Sarcoid-like lung granulomas in a hemodialysis patient treated with a dipeptidyl peptidase-4 inhibitor

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Abstract

It has been reported that the inhibition of dipeptidyl peptidase-4 (DPP-4)/CD26 on T-cells by DPP-4 enzymatic inhibitors suppresses lymphocyte proliferation and reduces the production of various cytokines, including tumor necrosis factor (TNF)-α. A 72-year-old female with diabetic nephropathy on hemodialysis developed multiple lung nodules following the administration of vildagliptin. A biopsy demonstrated the histology of granulomas without caseous necrosis. The discontinuation of vildagliptin resulted in the disappearance of the granulomas within 4 months. As granulomatosis often develops in patients under anti-TNF-α therapy, the accumulation of DPP-4 inhibitors or its metabolites is possibly linked to unrecognized complications, such as sarcoid-like lung granulomas.

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Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes.

Y. Kim, Sunny Jun, M. Park … (2012)

Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM). We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro. Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80(+) and F4/80(+)CD11b(+)CD11c(+) cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM. We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.

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Pharmacokinetics of dipeptidylpeptidase-4 inhibitors.

A J Scheen (2010)

Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug-drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice.

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Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences.

Alberto Corsini, Roberta Baetta (2011)

The dipeptidyl peptidase (DPP)-4 inhibitors, which enhance glucose-dependent insulin secretion from pancreatic β cells by preventing DPP-4-mediated degradation of endogenously released incretin hormones, represent a new therapeutic approach to the management of type 2 diabetes mellitus. The 'first-in-class' DPP-4 inhibitor, sitagliptin, was approved in 2006; it was followed by vildagliptin (available in the EU and many other countries since 2007, although approval in the US is still pending), saxagliptin (in 2009), alogliptin (in 2010, presently only in Japan) and linagliptin, which was approved in the US in May 2011 and is undergoing regulatory review in Japan and the EU. As the number of DPP-4 inhibitors on the market increases, potential differences among the different members of the class become important when deciding which agent is best suited for an individual patient. The aim of this review is to provide a comprehensive and updated comparison of the pharmacodynamic and pharmacokinetic properties of DPP-4 inhibitors, and to pinpoint pharmacological differences of potential interest for their use in therapy. Despite their common mechanism of action, these agents show significant structural heterogeneity that could translate into different pharmacological properties. At the pharmacokinetic level, DPP-4 inhibitors have important differences, including half-life, systemic exposure, bioavailability, protein binding, metabolism, presence of active metabolites and excretion routes. These differences could be relevant, especially in patients with renal or hepatic impairment, and when considering combination therapy. At the pharmacodynamic level, the data available so far indicate a similar glucose-lowering efficacy of DPP-4 inhibitors, either as monotherapy or in combination with other hypoglycaemic drugs, a similar weight-neutral effect, and a comparable safety and tolerability profile. Data on nonglycaemic parameters are scant at present and do not allow a comparison among DPP-4 inhibitors. Several phase III trials of DPP-4 inhibitors are currently ongoing; these trials, along with post-marketing surveillance data, will hopefully increase our knowledge about the long-term efficacy and safety of DPP-4 inhibitor therapy, the effect on pancreatic cell function and peripheral glucose metabolism, and the effect on cardiovascular outcomes in patients with type 2 diabetes.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Kidney J

Journal ID (iso-abbrev): Clin Kidney J

Journal ID (publisher-id): ckj

Journal ID (hwp): ndtplus

Title: Clinical Kidney Journal

Publisher: Oxford University Press

ISSN (Print): 2048-8505

ISSN (Electronic): 2048-8513

Publication date (Print): April 2014

Publication date (Electronic): 20 January 2014

Publication date PMC-release: 20 January 2014

Volume: 7

Issue: 2

Pages: 182-185

Affiliations

[1 ]Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , Okayama, Japan

[2 ]Department of Surgery, Kousei Hospital , Okayama, Japan

[3 ]Department of Radiology, Okayama University Medical School , Okayama, Japan

Author notes

Correspondence and offprint requests to: Ken-ei Sada; E-mail: sadakenn@ 123456md.okayama-u.ac.jp

Article

Publisher ID: sft172

DOI: 10.1093/ckj/sft172

PMC ID: 4377776

PubMed ID: 25852868

SO-VID: 5403c5b7-399e-4c42-92f6-070a37f905d4

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 8 November 2013

Date accepted : 29 December 2013

Page count

Pages: 4

Sarcoid-like lung granulomas in a hemodialysis patient treated with a dipeptidyl peptidase-4 inhibitor

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Karger: Nephrology

Most cited references 12

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes.

Pharmacokinetics of dipeptidylpeptidase-4 inhibitors.

Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences.

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