title: Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial.
abstract: OBJECTIVE
  To evaluate glucose-lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted.
  
  
  METHODS
  A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5-12.0%, were randomized 1:1 to double-blind, free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245).
  
  
  RESULTS
  The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by -2.8 ± 0.1% with linagliptin/metformin and -2.0 ± 0.1% with linagliptin; a treatment difference of -0.8% (95% confidence interval -1.1 to -0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of -2.7 ± 0.1% and -1.8 ± 0.1%, respectively; treatment difference of -0.9% (95% CI -1.3 to -0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (-1.3 kg between-group difference; p =0.0033).
  
  
  CONCLUSIONS
  Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy.
authors.affiliation: University of Calgary, LMC Endocrinology Centres, Calgary, Alberta, Canada.
authors.forename: S A
authors.initials: SA
authors.lastname: Ross
authors.forename: A E
authors.initials: AE
authors.lastname: Caballero
authors.forename: S
authors.initials: S
authors.lastname: Del Prato
authors.forename: B
authors.initials: B
authors.lastname: Gallwitz
authors.forename: D
authors.initials: D
authors.lastname: Lewis-D'Agostino
authors.forename: Z
authors.initials: Z
authors.lastname: Bailes
authors.forename: S
authors.initials: S
authors.lastname: Thiemann
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: H-J
authors.initials: HJ
authors.lastname: Woerle
authors.forename: M
authors.initials: M
authors.lastname: von Eynatten
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007391:International Cooperation; D000069476:Linagliptin; D008687:Metformin / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D008687:Metformin; D011687:Purines; D011799:Quinazolines; C517652:hemoglobin A1c protein, human
keywords: DPP-4 inhibitor; antidiabetes drug; clinical trial; metformin; type 2 diabetes