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Kenawy AS, Liu YS, Aiyeolemi A, Okoye G, Park C. Real-world evidence on the association of novel antidiabetic medication use with cancer risk and protective effects: a systematic review and network meta-analysis. Ther Adv Drug Saf 2025; 16:20420986251335214. [PMID: 40290515 PMCID: PMC12033536 DOI: 10.1177/20420986251335214] [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: 07/11/2024] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Background Novel antidiabetic medications (SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists) are commonly used worldwide; however, the available research lacks definitive conclusions on their protective effects or potential risks on cancer. Objectives Compared to other antidiabetics, our systematic review and network meta-analysis (NMA) aims to use real-world studies to assess the potential cancer risks or protective effects of these novel antidiabetics. Methods We comprehensively searched PubMed, CINAHL, and Web of Science from their inception until November 30, 2023. We included observational studies examining at least one novel antidiabetics in the systematic review. The novel antidiabetics include sodium-glucose cotransporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 agonists (GLP-1a). Design We focused on cohort studies that provided data on cancer incidence and sample size in the NMA. Using NetMetaXL®, the random effects model with informative priors was used in the NMA to estimate the pooled odds ratio (OR) with 95% credible intervals (CrI). Results The systematic review included 62 studies, of which 22 met the inclusion criteria for the NMA. SGLT-2i users had lower overall cancer risk compared to sulfonylureas (OR: 0.54; 95% CrI: 0.40-0.74, low certainty), GLP-1a (OR: 0.70; 95% CrI: 0.53-0.92, low certainty), and DPP-4i users (OR: 0.72; 95% CrI: 0.57-0.92, very low certainty). DPP-4i users also had a lower cancer risk than sulfonylureas users (OR: 0.76; 95% CrI: 0.60-0.96, low certainty). No other statistically significant ORs were found in other direct comparisons. Conclusion SGLT-2i users have a lower risk of developing cancers than sulfonylureas, GLP-1a, and DPP-4i users. These results may improve patient safety by guiding future clinical practice and medication choices. Future studies should investigate the mechanisms behind these observed associations. Trial registration This NMA was registered in PROSPERO (CRD42023469941).
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Affiliation(s)
- Ahmed S. Kenawy
- Health Outcomes Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
| | - Yi-Shao Liu
- Health Outcomes Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
| | - Ayobami Aiyeolemi
- Health Outcomes Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
| | - Godwin Okoye
- Health Outcomes Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
| | - Chanhyun Park
- Health Outcomes Division, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue MC A1930, Austin, TX 78712, USA
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Ruggeri RM, Grossrubatscher EM, Ciocca E, Hasballa I, Jaafar S, Oldani M, Rubino M, Russo F, Isidori AM, Colao A, Faggiano A. Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09958-5. [PMID: 40175622 DOI: 10.1007/s11154-025-09958-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/04/2025]
Abstract
Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.
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Affiliation(s)
- Rosaria M Ruggeri
- Endocrinology, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, Messina, Italy
| | | | - Eleonora Ciocca
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132, Genoa, Italy
| | - Simona Jaafar
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Monica Oldani
- Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy
| | - Manila Rubino
- Onco-Endocrinology Unit, European Institute of Oncology, Milan, Italy
| | - Flaminia Russo
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy.
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Kamrul-Hasan A, Alam MS, Dutta D, Sasikanth T, Aalpona FTZ, Nagendra L. Tirzepatide and Cancer Risk in Individuals with and without Diabetes: A Systematic Review and Meta-Analysis. Endocrinol Metab (Seoul) 2025; 40:112-124. [PMID: 39814031 PMCID: PMC11898313 DOI: 10.3803/enm.2024.2164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/11/2024] [Accepted: 11/14/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGRUOUND Data on the carcinogenic potential of tirzepatide from randomized controlled trials (RCTs) are limited. Furthermore, no meta-analysis has included all relevant RCTs to assess the cancer risk associated with tirzepatide. METHODS RCTs involving patients receiving tirzepatide in the intervention arm and either a placebo or any active comparator in the control arm were searched through electronic databases. The primary outcome was the overall risk of any cancer, and secondary outcomes were the risks of specific types of cancer in the tirzepatide versus the control groups. RESULTS Thirteen RCTs with 13,761 participants were analyzed. Over 26 to 72 weeks, the tirzepatide and pooled control groups had identical risks of any cancer (risk ratio, 0.78; 95% confidence interval, 0.53 to 1.16; P=0.22). The two groups had comparable cancer risks in patients with and without diabetes. In subgroup analyses, the risks were also similar in the tirzepatide versus placebo, insulin, and glucagon-like peptide-1 receptor agonist groups. The overall cancer risk was also comparable for different doses of tirzepatide compared to the control groups; only a 10-mg tirzepatide dose had a lower risk of any cancer than placebo. Furthermore, compared to the control groups (pooled or separately), tirzepatide did not increase the risk of any specific cancer types. Despite greater increments in serum calcitonin with 10- and 15-mg tirzepatide doses than with placebo, the included RCTs reported no cases of papillary thyroid carcinoma. CONCLUSION Tirzepatide use in RCTs over 26 to 72 weeks did not increase overall or specific cancer risk.
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Affiliation(s)
- A.B.M. Kamrul-Hasan
- Department of Endocrinology, Mymensingh Medical College, Mymensingh, Bangladesh
| | - Muhammad Shah Alam
- Department of Medicine, Army Medical College Cumilla, Cumilla, Bangladesh
| | - Deep Dutta
- Department of Endocrinology, CEDAR Superspeciality Clinics, New Delhi, India
| | - Thanikai Sasikanth
- Department of Endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka
| | | | - Lakshmi Nagendra
- Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
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Tuersun A, Mohetaer M, Tuerhong M, Hou G, Cheng G. Response to Letter Regarding Article, "Pancreatitis and Pancreatic Cancer Risk Among Patients with Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials". Clin Ther 2024; 46:1087-1088. [PMID: 39343648 DOI: 10.1016/j.clinthera.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/03/2024] [Indexed: 10/01/2024]
Affiliation(s)
- Adili Tuersun
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Munire Mohetaer
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
| | - Munire Tuerhong
- Xinjiang Key Laboratory of Novel Funtional Materials Chemistry, College of Chemistry and Environmental Sciences, Kashi University, Kashi, China
| | - Guanxin Hou
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Gang Cheng
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
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Gonzalez-Gutierrez L, Motiño O, Barriuso D, de la Puente-Aldea J, Alvarez-Frutos L, Kroemer G, Palacios-Ramirez R, Senovilla L. Obesity-Associated Colorectal Cancer. Int J Mol Sci 2024; 25:8836. [PMID: 39201522 PMCID: PMC11354800 DOI: 10.3390/ijms25168836] [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: 07/12/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.
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Affiliation(s)
- Lucia Gonzalez-Gutierrez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Omar Motiño
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Daniel Barriuso
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Juan de la Puente-Aldea
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Lucia Alvarez-Frutos
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006 Paris, France;
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Roberto Palacios-Ramirez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
| | - Laura Senovilla
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid–CSIC, 47003 Valladolid, Spain; (L.G.-G.); (O.M.); (D.B.); (J.d.l.P.-A.); (L.A.-F.); (R.P.-R.)
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006 Paris, France;
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
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Tuersun A, Hou G, Cheng G. Pancreatitis and Pancreatic Cancer Risk Among Patients With Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials. Clin Ther 2024; 46:650-656. [PMID: 39084911 DOI: 10.1016/j.clinthera.2024.06.015] [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: 02/14/2024] [Revised: 06/11/2024] [Accepted: 06/21/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE This meta-analysis sought to assess the relationship between dipeptidyl peptidase-4 inhibitors (DPP-4) and the risk of pancreatitis and pancreatic cancer by synthesizing data from randomized, controlled trials, in light of the conflicting findings from observational studies and previous meta-analyses. METHODS Cochrane, Embase, ClinicalTrials.gov, and PubMed databases that compared the use of DPP-4 inhibitors and that reported pancreatitis and pancreatic cancer events in patients with diabetes mellitus Type 2 (T2DM) were searched using specific terms. Studies were included if they satisfied the following inclusion criteria: They were randomized trials comparing DPP-4 inhibitors use in patients with T2DM; The study's duration was longer than 24 weeks; And they reported pancreatitis and pancreatic cancer events. Stata 15 MP was used to analyze the data, and odds ratios (OR) with 95% confidence intervals (CI) were used to represent the results. FINDINGS A total of 81,737 participants with T2DM were included in the analysis. The results showed that during a mean follow-up period of 24 to 520 weeks, The use of DPP-4 inhibitors was not associated with an increased risk of pancreatitis (Peto-OR 0.97; 95% CI: 0.74, 1.27) or pancreatic cancer (Peto-OR = 0.88; 95% CI: 0.59, 1.30). IMPLICATIONS Current evidence fails to validate a significant correlation between DPP-4 therapy and pancreatitis or pancreatic cancer. However, subgroup analyses showed that sitagliptin was associated with a significant reduction in pancreatitis risk compared to the control group; furthermore, when comparing different types of control medications, a significant decrease in pancreatic cancer risk was observed among DPP-4 users compared to GLP-1 users.
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Affiliation(s)
- Adili Tuersun
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Guanxin Hou
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Gang Cheng
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
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Lin Y, Xu G, Li L, Xiang J, Zhai L. Incretin-based drugs decrease the incidence of prostate cancer in type 2 diabetics: A pooling-up analysis. Medicine (Baltimore) 2024; 103:e38018. [PMID: 38758855 PMCID: PMC11098233 DOI: 10.1097/md.0000000000038018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 04/05/2024] [Indexed: 05/19/2024] Open
Abstract
Incretin-based drugs, a class of Antidiabetic medications (ADMs) used in the treatment of type 2 diabetes, may affect the incidence of prostate cancer (PCa). But real-world evidence for this possible effect is lacking. Therefore, the aim of this study is to assess the effect of incretin-based drugs on the incidence of PCa, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. We searched PubMed, Embase, and Cochrane Library databases for eligible studies through September 2023. Two independent reviewers performed screening and data extraction. We used the Cochrane Handbook for Systematic Reviews and the Newcastle-Ottawa Scale (NOS) to assess the quality of included randomized controlled trials (RCTs) and cohort studies. We did a meta-analysis of available trial data to calculate overall risk ratios (RRs) for PCa. A total of 1238 articles were identified in our search. After screening for eligibility, 7 high-quality studies met the criteria for meta-analysis, including 2 RCTs and 5 cohort studies, with a total of 1165,738 patients. Compared with the control group, we found that incretin-based drugs reduced the relative risk of PCa by 35% (95% confidence interval (CI), 0.17-0.49; P = .0006). In subgroup analysis, the RR values for GLP-1 receptor agonists and DPP-4 inhibitors were 62% (95% CI, 0.45-0.85; P = .003) and 72% (95% CI, 0.46-1.12; P = .14), respectively. Incretin-based drugs are associated with lower incidence of prostate cancer and may have a preventive effect on prostate cancer in patients with type 2 diabetes.
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Affiliation(s)
- Yuxiang Lin
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guangyong Xu
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liangyu Li
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jingyi Xiang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lingyun Zhai
- Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Fisher JL, Wilk EJ, Oza VH, Gary SE, Howton TC, Flanary VL, Clark AD, Hjelmeland AB, Lasseigne BN. Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates. FEBS Open Bio 2024; 14:803-830. [PMID: 38531616 PMCID: PMC11073506 DOI: 10.1002/2211-5463.13796] [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: 02/11/2024] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.
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Affiliation(s)
- Jennifer L. Fisher
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Elizabeth J. Wilk
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Vishal H. Oza
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Sam E. Gary
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Timothy C. Howton
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Victoria L. Flanary
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Amanda D. Clark
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Anita B. Hjelmeland
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
| | - Brittany N. Lasseigne
- Department of Cell, Developmental and Integrative Biology, Heersink School of MedicineThe University of Alabama at BirminghamALUSA
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Wang F, Hendryx M, Liu N, Bidulescu A, Mitra AK, Luo J. SGLT2 Inhibitor Use and Risk of Breast Cancer Among Adult Women with Type 2 Diabetes. Drug Saf 2024; 47:125-133. [PMID: 38070101 DOI: 10.1007/s40264-023-01373-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2023] [Indexed: 01/28/2024]
Abstract
INTRODUCTION Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic agents, with the potential to inhibit breast cancer development. However, the association between SGLT2 inhibitors and risk of breast cancer in human studies is unclear. OBJECTIVE The aim of our study is to use a large national claims database to assess the association between SGLT2 inhibitor use and risk of breast cancer. METHODS We considered a study population of 158,483 adult women with type 2 diabetes who newly initiated SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP4) inhibitors using Optum's deidentified Clinformatics Data Mart Database between 1 January 2013 and 31 March 2022. The association between SGLT2 inhibitor use and risk of breast cancer was examined using Cox proportional hazard models stratified by age in the overall sample and in a subsample based on propensity score and medication initiation time matching. The effect of medication use duration was explored. RESULTS With an average follow-up of 2.2 years, 2154 breast cancer cases were identified. There was no significant association between SGLT2 inhibitor use and the risk of breast cancer in overall sample (HR = 0.96; 95% CI 0.87, 1.06), in women younger than 51 years old (HR = 0.88; 95% CI 0.59, 1.32), or in women aged 51 years or older (HR = 0.95; 95% CI 0.86, 1.04). The results remained nonsignificant using matching, medication use duration, and sensitivity analyses. CONCLUSION Our findings suggest SGLT2 inhibitors use was not associated with breast cancer risk compared with DPP4 inhibitors use. Studies with longer follow-up and better adjustments are needed to confirm the finding.
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Affiliation(s)
- Fengge Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA.
| | - Michael Hendryx
- Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Nianjun Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Aurelian Bidulescu
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Anirban K Mitra
- School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
| | - Juhua Luo
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA
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Pradhan R, Yu OHY, Platt RW, Azoulay L. Dipeptidyl peptidase-4 inhibitors and the risk of skin cancer among patients with type 2 diabetes: a UK population-based cohort study. BMJ Open Diabetes Res Care 2023; 11:e003550. [PMID: 37949470 PMCID: PMC10649616 DOI: 10.1136/bmjdrc-2023-003550] [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: 05/23/2023] [Accepted: 09/16/2023] [Indexed: 11/12/2023] Open
Abstract
INTRODUCTION The dipeptidyl peptidase-4 (DPP-4) enzyme significantly influences carcinogenic pathways in the skin. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas. RESEARCH DESIGN AND METHODS Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96 739 DPP-4 inhibitor users and 209 341 sulfonylurea users, and 96 411 DPP-4 inhibitor users and 208 626 sulfonylurea users for non-melanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs of melanoma and non-melanoma skin cancer, separately. RESULTS Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs 65.3 per 100 000 person-years, respectively; HR 0.77, 95% CI 0.61 to 0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84 to 1.54; 2.1-5 years HR 0.44, 95% CI 0.29 to 0.66; >5 years HR 0.33, 95% CI 0.14 to 0.74). In contrast, these drugs were not associated with the incidence of non-melanoma skin cancer, compared with sulfonylureas (448.1 vs 426.1 per 100 000 person-years, respectively; HR 1.06, 95% CI 0.98 to 1.15). CONCLUSIONS In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not non-melanoma skin cancer, compared with sulfonylureas.
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Affiliation(s)
- Richeek Pradhan
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
| | - Oriana H Y Yu
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
- Division of Endocrinology, Jewish General Hospital, Montreal, Québec, Canada
| | - Robert W Platt
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
| | - Laurent Azoulay
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
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11
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Rojas A, Schneider I, Lindner C, Gonzalez I, Morales MA. Association between diabetes and cancer. Current mechanistic insights into the association and future challenges. Mol Cell Biochem 2023; 478:1743-1758. [PMID: 36565361 DOI: 10.1007/s11010-022-04630-x] [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: 05/19/2022] [Accepted: 11/30/2022] [Indexed: 12/25/2022]
Abstract
Compelling pieces of epidemiological, clinical, and experimental research have demonstrated that Diabetes mellitus (DM) is a major risk factor associated with increased cancer incidence and mortality in many human neoplasms. In the pathophysiology context of DM, many of the main classical actors are relevant elements that can fuel the different steps of the carcinogenesis process. Hyperglycemia, hyperinsulinemia, metabolic inflammation, and dyslipidemia are among the classic contributors to this association. Furthermore, new emerging actors have received particular attention in the last few years, and compelling data support that the microbiome, the epigenetic changes, the reticulum endoplasmic stress, and the increased glycolytic influx also play important roles in promoting the development of many cancer types. The arsenal of glucose-lowering therapeutic agents used for treating diabetes is wide and diverse, and a growing body of data raised during the last two decades has tried to clarify the contribution of therapeutic agents to this association. However, this research area remains controversial, because some anti-diabetic drugs are now considered as either promotors or protecting elements. In the present review, we intend to highlight the compelling epidemiological shreds of evidence that support this association, as well as the mechanistic contributions of many of these potential pathological mechanisms, some controversial points as well as future challenges.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile.
| | - Ivan Schneider
- Medicine Faculty, Catholic University of Maule, Talca, Chile
| | | | - Ileana Gonzalez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Miguel A Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
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12
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Katsi V, Papakonstantinou I, Tsioufis K. Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management. Int J Mol Sci 2023; 24:11786. [PMID: 37511551 PMCID: PMC10381022 DOI: 10.3390/ijms241411786] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/03/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice.
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Affiliation(s)
- Vasiliki Katsi
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
| | | | - Konstantinos Tsioufis
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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13
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de Andrade Mesquita L, Wayerbacher LF, Schwartsmann G, Gerchman F. Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 67:e000647. [PMID: 37364149 PMCID: PMC10660996 DOI: 10.20945/2359-3997000000647] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/22/2023] [Indexed: 06/28/2023]
Abstract
The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.
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Affiliation(s)
- Leonardo de Andrade Mesquita
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
| | - Laura Fink Wayerbacher
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Gilberto Schwartsmann
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Fernando Gerchman
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil,
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14
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Chung CT, Lakhani I, Chou OHI, Lee TTL, Dee EC, Ng K, Wong WT, Liu T, Lee S, Zhang Q, Cheung BMY, Tse G, Zhou J. Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in Type 2 diabetes mellitus: A population-based study. Cancer Med 2023; 12:12299-12315. [PMID: 37148547 PMCID: PMC10278500 DOI: 10.1002/cam4.5927] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 03/07/2023] [Accepted: 03/30/2023] [Indexed: 05/08/2023] Open
Abstract
BACKGROUND Cancer is currently the second leading cause of death globally. There is much uncertainty regarding the comparative risks of new-onset overall cancer and pre-specified cancer for Type 2 diabetes mellitus (T2DM) patients on sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus DPP4I. METHODS This population-based cohort study patients included patients who were diagnosed with T2DM and administered either SGLT2 or DPP4 inhibitors between 1 January 2015 and 31 December 2020 in public hospitals of Hong Kong. RESULTS This study included 60,112 T2DM patients (mean baseline age: 62.1 ± 12.4 years, male: 56.36%), of which 18,167 patients were SGLT2I users and 41,945 patients were dipeptidyl peptidase 4 inhibitor (DPP4I) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of all-cause mortality (HR: 0.92; 95% CI: 0.84-0.99; p= 0.04), cancer-related mortality (HR: 0.58; 95% CI: 0.42-0.80; p ≤ 0.001) and new diagnoses of any cancer (HR: 0.70; 95% CI: 0.59-0.84; p ≤ 0.001). SGLT2I use was associated with a lower risk of new-onset breast cancer (HR: 0.51; 95% CI: 0.32-0.80; p ≤ 0.001), but not of other malignancies. Subgroup analysis on the type of SGLT2I, dapagliflozin (HR: 0.78; 95% CI: 0.64-0.95; p = 0.01) and ertugliflozin (HR: 0.65; 95% CI: 0.43-0.98; p = 0.04) use was associated with lower risks of new cancer diagnosis. Dapagliflozin use was also linked to lower risks of breast cancer (HR: 0.48; 95% CI: 0.27-0.83; p = 0.001). CONCLUSION Sodium-glucose cotransporter 2 inhibitor use was associated with lower risks of all-cause mortality, cancer-related mortality and new-onset overall cancer compared to DPP4I use after propensity score matching and multivariable adjustment.
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Affiliation(s)
- Cheuk To Chung
- Diabetes Research UnitCardiovascular Analytics Group, China‐UK CollaborationHong KongChina
| | - Ishan Lakhani
- Diabetes Research UnitCardiovascular Analytics Group, China‐UK CollaborationHong KongChina
| | - Oscar Hou In Chou
- Diabetes Research UnitCardiovascular Analytics Group, China‐UK CollaborationHong KongChina
- Division of Clinical Pharmacology and Therapeutics, Department of Medicine, LKS Faculty of MedicineThe University of Hong KongHong KongChina
| | - Teddy Tai Loy Lee
- Diabetes Research UnitCardiovascular Analytics Group, China‐UK CollaborationHong KongChina
| | - Edward Christopher Dee
- Department of Radiation OncologyMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Kenrick Ng
- Department of Medical OncologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Wing Tak Wong
- School of Life SciencesChinese University of Hong KongHong KongChina
| | - Tong Liu
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinChina
| | - Sharen Lee
- Diabetes Research UnitCardiovascular Analytics Group, China‐UK CollaborationHong KongChina
| | - Qingpeng Zhang
- School of Data ScienceCity University of Hong KongHong KongChina
| | - Bernard Man Yung Cheung
- Division of Clinical Pharmacology and Therapeutics, Department of Medicine, LKS Faculty of MedicineThe University of Hong KongHong KongChina
| | - Gary Tse
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinChina
- Kent and Medway Medical SchoolUniversity of Kent and Canterbury Christ Church UniversityCanterburyUK
- School of Nursing and Health StudiesHong Kong Metropolitan UniversityHong KongChina
| | - Jiandong Zhou
- Diabetes Research UnitCardiovascular Analytics Group, China‐UK CollaborationHong KongChina
- Nuffield Department of MedicineUniversity of OxfordOxfordUK
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15
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Singh H, Singh J, Bhangu RK, Singla M, Singh J, Javid F. Potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus: current status and future prospects. Expert Rev Clin Pharmacol 2023; 16:49-59. [PMID: 36567479 DOI: 10.1080/17512433.2023.2163386] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Based on pharmacological properties and results from clinical studies, teneligliptin has a great potential to be used as an alternate-day therapy and also the daily dose can be reduced to 10 mg. Clinical data also suggest its excellent efficacy and safety among older subjects. AREAS COVERED We have reviewed and discussed potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus (T2DM) including alternate-day therapy and reduction of dose from 20 mg to 10 mg per day. We have also discussed the potential of teneligliptin to address the needs of older patients with T2DM. EXPERT OPINION It is an excellent option for use in older patients as studies in the geriatric population have shown encouraging results. Teneligliptin has a desirable pharmacokinetic profile that makes it a potential drug for use on an alternate-day basis. Teneligliptin has shown anti-diabetic efficacy even at a dose of 10 mg. These approaches may improve treatment satisfaction and patient compliance and can lower the cost; however, it is crucial to identify the subset of T2DM patients who can obtain maximum benefits. To verify these effects, large clinical investigations need to be planned and robust clinical evidence should be generated.
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Affiliation(s)
- Harmanjit Singh
- Department of Pharmacology, Government Medical College & Hospital, Chandigarh, India
| | - Jasbir Singh
- Department of Pharmacology, Government Medical College & Rajindra Hospital, Patiala, India
| | - Ravneet Kaur Bhangu
- Department of General Medicine, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Mandeep Singla
- Department of Medicine, Government Medical College & Hospital, Chandigarh, India
| | - Jagjit Singh
- Department of Pharmacology, Government Medical College & Hospital, Chandigarh, India
| | - Farideh Javid
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, UK
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16
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Søndergaard CS, Esquivel PN, Dalamaga M, Magkos F. Use of Antihyperglycemic Drugs and Risk of Cancer in Patients with Diabetes. Curr Oncol Rep 2023; 25:29-40. [PMID: 36445570 DOI: 10.1007/s11912-022-01344-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW Diabetes is associated with an increased risk for several types of cancer. Therefore, use of antihyperglycemic medications to lower blood glucose may modify cancer risk. Here we review available data on the link between the most common classes of antihyperglycemic agents and cancer risk among patients with diabetes. RECENT FINDINGS A database search was conducted between February 2022 and June 2022 on PubMed and Embase for systematic reviews and meta-analyses investigating the association between antihyperglycemic agents and risk of cancer. Use of biguanides such as metformin is associated with 20-30% lower risk for all cancer incidence, and somewhat greater benefit for cancer-related mortality. Alpha-glucosidase inhibitors, e.g., acarbose, have not been consistently associated with cancer. Similarly, no consistent effects have been reported for thiazolidinediones, but the relationship with cancer seems to depend on the type of drug, dose, and duration of treatment. Exposure to various types of incretin-based therapies (glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors) has not been found to significantly modify cancer risk. Inhibitors of sodium glucose cotransporter-2 may raise risk for bladder cancer and reduce risk for gastrointestinal cancer. Use of insulin and insulin analogs is associated with a significant increase in total cancer risk by almost 50% compared to other antihyperglycemic drugs. Likewise, insulin secretagogues like sulfonylureas have generally been linked to greater risk for cancer by ~ 20%, although these associations may be agent-specific and dose-dependent. Current evidence suggests that the risk of cancer associated with the use of antihyperglycemic medications among patients with diabetes depends on the class of drug and type of agent, dosage, and duration of treatment. More research is needed to delineate the mechanisms by which these agents affect the process of carcinogenesis.
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Affiliation(s)
- Christian Sümeghy Søndergaard
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958, Frederiksberg, Copenhagen, Denmark
| | - Paulina Nuñez Esquivel
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958, Frederiksberg, Copenhagen, Denmark
| | - Maria Dalamaga
- Department of Biological Chemistry, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Faidon Magkos
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958, Frederiksberg, Copenhagen, Denmark.
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17
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Dobrică EC, Banciu ML, Kipkorir V, Khazeei Tabari MA, Cox MJ, Simhachalam Kutikuppala LV, Găman MA. Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis. World J Clin Cases 2022; 10:11214-11225. [PMID: 36387789 PMCID: PMC9649529 DOI: 10.12998/wjcc.v10.i31.11214] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes and skin cancers have emerged as threats to public health worldwide. However, their association has been less intensively studied. In this narrative review, we explore the common risk factors, molecular mechanisms, and prognosis of the association between cutaneous malignancies and diabetes. Hyperglycemia, oxidative stress, low-grade chronic inflammation, genetic, lifestyle, and environmental factors partially explain the crosstalk between skin cancers and this metabolic disorder. In addition, diabetes and its related complications may interfere with the appropriate management of cutaneous malignancies. Antidiabetic medication seems to exert an antineoplastic effect, however, future large, observation studies with a prospective design are needed to clarify its impact on the risk of malignancy in diabetes. Screening for diabetes in skin cancers, as well as close follow-up for the development of cutaneous malignancies in subjects suffering from diabetes, is warranted.
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Affiliation(s)
- Elena-Codruta Dobrică
- Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Madalina Laura Banciu
- Department of Dermatology, "Elias" University Emergency Hospital, Bucharest 011461, Romania
| | - Vincent Kipkorir
- Department of Human Anatomy, University of Nairobi, College of Health Sciences, Nairobi 00100, Kenya
| | | | - Madeleine Jemima Cox
- University of New South Wales, University of New South Wales, Sydney 2052, Australia
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
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18
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Li Z, Lin C, Zhou J, Cai X, Zhu X, Hu S, Lv F, Yang W, Ji L. Dipeptidyl peptidase 4-inhibitor treatment was associated with a reduced incidence of neoplasm in patients with type 2 diabetes: a meta-analysis of 115 randomized controlled trials with 121961 participants. Expert Opin Investig Drugs 2022; 31:957-964. [DOI: 10.1080/13543784.2022.2113056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Zonglin Li
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Jinyu Zhou
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
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Zou P, Guo M, Hu J. Evogliptin for the treatment of type 2 diabetes: an update of the literature. Expert Rev Clin Pharmacol 2022; 15:747-757. [DOI: 10.1080/17512433.2022.2100348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Pin Zou
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 16 Gusaoshu Road, Wuhan, 430000, China
| | - Mingxing Guo
- Department of Traditional Chinese Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 16 Gusaoshu Road, Wuhan, 430000, China
| | - Jingbo Hu
- Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo, 315211, China
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20
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Zhu S, Bai Q, Li L, Xu T. Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents. Comput Struct Biotechnol J 2022; 20:2839-2847. [PMID: 35765655 PMCID: PMC9189996 DOI: 10.1016/j.csbj.2022.05.057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 12/19/2022] Open
Abstract
Repositioning or repurposing drugs account for a substantial part of entering approval pipeline drugs, which indicates that drug repositioning has huge market potential and value. Computational technologies such as machine learning methods have accelerated the process of drug repositioning in the last few decades years. The repositioning potential of type 2 diabetes mellitus (T2DM) drugs for various diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases have been widely studied. Hence, the related summary about repurposing antidiabetic drugs is of great significance. In this review, we focus on the machine learning methods for the development of new T2DM drugs and give an overview of the repurposing potential of the existing antidiabetic agents.
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Affiliation(s)
- Sha Zhu
- Key Lab of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Qifeng Bai
- Key Lab of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China
- Corresponding author.
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21
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Chou CL, Juan SH, Li CH, Chen HH, Kao CC, Chen LY, Chien LN, Fang TC. Association Between DPP-4 Inhibitors and Events of Colorectal and Liver Cancers in Patients With Diabetes Receiving Second-Line Agents: A Nested Case-Control Study. Front Oncol 2022; 12:840142. [PMID: 35600378 PMCID: PMC9120816 DOI: 10.3389/fonc.2022.840142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/12/2022] [Indexed: 12/20/2022] Open
Abstract
ObjectivePlasma dipeptidyl peptidase-4 (DPP4) levels were significantly lower in patients with colorectal and liver cancers, and animal studies also showed DPP4 inhibitors (DPP4is) have procarcinogenic effects in colorectal cancer. Until now, whether DPP4is therapy affects the progression of liver cancer and colorectal cancer in patients with T2DM has not been well investigated. We investigated the association between cumulative defined daily dose (cDDD) of DPP4is exposure and risks of liver and colorectal cancers in patients with type 2 diabetes.Materials and MethodsWe identified 268,520 patients with diabetes receiving DPP4is as second-line agents between March 1, 2009, and December 31, 2013, from Taiwan’s National Health Insurance Research Database, Taiwan Cancer Registry, and National Death Registry of Taiwan. The amount of DPP4is were divided into three groups (low, medium, and high) based on the interquartile range of the cDDD of the DPP4is.ResultsThe data showed that the low cDDD of DPP-4is was associated with a reducing risk of colorectal cancer [adjusted odds ratio (OR), 0.49; 95% CI, 0.32–0.75; P=0.001]. However, the high cDDD of DPP-4is was associated with an increasing risk of colorectal cancer (adjusted OR, 1.86; 95% CI, 1.32–2.61; P<0.001). No association between DPP4is use and liver cancer risk was observed.ConclusionsThis nested case study revealed a J-shaped association between the cDDD of DPP-4is and colorectal cancer risk, but not liver cancer risk. Therefore, the effects of long-term DPP4is use on colorectal cancer risk warrant further study.
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Affiliation(s)
- Chu-Lin Chou
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Shu-Hui Juan
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ching-Hao Li
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsi-Hsien Chen
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chih-Chin Kao
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Li-Ying Chen
- Health Data Analytics and Statistics Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan
| | - Li-Nien Chien
- School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan
- *Correspondence: Te-Chao Fang, ; Li-Nien Chien,
| | - Te-Chao Fang
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- *Correspondence: Te-Chao Fang, ; Li-Nien Chien,
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22
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Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease? Cancers (Basel) 2022; 14:cancers14092072. [PMID: 35565202 PMCID: PMC9103952 DOI: 10.3390/cancers14092072] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary There is growing interest in identifying the effects of antidiabetic agents on cancer risk, progression, and anti-cancer treatment due to the long-term use of these medications and the inherently increased risk of malignancies in diabetic patients. Tumor development and progression are affected by multiple mediators in the tumor microenvironment, several of which may be proteolytically modified by the multifunctional protease dipeptidyl peptidase-IV (DPP-IV, CD26). Currently, low-molecular-weight DPP-IV inhibitors (gliptins) are used in patients with type 2 diabetes based on the observation that DPP-IV inhibition enhances insulin secretion by increasing the bioavailability of incretins. However, the DPP-IV-mediated cleavage of other biopeptides and chemokines is also prevented by gliptins. The potential utility of gliptins in other areas of medicine, including cancer, is therefore being evaluated. Here, we critically review the existing evidence on the role of DPP-IV inhibitors in cancer pathogenesis, their potential to be used in anti-cancer treatment, and the possible perils associated with this approach. Abstract Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.
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The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells. Cancers (Basel) 2021; 13:cancers13235947. [PMID: 34885056 PMCID: PMC8657226 DOI: 10.3390/cancers13235947] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The transmembrane serine protease CD26/Dipeptidylpeptidase 4 modulates T-cell activation, proliferation, and effector function. Due to their remarkable tumoricidal properties CD26-positive T cells are considered promising candidates for T cell-based immunotherapies while in cutaneous T cell lymphoma CD26/DPP4 expression patterns are established markers for diagnosis and possibly prognosis. With a focus on T cells, we review current knowledge on the regulation of CD26/DPP4 expression and release, its implication in T-cell effector function and the suitability CD26/DPP4 as a diagnostic and/or prognostic factor in T-cell malignancies. Abstract CD26/Dipeptidylpeptidase 4 is a transmembrane serine protease that cleaves off N-terminal dipeptides. CD26/DPP4 is expressed on several immune cell types including T and NK cells, dendritic cells, and activated B cells. A catalytically active soluble form of CD26/DPP4 can be released from the plasma membrane. Given its wide array of substrates and interaction partners CD26/DPP4 has been implicated in numerous biological processes and effects can be dependent or independent of its enzymatic activity and are exerted by the transmembrane protein and/or the soluble form. CD26/DPP4 has been implicated in the modulation of T-cell activation and proliferation and CD26/DPP4-positive T cells are characterized by remarkable anti-tumor properties rendering them interesting candidates for T cell-based immunotherapies. Moreover, especially in cutaneous T-cell lymphoma CD26/DPP4 expression patterns emerged as an established marker for diagnosis and treatment monitoring. Surprisingly, besides a profound knowledge on substrates, interaction partners, and associated signal transduction pathways, the precise role of CD26/DPP4 for T cell-based immune responses is only partially understood.
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Saito A, Kitayama J, Horie H, Koinuma K, Kawashima R, Ohzawa H, Yamaguchi H, Kawahira H, Mimura T, Lefor AK, Sata N. Dipeptidyl Peptidase (DPP)-4 Inhibitor Impairs the Outcomes of Patients with Type 2 Diabetes Mellitus After Curative Resection for Colorectal Cancer. CANCER RESEARCH COMMUNICATIONS 2021; 1:106-114. [PMID: 36860286 PMCID: PMC9973397 DOI: 10.1158/2767-9764.crc-21-0042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/01/2021] [Accepted: 11/11/2021] [Indexed: 12/24/2022]
Abstract
Dipeptidyl peptidase IV inhibitor (DPP-4i) has been shown to act either as a promoter or as a suppressor for cancer. Although epidemiologic studies suggest that DPP-4i does not correlate with the development of malignancies, its effects on cancer metastases are controversial. We evaluated the impact of DPP-4i on postoperative outcomes of the diabetic patients with colorectal cancer and microscopic features of the resected tumors. In 260 consecutive patients with type 2 diabetes mellitus (T2DM) who underwent curative resection of colorectal cancer, the correlation between DPP-4i use and prognosis was retrospectively examined. Expression of Zeb1 on tumor cells and density of infiltrating immune cells were quantitatively evaluated with multicolor IHC in 40 tumors from DPP-4i users, 40 tumors from propensity score-matched users, and 40 tumors from nonusers. Postoperative disease-free survival (DFS) was significantly lower in 135 patients treated with DPP-4i compared with 125 nontreated patients [5-year DFS, 73.7% vs. 87.4%; HR, 1.98; 95% confidence interval (CI), 1.05-3.71; P = 0.035]. IHC revealed that the number of Zeb1+ tumor cells increased in tumors from DPP-4i-treated patients than tumors from nonusers (P < 0.01). The densities of CD3+ and CD8+ T cells were significantly lower in tumors from DPP-4i users (P < 0.01) with decreased density of tertiary lymphoid structures (P < 0.001). However, the density of M2-type tumor-associated macrophages with CD68+ CD163+ phenotypes was significantly higher (P < 0.01) in tumors from DPP-4i users. Exposure of colorectal cancer to DPP-4i may accelerate epithelial-to-mesenchymal transition (EMT) creating a tumor-permissive immune microenvironment, which might impair the outcomes of the patients with colorectal cancer and T2DM. Significance DPP-4i has been shown to enhance the antitumor effects of immunotherapy. However, we found that DPP-4i significantly impairs the outcomes of patients with colorectal cancer who underwent curative resection, possibly through acceleration of EMT and creation of a tumor-permissive immune microenvironment. This suggests that DPP-4i must be used with caution until its safety is fully confirmed by further studies of the mechanistic effects on existing cancers in humans.
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Affiliation(s)
- Akira Saito
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Joji Kitayama
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
- Corresponding Author: Joji Kitayama, Department of Gastrointestinal Surgery, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan. Phone: 812-8558-8941; Fax: 812-8544-6811; E-mail:
| | - Hisanaga Horie
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Koji Koinuma
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Rie Kawashima
- Department of Oral and Maxillofacial Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Departments of Clinical Oncology and Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hironori Yamaguchi
- Departments of Clinical Oncology and Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hiroshi Kawahira
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Toshiki Mimura
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Alan Kawarai Lefor
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
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Rokszin G, Kiss Z, Sütő G, Kempler P, Jermendy G, Fábián I, Szekanecz Z, Poór G, Wittmann I, Molnár GA. Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study. Front Oncol 2021; 11:725465. [PMID: 34778040 PMCID: PMC8581296 DOI: 10.3389/fonc.2021.725465] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/30/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND In diabetes mellitus, during the last years, cancer became of equivalent importance as a cardiovascular disease in terms of mortality. In an earlier study, we have analyzed data of the National Health Insurance Fund (NHIF) of Hungary with regards all patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) vs. those treated with dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4is) in a given timeframe. In propensity score-matched groups of SGLT2i- vs. DPP-4i-treated patients, we found a lower incidence of cancer in general. In this post-hoc analysis, we aimed to obtain data on the incidence of site-specific cancer. PATIENTS AND METHODS All patients starting an SGLT2i or a DPP-4i between 2014 and 2017 in Hungary were included; the two groups (SGLT2i vs. DPP-4i) were matched for 54 clinical and demographical parameters. The follow-up period was 639 vs. 696 days, respectively. Patients with a letter "C" International Classification of Diseases, 10th Revision (ICD-10) code have been chosen, and those with a known malignancy within a year before the onset of the study have been excluded from the analysis. RESULTS We found a lower risk of urinary tract [HR 0.50 (95% CI: 0.32-0.79) p = 0.0027] and hematological malignancies [HR 0.50 (95% CI: 0.28-0.88) p = 0.0174] in patients treated with SGLT2i vs. those on DPP-4i. Risk of other types of cancer (including lung and larynx, lower gastrointestinal (GI) tract, rectum, pancreas, non-melanoma skin cancers, breast, or prostate) did not differ significantly between the two groups. When plotting absolute risk difference against follow-up time, an early divergence of curves was found in case of prostate, urinary tract, and hematological malignancies, whereas late divergence can be seen in case of cancers of the lung and larynx, the lower GI tract, and the breast. CONCLUSIONS Urinary tract and hematological malignancies were less frequent in patients treated with SGLT2i vs. DPP-4i. An early vs. late divergence could be observed for different cancer types, which deserves further studies.
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Affiliation(s)
| | - Zoltán Kiss
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Gábor Sütő
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Péter Kempler
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | | | - Ibolya Fábián
- RxTarget Ltd, Szolnok, Hungary
- Faculty of Mathematics, University of Veterinary Medicine, Budapest, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gyula Poór
- National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
| | - István Wittmann
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Gergő Attila Molnár
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
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Ueda P, Wintzell V, Melbye M, Eliasson B, Svensson AM, Franzén S, Gudbjörnsdottir S, Hveem K, Jonasson C, Svanström H, Pasternak B. Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study. Diabetologia 2021; 64:2204-2214. [PMID: 34254177 PMCID: PMC8423638 DOI: 10.1007/s00125-021-05508-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/09/2021] [Indexed: 01/21/2023]
Abstract
AIMS/HYPOTHESIS Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. METHODS We used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. RESULTS The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). CONCLUSIONS/INTERPRETATION In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.
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Affiliation(s)
- Peter Ueda
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
| | - Viktor Wintzell
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Mads Melbye
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Björn Eliasson
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Ann-Marie Svensson
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- The Swedish National Diabetes Register, Västra Götalandsregionen, Gothenburg, Sweden
| | - Stefan Franzén
- The Swedish National Diabetes Register, Västra Götalandsregionen, Gothenburg, Sweden
- Health Metrics, Department of Public Health and Community Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Soffia Gudbjörnsdottir
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- The Swedish National Diabetes Register, Västra Götalandsregionen, Gothenburg, Sweden
| | - Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Science, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Center, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Levanger, Norway
| | - Christian Jonasson
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Science, NTNU-Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Center, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Levanger, Norway
- Division of Health Data and Digitalization, The Norwegian Institute of Public Health, Oslo, Norway
| | - Henrik Svanström
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Björn Pasternak
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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Zerovnik S, Kos M, Locatelli I. Cardiovascular morbidity and mortality in patients with type 2 diabetes using novel antidiabetic medicines as add-on therapy: an observational real-world study. BMJ Open 2021; 11:e051549. [PMID: 34518273 PMCID: PMC8438902 DOI: 10.1136/bmjopen-2021-051549] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To evaluate the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy on cardiovascular (CV) morbidity and mortality in patients with type 2 diabetes (T2D). DESIGN AND SETTING A nationwide cohort study using three linked healthcare databases from Slovenia (outpatient prescription claims data, hospitalisation claims data and death registry data). PARTICIPANTS Patients with T2D with newly introduced DPP-4i (n=3817), GLP-1RA (n=855) or SGLT2i (n=2851) add-on therapy between June 2014 and June 2018. PRIMARY AND SECONDARY OUTCOME MEASURES The primary outcome was a major adverse CV event (MACE), while the secondary outcomes were CV death and heart failure (HF). The effects of the antidiabetic medicine group on the risk of each outcome were estimated with Cox proportional hazards regression. Intention-to-treat and on-treatment approaches were used. RESULTS In the intention-to-treat analysis, SGLT2i as add-on therapy, when compared with DPP-4i, was associated with lower risk of MACE (HR=0.66; 95% CI 0.50 to 0.85; p=0.002) and CV death (HR=0.46; 95% CI 0.30 to 0.73; p=0.001). On-treatment analysis revealed lower HF risk in patients initiating SGLT2i (HR=0.54; 95% CI 0.30 to 0.99; p=0.047). In the intention-to-treat analysis, GLP-1RA add-on therapy was associated with a lower MACE risk when compared with DPP-4i (HR=0.64; 95% CI 0.43 to 0.97; p=0.034), but it had a non-significant effect on CV death (HR=0.62; 95% CI 0.34 to 1.14; p=0.128) and HF (HR=1.39; 95% CI 0.88 to 2.21; p=0.157). The results of on-treatment analyses were in agreement with the results of intention-to-treat analyses. CONCLUSIONS SGLT2i and GLP-1RA improved CV morbidity and mortality in patients with T2D when compared with DPP-4i as an add-on therapy. The results of this study may serve as a basis for the selection of an optimal add-on antidiabetic medicine to reduce CV morbidity and mortality in patients with T2D in clinical practice. TRIAL REGISTRATION NUMBER EUPAS32558.
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Affiliation(s)
- Spela Zerovnik
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia
| | - Mitja Kos
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia
| | - Igor Locatelli
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia
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Shi N, Shi Y, Xu J, Si Y, Yang T, Zhang M, Ng DM, Li X, Xie F. SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Front Public Health 2021; 9:668368. [PMID: 34164370 PMCID: PMC8215266 DOI: 10.3389/fpubh.2021.668368] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/03/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Currently, the association between sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and malignancy risk has yet to be fully elucidated. This meta-analysis aimed to determine the relationship between SGLT-2i and malignancy risk in type 2 diabetes (T2D) patients. Methods: We searched PubMed, ScienceDirect, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science to identify randomized controlled trials (RCTs) published up to August 2020 related to T2D patients treated with SGLT-2i vs. placebo or other hypoglycemic agents. The meta-analysis's primary outcome was malignancies' incidence, and the results were evaluated using risk ratio (RR) and 95% confidence interval (CI). Results: We reviewed 76 articles (77 RCTs), comprising 45,162 and 43,811 patients in SGLT-2i and control groups, respectively. Compared with the control group, SGLT-2i had no significant association with augmented overall malignancy risk in T2D patients (RR = 1.05, 95% CI = 0.97–1.14, P = 0.20), but ertugliflozin may upsurge the risk (RR = 1.80, 95% CI = 1.02–3.17, P = 0.04). Compared with active hypoglycemic agents, dapagliflozin may increase (RR = 2.71, 95% CI = 1.46–6.43, P = 0.02) and empagliflozin may decrease (RR = 0.67, 95% CI = 0.45–0.98, P = 0.04) the malignancy risk. Compared with placebo, empagliflozin may exhibit risk increase (RR = 1.25, 95% CI = 1.05–1.49, P = 0.01), primarily in digestive system (RR = 1.48, 95% CI = 0.99–2.21, P = 0.05). Conclusions: Our results proposed that in diverse comparisons, ertugliflozin and dapagliflozin seemed to increase the malignancy risk in T2D patients. Empagliflozin may cause malignancy risk reduction compared with active hypoglycemic agents but increase overall risk primarily in the digestive system compared with placebo. In short, the relationship between SGLT-2i and malignancy in T2D patients remains unclear.
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Affiliation(s)
- Nanjing Shi
- Department of Endocrinology, Affiliated Hangzhou First People' Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingsi Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tong Yang
- Department of Tumor High Intensity Focused Ultrasound Therapy, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | | | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fei Xie
- Department of Endocrinology, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
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Kawakita E, Koya D, Kanasaki K. CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology. Cancers (Basel) 2021; 13:cancers13092191. [PMID: 34063285 PMCID: PMC8124456 DOI: 10.3390/cancers13092191] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Dipeptidyl peptidase (DPP)-4 inhibitor is widely used for type 2 diabetes. Although DPP-4/CD26 has been recognized as both a suppressor and inducer in tumor biology due to its various functions, how DPP-4 inhibitor affects cancer progression in diabetic patients is still unknown. The aim of this review is to summarize one unfavorable aspect of DPP-4 inhibitor in cancer-bearing diabetic patients. Abstract DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.
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Affiliation(s)
- Emi Kawakita
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan;
| | - Daisuke Koya
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Japan;
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
| | - Keizo Kanasaki
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan;
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
- Correspondence: ; Tel.: +81-853-20-2183
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Dąbrowski M. Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors. Int J Mol Sci 2021; 22:1680. [PMID: 33562380 PMCID: PMC7915237 DOI: 10.3390/ijms22041680] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions-with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.
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Affiliation(s)
- Mariusz Dąbrowski
- College of Medical Sciences, University of Rzeszów, Al. Rejtana 16C, 35-959 Rzeszów, Poland
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Singla RK, Shen B. In Silico ADMET Evaluation of Natural DPP-IV Inhibitors for Rational Drug Design against Diabetes. Curr Drug Metab 2020; 21:768-777. [PMID: 32875983 DOI: 10.2174/1389200221999200901202945] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/03/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND As a metabolic and lifestyle disorder, diabetes mellitus poses a prodigious health risk. Out of the many key targets, DPP-IV is one of the very imperative therapeutic targets for the treatment of diabetic patients. METHODS In our current study, we have done the in silico simulations of ADME-T properties for naturally originated potent DPP-IV inhibitors like quinovic acid, stigmasterol, quinovic acid-3-beta-D-glycopyranoside, zygophyloside E, and lupeol. Structural topographies associated with different pharmacokinetic properties have been systematically assessed. RESULTS Glycosylation on quinovic acid is found to be noteworthy for the improvement of pharmacokinetic and toxicological properties, which leads to the prediction that zygophyloside E can be further tailored down to get the lead DPP-IV inhibitor. CONCLUSION This assessment provides useful insight into the future development of novel drugs for the treatment of diabetes mellitus.
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Affiliation(s)
- Rajeev K Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Xinchuan Road 2222, Chengdu, Sichuan, China
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Xinchuan Road 2222, Chengdu, Sichuan, China
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Milluzzo A, Vigneri P, Martorana F, Vigneri R, Sciacca L. Type 2 diabetes and cancer: problems and suggestions for best patient management. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Diabetes and cancer are widespread worldwide and the number of subjects presenting both diseases increased over the years. The management of cancer patients having diabetes represents a challenge not only because of the complexity and heterogeneity of these pathologies but also for the lack of standardised clinical guidelines. The diagnosis of cancer is traumatizing and monopolizes the attention of both patients and caregivers. Thus, pre-existent or new-onset diabetes can be overshadowed thus increasing the risk for short- and long-term adverse events. Moreover, drugs used for each disease can interfere with the clinical course of the concomitant disease, making challenging the management of these patients. Over the years, this issue has become more relevant because of the increased patients’ life expectancy due to the improved efficacy of diabetes and cancer therapies.
The purpose of this review is to highlight what is known and what should be taken into consideration to optimise the clinical management of patients with diabetes and cancer. Due to the complexity of these diseases, a multidisciplinary, shared approach, including all the protagonists involved, is necessary to improve patients’ quality of life and lifespan.
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Affiliation(s)
- Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy
| | - Paolo Vigneri
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico-Vittorio Emanuele, 95124 Catania, Italy
| | - Federica Martorana
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico-Vittorio Emanuele, 95124 Catania, Italy
| | - Riccardo Vigneri
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy; Institute of Crystallography, Catania Section, National Research Council, CNR, 95126 Catania, Italy
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy
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