title: Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis.
abstract: OBJECTIVE
  To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy.
  
  
  METHODS
  We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (≥ 1500 mg metformin or maximum tolerated dose; ≥ 50% of maximum sulphonylurea dose for ≥ 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed.
  
  
  RESULTS
  A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92-7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control.
  
  
  CONCLUSIONS
  When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents.
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.|University of Connecticut/Hartford Hospital Evidence-Based Practice Center, Hartford, CT, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Mearns
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.|University of Connecticut/Hartford Hospital Evidence-Based Practice Center, Hartford, CT, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Saulsberry
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.|University of Connecticut/Hartford Hospital Evidence-Based Practice Center, Hartford, CT, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: White
authors.affiliation: University of Saint Joseph School of Pharmacy, Hartford, CT, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Kohn
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sihabout
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.
authors.forename: I
authors.initials: I
authors.lastname: Salamucha
authors.affiliation: University of Connecticut School of Pharmacy, Department of Pharmacy Practice, Storrs, CT, USA.|University of Connecticut/Hartford Hospital Evidence-Based Practice Center, Hartford, CT, USA.
authors.forename: C I
authors.initials: CI
authors.lastname: Coleman
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D016903:Drug Monitoring; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000009:adverse effects; D019317:Evidence-Based Medicine; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D057285:Precision Medicine; D016032:Randomized Controlled Trials as Topic; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D013453:Sulfonylurea Compounds; C517652:hemoglobin A1c protein, human