Longer term safety of dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta‐analysis

Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic agents that hold the potential of slowing the progress of type 2 diabetes mellitus. Their long-term safety is still a subject of debate. A systematic review of randomized, controlled trials was undertaken to comprehensively profile the safety of chronic treatment of type 2 diabetes mellitus with DPP-4 inhibitors. We searched data sources including MEDLINE, CENTRAL, publishers' and manufacturers' databases. Eligible trials were double-blind, randomized, placebo or active-controlled trials with ≥18 weeks duration in patients with type 2 diabetes reporting safety outcomes. Meta-analysis was performed separately for trials in which the control group received placebo (44 studies), another gliptin (3 studies) and any other antidiabetic drug (20 studies). Risk ratios with 95% confidence intervals were computed using a Mantel-Haenszel fixed-effect model for general safety outcomes, hypoglycaemia and adverse events by system organ class. Of 307 publications retrieved, 67 randomized, controlled trials met the eligibility criteria and were included in this review (4 alogliptin, 8 linagliptin, 8 saxagliptin, 20 sitagliptin, and 27 vildagliptin trials). Adverse events with gliptin treatment were at placebo level (relative risk (RR) 1.02 [0.99, 1.04]). No increased risk of infections was detectable (RR 0.98 [0.93, 1.05] compared to placebo and 1.02 [0.97, 1.07] compared to other antidiabetic drugs). Asthenia (RR 1.57 [1.09, 2.27]) as well as cardiac (RR 1.37 [1.00, 1.89]) and vascular disorders (RR 1.74 [1.05, 2.86] for linagliptin) emerged as adverse events associated with DPP-4 inhibitor treatment. The risk of hypoglycaemia was low with DPP-4 inhibitor treatment (RR 0.92 [0.74, 1.15] compared to placebo, RR 0.20 [0.17, 0.24] compared to sulphonylureas) in the absence of sulphonylurea or insulin co-therapy, but significantly elevated for combination therapy of sulphonylurea or insulin with sitagliptin or linagliptin (RR 1.86 [1.46, 2.37] compared to placebo). A large body of data supports the long-term safety of gliptin treatment and refutes an increased risk of infections. Further research is needed to clarify a possible link to asthenia, cardiac and vascular events. For combination therapy with insulin or insulin secretagogues, a careful choice of the agent used may limit the risk of hypoglycaemia.

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

“…However, it is always difficult to confirm a causal relationship in such observational reports because of the presence of many confounding factors [37] . Pooled analyses of large clinical trials with sitagliptin [34] , vildagliptin [40] and linagliptin [48] (Table 2) as well as data from the two recently published major cardiovascular outcome studies reporting liver safety data with saxagliptin [45] and alogliptin [53] (Table 3) are reassuring. On the contrary, some preliminary data suggested that inhibition of DPP-4 might be beneficial in CLD [74,75] .…”

“…Thus, caution is recommended, especially in patients with advanced cirrhosis for whom the problem of controlling effectively and safely blood glucose becomes more crucial and most often requires insulin therapy. or (% CV)* Sitagliptin 100 mg [26] 157 (73) 170 (37) 150 (55) 103 (67) Saxagliptin 10 mg [42,43] [34] , vildagliptin [40] and linagliptin [48] .…”

“…In a systematic review and meta-analysis about the longer term safety of DPP-4 inhibitors in patients with T2DM, hepatotoxiticy was not considered as a concern [34] . No hepatotoxicity of sitagliptin has been shown in a pooled analysis of 25 clinical studies (Table 2).…”

GLP-1 receptor agonists or DPP-4 inhibitors: How to guide the clinician?

“…12,36 Le profil de tolérance et de sécurité des inhibiteurs de la DPP-4 est globalement excellent avec une incidence de manifestations indésirables non significativement différente par rapport à celle du placebo et moindre par comparaison à celle de la metformine (moins de troubles digestifs), des sulfamides (moins d'hypoglycémies) et des thiazolidinediones (moins d'oedème et de prise de poids). 39 Contrairement aux glitazones, les gliptines n'augmentent pas le risque de fractures osseuses et pourraient même être associées à une diminution de ce risque. 40 Une tendance à davantage d'infections bénignes des voies respiratoires supérieures a été rapportée incidemment, 41 mais non confirmée dans la plupart des essais cliniques contrôlés.…”

“…40 Une tendance à davantage d'infections bénignes des voies respiratoires supérieures a été rapportée incidemment, 41 mais non confirmée dans la plupart des essais cliniques contrôlés. 39,42 Un risque accru de pancréatite, voire de cancer du pancréas, a également été suspecté, mais sur la base de données rapportées exposées à des biais potentiels. 31 Les données collectées dans les essais cliniques sont rassurantes à cet égard.…”