To evaluate the comparative effectiveness and safety of monotherapy and metformin-based combination therapy for type 2 diabetes.
We searched MEDLINE®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) for English-language articles using the search developed for the prior review (2011), with date restrictions of April 2009 through April 2015. We searched Drugs@FDA and ClinicalTrials.gov for unpublished data.
Two reviewers independently reviewed titles, abstracts, and full-text articles to identify studies that assessed intermediate and clinical outcomes or safety for monotherapy (metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide-1 [GLP-1] agonists, and sodium glucose cotransporter-2 [SGLT-2] inhibitors) or metformin-based combination therapy (metformin plus one of these monotherapy drugs or insulin) comparisons. Two reviewers extracted data from included articles sequentially using standardized protocols; risk of bias was assessed independently. Two reviewers graded the strength of the evidence sequentially using a protocol adapted from the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria.
We included 216 studies and found moderate- or high-strength evidence for the following. Hemoglobin A1c (HbA1c) reduction was similar across all monotherapy comparisons and across metformin-based combination comparisons except DPP-4 inhibitors, which yielded smaller reductions than metformin. Metformin, DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors reduced or maintained body weight, while sulfonylureas, thiazolidinediones, and insulin increased weight; between-group differences ranged from 1 to 5 kilograms. SGLT-2 inhibitors and GLP-1 agonists plus metformin reduced systolic blood pressure by 3 to 5 mmHg compared with metformin. Cardiovascular mortality in studies over 2 years in duration was 50 to 70 percent higher for sulfonylureas than metformin (risk difference, 0.1% to 2.9% in randomized controlled trials). Sulfonylurea-based therapy increased the risk of total and severe hypoglycemia versus most comparisons. Gastrointestinal adverse events were higher with metformin than other drugs except GLP-1 agonists, which increased nausea/vomiting 1.5 times compared with metformin. SGLT-2 inhibitors increased the risk of genital mycotic infections over other drugs. The evidence did not support substantive conclusions for microvascular outcomes, congestive heart failure, cancer, pancreatitis, or other safety outcomes.
Evidence from this updated systematic review supports metformin as firstline therapy, given its beneficial effects on HbA1c, weight, and cardiovascular mortality (relative to sulfonylureas) and its relative safety profile. In addition, evidence on comparative outcomes associated with different medication classes can be used to facilitate personalized treatment choices by patients and clinicians, guideline development, and decisionmaking by payers and regulators.
Maruthur NM, Tseng E, Hutfless S, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med. [Epub ahead of print 19 April 2016] doi:10.7326/M15-2650.