5.2  Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

6  ADVERSE REACTIONS

6.1  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 of linagliptin has been eva luated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride.

TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18- and 24-weeks duration. Five placebo-controlled trials investigated linagliptin in combination with other oral anti-glycemic agents: two with metformin (12- and 24-weeks treatment duration); one with a sulfonylurea (18-weeks treatment duration); one with metformin and sulfonylurea (24-week treatment duration); and one with pioglitazone (24-week treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in ≥2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1.

Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy   Monotherapy*
n (%) Combination with Metformin#
n (%) Combination with SU
n (%) Combination with Metformin + SU
n (%) Combination with Pioglitazone
n (%)
  TRADJENTA
n = 765 Placebo
n = 458 TRADJENTA
n = 590  Placebo
n = 248 TRADJENTA
n = 161  Placebo
n = 84 TRADJENTA
n = 791 Placebo
n = 263 TRADJENTA
n = 259  Placebo
n = 130
SU = sulfonylurea
* Pooled data from 7 studies
# Pooled data from 2 studies
† Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)
Nasopharyngitis -- -- -- -- 7 (4.3) 1 (1.2) -- -- -- --
Hyperlipidemia -- -- -- -- -- -- -- -- 7 (2.7) 1 (0.8)
Cough  -- -- -- -- -- -- 19 (2.4) 3 (1.1) -- --
Hypertriglyceridemia† -- -- -- -- 4 (2.4) 0 (0.0) -- -- -- --
Weight increased -- -- -- -- -- -- -- -- 6 (2.3) 1 (0.8)

Following 52 weeks treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).

Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema,