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Mao X, Cheung KS, Tan JT, Mak LY, Lee CH, Cheng HM, Hui RWH, Chan EWY, Yu PLH, Yuen MF, Leung WK, Seto WK. Risk of colorectal cancer and cancer-related mortality in type 2 diabetes patients treated with metformin, SGLT-2 inhibitors, or their combination. Cancer Commun (Lond) 2025. [PMID: 40275591 DOI: 10.1002/cac2.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 04/03/2025] [Accepted: 04/10/2025] [Indexed: 04/26/2025] Open
Affiliation(s)
- Xianhua Mao
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, P. R. China
| | - Ka-Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, P. R. China
| | - Jing-Tong Tan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, P. R. China
| | - Chi-Ho Lee
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Ho Ming Cheng
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Esther Wai Yin Chan
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Philip Leung-Ho Yu
- Department of Computer Science, The University of Hong Kong, Hong Kong, P. R. China
- Department of Mathematics and Information Technology, The Education University of Hong Kong, Hong Kong, P. R. China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, P. R. China
| | - Wai K Leung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, P. R. China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, P. R. China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, P. R. China
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Simpson C, Leducq S, Venables Z, Yiu ZZN, Rhodes LE, Idris I, Gran S. Association between prescribed oral antidiabetic medication for type 2 diabetes mellitus and risk of skin cancer: a systematic review and meta-analysis. Br J Dermatol 2024; 192:165-167. [PMID: 39238081 DOI: 10.1093/bjd/ljae341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 08/09/2024] [Accepted: 09/11/2024] [Indexed: 09/07/2024]
Abstract
We conducted a systematic review to determine if there is a significant association between prescribed oral antidiabetic medication and the risk of developing skin cancer [basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and melanoma] in people with type 2 diabetes. Fourteen studies were included. Risk of bias ranged from low to moderate. Overall, no statistically significant association was identified between antidiabetic medication use and skin cancer. There was a dose–response relationship, with higher doses of metformin and rosiglitazone associated with a greater decrease in skin cancer risk than lower doses. The risk of BCC and cSCC reduced following metformin and rosiglitazone exposure vs. nonusers.
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Affiliation(s)
| | - Sophie Leducq
- Centre of Evidence Based Dermatology, School of Medicine, University of Nottingham, UK
- University Hospital of Tours, Tours, France
| | - Zoe Venables
- Norfolk and Norwich University Hospital, Norwich, UK
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Zenas Z N Yiu
- Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Department of Dermatology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Lesley E Rhodes
- Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Department of Dermatology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Sonia Gran
- Centre of Evidence Based Dermatology, School of Medicine, University of Nottingham, UK
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Feng H, Shang S, Chen K, Sun X, Yue X. Impact of metformin on melanoma: a meta-analysis and systematic review. Front Oncol 2024; 14:1399693. [PMID: 38846983 PMCID: PMC11153730 DOI: 10.3389/fonc.2024.1399693] [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: 03/12/2024] [Accepted: 05/06/2024] [Indexed: 06/09/2024] Open
Abstract
Background There is evidence of a modest reduction in skin cancer risk among metformin users. However, no studies have further examined the effects of metformin on melanoma survival and safety outcomes. This study aimed to quantitatively summarize any influence of metformin on the overall survival (OS) and immune-related adverse effects (irAEs) in melanoma patients. Methods Selection criteria: The inclusion criteria were designed based on the PICOS principles. Information sources: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for relevant literature published from the inception of these databases until November 2023 using 'Melanoma' and 'Metformin' as keywords. Survival outcomes were OS, progression-free survival (PFS), recurrence-free survival (RFS), and mortality; the safety outcome was irAEs. Risk of bias and data Synthesis: The Cochrane tool for assessing the risk of bias in randomized trial 2 (RoB2) and methodological index for non-randomized studies (MINORS) were selected to assess the risk of bias. The Cochrane Q and I 2 statistics based on Stata 15.1 SE were used to test the heterogeneity among all studies. Funnel plot, Egger regression, and Begg tests were used to evaluate publication bias. The leave-one-out method was selected as the sensitivity analysis tool. Results A total of 12 studies were included, involving 111,036 melanoma patients. The pooled HR for OS was 0.64 (95% CI [0.42, 1.00], p = 0.004, I2 = 73.7%), HR for PFS was 0.89 (95% CI [0.70, 1.12], p = 0.163, I2 = 41.4%), HR for RFS was 0.62 (95% CI [0.26, 1.48], p = 0.085, I2 = 66.3%), and HR for mortality was 0.53 (95% CI [0.46, 0.63], p = 0.775, I2 = 0.0%). There was no significant difference in irAEs incidence (OR = 1.01; 95% CI [0.42, 2.41]; p = 0.642) between metformin and no metformin groups. Discussion The improvement in overall survival of melanoma patients with metformin may indirectly result from its diverse biological targets and beneficial effects on multiple systemic diseases. While we could not demonstrate a specific improvement in the survival of melanoma patients, the combined benefits and safety of metformin for patients taking the drug are worthy of recognition. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024518182.
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Affiliation(s)
- Hua Feng
- Department of Dermatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shuxian Shang
- Hospital of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Kun Chen
- Hospital of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xuan Sun
- Interventional Neuroradiology Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xueping Yue
- Department of Dermatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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Zhang F, de Bock GH, Landman GW, Zhang Q, Sidorenkov G. Statin use as a moderator on the association between metformin and breast cancer risk in women with type 2 diabetes mellitus. Cancer Metab 2024; 12:12. [PMID: 38610045 PMCID: PMC11010330 DOI: 10.1186/s40170-024-00340-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
INTRODUCTION Metformin and statins are considered as potential agents for prevention of breast cancer, however, existing evidence does not uniformly substantiate this claim, and the data is scarce concerning their interaction in relation to breast cancer risk. This study aims to investigate whether the effect of metformin on breast cancer incidence varied by statin use among women with type 2 diabetes mellitus (T2DM). METHODS This study included women with T2DM, without a history of cancers, and followed up for more than one year from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) for the period 1998-2014. The dataset was structured using a person-time approach, where the cumulative medication usage was annually updated for each person. The extended Cox proportional hazards models were employed, reporting adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS During a median follow-up of 5 years, 515 of 29,498 women received a breast cancer diagnosis. Each additional year of metformin or statins use corresponded to a decrease in breast cancer incidence, while the magnitude attenuated over time. Noteworthily, statin use modified the effect of metformin on breast cancer incidence. For instance, after 5 years of follow-up, one-year increase of metformin use among women who used statins for 3 years was linked to a substantially reduced breast cancer risk (HR, 95% CI: 0.88, 0.84-0.93), however, there was no significant decrease in risk for those non-statins users (HR, 95% CI: 0.96, 0.89-1.04). CONCLUSIONS Extending metformin or statin usage by one year conferred breast cancer protection in women with T2DM. Enhanced protective effect of metformin was observed among those who also use statins. These results suggest the potential of combined metformin and statin therapy as promising breast cancer prevention strategies.
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Affiliation(s)
- Fan Zhang
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Oncology Research Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, People's Republic of China
- Department of Preventive Medicine, Shantou University Medical College, Shantou, People's Republic of China
| | - Geertruida H de Bock
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gijs W Landman
- Department of Internal Medicine, Gelre Hospital, Apeldoorn, The Netherlands
| | - Qingying Zhang
- Department of Preventive Medicine, Shantou University Medical College, Shantou, People's Republic of China
| | - Grigory Sidorenkov
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Pradhan R, Yu OHY, Platt RW, Azoulay L. Glucagon like peptide-1 receptor agonists and the risk of skin cancer among patients with type 2 diabetes: Population-based cohort study. Diabet Med 2024; 41:e15248. [PMID: 37876318 DOI: 10.1111/dme.15248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/11/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023]
Abstract
AIMS The objective of this study was to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. METHODS Using the United Kingdom Clinical Practice Research Datalink (2007-2019), we assembled two new-user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP-1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP-1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. RESULTS Compared with sulfonylureas, GLP-1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person-years, respectively; HR 0.96, 95% CI 0.53-1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person-years, respectively; HR 1.03, 95% CI 0.80-1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. CONCLUSIONS In this population-based cohort study, GLP-1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas.
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Affiliation(s)
- Richeek Pradhan
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Centre for Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, Canada
| | - Oriana H Y Yu
- Centre for Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, Canada
- Division of Endocrinology, Jewish General Hospital, Montreal, Quebec, Canada
| | - Robert W Platt
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Centre for Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, Canada
| | - Laurent Azoulay
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Centre for Clinical Epidemiology, Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
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Wang M, Noghabaei G, Raeisi T, Li D, Alizadeh H, Alizadeh M. Metformin and risk of hematological cancers in patients with diabetes: a systematic review and meta-analysis. Ann Saudi Med 2024; 44:126-134. [PMID: 38615182 PMCID: PMC11016148 DOI: 10.5144/0256-4947.2024.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/01/2024] [Indexed: 04/15/2024] Open
Abstract
FUNDING No external funding.
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Affiliation(s)
- Min Wang
- From the Department of Endocrinology, Huaihe Hospital of Henan University, Kaifeng, Henan, China
| | - Giti Noghabaei
- From the Department of Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Tahereh Raeisi
- From the Department of Medicine, Hormozgan University of Medical Sciences, Bandar-Abbas, Iran
| | - Dandan Li
- From the Department of Endocrinology, Huaihe Hospital of Henan University, Kaifeng, Henan, China
| | - Hamzeh Alizadeh
- From the Department of Genetics and Breeding, University of Guilan, Rasht, Gilan, Iran
| | - Mohammad Alizadeh
- From the Department of Medical Surgical Nursing, Mazandaran University of Medical Sciences, Sari, Iran
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Pradhan R, Yu OHY, Platt RW, Azoulay L. Dipeptidyl peptidase-4 inhibitors and the risk of skin cancer among patients with type 2 diabetes: a UK population-based cohort study. BMJ Open Diabetes Res Care 2023; 11:e003550. [PMID: 37949470 PMCID: PMC10649616 DOI: 10.1136/bmjdrc-2023-003550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/16/2023] [Indexed: 11/12/2023] Open
Abstract
INTRODUCTION The dipeptidyl peptidase-4 (DPP-4) enzyme significantly influences carcinogenic pathways in the skin. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas. RESEARCH DESIGN AND METHODS Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96 739 DPP-4 inhibitor users and 209 341 sulfonylurea users, and 96 411 DPP-4 inhibitor users and 208 626 sulfonylurea users for non-melanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs of melanoma and non-melanoma skin cancer, separately. RESULTS Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs 65.3 per 100 000 person-years, respectively; HR 0.77, 95% CI 0.61 to 0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84 to 1.54; 2.1-5 years HR 0.44, 95% CI 0.29 to 0.66; >5 years HR 0.33, 95% CI 0.14 to 0.74). In contrast, these drugs were not associated with the incidence of non-melanoma skin cancer, compared with sulfonylureas (448.1 vs 426.1 per 100 000 person-years, respectively; HR 1.06, 95% CI 0.98 to 1.15). CONCLUSIONS In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not non-melanoma skin cancer, compared with sulfonylureas.
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Affiliation(s)
- Richeek Pradhan
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
| | - Oriana H Y Yu
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
- Division of Endocrinology, Jewish General Hospital, Montreal, Québec, Canada
| | - Robert W Platt
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
| | - Laurent Azoulay
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
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Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep 2023; 5:100811. [PMID: 37575883 PMCID: PMC10413159 DOI: 10.1016/j.jhepr.2023.100811] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 08/15/2023] Open
Abstract
Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.
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Affiliation(s)
- Stephanie Talamantes
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Michela Lisjak
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Eduardo H. Gilglioni
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Camilo J. Llamoza-Torres
- Department of Hepatology, Virgen de la Arrixaca University Hospital, Murcia, 30120, Spain
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Esteban N. Gurzov
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
- WELBIO Department, WEL Research Institute, Avenue Pasteur 6, Wavre, 1300, Belgium
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Lu MZ, Li DY, Wang XF. Effect of metformin use on the risk and prognosis of ovarian cancer: an updated systematic review and meta-analysis. Panminerva Med 2023; 65:351-361. [PMID: 31290300 DOI: 10.23736/s0031-0808.19.03640-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Emerging evidence suggests that metformin has a potential antitumor effect both in vitro and in vivo. Increasing epidemiological studies indicate that diabetic patients receiving metformin therapy have lower incidences of cancer and have better survival rates. However, there are limited and inconsistent studies available about the effect of metformin therapy on ovarian cancer (OC). Thus, we conducted this meta-analysis to study the effect of metformin therapy on OC. Meanwhile, we systematically reviewed relevant studies to provide a framework for future research. EVIDENCE ACQUISITION We conducted a systematic literature search on PubMed, Web of Science, Springerlink, CNKI, VIP, SinoMed, and Wanfang up to the period of October 2018. A random-effects meta-analysis model was used to derive pooled effect estimates. EVIDENCE SYNTHESIS A total of 13 studies were retrieved of which 5 studies explained the prevention and 8 studies explained the treatment for OC. Our pooled results showed that metformin has a potential preventive effect on OC in diabetic women (pooled odds ratio [OR] 0.62, 95% confidence interval [95% CI] 0.34, 1.11; P<0.001). In addition, metformin can also significantly prolong progression-free survival (PFS) (pooled hazard ratio [HR] 0.49, 95% CI 0.34, 0.70; P=0.002), and overall survival (OS) (HR 0.71, 95%CI 0.61, 0.82; P<0.001) in patients with OC, regardless of whether they had diabetes. CONCLUSIONS The use of metformin can potentially reduce the risk of OC among diabetics, and it also can significantly improve PFS and OS in patients with OC. A further large clinical investigation would be needed to adopt our finding in practice, however, our systematic review provides an insight for future study designs.
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Affiliation(s)
- Min-Zhen Lu
- Second Clinical Medical College of Southern Medical University, Guangzhou, China -
| | - De-Yu Li
- Department of Oncology, Fujian Provincial Hospital, Fujian, China
| | - Xue-Feng Wang
- Department of Obstetrics and Gynecology, Third Hospital of Southern Medical University, Guangzhou, China
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10
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Yu OHY, Suissa S. Metformin and Cancer: Solutions to a Real-World Evidence Failure. Diabetes Care 2023; 46:904-912. [PMID: 37185680 DOI: 10.2337/dci22-0047] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/09/2023] [Indexed: 05/17/2023]
Abstract
The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.
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Affiliation(s)
- Oriana Hoi Yun Yu
- 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- 2Division of Endocrinology, Jewish General Hospital, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
| | - Samy Suissa
- 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
- 4Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
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Hanyuda A, Goto A, Katagiri R, Koyanagi YN, Nakatochi M, Sutoh Y, Nakano S, Oze I, Ito H, Yamaji T, Sawada N, Iwagami M, Kadota A, Koyama T, Katsuura-Kamano S, Ikezaki H, Tanaka K, Takezaki T, Imoto I, Suzuki M, Momozawa Y, Takeuchi K, Narita A, Hozawa A, Kinoshita K, Shimizu A, Tanno K, Matsuo K, Tsugane S, Wakai K, Sasaki M, Yamamoto M, Iwasaki M. Investigating the association between glycaemic traits and colorectal cancer in the Japanese population using Mendelian randomisation. Sci Rep 2023; 13:7052. [PMID: 37120602 PMCID: PMC10148817 DOI: 10.1038/s41598-023-33966-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 04/21/2023] [Indexed: 05/01/2023] Open
Abstract
Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99-1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60-1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97-2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.
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Grants
- 28-A-19 and 31-A-18 National Cancer Center Research and Development Fund
- 28-A-19 and 31-A-18 National Cancer Center Research and Development Fund
- 28-A-19 and 31-A-18 National Cancer Center Research and Development Fund
- 28-A-19 and 31-A-18 National Cancer Center Research and Development Fund
- 28-A-19 and 31-A-18 National Cancer Center Research and Development Fund
- 28-A-19 and 31-A-18 National Cancer Center Research and Development Fund
- No. 16H06277[CoBia] Japan Society for the Promotion of Science (JSPS) KAKENHI Grant
- No. 16H06277[CoBia] Japan Society for the Promotion of Science (JSPS) KAKENHI Grant
- No. 16H06277[CoBia] Japan Society for the Promotion of Science (JSPS) KAKENHI Grant
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- JP20km0105001, JP20km0105002, JP20km0105003, JP20km0105004 Japan Agency for Medical Research and Development
- 15ck0106095h0002, 16ck0106095h0003, and 17ck0106266h001 Japan Agency for Medical Research and Development
- a Grant-in-Aid for Cancer Research Ministry of Health, Labour and Welfare
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Affiliation(s)
- Akiko Hanyuda
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Atsushi Goto
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, 22-2 Seto, Kanazawa-Ku, Yokohama, 236-0027, Japan.
| | - Ryoko Katagiri
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan
| | - Yuriko N Koyanagi
- Division of Cancer Information and Control, Aichi Cancer Center, Nagoya, Aichi, Japan
| | - Masahiro Nakatochi
- Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yoichi Sutoh
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank, Morioka, Iwate, Japan
| | - Shiori Nakano
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Aichi, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Aichi Cancer Center, Nagoya, Aichi, Japan
- Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Masao Iwagami
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan
- Department of Health Services Research, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Aya Kadota
- NCD Epidemiology Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sakurako Katsuura-Kamano
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroaki Ikezaki
- Department of Comprehensive General Internal Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Toshiro Takezaki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Issei Imoto
- Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Midori Suzuki
- Core Facilities, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Akira Narita
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Atsushi Hozawa
- Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Kengo Kinoshita
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Atsushi Shimizu
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank, Morioka, Iwate, Japan
| | - Kozo Tanno
- Division of Clinical Research and Epidemiology, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Morioka, Iwate, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Aichi, Japan
- Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Shoichiro Tsugane
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
- National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Makoto Sasaki
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Morioka, Iwate, Japan
| | - Masayuki Yamamoto
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
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Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clin Mol Hepatol 2023; 29:51-64. [PMID: 35903020 PMCID: PMC9845683 DOI: 10.3350/cmh.2022.0095] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/03/2022] [Indexed: 02/02/2023] Open
Abstract
The incidence of diabetes mellitus and hepatocellular carcinoma (HCC) has been increasing worldwide during the last few decades, in the context of an increasing prevalence of obesity and non-alcoholic fatty liver disease (NAFLD). Epidemiologic studies have revealed that patients with diabetes have a 2- to 3-fold increased risk of developing HCC, independent of the severity and cause of the underlying liver disease. A bidirectional relationship exists between diabetes and liver disease: advanced liver disease promotes the onset of diabetes, and HCC is an important cause of death in patients with diabetes; conversely, diabetes is a risk factor for liver fibrosis progression and HCC development, and may worsen the long-term prognosis of patients with HCC. The existence of close interconnections among diabetes, obesity, and NAFLD causes insulin resistance-related hyperinsulinemia, increased oxidative stress, and chronic inflammation, which are assumed to be the underlying causes of hepatocarcinogenesis in patients with diabetes. No appropriate surveillance methods for HCC development in patients with diabetes have been established, and liver diseases, including HCC, are often overlooked as complications of diabetes. Although some antidiabetic drugs are expected to prevent HCC development, further research on the optimal use of antidiabetic drugs aimed at hepatoprotection is warranted. Given the increasing medical and socioeconomic impact of diabetes on HCC development, diabetologists and hepatologists need to work together to develop strategies to address this emerging health issue. This article reviews the current knowledge on the impact of diabetes on the development and progression of HCC.
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Affiliation(s)
- Takuma Nakatsuka
- 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,Corresponding author : Ryosuke Tateishi Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel: +81-3-3815-5411, Fax: +81-3-3814-0021, E-mail:
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13
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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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14
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Kim HM, Kang MJ, Song SO. Metformin and Cervical Cancer Risk in Patients with Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea. Endocrinol Metab (Seoul) 2022; 37:929-937. [PMID: 36604960 PMCID: PMC9816509 DOI: 10.3803/enm.2022.1613] [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: 10/23/2022] [Accepted: 11/01/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGRUOUND Cervical cancer is a prevalent malignancy that is a major health problem for women worldwide. The cancer-preventive properties of metformin are well-known, but insufficient data have been reported regarding its relationship to cervical cancer. Therefore, in a nationwide population-based study, we investigated the association between metformin use and cervical cancer incidence in patients with newly diagnosed type 2 diabetes. METHODS This retrospective cohort study used the Korean National Health Insurance claims database. Individuals newly diagnosed with type 2 diabetes between January 2005 and December 2009 were included. The occurrence of cervical cancer was explored by matching for age, economic status, region of residence, and use of anti-diabetic medication. RESULTS In total, 66,013 metformin users and 64,756 non-users were analyzed. Cervical cancer occurred in 219 metformin users (0.33%) and 274 metformin non-users (0.42%) (hazard ratio [HR], 0.783; 95% confidence interval [CI], 0.655 to 0.036; P=0.007). Moreover, cervical cancer risk was considerably reduced in those treated with a high dose (>1,200,000 mg) or for an extended period (≥2,000 days) compared to non-users (HR, 0.151; 95% CI, 0.093 to 0.243; P<0.001; and HR, 0.141; 95% CI, 0.077 to 0.258; P<0.001). The incidence was also significantly lower in metformin users among those over 50 years old (HR, 0.791; 95% CI, 0.650 to 0.961; P<0.001). CONCLUSION Metformin use in patients with newly diagnosed diabetes was associated with a lower risk of cervical cancer in Korea. Furthermore, a significant association was found between the use of metformin and cervical cancer in a dose- and duration-dependent manner and among those over 50 years old.
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Affiliation(s)
- Hyun Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Min Jin Kang
- Research Institute of National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Sun Ok Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
- Corresponding author: Sun Ok Song. Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, 100 Ilsan-ro, Ilsandong-gu, Goyang 10444, Korea Tel: +82-31-900-3470, Fax: +82-31-900-0519, E-mail:
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15
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Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, Hollenberg MD, Hill MA. Metformin: Is it a drug for all reasons and diseases? Metabolism 2022; 133:155223. [PMID: 35640743 DOI: 10.1016/j.metabol.2022.155223] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/22/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
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Affiliation(s)
- Chris R Triggle
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
| | - Ibrahim Mohammed
- Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Khalifa Bshesh
- Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Isra Marei
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Kevin Ye
- Department of Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
| | - Hong Ding
- Department of Pharmacology, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Department of Medical Education, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Ross MacDonald
- Distribution eLibrary, Weill Cornell Medicine in Qatar, P.O. Box 24144, Education City, Doha, Qatar
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, a Cumming School of Medicine, University of Calgary, T2N 4N1, Canada
| | - Michael A Hill
- Dalton Cardiovascular Research Center, Department of Medical Pharmacology & Physiology, School of Medicine, University of Missouri, Columbia 65211, MO, USA
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Incidence and Survival Outcomes of Colorectal Cancer in Long-Term Metformin Users with Diabetes: A Population-Based Cohort Study Using a Common Data Model. J Pers Med 2022; 12:jpm12040584. [PMID: 35455700 PMCID: PMC9031185 DOI: 10.3390/jpm12040584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/30/2022] [Accepted: 04/03/2022] [Indexed: 11/24/2022] Open
Abstract
Background and aims: Previous studies have reported that metformin use in patients with diabetes mellitus may reduce the risk of colorectal cancer (CRC) incidence and prognosis; however, the evidence is not definite. This population-based cohort study aimed to investigate whether metformin reduces the risk of CRC incidence and prognosis in patients with diabetes mellitus using a common data model of the Korean National Health Insurance Service database from 2002 to 2013. Methods: Patients who used metformin for at least 6 months were defined as metformin users. The primary outcome was CRC incidence, and the secondary outcomes were the all-cause and CRC-specific mortality. Cox proportional hazard model was performed and large-scaled propensity score matching was used to control for potential confounding factors. Results: During the follow-up period of 81,738 person-years, the incidence rates (per 1000 person-years) of CRC were 5.18 and 8.12 in metformin users and non-users, respectively (p = 0.001). In the propensity score matched cohort, the risk of CRC incidence in metformin users was significantly lower than in non-users (hazard ratio (HR), 0.58; 95% CI (confidence interval), 0.47–0.71). In the sensitivity analysis, the lag period extending to 1 year showed similar results (HR: 0.63, 95% CI: 0.51–0.79). The all-cause mortality was significantly lower in metformin users than in non-users (HR: 0.71, 95% CI: 0.64–0.78); CRC-related mortality was also lower among metformin users. However, there was no significant difference (HR: 0.55, 95% CI: 0.26–1.08). Conclusions: Metformin use was associated with a reduced risk of CRC incidence and improved overall survival.
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Chow E, Yang A, Chung CHL, Chan JCN. A Clinical Perspective of the Multifaceted Mechanism of Metformin in Diabetes, Infections, Cognitive Dysfunction, and Cancer. Pharmaceuticals (Basel) 2022; 15:ph15040442. [PMID: 35455439 PMCID: PMC9030054 DOI: 10.3390/ph15040442] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/30/2022] [Accepted: 03/30/2022] [Indexed: 12/16/2022] Open
Abstract
In type 2 diabetes, ecological and lifecourse factors may interact with the host microbiota to influence expression of his/her genomes causing perturbation of interconnecting biological pathways with diverse clinical course. Metformin is a plant-based or plant-derived medicinal product used for the treatment of type 2 diabetes for over 60 years and is an essential drug listed by the World Health Organization. By reducing mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) production, metformin increased AMP (adenosine monophosphate)-activated protein kinase (AMPK) activity and altered cellular redox state with reduced glucagon activity, endogenous glucose production, lipogenesis, and protein synthesis. Metformin modulated immune response by directly reducing neutrophil to lymphocyte ratio and improving the phagocytic function of immune cells. By increasing the relative abundance of mucin-producing and short-chain-fatty-acid-producing gut microbes, metformin further improved the host inflammatory and metabolic milieu. Experimentally, metformin promoted apoptosis and reduced proliferation of cancer cells by reducing their oxygen consumption and modulating the microenvironment. Both clinical and mechanistic studies support the pluripotent effects of metformin on reducing cardiovascular–renal events, infection, cancer, cognitive dysfunction, and all-cause death in type 2 diabetes, making this low-cost medication a fundamental therapy for individualization of other glucose-lowering drugs in type 2 diabetes. Further research into the effects of metformin on cognitive function, infection and cancer, especially in people without diabetes, will provide new insights into the therapeutic value of metformin in our pursuit of prevention and treatment of ageing-related as well as acute and chronic diseases beyond diabetes.
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Affiliation(s)
- Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
- The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
- Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
| | - Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
- The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
| | - Colin H. L. Chung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
| | - Juliana C. N. Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China; (E.C.); (A.Y.); (C.H.L.C.)
- The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-3505-3138
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18
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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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Hydes TJ, Cuthbertson DJ, Graef S, Berhane S, Teng M, Skowronska A, Singh P, Dhanaraj S, Tahrani A, Johnson PJ. The Impact of Diabetes and Glucose-Lowering Therapies on Hepatocellular Carcinoma Incidence and Overall Survival. Clin Ther 2022; 44:257-268. [DOI: 10.1016/j.clinthera.2021.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/08/2021] [Accepted: 12/31/2021] [Indexed: 12/15/2022]
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Vekic J, Zeljkovic A, Stefanovic A, Giglio RV, Ciaccio M, Rizzo M. Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents. Int J Mol Sci 2021; 22:12409. [PMID: 34830295 PMCID: PMC8622770 DOI: 10.3390/ijms222212409] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.
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Affiliation(s)
- Jelena Vekic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia; (J.V.); (A.Z.); (A.S.)
| | - Aleksandra Zeljkovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia; (J.V.); (A.Z.); (A.S.)
| | - Aleksandra Stefanovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia; (J.V.); (A.Z.); (A.S.)
| | - Rosaria Vincenza Giglio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90100 Palermo, Italy; (R.V.G.); (M.C.)
| | - Marcello Ciaccio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90100 Palermo, Italy; (R.V.G.); (M.C.)
- Department of Laboratory Medicine, University Hospital, 90100 Palermo, Italy
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90100 Palermo, Italy
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21
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Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, Zabuliene L, Urbonas V, Smailyte G. Positive effect of metformin treatment in colorectal cancer patients with type 2 diabetes: national cohort study. Eur J Cancer Prev 2021; 29:289-293. [PMID: 31567536 DOI: 10.1097/cej.0000000000000547] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We aimed to estimate colorectal cancer risk in patients with type 2 diabetes mellitus (T2DM) using metformin. Patients with colorectal cancer and diabetes from 2000 to 2012 were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Standardized incidence ratios (SIRs) for colorectal cancers as a ratio of observed number of cancer cases in people with diabetes to the expected number of cancer cases in the underlying general population was calculated. We analysed 111 109 patients with diabetes. Overall, 1213 colorectal cancers were observed versus 954.91 expected within a period of observation entailing an SIR of 1.27 [95% confidence interval (CI): 1.20-1.34]. Significantly higher risk of colorectal cancer was found both in male and female patients with diabetes in all age groups. Higher risk was found for both colon and rectum cancers 1.36 (95% CI: 1.27-1.46) and 1.11 (95% CI: 1.01-1.22), respectively. There were no differences in risk over time since initial diabetes diagnosis. Never-users of metformin had twice higher risk of colorectal cancer compared to general population (SIR: 2.14, 95% CI: 1.95-2.35). Among metformin users, risk was lover (SIR: 1.47, 95% CI: 1.36-1.58) and colorectal cancer risk decreased with increasing cumulative dose of metformin (P < 0.001). Patients with T2DM had increased risk of colorectal cancer compared with the general Lithuanian population. Decreasing colorectal cancer risk with increasing cumulative dose of metformin indicates that metformin may be a protective agent for colorectal cancer development.
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Affiliation(s)
- Audrius Dulskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute.,Faculty of Health Care, University of Applied Sciences.,Faculty of Medicine, Institute of Clinical Medicine, Vilnius University
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute.,Faculty of Medicine, Institute of Health Sciences
| | | | - Lina Zabuliene
- Faculty of Medicine, Institute of Clinical Medicine, Vilnius University
| | - Vincas Urbonas
- Department of Medical Oncology, Laboratory of Clinical Oncology, National Cancer Institute, Vilnius, Lithuania
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute.,Faculty of Medicine, Institute of Health Sciences
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22
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Liang PS, Shaukat A, Crockett SD. AGA Clinical Practice Update on Chemoprevention for Colorectal Neoplasia: Expert Review. Clin Gastroenterol Hepatol 2021; 19:1327-1336. [PMID: 33581359 DOI: 10.1016/j.cgh.2021.02.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/02/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
DESCRIPTION The purpose of this expert review is to describe the role of medications for the chemoprevention of colorectal neoplasia. Neoplasia is defined as precancerous lesions (e.g., adenoma and sessile serrated lesion) or cancer. The scope of this review excludes dietary factors and high-risk individuals with hereditary syndromes or inflammatory bowel disease. METHODS The best practice advice statements are based on a review of the literature to provide practical advice. A formal systematic review and rating of the quality of evidence or strength of recommendation were not performed. BEST PRACTICE ADVICE 1: In individuals at average risk for CRC who are (1) younger than 70 years with a life expectancy of at least 10 years, (2) have a 10-year cardiovascular disease risk of at least 10%, and (3) not at high risk for bleeding, clinicians should use low-dose aspirin to reduce CRC incidence and mortality. BEST PRACTICE ADVICE 2: In individuals with a history of CRC, clinicians should consider using aspirin to prevent recurrent colorectal neoplasia. BEST PRACTICE ADVICE 3: In individuals at average risk for CRC, clinicians should not use non-aspirin NSAIDs to prevent colorectal neoplasia because of a substantial risk of cardiovascular and gastrointestinal adverse events. BEST PRACTICE ADVICE 4: In individuals with type 2 diabetes, clinicians may consider using metformin to prevent colorectal neoplasia. BEST PRACTICE ADVICE 5: In individuals with CRC and type 2 diabetes, clinicians may consider using metformin to reduce mortality. BEST PRACTICE ADVICE 6: Clinicians should not use calcium or vitamin D (alone or together) to prevent colorectal neoplasia. BEST PRACTICE ADVICE 7: Clinicians should not use folic acid to prevent colorectal neoplasia. BEST PRACTICE ADVICE 8: In individuals at average risk for CRC, clinicians should not use statins to prevent colorectal neoplasia. BEST PRACTICE ADVICE 9: In individuals with a history of CRC, clinicians should not use statins to reduce mortality.
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Affiliation(s)
- Peter S Liang
- NYU Langone Health, New York, New York; VA New York Harbor Health Care System, New York, New York.
| | - Aasma Shaukat
- University of Minnesota, Minneapolis, Minnesota; Minneapolis VA Health Care System, Minneapolis, Minnesota
| | - Seth D Crockett
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
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23
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Li X, Celotto S, Pizzol D, Gasevic D, Ji MM, Barnini T, Solmi M, Stubbs B, Smith L, López Sánchez GF, Pesolillo G, Yu Z, Tzoulaki I, Theodoratou E, Ioannidis JPA, Veronese N, Demurtas J. Metformin and health outcomes: An umbrella review of systematic reviews with meta-analyses. Eur J Clin Invest 2021; 51:e13536. [PMID: 33709434 DOI: 10.1111/eci.13536] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND The objective was to capture the breadth of outcomes that have been associated with metformin use and to systematically assess the quality, strength and credibility of these associations using the umbrella review methodology. METHODS Four major databases were searched until 31 May 2020. Meta-analyses of observational studies and meta-analyses of randomized controlled trials (RCTs) (including active and placebo control arms) were included. RESULTS From 175 eligible publications, we identified 427 different meta-analyses, including 167 meta-analyses of observational studies, 147 meta-analyses of RCTs for metformin vs placebo/no treatment and 113 meta-analyses of RCTs for metformin vs active medications. There was no association classified as convincing or highly suggestive from meta-analyses of observational studies, but some suggestive/weak associations of metformin use with a lower mortality risk of CVD and cancer. In meta-analyses of RCTs, metformin was associated with a lower incidence of diabetes in people with prediabetes or no diabetes at baseline; lower ovarian hyperstimulation syndrome incidence (in women in controlled ovarian stimulation); higher success for clinical pregnancy rate in poly-cystic ovary syndrome (PCOS); and significant reduction in body mass index in people with type 1 diabetes mellitus, in women who have obesity/overweight with PCOS and in obese/overweight women. Of 175 publications, 166 scored as low or critically low quality per AMSTAR 2 criteria. CONCLUSIONS Observational evidence on metformin seems largely unreliable. Randomized evidence shows benefits for preventing diabetes and in some gynaecological and obstetrical settings. However, almost all meta-analyses are of low or critically low quality according to AMSTAR 2 criteria.
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Affiliation(s)
- Xue Li
- School of Public Health, Zhejiang University, Hangzhou, China
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Stefano Celotto
- MD, Primary Care Department, AAS3 Alto Friuli e Collinare e Medio Friuli, Udine, Italy
| | - Damiano Pizzol
- Italian Agency for Development Cooperation, Khartoum, Sudan
| | - Danijela Gasevic
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
| | - Meng-Meng Ji
- School of Public Health, Nanjing Medical University, Nanjing, China
| | | | - Marco Solmi
- Neurosciences Department, University of Padua, Padua, Italy
- Padua Neuroscience Center, University of Padua, Padua, Italy
| | - Brendon Stubbs
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, UK
| | - Guillermo F López Sánchez
- Faculty of Health, Education, Medicine and Social Care, School of Medicine, Vision and Eye Research Institute, Anglia Ruskin University-Cambridge Campus, Cambridge, UK
| | | | - Zengli Yu
- School of Public Health, Zhengzhou University, Zhengzhou, China
| | - Ioanna Tzoulaki
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - John P A Ioannidis
- Department of Medicine, Stanford University, Stanford, CA, USA
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
- Department of Statistics, Stanford University, Stanford, CA, USA
| | - Nicola Veronese
- Padua Neuroscience Center, University of Padua, Padua, Italy
| | - Jacopo Demurtas
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
- Primary Care Department USL Toscana Sud-Est, Grosseto, Italy
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24
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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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25
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Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol 2021; 27:1883-1904. [PMID: 34007128 PMCID: PMC8108031 DOI: 10.3748/wjg.v27.i17.1883] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.
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Affiliation(s)
- Ademar Dantas Cunha Júnior
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Felipe Osório Costa
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
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26
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Weltermann T, Schulz C, Macke L. Effect of frequently prescribed drugs on gastric cancer risk. Best Pract Res Clin Gastroenterol 2021; 50-51:101741. [PMID: 33975680 DOI: 10.1016/j.bpg.2021.101741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer is the fifth leading cancer worldwide. Infection with Helicobacter pylori represents the major risk factor, but only a small fraction of infected individuals will develop neoplasia. The progression of advanced gastric lesions to cancer is influenced by characteristics of the bacterial strain, host genetic and environmental factors. Recently, the effect of medications on gastric cancer risk has gained interest, because many commonly prescribed drugs affect gastric homeostasis. While non-steroidal anti-inflammatory drugs (NSAIDs) are a frequent cause of gastric ulcer disease, low-dose aspirin has been propagated for chemoprevention of various tumour entities. Beneficial effects of cyclooxygenase-inhibition for gastric cancer prevention is plausible, but its clinical relevance remains unclear. Furthermore, anti-tumorous effects have been postulated for statins and metformin. On the contrary, proton pump inhibitors (PPIs), which are commonly used for prevention of gastric ulcers and bleeding, have been associated with an increased gastric cancer risk in large observational studies. Most of these observations still require confirmation in prospective controlled trials. NSAIDs, statins and metformin have also been investigated as concomitant cancer treatment, but studies did not show convincing results to date. Here, we review the available evidence and possible mechanisms for the role of PPIs, NSAIDs, statins and metformin in gastric carcinogenesis, and discuss possible implications for clinical practice.
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Affiliation(s)
- Theresa Weltermann
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany, Marchioninistr. 15, 81377, Munich, Germany.
| | - Christian Schulz
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany, Marchioninistr. 15, 81377, Munich, Germany.
| | - Lukas Macke
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany, Marchioninistr. 15, 81377, Munich, Germany.
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27
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Nath M, Nath S, Choudhury Y. The impact of thiazolidinediones on the risk for prostate cancer in patients with type 2 diabetes mellitus: A review and meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2020.100840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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28
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Wang C, Chen B, Feng Q, Nie C, Li T. Clinical perspectives and concerns of metformin as an anti-aging drug. Aging Med (Milton) 2020; 3:266-275. [PMID: 33392433 PMCID: PMC7771567 DOI: 10.1002/agm2.12135] [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: 07/31/2020] [Revised: 10/20/2020] [Accepted: 10/20/2020] [Indexed: 12/27/2022] Open
Abstract
As percentages of elderly people rise in many societies, age-related diseases have become more prevalent than ever. Research interests have been shifting to delaying age-related diseases by delaying or reversing aging itself. We use metformin as an entry point to talk about the important molecular and genetic longevity-regulating mechanisms that have been extensively studied with it. Then we review a number of observational studies, animal studies, and clinical trials to reflect the clinical potentials of the mechanisms in lifespan extension, cardiovascular diseases, tumors, and neurodegeneration. Finally, we highlight remaining concerns that are related to metformin and future anti-aging research.
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Affiliation(s)
- Chuyao Wang
- BGI‐ShenzhenBeishan Industrial ZoneShenzhenChina
- Department of Biomedical EngineeringUniversity of RochesterRochesterNYUSA
| | - Bangwei Chen
- BGI‐ShenzhenBeishan Industrial ZoneShenzhenChina
- School of Biology and Biological EngineeringSouth China University of TechnologyGuangzhouChina
| | - Qian Feng
- BGI‐ShenzhenBeishan Industrial ZoneShenzhenChina
- China National GeneBankBGI‐ShenzhenShenzhenChina
| | - Chao Nie
- BGI‐ShenzhenBeishan Industrial ZoneShenzhenChina
- China National GeneBankBGI‐ShenzhenShenzhenChina
| | - Tao Li
- BGI‐ShenzhenBeishan Industrial ZoneShenzhenChina
- China National GeneBankBGI‐ShenzhenShenzhenChina
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29
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Undzyte G, Patasius A, Linkeviciute-Ulinskiene D, Zabuliene L, Stukas R, Dulskas A, Smailyte G. Increased kidney cancer risk in diabetes mellitus patients: a population-based cohort study in Lithuania. Aging Male 2020; 23:1241-1245. [PMID: 32342709 DOI: 10.1080/13685538.2020.1755249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Diabetes is associated with increased risk of various cancers but its association with kidney cancer is unclear. The objective of this study was to evaluate the association between T2DM with or without metformin use and the risk of kidney cancer in a population-based national cohort in Lithuania. METHODS The cohort was composed of diabetic patients identified in the NHIF database during 2000-2012. Cancer cases were identified by record linkage with the national Cancer Registry. Standardized incidence ratios (SIRs) for kidney cancer as a ratio of observed number of cancer cases in diabetic patients to the expected number of cancer cases in the underlying general population were calculated. RESULTS T2DM patients (11,592) between 2000 and 2012 were identified. Overall, 598 cases of primary kidney cancer were identified versus 393.95 expected yielding an overall SIR of 1.52 (95% CI: 1.40-1.64). Significantly higher risk was found in males and females. Significantly higher risk of kidney cancer was also found in both metformin users and never-users' groups (SIRs 1.45, 95% CI: 1.33-1.60 and 1.78 95% CI: 1.50-2.12, respectively). CONCLUSIONS The patients with T2DM have higher risk for kidney cancer compared with the general Lithuanian population.
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Affiliation(s)
- Greta Undzyte
- Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius, Lithuania
- Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Donata Linkeviciute-Ulinskiene
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Lina Zabuliene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Rimantas Stukas
- Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Audrius Dulskas
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
- Faculty of Health Care, University of Applied Sciences, Vilnius, Lithuania
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius, Lithuania
- Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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30
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Urpilainen E, Puistola U, Boussios S, Karihtala P. Metformin and ovarian cancer: the evidence. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1711. [PMID: 33490223 PMCID: PMC7812201 DOI: 10.21037/atm-20-1060] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In recent decades, great interest in the off-label use of metformin has arisen as a result of its broad effects on different signaling pathways, with only a few side effects, and low cost. Metformin has been shown to have multiple, dose-dependent preclinical anticancer effects, which can be roughly divided into either direct effects via inhibition of mitochondrial respiratory chain complex I, or indirect effects through lowered glucose, insulin and insulin-like growth factor levels. Further details on in vitro and in vivo anticancer effects specifically in ovarian cancer are continuously reported. Preclinically metformin has clear chemosensitizing effects in ovarian cancer and it is an effective negative regulator of angiogenesis. There are also some epidemiological studies on metformin use in ovarian cancer, but the results of these studies are not as promising as those preclinical studies would indicate. Most preclinical studies have involved metformin concentrations that are many times higher than the pharmacological doses used in patients, which might confound the clinical use of metformin as regards the above-mentioned aspects. In this review we evaluate preclinical and clinical evidence concerning metformin in ovarian cancer treatment.
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Affiliation(s)
- Elina Urpilainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, Oulu, Finland
| | - Ulla Puistola
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and University Hospital of Oulu, Oulu, Finland
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham, Kent, UK.,AELIA Organization, 9th Km Thessaloniki - Thermi, Thessaloniki, Greece
| | - Peeter Karihtala
- Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.,Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Centre, Helsinki, Finland
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31
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Simon TG, Chan AT. Lifestyle and Environmental Approaches for the Primary Prevention of Hepatocellular Carcinoma. Clin Liver Dis 2020; 24:549-576. [PMID: 33012445 PMCID: PMC7536356 DOI: 10.1016/j.cld.2020.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at increased risk of developing hepatocellular carcinoma (HCC). Most patients diagnosed with HCC have limited treatment options and a poor overall prognosis, with a 5-year survival less than 15%. Preventing the development of HCC represents the most important strategy. However, current guidelines lack specific recommendations for primary prevention. Lifestyle factors may be central in the pathogenesis of HCC, and primary prevention strategies focused on lifestyle modification could represent an important approach to the prevention of HCC. Both experimental and epidemiologic studies have identified promising chemopreventive agents for the primary prevention of HCC.
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Affiliation(s)
- Tracey G. Simon
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA
| | - Andrew T. Chan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston MA,Broad Institute, Boston MA,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston MA
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32
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Chang MS, Hartman RI, Xue J, Giovannucci EL, Nan H, Yang K. Risk of Skin Cancer Associated with Metformin Use: A Meta-Analysis of Randomized Controlled Trials and Observational Studies. Cancer Prev Res (Phila) 2020; 14:77-84. [PMID: 32958585 DOI: 10.1158/1940-6207.capr-20-0376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/26/2020] [Accepted: 09/15/2020] [Indexed: 11/16/2022]
Abstract
Previous studies demonstrate mixed evidence regarding the association between metformin and skin cancer risk. To synthesize prior evidence and evaluate the association between metformin and skin cancer risk in patients with diabetes/prediabetes, we conducted a meta-analysis. A systematic literature search was performed up to March 23, 2020 to identify randomized controlled trials (RCT) and observational studies of metformin that reported any event of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. In a meta-analysis of 6 trials involving 8,541 patients (Peto method), compared with controls, metformin was not significantly associated with decreased risk of melanoma [OR, 0.82; 95% confidence interval (CI), 0.27-2.43], BCC (OR, 0.75; 95% CI, 0.36-1.57), SCC (OR, 0.98; 95% CI, 0.06-15.60), total nonmelanoma skin cancer (NMSC; OR, 0.69; 95% CI, 0.38-1.24), or total skin cancer (OR, 0.71; 95% CI, 0.42-1.20). This nonsignificant association pattern was consistent with the random-effects meta-analysis of 4 cohort studies with 354,746 patients (melanoma: RR, 0.91; 95% CI, 0.62-1.33; NMSC: RR, 0.65; 95% CI, 0.35-1.18; total skin cancer: RR, 0.83; 95% CI, 0.59-1.16). In conclusion, meta-analyses of both RCT and cohort studies showed no statistically significant association between metformin and skin cancer risks, although suggestive evidence of modestly reduced risks of skin cancer among metformin users was observed. Further studies are needed. PREVENTION RELEVANCE: Meta-analyses of RCT and cohort studies showed no significant association between metformin and skin cancer, although suggestive evidence of modestly reduced skin cancer risks among metformin users was observed. These findings suggest metformin use should not influence current medical decision making for diabetes patients at risk of developing skin cancer.
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Affiliation(s)
- Michael S Chang
- Department of Dermatology, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts
| | - Rebecca I Hartman
- Department of Dermatology, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts.,Department of Dermatology, VA Integrated Service Network (VISN-1), Jamaica Plain, Massachusetts
| | - Junchao Xue
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Hongmei Nan
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana.,Department of Global Health, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana
| | - Keming Yang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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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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Gnesin F, Thuesen ACB, Kähler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2020; 6:CD012906. [PMID: 32501595 PMCID: PMC7386876 DOI: 10.1002/14651858.cd012906.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.
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Affiliation(s)
- Filip Gnesin
- Department of Endocrinology, Diabetes and Metabolism, Department 7652, Rigshospitalet, Copenhagen, Denmark
| | - Anne Cathrine Baun Thuesen
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | | | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Bianca Hemmingsen
- Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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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: 55] [Impact Index Per Article: 11.0] [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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Metformin: A Possible Option in Cancer Chemotherapy. Anal Cell Pathol (Amst) 2020; 2020:7180923. [PMID: 32399389 PMCID: PMC7201450 DOI: 10.1155/2020/7180923] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/20/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023] Open
Abstract
Metformin has been used for a long time as an antidiabetic medication for type 2 diabetes. It is used either as a monotherapy or in combination with other antidiabetic medications. The drug came into prominence in diabetes and other conditions with cardiovascular risk after the landmark study of 1995 by the United Kingdom Prospective Diabetes Study which emphasized its importance. However, the drug has been used in experimental trials in various aspects of medicine and pharmacology such as in reproductive medicine, cancer chemotherapy, metabolic diseases, and neurodegenerative diseases. It has been in use in the treatment of polycystic ovarian disease and obesity and is being considered in type 1 diabetes. This study seeks to evaluate the relevance of metformin in cancer management. Different mechanisms have been proposed for its antitumor action which involves the following: (a) the activation of adenosine monophosphate kinase, (b) modulation of adenosine A1 receptor (ADORA), (c) reduction in insulin/insulin growth factors, and (d) the role of metformin in the inhibition of endogenous reactive oxygen species (ROS); and its resultant damage to deoxyribonucleic acid (DNA) molecule is another paramount antitumor mechanism.
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The effect of metformin on gastric cancer in patients with type 2 diabetes: a systematic review and meta-analysis. Clin Transl Oncol 2020; 22:1580-1590. [PMID: 32060719 DOI: 10.1007/s12094-020-02304-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 01/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Metformin, a drug widely used in the treatment of diabetes, has proven preventive and survival benefits for various malignancies. However, the effect of metformin on gastric cancer risk and survival rate in T2DM patients remains controversial. Therefore, we conducted a systematic review and meta-analysis to evaluate the effect of metformin on gastric cancer in T2DM patients. METHODS We searched PubMed, EMBASE, Medline and the Cochrane Library for related studies up to October 22, 2019. Pooled hazard ratios with 95% confidence intervals were calculated using random-effects model. Heterogeneity was assessed. All articles were evaluated by Newcastle-Ottawa Scale. RESULTS A total of 11 cohort studies met eligibility criteria and were included in the meta-analysis. The use of metformin was related to a significant 21% reduction in GC incidence (HR 0.790; 95% CI 0.624-1.001). Subgroup analysis showed that the use of metformin significantly reduced the risk of gastric cancer in T2DM patients in Asian populations, but not in western populations. In a pooled analysis of 3 studies, metformin use was associated with increased overall survival rate (HR 0.817; 95% CI 0.600-1.113) and cancer-specific survival rate (HR 0.824; 95% CI 0.614-1.106) of T2DM patients. CONCLUSIONS Metformin could reduce the risk of gastric cancer in T2DM patients, particularly in Asian populations. However, it is debatable whether metformin use can improve the prognosis of gastric cancer in T2DM patients.
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Ghiasi B, Sarokhani D, Najafi F, Motedayen M, Dehkordi AH. The Relationship Between Prostate Cancer and Metformin Consumption: A Systematic Review and Meta-analysis Study. Curr Pharm Des 2020; 25:1021-1029. [PMID: 30767734 DOI: 10.2174/1381612825666190215123759] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/11/2019] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Prostate cancer is the most common malignant cancer in men worldwide and after lung cancer, it is the second leading cause of cancer mortality in men. The purpose of this study was to investigate the relationship between prostate cancer and metformin consumption in men. METHODS The current study is a systematic and meta-analysis review based on the PRISMA statement. To access the studies of domestic and foreign databases, Iran Medex, SID, Magiran, Iran Doc, Medlib, ProQuest, Science Direct, PubMed, Scopus, Web of Science and the Google Scholar search engine were searched during the 2009- 2018 period for related keywords. In order to evaluate the heterogeneity of the studies, Q test and I2 indicator were used. The data were analyzed using the STATA 15.1 software. RESULTS In 11 studies with a sample size of 877058, the odds ratio of metformin consumption for reducing prostate cancer was estimated at 0.89 (95%CI: 0.67-1.17). Meta-regression also showed there was no significant relationship between the odds ratio and the publication year of the study. However, there was a significant relationship between the odds ratio and the number of research samples. CONCLUSION Using metformin in men reduces the risk of prostate cancer but it is not statistically significant.
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Affiliation(s)
- Bahareh Ghiasi
- Department of Nephrology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Diana Sarokhani
- Research Center for Environmental Determinants of Health (RCEDH), School of Public Health, Kermanshah Uninversity of Medical Sciences, Kermanshah, Iran
| | - Farid Najafi
- Research Center for Environmental Determinants of Health (RCEDH), School of Public Health, Kermanshah Uninversity of Medical Sciences, Kermanshah, Iran
| | - Morteza Motedayen
- Cardiology Department, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Ali Hasanpour Dehkordi
- Department of Medical-Surgical, Faculty of Nursing and Midwifery, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Demb J, Yaseyyedi A, Liu L, Bustamante R, Earles A, Ghosh P, Gutkind JS, Gawron AJ, Kaltenbach TR, Martinez ME, Gupta S. Metformin Is Associated With Reduced Odds for Colorectal Cancer Among Persons With Diabetes. Clin Transl Gastroenterol 2019; 10:e00092. [PMID: 31770138 PMCID: PMC6890275 DOI: 10.14309/ctg.0000000000000092] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Metformin may be associated with reduced colorectal cancer (CRC) risk, but findings from previous studies have been inconsistent and had insufficient sample sizes to examine whether the association differs by anatomic site. This study examined whether metformin was associated with reduced CRC risk, both overall and stratified by anatomic site, in a large sample of persons with diabetes who underwent colonoscopy. METHODS We performed a case-control study of US Veterans with prevalent diabetes who underwent colonoscopy between 1999 and 2014 using Department of Veterans Affairs electronic health record data. Cases were defined by presence of CRC at colonoscopy, while controls had normal colonoscopy. The primary exposure was metformin use at time of colonoscopy (yes/no). Association of metformin exposure with CRC (further stratified by proximal, distal, or rectal subsite) was examined using multivariable and multinomial logistic regression and summarized by odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS We included 6,650 CRC patients and 454,507 normal colonoscopy patients. CRC cases were older and had lower metformin exposure. Metformin was associated with 8% relative reduction in CRC odds (OR: 0.92, 95% CI: 0.87-0.96). By subsite, metformin was associated with a 14% statistically significant reduced rectal cancer odds (OR: 0.86, 95% CI: 0.78-0.94) but no reduced distal or proximal cancer odds. DISCUSSION Metformin was associated with reduced CRC odds-particularly rectal cancer-in a large sample of persons with diabetes undergoing colonoscopy.
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Affiliation(s)
- Joshua Demb
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Moores Cancer Center, La Jolla, California, USA
| | - Armaan Yaseyyedi
- University of Colorado School of Medicine, Denver, Colorado, USA
| | - Lin Liu
- Moores Cancer Center, La Jolla, California, USA
- Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, USA
- Department of Research, VA San Diego Healthcare System, San Diego, California, USA
| | - Ranier Bustamante
- Department of Research, VA San Diego Healthcare System, San Diego, California, USA
| | - Ashley Earles
- Department of Research, VA San Diego Healthcare System, San Diego, California, USA
| | - Pradipta Ghosh
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Moores Cancer Center, La Jolla, California, USA
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - J. Silvio Gutkind
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Moores Cancer Center, La Jolla, California, USA
- Department of Pharmacology, University of California, San Diego, La Jolla, California, USA
| | - Andrew J. Gawron
- VA Salt Lake City Health Care System, Salt Lake City, Utah, USA
- University of Utah, Salt Lake City, Utah, USA
| | - Tonya R. Kaltenbach
- VA San Francisco Healthcare System, San Francisco, California, USA
- University of California, San Francisco, San Francisco, California, USA
| | - Maria Elena Martinez
- Moores Cancer Center, La Jolla, California, USA
- Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, USA
| | - Samir Gupta
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Moores Cancer Center, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
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Saif MW, Rajagopal S, Caplain J, Grimm E, Serebrennikova O, Das M, Tsichlis PN, Martell R. A phase I delayed-start, randomized and pharmacodynamic study of metformin and chemotherapy in patients with solid tumors. Cancer Chemother Pharmacol 2019; 84:1323-1331. [PMID: 31583436 DOI: 10.1007/s00280-019-03967-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 09/25/2019] [Indexed: 11/24/2022]
Abstract
PURPOSE Metformin activates AMP-related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors, crucial for cancer growth. Epidemiologic studies showed a reduced incidence and improved survival in cancer patients. We conducted a prospective phase I study to assess the safety of metformin in combination with chemotherapy in patients with solid tumors. METHODS We conducted a delayed-start randomized trial of non-diabetic patients in two stages. In Stage 1, we randomized patients to two arms: concurrent arm (metformin with chemo) vs. delayed arm (chemo alone). In Stage 2, patients in delayed arm were crossed over to receive metformin. Patients received metformin 500 mg twice daily with chemotherapy to define dose-limiting toxicities (DLTs) in both stages. Secondary endpoints assessed adverse events (AEs) and response rates. Translational correlates included effects of metformin on expression and phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) by western blot in PBMCs. RESULTS A total of 100 patients were enrolled (51 in delayed arm vs. 49 concurrent arm). Rate of DLTs in patients receiving metformin with chemotherapy was 6.1% vs. 7.8% in patients receiving chemotherapy alone. DLTs seen with addition of metformin included those associated with established chemo adverse events. No lactic acidosis or hypoglycemia occurred. Restaging showed stable disease in 46% at cessation of metformin. 28% of patients with measurable tumor markers showed improvement. AMPK phosphorylation showed a four- to sixfold increase in AMPK phosphorylation after metformin. CONCLUSIONS This is the largest phase I study of metformin combined with chemotherapy, which suggests that metformin can be given safely with chemotherapy, and offers a platform for future studies. Post-metformin increase in AMPK phosphorylation may potentially explain lack of disease progression in nearly half of our patients. FUNDING UL1 TR001064. CLINICAL TRIAL INFORMATION NCT01442870.
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Affiliation(s)
- Mohammad Wasif Saif
- Northwell Health Cancer Institute, 1111 Marcus Avenue, 2nd Floor, Lake Success, NY, 11042, USA.
- Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA.
| | | | | | | | | | - Madhumita Das
- Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA
| | | | - Robert Martell
- Tufts Cancer Center, Tufts Medical Center, Boston, MA, USA
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Bradley MC, Ferrara A, Achacoso N, Ehrlich SF, Quesenberry CP, Habel LA. A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus. Cancer Epidemiol Biomarkers Prev 2019; 27:525-530. [PMID: 29716927 DOI: 10.1158/1055-9965.epi-17-0424] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 09/05/2017] [Accepted: 11/22/2017] [Indexed: 12/29/2022] Open
Abstract
Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. ©2018 AACRSee related commentary by Jackson and García-Albéniz, p. 520.
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Affiliation(s)
- Marie C Bradley
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland
| | - Assiamira Ferrara
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Ninah Achacoso
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Samantha F Ehrlich
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | | | - Laurel A Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, California.
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Mocellin S, Goodwin A, Pasquali S. Risk-reducing medications for primary breast cancer: a network meta-analysis. Cochrane Database Syst Rev 2019; 4:CD012191. [PMID: 31032883 PMCID: PMC6487387 DOI: 10.1002/14651858.cd012191.pub2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole). OBJECTIVES To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer.Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity). SEARCH METHODS We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies. SELECTION CRITERIA We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons). MAIN RESULTS We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo.For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data. AUTHORS' CONCLUSIONS For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).
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Affiliation(s)
| | | | - Sandro Pasquali
- Fondazione IRCCS Istituto Nazionale dei TumoriSarcoma ServiceVia G. Venezian 1MilanoItaly20133
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Madsen KS, Kähler P, Kähler LKA, Madsbad S, Gnesin F, Metzendorf M, Richter B, Hemmingsen B. Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2019; 4:CD012368. [PMID: 30998259 PMCID: PMC6472662 DOI: 10.1002/14651858.cd012368.pub2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND The number of people with type 2 diabetes mellitus (T2DM) is increasing worldwide. The combination of metformin and sulphonylurea (M+S) is a widely used treatment. Whether M+S shows better or worse effects in comparison with other antidiabetic medications for people with T2DM is still controversial. OBJECTIVES To assess the effects of metformin and sulphonylurea (second- or third-generation) combination therapy for adults with type 2 diabetes mellitus. SEARCH METHODS We updated the search of a recent systematic review from the Agency for Healthcare Research and Quality (AHRQ). The updated search included CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. The date of the last search was March 2018. We searched manufacturers' websites and reference lists of included trials, systematic reviews, meta-analyses and health technology assessment reports. We asked investigators of the included trials for information about additional trials. SELECTION CRITERIA We included randomised controlled trials (RCTs) randomising participants 18 years old or more with T2DM to M+S compared with metformin plus another glucose-lowering intervention or metformin monotherapy with a treatment duration of 52 weeks or more. DATA COLLECTION AND ANALYSIS Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis, and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using the GRADE instrument. MAIN RESULTS We included 32 RCTs randomising 28,746 people. Treatment duration ranged between one to four years. We judged none of these trials as low risk of bias for all 'Risk of bias' domains. Most important events per person were all-cause and cardiovascular mortality, serious adverse events (SAE), non-fatal stroke (NFS), non-fatal myocardial infarction (MI) and microvascular complications. Most important comparisons were as follows:Five trials compared M+S (N = 1194) with metformin plus a glucagon-like peptide 1 analogue (N = 1675): all-cause mortality was 11/1057 (1%) versus 11/1537 (0.7%), risk ratio (RR) 1.15 (95% confidence interval (CI) 0.49 to 2.67); 3 trials; 2594 participants; low-certainty evidence; cardiovascular mortality 1/307 (0.3%) versus 1/302 (0.3%), low-certainty evidence; serious adverse events (SAE) 128/1057 (12.1%) versus 194/1537 (12.6%), RR 0.90 (95% CI 0.73 to 1.11); 3 trials; 2594 participants; very low-certainty evidence; non-fatal myocardial infarction (MI) 2/549 (0.4%) versus 6/1026 (0.6%), RR 0.57 (95% CI 0.12 to 2.82); 2 trials; 1575 participants; very low-certainty evidence.Nine trials compared M+S (N = 5414) with metformin plus a dipeptidyl-peptidase 4 inhibitor (N = 6346): all-cause mortality was 33/5387 (0.6%) versus 26/6307 (0.4%), RR 1.32 (95% CI 0.76 to 2.28); 9 trials; 11,694 participants; low-certainty evidence; cardiovascular mortality 11/2989 (0.4%) versus 9/3885 (0.2%), RR 1.54 (95% CI 0.63 to 3.79); 6 trials; 6874 participants; low-certainty evidence; SAE 735/5387 (13.6%) versus 779/6307 (12.4%), RR 1.07 (95% CI 0.97 to 1.18); 9 trials; 11,694 participants; very low-certainty evidence; NFS 14/2098 (0.7%) versus 8/2995 (0.3%), RR 2.21 (95% CI 0.74 to 6.58); 4 trials; 5093 participants; very low-certainty evidence; non-fatal MI 15/2989 (0.5%) versus 13/3885 (0.3%), RR 1.45 (95% CI 0.69 to 3.07); 6 trials; 6874 participants; very low-certainty evidence; one trial in 64 participants reported no microvascular complications were observed (very low-certainty evidence).Eleven trials compared M+S (N = 3626) with metformin plus a thiazolidinedione (N = 3685): all-cause mortality was 123/3300 (3.7%) versus 114/3354 (3.4%), RR 1.09 (95% CI 0.85 to 1.40); 6 trials; 6654 participants; low-certainty evidence; cardiovascular mortality 37/2946 (1.3%) versus 41/2994 (1.4%), RR 0.78 (95% CI 0.36 to 1.67); 4 trials; 5940 participants; low-certainty evidence; SAE 666/3300 (20.2%) versus 671/3354 (20%), RR 1.01 (95% CI 0.93 to 1.11); 6 trials; 6654 participants; very low-certainty evidence; NFS 20/1540 (1.3%) versus 16/1583 (1%), RR 1.29 (95% CI 0.67 to 2.47); P = 0.45; 2 trials; 3123 participants; very low-certainty evidence; non-fatal MI 25/1841 (1.4%) versus 21/1877 (1.1%), RR 1.21 (95% CI 0.68 to 2.14); P = 0.51; 3 trials; 3718 participants; very low-certainty evidence; three trials (3123 participants) reported no microvascular complications (very low-certainty evidence).Three trials compared M+S (N = 462) with metformin plus a glinide (N = 476): one person died in each intervention group (3 trials; 874 participants; low-certainty evidence); no cardiovascular mortality (2 trials; 446 participants; low-certainty evidence); SAE 34/424 (8%) versus 27/450 (6%), RR 1.68 (95% CI 0.54 to 5.21); P = 0.37; 3 trials; 874 participants; low-certainty evidence; no NFS (1 trial; 233 participants; very low-certainty evidence); non-fatal MI 2/215 (0.9%) participants in the M+S group; 2 trials; 446 participants; low-certainty evidence; no microvascular complications (1 trial; 233 participants; low-certainty evidence).Four trials compared M+S (N = 2109) with metformin plus a sodium-glucose co-transporter 2 inhibitor (N = 3032): all-cause mortality was 13/2107 (0.6%) versus 19/3027 (0.6%), RR 0.96 (95% CI 0.44 to 2.09); 4 trials; 5134 participants; very low-certainty evidence; cardiovascular mortality 4/1327 (0.3%) versus 6/2262 (0.3%), RR 1.22 (95% CI 0.33 to 4.41); 3 trials; 3589 participants; very low-certainty evidence; SAE 315/2107 (15.5%) versus 375/3027 (12.4%), RR 1.02 (95% CI 0.76 to 1.37); 4 trials; 5134 participants; very low-certainty evidence; NFS 3/919 (0.3%) versus 7/1856 (0.4%), RR 0.87 (95% CI 0.22 to 3.34); 2 trials; 2775 participants; very low-certainty evidence; non-fatal MI 7/890 (0.8%) versus 8/1374 (0.6%), RR 1.43 (95% CI 0.49 to 4.18; 2 trials); 2264 participants; very low-certainty evidence; amputation of lower extremity 1/437 (0.2%) versus 1/888 (0.1%); very low-certainty evidence.Trials reported more hypoglycaemic episodes with M+S combination compared to all other metformin-antidiabetic agent combinations. Results for M+S versus metformin monotherapy were inconclusive. There were no RCTs comparing M+S with metformin plus insulin. We identified nine ongoing trials and two trials are awaiting assessment. Together these trials will include approximately 16,631 participants. AUTHORS' CONCLUSIONS There is inconclusive evidence whether M+S combination therapy compared with metformin plus another glucose-lowering intervention results in benefit or harm for most patient-important outcomes (mortality, SAEs, macrovascular and microvascular complications) with the exception of hypoglycaemia (more harm for M+S combination). No RCT reported on health-related quality of life.
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Affiliation(s)
- Kasper S Madsen
- University of CopenhagenFaculty of Health and Medical SciencesBlegdamsvej 3BCopenhagen NDenmark2200
| | - Pernille Kähler
- Faculty of Health and Medical SciencesCopenhagen Medical UniversityBlegdamsvej 3CopenhagenDenmark2100Ø
| | | | - Sten Madsbad
- Hvidovre Hospital, University of CopenhagenDepartment of EndocrinologyHvidovreDenmark
| | - Filip Gnesin
- Department 7652, RigshospitaletDepartment of Endocrinology, Diabetes and MetabolismBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Maria‐Inti Metzendorf
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
| | - Bernd Richter
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
| | - Bianca Hemmingsen
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupMoorenstr. 5DüsseldorfGermany40225
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Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res 2019; 11:3295-3313. [PMID: 31114366 PMCID: PMC6497052 DOI: 10.2147/cmar.s200059] [Citation(s) in RCA: 243] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 02/19/2019] [Indexed: 12/19/2022] Open
Abstract
Metformin is a widely used drug in today’s prescriptions by physicians due to its specific effects in treating and curing type II diabetes. Diabetes is a common disease that may occur throughout human life, and can increase the likelihood of the occurrence of various types of cancer, such as colon, rectum, pancreas and liver cancers, compared to non-diabetic patients. Metformin inhibits mTOR activity by activating ATM (ataxia telangiectasia mutated) and LKB1 (liver kinase B1) and then adenosine monophosphate-activated kinase
(AMPK), and thus prevents protein synthesis and cell growth. Metformin can activate p53 by activating
AMPK and thereby ultimately stop the cell cycle. Given the potential of metformin in the treatment of cancer, it can be used in radiotherapy, chemotherapy and to improve the response to treatment in
androgen derivatives (ADT), and also, according to available evidence, metformin can also be used to prevent various types of cancers. Generally, metformin can: 1) reduce the incidence of cancers, 2) reduce the mortality from cancers, 3) increase the response to treatment in cancer cells when using radiotherapy and chemotherapy, 4) optimize tumor movement and reduce the malignancy, 5) reduce the likelihood of relapse, and 6) reduce the damaging effects of ADT. Therefore, this drug can be used as a complementary therapeutic agent for cancer treatment and prevention. In this review, we have summarized the data from various experimental and clinical studies and highlight the possible potential effects of metformin on cancer therapeutic responses. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/bfZuNyIztZA
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Affiliation(s)
- Pouya Saraei
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Ilia Asadi
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
| | - Muhammad Azam Kakar
- Director Planning and Development, L&DD Department, Quetta, Balochistan, Pakistan
| | - Nasroallah Moradi-Kor
- Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran.,Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
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Wen Q, Zhao Z, Wen J, Zhou J, Wu J, Lei S, Miao Y. The association between metformin therapy and risk of gynecological cancer in patients: Two meta-analyses. Eur J Obstet Gynecol Reprod Biol 2019; 237:33-41. [PMID: 31009857 DOI: 10.1016/j.ejogrb.2019.03.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 03/06/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Recently, metformin, first-line drug for type 2 diabetes, has been reported to treat some gynecological tumors. However, these epidemiological studies have never been formally summarized. Considering a single study may lack the power to provide reliable conclusion, we performed two meta-analyses with different indicators to assess metformin's role in reducing the risk of gynecological cancers. MATERIALS AND METHODS A systematic literature search was carried out in PubMed, Medline (Ovid), Embase database (last search was performed on August 15, 2018). The relative risk (RR) along with a random-effects model were performed on Revman 5.3 and STATA 15.1 for risks analyzing. RESULTS A total of 1,710,080 patients in 7 studies were included in first meta-analysis. The results suggested metformin may reduce the risk of gynecological cancers (RR=0.49, 95%CI=0.29-0.82, and p=0.006). In the subgroup analyses: significantly decreased risks were found among Asians (RR=0.27, 95%CI=0.17-0.41, and p<0.00001), ovarian cancer (RR=0.18, 95%CI=0.12-0.28, and p<0.00001), and cervical cancer (RR=0.60, 95%CI=0.43-0.83, and p=0.002), but not in Caucasians (RR=0.81, 95%CI=0.50-1.32, and p=0.40) or in endometrial cancer (RR=0.71, 95%CI=0.29-1.74, and p=0.45). Meanwhile, another total of 8,335,332 cumulative follow-up years, person years, were conducted in 8 studies. The results indicated no statistical significance in general (RR=0.59, 95%CI=0.32-1.10, p=0.10), and no difference in Caucasians (RR=1.15, 95%CI=0.88-1.48, and p=0.30), endometrial cancer (RR=0.89, 95%CI=0.27-2.95, and p=0.84) or ovarian cancer (RR=0.37, 95%CI=0.09-1.49, and p=0.16) when performing subgroup analyses. However, in the subgroup analyses, results in Asians (RR=0.26, 95%CI=0.17-0.40, and p<0.00001) and cervical cancer (RR=0.56, 95%CI=0.40-0.78, and p=0.0005) had an apparent significance. CONCLUSIONS The results suggested the metformin can be used as a potential anticarcinogenic drug for gynecological cancers' prevention, especially for Asians and cervical cancer. The question remains, still, whether metformin is beneficial for ovarian cancer. Also, we don't know whether it is worth to give metformin to non-diabetes to prevent gynecological cancer.
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Affiliation(s)
- Qiao Wen
- Department of Otolaryngology Head & Neck Surgery, West China Hospital, Sichuan University, Chengdu, China.
| | - Zhiwei Zhao
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.
| | - Jirui Wen
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.
| | - Jing Zhou
- West China School of Clinical Medicine, Sichuan University, Chengdu, China.
| | - Jiang Wu
- Deep Underground Space Medical Center, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu, China.
| | - Sun Lei
- NO. 4 West China Teaching Hospital, Sichuan University, Chengdu, China.
| | - Yali Miao
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, China.
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Wen Q, Zhao Z, Wen J, Zhou J, Wu J, Lei S, Miao Y. WITHDRAWN: The association between metformin therapy and risk of gynecological cancer in patients: two meta-analyses. Eur J Obstet Gynecol Reprod Biol X 2019. [DOI: 10.1016/j.eurox.2019.100010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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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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Ye JH, Qian MH, Shi LZ, Ye L. Association Between Metformin and Sulfonylurea Monotherapies and Cancer Incidence: A Real-World Cohort Study in Shanghai, China. Diabetes Ther 2019; 10:245-258. [PMID: 30623338 PMCID: PMC6349283 DOI: 10.1007/s13300-018-0557-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION Previous studies have shown that patients with type 2 diabetes mellitus have an increased risk of cancer. The use of antidiabetic medication (ADM) may play an important role in the cancer development. The relationship between oral ADM and cancer incidence has not been investigated in type 2 diabetes mellitus patients in mainland China yet. METHODS A community-based diabetes cohort was extracted from the Shanghai Community Diabetes Management System database, which is a patient registry from general practices. The cohort included 2353 newly onset type 2 diabetes mellitus patients from 2006 to 2010 aged 35 years or more. Patients were grouped into nonusers of antidiabetic medication (n = 722), metformin monotherapy (n = 374), sulfonylurea monotherapy (n = 653), metformin and sulfonylurea combination therapy (n = 302), and other medication therapies (n = 302) on the basis of initial treatment type at registry entry. Cancer incidence was identified from the Shanghai Cancer Registry Organization. Comparisons between monotherapy and nonuser of medication were conducted using Cox proportional hazards models. RESULTS A total of 94 cancer cases were identified during 5 years median follow-up. Compared with nonusers, sulfonylurea monotherapy was associated with significantly lower risk of cancer [adjusted HR = 0.50 (95% CI 0.29-0.85)] whereas risk was 49% lower with metformin monotherapy [adjusted HR = 0.51 (95% CI 0.27-0.99)]. CONCLUSION The real-world evidence suggested that the use of metformin or sulfonylurea was associated with lower risk of cancer incidence in a cohort of newly onset type 2 diabetes mellitus patients.
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Affiliation(s)
- Jing-Hong Ye
- Department of Health Economics, School of Public Health, Key Lab of Health Technology Assessment, National Health Commission, Fudan University, Shanghai, China
- Shanghai Hongkou Center for Disease Control and Prevention, Shanghai, China
| | - Meng-Hua Qian
- Shanghai Hongkou Center for Disease Control and Prevention, Shanghai, China
| | - Li-Zheng Shi
- Tulane University of School and Public Health and Tropical Medicine, New Orleans, LA, USA.
| | - Lu Ye
- Department of Health Economics, School of Public Health, Key Lab of Health Technology Assessment, National Health Commission, Fudan University, Shanghai, China.
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Shi J, Liu B, Wang H, Zhang T, Yang L. Association of metformin use with ovarian cancer incidence and prognosis: a systematic review and meta-analysis. Int J Gynecol Cancer 2019; 29:140-146. [PMID: 30640696 DOI: 10.1136/ijgc-2018-000060] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/20/2018] [Accepted: 10/24/2018] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Some clinical and basic research studies have indicated that exposure to metformin might have protective effects against ovarian cancer. However, results from epidemiologic studies have been inconsistent. We performed a meta-analysis to evaluate the effect of metformin use on the risk of ovarian cancer occurrence and mortality. METHODS Multiple databases were searched to identify studies on the association between use of metformin and risk of ovarian cancer or prognosis, up to August 2018. Relevant information for analysis was extracted. A random-effects model was used to calculate the pooled risk estimate. RESULTS Thirteen articles were included, of which six articles focused on ovarian cancer incidence and the others focused on prognosis. The pooled OR for ovarian cancer occurrence and mortality comparing metformin use with non-use or use of other hypoglycemic drugs was 0.76 (95% CI 0.62 to 0.93, p = 0.008) and 0.55 (95% CI 0.36 to 0.84, p = 0.006), respectively. Moderate to substantial heterogeneity was observed across included studies. CONCLUSIONS Our findings demonstrate that use of metformin was significantly associated with a lower incidence and a better prognosis of ovarian cancer in patients with diabetes. Well-designed interventional studies are warranted to confirm our findings.
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Affiliation(s)
- Jinghua Shi
- Department of Information, Taian City Central Hospital, Taian, People's Republic of China
| | - Baoli Liu
- Taian City Central Hospital, Taian, People's Republic of China
| | - Hongmei Wang
- Department of Endocrinology, Taian City Central Hospital, Taian, People's Republic of China
| | - Tie Zhang
- Department of Endocrinology, Taian City Central Hospital, Taian, People's Republic of China
| | - Libo Yang
- Department of Endocrinology, Taian City Central Hospital, Taian, People's Republic of China
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Vicentini M, Ballotari P, Giorgi Rossi P, Venturelli F, Sacchettini C, Greci M, Mangone L, Pezzarossi A, Manicardi V. Effect of different glucose-lowering therapies on cancer incidence in type 2 diabetes: An observational population-based study. Diabetes Res Clin Pract 2018; 143:398-408. [PMID: 29807100 DOI: 10.1016/j.diabres.2018.04.036] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 04/04/2018] [Accepted: 04/18/2018] [Indexed: 01/30/2023]
Abstract
AIM To assess the effect of metformin on cancer incidence in type 2 diabetes (T2DM), considering possible interactions with other glucose-lowering drugs and diabetes duration. METHODS Study cohort included diabetes patients aged 20-84 on December 2009, still alive and resident in Reggio Emilia province as of December 2011. Drug exposure was assessed for 2009-2011; subjects taking metformin continuously, with or without other hypoglycaemic drugs, were compared to subjects on diet-only therapy. The cohort was followed up from 2012 to 2014 through the cancer registry. Age- and sex-adjusted incidence rate ratios (IRRs) were computed using Poisson regression models for all sites, lung, breast, liver, colorectal, prostate and pancreatic cancer. RESULTS The cohort includes 17,026 people with T2DM, 7460 taking metformin. 887 cancers occurred during follow-up, 348 among metformin users. Cancer risk was similar in T2DM patients using metformin and those on diet-only. The risk for prostate (IRR = 0.65; 95%CI:0.36; 1.17), liver (IRR = 0.82; 95%CI:0.36; 1.85) and breast (IRR = 0.77; 95%CI:0.43; 1.40) cancers only was slightly reduced; for lung (IRR = 1.52; 95%CI:0.92; 2.50), pancreas (IRR = 1.51; 95%CI:0.59:3.89) and colon-rectum (IRR = 1.71; 95%CI:0.94; 3.08) the risk was slightly increased. CONCLUSIONS There is no evidence of antitumor effect of metformin. A possible decrease only for breast, liver and prostate cancer, is compatible with random fluctuations.
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Affiliation(s)
- Massimo Vicentini
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Paola Ballotari
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Paolo Giorgi Rossi
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Francesco Venturelli
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy; Specialization School of Hygiene and Preventive Medicine, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
| | - Claudio Sacchettini
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Marina Greci
- Primary Health Care, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Lucia Mangone
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Annamaria Pezzarossi
- Epidemiology Unit, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
| | - Valeria Manicardi
- Department of Internal Medicine, Hospital of Montecchio, Local Health Authority of Reggio Emilia-IRCCS, Reggio Emilia, Italy.
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