The Benefits and Risks of DPP4-inhibitors vs. Sulfonylureas for Patients With Type 2 Diabetes

Accumulated Evidence From Randomised Controlled Trial

J.-B. Zhou; L. Bai; Y. Wang; J.-K. Yang


Int J Clin Pract. 2016;70(2):132-141. 

In This Article

Abstract and Introduction


Aim: To assess the efficacy and safety of dipeptidyl peptidase 4-inhibitors (DPP4-I) compared with sulphonylureas in adults with type 2 diabetes (T2D) mellitus.

Method: Randomised controlled trials were collected from PubMed, EMBASE, Google Scholar and conference. The primary outcome was the change in HbA1c. Secondary outcomes included weight gain, the change in postprandial plasma glucose (PPG), insulin resistance and fasting plasma glucose (FPG), adverse event (AE) and incidence of hypoglycaemia.

Results: Fourteen studies including 5480 patients randomised to DPP4-I and 5214 patients randomised to sulphonylureas were eligible for the meta-analysis. Compared with sulphonylureas, DPP4-I were associated with a smaller decline in HbA1c (WMD, weighted mean differences 0.08%, 95% CI: 0.03–0.14, p = 0.001), and resulted in weight loss of 1.945 kg (95% CI: −2.237 to −1.653, p < 0.0001). The effect of DPP4-I lowering FPG was inferior to that of sulfonylureas (WMD, 0.268 mmol/l, 95% CI, 0.151–0.385, p < 0.0001), and similar in reducing PPG (WMD, 0.084, 95% CI, −0.701 to 0.869, p = 0.833). According to the follow-up period, the included trials were separated into three groups (group 1: less than half one year, group 2: from half one year to 1 year, group 3: more than 1 year). Subgroup analysis showed that the difference in HbA1c between DPP4-I and sulphonylureas presented a decline curve (group 1: 0.50, 95% CI: 0.15–0.84, group 2: 0.05, 95% CI: −0.05 to 0.15, group 3: 0.09, 95% CI: 0.03–0.15). DPP4-I had a favourable insulin resistance compared with sulfonylureas (WMD, −0.673, 95% CI, −1.248 to −0.097, p = 0.022). In addition, compared with sulfonylureas, DPP4-I was associated with a decrease in overall risk for AE (RR, 0.93, 95% CI, 0.91–0.96, p < 0.0001). The incidence of hypoglycaemia was lower with DPP4-I (RR, 0.24, 95% CI, 0.21–0.27, p < 0.001).

Conclusion: Patients with T2D who receive DPP4-I could achieve almost similar glycaemic targets with sulphonylureas, with favourable effects on body weight and lower incidence of hypoglycaemia.


The bihormonal nature of glucose control is involved in the pathophysiology of diabetes.[1] Long-term type 2 diabetes (T2D) is characterised by progressive loss of β-cell mass and function, which impairs the glucose-lowering potential of insulin secretagogues, particularly sulfonylureas.[2] Secondary failure of glucose control for sulfonylureas is attributed to this point. In contrast to the reduced β-cell function in long-standing T2D, pancreatic α cells release an increased amount of glucagon, which in turn enhances hepatic glucose production. This imbalance in β- and α-cell cross-talk undermines therapeutic glucose-lowering efforts, including sulfonylurea and dipeptidyl peptidase-4 inhibitors (DPP4-I).

Dipeptidyl peptidase-4 inhibitors stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner by the actions of glucagon-like peptide 1 (GLP-1). Furthermore, it suppresses glucagon secretion from α cell. It is postulated that DPP4-I exerted their glucose-lowering effects by the increase of insulin release in addition to the suppression of glucagon secretion.[3] Similarly, recent researches show that glycaemic-lowering effects of DPP4-I could be mediated via activation of the neural gut-to-brain-to-cell axis, which appears to be dependent on these factors like pituitary adenylate cyclase-activating peptide, portal neural sensing, while these mechanisms do not require endogenous GLP-1.[4]

Guidelines from the American Diabetes Association recommend a target of HbA1c < 7%. However, less than half of T2D patients attain adequate glycaemic control. Failure is partly because of both the progressive nature of T2D and inappropriate alternative of oral glucose-lowering agents, including DPP4-I and sulfonylurea.[5,6] Based on the pathophysiology of T2D, different action mechanisms between DPP4-I and sulfonylureas resolve the different alternative of applicable subjects. So it is necessary for the comparison between DPP4-I and sulfonylureas.

In the light of this significant development, an updated picture of accumulated evidence is depicted on the efficacy and safety profiles of DPP4-I with that of sulphonylureas in patients of T2D.