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CVOT Results

TRADJENTA was evaluated for CV safety in two separate CV outcome trials.

CVOT trials1-4

CARMELINA CVOT Program
CAROLINA CVOT Program

TRADJENTA was studied in CVOT trials, which included patients with established CVD and or multiple cardiovascular risk factors. Trials included a range of patient populations, including younger and older patients, and patients with normal and reduced kidney function.

CARMELINA

Randomized, double-blind, placebo-controlled, multicenter, noninferiority trial conducted at 605 clinical sites in 27 countries comparing the use of TRADJENTA administered once daily and placebo with usual care in patients with type 2 diabetes at high risk of CV and/or kidney events. A total of 6979 patients received TRADJENTA 5 mg (N=3494) or placebo (N=3485) and were followed for a median of 2.2 years. The primary endpoint was the reduction in risk of 3P-MACE, defined by the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke.1-2

CAROLINA

Multicenter, randomized, double-blind, active-controlled, noninferiority clinical trial of adults with type 2 diabetes conducted at more than 600 clinical sites in 43 countries comparing the use of TRADJENTA administered once daily and glimepiride with usual care in patients with early type 2 diabetes at increased CV risk. A total of 6033 patients received TRADJENTA 5 mg (N=3023) or glimepiride 1-4 mg (N=3010) and were followed for a median of 6.3 years. The primary endpoint was the reduction in risk of 3P-MACE events, defined by the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke.3-4

CARMELINA: Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of investigator-reported hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.

CAROLINA: Adverse events occurred in 2821 (93.6%) and 2855 (95.2%) patients in the linagliptin and glimepiride groups, respectively: 320 (10.6%) and 1132 (37.7%) had 1 or more episodes of investigator-reported hypoglycemia, and 15 (0.5%) and 16 (0.5%) events of adjudication-confirmed acute pancreatitis occurred (with 1 death [0.1%] from pancreatitis in the glimepiride arm).

Footnotes
  • * CARMELINA included 6,979 patients with high CV and renal risk. High CV risk was defined as a history of coronary artery disease, stroke or peripheral vascular disease, and microalbuminuria or macroalbuminuria, defined as urinary albumin:creatinine ratio (UACR) higher than 30 mg/g or equivalent; high renal risk was defined as (1) estimated glomerular filtration rate (eGFR) of 45 to 75 mL/min/1.73 m2 and UACR higher than 200 mg/g or equivalent or (2) eGFR of 15 to 45 mL/min/1.73 m2 regardless of UACR. The 3P-MACE primary outcome occurred in 434/3494 (12.4%) and 420/3485 (12.1%) patients in the TRADJENTA and placebo groups, respectively (HR=1.02 [95% Cl, 0.89-1.17]; P<0.001 for noninferiority).
  • † CAROLINA included 6,033 patients with A1C 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 3P-MACE primary outcome occurred in 356/3023 (11.8%) and 362/3010 (12.0%) patients in the TRADJENTA and glimepiride groups, respectively (HR=0.98 [95% CI, 0.84-1.14]; P<0.001 for noninferiority).
References
  1. Rosenstock J, Perkovic V, Johansen OE, et al; CARMELINA Investigators. 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.
  2. 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; 17:39.
  3. Marx N, Rosenstock J, Kahn SE, 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):164-174. doi: 10.1177/1479164115570301
  4. 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):1155-1166. doi:10.1001/jama.2019.13772

CARMELINA

Patients with established CV and/or kidney disease1-2

CARMELINA included nearly 7,000 T2D patients with established CV and/or kidney disease, and A1C levels from 6.5% up to 10%. In CARMELINA, TRADJENTA was non-inferior for 3P-MACE.

Demonstrated CV
Footnotes
  • * The primary endpoint was time to first occurrence of any of the following components: CV 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); p < 0.001 for non-inferiority; p = 0.74 for superiority).
  • † 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 TRADJENTA 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 3PMACE, 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 for the 3P-MACE and p = 0.62 for the composite kidney outcome).
References
  1. Rosenstock J, Perkovic V, Johansen OE, et al; CARMELINA Investigators. 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.
  2. 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; 17:39.
Demonstrated CV Non Inferiarity

CAROLINA

A second CV outcome trial1-2

CAROLINA is the only CVOT to assess CV safety (time to first occurrence of 3P-MACE) vs an active comparator. It included about 6,000 patients with T2D and one or more CV risks. In CAROLINA, TRADJENTA demonstrated long-term CV safety (11.8%) with non-inferiority vs. glimepiride (12%) for 3P-MACE.

Note: TRADJENTA is not indicated for the prevention of hypoglycaemic events nor for the prevention of weight gain.

Footnotes
  • * The CAROLINA primary endpoint was defined as non-inferiority of TRADJENTA 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); p < 0.001 for non-inferiority; p = 0.76 for superiority).
  • † P value for superiority. HR for time to 3P-MACE based on Cox regression analyses in patients treated with at least 1 dose of study drug.
References
  1. Marx N, Rosenstock J, Kahn SE, 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):164-174. doi: 10.1177/1479164115570301
  2. 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):1155-1166. doi:10.1001/jama.2019.13772
INDICATION AND LIMITATIONS OF USE

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA is not recommended in patients with type 1 diabetes mellitus.

TRADJENTA has not been studied in patients with a history of pancreatitis, and it is unknown if using TRADJENTA increases the risk of developing pancreatitis in these patients.

 

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS: Hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred.

WARNINGS AND PRECAUTIONS

Pancreatitis: Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking TRADJENTA. Take careful notice of potential signs and symptoms of pancreatitis and, if suspected, promptly discontinue and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRADJENTA.

Hypoglycemia: The use in combination with insulin or insulin secretagogues increases the risk of hypoglycemia. A lower dosage of insulin or insulin secretagogue may be required.

Hypersensitivity Reactions: Discontinue TRADJENTA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes mellitus. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA.

Severe and Disabling Arthralgia: Severe and disabling arthralgia has been reported in patients taking TRADJENTA. Consider TRADJENTA as a possible cause for severe joint pain and/or disabling arthralgia and discontinue, if appropriate.

Bullous Pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue TRADJENTA.

Heart Failure: Heart failure has been observed with two other members of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Consider the risks and benefits of TRADJENTA in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment. Monitor patients for signs and symptoms. Advise patients of the symptoms of heart failure and to immediately report such symptoms. If heart failure develops consider discontinuation of TRADJENTA.

MOST COMMON ADVERSE REACTIONS (≥5%): Nasopharyngitis, hypoglycemia (when used in combination with sulfonylurea).

DRUG INTERACTIONS: The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Alternative treatments should be used.

USE IN SPECIFIC POPULATIONS: Use during pregnancy only if clearly needed. Exercise caution when administering to a nursing woman.

CL-TJ-100060 06.16.2023

Please see Prescribing Information, including Medication Guide.