Elsevier

Clinical Therapeutics

Volume 33, Issue 11, November 2011, Pages 1609-1629
Clinical Therapeutics

Pharmacotherapy
Review article
Tolerability of Dipeptidyl Peptidase-4 Inhibitors: A Review

https://doi.org/10.1016/j.clinthera.2011.09.028Get rights and content

Abstract

Background

Oral glucose-lowering agents are used to treat patients with type 2 diabetes mellitus (T2DM). Most patients require multiple agents to maintain glycemic targets. Dipeptidyl peptidase-4 (DPP-4) inhibitors are administered as monotherapy and in combination therapy for the treatment of T2DM.

Objective

The aim of this article was to provide a thorough review of published tolerability data on 5 DPP-4 inhibitors.

Methods

PubMed and Web of Science were searched for English-language clinical trials published from January 2000 to June 2001, using the following key words: dipeptidyl peptidase-4 inhibitor, vildagliptin, alogliptin, sitagliptin, saxagliptin, linagliptin, safety, tolerability, efficacy, effect, AE, and adverse effect. Studies were considered for inclusion if they were randomized, double-blind trials performed in patients ≥18 years of age with T2DM and with a hemoglobin A1c of ≥6.5%; included ≥1 arm that received monotherapy with DPP-4; and reported adverse events (AEs). Studies in patients with a history of type 1 or secondary forms of diabetes, significant diabetic complications or cardiovascular disease within the 6 months before the start of the study, hepatic disease or abnormalities, and/or renal abnormalities were excluded.

Results

A total of 45 clinical trials, 5 pharmacokinetic studies, and 28 meta-analyses or reviews were included. The duration of studies ranged from 7 days to 104 weeks. The most commonly reported AEs were nasopharyngitis, upper respiratory infections, all-cause infections, headache, gastrointestinal symptoms, and musculoskeletal pain. Based on the findings from the studies, the DPP-4 inhibitors had minimal impact on weight and were not associated with an increased risk for hypoglycemia relative to placebo. Rates of nasopharyngitis were higher with the DDP-4 inhibitors than with placebo. Pancreatitis was reported at lower rates with the DPP-4 inhibitors compared with other oral antihyperglycemic agents. Cardiovascular events were limited, and postmarketing studies are ongoing.

Conclusions

The tolerability of DPP-4 inhibitors is supported by published clinical trials. The rates of weight gain, gastrointestinal AEs, and hypoglycemia were minimal with the DPP-4 inhibitors studied.

Introduction

Diabetes is a chronic disease that affects the multitude of physiologic pathways known to work together to achieve glycemic homeostasis. Therapeutic agents that enhance endogenous levels of active intestinal incretin hormones such as glucagon-like peptide (GLP)-1 help to modulate glucose.1, 2 Dipeptidyl peptidase (DPP)-4 is a serine protease located on the cell surfaces throughout the body. The DPP-4 enzyme is expressed in most tissues, including the kidneys, gastrointestinal (GI) tract, biliary tract, liver, placenta, uterus, prostate, skin, and lymphocytes.3, 4, 5 Selective inhibition of the DPP-4 enzyme has been a target for drug discovery. In plasma, GLP-1 is rapidly inactivated by the DPP-4 enzyme. GLP-1 molecules are highly responsive to nutrient absorption and affected by glucose elevations.6 The incretin effect can be regarded as a feedback loop that responds to the fluctuation of glucose in the bloodstream in a glucose-dependent manner, in which GLP-1 serves as a stimulus for pancreatic β-cell insulin release as well as an inhibitor of hepatic glucagon secretion.7, 8 Thus, the primary mechanism of action of the DPP-4 inhibitors is regulation of insulin release from the β cell to effect glucose homeostasis. Although DPP-4 inhibitors have an impact on fasting glucose, the glucose-dependent mechanism of action implies a greater effect on postprandial glucose lowering.7

Several DPP-4 inhibitors (“gliptins”) have been approved by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus (T2DM). These agents have reported efficacy in reducing hemoglobin (Hb) A1c levels as monotherapy or in combination with other commonly prescribed glucose-lowering medications.8, 9, 10, 11 In a recent meta-analysis of the efficacy of DPP-4 inhibitors as reported in 24-week studies in patients with T2DM, the mean reduction from baseline in HbA1c concentration was 0.6%.9

In 2006, sitagliptin, a β amino acid–based compound, became the first FDA-approved DPP-4 inhibitor. Other DPP-4 inhibitors include vildagliptin and saxagliptin, both of which are nitrile-containing inhibitors. The use of saxagliptin was approved by the FDA in July 2009, while vildagliptin, approved in Europe, is undergoing evaluation in the United States. One DPP-4 inhibitor under review by the FDA is alogliptin, a modified pyrimidinedione.7 The use of the xanthine-based derivative linagliptin was recently approved by the FDA.

Some pharmacokinetic differences exist between the DPP-4 inhibitors.12, 13, 14 The long half-lives of sitagliptin, alogliptin, and linagliptin allow for once-daily dosing. Saxagliptin is also administered once daily due to the presence of an active metabolite that is half as potent as the parent compound.14, 15 The half-life of vildagliptin is shorter, necessitating twice-daily dosing.16 A review and comparison of the 5 DPP-4 inhibitors reported that renal clearance varied.14 In patients with renal impairment, the doses of saxagliptin, sitagliptin, and most likely alogliptin, should be reduced; a dose reduction is not required with linagliptin in these patients. Vildagliptin should not be used in patients with a creatinine clearance rate of <50 mL/min.7 Among patients with T2DM and varying levels of renal dysfunction, saxagliptin has been associated with efficacy and tolerability17; however, saxagliptin is the only DPP-4 inhibitor that is a substrate for the cytochrome P450 3A4/5 isozyme and requires dose adjustment when coadministered with drugs known to interfere with the metabolic pathway, such as ketoconazole, diltiazem, rifampin, and cyclosporine.15 However, the findings from a review of drug–drug interactions with other DPP-4 inhibitors suggested that drug–drug interactions are rare, as the use of most of the agents (vildagliptin, alogliptin, sitagliptin, linagliptin) has not been associated with significant modification of the pharmacokinetic properties of many common drugs.12, 13, 14 As more knowledge is gained, a review of the adverse events (AEs) associated with the DPP-4 inhibitors is necessary to supplement the current literature.

Guidelines from the American Diabetes Association and the European Association for the Study of Diabetes include DPP-4 inhibitors as an option for the pharmacotherapeutic management of T2DM.18 However, the cost of these branded medications may be a limiting factor for some patients who do not have insurance coverage, as monthly prescriptions may cost substantially more than generic options from other classes. Many factors should be considered when selecting appropriate pharmacotherapy for patients with T2DM. Understanding the tolerability profile of the DPP-4 inhibitors can be useful for clinicians in this process. To evaluate the tolerability of the DPP-4 inhibitors, including a risk–benefit assessment of long-term therapy, this review summarizes the current data on the AEs reported in clinical trials and postmarketing surveillance of the DPP-4 inhibitors.

Section snippets

Data Sources and Searches

PubMed and Web of Science were searched for English-language DPP-4 inhibitor trials that included a tolerability assessment. The searches were conducted using the terms dipeptidyl peptidase-4 inhibitor (both key word and MeSH), vildagliptin, alogliptin, sitagliptin, saxagliptin, linagliptin, safety, tolerability, efficacy, effect, adverse event, and adverse effect. Clinical studies were included if they were conducted in patients aged ≥18 years with T2DM and an HbA1c concentration of ≥6.5%, and

Results

There were 144 clinical trials identified in PubMed using the search strategy with inclusion and exclusion limits applied. An additional search in PubMed, limited to meta-analyses and reviews, resulted in 170 citations. The search of the Web of Science did not allow the same limits and thus resulted in 882 citations containing cellular and animal studies as well as reviews. From these searches, a total of 45 clinical trials were included in the present analysis, and 28 reviews or meta-analyses

Discussion

The present review of data from 45 clinical trials that conformed to previously specified inclusion and exclusion criteria included AEs reported with the use of the DPP-4 inhibitors. Overall, the data suggest that these orally active glucose-lowering agents were well tolerated and that incidents of hypoglycemia were infrequent among the DPP-4 inhibitors. A few isolated reports were found in studies of up to 108 weeks' duration.39, 40, 59

With ∼85% of patients with T2DM being overweight or obese,

Conclusions

Based on the findings from the present review, DPP-4 inhibitors have an overall acceptable safety profile. Although clinical trials have identified several AEs with the use of DPP-4 inhibitors, clinically significant effects were minimal. The most commonly reported AEs included GI events, hyperglycemia, headache, nasopharyngitis, URI, UTI, cough, edema, hypertension, pain, arthralgias, and dizziness. The rates of nasopharyngitis were slightly higher with DPP-4 inhibitors than with placebo in

Acknowledgments

The authors thank Carol Hildebrandt, BA and Robyn Redus, PharmD for their assistance in cross-checking the database constructs and proofreading numerous drafts.

The authors have indicated that they have no conflicts of interest with regard to the content of the article. All authors contributed to the conception, literature search, data analysis, results interpretation, and manuscript preparation.

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