endpoint:
Weight Gain§

CAROLINA Weight Gain Endpoint

A modestly lower body weight for patients on Linagliptin (Trajenta®) compared to glimepiride.

References Open Icon
References Close Icon

Footnotes

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

§ Based on MMRM including treatment, week repeated within patients, week by treatment interaction, continuous baseline weight and baseline weight by week interaction. Weighted mean between-group difference of -1.54 kg (95% CI -1.80, -1.28) for Linagliptin (Trajenta®) vs. placebo. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
CAROLINA Patients
Elderly Subgroup Analyses

Elderly Subgroup Analyses

The long-term CV and kidney safety profile of Linagliptin (Trajenta®) has been comprehensively assessed via CARMELINA and CAROLINA subgroup analyses in 2,000+ patients aged 75 and older1,2. These two subgroup analyses were consistent with the results of CARMELINA and CAROLINA, independent of age. To learn more about the key outcomes for each subgroup analysis, click on the icons below.

References Open Icon References Close Icon CARMELINA Button CAROLINA Button
CARMELINA Button CAROLINA Button
  1. Cooper M, et al. Diabetes Obes Metab. 2020; 1–12.
  2. Espeland MA, et al. Diab Obes Met 2020. doi: 10.1111/dom.14254.
References Close Icon

Footnotes

  1. Cooper M, et al. Diabetes Obes Metab. 2020; 1–12.
  2. Espeland MA, et al. Diab Obes Met 2020. doi: 10.1111/dom.14254.
Close modal

CARMELINA1-2

 
 
CARMELINA Elderly Data

The subgroup analysis was consistent with the results of CARMELINA,* independent of age.

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR: 1.02 (95% CI, 0.89, 1.17)). HR for time to 3P-MACE based on Cox regression analyses in patients treated with at least 1 dose of study drug (for < 65 years, HR: 1.11 (95% CI, 0.89, 1.40), for 65 to < 75 years, HR: 1.09 (95% CI, 0.89, 1.33), for 75 years, HR: 0.76 (95% CI, 0.57, 1.02)). P value for treatment by age subgroup interaction = 0.0937. Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74).

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: Death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR: 1.04 (95% CI, 0.89, 1.22) p=0.62). HR for time to secondary kidney endpoint based on Cox regression analyses in patients treated with at least one dose of study drug (for < 65 years, HR: 1.05 (95% CI, 0.85, 1.29), for 65 to < 75 years, HR: 1.06 (95% CI, 0.81, 1.38), for ≥ 75 years, HR: 1.06 (95% CI, 0.64, 1.75)). P value for treatment by age subgroup interaction = 0.9968. Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR: 0.90 (95% CI, 0.74, 1.08) p=0.26). HR based on Cox regression analyses in patients treated with at least one dose of study drug (for < 65 years, HR: 0.87 (95% CI, 0.63, 1.21), for 65 to < 75 years, HR: 0.89 (95% CI, 0.67, 1.18), for ≥ 75 years, HR: 0.92 (95% CI, 0.63, 1.35)). P value for treatment by age subgroup interaction = 0.9788. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Cooper M, et al. Diabetes Obes Metab. 2020; 1–12.
Close modal

CAROLINA1-2

 
 
CAROLINA Elderly Data

The subgroup analysis was consistent with the results of CAROLINA,* independent of age.

References Open Icon
References Close Icon

Footnotes

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). The HRs for 3P-MACE for linagliptin compared with glimepiride were 1.11 [95% CI 0.88,1.41] for patients aged <65 years, 0.88 [0.69,1.12] for those aged 65 to <75 years, and 0.99 [0.74,1.31] for those aged ≥75 years. P value for treatment by age subgroup interaction = 0.3949. Overall median observation time and treatment duration were 6.3 and 5.9 years, respectively, in the linagliptin and glimepiride groups. Median observation times across age groups were very similar, while median treatment time declined slightly with age (6.1, 5.8, and 5.5 years in participants aged <65, 65 to <75 and ≥75 years, respectively). A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by a confirmatory superiority test (not statistically significant; p = 0.76).

‡ The CAROLINA key secondary endpoint was a composite endpoint of treatment sustainability: the proportion of participants with HbA1c ≤ 7.0% at the final visit without glycaemic rescue medication, without any episodes of moderate or severe hypoglycaemia and without >2% weight gain between the end of titration and final visit. The key secondary endpoint occurred in 16.0% and 10.2% of patients in the linagliptin and glimepiride groups, respectively (OR 1.68; 95% CI, 1.43, 1.96). For patients < 65 years, the key secondary endpoint occurred in 14.0% and 8.6% of patients in the linagliptin and glimepiride groups, respectively (OR 1.73; 95% CI, 1.37, 2.18); for patients ≥ 65 to < 75 years, the key secondary endpoint occurred in 18.5% and 11.7% of patients in the linagliptin and glimepiride groups, respectively (OR 1.71; 95% CI, 1.34, 2.18); for patients ≥ 75 years, the key secondary endpoint occurred in 17.1% and 11.9% of patients in the linagliptin and glimepiride groups, respectively (OR 1.52; 95% CI, 1.03, 2.24); P value for treatment by age subgroup interaction = 0.8446. Because the confirmatory test for superiority of the primary outcome, 3PMACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015;12:164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
  3. Espeland MA, et al. Diab Obes Met 2020. doi: 10.1111/dom.14254.

Asian Subgroup Analyses

The long-term CV and kidney safety profile of Linagliptin (Trajenta®) has been comprehensively assessed via CARMELINA and CAROLINA subgroup analyses in 1,700 Asian patients1,2. These two subgroup analyses were consistent with the results of CARMELINA and CAROLINA. To learn more about the key outcomes for each subgroup analysis, click on the icons below.

References Open Icon References Close Icon CARMELINA Button CAROLINA Button
Carousel Asian Carmelina Carousel Asian Carolina
  1. Inagaki N, et al. Diabetol Int. 2019 Oct 22; 11(2):129-141.
  2. Kadowaki, T, et al. Diabetol Int. 2020. doi.org/10.1007/s13340-020-00447-5.
References Close Icon

Footnotes

  1. Inagaki N, et al. Diabetol Int. 2019 Oct 22; 11(2):129-141.
  2. Kadowaki, T, et al. Diabetol Int. 2020. doi.org/10.1007/s13340-020-00447-5.
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CARMELINA1-2

 
 
CARMELINA Asian Data

The subgroup analysis was consistent with the results of CARMELINA.*

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR 1.02; 95% CI 0.89, 1.17). HR for time to 3P-MACE based on Cox regression analyses in patients treated with at least 1 dose of study drug. Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74). In Asian patients, the primary endpoint occurred in 29/272 (10.7%) and 33/283 (11.7%) patients in the linagliptin and placebo groups (HR 0.90; 95% CI 0.55, 1.48). P value for treatment by region interaction = 0.3349.

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR 1.04; 95% CI, 0.89, 1.22; p=0.62). HR for time to secondary kidney endpoint based on Cox regression analyses in patients treated with at least one dose of study drug. Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo. In Asian patients, the key secondary endpoint occurred in 29/272 (10.7%) and 31/283 (11.0%) patients in the linagliptin and placebo groups, respectively (HR 0.96; 95% CI 0.58, 1.59). P value for treatment by region interaction = 0.8215.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR 0.90; 95% CI 0.74, 1.08; p=0.26); in Asian patients, HHF occurred in 12/272 (4.4%) and 23/283 (8.1%) patients in the linagliptin and placebo groups, respectively (HR 0.47; 95% CI 0.24, 0.95). HR based on Cox regression analyses in patients treated with at least one dose of study drug. P value for treatment by region interaction = 0.0368. The treatment by region interaction test suggested a difference in the treatment effect among regions; however, consistent with the overall population, there was no increase in the risk of HHF with linagliptin versus placebo in Asian patients. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Inagaki N, et al. Diabetol Int. 2019 Oct 22;11(2):129-141.
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CAROLINA1-2

 
 
CAROLINA Asian Data

The subgroup analysis was consistent with the results of CAROLINA.*

References Open Icon
References Close Icon

Footnotes

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.76). In Asian patients, the primary endpoint occurred in 44/465 (9.5%) and 52/468 (11.1%) patients in the linagliptin and glimepiride groups, respectively (HR 0.85; 95% CI 0.57, 1.26). P value for treatment by region interaction = 0.1686.

‡ The CAROLINA key secondary endpoint was a composite endpoint of treatment sustainability: the proportion of participants with HbA1c ≤ 7.0% at the final visit without glycaemic rescue medication, without any episodes of moderate or severe hypoglycaemia and without >2% weight gain between the end of titration and final visit. The key secondary endpoint occurred in 16.0% and 10.2% of patients in the linagliptin and glimepiride groups, respectively (OR 1.68; 95% CI, 1.43, 1.96). In Asian patients, the key secondary endpoint occurred in 21.3% and 11.1% of patients in the linagliptin and glimepiride groups, respectively (OR 2.16; 95% CI .50, 3.11).; P-value for treatment by region interaction: 0.1210. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory

  1. Marx N, et al. Diab Vasc Res. 2015;12:164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
  3. Kadowaki, T, et al. Diabetol Int. 2020. doi.org/10.1007/s13340-020-00447-5.
Asian Subgroup Analyses
Renal Subgroup Analysis

Renal Subgroup Analysis

A CARMELINA* subgroup analysis demonstrated that Linagliptin (Trajenta®) compared to placebo did not increase the risk of CV and kidney events, regardless of baseline kidney function1, †. Furthermore, there was a significant reduction in risk for albuminuria progression for patients taking Linagliptin (Trajenta®) compared to placebo‡. To learn more about the key outcomes for this subgroup analysis, click on the icons below.

Note that Linagliptin (Trajenta®) is not indicated for the reduction of albuminuria.

References Open Icon References Close Icon Heart Icon Kidney Icon
Heart Icon Kidney Icon

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. There were consistent neutral effects on the primary CV outcome 3P-MACE (HR 1.02 [95% CI, 0.89, 1.17], p=0.7398) as well as on further CV, or HF outcomes, across all renal subgroups comparing linagliptin with placebo. P-value for treatment by baseline eGFR subgroup interaction: 0.8439. The key kidney composite outcome of ≥ 40% reduction in eGFR, ESKD or renal death was not different between the two treatment groups (HR 1.04 [95% CI 0.89, 1.22], p=0.6164), including across all kidney function subgroups. P-value for treatment by baseline eGFR subgroup interaction: 0.3591.

‡ Albuminuria-burden was modestly reduced with linagliptin as evident by significant reductions in risk of progression to albuminuria; with consistent effects (P-value for treatment by baseline eGFR interaction: 0.35) across eGFR categories G ≥ 2 to G ≤ 4, by reduction in geometric mean changes in albuminuria from similar baseline (e.g., adjusted geometric mean at week 36 for linagliptin 130.36 mg/g vs 150.19 mg/g for placebo [gMean ratio 0.87 (0.81, 0.93)], and at week 84 for linagliptin 128.81 mg/g vs 145.76 mg/g for placebo [gMean ratio 0.88 (0.82, 0.95)]), and by reduced proportions of participants that had albuminuria progression, or increased proportions with albuminuria regression. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Perkovic V, et al. Diabetes Care 2020 May; dc200279. https://doi.org/10.2337/dc20-0279
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. There were consistent neutral effects on the primary CV outcome 3P-MACE (HR 1.02 [95% CI, 0.89, 1.17], p=0.7398) as well as on further CV, or HF outcomes, across all renal subgroups comparing linagliptin with placebo. P-value for treatment by baseline eGFR subgroup interaction: 0.8439. The key kidney composite outcome of ≥ 40% reduction in eGFR, ESKD or renal death was not different between the two treatment groups (HR 1.04 [95% CI 0.89, 1.22], p=0.6164), including across all kidney function subgroups. P-value for treatment by baseline eGFR subgroup interaction: 0.3591.

‡ Albuminuria-burden was modestly reduced with linagliptin as evident by significant reductions in risk of progression to albuminuria; with consistent effects (P-value for treatment by baseline eGFR interaction: 0.35) across eGFR categories G ≥ 2 to G ≤ 4, by reduction in geometric mean changes in albuminuria from similar baseline (e.g., adjusted geometric mean at week 36 for linagliptin 130.36 mg/g vs 150.19 mg/g for placebo [gMean ratio 0.87 (0.81, 0.93)], and at week 84 for linagliptin 128.81 mg/g vs 145.76 mg/g for placebo [gMean ratio 0.88 (0.82, 0.95)]), and by reduced proportions of participants that had albuminuria progression, or increased proportions with albuminuria regression. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Perkovic V, et al. Diabetes Care 2020 May; dc200279. https://doi.org/10.2337/dc20-0279
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CARMELINA1-2

Heart Icon

Primary Endpoint:
3P-MACE†

 
CARMELINA Renal Primary Endpoint

The subgroup analysis was consistent with the results of CARMELINA,* independent of baseline kidney function.

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. There were consistent neutral effects on the primary CV outcome 3P-MACE (HR 1.02 [95% CI, 0.89, 1.17], p=0.7398) as well as on further CV, or HF outcomes, across all renal subgroups comparing linagliptin with placebo. P-value for treatment by baseline eGFR subgroup interaction: 0.8439. The key kidney composite outcome of ≥ 40% reduction in eGFR, ESKD or renal death was not different between the groups (HR 1.04 [95% CI 0.89, 1.22], p=0.6164), including across all kidney function subgroups. P-value for treatment by baseline eGFR subgroup interaction: 0.3591.

  1. Perkovic V, et al. Diabetes Care 2020 May; dc200279. https://doi.org/10.2337/dc20-0279
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CARMELINA1-2

Kidney Icon

Exploratory
Endpoint: Albuminuria‡

 
CARMELINA Renal Albuminuria Endpoint

There was a significant reduction in risk for albuminuria progression for patients taking Linagliptin (Trajenta®) compared to placebo.

References Open Icon
References Close Icon

Footnotes

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

‡ Albuminuria-burden was modestly reduced with linagliptin as evident by significant reductions in risk of progression to albuminuria; with consistent effects (P-value for treatment by baseline eGFR subgroup interaction: 0.35) across eGFR categories G ≥ 2 to G ≤ 4, by reduction in geometric mean changes in albuminuria from similar baseline (e.g., adjusted geometric mean at week 36 for linagliptin 130.36 mg/g vs 150.19 mg/g for placebo [gMean ratio 0.87 (0.81, 0.93)], and at week 84 for linagliptin 128.81 mg/g vs 145.76 mg/g for placebo [gMean ratio 0.88 (0.82, 0.95)]), and by reduced proportions of participants that had albuminuria progression, or increased proportions with albuminuria regression. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Perkovic V, et al. Diabetes Care 2020 May; dc200279. https://doi.org/10.2337/dc20-0279
Simplicity means

Simplicity means…

Relying on a DPP4i backed by 2 CVOTs covering a broad range of T2D patients

When you decide to use a DPP4i to lower HbA1C, you should rely on one with a demonstrated CV and kidney safety profile. Linagliptin (Trajenta®) has a unique and robust CVOT program, allowing confidence when treating a broad range of T2D patients*1-4.

References Open Icon References Close Icon
  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  4. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
Close Modal

Footnotes

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  4. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.

Boehringer Ingelheim (Philippines), Inc.
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8741 Paseo de Roxas, Bel-Air,
Makati City, Metro Manila
Phone +(632) 8867-0880
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BI.SKIES.ph@boehringer-ingelheim.com

10 Years of Simplicity

RIN Number: PC-PH-103185
Production Date: January 2023

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Overview Safety Overview Icon CVOT
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CARMELINA1-2

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Heart Icon

Primary Endpoint:
3P-MACE†

Linagliptin (Trajenta®) did not increase the risk of CV events vs. placebo.

CARMELINA Primary Endpoint
References Open Icon References Close Icon

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR: 1.02 (95% CI, 0.89, 1.17)). Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74).

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.

CARMELINA1-2

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Kidney Icon

Key Secondary
Endpoint:
Kidney Outcome‡

Linagliptin (Trajenta®) did not increase the risk of kidney events vs. placebo

CARMELINA Secondary Endpoint
References Open Icon References Close Icon

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: Death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR: 1.04 (95% CI, 0.89, 1.22) p=0.62). Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.

CARMELINA1-2

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HHF Icon

Exploratory
Endpoint: HHF§

Linagliptin (Trajenta®) was not associated with increased risk of HHF vs. placebo

CARMELINA HHF Endpoint
References Open Icon References Close Icon

Direct comparison should be interpreted with caution due to differences in study design, populations and methodology.

* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR: 0.90 (95% CI, 0.74, 1.08) p=0.26). HR based on Cox regression analyses in patients treated with at least one dose of study drug. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Scirica B, et al. N Engl J Med. 2013;369:1317-26.
  4. White W, et al. N Engl J Med. 2013;369:1327-35.
  5. Nesina® US Prescribing Information. June 2019.
  6. Green J, et al. N Engl J Med. 2015;373:232-42.

CAROLINA1-2

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Heart Icon

Primary Endpoint:
3P-MACE†

Linagliptin (Trajenta®) did not increase the risk of CV events vs. glimepiride.

CAROLINA Primary Endpoint
References Open Icon References Close Icon

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). Overall median observation time and treatment duration were 6.3 and 5.9 years, respectively, in the linagliptin and glimepiride groups. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by a confirmatory superiority test (not statistically significant; p = 0.76).

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.

CAROLINA1-2

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Hypoglycaemia Icon

Exploratory
Endpoint:
Hypoglycaemia‡

A lower risk of hypoglycaemia for patients on Linagliptin (Trajenta®) compared to glimepiride.

CAROLINA Hypoglycaemia Endpoint
References Open Icon References Close Icon

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

‡ Percentage of patients experiencing a hypoglycaemic event was 10.6% for linagliptin and 37.7% for glimepiride (HR 0.23 (95% CI, 0.21, 0.26) p<0.001). Kaplan-Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.

CAROLINA1-2

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Weight Icon

Exploratory
Endpoint:
Weight Gain§

A modestly lower body weight for patients on Linagliptin (Trajenta®) compared to glimepiride.

CAROLINA Weight Gain Endpoint
References Open Icon References Close Icon

* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

§ Based on MMRM including treatment, week repeated within patients, week by treatment interaction, continuous baseline weight and baseline weight by week interaction. Weighted mean between-group difference of -1.54 kg (95% CI -1.80, -1.28) for Linagliptin (Trajenta®) vs. placebo. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015; 12: 164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.

CARMELINA1-3

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The subgroup analysis was consistent with the results of CARMELINA,* independent of age.

CARMELINA Elderly Data
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* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR: 1.02 (95% CI, 0.89, 1.17)). HR for time to 3P-MACE based on Cox regression analyses in patients treated with at least 1 dose of study drug (for < 65 years, HR: 1.11 (95% CI, 0.89, 1.40), for 65 to < 75 years, HR: 1.09 (95% CI, 0.89, 1.33), for 75 years, HR: 0.76 (95% CI, 0.57, 1.02)). P value for treatment by age subgroup interaction = 0.0937. Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74).

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: Death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR: 1.04 (95% CI, 0.89, 1.22) p=0.62). HR for time to secondary kidney endpoint based on Cox regression analyses in patients treated with at least one dose of study drug (for < 65 years, HR: 1.05 (95% CI, 0.85, 1.29), for 65 to < 75 years, HR: 1.06 (95% CI, 0.81, 1.38), for ≥ 75 years, HR: 1.06 (95% CI, 0.64, 1.75)). P value for treatment by age subgroup interaction = 0.9968. Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR: 0.90 (95% CI, 0.74, 1.08) p=0.26). HR based on Cox regression analyses in patients treated with at least one dose of study drug (for < 65 years, HR: 0.87 (95% CI, 0.63, 1.21), for 65 to < 75 years, HR: 0.89 (95% CI, 0.67, 1.18), for ≥ 75 years, HR: 0.92 (95% CI, 0.63, 1.35)). P value for treatment by age subgroup interaction = 0.9788. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Cooper M, et al. Diabetes Obes Metab. 2020; 1–12.

CAROLINA1-3

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The subgroup analysis was consistent with the results of CAROLINA,* independent of age.

CAROLINA Elderly Data
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* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). The HRs for 3P-MACE for linagliptin compared with glimepiride were 1.11 [95% CI 0.88,1.41] for patients aged <65 years, 0.88 [0.69,1.12] for those aged 65 to <75 years, and 0.99 [0.74,1.31] for those aged ≥75 years. P value for treatment by age subgroup interaction = 0.3949. Overall median observation time and treatment duration were 6.3 and 5.9 years, respectively, in the linagliptin and glimepiride groups. Median observation times across age groups were very similar, while median treatment time declined slightly with age (6.1, 5.8, and 5.5 years in participants aged <65, 65 to <75 and ≥75 years, respectively). A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by a confirmatory superiority test (not statistically significant; p = 0.76).

‡ The CAROLINA key secondary endpoint was a composite endpoint of treatment sustainability: the proportion of participants with HbA1c ≤ 7.0% at the final visit without glycaemic rescue medication, without any episodes of moderate or severe hypoglycaemia and without >2% weight gain between the end of titration and final visit. The key secondary endpoint occurred in 16.0% and 10.2% of patients in the linagliptin and glimepiride groups, respectively (OR 1.68; 95% CI, 1.43, 1.96). For patients < 65 years, the key secondary endpoint occurred in 14.0% and 8.6% of patients in the linagliptin and glimepiride groups, respectively (OR 1.73; 95% CI, 1.37, 2.18); for patients ≥ 65 to < 75 years, the key secondary endpoint occurred in 18.5% and 11.7% of patients in the linagliptin and glimepiride groups, respectively (OR 1.71; 95% CI, 1.34, 2.18); for patients ≥ 75 years, the key secondary endpoint occurred in 17.1% and 11.9% of patients in the linagliptin and glimepiride groups, respectively (OR 1.52; 95% CI, 1.03, 2.24); P value for treatment by age subgroup interaction = 0.8446. Because the confirmatory test for superiority of the primary outcome, 3PMACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory.

  1. Marx N, et al. Diab Vasc Res. 2015;12:164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
  3. Espeland MA, et al. Diab Obes Met 2020. doi: 10.1111/dom.14254.

CARMELINA1-3

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The subgroup analysis was consistent with the results of CARMELINA.*

CARMELINA Asian Data
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* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. The primary endpoint occurred in 434/3,494 (12.4%) and 420/3,485 (12.1%) patients in the linagliptin and placebo groups, respectively (HR 1.02; 95% CI 0.89, 1.17). HR for time to 3P-MACE based on Cox regression analyses in patients treated with at least 1 dose of study drug. Median observation time was 2.2 (IQR, 1.5-2.9) years for Linagliptin (Trajenta®) and 2.2 (IQR, 1.5-2.8) years for placebo. The primary aim was to establish noninferiority of linagliptin compared with placebo for time to 3P-MACE, defined by the upper limit of the 2-sided 95% CI for the HR of linagliptin relative to placebo being less than 1.3. A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.74). In Asian patients, the primary endpoint occurred in 29/272 (10.7%) and 33/283 (11.7%) patients in the linagliptin and placebo groups (HR 0.90; 95% CI 0.55, 1.48). P value for treatment by region interaction = 0.3349.

‡ The CARMELINA key secondary endpoint was time to first occurrence of any of the following components: death due to kidney disease, sustained ESRD or a sustained decrease of ≥40% in eGFR from baseline. The key secondary kidney endpoint occurred in 327/3,494 (9.4%) and 306/3,485 (8.8%) patients in the linagliptin and placebo groups, respectively (HR 1.04; 95% CI, 0.89, 1.22; p=0.62). HR for time to secondary kidney endpoint based on Cox regression analyses in patients treated with at least one dose of study drug. Median observation time was 1.9 (IQR, 1.2-2.6) years for Linagliptin (Trajenta®) and 1.7 (IQR, 1.2-2.5) years for placebo. In Asian patients, the key secondary endpoint occurred in 29/272 (10.7%) and 31/283 (11.0%) patients in the linagliptin and placebo groups, respectively (HR 0.96; 95% CI 0.58, 1.59). P value for treatment by region interaction = 0.8215.

§ HHF was an exploratory endpoint. HHF occurred in 209/3,494 (6.0%) vs 226/3,485 (6.5%) patients in the linagliptin and placebo groups, respectively (HR 0.90; 95% CI 0.74, 1.08; p=0.26); in Asian patients, HHF occurred in 12/272 (4.4%) and 23/283 (8.1%) patients in the linagliptin and placebo groups, respectively (HR 0.47; 95% CI 0.24, 0.95). HR based on Cox regression analyses in patients treated with at least one dose of study drug. P value for treatment by region interaction = 0.0368. The treatment by region interaction test suggested a difference in the treatment effect among regions; however, consistent with the overall population, there was no increase in the risk of HHF with linagliptin versus placebo in Asian patients. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Rosenstock J, et al. JAMA 2019; 321: 69-79.
  2. Rosenstock J, et al. Cardiovasc Diabetol 2018; 17:39.
  3. Inagaki N, et al. Diabetol Int. 2019 Oct 22;11(2):129-141.

CAROLINA1-3

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The subgroup analysis was consistent with the results of CAROLINA.*

CAROLINA Asian Data
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* CAROLINA® included 6,033 patients with HbA1c 6.5-8.5% and elevated CV risk; elevated CV risk was defined as i) documented atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease, or peripheral artery disease), ii) multiple CV risk factors (at least 2 of: T2D > 10 years, systolic BP > 140mmHg, smoking, LDL-cholesterol ≥135 mg/dL, or lipid-lowering treatment), iii) age ≥70 years, or iv) evidence of microvascular complications (impaired kidney function, urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy).

† The CAROLINA primary endpoint was defined as non-inferiority of Linagliptin (Trajenta®) vs glimepiride in time to first occurrence of CV death, non-fatal MI, or non-fatal stroke. The primary endpoint occurred in 356/3,023 (11.8%) and 362/3,010 (12.0%) patients in the linagliptin and glimepiride groups, respectively (HR 0.98; 95% CI 0.84, 1.14). A sequentially rejective multiple test procedure was applied, first testing the primary hypothesis of noninferiority for linagliptin (p<0.001), and, only if this first test was significant, followed by 2 parallel confirmatory superiority tests (not statistically significant; p = 0.76). In Asian patients, the primary endpoint occurred in 44/465 (9.5%) and 52/468 (11.1%) patients in the linagliptin and glimepiride groups, respectively (HR 0.85; 95% CI 0.57, 1.26). P value for treatment by region interaction = 0.1686.

‡ The CAROLINA key secondary endpoint was a composite endpoint of treatment sustainability: the proportion of participants with HbA1c ≤ 7.0% at the final visit without glycaemic rescue medication, without any episodes of moderate or severe hypoglycaemia and without >2% weight gain between the end of titration and final visit. The key secondary endpoint occurred in 16.0% and 10.2% of patients in the linagliptin and glimepiride groups, respectively (OR 1.68; 95% CI, 1.43, 1.96). In Asian patients, the key secondary endpoint occurred in 21.3% and 11.1% of patients in the linagliptin and glimepiride groups, respectively (OR 2.16; 95% CI .50, 3.11).; P-value for treatment by region interaction: 0.1210. Because the confirmatory test for superiority of the primary outcome, 3P-MACE, in the overall population was not significant (p=0.76 for superiority), all subsequent analyses are considered exploratory

  1. Marx N, et al. Diab Vasc Res. 2015;12:164-74.
  2. Rosenstock J, et al. JAMA. 2019; doi:10.1001/jama.2019.13772.
  3. Kadowaki, T, et al. Diabetol Int. 2020. doi.org/10.1007/s13340-020-00447-5.

CARMELINA1-3

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Primary Endpoint:
3P-MACE†

The subgroup analysis was consistent with the results of CARMELINA,* independent of baseline kidney function.

CARMELINA Renal Primary Endpoint
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* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

† The CARMELINA primary endpoint was time to first occurrence of any of the following components: CV death, death, non-fatal MI, non-fatal stroke. There were consistent neutral effects on the primary CV outcome 3P-MACE (HR 1.02 [95% CI, 0.89, 1.17], p=0.7398) as well as on further CV, or HF outcomes, across all renal subgroups comparing linagliptin with placebo. P-value for treatment by baseline eGFR subgroup interaction: 0.8439. The key kidney composite outcome of ≥ 40% reduction in eGFR, ESKD or renal death was not different between the groups (HR 1.04 [95% CI 0.89, 1.22], p=0.6164), including across all kidney function subgroups. P-value for treatment by baseline eGFR subgroup interaction: 0.3591.

  1. Perkovic V, et al. Diabetes Care 2020 May; dc200279. https://doi.org/10.2337/dc20-0279

CARMELINA1-3

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Exploratory
Endpoint:
Albuminuria‡

There was a significant reduction in risk for albuminuria progression for patients taking Linagliptin (Trajenta®) compared to placebo.

CARMELINA Renal Albuminuria Endpoint
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* CARMELINA included 6,979 patients with albuminuria & previous macrovascular disease, and/or impaired kidney function with or without CV comorbidities.

‡ Albuminuria-burden was modestly reduced with linagliptin as evident by significant reductions in risk of progression to albuminuria; with consistent effects (P-value for treatment by baseline eGFR subgroup interaction: 0.35) across eGFR categories G ≥ 2 to G ≤ 4, by reduction in geometric mean changes in albuminuria from similar baseline (e.g., adjusted geometric mean at week 36 for linagliptin 130.36 mg/g vs 150.19 mg/g for placebo [gMean ratio 0.87 (0.81, 0.93)], and at week 84 for linagliptin 128.81 mg/g vs 145.76 mg/g for placebo [gMean ratio 0.88 (0.82, 0.95)]), and by reduced proportions of participants that had albuminuria progression, or increased proportions with albuminuria regression. Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory.

  1. Perkovic V, et al. Diabetes Care 2020 May; dc200279. https://doi.org/10.2337/dc20-0279