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TRAJENTA®

Side effects and safety

CARMELINA and CAROLINA provided reassuring Cardiovascular safety profile

Cardiovascular safety of TRAJENTA® was evaluated in the 2-year long CARMELINA trial

Primary endpoint: Time to 3P-MACE*

CARMELINA_Tim-to-3P-MACE_renew

CARMELINA is a randomized, double-blind, placebo-controlled, multicenter, noninferiority trial conducted at 605 clinical sites in 27 countries comparing the use of TRAJENTA® administered once daily and placebo with usual care in patients with type 2 diabetes at high risk of cardiovascular (CV) and/or kidney events. 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. A total of 6979 patients received TRAJENTA® 5 mg (N=3,494) or placebo (N=3,485) and were followed for a median of 2.2 years. The primary endpoint was the reduction in risk of 3-point major adverse cardiovascular event (3P-MACE), defined by the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke.1

 

Cardiovascular safety of TRAJENTA® was compared with a sulfonylurea in the 6-year long CAROLINA trial

Primary endpoint: Time to 3P-MACE†

CAROLINA_Time-to-3P-MACE_renew

CAROLINA trial is a multicenter, randomized, double-blind, active-controlled clinical trial examining the effect of treatment with TRAJENTA® versus glimepiride on cardiovascular safety in adult patients with relatively early type 2 diabetes and cardiovascular risk factors or established atherosclerotic cardiovascular disease. Six thousand and thirty-three patients were randomized and received at least 1 dose of 5 mg of once-daily linagliptin (n=3,023) or 1 to 4 mg of once-daily glimepiride (n=3,010). Glimepiride was started at 1 mg/day and up-titrated to a potential maximum dose of 4 mg/day every 4 weeks during the first 16 weeks. The primary endpoint was time to first occurrence of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke (3-point major cardiovascular event [3P-MACE] composite). Median follow-up was 6.3 years in both groups.2

Long-term kidney safety profile was demonstrated in CARMELINA

Reassuring long-term kidney outcomes from TRAJENTA® were shown in CARMELINA trial

CARMELINA-kidney-safety

CARMELINA is a randomized, double-blind, placebo-controlled, multicenter, noninferiority trial conducted at 605 clinical sites in 27 countries comparing the use of TRAJENTA® administered once daily and placebo with usual care in patients with type 2 diabetes at high risk of cardiovascular (CV) and/or kidney events. 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. A total of 6979 patients received TRAJENTA® 5 mg (N=3,494) or placebo (N=3,485) and were followed for a median of 2.2 years. The primary endpoint was the reduction in risk of 3-point major adverse cardiovascular event (3P-MACE), defined by the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. The composite of adjudication-confirmed ESRD, death due to renal failure, or a sustained decrease of at least 50% in eGFR from baseline, albuminuria, sustained ESRD, and death due to renal failure were all parts of exploratory outcomes.1

DPP-4 inhibitors is protective against the loss of muscle mass in patients with type 2 diabetes

DPP-4 inhibitors attenuate the decline of skeletal muscle mass

Skeletal-muscle-mass_renew

A retrospective, observational study investigated the effect of DPP-4 inhibitors on the decline of muscle mass in patients with type 2 diabetes who were at least 40 years old. Muscle strength was measured with a hand dynamometer Grip-D. Regional fat and fat-free mass were measured by the whole-body dual-energy X-ray absorptiometry. The appendicular skeletal muscle index (SMI) was calculated as the appendicular lean mass divided by the square of the height (kg/m2). Propensity score matching with confounders including age, gender, HbA1c, microvascular complications, and medications for diabetes was performed to eliminate possible treatment bias. Changes in appendicular SMI and SMI in lower extremities were significantly higher in the patients taking DPP-4 inhibitors (n=24) than in those who did not (n=24).3

DPP-4 inhibitors were associated with decreased risk of dementia, especially vascular dementia

DPP-4 inhibitors significantly reduced the risk of all-cause dementia

all-cause-dementia

A study utilizing the 7-year data from a national health insurance database investigated the association between DPP-4 inhibitors use and the different types of dementia among patients with diabetes. Total of 2,903 patients on DPP-4 inhibitors (DPP-4i group) and 11,612 patients without DPP-4 inhibitors (non-DPP-4i group) were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication and index year. Dementia developed in 191 (6.5%) patients of the DPP-4i group and in 913 (7.8%) of the non-DPP-4i group. The cumulative incidence of dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (adjusted HR 0.798; 95% CI 0.681-0.883); p < 0.001). Compared with the non-DPP-4i group, the DPP-4i group had associated decreased risks for developing vascular dementia (adjusted HR 0.575; 95% CI 0.404–0.681; p < 0.001) and the other types of dementia (adjusted HR 0.684; 95% CI 0.556–0.749; p < 0.001).4

DPP-4 inhibitors was not associated with adverse covid-19-related outcomes

DPP-4 inhibitors demonstrated significant reduction in all-cause mortality and severe manifestation from COVID-19 in patients with type 2 diabetes mellitus

COVID-19_renew

A nationwide cohort study was conducted to determine whether use of DPP-4 inhibitors reduced the risk of adverse COVID-19–related outcomes among patients with type 2 diabetes mellitus. Total of 586 patients with confirmed COVID-19 were included. There were 47 deaths among 453 users of DPP-4 inhibitors (incidence rate 1.73 per 1,000 person-days) and 22 deaths among 133 users of other second- or third-line antidiabetics (3.18 per 1,000 person-days). The unadjusted survival curves demonstrated a significantly lower probability of all-cause mortality (P = 0.0442) and severe manifestations of COVID-19 (P = 0.0080) among DPP-4 inhibitor users.5

Trajenta safety profile was demonstrated in more than 6,000 patient

Adverse reactions reported in ≥2% of adult patients treated with TRAJENTA® and greater than placebo in placebo-controlled clinical studies of TRAJENTA® monotherapy or combination therapy.6

  TRAJENTA® 5 mg
n(%)
n=3,625		 Placebo
n(%)
n=2,176
Nasopharyngitis 254 (7.0) 132 (6.1)
Diarrhea 119 (3.3) 65 (3.0)
Cough 76 (2.1) 30 (1.4)
  • Other adverse reactions reported in clinical trials with treatment of TRAJENTA® tablets were hypersensitivity (eg, urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.6
  • In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRAJENTA® compared with 3.7 cases per 10,000 patient-years of 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.6
  • Incidences of hypoglycemia and severe hypoglycemia were similar in patients who received TRAJENTA® and in those who received placebo in the placebo-controlled clinical studies.6
Add-on to sulfonylureas (18 weeks) Placebo (N=84) TRAJENTA® (N=161)
Hypoglycemia (blood glucose
< 54 mg/dL)		 1.2% 1.9%
Severe hypoglycemia‡ 0% 0%
Add-on to metformin + sulfonylurea
(24 weeks)		 Placebo (N=263) TRAJENTA® (N=792)
Hypoglycemia (blood glucose
< 54 mg/dL)		 5.3% 8.1%
Severe hypoglycemia‡ 0% 0%
Add-on to basal insulin (52 weeks) Placebo (N=630) TRAJENTA® (N=631)
Hypoglycemia (blood glucose
< 54 mg/dL)		 21.6% 19.8%
Severe hypoglycemia‡ 1.1% 1.7%

When TRAJENTA® is used in combination with an insulin secretagogue (eg, sulfonylurea) or insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.6

Footnotes:

  • * HR=1.02 [95% CI: 0.89-1.17]; P<0.001 for noninferiority, P=0.74 for superiority.
  • † HR=0.98 [95% CI: 0.84-1.14]; P<0.001 for noninferiority.
  • ‡ Require assistance from others to administer carbohydrates, glucagon or emergency medical aids due to hypoglycemia.
  • COVID-19, coronavirus disease 2019; CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MI, myocardial infarction; SMI, skeletal muscle index; UACR, urinary albumin:creatinine ratio; 3P-MACE, 3-point major adverse cardiovascular event.

References:

  1. Rosenstock J, Perkovic V, Johansen OE, et al. JAMA. 2019 Jan 1;321(1):69-79.

  2. Rosenstock J, Kahn SE, Johansen OE, et al. JAMA. 2019 Sep 24;322(12):1155-1166.

  3. Bouchi R, Fukuda T, Takeuchi T, et al. Diabetes Metab Res Rev. 2018 Feb;34(2).

  4. Chen KC, Chung CH, Lu CH, et al. J Clin Med. 2020 Feb 29;9(3):660.

  5. Noh Y, Oh IS, Jeong HE, et al. Diabetes Care. 2021 Apr;44(4):e64-e66.

  6. Trajenta® approved package insert. Updated in May 2020.

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