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Popović L, Bulum T. New Onset Diabetes After Organ Transplantation: Risk Factors, Treatment, and Consequences. Diagnostics (Basel) 2025; 15:284. [PMID: 39941214 PMCID: PMC11816453 DOI: 10.3390/diagnostics15030284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/15/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
New onset diabetes mellitus after organ transplantation (NODAT) is a frequent and serious complication of solid organ transplantation. It significantly impacts graft function, patient survival, and quality of life. NODAT is diagnosed based on the criteria for type 2 diabetes, with the oral glucose tolerance test (OGTT) serving as the gold standard for diagnosis. The development of NODAT is influenced by a range of risk factors, which are classified into modifiable and non-modifiable categories. Post-transplant, regular glycemic monitoring at specific intervals is essential for timely diagnosis and initiation of therapy. Early intervention can help prevent or delay the onset of diabetes-related complications. The treatment strategy for NODAT involves lifestyle modifications and pharmacological interventions. These include medications such as metformin, sulfonylureas, glinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and insulin. Adjusting immunosuppressive therapy-either by reducing dosages or substituting drugs with lower diabetogenic potential-is a common preventative and therapeutic measure. However, this must be performed cautiously to avoid acute graft rejection, which poses a greater risk to the patient compared to NODAT itself. In addition to managing diabetes, addressing comorbidities such as hypertension and dyslipidemia is crucial, as they elevate the risk of cardiovascular events and mortality. Patients with NODAT are also prone to developing common diabetes-related complications, including diabetic nephropathy, neuropathy, retinopathy, and peripheral vascular disease. Therefore, regular follow-ups and appropriate treatment are vital to maintaining quality of life and improving long-term outcomes.
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Affiliation(s)
- Lucija Popović
- Department of Emergency Medicine, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia
| | - Tomislav Bulum
- School of Medicine, University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
- Department of Diabetes and Endocrinology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Dugi dol 4a, 10000 Zagreb, Croatia
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Srivastava SP, Zhou H, Shenoi R, Morris M, Lainez-Mas B, Goedeke L, Rajendran BK, Setia O, Aryal B, Kanasaki K, Koya D, Inoki K, Dardik A, Bell T, Fernández-Hernando C, Shulman GI, Goodwin JE. Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease. SCIENCE ADVANCES 2024; 10:eadn6068. [PMID: 39630889 PMCID: PMC11616692 DOI: 10.1126/sciadv.adn6068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 10/30/2024] [Indexed: 12/07/2024]
Abstract
Angiopoietin-like 4 (ANGPTL4), a key protein involved in lipoprotein metabolism, has diverse effects. There is an association between Angptl4 and diabetic kidney disease; however, this association has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in stimulator of interferon genes pathway activation, expression of pro-inflammatory cytokines, reduced epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, lessened mitochondrial damage, and increased fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Angptl4 interacts with Integrin β1 and influences the association between dipeptidyl-4 with Integrin β1. We demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the kidneys and protects diabetic kidneys from proteinuria and fibrosis. Together, these data demonstrate that podocyte- and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Han Zhou
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
| | - Rachel Shenoi
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Myshal Morris
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Begoña Lainez-Mas
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
| | - Leigh Goedeke
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Medicine (Cardiology), The Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Ocean Setia
- Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT, USA
| | - Binod Aryal
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Keizo Kanasaki
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- The Center for Integrated Kidney Research and Advance, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Ken Inoki
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Alan Dardik
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT, USA
| | | | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Gerald I. Shulman
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
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Yu SJ, Wang Y, Shen H, Bae EK, Li Y, Sambamurti K, Tones MA, Zaleska MM, Hoffer BJ, Greig NH. DPP-4 inhibitors sitagliptin and PF-00734,200 mitigate dopaminergic neurodegeneration, neuroinflammation and behavioral impairment in the rat 6-OHDA model of Parkinson's disease. GeroScience 2024; 46:4349-4371. [PMID: 38563864 PMCID: PMC11336009 DOI: 10.1007/s11357-024-01116-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70-80% plasma and 20-30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD.
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Affiliation(s)
- Seong-Jin Yu
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan.
- National Institute On Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.
| | - Hui Shen
- National Institute On Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Eun-Kyung Bae
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan
| | - Yazhou Li
- National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Kumar Sambamurti
- Department of Neurosciences, the Medical University of South Carolina, Charleston, SC, 29425, USA
| | | | | | - Barry J Hoffer
- Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Nigel H Greig
- National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.
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Li Y, Vaughan KL, Wang Y, Yu SJ, Bae EK, Tamargo IA, Kopp KO, Tweedie D, Chiang CC, Schmidt KT, Lahiri DK, Tones MA, Zaleska MM, Hoffer BJ, Mattison JA, Greig NH. Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders. GeroScience 2024; 46:4397-4414. [PMID: 38532069 PMCID: PMC11335710 DOI: 10.1007/s11357-024-01120-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/01/2024] [Indexed: 03/28/2024] Open
Abstract
The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.
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Affiliation(s)
- Yazhou Li
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Kelli L Vaughan
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053
| | - Seong-Jin Yu
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053
| | - Eun-Kyung Bae
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053
| | - Ian A Tamargo
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Katherine O Kopp
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - David Tweedie
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Cheng-Chuan Chiang
- Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Keith T Schmidt
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Debomoy K Lahiri
- Departments of Psychiatry and Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | | | | | - Barry J Hoffer
- Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Julie A Mattison
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Nigel H Greig
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.
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Terui S, Igari M, Tsuno T, Okuyama T, Inoue R, Kyohara M, Terauchi Y, Shirakawa J. Immediate Impact of Switching from Dipeptidyl Peptidase 4 (DPP4) Inhibitors to Low-Dose (0.3 mg) Liraglutide on Glucose Profiles: A Retrospective Observational Study. Diabetes Ther 2024; 15:1139-1153. [PMID: 38494572 PMCID: PMC11043256 DOI: 10.1007/s13300-024-01557-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
INTRODUCTION As treatment agents for diabetes, liraglutide is a long-acting glucagon-like peptide 1 receptor agonist, and dipeptidyl peptidase 4 (DPP4) inhibitors are widely used because of their safety and tolerability. Regular treatment with liraglutide has been reported to significantly reduce blood glucose levels, but the impact of low-dose (0.3 mg) liraglutide on blood glucose levels immediately after treatment switching from a DPP4 inhibitor remains unknown. METHODS We conducted a single-arm, retrospective, observational study in 55 inpatients with type 2 diabetes (T2D) to investigate the changes (Δ) in their blood glucose levels at six time points (6-point) from the day before (day -1) to the day after (day 1) by switching the antidiabetic treatment from a DPP4 inhibitor to liraglutide 0.3 mg (low-dose liraglutide) once daily. We also attempted to identify factors associated with the blood glucose-lowering effects of liraglutide. RESULTS The median values of the changes in fasting, preprandial, and postprandial blood glucose levels and the fluctuations in the blood glucose levels expressed as the standard deviation of the 6-point blood glucose levels were significantly lower on day 1 than on day -1 (P < 0.05, P < 0.0001, P < 0.0001, P < 0.01, respectively); there were no cases of severe hypoglycemia. The Δ blood glucose levels were not associated with the baseline serum hemoglobin A1c values or with any markers of the insulin secreting capacity. There were no associations between the previously used blood glucose-lowering drug and the Δ blood glucose levels. CONCLUSION Switching from a DPP4 inhibitor to low-dose (0.3 mg) liraglutide once daily significantly reduced the blood glucose levels and excursions of the blood glucose levels even from the very day after the treatment switch, with no serious adverse events.
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Affiliation(s)
- Sakiko Terui
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Mari Igari
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, 236-0004, Japan.
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan.
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Alade AA, Ahmed SA, Mujwar S, Kikiowo B, Akinnusi PA, Olubode SO, Olufemi OM, Ohilebo AA. Identification of levomenthol derivatives as potential dipeptidyl peptidase-4 inhibitors: a comparative study with gliptins. J Biomol Struct Dyn 2024; 42:4029-4047. [PMID: 37261796 DOI: 10.1080/07391102.2023.2217927] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/20/2023] [Indexed: 06/02/2023]
Abstract
Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Adebowale A Alade
- Department of Biochemistry, Adekunle Ajasin University, Ondo, Nigeria
| | - Samad A Ahmed
- Department of Biochemistry, Adekunle Ajasin University, Ondo, Nigeria
| | - Somdutt Mujwar
- Chitkara College of Pharmacy, Chitkara University, Punjab, Rajpura, India
| | | | | | - Samuel O Olubode
- Department of Biochemistry, Adekunle Ajasin University, Ondo, Nigeria
| | | | - Abass A Ohilebo
- Department of Biochemistry, Faculty of Life Sciences, Ambrose Ali University Ekpoma, Edo, Nigeria
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Cui C, Cao F, Kong II, Wu Q, Li F, Li H, Liu D. A model-informed approach to accelerate the clinical development of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 inhibitor. Diabetes Obes Metab 2024; 26:592-601. [PMID: 37953687 DOI: 10.1111/dom.15348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 11/14/2023]
Abstract
AIM To employ a model-informed drug development approach in facilitating decision making and expediting the clinical progress of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of type 2 diabetes (T2D) via a biweekly dosing regimen. METHODS Firstly, a population pharmacokinetics and pharmacodynamics (PopPKPD) model was developed using PK and PD data from a single ascending dose study to simulate the PK and PD time profiles of HSK7653 after multiple doses. Secondly, model-based meta-analysis (MBMA) was performed on published clinical studies of Eastern Asian subjects for all DPP-4 inhibitors. We hypothesized a consistent relationship between PK and DPP-4 inhibition in both healthy individuals and in those with T2D, establishing a quantitative correlation between DPP-4 inhibition and HbA1c. Finally, the predicted PK/DPP-4 inhibition/HbA1c profiles were validated by T2D patients in late clinical trials. RESULTS The PK/DPP-4 inhibition/HbA1c profiles of T2D patients treated with HSK7653 matched the modelled data. Our PopPKPD and MBMA models predict multiple ascending dosing PK and PD characteristics from single ascending dosing data, as well as the long-term efficacy in T2D patients, based on healthy subjects. CONCLUSIONS Successful waiver approval for the phase 2b dose-finding study was achieved through model-informed recommendations, facilitating the clinical development of HSK7653 and other DPP-4 inhibitors.
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Affiliation(s)
- Cheng Cui
- Geriatrics Department, Peking University Third Hospital, Beijing, China
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Fangrui Cao
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Iok Ian Kong
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
- School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China
| | - Qinghe Wu
- Haisco Pharmaceutical Group Co. Ltd, Chengdu, China
| | - Fangqiong Li
- Haisco Pharmaceutical Group Co. Ltd, Chengdu, China
| | - Haiyan Li
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China
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Złotek M, Kurowska A, Herbet M, Piątkowska-Chmiel I. GLP-1 Analogs, SGLT-2, and DPP-4 Inhibitors: A Triad of Hope for Alzheimer's Disease Therapy. Biomedicines 2023; 11:3035. [PMID: 38002034 PMCID: PMC10669527 DOI: 10.3390/biomedicines11113035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/07/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Alzheimer's is a prevalent, progressive neurodegenerative disease marked by cognitive decline and memory loss. The disease's development involves various pathomechanisms, including amyloid-beta accumulation, neurofibrillary tangles, oxidative stress, inflammation, and mitochondrial dysfunction. Recent research suggests that antidiabetic drugs may enhance neuronal survival and cognitive function in diabetes. Given the well-documented correlation between diabetes and Alzheimer's disease and the potential shared mechanisms, this review aimed to comprehensively assess the potential of new-generation anti-diabetic drugs, such as GLP-1 analogs, SGLT-2 inhibitors, and DPP-4 inhibitors, as promising therapeutic approaches for Alzheimer's disease. This review aims to comprehensively assess the potential therapeutic applications of novel-generation antidiabetic drugs, including GLP-1 analogs, SGLT-2 inhibitors, and DPP-4 inhibitors, in the context of Alzheimer's disease. In our considered opinion, antidiabetic drugs offer a promising avenue for groundbreaking developments and have the potential to revolutionize the landscape of Alzheimer's disease treatment.
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Affiliation(s)
| | | | | | - Iwona Piątkowska-Chmiel
- Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 8b Street, 20-090 Lublin, Poland; (M.Z.); (A.K.); (M.H.)
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Scheen AJ. Pharmacokinetic, toxicological, and clinical considerations for the treatment of type 2 diabetes in patients with liver disease: a comprehensive update. Expert Opin Drug Metab Toxicol 2023; 19:543-553. [PMID: 37620287 DOI: 10.1080/17425255.2023.2252333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 08/26/2023]
Abstract
INTRODUCTION Type 2 diabetes and liver disease, mainly metabolic-associated fatty liver disease (MAFLD) and more rarely cirrhosis, coexist in many patients. This duality has direct implications for the physician when choosing glucose-lowering agents, with classical concerns but also recent new hopes. AREAS COVERED This updated comprehensive review will consider the pharmacokinetics, the tolerance/safety profile, the benefit/risk balance in cirrhosis, the effects on MAFLD and the risk of hepatocellular carcinoma of old and new glucose-lowering compounds in patients with liver disease, with a special focus on glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. EXPERT OPINION We are currently facing a new paradigm in the management of patients with diabetes and liver disease. From previous reluctance when using antidiabetic agents (except insulin) in diabetic patients with hepatic impairment because of safety concerns, the commercialization of novel glucose-lowering agents has changed the scene. These agents, which have a good safety profile, are associated with weight loss and pleiotropic effects. They have proven their efficacy in improving MAFLD. However, more specific studies are still needed to prove their efficacy in preventing the progression to fibrosis/cirrhosis and confirm this new opportunity for the management of patients with diabetes and liver disease.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium
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Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front Mol Biosci 2023; 10:1130625. [PMID: 37287751 PMCID: PMC10242023 DOI: 10.3389/fmolb.2023.1130625] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/08/2023] [Indexed: 06/09/2023] Open
Abstract
DPP-4 inhibition is an interesting line of therapy for treating Type 2 Diabetes Mellitus (T2DM) and is based on promoting the incretin effect. Here, the authors have presented a brief appraisal of DPP-4 inhibitors, their modes of action, and the clinical efficiency of currently available drugs based on DPP-4 inhibitors. The safety profiles as well as future directions including their potential application in improving COVID-19 patient outcomes have also been discussed in detail. This review also highlights the existing queries and evidence gaps in DPP-4 inhibitor research. Authors have concluded that the excitement surrounding DPP-4 inhibitors is justified because in addition to controlling blood glucose level, they are good at managing risk factors associated with diabetes.
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11
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Scheen AJ. Clinical pharmacology of antidiabetic drugs: What can be expected of their use? Presse Med 2023; 52:104158. [PMID: 36565754 DOI: 10.1016/j.lpm.2022.104158] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
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12
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Comparison of Adverse Events Occurred During Administration of Dipeptidyl Peptidase-4 Inhibitor in Patients with Diabetes Using FDA Adverse Event Reporting System. Clin Drug Investig 2023; 43:129-140. [PMID: 36637688 DOI: 10.1007/s40261-022-01242-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND OBJECTIVE Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been approved for the treatment of diabetes. The frequencies of known serious side effects might differ among DPP-4 inhibitors, therefore a large sample size is needed to study them in prospective clinical trials. We examined the adverse events that occurred during the administration of a DPP-4 inhibitor in patients with diabetes using FDA Adverse Event Reporting System (FAERS) data. METHODS We used FAERS data reported between January 2013 and March 2022 in patients with diabetes who received a DPP-4 inhibitor. Statistical analyses were conducted to calculate reporting odds ratio (ROR) and adjusted ROR (aROR) controlling for differences in patient background. RESULTS The 9 target DPP-4 inhibitors were sitagliptin (N = 26,843), vildagliptin (N = 4767), alogliptin (N = 2085), linagliptin (N = 7969), saxagliptin (N = 3334), teneligliptin (N = 461), anagliptin (N = 102), trelagliptin (N = 17), and omarigliptin (N = 12). Compared with sitagliptin, aROR of acute kidney injury was significantly < 1.000 for alogliptin (0.247 [95% confidence interval (CI) 0.150-0.408], p < 0.001) but aROR of pemphigoid was significantly > 1.000 for alogliptin (3.082 [95% CI 2.156-4.406], p < 0.001). Similar statistical analyses were conducted for other adverse events and the types of adverse events with aROR of significantly < 1.000 or > 1.000 differed depending on the type of DPP-4 inhibitor. CONCLUSIONS Although it is impossible to select a DPP-4 inhibitor with aROR of < 1.000 of all occurrences of adverse events, these results may be used for drug selection when the patient has adverse events that need to be avoided. We provided the sample code of software R that can reproduce the results.
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13
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Ferrari F, Moretti A, Villa RF. Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives. Pharmacol Ther 2022; 239:108277. [DOI: 10.1016/j.pharmthera.2022.108277] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
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14
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Xu J, Ling H, Geng J, Investigators, Huang Y, Xie Y, Zheng H, Niu H, Zhang T, Yuan J, Xiao X. Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes: A 24-week, multi-centre, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial. Diabetes Obes Metab 2022; 24:2232-2240. [PMID: 35791646 PMCID: PMC9796963 DOI: 10.1111/dom.14810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/24/2022] [Accepted: 07/01/2022] [Indexed: 01/07/2023]
Abstract
AIM To evaluate the efficacy and safety of DBPR108 (prusogliptin), a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, as an add-on therapy in patients with type 2 diabetes (T2D) that is inadequately controlled with metformin. MATERIALS AND METHODS In this 24-week, multi-centre, randomized, double-blind, placebo-controlled, superiority, phase III study, adult T2D patients with HbA1c levels ranging from 7.0% to 9.5% on stable metformin were enrolled and randomized (2:1) into the DBPR108 + metformin and placebo + metformin groups. The primary endpoint was the change from baseline in HbA1c at week 24 of DBPR108 versus placebo as an add-on therapy to metformin. RESULTS At week 24, the least-square mean (standard error) change from baseline in HbA1c was significantly greater in the DBPR108 group (-0.70% [0.09%]) than in the placebo group (-0.07% [0.11%]) (P < .001), with a treatment difference of -0.63% (95% confidence interval: -0.87%, -0.39%) on the full analysis set. A higher proportion of patients achieved an HbA1c of 6.5% or less (19.7% vs. 8.5%) and an HbA1c of 7.0% or less (50.0% vs. 21.1%) at week 24 in the DBPR108 + metformin group. Furthermore, add-on DBPR108 produced greater reductions from baseline in fasting plasma glucose and 2-hour postprandial plasma glucose without causing weight gain. The overall frequency of adverse events was similar between the two groups. CONCLUSIONS DBPR108 as add-on therapy to metformin offered a significant improvement in glycaemic control, was superior to metformin monotherapy (placebo) and was safe and well-tolerated in patients with T2D that is inadequately controlled with metformin.
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Affiliation(s)
- Jianping Xu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College HospitalPeking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
| | - Hongwei Ling
- Department of EndocrinologyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
| | - Jianlin Geng
- Department of EndocrinologyHarrison International Peace HospitalHengshuiChina
| | - Investigators
- Details of the rest investigators can be found in the supporting informationlist of investigators
| | - Yanli Huang
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.ShijiazhuangChina
| | - Ying Xie
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.ShijiazhuangChina
| | - Huiping Zheng
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.ShijiazhuangChina
| | - Huikun Niu
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.ShijiazhuangChina
| | - Tianhao Zhang
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.ShijiazhuangChina
| | - Jing Yuan
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.ShijiazhuangChina
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College HospitalPeking Union Medical College, Chinese Academy of Medical SciencesBeijingChina
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15
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Li JH, Florez JC. On the Verge of Precision Medicine in Diabetes. Drugs 2022; 82:1389-1401. [PMID: 36123514 PMCID: PMC9531144 DOI: 10.1007/s40265-022-01774-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 11/03/2022]
Abstract
The epidemic of type 2 diabetes (T2D) is a significant global public health challenge and a major cause of morbidity and mortality. Despite the recent proliferation of pharmacological agents for the treatment of T2D, current therapies simply treat the symptom, i.e. hyperglycemia, and do not directly address the underlying disease process or modify the disease course. This article summarizes how genomic discovery has contributed to unraveling the heterogeneity in T2D, reviews relevant discoveries in the pharmacogenetics of five commonly prescribed glucose-lowering agents, presents evidence supporting how pharmacogenetics can be leveraged to advance precision medicine, and calls attention to important research gaps to its implementation to guide treatment choices.
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Affiliation(s)
- Josephine H Li
- Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Simches Research Building, CPZN 5.250, 185 Cambridge St, Boston, MA, 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Simches Research Building, CPZN 5.250, 185 Cambridge St, Boston, MA, 02114, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
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Mozafari N, Dehshahri A, Ashrafi H, Mohammadi-Samani S, Shahbazi MA, Heidari R, Azarpira N, Azadi A. Vesicles of yeast cell wall-sitagliptin to alleviate neuroinflammation in Alzheimer's disease. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 44:102575. [PMID: 35714923 DOI: 10.1016/j.nano.2022.102575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/26/2022] [Accepted: 06/05/2022] [Indexed: 06/15/2023]
Abstract
A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the "Trojan Horse" effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.
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Affiliation(s)
- Negin Mozafari
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Dehshahri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hajar Ashrafi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soliman Mohammadi-Samani
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad-Ali Shahbazi
- Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, 45139-56184 Zanjan, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Azadi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran.
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17
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Guo Z, Kong F, Xie N, Chen Z, Hu J, Chen X. Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite. Pharm Res 2022; 39:2147-2162. [PMID: 35790618 DOI: 10.1007/s11095-022-03324-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/24/2022] [Indexed: 12/01/2022]
Abstract
PURPOSE To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 μM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.
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Affiliation(s)
- Zitao Guo
- School of Environmental Chemistry and Engineering, Shanghai University, 99 Shangda Road BaoShan District, Shanghai, 200444, China.,Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Fandi Kong
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ningjie Xie
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhendong Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Jiafeng Hu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyan Chen
- School of Environmental Chemistry and Engineering, Shanghai University, 99 Shangda Road BaoShan District, Shanghai, 200444, China. .,Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
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18
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Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules 2022; 27:3055. [PMID: 35630534 PMCID: PMC9147686 DOI: 10.3390/molecules27103055] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/02/2022] [Accepted: 05/07/2022] [Indexed: 02/07/2023] Open
Abstract
In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.
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Affiliation(s)
| | | | | | | | - Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China; (R.Y.); (Y.X.); (X.W.); (L.Y.)
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19
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Mottl AK, Alicic R, Argyropoulos C, Brosius FC, Mauer M, Molitch M, Nelson RG, Perreault L, Nicholas SB. KDOQI US Commentary on the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD. Am J Kidney Dis 2022; 79:457-479. [PMID: 35144840 PMCID: PMC9740752 DOI: 10.1053/j.ajkd.2021.09.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/14/2022]
Abstract
In October 2020, KDIGO (Kidney Disease: Improving Global Outcomes) published its first clinical practice guideline directed specifically to the care of patients with diabetes and chronic kidney disease (CKD). This commentary presents the views of the KDOQI (Kidney Disease Outcomes Quality Initiative) work group for diabetes in CKD, convened by the National Kidney Foundation to provide an independent expert perspective on the new guideline. The KDOQI work group believes that the KDIGO guideline takes a major step forward in clarifying glycemic targets and use of specific antihyperglycemic agents in diabetes and CKD. The purpose of this commentary is to carry forward the conversation regarding optimization of care for patients with diabetes and CKD. Recent developments for prevention of CKD progression and cardiovascular events in people with diabetes and CKD, particularly related to sodium/glucose cotransporter 2 (SGLT2) inhibitors, have filled a longstanding gap in nephrology's approach to the care of persons with diabetes and CKD. The multifaceted benefits of SGLT2 inhibitors have facilitated interactions between nephrology, cardiology, endocrinology, and primary care, underscoring the need for innovative approaches to multidisciplinary care in these patients. We now have more interventions to slow kidney disease progression and prevent or delay kidney failure in patients with diabetes and kidney disease, but methods to streamline their implementation and overcome barriers in access to care, particularly cost, are essential to ensuring all patients may benefit.
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20
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Lin C, Kong Y, Wang F, Rong R, Li X, Xiao R, Wu Z, Zhang Q, Wang L. Design, synthesis and evaluation of a series of novel long-acting dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. Bioorg Chem 2022; 123:105767. [PMID: 35381556 DOI: 10.1016/j.bioorg.2022.105767] [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: 08/15/2021] [Revised: 01/25/2022] [Accepted: 03/24/2022] [Indexed: 11/19/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most popular chronic diseases around the whole world. To improve the compliance of patients, long-acting antidiabetic drugs needed to be developed. Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming increasingly important in the T2DM treatment due to the favorable properties. In the present study, a series of new substituted dihydropyrido [4',3':3,4] pyrazolo [1,5-a] pyrimidin-9(10H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine were designed and synthesized as potent DPP-4 inhibitors. All compounds were characterized by 1H NMR, 13C NMR and HRMS and were evaluated in vitro. The inhibitory activity ranged from 0.43 to 12.70 μM while the inhibitory activity of positive control (omarigliptin) was 3.63 μM on DPP-4 in Caco-2 cells. Then pharmacokinetic studies were carried out in rats and compound 6c was finally selected for the further study because of its better pharmacokinetic profile. Additionally, preclinical pharmacological study of compound 6c exhibited extraordinary efficacy in vivo and good safety profile. In conclusion, compound 6c was considered as a promising DPP-4 inhibitor, which could be taken once a week or once every two weeks for the treatment of T2DM. More comprehensive researches will be carried out in the future for the further development of compound 6c.
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Affiliation(s)
- Chao Lin
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
| | - Ying Kong
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
| | - Furong Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Rong Rong
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
| | - Xiangping Li
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
| | - Rensong Xiao
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Ziqi Wu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China
| | - Qiuyan Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China.
| | - Lin Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
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21
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Montero N, Oliveras L, Soler MJ, Cruzado JM. Management of post-transplant diabetes mellitus: an opportunity for novel therapeutics. Clin Kidney J 2022; 15:5-13. [PMID: 35265335 PMCID: PMC8901587 DOI: 10.1093/ckj/sfab131] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Indexed: 12/16/2022] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common problem after kidney transplantation (KT), occurring in 50% of high-risk recipients. The clinical importance of PTDM lies in its impact as a significant risk factor for cardiovascular and chronic kidney disease (CKD) after solid organ transplantation. Kidney Disease: Improving Global Outcomes (KDIGO) has recently updated the treatment guidelines for diabetes management in CKD with emphasis on the newer antidiabetic agents such as dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors as add-on therapy to metformin. Given all these new diabetes treatments and the updated KDIGO guidelines, it is necessary to evaluate and give guidance on their use for DM management in KT recipients. This review summarizes the scarce published literature about the use of these new agents in the KT field. In summary, it is absolutely necessary to generate evidence in order to be able to safely use these new treatments in the KT population to improve blood glucose control, but specially to evaluate their potential cardiovascular and renal benefits that would seem to be independent of blood glucose control in PTDM patients.
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Affiliation(s)
- Nuria Montero
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Laia Oliveras
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Maria José Soler
- Department of Nephrology, Hospital Vall d'Hebron, Barcelona, Spain
| | - Josep Maria Cruzado
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
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22
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Wang L, Li X, Kong Y, Wang F, Zhang Q, Lin C, Rong R. Pharmacokinetics, tissue distribution and excretion of compound 6c, a novel DPP-4 inhibitor, following intragastric administration in rats by ultra-performance liquid chromatography-tandem mass spectrometry. Eur J Pharm Sci 2022; 173:106162. [PMID: 35248731 DOI: 10.1016/j.ejps.2022.106162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 12/16/2021] [Accepted: 03/02/2022] [Indexed: 11/03/2022]
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Nasr NE, Sadek KM. Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:18408-18422. [PMID: 35031999 DOI: 10.1007/s11356-022-18534-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/03/2022] [Indexed: 06/14/2023]
Abstract
Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.
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Affiliation(s)
- Nasr E Nasr
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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Di Mizio G, Marcianò G, Palleria C, Muraca L, Rania V, Roberti R, Spaziano G, Piscopo A, Ciconte V, Di Nunno N, Esposito M, Viola P, Pisani D, De Sarro G, Raffi M, Piras A, Chiarella G, Gallelli L. Drug-Drug Interactions in Vestibular Diseases, Clinical Problems, and Medico-Legal Implications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:12936. [PMID: 34948545 PMCID: PMC8701970 DOI: 10.3390/ijerph182412936] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/28/2021] [Accepted: 12/03/2021] [Indexed: 12/23/2022]
Abstract
Peripheral vestibular disease can be treated with several approaches (e.g., maneuvers, surgery, or medical approach). Comorbidity is common in elderly patients, so polytherapy is used, but it can generate the development of drug-drug interactions (DDIs) that play a role in both adverse drug reactions and reduced adherence. For this reason, they need a complex kind of approach, considering all their individual characteristics. Physicians must be able to prescribe and deprescribe drugs based on a solid knowledge of pharmacokinetics, pharmacodynamics, and clinical indications. Moreover, full information is required to reach a real therapeutic alliance, to improve the safety of care and reduce possible malpractice claims related to drug-drug interactions. In this review, using PubMed, Embase, and Cochrane library, we searched articles published until 30 August 2021, and described both pharmacokinetic and pharmacodynamic DDIs in patients with vestibular disorders, focusing the interest on their clinical implications and on risk management strategies.
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Affiliation(s)
- Giulio Di Mizio
- Department of Law, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Gianmarco Marcianò
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
| | - Caterina Palleria
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
| | - Lucia Muraca
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
- Department of Primary Care, ASP 7, 88100 Catanzaro, Italy
| | - Vincenzo Rania
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
| | - Roberta Roberti
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
| | - Giuseppe Spaziano
- Department of Experimental Medicine L. Donatelli, Section of Pharmacology, School of Medicine, University of Campania Luigi Vanvitelli, 80123 Naples, Italy
| | - Amalia Piscopo
- Department of Law, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Valeria Ciconte
- Department of Law, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
| | - Nunzio Di Nunno
- Department of History, Society and Studies on Humanity, University of Salento, 83100 Lecce, Italy
| | - Massimiliano Esposito
- Department of Medical, Surgical Sciences and Advanced Technologies "G. F. Ingrassia", University of Catania, 95121 Catania, Italy
| | - Pasquale Viola
- Unit of Audiology, Department of Experimental and Clinical Medicine, Regional Centre of Cochlear Implants and ENT Diseases, Magna Graecia University, 88100 Catanzaro, Italy
| | - Davide Pisani
- Unit of Audiology, Department of Experimental and Clinical Medicine, Regional Centre of Cochlear Implants and ENT Diseases, Magna Graecia University, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
- Research Center FAS@UMG, Department of Health Science, University of Catanzaro, 88100 Catanzaro, Italy
| | - Milena Raffi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
| | - Alessandro Piras
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
| | - Giuseppe Chiarella
- Unit of Audiology, Department of Experimental and Clinical Medicine, Regional Centre of Cochlear Implants and ENT Diseases, Magna Graecia University, 88100 Catanzaro, Italy
| | - Luca Gallelli
- Department of Health Science, School of Medicine, University of Catanzaro, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, 88100 Catanzaro, Italy
- Research Center FAS@UMG, Department of Health Science, University of Catanzaro, 88100 Catanzaro, Italy
- Medifarmagen SRL, University of Catanzaro, 88100 Catanzaro, Italy
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Daza-Arnedo R, Rico-Fontalvo JE, Pájaro-Galvis N, Leal-Martínez V, Abuabara-Franco E, Raad-Sarabia M, Montejo-Hernández J, Cardona-Blanco M, Cabrales-Juan J, Uparella-Gulfo I, Montiel LS. Dipeptidyl Peptidase-4 Inhibitors and Diabetic Kidney Disease: A Narrative Review. Kidney Med 2021; 3:1065-1073. [PMID: 34939016 PMCID: PMC8664739 DOI: 10.1016/j.xkme.2021.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Diabetic kidney disease is one of the most frequent complications in patients with diabetes mellitus and affects morbidity and mortality. The recent therapies include oral hypoglycemic drugs that, in addition to optimizing glycemic control and reducing the risk of hypoglycemia, may affect the development and progression of diabetic kidney disease; these novel therapies include inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4), a group of oral hypoglycemic therapeutic agents that act at the level of the incretin system. DPP-4 inhibitors show additional pleiotropic effects in in vitro models, reducing inflammation, fibrosis, and oxidative damage, further suggesting potential kidney protective effects. Although existing trials suggest a possible benefit in the progression of diabetic kidney disease, further studies are needed to demonstrate kidney-specific benefits of DPP-4 inhibitors.
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Affiliation(s)
- Rodrigo Daza-Arnedo
- Nuevo Hospital Bocagrande, Comité de Nefrodiabetes, Asociación Colombiana de Nefrología, Cartagena, Colombia
| | | | | | | | | | - María Raad-Sarabia
- Departamento de Medicina Interna, Universidad del Sinú, Cartagena, Colombia
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Kosman VM, Karlina MV, Faustova NM, Makarov VG, Makarova MN. Comparison of biomarker and chromatographic analytical approaches to pharmacokinetic study of sitagliptin. Biopharm Drug Dispos 2021; 43:3-10. [PMID: 34724222 DOI: 10.1002/bdd.2305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 09/29/2021] [Accepted: 10/26/2021] [Indexed: 11/06/2022]
Abstract
The pharmacokinetic profiling of active compounds is necessary for drug development and application. Approaches to a pharmacokinetic study based on biological markers are alternatives to traditional approaches based on chromatographic methods. The aim of the study was to compare two analytical approaches to pharmacokinetics investigation for an example of sitagliptin in rabbits after one dose oral administration. The method for sitagliptin quantification in rabbit plasma samples based on a correlation between its concentration and dipeptidyl peptidase IV activity was proposed, validated, and applied. The high-performance liquid chromatography (HPLC)-ultraviolet (UV) method was also validated and applied for the same sample analysis. The plasma pharmacokinetics of sitagliptin after oral administration to the rabbits in one dose was characterized after two analytical assays. The close values of the main pharmacokinetic parameters were obtained after two approaches. The nontraditional approach based on correlation of special marker activity and active substance concentration appears to be more sensitive than HPLC-UV. Thus, the sitagliptin concentrations determined by biomarker assay were higher than the lower limit of quantification (LLOQ) for a longer period (more timepoints) than after the HPLC-UV assay. This feature may influence the values of some calculated concentration-dependent (area under the curve [AUC]0-t , etc.) and time-dependent parameters (mean residence time [MRT], T1/2 , etc.). The values of Tmax obtained by the two approaches were similar and adequate for oral drug administration that confirms the correctness of biomarker selection for pharmacokinetics assessment. The obtained results on the example of sitagliptin confirms that the biomarker approach is adequate and applicable for a pharmacokinetics study. Similar approaches may be effective for individual compounds and complex mixtures when it is difficult or impossible to analyze them traditionally by chromatographic methods.
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Affiliation(s)
- Vera M Kosman
- St.-Petersburg Institute of Pharmacy, Leningrad region, Russian Federation
| | - Marina V Karlina
- St.-Petersburg Institute of Pharmacy, Leningrad region, Russian Federation
| | - Natalia M Faustova
- St.-Petersburg Institute of Pharmacy, Leningrad region, Russian Federation
| | - Valery G Makarov
- St.-Petersburg Institute of Pharmacy, Leningrad region, Russian Federation
| | - Marina N Makarova
- St.-Petersburg Institute of Pharmacy, Leningrad region, Russian Federation
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28
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Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol 2021; 17:227-244. [PMID: 33219281 DOI: 10.1038/s41581-020-00367-2] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 01/30/2023]
Abstract
As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.
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Affiliation(s)
- Radica Z Alicic
- Providence Medical Research Center, Providence Health Care, Spokane, WA, USA.,Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, WA, USA
| | - Emily J Cox
- Providence Medical Research Center, Providence Health Care, Spokane, WA, USA
| | - Joshua J Neumiller
- Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| | - Katherine R Tuttle
- Providence Medical Research Center, Providence Health Care, Spokane, WA, USA. .,Nephrology Division, Kidney Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, WA, USA.
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29
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Duan S, Lu F, Song D, Zhang C, Zhang B, Xing C, Yuan Y. Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2021; 12:661185. [PMID: 34177803 PMCID: PMC8223745 DOI: 10.3389/fendo.2021.661185] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/21/2021] [Indexed: 12/29/2022] Open
Abstract
Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.
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Baksh SN, Segal JB, McAdams-DeMarco M, Kalyani RR, Alexander GC, Ehrhardt S. Dipeptidyl peptidase-4 inhibitors and cardiovascular events in patients with type 2 diabetes, without cardiovascular or renal disease. PLoS One 2020; 15:e0240141. [PMID: 33057387 PMCID: PMC7561135 DOI: 10.1371/journal.pone.0240141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/20/2020] [Indexed: 12/13/2022] Open
Abstract
Background Cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) in patients without cardiovascular or renal disease, a majority of newly diagnosed patients with type 2 diabetes often excluded from clinical trials on this association, is poorly understood. Thus, we investigate the risk of major adverse cardiovascular events (MACE) associated with DPP-4i in low-risk patients with diabetes Methods Using a new-user retrospective cohort derived from IBM MarketScan Commercial Claims and Encounters (2010–2015), we identified patients aged 35–65 with type 2 diabetes, without cardiovascular or renal disease, initiating DPP-4i, sulfonylureas, or metformin. Primary composite outcome of time to first MACE was defined as the first of any of the following: myocardial infarction, cardiac arrest, coronary artery bypass graft, coronary angioplasty, heart failure, and stroke. Secondary outcomes were time to first heart failure, acute myocardial infarction, and stroke. We compared outcomes for DPP-4i versus sulfonylurea and DPP-4i versus metformin using propensity score weighted Cox proportional hazards, adjusting for demographics, baseline comorbidities, concomitant medications, and cumulative exposure. Results Of 445,701 individuals, 236,431 (53.0%) were male, median age was 51 (interquartile range: [44, 57]), 30,267 (6.79%) initiated DPP-4i, 52,138 (11.70%) initiated sulfonylureas, and 367,908 (82.55%) initiated metformin. After adjustment, DPP-4i was associated with lower risk of MACE than sulfonylurea (adjusted hazard ratio (aHR) = 0.87; 95% confidence interval (CI): 0.78–0.98), and similar risk to metformin (aHR = 1.07; 95% CI: 0.97–1.18). Risk for acute myocardial infarction (aHR = 0.70; 95% CI: 0.51–0.96), stroke (aHR = 0.57; 95% CI: 0.41–0.79), and heart failure (aHR = 0.57; 95% CI: 0.41–0.79) with DPP-4i was lower compared to sulfonylureas. Conclusion Our findings show that for this cohort of low-risk patients newly treated for type 2 diabetes, DPP-4i exhibited 13% lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin, suggesting DPP-4i is a low cardiovascular risk option for low-risk patients initiating antihyperglycemic treatment.
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Affiliation(s)
- Sheriza N. Baksh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MD, United States of America
- * E-mail:
| | - Jodi B. Segal
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MD, United States of America
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Center for Health Services and Outcomes Research, Johns Hopkins University, Baltimore, MD, United States of America
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, United States of America
| | - Mara McAdams-DeMarco
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MD, United States of America
| | - Rita R. Kalyani
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - G. Caleb Alexander
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MD, United States of America
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, United States of America
| | - Stephan Ehrhardt
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
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Formulation development of linagliptin solid lipid nanoparticles for oral bioavailability enhancement: role of P-gp inhibition. Drug Deliv Transl Res 2020; 11:1166-1185. [PMID: 32804301 DOI: 10.1007/s13346-020-00839-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Linagliptin (LGP), a novel anti-diabetic drug, is a DPP-4 inhibitor used in the treatment of type II diabetes. One of the major disadvantages of LGP is its low oral bioavailability (29.5%) due to first-pass metabolism and P-gp efflux. In an attempt to increase the oral bioavailability, LGP solid lipid nanoparticles (LGP-SLNs) were developed with poloxamer 188 and Tween 80 as P-gp inhibitors. LGP-SLNs were formulated using palmitic acid, poloxamer 188 and Tween 80 as lipid, surfactant and co-surfactant, respectively, by hot homogenization ultrasonication method and optimized using 32 full factorial designs. Particle size, entrapment efficiency (%EE) and drug release at 24 h were evaluated as responses. An optimized batch of LGP-SLNs (L12) was evaluated for intestinal transport of LGP by conducting in situ single-pass intestinal perfusion (SPIP), everted gut sac and Caco-2 permeability study. The pharmacokinetic and pharmacodynamic evaluation of L12 was carried out in albino Wistar rats. The mean particle size, polydispersity index, zeta potential and %EE of L12 were found to be 225.96 ± 2.8 nm, 0.180 ± 0.034, - 5.4 ± 1.07 mV and 73.8 ± 1.73%, respectively. %CDR of 80.96 ± 3.13% was observed in 24 h. The permeability values of LGP-SLNs in the absorptive direction were 1.82-, 1.76- and 1.74-folds higher than LGP-solution (LGP-SOL) in SPIP, everted gut sac and Caco-2 permeability studies, respectively. LGP-SLNs exhibited relative bioavailability of 300% and better reduction in glucose levels in comparison with LGP-SOL in rats. The enhanced oral bioavailability exhibited by LGP-SLNs bioavailability may be due to P-gp efflux inhibition and lymphatic targeting. Improved bioabsorption can cause reduction in dose, dose-related side effects and frequency of administration. Thus, LGP-SLNs can be considered promising carriers for oral delivery but clinical studies are required to confirm the proof of concept.Graphical abstract.
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32
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Wang W, Yao J, Guo X, Guo Y, Yan C, Liu K, Zhang Y, Wang X, Li H, Wen Z, Wang X, Li S, Xiao X, Liu W, Li Z, Zhang L, Shao S, Ye S, Qin G, Li Y, Li F, Zhang X, Li X, Peng Y, Deng H, Xu X, Zhou L, Huang Y, Cao M, Xia X, Shi M, Dou J, Yuan J. Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial. Curr Med Res Opin 2020; 36:1107-1115. [PMID: 32338063 DOI: 10.1080/03007995.2020.1761311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 ± 0.77 in placebo group, -0.51 ± 0.71, -0.75 ± 0.73, and -0.57 ± 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c ≤7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.
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Affiliation(s)
- Wei Wang
- Peking University First Hospital, Beijing, China
| | - Jun Yao
- Peking University First Hospital, Beijing, China
| | - Xiaohui Guo
- Peking University First Hospital, Beijing, China
| | - Yushan Guo
- Affiliated Hospital of Beihua University, Jilin, China
| | - Chaoli Yan
- The Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia, China
| | - Kuanzhi Liu
- The Third Hospital of Hebei Medical University, Hebei, China
| | - Ying Zhang
- The Third Affiliated Hospital of Guangzhou Medical University, Guangdong, China
| | - Xiaoyue Wang
- The First People's Hospital of Yueyang, Hunan, China
| | - Hongmei Li
- Emergency General Hospital, Beijing, China
| | | | - Xinling Wang
- Xinjiang Uiger Municipal People's Hospital, Xinjiang, China
| | - Shuangqing Li
- West China Hospital, Sichuan University, Sichuan, China
| | - Xinhua Xiao
- Peking Union Medical College Hospital, Beijing, China
| | - Weijuan Liu
- Chongqing Three Gorges Central Hospital, Chongqing, China
| | - Ziling Li
- Inner Mongolia Baogang Hospital, Inner Mongolia, China
| | - Lihui Zhang
- The second Hospital of Hebei Medical University, Hebei, China
| | - Shiying Shao
- Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | | | - Guijun Qin
- The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Yiming Li
- Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Feng Li
- Jining First People's Hospital, Shandong, China
| | - Xiaomei Zhang
- The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | | | | | | | - Xiangjin Xu
- 900 Hospital of the Joint Logistics Support Force of Chinese PLA, Fujian, China
| | | | - Yanli Huang
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Hebei, China
| | - Mengya Cao
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Hebei, China
| | - Xuefang Xia
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Hebei, China
| | - Mingbiao Shi
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Hebei, China
| | - Jing Dou
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Hebei, China
| | - Jing Yuan
- CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Hebei, China
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Ferrari F, Moretti A, Villa RF. The treament of hyperglycemia in acute ischemic stroke with incretin-based drugs. Pharmacol Res 2020; 160:105018. [PMID: 32574826 DOI: 10.1016/j.phrs.2020.105018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/21/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022]
Abstract
Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy. The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM. This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.
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Affiliation(s)
- Federica Ferrari
- Department of Advanced Diagnostic and Therapeutic Technologies, Section of Neuroradiology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy; Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Antonio Moretti
- Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Roberto Federico Villa
- Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". J Nephrol 2020; 33:9-35. [PMID: 31576500 PMCID: PMC7007429 DOI: 10.1007/s40620-019-00650-x] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
- Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Whitlock RH, Hougen I, Komenda P, Rigatto C, Clemens KK, Tangri N. A Safety Comparison of Metformin vs Sulfonylurea Initiation in Patients With Type 2 Diabetes and Chronic Kidney Disease: A Retrospective Cohort Study. Mayo Clin Proc 2020; 95:90-100. [PMID: 31902433 DOI: 10.1016/j.mayocp.2019.07.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 07/06/2019] [Accepted: 07/31/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To compare the safety of metformin vs sulfonylureas in patients with type 2 diabetes by chronic kidney disease (CKD) stage. PATIENTS AND METHODS This retrospective cohort study included adults in Manitoba, Canada, with type 2 diabetes, an incident monotherapy prescription for metformin or a sulfonylurea, and a serum creatinine measurement from April 1, 2006, to March 31, 2017. Patients were stratified by estimated glomerular filtration rate (eGFR) into the following groups: eGFR of 90 or greater, 60 to 89, 45 to 59, 30 to 44, or less than 30 mL/min/1.73 m2. Outcomes included all-cause mortality, cardiovascular events, and major hypoglycemic episodes. Baseline characteristics were used to calculate propensity scores and perform inverse probability of treatment weights analysis, and eGFR group was examined as an effect modifier for each outcome. RESULTS The cohort consisted of 21,996 individuals (19,990 metformin users and 2006 sulfonylurea users). Metformin use was associated with lower risk for all-cause mortality (hazard ratio [HR], 0.48; 95% CI, 0.40-0.58; P<.001), cardiovascular events (HR, 0.67; 95% CI, 0.52-0.86; P=.002), and major hypoglycemic episodes (HR, 0.14; 95% CI, 0.09-0.20; P<.001) when compared with sulfonylureas. CKD was a significant effect modifier for all-cause mortality (P=.002), but not for cardiovascular events or major hypoglycemic episodes. CONCLUSION Sulfonylurea monotherapy is associated with higher risk for all-cause mortality, major hypoglycemic episodes, and cardiovascular events compared with metformin. Although the presence of CKD attenuated the mortality benefit, metformin may be a safer alternative to sulfonylureas in patients with CKD.
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Affiliation(s)
- Reid H Whitlock
- Seven Oaks General Hospital, Chronic Disease Innovation Centre, Winnipeg, MB, Canada
| | - Ingrid Hougen
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Paul Komenda
- Seven Oaks General Hospital, Chronic Disease Innovation Centre, Winnipeg, MB, Canada; Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Claudio Rigatto
- Seven Oaks General Hospital, Chronic Disease Innovation Centre, Winnipeg, MB, Canada; Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Kristin K Clemens
- Institute of Clinical Evaluative Sciences, London, ON, Canada; Division of Endocrinology, Department of Medicine, London, ON, Canada; Department of Epidemiology and Biostatistics, Western University, London, ON, Canada; St. Joseph's Health Care London, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada
| | - Navdeep Tangri
- Seven Oaks General Hospital, Chronic Disease Innovation Centre, Winnipeg, MB, Canada; Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: New clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". Nutr Metab Cardiovasc Dis 2019; 29:1127-1150. [PMID: 31586514 DOI: 10.1016/j.numecd.2019.07.017] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Papazafiropoulou A, Melidonis A. Antidiabetic agents in patients with hepatic impairment. World J Meta-Anal 2019; 7:380-388. [DOI: 10.13105/wjma.v7.i8.380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/07/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023] Open
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Hu J, Yang C, Wang H, Li J, Tan X, Wang J, Zhang B, Zhao Y. An up-to-date evaluation of alogliptin benzoate for the treatment of type 2 diabetes. Expert Opin Pharmacother 2019; 20:1679-1687. [PMID: 31335214 DOI: 10.1080/14656566.2019.1645124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.
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Affiliation(s)
- Jingbo Hu
- Institute of Drug Discovery Technology, Ningbo University , Ningbo , China
| | - Chunlin Yang
- Department of pharmacy, Ningbo University affiliated Yangming Hospital , Yuyao , China
| | - Hongbo Wang
- Department of pharmacy, Ningbo University affiliated Yangming Hospital , Yuyao , China
| | - Jing Li
- Department of pharmacy, Ningbo University affiliated Yangming Hospital , Yuyao , China
| | - Xueying Tan
- College of pharmacy, Zhejiang Pharmaceutical College , Ningbo , China
| | - Jinhui Wang
- Institute of Drug Discovery Technology, Ningbo University , Ningbo , China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, College of Food and Pharmaceutical Sciences, Ningbo University , Ningbo , China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University , Ningbo , China
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Pharmacokinetic interaction between linagliptin and tadalafil in healthy Egyptian males using a novel LC–MS method. Bioanalysis 2019; 11:1321-1336. [DOI: 10.4155/bio-2018-0097] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aim: Assessment of pharmacokinetic interaction between linagliptin (LNG) and tadalafil (TDL) in healthy males. Methods: First, a novel LC–MS method was developed; second, a Phase IV, open-label, cross-over study was performed. Volunteers took single 20-mg TDL dose on day 1 followed by wash out period of 2 weeks then multiple oral dosing of 5-mg/day LNG for 13 days. On day 13, volunteers were co-administered 20-mg TDL. Results: LNG and TDL single doses did not affect QTc interval. Smoking did not alter pharmacokinetics/pharmacodynamics of LNG and TDL. Co-administration of LNG with TDL resulted in TDL longer time to reach maximum plasma concentration (Tmax), decreased oral clearance (Cl/F) and oral volume of distribution (Vd/F), increased its maximum plasma concentration (Cmax), area under concentration-time curve (AUC), muscle pain and QTc prolongation. Conclusion: LNG and TDL co-administration warrants monitoring and/or TDL dose adjustment.
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Schernthaner G, Wanner C, Jurišić-Eržen D, Guja C, Gumprecht J, Jarek-Martynowa IR, Karasik A, Lalić N, Mankovsky BN, Prázný M, Tankova T, Tsur A, Wascher TC, Wittmann I. CARMELINA: An important piece of the DPP-4 inhibitor CVOT puzzle. Diabetes Res Clin Pract 2019; 153:30-40. [PMID: 31121272 DOI: 10.1016/j.diabres.2019.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 04/30/2019] [Accepted: 05/13/2019] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of glucose-lowering agent for type 2 diabetes (T2D) that are commonly used in clinical practice. With the recent disclosure of data from the CARMELINA cardiovascular outcomes trial (CVOT), which investigated linagliptin, CV and renal outcomes data are now available for four agents in the DPP-4 inhibitor class that are approved in most markets. To consider how the CARMELINA study may be interpreted, and the relevance for our clinical practice, we convened as an expert group of diabetes specialists from the Central and Eastern Europe region to discuss the new disclosures. Our discussions revealed a general confidence in safety across the class that is further supported by CARMELINA. However, we also concluded that there are important differences in the available evidence level between agents in the setting of heart failure and data on renal outcomes. Here, we noted the clinical relevance to our practice of the study population in CARMELINA, which is unique among CVOTs in including a majority of patients with chronic kidney disease (CKD). Given the risk for future development of renal impairment that is associated with T2D even in patients without current overt CKD, we believe that the CARMELINA study provides important new insights that are clinically relevant for a broad range of patients. Finally, we discuss how these insights can be integrated into the approach to the pharmacotherapeutic management of hyperglycaemia that is recommended in newly updated guidelines.
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Affiliation(s)
| | - Christoph Wanner
- Division of Nephrology, Department of Medicine, Würzburg University Clinic, Würzburg, Germany.
| | - Dubravka Jurišić-Eržen
- Department of Endocrinology and Diabetology, University Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Cristian Guja
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | | | | | - Avraham Karasik
- Sheba Medical Center and Tel Aviv University, Tel Aviv, Israel
| | - Nebojša Lalić
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, CCS, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Martin Prázný
- 3rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | | | - Anat Tsur
- Endocrinology Clinic, Clalit Health Services, Jerusalem, Israel
| | | | - István Wittmann
- 2nd Department of Medicine and Nephrological Center, Faculty of Medicine, University of Pécs, Hungary
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Shaik M, Vanapatla SR. Enhanced oral bioavailability of linagliptin by the influence of gallic acid and ellagic acid in male Wistar albino rats: involvement of p-glycoprotein inhibition. Drug Metab Pers Ther 2019; 34:/j/dmdi.2019.34.issue-2/dmpt-2018-0020/dmpt-2018-0020.xml. [PMID: 31256062 DOI: 10.1515/dmpt-2018-0020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 02/08/2019] [Indexed: 06/09/2023]
Abstract
Background Linagliptin is an antidiabetic drug used for the treatment of type-2 diabetes. The oral bioavailability of linagliptin is low (29.5%) due to its first pass metabolism in the intestine and liver. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. Gallic acid and ellagic acid have been reported to inhibit p-glycoprotein (p-gp) and enhance the bioavailability of p-gp substrate drugs. Hence, the purpose of the study was to evaluate the effect of gallic acid and ellagic acid on intestinal transport and bioavailability of linagliptin, a p-gp substrate in diabetic rats. Methods The intestinal transport of linagliptin was assessed by conducting an in situ single-pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study in diabetic rats. Results After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of linagliptin was observed at the ileum part of the rat intestine. A significant improvement in the peak serum concentration (Cmax) and area under the serum concentration time profile (AUC), AUMC, AUCtotal and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid. Conclusions This study demonstrates that gallic acid and ellagic acids increase the bioavailability of oral linagliptin in rats due to the inhibition of p-gp. These animal data need to be confirmed in a clinical setting to determine whether linagliptin dosing should be adjusted when given concomitantly with these phytochemicals or gallic acid/ellagic acid-containing dietary supplements.
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Affiliation(s)
- Munthaj Shaik
- Department of Pharmacognosy and phytochemistry, Kakatiya University, Warangal, Telangana, India
| | - Swaroopa Rani Vanapatla
- Department of Pharmacognosy and phytochemistry, Kakatiya University, Warangal, Telangana, India
- University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana-506009, India
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Kern JS, Schwieger-Briel A, Löwe S, Sumeray M, Davis C, Martinez AE. Oleogel-S10 Phase 3 study "EASE" for epidermolysis bullosa: study design and rationale. Trials 2019; 20:350. [PMID: 31186047 PMCID: PMC6560757 DOI: 10.1186/s13063-019-3362-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 04/15/2019] [Indexed: 12/25/2022] Open
Abstract
Background Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016–002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. Methods EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm2) present for > 21 days and < 9 months, are randomized in a 1:1 ratio to receive wound dressings according to local standard of care with or without Oleogel-S10. Placebo is based on the Oleogel-S10 vehicle, which is sunflower oil formulated to have a consistency indistinguishable from that of the active product. The primary endpoint of the trial, directed by the US health authority according to the required study endpoints for chronic cutaneous ulcer and burn wounds, is to compare the efficacy of Oleogel-S10 versus placebo according to the proportion of patients with complete closure of the target wound within 45 ± 7 days of treatment. Additional EB-focused endpoints include wound burden, patient-reported outcomes, and safety. Results Results of the primary endpoint are anticipated to be available by H2 2019. Trial registration ClinicalTrials.gov, NCT03068780. EudraCT, 2016–002066-32. Registered on 3 March 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3362-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Johannes S Kern
- Dermatology Department, Royal Melbourne Hospital, Faculy of Medicine, Dentistry and Health Science, The University of Melbourne, Parkville, Victoria, Australia. .,Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
| | - Agnes Schwieger-Briel
- Department of Dermatology, University Childrens' Hospital Zurich, Zurich, Switzerland
| | | | | | | | - Anna E Martinez
- Department of Paediatric Dermatology, Great Ormond Street Hospital NHS Foundation Trust, London, UK
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Davis H, Jones Briscoe V, Dumbadze S, Davis SN. Using DPP-4 inhibitors to modulate beta cell function in type 1 diabetes and in the treatment of diabetic kidney disease. Expert Opin Investig Drugs 2019; 28:377-388. [PMID: 30848158 DOI: 10.1080/13543784.2019.1592156] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION DPP-4 inhibitors have pleomorphic effects that extend beyond the anti-hyperglycemic labeled use of the drug. DPP-4 inhibitors have demonstrated promising renal protective effects in T2DM and T1DM and protective effects against immune destruction of pancreatic beta-cells in T1DM. AREAS COVERED The efficacy of DPP-4 inhibitors in the treatment of diabetic kidney disease and possible adjunct with insulin in the treatment of T1DM to preserve beta-cell function. Pertinent literature was identified through Medline, PubMed and ClinicalTrials.gov (1997-November 2018) using the search terms T1DM, sitagliptin, vildagliptin, linagliptin, beta-cell function, diabetic nephropathy. Only articles are written in the English language, and clinical trials evaluating human subjects were used. EXPERT OPINION DPP-4 inhibitors can be used safely in patients with diabetic kidney disease and do not appear to exacerbate existing diabetic nephropathy. Linagliptin reduces albuminuria and protects renal endothelium from the deleterious effects of hyperglycemia. The effects of DPP-4 inhibitors on preserving beta-cell function in certain subtypes of T1DM [e.g. Latent Autoimmune Diabetes in Adult (LADA) and Slowly Progressive Type 1 Diabetes (SPIDDM)] are encouraging and show promise.
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Fayfman M, Galindo RJ, Rubin DJ, Mize DL, Anzola I, Urrutia MA, Ramos C, Pasquel FJ, Haw JS, Vellanki P, Wang H, Albury BS, Weaver R, Cardona S, Umpierrez GE. A Randomized Controlled Trial on the Safety and Efficacy of Exenatide Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes. Diabetes Care 2019; 42:450-456. [PMID: 30679302 PMCID: PMC6905476 DOI: 10.2337/dc18-1760] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 11/21/2018] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This multicenter, open-label, randomized trial examined the safety and efficacy of exenatide alone or in combination with basal insulin in non-critically ill patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS A total of 150 patients with blood glucose (BG) between 140 and 400 mg/dL, treated at home with diet, oral agents, or insulin at a total daily dose <0.5 units/kg, were randomized to exenatide alone (5 μg twice daily), exenatide plus basal insulin, or a basal-bolus insulin regimen. The primary end point was difference in mean daily BG concentration among groups. RESULTS Mean daily BG was similar between patients treated with exenatide plus basal and a basal-bolus regimen (154 ± 39 vs. 166 ± 40 mg/dL, P = 0.31), and exenatide plus basal resulted in lower daily BG than did exenatide alone (177 ± 41 mg/dL, P = 0.02). Exenatide plus basal resulted in a higher proportion of BG levels in target range between 70 and 180 mg/dL compared with exenatide and basal-bolus (78% vs. 62% vs. 63%, respectively, P = 0.023). More patients in the exenatide and exenatide plus basal groups experienced nausea or vomiting than in the basal-bolus group (10% vs. 11% vs. 2%, P = 0.17), with three patients (6%) discontinued exenatide owing to adverse events. There were no differences in hypoglycemia <54 mg/dL (2% vs. 0% vs. 4%, P = 0.77) or length of stay (5 vs. 4 vs. 4 days, P = 0.23) among basal plus exenatide, exenatide, and basal-bolus groups. CONCLUSIONS The results of this pilot study indicate that exenatide alone or in combination with basal insulin is safe and effective for the management of hospitalized general medical and surgical patients with T2D.
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Affiliation(s)
- Maya Fayfman
- Department of Medicine, Emory University, Atlanta, GA
| | | | - Daniel J Rubin
- Department of Medicine, Temple University, Philadelphia, PA
| | - Dara L Mize
- School of Medicine, Vanderbilt University, Nashville, TN
| | - Isabel Anzola
- Department of Medicine, Emory University, Atlanta, GA
| | | | | | | | - J Sonya Haw
- Department of Medicine, Emory University, Atlanta, GA
| | | | - Heqiong Wang
- Rollins School of Public Health, Emory University, Atlanta, GA
| | | | - Rita Weaver
- School of Medicine, Vanderbilt University, Nashville, TN
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Yamamoto Y, Yamamoto Y, Saita T, Shin M. Immunohistochemistry for Anti-diabetes Drug, Alogliptin Using a Newly Prepared Monoclonal Antibody: Its Precise Localization in Rat Small Intestine. Acta Histochem Cytochem 2019; 52:27-34. [PMID: 30923413 PMCID: PMC6434317 DOI: 10.1267/ahc.18036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/10/2019] [Indexed: 12/17/2022] Open
Abstract
Knowledge of time sequence of localization of drugs in cells and tissues of animals may help in developing a better understanding of the actual overall pharmacokinetics of the drugs. We produced monoclonal antibody (mAb) against alogliptin (AG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, conjugated to BSA with N-(γ-maleimidobutyryloxy)-succinimide. The mAb was specific for AG and did not cross-react with sitagliptin, vancomycin or amoxicillin. The mAb enabled us to develop an immunohistochemical method for detecting the localization of AG in the rat small intestine. One hour after a single oral administration of AG, immunohistochemistry revealed that the immunoreactivity of AG was observed in almost all of cells and tissues of the duodenum. The microvilli of the absorptive epithelial cells were moderately stained. The staining pattern of AG at jejunum and ilium was almost the same as that of duodenum, but the staining intensity, especially at absorptive epithelial cells and intestinal gland epithelial cells, became stronger towards the distal part of the small intestine. These results suggested that AG may be more actively absorbed from the lower part of the small intestine than in the upper part. It may affect the function of cells with membrane-bound DPP-4 because it was reported that membrane-bound form of DPP-4 exists in the microvilli of the absorptive epithelial cells.
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Affiliation(s)
- Yuta Yamamoto
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
| | - Yutaro Yamamoto
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
| | - Tetsuya Saita
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
| | - Masashi Shin
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
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Fayfman M, Davis G, Duggan EW, Urrutia M, Chachkhiani D, Schindler J, Pasquel FJ, Galindo RJ, Vellanki P, Reyes-Umpierrez D, Wang H, Umpierrez GE. Sitagliptin for prevention of stress hyperglycemia in patients without diabetes undergoing general surgery: A pilot randomized study. J Diabetes Complications 2018; 32:1091-1096. [PMID: 30253968 PMCID: PMC6668912 DOI: 10.1016/j.jdiacomp.2018.08.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 08/23/2018] [Accepted: 08/24/2018] [Indexed: 01/04/2023]
Abstract
AIM We investigated if a dipeptidyl peptidase-4 inhibitor, sitagliptin, can prevent perioperative stress hyperglycemia in patients without prior history of diabetes mellitus undergoing general surgery. METHODS This double-blind pilot trial randomized general surgery patients to receive sitagliptin (n = 44) or placebo (n = 36) once daily, starting one day prior to surgery and continued during the hospital stay. The primary outcome was occurrence of stress hyperglycemia, defined by blood glucose (BG) >140 mg/dL and >180 mg/dL after surgery. Secondary outcomes included: length-of-stay, ICU transfers, hypoglycemia, and hospital complications. RESULTS BG >140 mg/dL was present in 44 (55%) of subjects following surgery. There were no differences in hyperglycemia between placebo and sitagliptin (56% vs. 55%, p = 0.93). BG >180 mg/dL was observed in 19% and 11% of patients treated with placebo and sitagliptin, respectively, p = 0.36. Both treatment groups had resulted in similar postoperative BG (148.9 ± 29.4 mg/dL vs. 146.9 ± 35.2 mg/dL, p = 0.73). There were no differences in length-of-stay (4 vs. 3 days, p = 0.84), ICU transfer (3% vs. 5%, p = 1.00), hypoglycemia <70 mg/dL (6% vs. 11%, p = 0.45), and complications (14% vs. 18%, p = 0.76). CONCLUSION Preoperative treatment with sitagliptin did not prevent stress hyperglycemia or complications in individuals without diabetes undergoing surgery.
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Affiliation(s)
- Maya Fayfman
- Emory University, Department of Medicine, Atlanta, GA, United States of America.
| | - Georgia Davis
- Emory University, Department of Medicine, Atlanta, GA, United States of America
| | - Elizabeth W Duggan
- Emory University, Department of Anesthesiology, United States of America
| | - Maria Urrutia
- Emory University, Department of Medicine, Atlanta, GA, United States of America
| | - David Chachkhiani
- Emory University, Department of Medicine, Atlanta, GA, United States of America
| | - Joanna Schindler
- Emory University, Department of Anesthesiology, United States of America
| | - Francisco J Pasquel
- Emory University, Department of Medicine, Atlanta, GA, United States of America
| | - Rodolfo J Galindo
- Emory University, Department of Medicine, Atlanta, GA, United States of America
| | - Priyathama Vellanki
- Emory University, Department of Medicine, Atlanta, GA, United States of America
| | | | - Heqiong Wang
- Emory Rollins School of Public Health, United States of America
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Scheen AJ. Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes. DIABETES & METABOLISM 2018; 45:110-121. [PMID: 30477733 DOI: 10.1016/j.diabet.2018.10.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/17/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022]
Abstract
Diabetic kidney disease (DKD) represents an enormous burden in patients with type 2 diabetes mellitus (T2DM). Preclinical studies using most glucose-lowering agents have suggested renal-protective effects, but the proposed mechanisms of renoprotection have yet to be defined, and the promising results from experimental studies remain to be translated into human clinical findings to improve the prognosis of patients at risk of DKD. Also, it is important to distinguish effects on surrogate endpoints, such as decreases in albuminuria and estimated glomerular filtration rate (eGFR), and hard clinical endpoints, such as progression to end-stage renal disease (ESRD) and death from renal causes. Data regarding insulin therapy are surprisingly scarce, and it is nearly impossible to separate the effects of better glucose control from those of insulin per se, whereas favourable preclinical data with metformin, thiazolidinediones and dipeptidyl peptidase (DPP)-4 inhibitors are plentiful, and positive effects have been observed in clinical studies, at least for surrogate endpoints. The most favourable renal results have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR decline have been reported with these classes of glucose-lowering medications compared with placebo and other glucose-lowering agents. Moreover, in large prospective cardiovascular outcome trials using composite renal outcomes as secondary endpoints, both GLP-1RAs and SGLT2is added to standard care reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine, progression to ESRD and kidney-related death; however, to date, only SGLT2is have been clearly shown to reduce such hard clinical outcomes. Yet, as the renoprotective effects of SGLT2is and GLP-1RAs appear to be independent of glucose-lowering activity, the underlying mechanisms are still a matter of debate. For this reason, further studies with renal outcomes as primary endpoints are now awaited in T2DM patients at high risk of DKD, including trials evaluating the potential add-on benefits of combined GLP-1RA-SGLT2i therapies.
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Affiliation(s)
- A J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU de Liège, Liège, Belgium.
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Olivares M, Neyrinck AM, Pötgens SA, Beaumont M, Salazar N, Cani PD, Bindels LB, Delzenne NM. The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice. Diabetologia 2018; 61:1838-1848. [PMID: 29797022 PMCID: PMC6061172 DOI: 10.1007/s00125-018-4647-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/25/2018] [Indexed: 12/15/2022]
Abstract
AIMS/HYPOTHESIS Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD). METHODS Twenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks. RESULTS Vildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue. CONCLUSIONS/INTERPRETATION Our study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts. DATA AVAILABILITY The sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.
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Affiliation(s)
- Marta Olivares
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium
| | - Sarah A Pötgens
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium
| | - Martin Beaumont
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium
| | - Nuria Salazar
- Department of Microbiology and Biochemistry, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Spain
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium
- Walloon Excellence in Life sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 73 av. E. Mounier, Box B1.73.11, 1200, Brussels, Belgium.
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Scheen AJ. Cardiovascular safety of DPP-4 inhibitors compared with sulphonylureas: Results of randomized controlled trials and observational studies. DIABETES & METABOLISM 2018; 44:386-392. [PMID: 30126735 DOI: 10.1016/j.diabet.2018.05.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/03/2018] [Accepted: 05/23/2018] [Indexed: 02/07/2023]
Abstract
After failure of metformin monotherapy, another glucose-lowering agent should be added to improve glucose control. The clinician has several pharmacological choices, including the addition of a sulphonylurea (SU) or a dipeptidyl peptidase-4 inhibitor (DPP-4i). While the cardiovascular safety of SUs remains a matter of controversy, DPP-4is have proven their non-inferiority vs placebo in recent cardiovascular (CV) outcome trials. In the absence of a head-to-head CV outcome trial-the CAROLINA, comparing linagliptin with glimepiride, is still ongoing-only indirect information can be found in the literature to compare CV outcomes (major CV events, myocardial infarction, ischaemic stroke, CV death and all-cause mortality) in patients with type 2 diabetes mellitus (T2DM) treated with SUs or DPP-4is. Thus, this comprehensive review summarizes the CV outcomes (excluding heart failure) reported in meta-analyses of randomized controlled trials (RCTs) of SUs vs placebo or other glucose-lowering agents, DPP-4is vs placebo or other glucose-lowering agents and SUs vs DPP-4is in phase-II/III studies. Also, the results of observational studies reporting CV events in patients treated with either SUs or DPP-4is have been carefully examined. Overall, the CV safety of SUs appears to be poorer than that of DPP-4is in both RCTs and cohort studies. However, the results are somewhat disparate, and such heterogeneity may be explained by different patient characteristics across studies, but also perhaps by differences between various molecules in each pharmacological class. In particular, some doubt about a class effect affecting SU CV safety has been raised. The results of CAROLINA are expected to shed more light on SU CV concerns, especially compared with DPP-4is.
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Affiliation(s)
- A J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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Deshpande PB, Butle SR. Determination of Dipeptidyl Peptidase-4 Inhibitors by Spectrophotometric and Chromatographic Methods. JOURNAL OF ANALYTICAL CHEMISTRY 2018. [DOI: 10.1134/s1061934818040032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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