Objective To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus.
Design Systematic review and meta-analysis of randomised controlled trials.
Data sources Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers’ websites.
Eligibility criteria Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA1c).
Data extraction The primary outcome was the change in HbA1c. Secondary outcomes included the proportion of patients achieving the goal of HbA1c <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea.
Results 27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA1c (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, −0.07 to 0.24) in reducing HbA1c and had no advantage over sulfonylureas in the attainment of the HbA1c goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference −1.92, −2.34 to −1.49) or pioglitazone (−2.96, −4.13 to −1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators.
Conclusion In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA1c, in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered.
Comment: Mostly the meta-analysis confirms current ADA and NICE guidelines. Metformin is superior to the DPP-IV inhibitors as initial monotherapy. In terms of cost and effectiveness the sulfonylureas and insulin are superior second and/or third line agents, but they are associated with weight gain and hypoglycemia, which are not concerns with the DPP-IV inhibitors. GLP-1 agonists result in weight loss and are not associated with hypoglycemia, but are injectables and expensive. The glitozones are more effective in lowering A1C and are not associated with hypoglycemia when combined with metformin, but weight gain is an issue. Generally, improvement in A1C using any agent is associated with improvement in cardiovascular risk factors, but np study reported to date has shown improvements in cardiovascular ourcomes with these agents. The bottom line is that for most patients the tried and true agents (metformin, the sulfonylureas and insulin) are the starting point with individualization necessary as the disease progresses.