Karagiannis T, Paschos P, et al.
BMJ. 2012 Mar 12;344:e1369. doi: 10.1136/bmj.e1369.

DPP-4 inhibitors can be used as second line treatment in patients with type 2 diabetes who do not achieve their glycaemic targets with metformin alone. Their long term safety remains to be further evaluated in ongoing trials.

Background

From indirect meta-analyses assessing the efficacy of various hypoglycaemic drugs, it seems that DPP-4 inhibitors achieve similar reductions in HbA1c compared with other second line treatments.
There is insufficient evidence has been insufficient to advise on the therapeutic role of DPP-4 inhibitors for type 2 diabetes mellitus in current guidelines. This meta-analysis was performed to get an updated insight into the efficacy and safety of DPP-4 inhibitors as monotherapy or in combination with other hypoglycaemic drugs.

Methods

A systematic review and meta-analysis was performed based on 27 reports of 19 trials including 7136 patients randomized to a DPP-4 inhibitor and 6745 patients randomized to another hypoglycaemic drug.

Main results

As monotherapy, metformin is superior to DPP-4 inhibitors in reducing HbA1c and body weight but is associated with a higher incidence of diarrhoea, nausea, and vomiting.

• Compared with metformin 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, 95% prediction interval −0.14 to 0.54; I2=60%) (fig 1) and a lower chance of attainment of the HbA1c goal of less than 7% (risk ratio in favour of metformin 1.18, 95% confidence interval 1.07 to 1.29, I2=34%)

Combined with metformin, DPP-4 inhibitors seem to have similar glycaemic efficacy to sulfonylureas but have a neutral effect on body weight and low risk for hypoglycaemia.

• As a second line treatment, DPP-4 inhibitors achieved a smaller decline in HbA1c than the other hypoglycaemic drugs (overall weighted mean difference 0.12, 0.04 to 0.2, 95% prediction interval −0.13 to 0.37; I2=70%). Analysing data separately for each type of active comparator, DPP-4 inhibitors were less effective than sulfonylureas in reducing HbA1c (weighted mean difference 0.07, 0.03 to 0.11, 95% prediction interval 0.02 to 0.13; I2=0%) (fig 1). There was no significant difference, however, in the attainment of the HbA1c goal of less than 7% (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14; I2=26%)

Conclusion

In patients with type 2 diabetes who do not achieve their glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA1c similar to sulfonylureas or pioglitazone, with neutral effects on body weight. Costs and less data on long term safety should be considered.

Editorial comment [1]

“The findings of this paper support the approaches taken by the European and American consensus statements and by NICE. There is no compelling evidence that DPP-4 inhibitors play a major role in the management of type 2 diabetes, but the low incidence of hypoglycaemia associated with these drugs might be useful in certain patients. The risk of hypoglycaemia is an important consideration when deciding which hypoglycaemic agent to prescribe, yet there is no standard definition of
hypoglycaemia in diabetes trials, which precludes meta-analysis focused on this outcome.
Although early and sustained improvement in HbA1c is associated with a long term reduction in cardiovascular risk, using HbA1c alone as a short term surrogate is not a reliable indicator for reduction in cardiovascular risk. Trials that are powered to detect differences in cardiovascular events in the long term are therefore needed. Three ongoing randomised trials and one observational study of DPP-4 inhibitors aim to investigate this research question. Awaiting the results of these studies, the position of DPP-4 inhibitors in treatment algorithms will remain peripheral and uncertain.”

1. Lasserson D, Mant J. The role of dipeptidyl peptidase-4 inhibitors. BMJ. 2012 Mar 12;344:e1213. doi: 10.1136/bmj.e1213.

Abstract

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 (HbA(1c)).
DATA EXTRACTION: The primary outcome was the change in HbA(1c). Secondary outcomes included the proportion of patients achieving the goal of HbA(1c) <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 HbA(1c) (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 HbA(1c) and had no advantage over sulfonylureas in the attainment of the HbA(1c) 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 HbA(1c), 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.