title: Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis.
abstract: To quantify the risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas compared with placebo and sulphonylureas.
  
  
  
  Systematic review and meta-analysis.
  
  
  
  Medline, ISI Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, and clinicaltrial.gov were searched without any language restriction.
  
  
  
  Placebo controlled randomised trials comprising at least 50 participants with type 2 diabetes treated with DPP-4 inhibitors and sulphonylureas.
  
  
  
  Risk of bias in each trial was assessed using the Cochrane Collaboration tool. The risk ratio of hypoglycaemia with 95% confidence intervals was computed for each study and then pooled using fixed effect models (Mantel Haenszel method) or random effect models, when appropriate. Subgroup analyses were also performed (eg, dose of DPP-4 inhibitors). The number needed to harm (NNH) was estimated according to treatment duration.
  
  
  
  10 studies were included, representing a total of 6546 participants (4020 received DPP-4 inhibitors plus sulphonylureas, 2526 placebo plus sulphonylureas). The risk ratio of hypoglycaemia was 1.52 (95% confidence interval 1.29 to 1.80). The NNH was 17 (95% confidence interval 11 to 30) for a treatment duration of six months or less, 15 (9 to 26) for 6.1 to 12 months, and 8 (5 to 15) for more than one year. In subgroup analysis, no difference was found between full and low doses of DPP-4 inhibitors: the risk ratio related to full dose DPP-4 inhibitors was 1.66 (1.34 to 2.06), whereas the increased risk ratio related to low dose DPP-4 inhibitors did not reach statistical significance (1.33, 0.92 to 1.94).
  
  
  
  Addition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia and to one excess case of hypoglycaemia for every 17 patients in the first six months of treatment. This highlights the need to respect recommendations for a decrease in sulphonylureas dose when initiating DPP-4 inhibitors and to assess the effectiveness of this risk minimisation strategy.
authors.affiliation: University of Bordeaux, UMR1219, F-33000 Bordeaux, France INSERM, UMR1219, Bordeaux Population Health Research Center, Pharmacoepidemiology team, Bordeaux, France  CHU Bordeaux, Bordeaux, France francesco.salvo@u-bordeaux.fr.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvo
authors.affiliation: University of Bordeaux, UMR1219, F-33000 Bordeaux, France INSERM, UMR1219, Bordeaux Population Health Research Center, Pharmacoepidemiology team, Bordeaux, France  CHU Bordeaux, Bordeaux, France CIC Bordeaux CIC1401, Bordeaux, France.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Moore
authors.affiliation: University of Bordeaux, UMR1219, F-33000 Bordeaux, France INSERM, UMR1219, Bordeaux Population Health Research Center, Pharmacoepidemiology team, Bordeaux, France
authors.forename: Mickael
authors.initials: M
authors.lastname: Arnaud
authors.affiliation: CIC Bordeaux CIC1401, Bordeaux, France ADERA, Pessac, France.
authors.forename: Philip
authors.initials: P
authors.lastname: Robinson
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Raschi
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Ponti
authors.affiliation: University of Bordeaux, UMR1219, F-33000 Bordeaux, France INSERM, UMR1219, Bordeaux Population Health Research Center, Pharmacoepidemiology team, Bordeaux, France  CHU Bordeaux, Bordeaux, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Bégaud
authors.affiliation: University of Bordeaux, UMR1219, F-33000 Bordeaux, France INSERM, UMR1219, Bordeaux Population Health Research Center, Pharmacoepidemiology team, Bordeaux, France  CHU Bordeaux, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Pariente
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D004359:Drug Therapy, Combination / Q000009:adverse effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D013453:Sulfonylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds