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1
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Zhou Y, Xue F. Revolutionary drug repositioning: the preventive and therapeutic potential of metformin and other antidiabetic drugs in age-related macular degeneration. Front Pharmacol 2024; 15:1507860. [PMID: 39720591 PMCID: PMC11666363 DOI: 10.3389/fphar.2024.1507860] [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: 10/08/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly worldwide. Anti-vascular endothelial growth factor (anti-VEGF) injections remain the first-line therapy for AMD. However, their high cost and the need for frequent administration pose challenges to long-term adherence, highlighting the need for accessible and cost-effective preventive strategies. Emerging evidence suggests that traditional antidiabetic drugs, such as metformin, sulfonylureas, and thiazolidinediones, may offer neuroprotective benefits, opening new avenues for AMD prevention. Among these, metformin has emerged as the most promising candidate, demonstrating significant potential in reducing AMD risk, even at low cumulative doses, primarily through AMP-activated protein kinase (AMPK) activation. Sulfonylureas, although effective in stimulating insulin secretion, carry risks such as hypoglycemia, hyperinsulinemia, and a possible association with increased cancer risk. Similarly, thiazolidinediones, while improving insulin sensitivity, are associated with adverse effects, including cardiovascular risks and macular edema, limiting their broader application in AMD prevention. This paper explores the preventive potential and underlying mechanisms of these antidiabetic drugs in AMD and discusses the role of artificial intelligence in optimizing individualized prevention strategies. By advancing precision medicine, these approaches may improve public health outcomes and reduce the burden of aging-related vision loss.
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Ghareghomi S, Arghavani P, Mahdavi M, Khatibi A, García-Jiménez C, Moosavi-Movahedi AA. Hyperglycemia-driven signaling bridges between diabetes and cancer. Biochem Pharmacol 2024; 229:116450. [PMID: 39059774 DOI: 10.1016/j.bcp.2024.116450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/21/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
Growing epidemiological evidence indicates an association between obesity, type 2 diabetes, and certain cancers, suggesting the existence of common underlying mechanisms in these diseases. Frequent hyperglycemias in type 2 diabetes promote pro-inflammatory responses and stimulate intracellular metabolic flux which rewires signaling pathways and influences the onset and advancement of different types of cancers. Here, we review the provocative impact of hyperglycemia on a subset of interconnected signalling pathways that regulate (i) cell growth and survival, (ii) metabolism adjustments, (iii) protein function modulation in response to nutrient availability (iv) and cell fate and proliferation and which are driven respectively by PI3K (Phosphoinositide 3-kinase), AMPK (AMP-activated protein kinase), O-GlcNAc (O-linked N-acetylglucosamine) and Wnt/β-catenin. Specifically, we will elaborate on their involvement in glucose metabolism, inflammation, and cell proliferation, highlighting their interplay in the pathogenesis of diabetes and cancer. Furthermore, the influence of antineoplastic and antidiabetic drugs on the unbridled cellular pathways will be examined. This review aims to inspire the next molecular studies to understand how type 2 diabetes may lead to certain cancers. This will contribute to personalized medicine and direct better prevention strategies.
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Affiliation(s)
- Somayyeh Ghareghomi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Payam Arghavani
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Majid Mahdavi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Ali Khatibi
- Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran.
| | - Custodia García-Jiménez
- Department of Basic Health Sciences, Faculty of Health Sciences, University Rey Juan Carlos. Alcorcón, Madrid, Spain.
| | - Ali A Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran, Iran.
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3
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Tseng CH. Metformin-associated lactic acidosis and mortality in type 2 diabetes patients hospitalized with heart failure and/or acute coronary syndrome: A neglected clinical scenario and the potential role of insulin. Int J Cardiol 2024; 414:132400. [PMID: 39089483 DOI: 10.1016/j.ijcard.2024.132400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 07/26/2024] [Indexed: 08/04/2024]
Affiliation(s)
- Chin-Hsiao Tseng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Far Eastern Polyclinic, Taipei 10043, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
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Ramzan NUH, Shahjahan K, Dhillon RA, Khan NTA, Hashmat MB, Anwer MU, Ahmed D, Afzal F, Tahir MM, Muzaffar A. Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations. Cureus 2024; 16:e68550. [PMID: 39233729 PMCID: PMC11374140 DOI: 10.7759/cureus.68550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 09/03/2024] [Indexed: 09/06/2024] Open
Abstract
Metformin is a cornerstone therapy for type 2 diabetes mellitus due to its glucose-lowering efficacy and additional benefits such as reducing cardiovascular mortality. However, accumulating evidence suggests an association between long-term metformin use and vitamin B12 deficiency, which can lead to serious clinical consequences. This review aims to synthesize current knowledge on the pathogenesis, prevalence, clinical implications, and management of metformin-induced vitamin B12 deficiency. Given the significant clinical implications, it is crucial to monitor and manage vitamin B12 levels in patients using metformin. This review emphasizes the importance of early detection and supplementation to prevent adverse outcomes. By analyzing the current evidence, the review aims to inform healthcare professionals about best practices for managing vitamin B12 deficiency in patients on metformin, offering insights to guide future clinical practices and research directions.
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Affiliation(s)
| | | | | | | | | | | | - Dawood Ahmed
- Medicine, Faisalabad Medical University, Faisalabad, PAK
| | - Fazila Afzal
- Medicine, Faisalabad Medical University, Faisalabad, PAK
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Wang T, Chai B, Chen WY, Holmes MD, Erdrich J, Hu FB, Rosner BA, Tamimi RM, Willett WC, Kang JH, Eliassen AH. Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies. Int J Cancer 2024; 155:211-225. [PMID: 38520039 PMCID: PMC11096056 DOI: 10.1002/ijc.34917] [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: 10/31/2023] [Revised: 02/13/2024] [Accepted: 02/20/2024] [Indexed: 03/25/2024]
Abstract
We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.
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Affiliation(s)
- Tengteng Wang
- Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
- Division of Medical Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
| | - Boyang Chai
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
| | - Wendy Y. Chen
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Michelle D. Holmes
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
| | | | - Frank B. Hu
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA
| | - Bernard A. Rosner
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA
| | - Rulla M. Tamimi
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY
| | - Walter C. Willett
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA
| | - Jae H. Kang
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
| | - A. Heather Eliassen
- Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA
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Lee YM, Lin PR, Sia HK. Oral antidiabetic therapy versus early insulinization on glycemic control in newly diagnosed type 2 diabetes patients: a retrospective matched cohort study. Sci Rep 2024; 14:15491. [PMID: 38969701 PMCID: PMC11226661 DOI: 10.1038/s41598-024-66468-1] [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: 02/29/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024] Open
Abstract
Our study aims to compare the efficacy of oral antidiabetic therapy to early insulinization on glycemic control among newly diagnosed type 2 diabetes patients in real-world clinical practice. A retrospective cohort study conducted at a medical center in Taiwan analyzed 1256 eligible patients from January 2007 to December 2017. Propensity score matching resulted in well-balanced groups of 94 patients each in the oral antidiabetic drug (OAD) and early insulinization cohorts. Glycemic outcomes were assessed in both groups. Patients exclusively using OAD showed consistently lower glycated hemoglobin (HbA1c) levels at 3, 12, 24, and 36 months compared to insulin users. At later periods, 77.7% of OAD users achieved glycemic control versus 64.9% of insulin users, with a marginally significant difference. Subgroup analyses suggested a trend favoring well-controlled diabetes in the OAD group, though not statistically significant. Our study finds oral antidiabetic therapy is not inferior to early insulinization for glycemic control in newly diagnosed type 2 diabetes patients, irrespective of initial HbA1c levels. This supports oral therapy as a rational treatment option, even in cases with elevated HbA1c at diagnosis.
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Affiliation(s)
- Yang-Ming Lee
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
- Department of Endocrinology and Metabolism, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 500, Taiwan.
| | - Pei Ru Lin
- Big Data Center, Changhua Christian Hospital, Changhua, 500, Taiwan
- Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, 500, Taiwan
| | - Hon-Ke Sia
- Department of Endocrinology and Metabolism, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 500, Taiwan.
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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8
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Tseng CH. Rosiglitazone has a null association with the risk of prostate cancer in type 2 diabetes patients. Front Endocrinol (Lausanne) 2023; 14:1185053. [PMID: 37560306 PMCID: PMC10407244 DOI: 10.3389/fendo.2023.1185053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 07/10/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND This study investigated the risk of prostate cancer in ever users and never users of rosiglitazone in diabetes patients in Taiwan. METHODS The nationwide database of the National Health Insurance was used to enroll male patients who had a new diagnosis of type 2 diabetes mellitus at an age ≥ 25 years from 1999 to 2005. A total of 11,495 ever users and 11,495 never users of rosiglitazone matched on propensity score were selected and they were followed up for the incidence of prostate cancer from January 1, 2006 until December 31, 2011. Cox proportional hazard model incorporated with the inverse probability of treatment weighting using the propensity score was used to estimate hazard ratios. RESULTS At the end of follow-up, incident cases of prostate cancer were found in 84 never users and 90 ever users of rosiglitazone. The calculated incidence was 173.20 per 100,000 person-years in never users and was 187.59 per 100,000 person-years in ever users. The overall hazard ratio (95% confidence intervals) for ever versus never users was 1.089 (0.808-1.466). The hazard ratios were 0.999 (0.643-1.552) for the first tertile (< 672 mg), 1.147 (0.770-1.709) for the second tertile (672-3584 mg) and 1.116 (0.735-1.695) for the third tertile (> 3584 mg) of cumulative dose. Sensitivity analyses consistently showed a null association between rosiglitazone and prostate cancer risk. CONCLUSION Rosiglitazone has a null effect on the risk of prostate cancer.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- National Institute of Environmental Health Sciences of the National Health Research Institutes, Zhunan, Taiwan
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9
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Hu J, Fan HD, Gong JP, Mao QS. The relationship between the use of metformin and the risk of pancreatic cancer in patients with diabetes: a systematic review and meta-analysis. BMC Gastroenterol 2023; 23:50. [PMID: 36829129 PMCID: PMC9951539 DOI: 10.1186/s12876-023-02671-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
OBJECTIVE We aim to evaluate the relationship between the use of metformin and the risk of pancreatic cancer in type 2 diabetes patients. METHOD We systematically searched the observational studies on PubMed, Embase, Web of Science, Cochrane Library, clinicalrials.gov, and CNKI databases, extracted relevant data, combined the OR value and 95% CI using the random effect model, and conducted a sensitivity analysis, subgroup analysis, and meta-regression to evaluate the size and stability of this relationship. RESULT Twenty-nine studies from twenty-four articles met our inclusion criteria, including more than 2 million subjects. Overall analysis showed that compared with no use of metformin, the use of metformin could reduce the risk of pancreatic cancer in patients with type 2 diabetes (OR = 0.82, 95% CI (0.69, 0.98)). Subgroup analysis showed that compared with the use of hypoglycemic drugs, the use of metformin could reduce the risk of pancreatic cancer in patients with type 2 diabetes (OR = 0.79, 95% CI (0.66, 0.94)). However, compared with no drugs or only diet therapy, metformin users might increase the risk of pancreatic cancer (OR = 2.19, 95% CI (1.08, 4.44)). Sensitivity analysis confirmed the stability of the study, and there was no significant publication bias. CONCLUSION Compared with the no-use of metformin, metformin users with diabetes can reduce the risk of pancreatic cancer. More research is needed to prove it works.
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Affiliation(s)
- Jian Hu
- grid.412461.40000 0004 9334 6536Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000 China ,Department of Hepatobiliary Surgery, Dianjiang People’s Hospital of Chongqing, Chongqing, 408300 China
| | - Hong-Dan Fan
- grid.412461.40000 0004 9334 6536Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000 China
| | - Jian-Ping Gong
- grid.412461.40000 0004 9334 6536Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000 China
| | - Qing-Song Mao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
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Wang NF, Jue TR, Holst J, Gunter JH. Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models. BJUI COMPASS 2023; 4:44-58. [PMID: 36569495 PMCID: PMC9766874 DOI: 10.1002/bco2.187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/07/2022] [Accepted: 08/08/2022] [Indexed: 12/27/2022] Open
Abstract
Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.
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Affiliation(s)
- Nan Fang Wang
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Toni Rose Jue
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jeff Holst
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jennifer H. Gunter
- Australian Prostate Cancer Research Centre‐Queensland, Centre for Genomic and Personalised Health, School of Biomedical Sciences, Faculty of Health, Translational Research InstituteQueensland University of Technology (QUT)BrisbaneQLDAustralia
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11
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Lu Y, Hajjar A, Cryns VL, Trentham‐Dietz A, Gangnon RE, Heckman‐Stoddard BM, Alagoz O. Breast cancer risk for women with diabetes and the impact of metformin: A meta‐analysis. Cancer Med 2022. [DOI: 10.1002/cam4.5545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 10/14/2022] [Accepted: 12/03/2022] [Indexed: 12/23/2022] Open
Affiliation(s)
- Yifan Lu
- Department of Industrial and Systems Engineering University of Wisconsin‐Madison Madison Wisconsin USA
| | - Ali Hajjar
- Massachusetts General Hospital Institute for Technology Assessment, Harvard Medical School Boston Massachusetts USA
| | - Vincent L. Cryns
- Department of Medicine University of Wisconsin Carbone Cancer Center, University of Wisconsin‐Madison Madison Wisconsin USA
| | - Amy Trentham‐Dietz
- Department of Population Health Sciences and the Carbone Cancer Center School of Medicine and Public Health, University of Wisconsin‐Madison Madison Wisconsin USA
| | - Ronald E. Gangnon
- Departments of Biostatistics & Medical Informatics and Population Health Sciences University of Wisconsin‐Madison Madison Wisconsin USA
| | | | - Oguzhan Alagoz
- Department of Industrial and Systems Engineering and Department of Population Health Sciences University of Wisconsin‐Madison Madison Wisconsin USA
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12
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Dhawan A, Pifer PM, Sandulache VC, Skinner HD. Metabolic targeting, immunotherapy and radiation in locally advanced non-small cell lung cancer: Where do we go from here? Front Oncol 2022; 12:1016217. [PMID: 36591457 PMCID: PMC9794617 DOI: 10.3389/fonc.2022.1016217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/24/2022] [Indexed: 12/15/2022] Open
Abstract
In the US, there are ~250,000 new lung cancer diagnoses and ~130,000 deaths per year, and worldwide there are an estimated 1.6 million deaths per year from this deadly disease. Lung cancer is the most common cause of cancer death worldwide, and it accounts for roughly a quarter of all cancer deaths in the US. Non-small cell lung cancer (NSCLC) represents 80-85% of these cases. Due to an enormous tobacco cessation effort, NSCLC rates in the US are decreasing, and the implementation of lung cancer screening guidelines and other programs have resulted in a higher percentage of patients presenting with potentially curable locoregional disease, instead of distant disease. Exciting developments in molecular targeted therapy and immunotherapy have resulted in dramatic improvement in patients' survival, in combination with new surgical, pathological, radiographical, and radiation techniques. Concurrent platinum-based doublet chemoradiation therapy followed by immunotherapy has set the benchmark for survival in these patients. However, despite these advances, ~50% of patients diagnosed with locally advanced NSCLC (LA-NSCLC) survive long-term. In patients with local and/or locoregional disease, chemoradiation is a critical component of curative therapy. However, there remains a significant clinical gap in improving the efficacy of this combined therapy, and the development of non-overlapping treatment approaches to improve treatment outcomes is needed. One potential promising avenue of research is targeting cancer metabolism. In this review, we will initially provide a brief general overview of tumor metabolism as it relates to therapeutic targeting. We will then focus on the intersection of metabolism on both oxidative stress and anti-tumor immunity. This will be followed by discussion of both tumor- and patient-specific opportunities for metabolic targeting in NSCLC. We will then conclude with a discussion of additional agents currently in development that may be advantageous to combine with chemo-immuno-radiation in NSCLC.
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Affiliation(s)
- Annika Dhawan
- Department of Radiation Oncology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, United States
| | - Phillip M. Pifer
- Department of Radiation Oncology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, United States
| | - Vlad C. Sandulache
- Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Heath D. Skinner
- Department of Radiation Oncology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, United States,*Correspondence: Heath D. Skinner,
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14
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Tseng CH. Metformin's effects on varicocele, erectile dysfunction, infertility and prostate-related diseases: A retrospective cohort study. Front Pharmacol 2022; 13:799290. [PMID: 35935880 PMCID: PMC9355151 DOI: 10.3389/fphar.2022.799290] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 06/30/2022] [Indexed: 12/20/2022] Open
Abstract
Objectives: To investigate the risk of varicocele, erectile dysfunction (ED), infertility, prostatitis, benign prostate hyperplasia (BPH) and prostate cancer associated with metformin use. Materials and methods: A total of 261,838 males, mean age 52.39 years (SD: 11.39), with a new-onset type 2 diabetes mellitus in 1999-2009 were identified from Taiwan's National Health Insurance. Among them, 175,171 were metformin initiators [metformin (+)] and 86,667 were non-metformin initiators [metformin (-)] in the initial 12-month prescriptions of antidiabetic drugs. Follow-up started after the initial 12-month prescriptions. Outcomes were followed up until 31 December 2011. Intention-to-treat (ITT) and per-protocol (PP) hazard ratios comparing metformin (+) to metformin (-) were estimated by Cox regression incorporated with the inverse probability of treatment-weighting using propensity scores. Results: The median follow-up time ranged 5.55-6.82 years in metformin (-) and 4.36-5.17 years in metformin (+) for different outcomes in ITT analyses. The respective median follow-up time in PP analyses ranged 2.20-2.61 years in metformin (-) and ranged 3.99-4.65 years in metformin (+). In the ITT analyses, for metformin (-), the incidence rates (per 100,000 person-years) of varicocele, ED, infertility, prostatitis, BPH and prostate cancer were 26.42, 455.89, 22.82, 590.23, 4226.19, and 141.69, respectively; and the respective incidence rates for metformin (+) were 25.65, 488.10, 32.60, 510.30, 3685.66, and 116.57. The hazard ratios (95% confidence intervals) comparing metformin (+) to metformin (-) in the ITT analyses were 0.960 (0.784-1.174) for varicocele, 1.077 (1.026-1.130) for ED, 1.368 (1.116-1.676) for infertility, 0.887 (0.849-0.927) for prostatitis, 0.883 (0.868-0.899) for BPH and 0.878 (0.802-0.961) for prostate cancer. The hazard ratios for the respective outcomes in the PP analyses were 0.845 (0.662-1.078), 1.350 (1.264-1.441), 1.396 (1.078-1.808), 0.800 (0.756-0.846), 0.875 (0.855-0.895), and 0.613 (0.548-0.686). Conclusion: Metformin use in patients with type 2 diabetes mellitus is associated with a neutral effect on varicocele, a higher risk of sexual dysfunction (ED and infertility) and a reduced risk of prostate-related health (prostatitis, BPH and prostate cancer).
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, Taiwan
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15
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Leitner BP, Siebel S, Akingbesote ND, Zhang X, Perry RJ. Insulin and cancer: a tangled web. Biochem J 2022; 479:583-607. [PMID: 35244142 PMCID: PMC9022985 DOI: 10.1042/bcj20210134] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/13/2022] [Accepted: 02/15/2022] [Indexed: 12/13/2022]
Abstract
For a century, since the pioneering work of Otto Warburg, the interwoven relationship between metabolism and cancer has been appreciated. More recently, with obesity rates rising in the U.S. and worldwide, epidemiologic evidence has supported a link between obesity and cancer. A substantial body of work seeks to mechanistically unpack the association between obesity, altered metabolism, and cancer. Without question, these relationships are multifactorial and cannot be distilled to a single obesity- and metabolism-altering hormone, substrate, or factor. However, it is important to understand the hormone-specific associations between metabolism and cancer. Here, we review the links between obesity, metabolic dysregulation, insulin, and cancer, with an emphasis on current investigational metabolic adjuncts to standard-of-care cancer treatment.
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Affiliation(s)
- Brooks P. Leitner
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Stephan Siebel
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Pediatrics, Yale School of Medicine, New Haven, CT, U.S.A
| | - Ngozi D. Akingbesote
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Xinyi Zhang
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Rachel J. Perry
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
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16
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Li Q, Xu H, Sui C, Zhang H. Impact of metformin use on risk and mortality of hepatocellular carcinoma in diabetes mellitus. Clin Res Hepatol Gastroenterol 2022; 46:101781. [PMID: 34332136 DOI: 10.1016/j.clinre.2021.101781] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/22/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND The views regarding the associations between metformin use and hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients are divisive. Thus we summarized all available published studies evaluating the relationship between metformin therapy and HCC survival and risk, and aim to conduct an updated meta-analysis study to more accurately clarify the association. METHODS We searched for articles regarding impact of metformin use on risk and mortality of HCC in DM and published before April 2021 in databases (PubMed and Web of Science). We used STATA 12.0 software to compute odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) to generate a computed effect size and 95% CI. RESULTS The present study showed that metformin use was associated with a decreased risk of HCC in DM with a random effects model (OR/RR = 0.59, 95% CI 0.51-0.68, I2 = 96.5%, p < 0.001). In addition, the study indicated that metformin use was associated with a decreased all-cause mortality of HCC in DM with a random effects model (HR = 0.74, 95% CI 0.66-0.83, I2 = 49.6%, p = 0.037). CONCLUSION In conclusion, our studies support that the use of metformin in DM patients is significantly associated with reduced risk and all-cause mortality of HCC. And more prospective studies focusing on the metformin therapy as a protective factor for HCC are needed to verify the accuracy of the findings.
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Affiliation(s)
- Qiaomei Li
- Department of Hepatic Surgery, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China
| | - Hairong Xu
- Second department of biliary tract, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China
| | - Chengjun Sui
- Department of special treatment, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China
| | - Hongjuan Zhang
- Department of Oncology Biotherapy, The Third Affiliated Hospital of Naval Medical University, No. 700 North Moyu road, Jiading district, 201805 Shanghai, China.
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17
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Cui H, Wang Y, Yang S, He G, Jiang Z, Gang X, Wang G. Antidiabetic Medications and the Risk of Prostate Cancer in Patients with Diabetes Mellitus: A Systematic Review and Meta-analysis. Pharmacol Res 2022; 177:106094. [PMID: 35074527 DOI: 10.1016/j.phrs.2022.106094] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/19/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Antidiabetic medications (ADMs) may modify prostate cancer (PCa) risk in patients with diabetes mellitus (DM). Accordingly, the current study assessed the possible associations between ADMs and the risk of PCa in diabetics. METHODS A systematic literature search (PubMed, Embase and Cochrane Library) identified studies evaluating the associations between ADMs and incidence of PCa. A meta-analysis followed PRISMA was performed using odds ratio (OR) with 95% confidence interval (CI) as effect measures. RESULTS In total of 47 studies involving 3,094,152 patients with diabetes were included. Results of meta-analysis of the observational studies suggested no significant association between metformin, thiazolidinediones, sulfonylureas, insulin or dipeptidyl peptidase-4 inhibitors administration and the risk of PCa (All p-values > 0.05). Separate analysis of randomized controlled trials (RCTs) revealed a significant reduction in PCa risk with thiazolidinediones (OR = 0.55, p = 0.04) or glucagon-like peptide-1 receptor agonists (GLP-1RA) administration (OR = 0.53, p = 0.006), whereas no significant association was found in SGLT2 inhibitors (p = 0.3). CONCLUSION Thiazolidinediones or GLP-1RA administration may have benefits in PCa based on RCTs, however, further research is needed to confirm these findings.
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Affiliation(s)
- Haiying Cui
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yao Wang
- Department of Orthopedics, The Second Hospital Jilin University, Changchun 130021, Jilin Province, China
| | - Shuo Yang
- Department of Clinical Nutrition, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guangyu He
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zongmiao Jiang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
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18
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Ding N, Zheng C. Jiangtang Tongmai Prescription Reduced Diabetic Lung Injury Through SnoN and TGF-β1/Smads Signaling Pathway. Front Endocrinol (Lausanne) 2022; 13:846583. [PMID: 35784541 PMCID: PMC9248361 DOI: 10.3389/fendo.2022.846583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/21/2022] [Indexed: 11/27/2022] Open
Abstract
By establishing a rat diabetes model in rats with intervening treatment by Jiangtang Tongmai Prescription (JTTMP), this study explored the restorative pairing effect of JTTMP on diabetic lung injury. The model of type II diabetes model was used to establish the rat diabetes model, using a high-fat diet and streptozotocin (STZ) induction. Different doses of JTTMP and metformin were administered as a therapeutic to intervene, and blood was collected to assess the blood glucose level of each group of rats. HE (Hematoxylin and eosin (H&E) staining was performed to detect the morphological changes in rat lung tissue and enzyme-linked immunoassay ELISA was used to detect and quantify the expression of interleukin (IL)-6, TNF tumor necrosis factor-ɑa, and IL-1β in serum and the lung tissue of each group of rats. The level expression of TGF-β1 [transforming growth factor (TGF)-β1), SnoN (transcriptional co-repressor Ski-N terminal (SnoN)], Smad2, Smad3, Smad7, and other signaling pathway proteins were assessed by Western blot. In comparison with the normal control (NC) group, rats in the diabetes model (DM) group lost weight and showed significantly increased blood sugar levels. The levels of TGF-β1 and Smad2/3 were increased in the DM group but Smad7 decreased. After 8 weeks of JTTMP intervention, the level of TGF-β1 and Smad2/3 decreased but Smad7 increased, blood sugar decreased significantly and the expression of inflammatory factors in lung tissue decreased. Therefore, JTTMP may activate SnoN and the downstream TGF-β1/Smads signaling pathway to repair diabetic lung injury, which suggests its application has potential for future clinical treatment of diabetes with lung injury.
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Affiliation(s)
- Nian Ding
- Clinical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Medical Ward, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Chenghong Zheng
- Clinical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China
- Medical Ward, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, China
- *Correspondence: Chenghong Zheng,
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19
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Yang J, Fang W, Wu W, Tian Z, Gao R, Yu L, Chen D, Weng X, Zhu S, Yang C. A Novel Diagnostic Biomarker, PZP, for Detecting Colorectal Cancer in Type 2 Diabetes Mellitus Patients Identified by Serum-Based Mass Spectrometry. Front Mol Biosci 2021; 8:736272. [PMID: 34917649 PMCID: PMC8670180 DOI: 10.3389/fmolb.2021.736272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/16/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Growing evidence has confirmed that populations with type 2 diabetes mellitus (T2DM) have an increasing risk of developing colorectal cancer (CRC). Thus, convenient and effective screening strategies for CRC should be developed for the T2DM population to increase the detection rate of CRC. Methods: Twenty serum samples extracted from five healthy participants, five T2DM patients, five CRC patients and five T2DM patients with CRC (T2DM + CRC) were submitted to data-independent acquisition mass spectrometry (DIA-MS) analysis to discover unique differentially altered proteins (DAPs) for CRC in patients with T2DM. Then, the diagnostic value of pregnancy zone protein (PZP) was validated by ELISA analysis in the validated cohort. Results: Based on DIA-MS analysis, we found eight unique proteins specific to T2DM patients with CRC. Among these proteins, four proteins showed different expression between the T2DM + CRC and T2DM groups, and PZP exhibited the largest difference. Next, the diagnostic value of serum PZP was validated by ELISA analysis with an AUC of 0.713. Moreover, the combination of PZP, CA199 and CEA exhibited encouraging diagnostic value, and the AUC reached 0.916. Conclusion: Overall, our current research implied that PZP could be regarded as a newfound serum biomarker for CRC medical diagnosis in T2DM patients.
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Affiliation(s)
- Jiayue Yang
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Weigang Fang
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Wenjun Wu
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Zhen Tian
- Department of Clinical Laboratory, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Rong Gao
- Department of Clinical Laboratory, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Lu Yu
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Dayang Chen
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Xiaohua Weng
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Shengwei Zhu
- Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Cheng Yang
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
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20
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Durrani IA, Bhatti A, John P. The prognostic outcome of 'type 2 diabetes mellitus and breast cancer' association pivots on hypoxia-hyperglycemia axis. Cancer Cell Int 2021; 21:351. [PMID: 34225729 PMCID: PMC8259382 DOI: 10.1186/s12935-021-02040-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Type 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.
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Affiliation(s)
- Ilhaam Ayaz Durrani
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
| | - Attya Bhatti
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan.
| | - Peter John
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
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21
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Minami T, Tateishi R, Fujiwara N, Nakagomi R, Nakatsuka T, Sato M, Uchino K, Enooku K, Nakagawa H, Fujinaga H, Izumiya M, Hanajiri K, Asaoka Y, Kondo Y, Tanaka Y, Otsuka M, Ohki T, Arai M, Tanaka A, Yasuda K, Miura H, Ogata I, Kamoshida T, Inoue K, Koike Y, Akamatsu M, Mitsui H, Fujie H, Ogura K, Yoshida H, Wada T, Kurai K, Maekawa H, Obi S, Teratani T, Masaki N, Nagashima K, Ishikawa T, Kato N, Moriya K, Yotsuyanagi H, Koike K. Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals. Liver Cancer 2021; 10:309-319. [PMID: 34414119 PMCID: PMC8339497 DOI: 10.1159/000513705] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 12/08/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. METHODS In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. RESULTS Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33). CONCLUSIONS Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.
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Affiliation(s)
- Tatsuya Minami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoto Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryo Nakagomi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji Uchino
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hidetaka Fujinaga
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masashi Izumiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuyuki Hanajiri
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Gastroenterology, Sanraku Hospital, Tokyo, Japan
| | - Yoshinari Asaoka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yuji Kondo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Gastroenterology and Hepatology, Kyoundo Hospital, Tokyo, Japan
| | - Yasuo Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takamasa Ohki
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Masahiro Arai
- Department of Gastroenterology, Toshiba General Hospital, Toshiba, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Kiyomi Yasuda
- Department of Gastroenterology, Kiyokawa Hospital, Tokyo, Japan
| | - Hideaki Miura
- Department of Gastroenterology, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Itsuro Ogata
- Department of Gastroenterology, Kawakita General Hospital, Tokyo, Japan
| | - Toshiro Kamoshida
- Department of Gastroenterology, Hitachi General Hospital, Hitachi, Japan
| | - Kazuaki Inoue
- Department of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Yukihiro Koike
- Department of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teacher, Tokyo, Japan
| | | | - Hiroshi Mitsui
- Department of Gastroenterology, Tokyo Teishin Hospital, Tokyo, Japan
| | - Hajime Fujie
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, Tokyo, Japan
| | - Keiji Ogura
- Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo, Japan
| | - Hideo Yoshida
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Tomonori Wada
- Department of Gastroenterology, Sanraku Hospital, Tokyo, Japan
| | | | - Hisato Maekawa
- Department of Gastroenterology and Hepatology, Tokyo Takanawa Hospital, Tokyo, Japan
| | - Shuntaro Obi
- Department of Gastroenterology and Hepatology, Kyoundo Hospital, Tokyo, Japan
| | - Takuma Teratani
- Department of Hepato-Biliary-Pancreatic medicine, NTT Medical Center Tokyo, Tokyo, Japan
| | - Naohiko Masaki
- Clinical Laboratory Department, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
| | - Kayo Nagashima
- Department of Gastroenterology, National Disaster Medical Center, Tachikawa, Japan
| | | | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Disease and Applied Immunology, The Institute of Medical Science Research Hospital, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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22
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Cheung KS, Chung KL, Leung WK. Chemopreventive Effect of Metformin on Gastric Cancer Development. Gut Liver 2021; 16:147-156. [PMID: 34158423 PMCID: PMC8924804 DOI: 10.5009/gnl210132] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/17/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Although Helicobacterpylori infection is the most important causative factor for gastric cancer (GC), H. pylori eradication alone does not completely eliminate the GC risk. In addition to H. pylori eradication, other risk factors for GC should be identified and targeted. Diabetes mellitus (DM) confers a 20% increased risk of GC, which could be mediated via several biological mechanisms including the stimulation of cell proliferation via hyperinsulinemia and increased insulin-growth factor production, the promotion of angiogenesis, and DNA damage. With a current global prevalence of 9.3% and a predicted rise to 10.2% by 2030, DM could contribute substantially to the burden of GC cases worldwide. Emerging evidence showed that metformin possesses chemopreventive effects via both direct (e.g., adenosine monophosphate-activated protein kinase activation and subsequent inhibition of the mammalian target of rapamycin pathway) and indirect (e.g., modulation of the interaction between tumor cells and their microenvironment and gut microbiota) pathways. A recent meta-analysis of observational studies showed that metformin use was associated with 24% lower GC risk. However, many available observational studies related to metformin effects suffered from biases including the failure to adjust for the H. pylori infection status and serial glycemic control and time-related biases. Future prospective studies addressing these pitfalls are needed.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Kit Lam Chung
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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23
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Szymczak-Pajor I, Fleszar K, Kasznicki J, Gralewska P, Śliwińska A. A potential role of calpains in sulfonylureas (SUs) -mediated death of human pancreatic cancer cells (1.2B4). Toxicol In Vitro 2021; 73:105128. [PMID: 33652124 DOI: 10.1016/j.tiv.2021.105128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/01/2021] [Accepted: 02/25/2021] [Indexed: 12/25/2022]
Abstract
Sulfonylureas (SUs) are suggested to accelerate the pancreatic β-cells mass loss via apoptosis. However, little is known whether calpains mediate this process. The aim of the present study is to evaluate the involvement of calpains in SUs-induced death of human pancreatic cancer (PC) cell line 1.2B4. The cells were exposed to: glibenclamide, glimepiride and gliclazide for 72 h. The expression analysis of caspase-3 (CASP-3), TP53, calpain 1 (CAPN-1), calpain 2 (CAPN-2) and calpain 10 (CAPN-10) was detected using RT-PCR method. Intracellular Ca2+ concentrations, CASP-3 activity and total calpain activity were also evaluated. Our results have shown that glibenclamide and glimepiride decrease 1.2B4 cells viability with accompanied increase in intracellular Ca2+ concentration and increased expression of apoptosis-related CASP-3 and TP53. Gliclazide did not affect 1.2B4 cell viability and Ca2+ concentration, however, it downregulated CASP-3 and upregulated TP53. Interestingly, 50 μM glimepiride increased expression of CAPN-1, CAPN-2 and CAPN-10 whereas 50 μM glibenclamide solely upregulated CAPN-2 expression. We have shown that 10 μM and 50 μM glibenclamide and glimepiride increased the activity of CASP-3, but decreased total calpain activity. Our results suggest that calpains may be involved in glibenclamide- and glimepiride-induced death of PC cells. However, further investigation is required to confirm the engagement of calpains in SUs-mediated death of PC cells, especially studies on protein level of particular isoforms of calpains should be conducted.
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Affiliation(s)
- Izabela Szymczak-Pajor
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
| | - Krzysztof Fleszar
- Student Scientific Society of Civilization Diseases, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
| | - Jacek Kasznicki
- Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
| | - Patrycja Gralewska
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland.
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24
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Wang G, Xu M, Xie M. [Research Advance in Anti-lung Cancer Mechanism of Metformin]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 23:282-285. [PMID: 32316716 PMCID: PMC7210087 DOI: 10.3779/j.issn.1009-3419.2020.102.02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
二甲双胍作为治疗2型糖尿病的一线用药，安全性及有效性得到证实。近年来流行病学研究发现二甲双胍具有抑制肺癌细胞增殖及转移等特性，有望成为一种新的抗肺癌药物。肺癌是一种严重危害人类健康的疾病，其发病率和死亡率一直居所有恶性肿瘤之首，且预后差。近年来大量证据表明二甲双胍能降低肺癌等肿瘤的发病风险及死亡率，其机制主要包括激活单磷酸腺苷活化的蛋白激酶通路、改善高胰岛素血症及胰岛素抵抗、促进肺癌细胞凋亡、抑制相关炎症反应等。本文就二甲双胍对肺癌的研究做一综述。
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Affiliation(s)
- Gaoxiang Wang
- Department of Thoracic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Meiqing Xu
- Department of Thoracic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China.,Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Mingran Xie
- Department of Thoracic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China.,Department of Thoracic Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
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25
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Wang YB, Tan LM, Luo L, Yan S, Huang Q, Wang Y, Deng T, Shi Y, Deng Y, Jin YH. Immortal time bias exaggerates the effect of metformin on the risk of gastric cancer: A meta-analysis. Pharmacol Res 2021; 165:105425. [PMID: 33453371 DOI: 10.1016/j.phrs.2021.105425] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/19/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023]
Abstract
High heterogeneity has been reported among epidemiological studies exploring the relationship between metformin and the risk of gastric cancer. Immortal time bias might be one of the vital factors causing heterogeneity because of its widespread existence in pharmacological observational studies and it could severely exaggerate the drug's effectiveness. Immortal time bias could occur in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. In this study, we aimed to assess whether immortal time bias is responsible for the false assumption that metformin reduces the risk of gastric cancer. We searched PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies from the inception to August 9, 2020. The strength of the relationship was assessed using pooled relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Statistical analyses were carried out using a random-effects model. Pooled RR from 6 cohort studies with immortal time bias found a clear 33% reduced risk associated with metformin use (RR = 0.67, 95% CI = 0.59, 0.77; P < 0.001; I2 = 48.5%). However, pooled RR from 8 cohort studies without immortal time bias indicated no association between the use of metformin and gastric cancer risk (RR = 0.95, 95% CI = 0.85, 1.05; P = 0.317; I2 = 64.5%). From a univariate meta-regression model, the presence of immortal time bias was associated with a significant reduction of 29% in the effect estimate of metformin on gastric cancer risk (ratio of RR = 0.71, 95% CI = 0.58, 0.86; P = 0.002). This meta-analysis indicates that metformin use has no protective effect on gastric cancer risk. The relationship between metformin use and gastric cancer risk has been exaggerated as a result of the presence of immortal time bias. Further studies are required to confirm the results by controlling for immortal time bias based on appropriate study designs and statistical methods.
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Affiliation(s)
- Yong-Bo Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China
| | - Li-Ming Tan
- The Second People's Hospital of Huaihua, Huaihua, Hunan, 418200, China
| | - Lisha Luo
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China
| | - Siyu Yan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China
| | - Qiao Huang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China
| | - Yunyun Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China
| | - Tong Deng
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China
| | - Yuexian Shi
- School of Nursing, Peking University, Beijing, 100161, China
| | - Yuqing Deng
- Department of Thyroid Breast Surgery, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Ying-Hui Jin
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China.
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26
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Phan DV, Chan CL, Li AHA, Chien TY, Nguyen VC. Liver cancer prediction in a viral hepatitis cohort: A deep learning approach. Int J Cancer 2020; 147:2871-2878. [PMID: 32761609 DOI: 10.1002/ijc.33245] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/15/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022]
Abstract
Viral hepatitis is the primary cause of liver diseases, among which liver cancer is the leading cause of death from cancer. However, this cancer is often diagnosed in the later stages, which makes treatment difficult or even impossible. This study applied deep learning (DL) models for the early prediction of liver cancer in a hepatitis cohort. In this study, we surveyed 1 million random samples from the National Health Insurance Research Database (NHIRD) to analyze viral hepatitis patients from 2002 to 2010. Then, we used DL models to predict liver cancer cases based on the history of diseases of the hepatitis cohort. Our results revealed the annual prevalence of hepatitis in Taiwan increased from 2002 to 2010, with an average annual percentage change (AAPC) of 5.8% (95% CI: 4.2-7.4). However, young people (aged 16-30 years) exhibited a decreasing trend, with an AAPC of -5.6 (95% CI: -8.1 to -2.9). The results of applying DL models showed that the convolution neural network (CNN) model yielded the best performance in terms of predicting liver cancer cases, with an accuracy of 0.980 (AUC: 0.886). In conclusion, this study showed an increasing trend in the annual prevalence of hepatitis, but a decreasing trend in young people from 2002 to 2010 in Taiwan. The CNN model may be applied to predict liver cancer in a hepatitis cohort with high accuracy.
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Affiliation(s)
- Dinh-Van Phan
- Department of Information Management, Yuan Ze University, Taoyuan, Taiwan.,University of Economics, The University of Danang, Danang, Vietnam.,Teaching and Research Team for Business Intelligence, University of Economics, The University of Danang, Danang, Vietnam
| | - Chien-Lung Chan
- Department of Information Management, Yuan Ze University, Taoyuan, Taiwan.,Innovation Center for Big Data and Digital Convergence, Yuan Ze University, Taoyuan, Taiwan
| | - Ai-Hsien Adams Li
- Division of Cardiology, Far Eastern Memorial Hospital, Taipei, Taiwan
| | - Ting-Ying Chien
- Department of Computer Science and Engineering, Yuan Ze University, Taoyuan, Taiwan
| | - Van-Chuc Nguyen
- University of Economics, The University of Danang, Danang, Vietnam.,Teaching and Research Team for Business Intelligence, University of Economics, The University of Danang, Danang, Vietnam
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27
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Kang J, Jeong SM, Shin DW, Cho M, Cho JH, Kim J. The Associations of Aspirin, Statins, and Metformin With Lung Cancer Risk and Related Mortality: A Time-Dependent Analysis of Population-Based Nationally Representative Data. J Thorac Oncol 2020; 16:76-88. [PMID: 32950701 DOI: 10.1016/j.jtho.2020.08.021] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 08/24/2020] [Accepted: 08/31/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The aim of this study was to investigate the associations of aspirin, metformin, and statins with lung cancer risk and mortality using population-based nationwide cohort data. METHODS This study included a total of 732,199 participants who underwent a national health check-up from 2002 to 2003. Lung cancer incidence and mortality were identified using a registered lung cancer diagnosis code (International Classification of Diseases, 10th revision, code C34) and the Korean National Death Registry. The study participants were followed up from January 1, 2004 to December 31, 2013. Medication exposure was defined by the cumulative duration of use and cumulative defined daily dose per 2-year interval. To avoid immortal-time bias, drug exposure was inserted as a time-dependent variable in Cox analysis, which evaluated the associations of these medications with lung cancer. RESULTS Metformin use had a protective association with lung cancer incidence (p's for trend 0.008) and mortality (p's for trend < 0.001) in a dose-response fashion, and these associations were prominent among participants with a metformin cumulative defined daily dose of 547.5 and above compared with patients without diabetes. Lung cancer mortality was dose-dependently reduced with the use of aspirin (p's for trends 0.046) and statin (p's for trends < 0.001). The combined use of aspirin, statins, and metformin exhibited more prominent protective associations with lung cancer risk and mortality. CONCLUSIONS The use of aspirin, metformin, and statins had independent protective associations with lung cancer mortality, and metformin had an inverse association with lung cancer risk. Further studies are necessary to develop clinically applicable anticancer strategies using these drugs for the reduction of lung cancer and related mortality.
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Affiliation(s)
- Jihun Kang
- Department of Family Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Su-Min Jeong
- Department of Family Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Dong Wook Shin
- Supportive Care Center, Samsung Comprehensive Cancer Center, Seoul, Korea; Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Korea; Center for Clinical Epidemiology, SAIHST, Sungkyunkwan University, Seoul, Korea.
| | - Mihee Cho
- Samsung C&T Medical Clinic, Kangbuk Samsung Hospital, Seoul, Korea
| | - Jong Ho Cho
- Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul, Korea
| | - Jehun Kim
- Division of Pulmonology, Department of Internal Medicine, Kosin University Gospel Hospital, Busan, South Korea
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28
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Metabolic Responses to Metformin in Inoperable Early-stage Non-Small Cell Lung Cancer Treated With Stereotactic Radiotherapy: Results of a Randomized Phase II Clinical Trial. Am J Clin Oncol 2020; 43:231-235. [PMID: 31990759 DOI: 10.1097/coc.0000000000000632] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Metformin reduces glucose uptake in physiologic tissues and has been shown to affect non-small cell lung cancer (NSCLC) metabolism. We hypothesized that positron emission tomography (PET) scans could detect the impact of metformin on glucose uptake in NSCLC and we sought to test this hypothesis in a prospective clinical trial. MATERIALS AND METHODS A single-blinded phase II clinical trial was performed with subjects randomized 6:1 to 3 to 4 weeks of metformin versus placebo for inoperable early-stage NSCLC. PET scans were performed at baseline, mid-treatment (after 2 wk study medication), and 6 months postradiation. The primary endpoint of the trial was tumor metabolic response to metformin by PERCIST before definitive radiation. Stereotactic body radiotherapy to 50 Gy in 4 fractions was used for peripheral tumors and 70 Gy in 10 fractions for central tumors. RESULTS There were 14 subjects randomized to the metformin and 1 to placebo. Histologies were 60% adenocarcinoma, 33.3% squamous cell carcinoma, and 6.7% poorly differentiated carcinoma. At mid-treatment PET scan, 57% of subjects randomized to metformin met PERCIST criteria for metabolic response, of which 75% had progressive metabolic disease and 25% had partial metabolic response, whereas the placebo subject had stable metabolic disease. At 6 months, the metformin arm had 69% complete metabolic response, 23% partial metabolic response and 1 progressive metabolic disease, and the subject treated with placebo had a complete metabolic response. There were no CTCAE grade ≥3 toxicities. CONCLUSIONS Despite low accrual, majority of subjects treated with metformin had metabolic responses by PERCIST criteria on PET imaging. Contrary to the effect of metformin on most physiologic tissues, most tumors had increased metabolic activity in response to metformin.
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29
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Ng CAW, Jiang AA, Toh EMS, Ng CH, Ong ZH, Peng S, Tham HY, Sundar R, Chong CS, Khoo CM. Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression. Int J Colorectal Dis 2020; 35:1501-1512. [PMID: 32592092 DOI: 10.1007/s00384-020-03676-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/17/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Metformin may have a role in reducing the incidence of colorectal cancer (CRC) and improving survival outcome. This meta-analysis explored the effect of metformin use on colorectal adenoma and cancer incidence, and colorectal oncological outcomes. METHODS A database search was conducted on Medline, Embase and CNKI for studies comparing metformin vs. non-metformin users, metformin users vs. non-diabetics and metformin users vs. diabetics with diet-only treatment. Meta-analysis was done with DerSimonian and Laird with risk ratios (RR), and hazard ratios (HR) for survival outcomes. RESULTS We included 58 studies and summarized incidences of colorectal adenoma and cancer, as well as cancer survival outcomes. Metformin users had a significant lower incidence of colorectal adenoma (RR 0.77, CI 0.67-0.88, p < 0.001), advanced adenoma (0.61, CI 0.42-0.88, p = 0.008) and CRC (RR 0.76, CI 0.69-0.84, p < 0.001) respectively compared with non-metformin users. Overall survival (HR 0.6, CI 0.53-0.67, p < 0.001) and CRC-specific survival (HR 0.66, CI 0.59-0.74, p < 0.001) were higher among metformin users compared with non-metformin users. Further analysis on overall survival of metastatic CRC patients revealed significantly higher survival rates in metformin users (HR 0.77, CI 0.68-0.87, p < 0.001). CONCLUSION This meta-analysis showed that metformin use significantly reduces colorectal adenoma and cancer incidence and improves colorectal cancer outcomes.
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Affiliation(s)
- Cheng-Ann Winston Ng
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Amy Aimei Jiang
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Emma Min Shuen Toh
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Zhi Hao Ong
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Siyu Peng
- Department of Haematology-Oncology, National University Cancer Institute, NUH Medical Centre, Singapore, 119074, Singapore
| | - Hui Yu Tham
- Division of Colorectal Surgery, University Surgical Cluster, National University Hospital, 5 Lower Kent Ridge Rd, Singapore, 119074, Singapore
| | - Raghav Sundar
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.,Department of Haematology-Oncology, National University Cancer Institute, NUH Medical Centre, Singapore, 119074, Singapore
| | - Choon Seng Chong
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.,Division of Colorectal Surgery, University Surgical Cluster, National University Hospital, 5 Lower Kent Ridge Rd, Singapore, 119074, Singapore
| | - Chin Meng Khoo
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore. .,Division of Endocrinology, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Rd, Singapore, 119074, Singapore.
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30
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Rennert G, Rennert HS, Gronich N, Pinchev M, Gruber SB. Use of metformin and risk of breast and colorectal cancer. Diabetes Res Clin Pract 2020; 165:108232. [PMID: 32446797 DOI: 10.1016/j.diabres.2020.108232] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 04/15/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes has been associated with increased risk of cancer, including breast cancer and colorectal cancer. Metformin, an oral hypoglycemic drug, but not other anti-diabetic drugs, has been associated with reduced risk of breast and of colon cancers in some, but not in other, studies. METHODS Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 were analyzed to evaluate the association between regular use (>3 times) of metformin prior to diagnosis and risk of developing cancer. The multivariate analyses for both cancer sites included age, family history of breast/colorectal cancer, history of diabetes, sports participation, fruits/vegetables consumption, aspirin and statins use, and for breast cancer, also included use of oral contraceptives and postmenopausal hormones and number of pregnancies. Use of metformin and diabetes status were determined based on valid electronic medical records of the participants. RESULTS Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726-0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623-0.912, p = 0.004). An inverse association was not identified with use of other anti-diabetic medications. Diabetes was found to be associated with risk of colorectal cancer (OR = 1.204, 1.014-1.431, p = 0.034) but not of breast cancer. No dose response by years of use of metformin was found. CONCLUSION These analyses of large population-based studies provide evidence of a strong inverse association of metformin with breast and, even more so, with colorectal cancer risk.
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Affiliation(s)
- Gad Rennert
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Clalit Health Services National Cancer Control Center (NICCC), Haifa, Israel.
| | - Hedy S Rennert
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Naomi Gronich
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Mila Pinchev
- Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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31
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Cheung KS, Chan EW, Wong AYS, Chen L, Seto WK, Wong ICK, Leung WK. Metformin Use and Gastric Cancer Risk in Diabetic Patients After Helicobacter pylori Eradication. J Natl Cancer Inst 2020; 111:484-489. [PMID: 30329127 DOI: 10.1093/jnci/djy144] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/11/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Although prior studies showed metformin could reduce gastric cancer (GC) risk in patients with diabetes mellitus, they failed to adjust for Helicobacter pylori infection and glycemic control. We aimed to investigate whether metformin reduced GC risk in H. pylori-eradicated diabetic patients and its association with glycemic control. METHODS This was a territory-wide cohort study using hospital registry database, recruiting all diabetic patients who were prescribed clarithromycin-based triple therapy for H. pylori infection from 2003 to 2012. Subjects were observed from H. pylori therapy prescription until GC diagnosis, death, or end of study (December 2015). Exclusion criteria included GC diagnosed within first year of H. pylori therapy, prior history of GC or gastrectomy, and failure of H. pylori eradication. The hazard ratio (HR) of GC with metformin (defined as at least 180-day use) was estimated by Cox model with propensity score adjustment for covariates (age, sex, comorbidities, medications [including insulin], and time-weighted average hemoglobin A1c [HbA1c]). All statistical tests were two-sided. RESULTS During a median follow-up of 7.1 years (IQR = 4.7-9.8), 37 (0.51%) of 7266 diabetic patients developed GC at a median age of 76.4 years (IQR = 64.8-81.5 years). Metformin use was associated with a reduced GC risk (adjusted HR = 0.49, 95% CI = 0.24 to 0.98). There was a trend towards a lower GC risk with increasing duration (Ptrend = .01) and dose of metformin (Ptrend = .02). HbA1c level was not an independent risk factor for GC. CONCLUSIONS Metformin use was associated with a lower GC risk among H. pylori-eradicated diabetic patients in a duration- and dose-response manner, which was independent of HbA1c level.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Esther W Chan
- Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, The University of Hong Kong, Hong Kong
| | - Angel Y S Wong
- Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, The University of Hong Kong, Hong Kong.,Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Lijia Chen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Wai Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Ian C K Wong
- Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, The University of Hong Kong, Hong Kong.,UCL School of Pharmacy, University College London, London, UK
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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Pancreatic cystic lesions in diabetes mellitus patients. GASTROENTEROLOGY REVIEW 2020; 16:62-66. [PMID: 33986890 PMCID: PMC8112270 DOI: 10.5114/pg.2020.96080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 05/05/2020] [Indexed: 11/17/2022]
Abstract
Introduction According to the literature exocrine pancreatic insufficiency is relatively common among patients with diabetes mellitus (DM). Pseudocysts are the most common cystic lesions and may be formed in the setting of acute or chronic pancreatitis. However, whether DM is involved or not in pancreatic cyst formation is still not well established. Aim To investigate the frequency and risk factors of cystic lesions in diabetic patients. Material and methods One hundred and sixty-one patients with DM, with no previous history of pancreatic diseases, were prospectively included in the study. Endosonography followed by fine needle aspiration biopsy was then performed. Results Finally, 33 of 161 patients (20.5%) were recognized with cystic lesions of the pancreas. Among them 5 patients were classified as cystic neoplasms, and 28 as pseudocysts. In the group of patients with pseudocysts, cystic lesions were significantly more prevalent in individuals with DM lasting less than 3 years. Prevalence of cystic lesions was significantly higher in metformin users in comparison to other diabetic patients (p < 0.05). Cystic lesions were more frequent in patients above 50 years of age (p < 0.05). Conclusions The prevalence of cystic lesions in the diabetic population is higher than in the general population. DM seems to play a major role in the process of cyst development, especially in patients without previous history of pancreatitis. Higher prevalence of cystic lesions in early diabetes seems to be the first stage of pancreatic injury. The exact role of diabetes duration and type of treatment should be established.
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Partridge L, Fuentealba M, Kennedy BK. The quest to slow ageing through drug discovery. Nat Rev Drug Discov 2020; 19:513-532. [DOI: 10.1038/s41573-020-0067-7] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
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Xiao K, Liu F, Liu J, Xu J, Wu Q, Li X. The effect of metformin on lung cancer risk and survival in patients with type 2 diabetes mellitus: A meta-analysis. J Clin Pharm Ther 2020; 45:783-792. [PMID: 32406122 DOI: 10.1111/jcpt.13167] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 04/17/2020] [Accepted: 04/18/2020] [Indexed: 12/13/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Metformin has received increasing attention owing to its potential protective effect against cancer. We aimed to summarize evidence regarding the association between metformin and the risk or survival in lung cancer patients with type 2 diabetes. METHODS We selected observational studies examining the association between exposure to metformin and the risk or survival in lung cancer. Available publications were searched in PubMed, Cochrane Library, ScienceDirect, Wiley and SpringerLink databases. Meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures for risk or survival in lung cancer. RESULTS Eighteen studies (eight on lung cancer risk and ten on lung cancer survival) were included. Metformin treatment was associated with decreased lung cancer incidence (HR 0.78; 95% CI 0.70-0.86) and increased lung cancer survival (HR 0.65; 95% CI 0.55-0.77). In the subgroup analysis by ethnicity, a significant protective effect of metformin use on lung cancer risk was observed among Asian patients (HR 0.66; 95% CI 0.56-0.76), but not in European patients. On the other hand, the protective effect of metformin use on lung cancer survival was observed in both Asian (HR 0.57; 95% CI 0.49-0.66) and non-Asian (HR 0.79; 95% CI 0.71-0.88) patients. In the subgroup analysis by histology, a protective effect of metformin on lung cancer survival was observed in both non-small-cell lung cancer (HR 0.68; 95% CI 0.54-0.84) and small-cell lung cancer (HR 0.52; 95% CI 0.39-0.69). Funnel plot showed that no significant publication bias existed. CONCLUSIONS Our findings demonstrate that metformin is significantly associated with a decreased risk and increased survival in lung cancer.
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Affiliation(s)
- Kang Xiao
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University, Jinan, China.,Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Fengxi Liu
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University, Jinan, China.,Department of Clinical pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Juan Liu
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University, Jinan, China
| | - Jiwei Xu
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University, Jinan, China
| | - Qiuyun Wu
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University, Jinan, China
| | - Xiao Li
- Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University, Jinan, China.,Department of Clinical pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
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Zhang C, Sha Y, Liu H, Guo D, Jiang Y, Hong L, Shi L, Huang H. Type 2 diabetes mellitus does not increase the risk of multiple myeloma: a systematic review and meta-analysis. Transl Cancer Res 2020; 9:2884-2894. [PMID: 35117645 PMCID: PMC8798954 DOI: 10.21037/tcr.2020.03.36] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/28/2020] [Indexed: 01/11/2023]
Abstract
Background Epidemiological studies have shown that patients with type 2 diabetes mellitus (T2DM) are at a higher risk of secondary tumors. However, no consensus has been made about whether T2DM can increase the risk of multiple myeloma (MM). Methods We searched the databases of PubMed, Cochrane Library and EMBASE and cross-checked the bibliography. Data quality was assessed using the Newcastle-Ottawa scale (NOS). Heterogeneity was calculated as the odds ratio (OR) using a random-effects model. Data were analyzed using Stata version 12.0 software. Results A total of 13 articles were selected into this meta-analysis. Initially, we found that diabetic patients had a higher risk of myeloma than non-diabetic patients (OR =1.60, 95% CI: 1.13–2.26, I2=98%, P=0.000). But the data in these articles were highly heterogeneous (I2>75%). Therefore, eight of the included articles showed a moderate heterogeneity (I2=71.6%). We used Galbraith heterogeneity map to analyze the causes of heterogeneity. Two articles with high heterogeneity were excluded. Then, we found the heterogeneity of the left six articles was reduced from moderate to mild (I2=45.9%, P=0.100). The final results of this meta-analysis showed that T2DM was not a risk factor for increased incidence of MM (OR =1.05, 95% CI: 0.83–1.33, I2=45.9%, P=0.100). Also, the subgroup analysis (case-control studies vs. cohort studies) showed no statistical difference (OR =1.19, 95% CI: 0.76–1.85, I2=1%, P=0.364; OR =1.00, 95% CI: 0.75–1.33, I2=71.2%, P=0.031; respectively). Conclusions T2DM is not a risk factor for the increased incidence of MM, a finding that should be validated with more strictly designed randomized controlled trials (RCTs).
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Affiliation(s)
- Chenlu Zhang
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yuou Sha
- Department of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Haiyan Liu
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Dan Guo
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yijing Jiang
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Lemin Hong
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Lili Shi
- Department of Medical Informatics, Medical School of Nantong University, Nantong 226001, China
| | - Hongming Huang
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, China
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Dulskas A, Patasius A, Kaceniene A, Linkeviciute-Ulinskiene D, Zabuliene L, Smailyte G. A Cohort Study of Antihyperglycemic Medication Exposure and Gastric Cancer Risk. J Clin Med 2020; 9:E435. [PMID: 32033451 PMCID: PMC7073990 DOI: 10.3390/jcm9020435] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/07/2020] [Accepted: 02/04/2020] [Indexed: 12/24/2022] Open
Abstract
We assessed gastric cancer risk in type 2 diabetes mellitus patients. Gastric cancer patients with diabetes between 2001-2012 were identified. Four groups were analysed: combination therapy with metformin users; insulin and other medication users; metformin and insulin users; and sulfonylurea users. Standardised incidence ratios (SIRs) for gastric cancers as a ratio of the observed number of cancer cases in people with diabetes to the expected number of cancer cases in the underlying general population were calculated. A total of 99,992 patients with diabetes were analysed and 337 gastric cancer cases in patients with diabetes were observed when compared to the expected number of 400.54 gastric cancer cases, according to the cancer rates of the general population (SIR 0.84, 95% confidence interval (CI): 0.76-0.94). Lower risk of gastric cancer was found both in male and female patients with diabetes, however, risk among females was insignificantly lower. Higher gastric cancer risk was found in the group of diabetic patients treated with sulfonylureas (SIR 1.31, 95% CI: 1.04-1.65) and significantly lower risk than expected from the general population was found in the group of metformin users (SIR 0.75, 95% CI: 0.66-0.86). Type 2 diabetes mellitus was not associated with increased risk of gastric cancer. Metformin might decrease the risk of gastric cancer in patients with diabetes, while sulfonylureas may increase gastric cancer risk.
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Affiliation(s)
- Audrius Dulskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania
- University of Applied Sciences, Faculty of Health Care, 45 Didlaukio Str., LT-08303 Vilnius, Lithuania
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 21/27 M. K. Ciurlionio Str., LT-03101 Vilnius, Lithuania;
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania; (A.P.); (A.K.); (G.S.)
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, 21/27 M. K. Ciurlionio Str., LT-03101 Vilnius, Lithuania
| | - Auguste Kaceniene
- Laboratory of Cancer Epidemiology, National Cancer Institute, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania; (A.P.); (A.K.); (G.S.)
| | - Donata Linkeviciute-Ulinskiene
- Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 21/27 M. K. Ciurlionio Str., LT-03101 Vilnius, Lithuania;
| | - Lina Zabuliene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 21/27 M. K. Ciurlionio Str., LT-03101 Vilnius, Lithuania;
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, 1 Santariskiu Str., LT-08406 Vilnius, Lithuania; (A.P.); (A.K.); (G.S.)
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, 21/27 M. K. Ciurlionio Str., LT-03101 Vilnius, Lithuania
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Wang Y, Liu X, Yan P, Tang J, Chen T, Sun Y, Zhou W, Bi Y, Zhang ZJ. Effect of metformin on the risk of prostate cancer in patients with type 2 diabetes by considering different confounding factors: a meta-analysis of observational studies. Eur J Cancer Prev 2020; 29:42-52. [PMID: 30950925 DOI: 10.1097/cej.0000000000000514] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Preclinical studies have suggested the antitumorigenic properties of metformin on prostate cancer; results from epidemiological studies remain contradictory. We aim to investigate the evidence of metformin and the risk of prostate cancer. PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies. Meta-analyses were carried out using the most fully adjusted hazard ratios and the corresponding 95% confidence intervals. Eighteen cohort studies and six case-control studies representing 2 009 504 male patients with type 2 diabetes mellitus were identified. The pooled HR of prostate cancer for metformin therapy was 0.97 (0.84-1.12) in case-control studies and 0.94 (0.79-1.12) in cohort studies, respectively. In cohort studies, we found that there was a modest association in studies with samples from Europe, but not in studies with samples from North America, Asia, and Oceania. In addition, metformin showed a slightly protective effect compared with sulfonylurea, but not insulin and other comparators. Meta-regression analyses found that obesity and prostate-specific antigen adjustment in statistical models may be the sources of heterogeneity. However, there were no significant differences in subgroups stratified by time-related biases, analytical approaches, types of risk estimates, study quality, publication year, and whether adjusted for smoking, alcohol abuse, hemoglobin A1c, diabetes duration, and other confounding factors. Our study showed that metformin therapy was not associated with the risk of prostate cancer in patients with type 2 diabetes mellitus. However, exploratory analyses suggest that metformin use may be protective in a certain subgroup of patients.
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Affiliation(s)
- Yongbo Wang
- Department of Epidemiology and Health Statistics, School of Health Sciences, Wuhan University, Wuhan, China
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Wang X, Wang H, Zhang T, Cai L, Dai E, He J. Diabetes and its Potential Impact on Head and Neck Oncogenesis. J Cancer 2020; 11:583-591. [PMID: 31942181 PMCID: PMC6959048 DOI: 10.7150/jca.35607] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/27/2019] [Indexed: 12/25/2022] Open
Abstract
In recent years, the incidence of diabetes mellitus and cancer has increased sharply; indeed, these have become the two most important diseases threatening health and survival. Head and neck (HN) tumors are the sixth most common malignancies in humans. Numerous studies have shown that there are many common risk factors for diabetes mellitus and HN squamous cell carcinoma, including advanced age, poor diet and lifestyle, and environmental factors. However, the mechanism linking the two diseases has not been identified. A number of studies have shown that diabetes affects the development, metastasis, and prognosis of HN cancer, potentially through the associated hyperglycemia, hyperinsulinemia and insulin resistance, or chronic inflammation. More recent studies show that metformin, the first-line drug for the treatment of type 2 diabetes, can significantly reduce the risk of HN tumor development and reduce mortality in diabetic patients. Here, we review recent progress in the study of the relationship between diabetes mellitus and HN carcinogenesis, and its potential mechanisms, in order to provide a scientific basis for the early diagnosis and effective treatment of these diseases.
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Affiliation(s)
- Xiaofeng Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China.,Pediatric Research Institute, Department of Pediatrics, The University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Huiyu Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Tianfu Zhang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, The University of Louisville School of Medicine, Louisville, KY 40292, USA.,Departments of Radiation Oncology, Pharmacology, and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Enyong Dai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Jinting He
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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Deng M, Lei S, Huang D, Wang H, Xia S, Xu E, Wu Y, Zhang H. Suppressive effects of metformin on colorectal adenoma incidence and malignant progression. Pathol Res Pract 2019; 216:152775. [PMID: 31818523 DOI: 10.1016/j.prp.2019.152775] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND The linear progression from normal colonic epithelium to adenoma initiation, carcinoma transformation and metastasis is considered the classical model of colorectal cancer (CRC) development. Although metformin has been extensively reported to be negatively related to cancer incidence, the effect of metformin on CRC development remains unclear. We aimed to evaluate the role of metformin in the entire CRC linear progression. METHODS Systematic searches and data extraction were performed in the PubMed, Embase, and Cochrane Library databases on Jan 31, 2019. The combined relative ratios (RRs) of colorectal tumor incidence and the hazard ratios (HRs) of overall survival (OS) and cancer-specific survival (CSS) were evaluated by a random-effects model. Then, the effects of metformin were further assessed through stratified analyses by population, medication duration and dosage, dose-response analysis and comparison with other antidiabetic agents. RESULTS A total of 50 studies consisting of 238,540 cases of diabetes mellitus (DM) were included in this study. Metformin use was negatively associated with the incidence of colorectal adenoma (RR: 0.75, 95% CI: 0.65-0.86) and CRC (RR: 0.73, 95% CI: 0.58-0.90). Moreover, CRC patients benefited from metformin in terms of both OS (HR: 0.73, 95% Cl: 0.63-0.84) and CSS (HR: 0.60, 95% Cl: 0.50-0.73). Stratified analyses suggested that a long duration of high-dose metformin (RR: 0.52, 95% Cl: 0.36-0.83) was more effective than a short duration in Asian populations against colorectal adenoma (RR: 0.66, 95% Cl: 056-0.70) and CRC (RR: 0.45, 95% Cl: 0.29-0.70). Interestingly, metformin use decreased CRC risk in a dose-dependent manner (RR: 0.91, 95% CI: 0.87-0.95). In addition, the benefit of metformin on CRC was more significant than that of other antidiabetic agents, including insulin. CONCLUSIONS The use of metformin is associated with a lower incidence of adenoma and CRC and a better prognosis, especially in Asian populations.
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Affiliation(s)
- Min Deng
- Department of Pathology, The First People's Hospital of Fuyang, Hangzhou, 311400, PR China.
| | - Siqin Lei
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Dongdong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Hui Wang
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Shuli Xia
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Enping Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yihua Wu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Honghe Zhang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
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Metformin use and risk of gastric adenocarcinoma in a Swedish population-based cohort study. Br J Cancer 2019; 121:877-882. [PMID: 31591459 PMCID: PMC6889304 DOI: 10.1038/s41416-019-0598-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/17/2019] [Accepted: 09/19/2019] [Indexed: 02/06/2023] Open
Abstract
Background Whether or not the use of metformin decreases the risk of gastric adenocarcinoma is unclear. Methods This was a population-based cohort study in 2005–2015. Associations between metformin use and gastric non-cardia and cardia adenocarcinomas were examined within two cohorts; a diabetes cohort of participants using anti-diabetes medications, and a matched cohort of common-medication users, where metformin non-users were frequency matched (10:1) with metformin users for sex and age. Multivariable Cox proportional hazard regression analyses provided hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sex, age, calendar year, comorbidity, Helicobacter pylori eradication treatment, use of non-steroidal anti-inflammatory drugs or aspirin and use of statins. Results During the follow-up for a median of 5.8 years, 892 (0.1%) participants in the diabetes cohort and 6395 (0.1%) participants in the matched cohort of common-medication users developed gastric adenocarcinoma. Metformin users had no significantly decreased risk of gastric non-cardia adenocarcinoma (diabetes cohort: HR 0.93, 95% CI 0.78–1.12; matched cohort: HR 1.30, 95% CI 1.18–1.42) or cardia adenocarcinoma (diabetes cohort: HR 1.49, 95% CI 1.09–2.02; matched cohort: HR 1.58, 95% CI 1.38–1.81) compared with non-users in both cohorts. Conclusions This cohort study with <10 years of follow-up suggests metformin use may not prevent gastric adenocarcinoma.
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Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, Zabuliene L, Smailyte G. A cohort study of antihyperglycemic medication exposure and survival in patients with gastric cancer. Aging (Albany NY) 2019; 11:7197-7205. [PMID: 31518336 PMCID: PMC6756873 DOI: 10.18632/aging.102245] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 08/22/2019] [Indexed: 12/14/2022]
Abstract
Objective: We aimed to estimate survival in gastric cancer patients with type 2 diabetes mellitus (T2DM) using different antihyperglycemic medication. Methods: Patients with gastric cancer and diabetes between 2003-2013 were identified form The Lithuanian Cancer Registry and The National Health Insurance Fund database. Cohort members were classified into five groups: four groups of T2DM patients according to treatment: metformin users; metformin and other medication users; sulphonylurea users; insulin and other medication users; and non-diabetic group. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate gastric cancer-specific survival and overall survival. Results: 8423 patients met eligibility criteria. Survival analysis showed no differences in gastric cancer-specific survival between non-diabetic and diabetic patient groups. Better survival was observed in the groups of patients using antihyperglycemic medication combinations with metformin, metformin alone or insulin. Lowest survival was observed in diabetic patients who were sulphonylurea users. Survival analysis comparing overall survival between non-diabetic and diabetic patients (p = 0.89) showed no evidence of survival difference between groups and survival differences between antihyperglycemic medication user groups were of borderline significance (p = 0.052). Conclusions: Antihyperglycemic medication use was not associated with a significant effect on survival in patients with gastric cancer and T2DM.
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Affiliation(s)
- Audrius Dulskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius LT-08406, Lithuania.,University of Applied Sciences, Faculty of Health Care, Vilnius ELT-08303, Lithuania.,Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius LT-08406, Lithuania.,Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania
| | | | - Lina Zabuliene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius LT-08406, Lithuania.,Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania
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Hendriks AM, Schrijnders D, Kleefstra N, de Vries EGE, Bilo HJG, Jalving M, Landman GWD. Sulfonylurea derivatives and cancer, friend or foe? Eur J Pharmacol 2019; 861:172598. [PMID: 31408647 DOI: 10.1016/j.ejphar.2019.172598] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/07/2019] [Accepted: 08/08/2019] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.
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Affiliation(s)
- Anne M Hendriks
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Dennis Schrijnders
- Langerhans Medical Research Group, Zwolle, the Netherlands; Diabetes Center, Isala Hospital, Zwolle, the Netherlands
| | | | - Elisabeth G E de Vries
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Henk J G Bilo
- Diabetes Center, Isala Hospital, Zwolle, the Netherlands; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Gijs W D Landman
- Langerhans Medical Research Group, Zwolle, the Netherlands; Department of Internal Medicine, Gelre Hospital, Apeldoorn, the Netherlands
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Hosio M, Urpilainen E, Marttila M, Hautakoski A, Arffman M, Sund R, Puistola U, Läärä E, Jukkola A, Karihtala P. Association of antidiabetic medication and statins with breast cancer incidence in women with type 2 diabetes. Breast Cancer Res Treat 2019; 175:741-748. [PMID: 30895533 PMCID: PMC6534663 DOI: 10.1007/s10549-019-05185-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 02/20/2019] [Indexed: 12/16/2022]
Abstract
Purpose To address the possible association between the use of metformin, other forms of antidiabetic medication (ADM) and statins with the incidence of breast cancer in women with type 2 diabetes (T2D). Methods Data were collected from a Finnish nationwide diabetes database (FinDM). The study cohort consisted of women diagnosed with T2D in 1996–2011 in Finland. In full-cohort analysis, Poisson regression was used to estimate hazard ratios (HRs) in relation to use of metformin, insulin, other forms of oral ADM and statins. In nested case–control analysis, up to 20 controls were matched for age and duration of diabetes to each case of breast cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different forms of ADM, and statins. Results 2300 women were diagnosed with breast cancer during follow-up. No difference in breast cancer incidence was observed between metformin users [HR 1.02, 95% confidence interval (CI) 0.93–1.11] or statin users (HR 0.97, 95% CI 0.89–1.05) compared with non-users. In nested case–control analysis the results were similar. Use of insulin (HR 1.18, 95% CI 1.03–1.36) was associated with a slightly increased incidence of breast cancer. Conclusions No evidence of an association between the use of metformin or statins and the incidence of breast cancer in women with T2D was found. Among insulin users, a slightly higher incidence of breast cancer was observed. Electronic supplementary material The online version of this article (10.1007/s10549-019-05185-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mayu Hosio
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 50, 90029, Oulu, Finland
| | - Elina Urpilainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, 90029, Oulu, Finland
| | - Mikko Marttila
- Children, Adolescents and Families Unit, Department of Welfare, National Institute for Health and Welfare, P.O. Box 310, 90101, Oulu, Finland.,Orion Corporation, Orionintie 1, P.O. Box 65, 02101, Espoo, Finland
| | - Ari Hautakoski
- Research Unit of Mathematical Sciences, University of Oulu, P.O. Box 3000, 90014, Oulu, Finland
| | - Martti Arffman
- Service System Research Unit, National Institute for Health and Welfare, P.O. Box 30, 00271, Helsinki, Finland
| | - Reijo Sund
- Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Ulla Puistola
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, P.O. Box 23, 90029, Oulu, Finland
| | - Esa Läärä
- Research Unit of Mathematical Sciences, University of Oulu, P.O. Box 3000, 90014, Oulu, Finland
| | - Arja Jukkola
- Department of Oncology and Radiotherapy, Tampere University Hospital, P.O. Box 2000, 33521, Tampere, Finland
| | - Peeter Karihtala
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 50, 90029, Oulu, Finland.
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Metformin Use and Lung Cancer Risk in Diabetic Patients: A Systematic Review and Meta-Analysis. DISEASE MARKERS 2019; 2019:6230162. [PMID: 30881522 PMCID: PMC6387718 DOI: 10.1155/2019/6230162] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 12/16/2018] [Indexed: 02/06/2023]
Abstract
Background Antidiabetic medications (ADMs) can alter the risk of different types of cancer, but the relationship between lung cancer incidence and metformin remains controversial. Our aim was to quantitatively estimate the relationship between incidences of lung cancer and metformin in patients with diabetes in this meta-analysis. Methods We performed a search in PubMed, Embase, ISI Web of Science, and Cochrane Library until September 20, 2017. The odds ratio (OR), relative risk (RR) or hazard ratio (HR), and 95% confidence interval (95% CI) were estimated using the random-effect model. The Newcastle-Ottawa Scale (NOS) was used to assess the study quality. Results A total of 13 studies (10 cohort studies and 3 case-control studies) were included in the meta-analysis. Compared to nonmetformin users, metformin probably decreased lung cancer incidence in diabetic patients (RR = 0.89; 95% CI, 0.83-0.96; P = 0.002) with significant heterogeneity (Q = 35.47, I2 = 66%, P = 0.0004). Subgroup analysis showed that cohort studies (RR = 0.91; 95% CI, 0.85-0.98; P = 0.008), location in Europe (RR = 0.90; 95% CI, 0.86-0.94; P < 0.0001), the control drug of the sulfonylurea group (RR = 0.91; 95% CI, 0.86-0.96; P = 0.001), and adjusting for smoking (RR = 0.86; 95% CI, 0.75-1.00; P = 0.05) may be related to lower lung cancer risk. No significant publication bias was detected using a funnel plot. Conclusion Metformin use was related to a lower lung cancer risk in diabetic patients compared to nonusers, but this result was retrieved from observational studies and our findings need more well-designed RCTs to confirm the association.
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Mekuria AN, Ayele Y, Tola A, Mishore KM. Monotherapy with Metformin versus Sulfonylureas and Risk of Cancer in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis. J Diabetes Res 2019; 2019:7676909. [PMID: 31828167 PMCID: PMC6885827 DOI: 10.1155/2019/7676909] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 11/02/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Accumulating evidence suggests that patients with type 2 diabetes mellitus and hyperinsulinemia are at an increased risk of developing malignancies. It remains to be fully elucidated whether the use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affects cancer incidence in subjects with type 2 diabetes mellitus. OBJECTIVE A systematic review and meta-analysis was performed to compare the risk of cancer incidence associated with monotherapy with metformin compared with monotherapy with sulfonylureas in type 2 diabetes mellitus patients. METHODS Search was performed throughout MEDLINE/PubMed, EMBASE, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov up until December 2018. In this meta-analysis, each raw data (unadjusted) and study-specific (adjusted) relative risks (RRs) was combined and the pooled unadjusted and adjusted RRs with the 95% CI were calculated using the random-effects model with inverse-variance weighting. Heterogeneity among the studies was evaluated using I 2 statistics. Publication bias was evaluated using the funnel plot asymmetry test. The Newcastle-Ottawa scale (NOS) was used to assess the study quality. RESULTS A total of 8 cohort studies were included in the meta-analysis. Obvious heterogeneity was noted, and monotherapy with metformin was associated with a lower risk of cancer incidence (unadjusted RR = 0.74, 95% CI: 0.55-0.99, I 2 = 97.89%, p < 0.00001; adjusted RR = 0.76, 95% CI: 0.54-1.07, I 2 = 98.12%, p < 0.00001) compared with monotherapy with sulfonylurea, using the random-effects model with inverse-variance weighting. CONCLUSIONS According to this review, the monotherapy with metformin appears to be associated with a lower risk of cancer incidence than monotherapy with sulfonylurea in patients with type 2 diabetes. This analysis is mainly based on cohort studies, and our findings underscore the need for large-scale randomized controlled trials to establish the effect of metformin monotherapy, relative to sulfonylureas monotherapy on cancer.
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Affiliation(s)
- Abraham Nigussie Mekuria
- Department of Pharmacology, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Yohanes Ayele
- Department of Clinical Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Assefa Tola
- Department of Epidemiology and Biostatistics, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Kirubel Minsamo Mishore
- Department of Clinical Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
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Kobayashi D, Kuriyama N, Hirano K, Takahashi O, Noto H. Malignancy incidences by glycemic control among diabetic patients. Endocr Connect 2018; 7:1457-1463. [PMID: 30508417 PMCID: PMC6300859 DOI: 10.1530/ec-18-0355] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 11/29/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND The aim of this study was to evaluate the difference in malignancy incidence by evaluating time-dependent HbA1c levels among diabetic patients in a longitudinal study. METHODS We conducted a retrospective longitudinal study at large academic hospital, Tokyo, Japan, from 2006 to 2016. We included all diabetic patients who were 50 years or older and who underwent health check-ups at the Center for Preventive Medicine. Those patients with a prior history of malignancies were excluded. We categorized patients into five groups on the basis of HbA1c measurements: <5.4, 5.5-6.4, 6.5-7.4, 7.5-8.5, >8.5%. Our primary outcome was the development of any types of malignancy. Longitudinal analyses by a mixed effect model with time-dependent HbA1c levels were applied in order to take into account fluctuations in HbA1c levels within the same patient. RESULTS In total, 2729 participants were included in this study, where the mean age was 62.6 (standard deviation (s.d.): 7.8) and 2031 (74.4%) were male. The mean disease duration of diabetes was 7.6 (s.d.: 7.6) years, and 1688 (61.8%) were prescribed medications. Median follow-up was 1443.5 (interquartile range (IQR): 2508) days and 376 (13.8%) developed malignancies. Compared to the reference range of HbA1c (5.5-6.4%), the odds ratios for developing malignancies among the other HbA1c level groups were similar and not statistically different (OR: 0.98, 95% CI:0.31-3.15 (for HbA1c <5.4%); OR: 0.88, 95% CI: 0.69-1.12 (for HbA1c 6.5-7.4%); OR: 0.88, 95% CI: 0.64-1.22 (for HbA1c 7.5-8.4%); OR 1.07, 95% CI: 0.70-1.66 (for HbA1c >8.5%)). CONCLUSION In our study, there was no association between glycemic control and the development of future malignancies. Compared to very strictly controlled HbA1c levels, both excessive control and good or bad control had a statistically similar risk of developing malignancies.
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Affiliation(s)
- Daiki Kobayashi
- Division of General Internal MedicineDepartment of Medicine, St. Luke’s International Hospital, Tokyo, Japan
- Department of EpidemiologySt. Luke’s International University Graduate School of Public Health, Tokyo, Japan
- Fujita Health UniversityToyoake, Japan
- Correspondence should be addressed to D Kobayashi:
| | - Nagato Kuriyama
- Department of Epidemiology for Community Health and MedicineKyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keita Hirano
- Department of NephrologyKyoto University Graduate School of Medicine, Kyoto, Japan
| | - Osamu Takahashi
- Division of General Internal MedicineDepartment of Medicine, St. Luke’s International Hospital, Tokyo, Japan
- Department of EpidemiologySt. Luke’s International University Graduate School of Public Health, Tokyo, Japan
| | - Hiroshi Noto
- Department of EndocrinologySt. Luke’s International Hospital, Tokyo, Japan
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Development of a Prediction Model for Colorectal Cancer among Patients with Type 2 Diabetes Mellitus Using a Deep Neural Network. J Clin Med 2018; 7:jcm7090277. [PMID: 30213141 PMCID: PMC6162847 DOI: 10.3390/jcm7090277] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 09/08/2018] [Accepted: 09/10/2018] [Indexed: 12/25/2022] Open
Abstract
Objectives: Observational studies suggested that patients with type 2 diabetes mellitus (T2DM) presented a higher risk of developing colorectal cancer (CRC). The current study aims to create a deep neural network (DNN) to predict the onset of CRC for patients with T2DM. Methods: We employed the national health insurance database of Taiwan to create predictive models for detecting an increased risk of subsequent CRC development in T2DM patients in Taiwan. We identified a total of 1,349,640 patients between 2000 and 2012 with newly diagnosed T2DM. All the available possible risk factors for CRC were also included in the analyses. The data were split into training and test sets with 97.5% of the patients in the training set and 2.5% of the patients in the test set. The deep neural network (DNN) model was optimized using Adam with Nesterov’s accelerated gradient descent. The recall, precision, F1 values, and the area under the receiver operating characteristic (ROC) curve were used to evaluate predictor performance. Results: The F1, precision, and recall values of the DNN model across all data were 0.931, 0.982, and 0.889, respectively. The area under the ROC curve of the DNN model across all data was 0.738, compared to the ideal value of 1. The metrics indicate that the DNN model appropriately predicted CRC. In contrast, a single variable predictor using adapted the Diabetes Complication Severity Index showed poorer performance compared to the DNN model. Conclusions: Our results indicated that the DNN model is an appropriate tool to predict CRC risk in patients with T2DM in Taiwan.
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Cheung KS, Leung WK. Risk of gastric cancer development after eradication of Helicobacter pylori. World J Gastrointest Oncol 2018; 10:115-123. [PMID: 29770171 PMCID: PMC5952268 DOI: 10.4251/wjgo.v10.i5.115] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 03/23/2018] [Accepted: 04/16/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is the most important risk factor for gastric cancer (GC) development through the Correa’s gastric carcinogenesis cascade. However, H. pylori eradication alone does not eliminate GC, as pre-neoplastic lesions (atrophic gastritis, intestinal metaplasia and dysplasia) may have already developed in some patients. It is therefore necessary to identify patients at high-risk for gastric cancer after H. pylori eradication to streamline the management plan. If the patients have not undergone endoscopy with histologic assessment, the identification of certain clinical risk factors and non-invasive testing (serum pepsinogen) can predict the risk of atrophic gastritis. For those with suspected atrophic gastritis, further risk stratification by endoscopy with histologic assessment according to validated histologic staging systems would be advisable. Patients with higher stages may require long-term endoscopic surveillance. Apart from secondary prevention to reduce deaths by diagnosing GC at an early stage, identifying medications that could potentially modify the GC risk would be desirable. The potential roles of a number of medications have been suggested by various studies, including proton pump inhibitors (PPIs), aspirin, statins and metformin. However, there are currently no randomized clinical trials to address the impact of these medications on GC risk after H. pylori eradication. In addition, most of these studies failed to adjust for the effect of concurrent medications on GC risk. Recently, large population-based retrospective cohort studies have shown that PPIs were associated with an increased GC risk after H. pylori eradication, while aspirin was associated with a lower risk. The roles of other agents in reducing GC risk after H. pylori eradication remain to be determined.
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Affiliation(s)
- Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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Farmer RE, Ford D, Forbes HJ, Chaturvedi N, Kaplan R, Smeeth L, Bhaskaran K. Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. Int J Epidemiol 2018; 46:728-744. [PMID: 28031313 PMCID: PMC5837266 DOI: 10.1093/ije/dyw275] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2016] [Indexed: 12/16/2022] Open
Abstract
Background: Existing observational studies provide conflicting evidence for the causal effect of metformin use on cancer risk in patients with type-2 diabetes, and there are concerns about bias affecting a number of studies. Methods: MEDLINE was used to identify observational studies investigating the association between metformin and overall or site-specific cancer in people with type-2 diabetes. A systematic data extraction and bias assessment was conducted, in which risk of eight bias domains (outcome, exposure, control selection, baseline confounding, time-dependent confounding, immortal time, missing data, censoring methods) were assessed against pre-defined criteria, and rated as unlikely, low, medium or high. Results: Of 46 studies identified, 21 assessed the effect of metformin on all cancer. Reported relative risks ranged from 0.23 to 1.22, with 12/21 reporting a statistically significant protective effect and none a harmful effect. The range of estimates was similar for site-specific cancers; 3/46 studies were rated as low or unlikely risk of bias in all domains. Two of these had results consistent with no effect of metformin; one observed a moderate protective effect overall, but presented further analyses that the authors concluded were inconsistent with causality. However, 28/46 studies were at risk from bias through exposure definition, 22 through insufficient baseline adjustment and 35 from possible time-dependent confounding. Conclusions: Observational studies on metformin and cancer varied in design, and the majority were at risk of a range of biases. The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk.
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Affiliation(s)
- Ruth E Farmer
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.,MRC Clinical Trials Unit at UCL, London, UK and
| | | | - Harriet J Forbes
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Nishi Chaturvedi
- Institute of Cardiovascular Science, University College London, London, UK
| | | | - Liam Smeeth
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Krishnan Bhaskaran
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
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50
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Tang GH, Satkunam M, Pond GR, Steinberg GR, Blandino G, Schünemann HJ, Muti P. Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2018; 27:627-635. [PMID: 29618465 DOI: 10.1158/1055-9965.epi-17-0936] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 12/15/2017] [Accepted: 03/30/2018] [Indexed: 11/16/2022] Open
Abstract
Background: Preclinical data suggest that metformin may reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence of breast cancer and all-cause mortality in patients with type II diabetes (T2D).Methods: A literature search was performed on Medline, EMBASE, and the Cochrane library from inception to November 2016. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall certainty of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. Meta-analyses were performed using the most fully adjusted ORs or HRs and 95% confidence intervals (95% CI) as effect measures.Results: A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR = 0.93; 95% CI, 0.85-1.03; I2 = 35%). A 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI, 0.44-0.70; I2 = 81%). Presence of publication bias is strongly suspected for both outcomes using Egger's funnel plots.Conclusions: The use of metformin may improve overall survival in patients with T2D and breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and resulting biases.Impact: Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. Cancer Epidemiol Biomarkers Prev; 27(6); 627-35. ©2018 AACR.
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Affiliation(s)
- Grace H Tang
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Meloja Satkunam
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Pond
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.,Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Steinberg
- Department of Medicine, Division of Endocrinology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.,Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Giovanni Blandino
- Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.,Oncogenomic and Epigenetic Unit, Italian National Cancer Institute 'Regina Elena,' Rome, Italy
| | - Holger J Schünemann
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Paola Muti
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. .,Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
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