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Patil VS, Seth BK, Chaudhari HK. In silico ADME and target prediction studies of Alogliptin as drug molecule. Drug Metab Rev 2025; 57:1-8. [PMID: 39636221 DOI: 10.1080/03602532.2024.2439102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
Alogliptin is an oral hypoglycemic agent selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Inhibition of DPP-4 increases the levels of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by preventing their degradation. The main goal is to study the predicted and experimental properties of absorption, distribution, metabolism, and elimination (ADME), compare them, examine predicted targets, and understand the use of SwissADME in designing other drug molecules. SwissADME, an online tool for ADME prediction, was used together with Swiss Target Prediction to understand drug targets. In addition, we obtained experimental data from the available scientific literature. Molecular docking studies against human DPP-4 were also conducted. We found similarities between the predicted and experimental data; however, some errors depended on the test conditions. The results are interpreted in the first half of the article. We describe the predicted ADME properties of Alogliptin, and based on the results, we can conclude that these tools can be used to predict other drug molecules similarly. It can also reconfigure and manufacture several different formulations of the drug based on predictive data.
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Affiliation(s)
- Vaishnavi Sanjay Patil
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Bhavika Kapil Seth
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Hemchandra K Chaudhari
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
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Kondo Y, Satoh S, Terauchi Y. Effects of dulaglutide and trelagliptin on beta-cell function in patients with type 2 diabetes: a randomized controlled study: DUET-beta study. Diabetol Int 2024; 15:474-482. [PMID: 39101164 PMCID: PMC11291836 DOI: 10.1007/s13340-024-00717-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 03/18/2024] [Indexed: 08/06/2024]
Abstract
Aims This randomized, open-label, parallel-group, controlled trial compared the effects of dulaglutide and trelagliptin on beta-cell function in patients with type 2 diabetes. Materials and methods For 24 weeks, participants received dulaglutide (0.75 mg/week) or trelagliptin (100 mg/week), after which beta-cell function was evaluated using a glucagon stimulation test-based disposition index. The primary endpoint was the change in disposition index over the 24-week treatment period. Results Fifty patients with type 2 diabetes who received metformin with or without basal insulin were randomized to receive dulaglutide or trelagliptin. Forty-eight patients completed the 24-week dulaglutide (n = 23) or trelagliptin (n = 25) treatment. The dulaglutide group reduced HbA1c levels more than the trelagliptin group (dulaglutide: - 0.77% ± 0.07% vs. trelagliptin: - 0.57% ± 0.07%; p = 0.04). Change in disposition index during the 24 weeks did not differ between the groups (dulaglutide: - 0.07 ± 1.08 vs. trelagliptin: + 0.59 ± 1.04; p = 0.66), but the dulaglutide group increased HOMA2-%β levels more than the trelagliptin group (dulaglutide: + 26.2 ± 4.3% vs. trelagliptin: + 5.4 ± 4.1%; p = 0.001). The dulaglutide group showed greater body fat mass reduction than the trelagliptin group (dulaglutide: - 1.2 ± 0.3 kg vs. trelagliptin: - 0.3 ± 0.2 kg; p = 0.02) without skeletal muscle mass loss. Conclusion Dulaglutide and trelagliptin had similar effects on beta-cell function according to the glucagon stimulation test-based disposition index. However, dulaglutide promoted improved HOMA2-%β levels compared to trelagliptin and body fat mass was reduced without loss of skeletal muscle mass (UMIN-CTR 000024164). Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00717-6.
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Affiliation(s)
- Yoshinobu Kondo
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
- Department of Endocrinology and Metabolism, Chigasaki Municipal Hospital, 5-15-1 Honson, Chigasaki, Kanagawa 253-0042 Japan
- Tsunashima-East Internal Medicine and Diabetes Clinic, 2-2-14 Tsunashima-Higashi, Kouhoku-ku, Yokohama, Kanagawa 223-0052 Japan
| | - Shinobu Satoh
- Department of Endocrinology and Metabolism, Chigasaki Municipal Hospital, 5-15-1 Honson, Chigasaki, Kanagawa 253-0042 Japan
- Department of Diabetes and Metabolism, Fujisawa Shonandai Hospital, 2345 Takakura, Fujisawa, Kanagawa 252-0802 Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
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Rathod R, Ali F, Chandra A, Kumar R, Dahiya M, Singh GN. Simultaneous Determination of Alogliptin, Linagliptin, Saxagliptin, and Sitagliptin in Bulk Drug and Formulation by UPLC Q-TOF-MS. CURR PHARM ANAL 2020. [DOI: 10.2174/1573412915666190708162012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
A simple and sensitive Ultra Performance Liquid Chromatography-Mass Spectrometry
method was developed and validated to measure the concentrations of Alogliptin (ALO),
Linagliptin (LIN), Saxagliptin (SAX), and Sitagliptin (SIT) using Pioglitazone (PIO) as an internal
standard.
Methods:
Chromatographic separation of six gliptins was achieved on a C-18 column (100×2.1 mm,
2.7 μm) using a mobile phase consisting of formic acid in water, 0.1%v/v: acetonitrile in gradient elution.
Electrospray ionization (ESI) source was operated in the positive ion mode. Targeted MS/MS mode
on a QTOF MS was used to quantify the drug utilizing the transitions of 340.1(m/z), 473.2 (m/z), 316.2 (m/z),
408.1 (m/z), and 357.1 (m/z) for ALO, LIN, SAX, SIT and PIO respectively.
Results:
As per ICH Q2R1 guidelines, a detailed validation of the method was carried out and the
standard curves were found to be linear over the concentration ranges of 1516.0-4548.1 ng mL-1, 519.8-
1559.4 ng mL-1, 1531.4-4594.3 ng mL-1and 1519.6-4558.8 ng mL-1 for ALO, LIN, SAX and SIT respectively.
Precision and accuracy results were within the acceptable limits. The mean recovery was found to be
98.8 _ 0.76 % (GEM), 102.2 _ 1.59 % (LIN), 95.3 _ 2.74 % (SAX) and 99.2 _ 1.75 % (SIT) respectively.
Conclusions:
The optimized validated UPLC QTOF-MS/MS method offered the advantage of shorter
analytical times and higher sensitivity and selectivity. The optimized method is suitable for application
in quantitative analysis of pharmaceutical dosage forms for QC laboratory.
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Affiliation(s)
- Ramji Rathod
- Central Drugs Standard Control Organisation, Ministry of Health and Family Welfare, Govt. of India, New Delhi, India
| | - Faraat Ali
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector- 23, Rajnagar, Ghaziabad, Uttar Pradesh 201002, India
| | - Amrish Chandra
- Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh 201313, India
| | - Robin Kumar
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector- 23, Rajnagar, Ghaziabad, Uttar Pradesh 201002, India
| | - Meenakshi Dahiya
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector- 23, Rajnagar, Ghaziabad, Uttar Pradesh 201002, India
| | - Gyanendra Nath Singh
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector- 23, Rajnagar, Ghaziabad, Uttar Pradesh 201002, India
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Chen XW, He ZX, Zhou ZW, Yang T, Zhang X, Yang YX, Duan W, Zhou SF. An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2016. [PMID: 26218204 DOI: 10.1111/1440-1681.12469] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.
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Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA
| | - Xueji Zhang
- Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Vic., Australia
| | - Shu-Feng Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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Yabe D, Seino Y. Alogliptin for the treatment of type 2 diabetes: a drug safety evaluation. Expert Opin Drug Saf 2016; 15:249-64. [PMID: 26607297 DOI: 10.1517/14740338.2016.1125467] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin are becoming more widely established as treatment options for patients with type 2 diabetes (T2DM) because of their ability to improve glycemic control without increasing the risk of hypoglycemia or weight gain. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM. AREAS COVERED In this article, the overall safety and tolerability of alogliptin are evaluated based upon a review of the literature. In particular, adverse events (AEs) that have been of interest for the DPP-4 class of drugs, such as the risk of major cardiovascular (CV) events and acute pancreatitis, will be investigated in detail. EXPERT OPINION Alogliptin is generally well-tolerated in a broad range of patient populations including different ethnic groups and the elderly. In the pivotal EXAMINE clinical trial, alogliptin was found not to be associated with an increased risk of major CV events or acute pancreatitis/pancreatic cancer.
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Affiliation(s)
- Daisuke Yabe
- a Yutaka Seino Distinguished Center for Diabetes Research , Kansai Electric Power Medical Research Institute , Kobe , Japan.,b Center for Diabetes, Endocrinology and Metabolism , Kansai Electric Power Hospital , Osaka , Japan.,c Center for Clinical Nutrition and Metabolism , Kansai Electric Power Hospital , Osaka , Japan
| | - Yutaka Seino
- a Yutaka Seino Distinguished Center for Diabetes Research , Kansai Electric Power Medical Research Institute , Kobe , Japan.,b Center for Diabetes, Endocrinology and Metabolism , Kansai Electric Power Hospital , Osaka , Japan
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Chen XW, He ZX, Zhou ZW, Yang T, Zhang X, Yang YX, Duan W, Zhou SF. Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2016; 42:999-1024. [PMID: 26173919 DOI: 10.1111/1440-1681.12455] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 06/11/2015] [Accepted: 07/06/2015] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.
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Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Centre, Salt Lake City, UT, USA
| | - Xueji Zhang
- Research Centre for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Vic., Australia
| | - Shu-Feng Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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Hamamoto H, Nakanishi K, Noda M. Analyzing the Factors Contributing to Withdrawal from Insulin Therapy Following Additional Administration of Alogliptin: Retrospective Study after Removing Glucotoxicity with Insulin. JAPANESE CLINICAL MEDICINE 2015; 6:15-20. [PMID: 26441486 PMCID: PMC4578556 DOI: 10.4137/jcm.s27202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 08/20/2015] [Accepted: 08/22/2015] [Indexed: 11/17/2022]
Abstract
We attempted to examine whether withdrawal from insulin therapy is or is not possible with administration of additional alogliptin and identify the contributing factors. The subjects were 43 adult patients with type 2 diabetes undergoing insulin therapy after admission. After glucotoxicity was removed, 25 mg alogliptin was additionally administered. Insulin was reduced by 15.6 ± 13.0 units (mean ± SD), and 17 patients (39.5%) completely withdrew from insulin therapy. Several factors were compared between the two groups of patients: those who could withdraw from insulin therapy and those who could not. The former group showed lower HbA1c levels on admission, a lower insulin dose before adding alogliptin, lower injection frequencies, and longer treatment histories prior to admission. Logistic regression analysis showed that lower insulin dose contributed significantly to withdrawal. These results suggest that a lower insulin dose is the best predictor for withdrawal from insulin therapy after adding alogliptin.
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Affiliation(s)
- Hiromi Hamamoto
- Department of Internal Medicine, Fukuyama City Hospital, Fukuyama, Hiroshima, Japan
| | - Koji Nakanishi
- Minami Isshiki Central Naika, Nagaizumi, Sunto, Shizuoka, Japan
| | - Mitsuhiko Noda
- Department of Diabetes Research, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
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Affiliation(s)
- André J Scheen
- Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium,
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Scheen AJ. Pharmacokinetics and clinical evaluation of the alogliptin plus pioglitazone combination for type 2 diabetes. Expert Opin Drug Metab Toxicol 2015; 11:1005-20. [PMID: 25936384 DOI: 10.1517/17425255.2015.1041499] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin). AREA COVERED An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy. EXPERT OPINION Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post-meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated.
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Affiliation(s)
- André J Scheen
- University of Liège, Center for Interdisciplinary Research on Medicines (CIRM), Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, CHU Sart Tilman , Liège , Belgium +32 4 3667238 ; +32 4 3667068 ; andre.scheen@ chu.ulg.ac.be
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Akita K, Isoda K, Shimada K, Daida H. Dipeptidyl-peptidase-4 inhibitor, alogliptin, attenuates arterial inflammation and neointimal formation after injury in low-density lipoprotein (LDL) receptor-deficient mice. J Am Heart Assoc 2015; 4:e001469. [PMID: 25770025 PMCID: PMC4392431 DOI: 10.1161/jaha.114.001469] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background The results of recent studies suggest that dipeptidyl‐peptidase‐4 inhibitors have antiatherogenic effects. However, whether or not dipeptidyl‐peptidase‐4 inhibitors could suppress arterial inflammation and intimal hyperplasia after injury remains undetermined. The present study aims to clarify the anti‐inflammatory effects of the dipeptidyl‐peptidase‐4 inhibitor, alogliptin (AGP), on the arteries of atherogenic low‐density lipoprotein receptor‐deficient (LKO) mice. Methods and Results We compared intimal hyperplasia in LKO mice 2 weeks after femoral artery injury using an external vascular cuff model. All mice received oral injection of AGP (20 mg/kg per day) or normal saline (control) once daily for 14 days. Fasting blood sugar levels, serum cholesterol levels, or blood pressure did not significantly differ between the 2 groups. Plasma levels of active glucagon‐like peptide‐1 were higher in the AGP than in the control LKO mice (22.2±1.9 versus 15.6±0.9 pg/mL; P<0.05). Compared with saline, AGP significantly reduced intimal hyperplasia (1087±127 versus 1896±140 μm2; P<0.001) as well as the intima/media ratio (0.08±0.01 versus 0.16±0.02; P<0.001). Immunostaining showed that AGP reduced proliferating cells (proliferating cell nuclear antigen–positive nuclei; P<0.001), percent smooth‐muscle cell area (α‐SMA‐positive cells; P<0.001), inflammatory cells infiltration (lymphocyte antigen 6 complex–positive cells; P<0.05), tumor necrosis factor‐α expression (P<0.05), and percent phospho‐NF‐κB‐positive cell compared with saline. Levels of tumor necrosis factor ‐α (0.5‐fold P<0.05), monocyte chemoattractant protein 1 (0.3‐fold P<0.01), and interleukin‐1β (0.2‐fold P<0.05) mRNA were lower in the injured arteries of the AGP than in the control group. Conclusions AGP appeared to suppress neointimal formation by inhibiting inflammation, independently of its effects on glucose or cholesterol metabolism in atherogenic LKO mice.
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Affiliation(s)
- Koji Akita
- Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.)
| | - Kikuo Isoda
- Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.) Division of Cardiovascular Medicine, Department of Internal Medicine 1, National Defense Medical College, Tokorozawa, Japan (K.I.)
| | - Kazunori Shimada
- Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.)
| | - Hiroyuki Daida
- Division of Cardiology, Juntendo University, Hongo, Tokyo, Japan (K.A., K.I., K.S., H.D.)
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Abstract
INTRODUCTION Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety concerns have been raised in recent years. AREAS COVERED An updated review providing an analysis of available safety data (meta-analyses, randomized controlled trials, observational cohort and case-control studies and pharmacovigilance reports) with five commercialized DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin). A special focus is given to overall safety profile; pancreatic adverse events (AEs) (acute pancreatitis, pancreatic cancer); overall cardiovascular safety (myocardial infarction and stroke); congestive heart failure concern and finally, safety in special populations (elderly, renal impairment). EXPERT OPINION The good tolerance/safety profile of DPP-4 inhibitors has been largely confirmed, including in more fragile populations (elderly, renal impairment) with almost no increased risk of infection or gastrointestinal AEs, no weight gain and a minimal risk of hypoglycemia. Although an increased risk of acute pancreatitis and pancreatic cancer was suspected, the complete set of available data appears reassuring so far. Cardiovascular safety of DPP-4 inhibitors has been proven but an unexpected increased risk of heart failure has been reported which should be confirmed in ongoing trials and better understood. Further postmarketing surveillance is recommended.
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Affiliation(s)
- André J Scheen
- University of Liège, CHU Sart Tilman, Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , (B35), B-4000 Liege 1 , Belgium +32 4 3667238 ; +32 4 3667068 ; andre.scheen @ chu.ulg.ac.be
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Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5:817-834. [PMID: 25512784 PMCID: PMC4265868 DOI: 10.4239/wjd.v5.i6.817] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/10/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
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Kaku K, Mori M, Kanoo T, Katou M, Seino Y. Efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes: a randomized, double-blind, 12-week, placebo-controlled trial followed by an open-label, long-term extension phase. Expert Opin Pharmacother 2014; 15:2121-30. [DOI: 10.1517/14656566.2014.956722] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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