Comparative efficacy and safety of antidiabetic drug regimens added to metformin monotherapy in patients with type 2 diabetes: a network meta-analysis.
BACKGROUND
When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone.


METHODS
A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3-12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥ 1500 mg daily or maximally tolerated dose for ≥ 4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI).


RESULTS
Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00-11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15-2.26 kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19-2.44 kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88-5.43 mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16-8.03).


CONCLUSIONS
Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America; Evidence-Based Practice Center, Hartford Hospital, Hartford, Connecticut, United States of America.
Elizabeth S
ES
Mearns
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America; Evidence-Based Practice Center, Hartford Hospital, Hartford, Connecticut, United States of America.
Diana M
DM
Sobieraj
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America; Evidence-Based Practice Center, Hartford Hospital, Hartford, Connecticut, United States of America.
C Michael
CM
White
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America; Evidence-Based Practice Center, Hartford Hospital, Hartford, Connecticut, United States of America.
Whitney J
WJ
Saulsberry
Department of Pharmacy Practice, School of Pharmacy, University of Saint Joseph, Hartford, Connecticut, United States of America.
Christine G
CG
Kohn
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
Yunes
Y
Doleh
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
Eric
E
Zaccaro
Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America; Evidence-Based Practice Center, Hartford Hospital, Hartford, Connecticut, United States of America.
Craig I
CI
Coleman
D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013599:Systole / Q000187:drug effects; D016896:Treatment Outcome
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin