title: Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses.
abstract: OBJECTIVE
  In search of add-on treatments to metformin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors are potential candidates. This meta-analysis examines the potential use of SGLT-2 inhibitors in combination with metformin as a therapeutic option for type 2 diabetes management in patients with inadequate control with metformin.
  
  
  METHODS
  A literature search was made in several databases for randomized controlled trials (RCTs) utilizing metformin therapy combined with SGLT-2 inhibitors or placebo. Heterogeneity was estimated with I(2) statistics and random effect model was chosen for the meta-analyses of mean differences in changes from baseline in both SGLT-2 inhibitor treated and control groups.
  
  
  RESULTS
  Seven RCTs were selected for the meta-analysis. In comparison with placebo-MET, the SGLT-2 inhibitor-MET combination therapy resulted in significant HbA1c decline in 12-24 week duration, to less extent after 1 year (-0.37 [-0.77, 0.03]; P=0.07) but not by 2 year (-0.41 [-1.09, 0.28]; P=0.24) duration. SGLT-2 inhibitor-MET significantly lowered FPG and body weight after 24 weeks, 1 year, and 2 years. Systolic and diastolic blood pressure declined only in the short-term (12-24 weeks). After 2 years, neither systolic (-1.80 [-6.18, 2.58]; P=0.42) nor diastolic blood pressure (-0.20 [-2.94, 2.54]; P=0.89) declined significantly more than control. Incidence of suspected genital infections was slightly more in SGLT-2 inhibitor-MET group.
  
  
  CONCLUSIONS
  SGLT-2 inhibition in combination with metformin is a potential therapeutic option based on its effects on glycemic control, body weight, and blood pressure, but further trials are required to refine this evidence.
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China; Chinese PLA General Hospital, Beijing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Dou
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China. Electronic address: lujuming_301@126.com.
authors.forename: Juming
authors.initials: J
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D001786:Blood Glucose; D001794:Blood Pressure; D001835:Body Weight; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000627:therapeutic use
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D000068896:Canagliflozin; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C517652:hemoglobin A1c protein, human; C529054:dapagliflozin; C572941:ipragliflozin; C570240:empagliflozin
keywords: Body mass index; Childhood obesity; Diabetes mellitus; Insulin sensitivity; Metformin