1 2 Testing the Therapeutic Equivalence of Alogliptin , 3 Linagliptin , Saxagliptin , Sitagliptin or Vildagliptin 4 as Monotherapy or in Combination with Metformin 5 in Patients with Type 2 Diabetes

12 Background: In studying the therapeutic 13 evidence of innovative drug treatments, 14 increasing attention is being devoted to 15 differentiating between results that indicate no 16 significant differences among the treatments 17 under examination (‘‘no proof of difference’’) 18 and results that demonstrate the therapeutic 19 equivalence among the treatments (‘‘proof of no 20 difference’’). 21 Aim: Our analysis was aimed at evaluating the 22 degree of therapeutic equivalence for 23 dipeptidylpeptidase-4 (DPP-4) inhibitors given 24 in type 2 diabetes as monotherapy or in 25 combination with metformin. 26 Methods: Equivalence was determined by 27 developing a standard Forest plot that 28 incorporated the information on margins 29 previously reported in randomized trials on 30 these agents. The end point was HbA1c change 31 from baseline; the equivalence margin was set at 32 ±0.25% change in HbA1c. The clinical material 33 was obtained from a systematic review on this 34 topic. 35 Results: Given as monotherapy, linagliptin, 36 sitagliptin, and vildagliptin (but not 37 saxagliptin) met the equivalence criterion 38 when compared with one another. Given in 39 combination with metformin, linagliptin, 40 saxagliptin, sitagliptin, and vildagliptin 41 showed an equivalent effect whereas alogliptin 42 did not satisfy the equivalence criterion. 43 Conclusions: Considering the most recent 44 therapeutic guidelines, our results are of 45 interest particularly as regards the information 46 on DPP-4 inhibitors in combination with 47 metformin. Four of the five DPP-4 inhibitors 48 under examination clearly showed to have the 49 same effectiveness; the fifth agent—alogliptin— 50 failed to meet the equivalence criterion, but only 51 because its superiority could not be excluded.