title: Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis.
abstract: OBJECTIVE
  To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus.
  
  
  METHODS
  Systematic review and meta-analysis of randomised controlled trials.
  
  
  METHODS
  Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers' websites.
  
  
  METHODS
  Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA(1c)).
  
  
  METHODS
  The primary outcome was the change in HbA(1c). Secondary outcomes included the proportion of patients achieving the goal of HbA(1c) <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea.
  
  
  RESULTS
  27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA(1c) (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, -0.07 to 0.24) in reducing HbA(1c) and had no advantage over sulfonylureas in the attainment of the HbA(1c) goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference -1.92, -2.34 to -1.49) or pioglitazone (-2.96, -4.13 to -1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators.
  
  
  CONCLUSIONS
  In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA(1c), in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered.
authors.affiliation: Metabolic Diseases Unit, Second Medical Department, Aristotle University, Konstantinupoleos 49, 54642, Thessaloniki, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karagiannis
authors.forename: Paschalis
authors.initials: P
authors.lastname: Paschos
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Paletas
authors.forename: David R
authors.initials: DR
authors.lastname: Matthews
authors.forename: Apostolos
authors.initials: A
authors.lastname: Tsapas
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis*; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D019468:Disease Management; D016903:Drug Monitoring; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D013453:Sulfonylurea Compounds