Tradjenta Drug Information
Generic name: LINAGLIPTIN
Dipeptidyl Peptidase 4 Inhibitor [EPC]
Uses of Tradjenta
TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using TRADJENTA.
Dosage & Administration of Tradjenta
Recommended Dosage and Administration
The recommended dosage of TRADJENTA is 5 mg taken orally once daily, with or without food.
Side Effects of Tradjenta
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes mellitus is based on 14 placebo-controlled trials, 1 active-controlled trial, and one trial in patients with severe renal impairment. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks.
The maximum follow-up was 78 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks' treatment duration); one with a sulfonylurea (18 weeks' treatment duration); one with metformin and sulfonylurea (24 weeks' treatment duration); one with pioglitazone (24 weeks' treatment duration); and one with insulin (primary endpoint at 24 weeks). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.
In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA.
The incidence of hypoglycemia increased when TRADJENTA was administered with sulfonylurea or insulin. Table 2 Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type 2 Diabetes Mellitus In an active-controlled (glimepiride) cardiovascular safety trial with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRADJENTA group (N=3,014) and 2.2% in glimepiride group (N=3,000). Use in Renal Impairment TRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min).
For the initial 12 weeks of the trial, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dosage adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials.
The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA-treated patients and 3 (4.6%) placebo-treated patients. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks' treatment compared to placebo.
Laboratory Test Abnormalities in Clinical Trials Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). Increase in Lipase: In a placebo-controlled clinical trial with TRADJENTA in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to a mean decrease of 2% in the placebo arm.
Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively. Increase in Amylase: In a cardiovascular safety trial comparing TRADJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively. The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis.
Vital Signs No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Acute pancreatitis, including fatal pancreatitis, mouth ulceration, stomatitis Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid, rash
| Adverse Reactions | TRADJENTA 5 mg (%) n = 3,625 | Placebo (%) n = 2,176 |
|---|---|---|
| Nasopharyngitis | 7.0 | 6.1 |
| Diarrhea | 3.3 | 3.0 |
| Cough | 2.1 | 1.4 |
| *Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. | ||
| Add-on to Sulfonylurea (18 Weeks) | Placebo (N=84) | TRADJENTA (N=161) |
| Hypoglycemia with plasma glucose <54 mg/dL (%) | 1.2 | 1.9 |
| Severe* hypoglycemia (%) | 0 | 0 |
| Add-on to Metformin and Sulfonylurea (24 Weeks) | Placebo (N=263) | TRADJENTA (N=792) |
| Hypoglycemia with plasma glucose <54 mg/dL (%) | 5.3 | 8.1 |
| Severe* hypoglycemia (%) | 0.8 | 0.6 |
| Add-on to Basal Insulin (52 Weeks) | Placebo (N=630) | TRADJENTA (N=631) |
| Hypoglycemia with plasma glucose <54 mg/dL (%) | 21.6 | 19.8 |
| Severe* hypoglycemia (%) | 1.1 | 1.7 |
Warnings & Cautions for Tradjenta
Pancreatitis
Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with TRADJENTA. Two patients treated with TRADJENTA in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with TRADJENTA.
Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA 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 with Concomitant Use with Insulin and Insulin Secretagogues Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRADJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia.
Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.
Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with TRADJENTA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with TRADJENTA, with some reports occurring after the first dose.
If a serious hypersensitivity reaction is suspected, discontinue TRADJENTA, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. 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 There have been postmarketing reports of severe and disabling arthralgia in patients taking TRADJENTA. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication.
A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider the drug as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous Pemphigoid
Bullous pemphigoid was reported in 7 (0.2%) patients treated with TRADJENTA compared to none in patients treated with placebo in the CARMELINA trial, and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor.
Tell patients to report development of blisters or erosions while receiving TRADJENTA. If bullous pemphigoid is suspected, TRADJENTA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Heart Failure
An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of TRADJENTA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy.
Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of TRADJENTA.
Drug Interactions with Tradjenta
Inducers of P-glycoprotein or CYP3A4 Enzymes
Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.
Insulin Secretagogues or Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when linagliptin is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Pregnancy Safety for Tradjenta
Pregnancy Risk Summary The limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure.
The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure.
No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
Pediatric Use of Tradjenta
Pediatric Use The safety and effectiveness of TRADJENTA have not been established in pediatric patients.
Contraindications for Tradjenta
TRADJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred.
Overdosage Information for Tradjenta
In the event of an overdose with TRADJENTA, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.
Clinical Studies of Tradjenta
Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus TRADJENTA has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone, and insulin. TRADJENTA has also been studied in patients with type 2 diabetes mellitus and severe chronic renal impairment. In patients with type 2 diabetes mellitus, treatment with TRADJENTA produced clinically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared with placebo.
In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent and underwent a diet, exercise, and drug washout period of about 6 weeks that included an open-label placebo run-in during the last 2 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week trial, only patients ineligible for metformin were recruited.
Patients who failed to meet specific glycemic goals during the 18-week trial received rescue therapy with pioglitazone and/or insulin; metformin rescue therapy was used in the 24-week trial. Treatment with TRADJENTA 5 mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). In the 18-week trial, 12% of patients receiving TRADJENTA 5 mg and 18% who received placebo required rescue therapy.
In the 24-week trial, 10.2% of patients receiving TRADJENTA 5 mg and 20.9% of patients receiving placebo required rescue therapy. The improvement in A1C compared with placebo was not affected by gender, age, race, prior antihyperglycemic therapy, baseline BMI, or a standard index of insulin resistance (HOMA-IR). As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in A1C with TRADJENTA appears to be related to the degree of A1C elevation at baseline.
Change from baseline in body weight did not differ significantly between the groups. Table 5 Glycemic Parameters in Placebo-Controlled Monotherapy Trials of TRADJENTA* Patients achieving A1C Add-on Combination Therapy with Metformin A total of 701 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of TRADJENTA in combination with metformin. Patients already on metformin (n = 491) at a dosage of at least 1,500 mg per day were randomized after completing a 2-week, open-label, placebo run-in period.
Patients on metformin and another antihyperglycemic agent (n = 207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dosage of at least 1,500 mg per day) in monotherapy. Patients were randomized to the addition of either TRADJENTA 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue.
In combination with metformin, TRADJENTA provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 6). Rescue glycemic therapy was used in 7.8% of patients treated with TRADJENTA 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
Table 6 Glycemic Parameters in Placebo-Controlled Trial for TRADJENTA in Combination with Metformin* Initial Combination Therapy with Metformin A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial trial designed to assess the efficacy of TRADJENTA as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks' duration. After the washout period and after completing a 2-week single-blind placebo run-in period, patients with inadequate glycemic control (A1C ≥7.0% to ≤10.5%) were randomized.
Patients with inadequate glycemic control (A1C ≥7.5% to <11.0%) not on antihyperglycemic agents at trial entry (48%) immediately entered the 2-week, single-blind, placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or one of 5 active-treatment arms.
Patients who failed to meet specific glycemic goals during the trial were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy. Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 7). Lipid effects were generally neutral.
No meaningful change in body weight was noted in any of the 6 treatment groups. Table 7 Glycemic Parameters at Final Visit (24-Week Trial) for Linagliptin and Metformin, Alone and in Combination in Randomized Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise* Patients achieving A1C Active-Controlled Trial vs Glimepiride in Combination with Metformin The efficacy of TRADJENTA was evaluated in a 104-week, double-blind, glimepiride-controlled, non-inferiority trial in patients with type 2 diabetes mellitus with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks' duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks' duration with metformin monotherapy (dosage of ≥1,500 mg/day) and washout of the other agent.
Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dosage of 1 mg/day and then electively titrated over the next 12 weeks to a maximum dosage of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dosage was to be kept constant, except for down-titration to prevent hypoglycemia.
These results were consistent with the completers analysis. Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p<0.0001 for both timepoints). Therapy was stopped in patients on oral antihyperglycemic therapy for a period of 6 weeks (4 weeks followed by a 2-week, open-label, placebo run-in period).
Drug-naïve patients entered directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to receive either TRADJENTA 5 mg or placebo, both in addition to pioglitazone 30 mg daily. Glycemic endpoints measured were A1C and FPG.
In initial combination with pioglitazone 30 mg, TRADJENTA 5 mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 9). Table 9 Glycemic Parameters in Placebo-Controlled Trial for TRADJENTA in Combination Therapy with Pioglitazone* Add-On Combination with Sulfonylureas A total of 245 patients with type 2 diabetes mellitus participated in an 18-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of TRADJENTA in combination with sulfonylurea (SU). Patients on sulfonylurea monotherapy (n = 142) were randomized after completing a 2-week, single-blind, placebo run-in period.
Patients on a sulfonylurea plus one additional oral antihyperglycemic agent (n = 103) were randomized after a wash-out period of 4 weeks and a 2-week, single-blind, placebo run-in period. Glycemic endpoints measured included A1C and FPG. In combination with a sulfonylurea, TRADJENTA provided statistically significant improvements in A1C compared with placebo following 18 weeks' treatment; the improvements in FPG observed with TRADJENTA were not statistically significant compared with placebo (Table 10).
Rescue therapy was used in 7.6% of patients treated with TRADJENTA 5 mg and 15.9% of patients treated with placebo. There was no significant difference between TRADJENTA and placebo in body weight. Table 10 Glycemic Parameters in Placebo-Controlled Trial for TRADJENTA in Combination with Sulfonylurea* Add-On Combination Therapy with Metformin and a Sulfonylurea A total of 1,058 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of TRADJENTA in combination with a sulfonylurea and metformin.
The most common sulfonylureas used by patients in the trial were: glimepiride (31%), glibenclamide (26%), and gliclazide (26%, not available in the United States). Patients on a sulfonylurea and metformin were randomized to receive TRADJENTA 5 mg or placebo, each administered once daily. In combination with a sulfonylurea and metformin, TRADJENTA provided statistically significant improvements in A1C and FPG compared with placebo (Table 11).
In the entire trial population (patients on TRADJENTA in combination with sulfonylurea and metformin), a mean reduction from baseline relative to placebo in A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with TRADJENTA 5 mg and in 13% of patients treated with placebo. Table 11 Glycemic Parameters in Placebo-Controlled Trial for TRADJENTA in Combination with Metformin and Sulfonylurea* Add-On Combination Therapy with Insulin A total of 1,261 patients with type 2 diabetes mellitus inadequately controlled on basal insulin alone or basal insulin in combination with oral drugs participated in a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy of TRADJENTA as add-on therapy to basal insulin over 24 weeks.
Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), renal function impairment status (based on baseline eGFR), and concomitant use of oral antidiabetic drugs (none, metformin only, pioglitazone only, metformin + pioglitazone). Patients entered a 2 week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or pioglitazone background therapy. Patients were maintained on a stable dosage of insulin prior to enrollment, during the run-in period, and during the first 24 weeks of treatment.
Patients who failed to meet specific glycemic goals during the double-blind treatment period were rescued by increasing background insulin dosage. TRADJENTA used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically significant improvements in A1C and FPG compared to placebo (Table 12) after 24 weeks of treatment. The mean total daily insulin dosage at baseline was 42 units for patients treated with TRADJENTA and 40 units for patients treated with placebo.
The mean change from baseline to Week 24 in the daily dosage of insulin was +1.3 IU in the placebo group and +0.6 IU in the TRADJENTA group. The mean change in body weight from baseline to Week 24 was similar in the two treatment groups. Table 12 Glycemic Parameters in Placebo-Controlled Trial for TRADJENTA in Combination with Insulin* The difference between treatment with linagliptin and placebo in terms of adjusted mean change from baseline in HbA1c after 24 weeks was comparable for patients with no renal impairment (eGFR ≥90 mL/min, n=539), with mild renal impairment (eGFR 60 to <90 mL/min, n= 565), or with moderate renal impairment (eGFR 30 to <60 mL/min, n=124).
Renal Impairment A total of 133 patients with type 2 diabetes mellitus participated in a 52 week, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TRADJENTA in patients with both type 2 diabetes mellitus and severe chronic renal impairment. Participants with an estimated (based on the four variables modified diet in renal disease equation) GFR value of <30 mL/min were eligible to participate in the trial. Randomization was stratified by baseline HbA1c (≤8% and >8%) and background antidiabetic therapy (insulin or any combination with insulin, SU or glinides as monotherapy and pioglitazone or any other antidiabetics excluding any other DPP-4 inhibitors).
For the initial 12 weeks of the trial, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dosage adjustments in antidiabetic background therapy were allowed. At baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes mellitus therapy, and 12.5% were receiving sulfonylurea alone.
With adjustments in antidiabetic background therapy after the initial 12 weeks, efficacy was maintained for 52 weeks, with an adjusted mean change from baseline in A1C of -0.7% compared to placebo (95% confidence interval -1.0, -0.4) based on analysis using LOCF.
Cardiovascular Safety Trials in Patients with Type 2 Diabetes Mellitus CARMELINA The cardiovascular risk of TRADJENTA was evaluated in CARMELINA, a multi-national, multi-center, placebo-controlled, double-blind, parallel group trial comparing TRADJENTA (N=3,494) to placebo (N=3,485) in adult patients with type 2 diabetes mellitus and a history of established macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events (MACE) between TRADJENTA and placebo when these were added to standard of care treatments for diabetes mellitus and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.
Patients were eligible to enter the trial if they were adults with type 2 diabetes mellitus, with HbA1c of 6.5% to 10%, and had either albuminuria and previous macrovascular disease (39% of enrolled population), or evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio (UACR) criteria (42% of enrolled population), or both (18% of enrolled population). Mean HbA1c was 8.0% and mean duration of type 2 diabetes mellitus was 15 years. The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.
The trial was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The results of CARMELINA, including the contribution of each component to the primary composite endpoint, are shown in Table 13. The estimated hazard ratio for MACE associated with TRADJENTA relative to placebo was 1.02 with a 95% confidence interval of.
The upper bound of this confidence interval, 1.17, excluded the risk margin of 1.3. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 1. Table 13 Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CARMELINA Trial 0.88 Figure 1 Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial Figure 1 CAROLINA The cardiovascular risk of TRADJENTA was evaluated in CAROLINA, a multi-center, multi-national, randomized, double-blind, parallel group trial comparing TRADJENTA (N=3,023) to glimepiride (N=3,010) in adult patients with type 2 diabetes mellitus and a history of established cardiovascular disease and/or multiple cardiovascular risk factors.
Patients were eligible to enter the trial if they were adults with type 2 diabetes mellitus with insufficient glycemic control (defined as HbA1c of depending on whether treatment-naïve, on monotherapy or on combination therapy), and were defined to be at high cardiovascular risk with previous vascular disease, evidence of vascular related end-organ damage, age ≥70 years, and/or two cardiovascular risk factors (duration of diabetes mellitus >10 years, systolic blood pressure >140 mmHg, current smoker, LDL cholesterol ≥135 mg/dL). The mean HbA1c was 7.15% and mean duration of type 2 diabetes mellitus was 7.6 years. The mean eGFR was 77 mL/min/1.73m 2.
Patients were taking at least one antidiabetic drug (91%) and the most common were metformin (83%) and sulfonylurea (28%). The results of CAROLINA, including the contribution of each component to the primary composite endpoint, are shown in Table 14.
| 18-Week Trial | 24-Week Trial | |||
|---|---|---|---|---|
| TRADJENTA 5 mg | Placebo | TRADJENTA 5 mg | Placebo | |
| *Full analysis population using last observation on trial | ||||
| *18-week trial: Placebo, n=68; TRADJENTA, n=136 24-week trial: Placebo, n=147; TRADJENTA, n=306 | ||||
| *18-week trial. HbA1c: ANCOVA model included treatment, reason for metformin intolerance and number of prior oral anti-diabetic medicine(s) (OADs) as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, reason for metformin intolerance and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. 24-week trial. HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate. | ||||
| A1C (%) | ||||
| Number of patients | n = 147 | n = 73 | n = 333 | n = 163 |
| Baseline (mean) | 8.1 | 8.1 | 8.0 | 8.0 |
| Change from baseline (adjusted mean*) | -0.4 | 0.1 | -0.4 | 0.3 |
| Difference from placebo (adjusted mean) (95% CI) | -0.6 (-0.9, -0.3) | -- | -0.7 (-0.9, -0.5) | -- |
| Patients [n (%)] achieving A1C <7% | 32 (23.5) | 8 (11.8) | 77 (25) | 17 (12) |
| FPG (mg/dL) | ||||
| Number of patients | n = 138 | n = 66 | n = 318 | n = 149 |
| Baseline (mean) | 178 | 176 | 164 | 166 |
| Change from baseline (adjusted mean*) | -13 | 7 | -9 | 15 |
| Difference from placebo (adjusted mean) (95% CI) | -21 (-31, -10) | -- | -23 (-30, -16) | -- |
| 2-hour PPG (mg/dL) | ||||
| Number of patients | Data not available | Data not available | n = 67 | n = 24 |
| Baseline (mean) | -- | -- | 258 | 244 |
| Change from baseline (adjusted mean*) | -- | -- | -34 | 25 |
| Difference from placebo (adjusted mean) (95% CI) | -- | -- | -58 (-82, -34) | -- |
| TRADJENTA 5 mg + Metformin | Placebo + Metformin | |
|---|---|---|
| *Full analysis population using last observation on trial | ||
| *TRADJENTA 5 mg + Metformin, n=485; Placebo + Metformin, n=163 | ||
| *HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate. | ||
| A1C (%) | ||
| Number of patients | n = 513 | n = 175 |
| Baseline (mean) | 8.1 | 8.0 |
| Change from baseline (adjusted mean*) | -0.5 | 0.15 |
| Difference from placebo + metformin (adjusted mean) (95% CI) | -0.6 (-0.8, -0.5) | -- |
| Patients [n (%)] achieving A1C <7% | 127 (26.2) | 15 (9.2) |
| FPG (mg/dL) | ||
| Number of patients | n = 495 | n = 159 |
| Baseline (mean) | 169 | 164 |
| Change from baseline (adjusted mean*) | -11 | 11 |
| Difference from placebo + metformin (adjusted mean) (95% CI) | -21 (-27, -15) | -- |
| 2-hour PPG (mg/dL) | ||
| Number of patients | n = 78 | n = 21 |
| Baseline (mean) | 270 | 274 |
| Change from baseline (adjusted mean*) | -49 | 18 |
| Difference from placebo + metformin (adjusted mean) (95% CI) | -67 (-95, -40) | -- |
| Placebo | TRADJENTA 5 mg Once Daily* | Metformin 500 mg Twice Daily | Linagliptin 2.5 mg Twice Daily* + Metformin 500 mg Twice Daily | Metformin 1,000 mg Twice Daily | Linagliptin 2.5 mg Twice Daily* + Metformin 1,000 mg Twice Daily | |
|---|---|---|---|---|---|---|
| *Total daily dosage of TRADJENTA is equal to 5 mg | ||||||
| *Full analysis population using last observation on trial | ||||||
| *Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice daily + Metformin 500 twice daily, n=136; Metformin 1,000 mg twice daily, n=137; Linagliptin 2.5 mg twice daily + Metformin 1,000 mg twice daily, n=138 | ||||||
| *HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. | ||||||
| A1C (%) | ||||||
| Number of patients | n = 65 | n = 135 | n = 141 | n = 137 | n = 138 | n = 140 |
| Baseline (mean) | 8.7 | 8.7 | 8.7 | 8.7 | 8.5 | 8.7 |
| Change from baseline (adjusted mean*) | 0.1 | -0.5 | -0.6 | -1.2 | -1.1 | -1.6 |
| Difference from placebo (adjusted mean) (95% CI) | -- | -0.6 (-0.9, -0.3) | -0.8 (-1.0, -0.5) | -1.3 (-1.6, -1.1) | -1.2 (-1.5, -0.9) | -1.7 (-2.0, -1.4) |
| Patients [n (%)] achieving A1C <7% | 7 (10.8) | 14 (10.4) | 26 (18.6) | 41 (30.1) | 42 (30.7) | 74 (53.6) |
| Patients (%) receiving rescue medication | 29.2 | 11.1 | 13.5 | 7.3 | 8.0 | 4.3 |
| FPG (mg/dL) | ||||||
| Number of patients | n = 61 | n = 134 | n = 136 | n = 135 | n = 132 | n = 136 |
| Baseline (mean) | 203 | 195 | 191 | 199 | 191 | 196 |
| Change from baseline (adjusted mean*) | 10 | -9 | -16 | -33 | -32 | -49 |
| Difference from placebo (adjusted mean) (95% CI) | -- | -19 (-31, -6) | -26 (-38, -14) | -43 (-56, -31) | -42 (-55, -30) | -60 (-72, -47) |
| Week 52 | Week 104 | |||
|---|---|---|---|---|
| TRADJENTA 5 mg + Metformin | Glimepiride + Metformin (mean Glimepiride dosage 3 mg) | TRADJENTA 5 mg + Metformin | Glimepiride + Metformin (mean Glimepiride dosage 3 mg) | |
| *p<0.0001 vs glimepiride; p=0.0012 vs glimepiride | ||||
| *Full analysis population using last observation on trial | ||||
| *Hypoglycemic incidence included both asymptomatic events (not accompanied by typical symptoms and plasma glucose concentration of ≤70 mg/dL) and symptomatic events with typical symptoms of hypoglycemia and plasma glucose concentration of ≤70 mg/dL. | ||||
| *HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. Hypoglycemia incidence (%): Cochran-Mantel-Haenszel test was performed on the patient population contained in the treated set, to compare the proportion of patients with hypoglycemic events between patients treated with linagliptin and patients treated with glimepiride. | ||||
| A1C (%) | ||||
| Number of patients | n = 764 | n = 755 | n = 764 | n = 755 |
| Baseline (mean) | 7.7 | 7.7 | 7.7 | 7.7 |
| Change from baseline (adjusted mean*) | -0.4 | -0.6 | -0.2 | -0.4 |
| Difference from glimepiride (adjusted mean) (97.5% CI) | 0.2 (0.1, 0.3) | -- | 0.2 (0.1, 0.3) | -- |
| FPG (mg/dL) | ||||
| Number of patients | n = 733 | n = 725 | n = 733 | n = 725 |
| Baseline (mean) | 164 | 166 | 164 | 166 |
| Change from baseline (adjusted mean*) | -8* | -15 | -2 | -9 |
| Hypoglycemia incidence (%) | ||||
| Number of patients | n = 776 | n = 775 | n = 776 | n = 775 |
| Incidence* | 5.3* | 31.1 | 7.5* | 36.1 |
| TRADJENTA 5 mg + Pioglitazone | Placebo + Pioglitazone | |
|---|---|---|
| *Full analysis population using last observation on trial | ||
| *HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. | ||
| A1C (%) | ||
| Number of patients | n = 252 | n = 128 |
| Baseline (mean) | 8.6 | 8.6 |
| Change from baseline (adjusted mean*) | -1.1 | -0.6 |
| Difference from placebo + pioglitazone (adjusted mean) (95% CI) | -0.5 (-0.7, -0.3) | -- |
| Patients [n (%)] achieving A1C <7% | 108 (42.9) | 39 (30.5) |
| FPG (mg/dL) | ||
| Number of patients | n = 243 | n = 122 |
| Baseline (mean) | 188 | 186 |
| Change from baseline (adjusted mean*) | -33 | -18 |
| Difference from placebo + pioglitazone (adjusted mean) (95% CI) | -14 (-21, -7) | -- |
| TRADJENTA 5 mg + SU | Placebo + SU | |
|---|---|---|
| SU = sulfonylurea | ||
| *Full analysis population using last observation on trial | ||
| *TRADJENTA 5 mg + SU, n=156; Placebo + SU, n=82 | ||
| *HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates | ||
| A1C (%) | ||
| Number of patients | n = 158 | n = 82 |
| Baseline (mean) | 8.6 | 8.6 |
| Change from baseline (adjusted mean*) | -0.5 | -0.1 |
| Difference from placebo + SU (adjusted mean) (95% CI) | -0.5 (-0.7, -0.2) | -- |
| Patients [n (%)] achieving A1C <7% | 23 (14.7) | 3 (3.7) |
| FPG (mg/dL) | ||
| Number of patients | n = 155 | n = 78 |
| Baseline (mean) | 180 | 171 |
| Change from baseline (adjusted mean*) | -8 | -2 |
| Difference from placebo + SU (adjusted mean) (95% CI) | -6 (-17, 4) | -- |
| TRADJENTA 5 mg + Metformin + SU | Placebo + Metformin + SU | |
|---|---|---|
| SU = sulfonylurea | ||
| *Full analysis population using last observation on trial | ||
| *TRADJENTA 5 mg + Metformin + SU, n=742; Placebo + Metformin + SU, n=247 | ||
| *HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. | ||
| A1C (%) | ||
| Number of patients | n = 778 | n = 262 |
| Baseline (mean) | 8.2 | 8.1 |
| Change from baseline (adjusted mean*) | -0.7 | -0.1 |
| Difference from placebo (adjusted mean) (95% CI) | -0.6 (-0.7, -0.5) | -- |
| Patients [n (%)] achieving A1C <7% | 217 (29.2) | 20 (8.1) |
| FPG (mg/dL) | ||
| Number of patients | n = 739 | n = 248 |
| Baseline (mean) | 159 | 163 |
| Change from baseline (adjusted mean*) | -5 | 8 |
| Difference from placebo (adjusted mean) (95% CI) | -13 (-18, -7) | -- |
| TRADJENTA 5 mg + Insulin | Placebo + Insulin | |
|---|---|---|
| *Full analysis population using last observation carried forward (LOCF) method on trial | ||
| *TRADJENTA + Insulin, n=595; Placebo + Insulin, n=593 | ||
| *HbA1c: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. | ||
| A1C (%) | ||
| Number of patients | n = 618 | n = 617 |
| Baseline (mean) | 8.3 | 8.3 |
| Change from baseline (adjusted mean*) | -0.6 | 0.1 |
| Difference from placebo (adjusted mean) (95% CI) | -0.7 (-0.7, -0.6) | -- |
| Patients [n (%)] achieving A1C <7% | 116 (19.5) | 48 (8.1) |
| FPG (mg/dL) | ||
| Number of patients | n = 613 | n = 608 |
| Baseline (mean) | 147 | 151 |
| Change from baseline (adjusted mean*) | -8 | 3 |
| Difference from placebo (adjusted mean) (95% CI) | -11 (-16, -6) | -- |
| TRADJENTA 5 mg n = 3,494 | Placebo n = 3,485 | Hazard Ratio | |||
|---|---|---|---|---|---|
| Number of Subjects (%) | Incidence Rate per 1,000 PY* | Number of Subjects (%) | Incidence Rate per 1,000 PY* | (95% CI) | |
| *PY=patient years | |||||
| *A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome. | |||||
| Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE) | 434 (12.4) | 57.7 | 420 (12.1) | 56.3 | 1.02 (0.89, 1.17) |
| CV death* | 255 (7.3) | 32.6 | 264 (7.6) | 34.0 | 0.96 (0.81, 1.14) |
| Non-fatal MI* | 156 (4.5) | 20.6 | 135 (3.9) | 18.0 | 1.15 (0.91, 1.45) |
| Non-fatal stroke* | 65 (1.9) | 8.5 | 73 (2.1) | 9.6 | 0.88 (0.63, 1.23) |
| TRADJENTA 5 mg n=3,023 | Glimepiride (1 mg to 4 mg) n=3,010 | Hazard Ratio | |||
|---|---|---|---|---|---|
| Number of Subjects (%) | Incidence Rate per 1,000 PY* | Number of Subjects (%) | Incidence Rate per 1,000 PY* | (95% CI) | |
| *PY=patient years | |||||
| *A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome | |||||
| Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE) | 356 (11.8) | 20.7 | 362 (12.0) | 21.2 | 0.98 (0.84, 1.14) |
| CV death* | 169 (5.6) | 9.2 | 168 (5.6) | 9.2 | 1.00 (0.81, 1.24) |
| Non-fatal MI* | 145 (4.8) | 8.3 | 142 (4.7) | 8.2 | 1.01 (0.80, 1.28) |
| Non-fatal stroke* | 91 (3.0) | 5.2 | 104 (3.5) | 6.0 | 0.87 (0.66, 1.15) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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