network meta-analysis of safety with SGLT2 inhibitors1

Network meta-analysis study design:

Study published in the August 2016 issue of Diabetes, Obesity and Metabolism: A network meta-analysis of 38 randomized, placebo-controlled trials (N=23,997) to indirectly assess comparative efficacy and safety of SGLT2 inhibitors (INVOKANA® 100 mg and INVOKANA® 300 mg, Jardiance® [empagliflozin] 10 mg and Jardiance® 25 mg, and Farxiga® [dapagliflozin] 5 mg and Farxiga® 10 mg) based on data published up to November 3, 2015. All randomized controlled trials lasted ≥24 weeks and reported data on ≥1 cardiometabolic or safety outcomes. Cardiometabolic outcomes consisted of A1C, fasting plasma glucose, body weight (primary outcomes), systolic blood pressure, diastolic blood pressure, total cholesterol, LDL and HDL cholesterol, and triglycerides. Safety outcomes included all hypoglycemic events, urinary tract infection, genital infection, diabetic ketoacidosis, and bone fractures. Study quality was assessed using the Cochrane Risk of Bias Tool.1

Limitations of the network meta-analysis1:

  • Data were sourced only from journal articles or from ClinicalTrials.gov, which could risk publication bias
  • In some studies, outcomes may not be reported or it may not be possible to extract them in a suitable way; however, information was retrieved from all 38 trials for A1C and from 37 trials for body weight
  • Diabetic ketoacidosis and bone fractures were reported in 3 and 9 studies, respectively; therefore, a formal analysis was not performed
  • Across randomized controlled trials, ethnicities of participants, follow-up durations, outcomes selection, definition, and ascertainment could differ; however, the authors deemed the network used in this analysis as consistent for A1C outcomes

safety analysis1

Risk vs placebo

  Hypoglycemia Urinary tract infection Genital infection
Farxiga® 5 mg
Farxiga® 10 mg
Jardiance® 10 mg
Jardiance® 25 mg
INVOKANA® 100 mg
INVOKANA® 300 mg

Increased risk vs placebo

Similar risk vs placebo

  • In an analysis excluding studies with a background sulfonylurea (SU) or insulin, the risk of hypoglycemia was similar to placebo for all SGLT2 inhibitors, suggesting an imbalance of an SU or insulin use across studies where SGLT2 inhibitors were compared with placebo

There have been no head-to-head clinical trials comparing the efficacy or safety of SGLT2 inhibitors. No direct evaluation of comparative clinical profiles can be made.

SGLT2=sodium-glucose co-transporter 2.

Reference: 1. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783-794.