­­Choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea: a systematic review and mixed-treatment comparison meta-analysis

BACKGROUND: Metformin and a sulphonylurea are often used in combination for the treatment of type 2 diabetes mellitus. We conducted a systematic review and meta-analysis to evaluate the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled with metformin and sulphonylurea combination therapy. METHODS: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to November 2009. Additional citations were obtained from the grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected the studies, extracted the data and assessed risk of bias. Key outcomes of interest were hemoglobin A(1c), body weight, hypoglycemia, patients’ satisfaction with treatment, quality of life, long-term diabetes-related complications, withdrawals due to adverse events, serious adverse events and mortality. Mixed-treatment comparison meta-analyses were conducted to calculate mean differences between drug classes for changes in hemoglobin A(1c) and body weight. When appropriate, pairwise meta-analyses were used to estimate differences for other outcomes. RESULTS: We identified 33 randomized controlled trials meeting the inclusion criteria. The methodologic quality of the studies was generally poor. Insulins (basal, biphasic, bolus), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues and thiazolidinediones (TZDs) all produced statistically significant reductions in hemoglobin A(1c) in combination with metformin and a sulphonylurea (–0.89% to –1.17%), whereas meglitinides and alpha-glucosidase inhibitors did not. Biphasic insulin, bolus insulin, and TZDs were associated with weight gain (1.85–5.00 kg), whereas DPP-4 inhibitors and alpha-glucosidase inhibitors were weight-neutral, and GLP-1 analogues were associated with modest weight loss. Treatment regimens containing insulin were associated with increased hypoglycemia relative to comparators, but severe hypoglycemia was rare across all treatments. INTERPRETATION: Third-line agents for the treatment of type 2 diabetes are similar in terms of glycemic control but differ in their propensity to cause weight gain and hypoglycemia. Longer-term studies with larger sample sizes are required to determine if any of the drug classes are superior with regard to reducing diabetes-related complications.