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Chan JCN, Yang A, Chu N, Chow E. Current type 2 diabetes guidelines: Individualized treatment and how to make the most of metformin. Diabetes Obes Metab 2024; 26 Suppl 3:55-74. [PMID: 38992869 DOI: 10.1111/dom.15700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 05/24/2024] [Accepted: 05/24/2024] [Indexed: 07/13/2024]
Abstract
Evidence-based guidelines provide the premise for the delivery of quality care to preserve health and prevent disabilities and premature death. The systematic gathering of observational, mechanistic and experimental data contributes to the hierarchy of evidence used to guide clinical practice. In the field of diabetes, metformin was discovered more than 100 years ago, and with 60 years of clinical use, it has stood the test of time regarding its value in the prevention and management of type 2 diabetes. Although some guidelines have challenged the role of metformin as the first-line glucose-lowering drug, it is important to point out that the cardiovascular-renal protective effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were gathered from patients with type 2 diabetes, the majority of whom were treated with metformin. Most national, regional and international guidelines recommend metformin as a foundation therapy with emphasis on avoidance of therapeutic inertia and early attainment of multiple treatment goals. Moreover, real-world evidence has confirmed the glucose-lowering and cardiovascular-renal benefits of metformin accompanied by an extremely low risk of lactic acidosis. In patients with type 2 diabetes and advanced chronic kidney disease (estimated glomerular filtration rate 15-30 mL/min/1.73m2), metformin discontinuation was associated with an increased risk of cardiovascular-renal events compared with metformin persistence. Meanwhile, it is understood that microbiota, nutrients and metformin can interact through the gut-brain-kidney axis to modulate homeostasis of bioactive molecules, systemic inflammation and energy metabolism. While these biological changes contribute to the multisystem effects of metformin, they may also explain the gastrointestinal side effects and vitamin B12 deficiency associated with metformin intolerance. By understanding the interactions between metformin, foods and microbiota, healthcare professionals are in a better position to optimize the use of metformin and mitigate potential side effects. The United Kingdom Prospective Diabetes Study and the Da Qing Diabetes Prevention Program commenced 40 years ago provided the first evidence that type 2 diabetes is preventable and treatable. To drive real-world impact from this evidence, payors, practitioners and planners need to co-design and implement an integrated, data-driven, metformin-based programme to detect people with undiagnosed diabetes and prediabetes (intermediate hyperglycaemia), notably impaired glucose tolerance, for early intervention. The systematic data collection will create real-world evidence to bring out the best of metformin and make healthcare sustainable, affordable and accessible.
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Affiliation(s)
- Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Natural Chu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
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Wei H, Cheng X, Wang G, Li Z, Du W, Ju L, Shan D, Yu M, Fang Y, Qian K, Zhang Y, Xiao Y, Wang X. Causal association of smoking, blood lipids, and bladder cancer: Insights from a multivariable and mediation mendelian randomization investigation. J Cancer 2024; 15:1929-1939. [PMID: 38434974 PMCID: PMC10905390 DOI: 10.7150/jca.92306] [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: 11/16/2023] [Accepted: 01/31/2024] [Indexed: 03/05/2024] Open
Abstract
We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.
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Affiliation(s)
- Houyi Wei
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiangqun Cheng
- Physical Examination Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhilong Li
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wenzhi Du
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lingao Ju
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Danni Shan
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengxue Yu
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yayun Fang
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kaiyu Qian
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Euler Technology, ZGC Life Sciences Park, Beijing, China
- Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China
| | - Yu Xiao
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, China
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Wakabayashi R, Hirano T, Laurent T, Kuwatsuru Y, Kuwatsuru R. Impact of "time zero" of Follow-Up Settings in a Comparative Effectiveness Study Using Real-World Data with a Non-user Comparator: Comparison of Six Different Settings. Drugs Real World Outcomes 2022; 10:107-117. [PMID: 36441486 PMCID: PMC9944480 DOI: 10.1007/s40801-022-00343-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Time-related bias can lead to misleading conclusions. Properly setting the "time zero" of follow-up is crucial for avoiding these biases. However, the time-zero setting is challenging when comparing users and non-users of a study drug because the latter do not have a time point for starting treatment. OBJECTIVE This methodological study aimed to illustrate the impact of different time-zero settings on effect estimates in a comparative effectiveness study using real-world data with a non-user comparator. METHODS Data for type 2 diabetes patients were extracted from an administrative claims database, and the onset of diabetic retinopathy (study outcome) was compared between users (treatment group) and non-users (non-use group) of lipid-lowering agents. We applied six time-zero settings to the same dataset. The adjusted hazard ratio (HR) for the outcome was estimated using a Cox regression model in each time-zero setting, and the obtained results were compared among the settings. RESULTS Of the six settings, three (study entry date [SED] vs SED [naïve approach], treatment initiation [TI] vs SED, TI vs Matched [random order]) showed that the treatment had a reduced risk of the outcome (HR [95% CI]: 0.65 [0.61-0.69], 0.92 [0.86-0.97], and 0.76 [0.71-0.82], respectively), one (TI vs Random) had an increased risk (HR [95% CI]: 1.52 [1.40-1.64]) , and two (SED vs SED [cloning method], and TI vs Matched [systematic order]) had neither increased nor decreased risk (HR [95% CI]: 0.95 [0.93-1.13], and 0.99 [0.93-1.07], respectively). CONCLUSIONS This study demonstrates that different time-zero settings can lead to different conclusions, even if the same dataset is analyzed for the same research question, probably because improper settings can introduce bias. To minimize such biases, researchers should carefully define time zero, particularly when designing a non-user comparator study using real-world data.
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Affiliation(s)
- Ryozo Wakabayashi
- Real-World Evidence and Data Assessment (READS), Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,Clinical Study Support, Inc., Nagoya, Japan.
| | - Takahiro Hirano
- grid.258269.20000 0004 1762 2738Real-World Evidence and Data Assessment (READS), Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan ,Clinical Study Support, Inc., Nagoya, Japan
| | - Thomas Laurent
- grid.258269.20000 0004 1762 2738Real-World Evidence and Data Assessment (READS), Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan ,Clinical Study Support, Inc., Nagoya, Japan
| | - Yoshiki Kuwatsuru
- grid.258269.20000 0004 1762 2738Department of Radiology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Ryohei Kuwatsuru
- grid.258269.20000 0004 1762 2738Real-World Evidence and Data Assessment (READS), Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan ,grid.258269.20000 0004 1762 2738Department of Radiology, School of Medicine, Juntendo University, Tokyo, Japan
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Li L, Meng F, Xu D, Xu L, Qiu J, Shu X. Synergism between the metabolic syndrome components and cancer incidence: results from a prospective nested case-control study based on the China Health and Retirement Longitudinal Study (CHARLS). BMJ Open 2022; 12:e061362. [PMID: 36115664 PMCID: PMC9486362 DOI: 10.1136/bmjopen-2022-061362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVES Synergism between the metabolic syndrome (MetSyn) components and cancer incidence still remains inconclusive. We aimed to investigate the unique or joint role of MetSyn components in cancer onset. DESIGN We conducted a prospective nested case-control study based on the China Health and Retirement Longitudinal Study. SETTING An ongoing national representative longitudinal study included follow-up survey of people aged 45 years and older and their partners living in private households in China. PARTICIPANTS There were 17 708 individuals included at baseline. A total of 306 incident cancers was identified during the follow-up. For every case, we used incidence-density sampling to match three concurrent cancer-free controls by age, sex, and both duration and calendar time of follow-up. Exposure of interest was any MetSyn diagnosis at baseline. RESULTS We observed elevation in cancer risk associated with MetSyn in a significant way when the number of MetSyn components was over three (OR: 1.88; 95% CI: 1.19 to 2.97), or when components contained any of elevated triglycerides (OR: 1.61; 95% CI: 1.05 to 2.48), reduced high-density lipoprotein (HDL) cholesterol (OR: 2.33; 95% CI: 1.40 to 3.86) or elevated blood pressure (OR: 1.65; 95% CI: 1.04 to 2.59) after consistent multiple adjustments in different models. The highest cancer risk was in the female reproductive system and breast cancer (OR: 4.22; 95% CI: 1.62 to 10.95) followed by digestive system (OR: 1.67; 95% CI: 1.11 to 2.53). Sensitivity analyses showed similar results after first follow-up was excluded. However, any unique MetSyn component was not associated with increased cancer risk. Interestingly, the reduced HDL was observed to be widely associated with over twofold increased risk of cancer, only when together with other MetSyn components. CONCLUSION MetSyn components, in a collaborative manner rather than its unique component, were associated with elevated cancer risk. Not only obesity but even subtle metabolic disturbances may give rise to cancer.
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Affiliation(s)
- Lin Li
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, People's Republic of China
| | - Fang Meng
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Suzhou Institute of Systems Medicine, Suzhou, China
| | - Dongkui Xu
- VIP Department, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Lingkai Xu
- Department for Communicable Disease Control and Prevention, Suzhou Wuzhong Centre for Disease Prevention and Control, Suzhou, China
| | - Junlan Qiu
- Department of Oncology and Hematology, the Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Xiaochen Shu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, People's Republic of China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, People's Republic of China
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Şaylık F, Çınar T, Akbulut T, Selçuk M. Serum Uric Acid to Albumin Ratio Can Predict Contrast-Induced Nephropathy in ST-Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention. Angiology 2022:33197221091605. [PMID: 35451314 DOI: 10.1177/00033197221091605] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Contrast-induced nephropathy (CIN) is one of the common complication of ST-elevation myocardial infarction (STEMI) following primary percutaneous coronary intervention (pPCI). Serum uric acid to albumin ratio (UAR) is a novel marker, which is associated with acute kidney injury in intensive care unit patients. We investigated the predictive value of UAR for the development of CIN in STEMI patients (n = 1379) after pPCI. The diagnosis of CIN was made based on an increase of basal creatinine levels >.5 mg/dL or 25% within 72 h after pPCI; 128 patients were in the CIN (+) group and 1251 patients were in the CIN (-) group. CIN (+) patients had higher serum uric acid (SUA), UAR, and lower albumin levels than CIN (-) patients. Age, diabetes, hypertension, hemoglobin, glucose at admission, basal creatinine, peak troponin I, total bilirubin, contrast volume/glomerular filtration rate, and UAR were independent predictors of CIN. A cutoff value of 1.62 for UAR detected CIN development with a sensitivity of 54% and specificity of 87.4%, and the discrimination ability of UAR was better than that of SUA or albumin. In conclusion, UAR was an independent predictor of the development of CIN.
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Affiliation(s)
- Faysal Şaylık
- 215299Van Education and Research Hospital, Van, Turkey
| | - Tufan Çınar
- 506079Sultan Abdulhamid Han Education and Research Hospital, Istanbul, Turkey
| | | | - Murat Selçuk
- 506079Sultan Abdulhamid Han Education and Research Hospital, Istanbul, Turkey
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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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Zhang K, Bai P, Dai H, Deng Z. Metformin and risk of cancer among patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Prim Care Diabetes 2021; 15:52-58. [PMID: 32605879 DOI: 10.1016/j.pcd.2020.06.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022]
Abstract
AIM We carried out this meta-analysis on all published studies to estimate the overall cancer risk of the use of metformin in T2DM patients. METHODS We searched the PubMed, Embase and CNKI databases for all articles within a range of published years from 2007 to 2019 on the association between the use of metformin and cancer risk in T2DM patients. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the association using a random-effect meta-analysis. RESULTS Finally, 67 studies met the inclusion criteria for this study, with 10,695,875 T2DM patients and 145,108 cancer cases. Overall, For T2DM patients of ever vs. never metformin users, there was statistical evidence of significantly decreased cancer risk was found to be associated with ever metformin users (OR=0.70, 95% CI=0.65-0.76). Considering T2DM may be a specific and independent risk factor for various forms of cancer, due to its particular metabolic characteristics of glucose intolerance and hyperinsulinemia, we performed a comparison to estimate the effects of metformin on cancer risk with other anti-diabetes medications (ADMs), our results found significantly decreased cancer risk to be associated with the use of metformin (OR=0.80, 95% CI=0.73-0.87). CONCLUSION Our meta-analysis indicated that metformin may be a independent protective factor for cancer risk in T2DM patients.
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Affiliation(s)
- Kui Zhang
- Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Peng Bai
- Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Hao Dai
- Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Zhenhua Deng
- Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
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Kanwal F, Kramer JR, Li L, Dai J, Natarajan Y, Yu X, Asch SM, El-Serag HB. Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease. Hepatology 2020; 71:808-819. [PMID: 31675427 DOI: 10.1002/hep.31014] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 10/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is now the most common liver condition. Predicting its progression could help clinicians manage and potentially prevent complications. We evaluated the independent and joint effects of metabolic traits on the risk of cirrhosis and hepatocellular carcinoma (HCC) among patients with NAFLD. APPROACH AND RESULTS We assembled a retrospective cohort of patients with NAFLD diagnosed at 130 facilities in the Veterans Administration between January 1, 2004, and December 31, 2008, with follow-up through December 31, 2015. We performed competing risk-adjusted cause-specific Cox models to evaluate the effects of metabolic traits (diabetes, hypertension, dyslipidemia, obesity) as additive or combined indicators on time to develop cirrhosis or HCC or a composite endpoint of both. Of the 271,906 patients, 22,794 developed cirrhosis, and 253 developed HCC during a mean of 9 years follow-up. At baseline, the mean body mass index was 31.6 (SD, 5.6), 28.7% had diabetes, 70.3% had hypertension, and 62.3% had dyslipidemia with substantial overlap among these traits. The risk of progression was the lowest in patients with only one or no metabolic trait. There was a stepwise increase in risk with each additional metabolic trait. Compared with patients with no metabolic trait, patients with both hypertension and dyslipidemia had 1.8-fold higher risk of progression to cirrhosis/HCC (hazard ratio [HR] = 1.8, 95% confidence interval [CI] = 1.59-2.06); the risk was 2.6-fold higher in patients with diabetes, obesity, dyslipidemia, and hypertension (HR = 2.6, 95% CI = 2.3-2.9). These associations were stronger for HCC. Diabetes had the strongest association with HCC in this cohort. CONCLUSIONS Each additional metabolic trait increased the risk of cirrhosis and HCC in patients with NAFLD. Diabetes conferred the highest risk of progression to HCC. Patients with diabetes and coexisting hypertension and obesity may be important targets for secondary prevention.
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Affiliation(s)
- Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.,Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Jennifer R Kramer
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.,Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Liang Li
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jianliang Dai
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yamini Natarajan
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Xian Yu
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.,Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Steven M Asch
- Center for Innovation to Implementation (Ci2i), Palo Alto Veterans Affairs Medical Center, Palo Alto, CA.,Division of Primary Care and Population Health, Stanford University, Palo Alto, CA
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.,Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
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Au Yeung SL, Schooling CM. Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study. BMJ Open Diabetes Res Care 2019; 7:e000872. [PMID: 31908803 PMCID: PMC6936416 DOI: 10.1136/bmjdrc-2019-000872] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 11/12/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022] Open
Abstract
Objectives Observational studies suggest glycemic traits and type 2 diabetes are positively associated, and metformin inversely associated with breast and prostate cancer risk. However, observational studies are susceptible to unmeasured confounding while studies of metformin use are also vulnerable to immortal time bias. The use of Mendelian randomization may reduce confounding due to random allocation of relevant genetic markers at birth, and may reduce immortal time bias (for metformin-related variants analysis) since the start of exposure is at birth. Research design and methods We identified strong genetic predictors of fasting glucose, glycated hemoglobin, and type 2 diabetes from the Meta-Analyses of Glucose and Insulin-related traits Consortium and Diabetes Genetics Replication And Meta-analysis Consortium (n=140 595 for glucose; n=123 665 for HbA1c; n=898 130 for type 2 diabetes) and of AMPK-instrumented HbA1c reduction as a proxy of metformin and applied them to large genome-wide association studies of breast cancer (Breast Cancer Association Consortium; BCAC) and prostate cancer (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome; PRACTICAL). We used inverse variance weighting to obtain estimates. Sensitivity analyses included use of MR-Egger, weighted median, exclusion of pleiotropic instruments, and validation using UK Biobank (breast cancer only). Results There was no association of fasting glucose (OR 1.03 per mmol/L, 95% CI 0.85 to 1.25), HbA1c (OR 1.02 per %, 95% CI 0.73 to 1.45), or type 2 diabetes (OR 0.98 per log odds, 95% CI 0.95 to 1.01) with breast cancer in BCAC, with similar findings from UK Biobank. There was no association of fasting glucose (OR 0.93 per mmol/L, 95% CI 0.73 to 1.17), HbA1c (OR 0.90 per %, 95% CI 0.58 to 1.40) or type 2 diabetes (OR 1.02 per log odds, 95% CI 0.97 to 1.07) with prostate cancer in PRACTICAL. No strong evidence was observed for AMPK-instrumented HbA1c reduction on cancer risk. Conclusion Glycemic traits and type 2 diabetes unlikely cause breast and prostate cancer. Whether metformin can be repurposed for cancer prevention remains unclear.
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Affiliation(s)
- Shiu Lun Au Yeung
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Catherine Mary Schooling
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Graduate School of Public Health and Health Policy, City University of New York, New York City, New York, USA
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10
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Sun J, Mei H, Xie S, Wu L, Wang Y, Mei W, Zhang J. The interactive effect of pre-pregnancy overweight and obesity and hypertensive disorders of pregnancy on the weight status in infancy. Sci Rep 2019; 9:15960. [PMID: 31685839 PMCID: PMC6828655 DOI: 10.1038/s41598-019-52140-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 10/10/2019] [Indexed: 01/19/2023] Open
Abstract
We aimed to assess whether hypertensive disorders of pregnancy (HDP) could modify the effect of pre-pregnancy overweight or obesity (OWO) on the risk of offspring high body mass index (BMI) in infancy. A total of 3,765 mother-child pairs were recruited from two Chinese birth cohorts. BMI ≥ 85th percentile, based on World Health Organization criteria, was defined as a high BMI for the risk of developing severe obesity in later life. Logistic regression analysis was used to assess the combined effects and multiplicative interactions of pre-pregnancy OWO + HDP on offspring high BMI. Relative excess risk due to interaction (RERI) or attributable proportion (AP) was used to estimate additive interactions. RERI > 0 or AP > 0 indicates a significant additive interaction. Compared with the non-OWO and normal blood pressure group, the combination of OWO + HDP was positively associated with offspring high BMI at 12 months of age [OR 3.10 (95%CI 1.59, 6.04)], with 51% of the effects attributed to an additive interaction [AP 0.51 (95%CI 0.13, 0.89)]. An interactive effect was found between the pre-pregnancy OWO + HDP and offspring high BMI in infancy. Interventions to control pre-pregnancy OWO and HDP are important to prevent obesity and associated adverse outcomes in offspring.
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Affiliation(s)
- Jiahong Sun
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, 430030, Hubei, China
| | - Hong Mei
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, 430030, Hubei, China
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, 100 Hongkong Rd., Wuhan, 430016, Hubei, China
| | - Shuixian Xie
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, 430030, Hubei, China
| | - Lisha Wu
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, 430030, Hubei, China
| | - Yulong Wang
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, 430030, Hubei, China
| | - Wenhua Mei
- Department of Information, Zhuhai Public Hospital Authority, 351 East Meihua Rd., Zhuhai, 519000, Guangdong, China.
- Department of Epidemiology, Jinan University, 601 Huangpuxi Rd., Guangzhou, 510632, Guangdong, China.
| | - Jianduan Zhang
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, 430030, Hubei, China.
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11
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Zhang ZJ. Metformin and Reduced Risk of Cancer in the Hong Kong Diabetes Registry: Real Effect or Immortal Time Bias? J Gen Intern Med 2019; 34:1154-1157. [PMID: 31025306 PMCID: PMC6614235 DOI: 10.1007/s11606-019-04982-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 12/10/2018] [Accepted: 03/07/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND Whether metformin reduces cancer risk has been hotly debated. One common opinion is that the observed beneficial effects of metformin are the consequence of immortal time bias. OBJECTIVE To examine whether the observed beneficial effects of metformin on cancer risk are the consequence of immortal time bias. DESIGN Retrospective cohort study. PARTICIPANTS A cohort of 3485 patients who started metformin before or at enrollment, 1226 patients who initiated metformin after enrollment, and an unexposed group of 1392 patients who never used metformin. MAIN MEASURES Metformin users were categorized into 11 groups in terms of length of time between metformin initiation and enrollment. The percent changes in immortal person-time were calculated for each group. RESULTS As the groups of current metformin users (n = 3485) were added sequentially to the metformin group with potential immortal time bias (n = 1226), the proportion of immortal person-time decreased gradually by 74%. As the immortal time decreased, the association between metformin and cancer risk remained statistically significant (uncorrected hazard ratio 0.54, 95% confidence interval 0.42-0.69, P < 0.0001). CONCLUSION The change in the association between metformin and cancer is small compared with the changes in the proportion of immortal time, suggesting that immortal time bias does not account for the observed beneficial effect of metformin on cancer risk. Further studies are warranted to confirm this finding in other cohort studies.
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Affiliation(s)
- Zhi-Jiang Zhang
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China.
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12
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Ren Y, Gao L, Guo X, Huo X, Lu J, Li J, Ji L, Yang X. Interactive effect of serum uric acid and total bilirubin for micro-vascular disease of type 2 diabetes in China. J Diabetes Complications 2018; 32:1000-1005. [PMID: 30224234 DOI: 10.1016/j.jdiacomp.2018.09.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 04/22/2018] [Accepted: 09/02/2018] [Indexed: 01/08/2023]
Abstract
AIMS Serum uric acid (SUA) and bilirubin at high levels had both pro-oxidant and anti-oxidant properties. The present study aimed to examine additive interactions between SUA and total bilirubin (TBIL) for the risk of micro-vascular disease (MVD) in type 2 diabetes mellitus (T2DM). METHODS A cross-sectional survey of 6713 inpatients with T2DM was conducted in 81 tertiary care hospitals in China. MVD was defined as having either prior diabetic retinopathy (DR) or diabetic nephropathy (DN). Binary logistic regression was used to estimate odds ratios of SUA and TBIL for MVD. Additive interaction was measured by three indices, i.e., relative excess risk due to interaction, attributable proportion due to interaction and synergy index. RESULTS Among 6713 inpatients, 408 (6.08%) suffered from MVD. SUA ≥ 283 μmol/l (i.e., its media) was defined as high SUA, and TBIL <11.5 μmol/l (n = 2290 or 34.11%) was defined as low TBIL. Overall, 621 patients were exposed to co-presence of high SUA and low TBIL. The co-presence of both factors greatly increased the effect sizes from 1.03(95%CI: 0.72-1.46) (high SUA alone) or 0.70(95%CI: 0.48-1.05) (low TBIL alone) to 1.90 (95%CI: 1.26-2.87) for MVD in multivariable analysis. The additive interaction of both factors was significant for MVD in both univariable analysis and multivariable analysis. CONCLUSIONS Co-presence of both high SUA and low TBIL indentified a group of patients at a markedly increased risk of MVD in high-risk Chinese patients with T2DM.
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Affiliation(s)
- Yanfeng Ren
- Department of Health Statistics, School of Public Health and Management, Weifang Medical University, Shandong, China; Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Leili Gao
- Department of Endocrinology, Peking University People's Hospital, Beijing, China
| | - Xiaohui Guo
- Department of Endocrinology, Peking University First Hospital, Beijing, China
| | - Xiaoxu Huo
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Juming Lu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Jing Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Linong Ji
- Department of Endocrinology, Peking University People's Hospital, Beijing, China.
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China.
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13
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Farmer RE, Ford D, Forbes HJ, Chaturvedi N, Kaplan R, Smeeth L, Bhaskaran K. Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. Int J Epidemiol 2018; 46:728-744. [PMID: 28031313 PMCID: PMC5837266 DOI: 10.1093/ije/dyw275] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2016] [Indexed: 12/16/2022] Open
Abstract
Background: Existing observational studies provide conflicting evidence for the causal effect of metformin use on cancer risk in patients with type-2 diabetes, and there are concerns about bias affecting a number of studies. Methods: MEDLINE was used to identify observational studies investigating the association between metformin and overall or site-specific cancer in people with type-2 diabetes. A systematic data extraction and bias assessment was conducted, in which risk of eight bias domains (outcome, exposure, control selection, baseline confounding, time-dependent confounding, immortal time, missing data, censoring methods) were assessed against pre-defined criteria, and rated as unlikely, low, medium or high. Results: Of 46 studies identified, 21 assessed the effect of metformin on all cancer. Reported relative risks ranged from 0.23 to 1.22, with 12/21 reporting a statistically significant protective effect and none a harmful effect. The range of estimates was similar for site-specific cancers; 3/46 studies were rated as low or unlikely risk of bias in all domains. Two of these had results consistent with no effect of metformin; one observed a moderate protective effect overall, but presented further analyses that the authors concluded were inconsistent with causality. However, 28/46 studies were at risk from bias through exposure definition, 22 through insufficient baseline adjustment and 35 from possible time-dependent confounding. Conclusions: Observational studies on metformin and cancer varied in design, and the majority were at risk of a range of biases. The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk.
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Affiliation(s)
- Ruth E Farmer
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.,MRC Clinical Trials Unit at UCL, London, UK and
| | | | - Harriet J Forbes
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Nishi Chaturvedi
- Institute of Cardiovascular Science, University College London, London, UK
| | | | - Liam Smeeth
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Krishnan Bhaskaran
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
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14
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Ng IHY, Cheung KKT, Yau TTL, Chow E, Ozaki R, Chan JCN. Evolution of Diabetes Care in Hong Kong: From the Hong Kong Diabetes Register to JADE-PEARL Program to RAMP and PEP Program. Endocrinol Metab (Seoul) 2018; 33:17-32. [PMID: 29589385 PMCID: PMC5874192 DOI: 10.3803/enm.2018.33.1.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 12/14/2022] Open
Abstract
The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications, posing a major health burden to countries worldwide. Asians are commonly observed to have poorer β-cell function and greater insulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This "double phenotype" as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high risk of cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experience from Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technological advances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, and mortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoning health problem of diabetes at a societal level.
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Affiliation(s)
- Ivy H Y Ng
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong
| | - Kitty K T Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Tiffany T L Yau
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Elaine Chow
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Risa Ozaki
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
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15
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Chang SH, Luo S, O'Brian KK, Thomas TS, Colditz GA, Carlsson NP, Carson KR. Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study. LANCET HAEMATOLOGY 2017; 2:e30-6. [PMID: 26034780 DOI: 10.1016/s2352-3026(14)00037-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. METHODS We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. FINDINGS We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49–96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0·47, 95% CI 0·25–0·87). INTERPRETATION For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. FUNDING Barnes-Jewish Hospital Foundation, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society.
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16
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Gong S, Xu C, Wang L, Liu Y, Owusu D, Bailey BA, Li Y, Wang K. Genetic association analysis of polymorphisms in PSD3 gene with obesity, type 2 diabetes, and HDL cholesterol. Diabetes Res Clin Pract 2017; 126:105-114. [PMID: 28237857 DOI: 10.1016/j.diabres.2017.02.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 02/02/2017] [Indexed: 01/29/2023]
Abstract
BACKGROUND The pleckstrin and Sec7 domain-containing 3 (PSD3) gene has been linked to immune diseases. We examined whether the genetic variants within the PSD3 gene are associated with obesity, type 2 diabetes (T2D), and high-density lipoprotein (HDL) cholesterol level. METHODS Multiple logistic regression model and linear regression model were used to examine the associations of 259 single nucleotide polymorphisms (SNPs) within the PSD3 gene with obesity and T2D as binary traits, and HDL level as a continuous trait using the Marshfield data, respectively. A replication study of obesity was conducted using the Health Aging and Body Composition (Health ABC) sample. RESULTS 23SNPs were associated with obesity (p<0.05) in the Marshfield sample and rs4921966 revealed the strongest association (p=3.97×10-6). Of the 23SNPs, 20 were significantly associated with obesity in the meta-analysis of two samples (p<0.05). Furthermore, 6SNPs revealed associations with T2D in the Marshfield data (top SNP rs12156368 with p=3.05×10-3); while two SNPs (rs6983992 and rs7843239) were associated with both obesity and T2D (p=0.0188 and 0.023 for obesity and p=8.47×10-3 and 0.0128 for T2D, respectively). Furthermore, 11SNPs revealed associations with HDL level (top SNP rs13254772 with p=2.79×10-3) in the Marshfield data; meanwhile rs7009615 was associated with both T2D (p=0.038) and HDL level (p=4.44×10-3). In addition, haplotype analyses further supported the results of single SNP analysis. CONCLUSIONS Common variants in PSD3 were associated with obesity, T2D and HDL level. These findings add important new insights into the pathogenesis of obesity, T2D and HDL cholesterol.
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Affiliation(s)
- Shaoqing Gong
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA
| | - Chun Xu
- Department of Health and Biomedical Science, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Liang Wang
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA
| | - Ying Liu
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA
| | - Daniel Owusu
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA
| | - Beth A Bailey
- Department of Family Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Yujing Li
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Kesheng Wang
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN, USA.
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17
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McFadden N, Daniel B, Hoyt R, Snider D. Development of a Web-Based Registry to Support Diabetes Care in Free Medical Clinics. PERSPECTIVES IN HEALTH INFORMATION MANAGEMENT 2017; 14:1a. [PMID: 28566990 PMCID: PMC5430109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The United States has more than 1,000 free medical clinics. Because these clinics do not bill Medicare or Medicaid, they are not eligible for federal reimbursement for electronic health record (EHR) adoption. As a result, most do not have EHRs or electronic disease registries. A web-based diabetes registry was created with all open-source components for use in an urban free clinic to manage patients with type 2 diabetes and comorbidities. The registry was modeled after the Chronic Disease Electronic Management System and recommendations of the American Diabetes Association. The software was enhanced to include multiple other features, such as progress notes, so that it can function as a simple EHR. The configuration permits other free clinics to join securely, and the software can be shared.
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Affiliation(s)
- Norman McFadden
- Our Lady of the Angel St. Joseph Medical Clinic in Pensacola, FL
| | | | - Robert Hoyt
- College of Health at the University of West Florida in Pensacola, FL
| | - Dallas Snider
- Hal Marcus College of Science and Engineering at the University of West Florida in Pensacola, FL
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18
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Cheung KKT, Lau ESH, So WY, Ma RCW, Ozaki R, Kong APS, Chow FCC, Chan JCN, Luk AOY. Low testosterone and clinical outcomes in Chinese men with type 2 diabetes mellitus - Hong Kong Diabetes Registry. Diabetes Res Clin Pract 2017; 123:97-105. [PMID: 27997863 DOI: 10.1016/j.diabres.2016.11.012] [Citation(s) in RCA: 14] [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] [Received: 01/16/2016] [Revised: 11/13/2016] [Accepted: 11/16/2016] [Indexed: 01/23/2023]
Abstract
AIMS To assess the implications of low testosterone on cardiovascular risk factors, metabolic syndrome (MES) and clinical outcomes in Chinese men with Type 2 Diabetes (T2D). METHODS A prospective cohort study carried out in a university hospital involving a consecutive cohort of 1239 Chinese men with T2D and a median disease duration of 9years followed up for 4.8years. Clinical characteristics, frequency of MES, serum total testosterone and clinical events were analyzed. Multivariate logistic regression was performed to examine the independent association of low testosterone with MES after adjustment for confounding covariates. Cox proportional hazards regression analysis was used to derive hazard ratio for clinical outcomes. RESULTS More men with low testosterone had cardiovascular-renal disease and MES than those with normal testosterone. The adjusted odds ratio (OR) of low testosterone for MES was 2.63 (95% Confidence Interval [CI] 1.56-4.61). After a median follow-up of 4.8years, the hazard ratio (HR) of low testosterone was 2.22 (95% CI 1.23-4.01) for incident non-prostate cancer. In a multivariate Cox-regression model, the HRs were attenuated but remained significant with adjustment for MES and renal parameters. CONCLUSIONS Chinese men with low testosterone had high prevalence of cardiovascular disease and MES with high incidence non-prostate cancer.
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Affiliation(s)
- Kitty Kit-Ting Cheung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
| | - Eric Siu-Him Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Wing-Yee So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Ronald Ching-Wan Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Risa Ozaki
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Francis Chun-Chung Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Juliana Chung-Ngor Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
| | - Andrea On-Yan Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
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19
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Interactive effect of serum uric acid and total bilirubin for cardiovascular disease in Chinese patients with type 2 diabetes. Sci Rep 2016; 6:36437. [PMID: 27805038 PMCID: PMC5090353 DOI: 10.1038/srep36437] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 10/17/2016] [Indexed: 01/16/2023] Open
Abstract
Serum uric acid (SUA) at high levels and bilirubin at low levels were potent antioxidant but it was uncertain that whether SUA and total bilirubin (TBIL) had additive interaction for the risk of CVD in type 2 diabetes mellitus (T2DM). We conducted a cross-sectional survey of 6713 inpatients with T2DM and admitted to 81 tertiary care hospitals. CVD was defined as having either prior coronary heart disease or stroke or peripheral arterial disease. Binary logistic regression was used to estimate odds ratios of SUA and TBIL for CVD. The effect size of additive interaction was estimated by three measures, i.e., relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Among 6713 patients with T2DM, 561 (8.36%) suffered from CVD. Using ≥283 umol/L (median) to define high SUA and <11.5 umol/L (n = 2290 or 34.11%) to define low TBIL, copresence of both factors (n = 621 or 9.25%) was associated with 5.18-fold (95% CI, 4.00–6.72) risk of CVD with significant additive interactions in multivariable analysis as compared to absence of both risk factors. The copresence of both high SUA and low TBIL was associated with a large increased risk of CVD in high-risk Chinese patients with type 2 diabetes.
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Ren Y, Ji L, Mu Y, Hong T, Ji Q, Guo L, Huang Q, Yang X. Uric acid, renal function and risk of hypoglycaemia in Chinese type 2 diabetes patients. Diabetes Metab Res Rev 2016; 32:875-882. [PMID: 27093645 DOI: 10.1002/dmrr.2809] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 02/26/2016] [Accepted: 04/08/2016] [Indexed: 11/06/2022]
Abstract
BACKGROUND This study aimed to explore independent associations between serum uric acid and hypoglycaemia, and whether mildly increased serum uric acid exacerbated the association between mild decline in estimated glomerular filtration rate (eGFR) and hypoglycaemia. METHODS A cross-sectional survey of 6713 inpatients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 and admitted to 81 tertiary care hospitals in China was conducted. Self-reported asymptotic hypoglycaemia with plasma glucose ≤3.9 mmol/L, hypoglycaemia episodes with symptoms in 1 month or hypoglycaemia that needed assistance from other people in 3 months before hospitalization was used to define hypoglycaemia. Binary logistic regression was used to estimate odds ratios of serum uric acid for hypoglycaemia. Three measures, that is, relative excess risk due to interaction (RERI), attributable proportion due to interaction and synergy index (S) were used to estimate the effect of mildly decreased eGFR on the association of serum uric acid with hypoglycaemia. RESULTS Serum uric acid was associated with hypoglycaemia in an ordinal manner (P for trend <0.01) with an odds ratio of top quartile versus the lowest quartile up to 3.03 (95% confidence interval: 2.13-4.32). The odds ratio of serum uric acid levels ≥ versus <283 µmol/L (i.e. the median) was 1.98 (95% confidence interval:1.58-2.48). Serum uric acid levels ≥ versus <283 µmol/L greatly enhanced the association between mild decline in eGFR (eGFR < 90 mL/min/1.73 m2 ) and hypoglycaemia from 0.94 (0.36-2.43) to 3.90 (2.55-5.95), with a significant additive interaction (P < 0.05 for RERI, AP and S). CONCLUSIONS Mildly increased serum uric acid was associated with increased risk of hypoglycaemia and enhanced the association between mildly decreased eGFR and hypoglycaemia in type 2 diabetes. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Yanfeng Ren
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Linong Ji
- Department of Endocrinology, Peking University People's Hospital, Beijing, China
| | - Yiming Mu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Tianpei Hong
- Department of Endocrinology, Peking University Third Hospital, Beijing, China.
| | - Qiuhe Ji
- Department of Endocrinology, The Fourth Military Medical University Xi Jing Hospital, Xi'an, China
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, Beijing, China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital of Shanghai, Shanghai, China
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China. ,
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Hypoglycaemia, Abnormal Lipids, and Cardiovascular Disease among Chinese with Type 2 Diabetes. BIOMED RESEARCH INTERNATIONAL 2015; 2015:862896. [PMID: 26504840 PMCID: PMC4609392 DOI: 10.1155/2015/862896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/17/2015] [Accepted: 03/19/2015] [Indexed: 12/22/2022]
Abstract
We recruited a group of 6713 consecutive Chinese patients with T2D but normal renal and liver function who were admitted to one of 81 top tertiary care hospitals in China. Mild hypoglycaemia was defined as having symptomatic hypoglycaemia in one month before hospitalization. Severe hypoglycaemia was defined as having hypoglycaemia that needed assistance from other people in three months before hospitalization. Prior cardiovascular disease (CVD) was defined as having coronary heart disease, stroke, or peripheral arterial disease. Of 6713 patients, 80 and 304 had severe and mild hypoglycaemia episodes, respectively, and 561 had CVD. Patients with severe and mild hypoglycaemia episodes were more likely to have prior CVD (32.5% versus 16.5% versus 7.7%, P < 0.0001). Both mild and severe hypoglycaemia were associated with increased risk of CVD (adjusted odds ratios (ORs): 2.64, 95% CI: 1.85–3.76 for mild hypoglycaemia; 6.59, 95% CI: 3.79–11.45 for sever hypoglycaemia) than those patients free of hypoglycaemia. Further adjustment for lipid profile did not change these two ORs. In the same way, the ORs of lipid profile for CVD were similar before and after adjustment for hypoglycaemia. We concluded that hypoglycaemia and lipid profile were independently associated with increased risk of CVD.
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Yang XL, Huo XX, Chan JCN. Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes. World J Methodol 2015; 5:122-126. [PMID: 26413484 PMCID: PMC4572024 DOI: 10.5662/wjm.v5.i3.122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 06/12/2015] [Accepted: 08/14/2015] [Indexed: 02/06/2023] Open
Abstract
There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.
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Abstract
On the basis of data obtained from a prospective cohort of Chinese patients with type 2 diabetes mellitus (T2DM), we discuss cancer subphenotypes (risk factors) in patients with T2DM, which can lead to drug-cancer subphenotype interactions. These subphenotypes include HDL cholesterol levels <1.0 mmol/l, co-occurrence of LDL cholesterol levels <2.8 mmol/l and triglyceride levels <1.7 mmol/l, and co-occurrence of LDL cholesterol levels <2.8 mmol/l and albuminuria. The increased risk of cancer associated with low levels of HDL cholesterol, low LDL cholesterol levels plus low triglyceride levels, and low levels of LDL cholesterol plus albuminuria can be reduced by treatment with metformin, renin-angiotensin system (RAS) inhibitors and statins, respectively. Mechanistic studies support the hypothesis that dysregulation of the 5'-AMP-activated protein kinase pathway and crosstalk between the RAS and insulin-like growth factor 1-cholesterol pathways create a cancer-promoting milieu in patients with T2DM. These findings highlight that in Chinese individuals, multiple pathways are implicated in the link between T2DM and cancer, which can generate multiple subphenotypes as well as drug-subphenotype interactions.
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Affiliation(s)
- Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Heung M Lee
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR, China
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR, China
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Faillie JL, Suissa S. Le biais de temps immortel dans les études pharmacoépidémiologiques : définition, solutions et exemples. Therapie 2015; 70:259-63. [DOI: 10.2515/therapie/2014207] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 09/22/2014] [Indexed: 11/20/2022]
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Zhao W, Guan J, Horswell R, Li W, Wang Y, Wu X, Hu G. HDL cholesterol and cancer risk among patients with type 2 diabetes. Diabetes Care 2014; 37:3196-203. [PMID: 25216507 PMCID: PMC4237978 DOI: 10.2337/dc14-0523] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients. RESEARCH DESIGN AND METHODS We performed a retrospective cohort study of 14,169 men and 23,176 women with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of various levels of HDL cholesterol (HDL-C) with cancer risk. RESULTS During a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30-39.9, 40-49.9, 50-59.9, 60-69.9, 70-79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (Ptrend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (Ptrend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up. CONCLUSIONS The study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation.
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Affiliation(s)
- Wenhui Zhao
- Pennington Biomedical Research Center, Baton Rouge, LA Department of Endocrinology, China Japan Friendship Hospital, Beijing, China
| | - Jing Guan
- Pennington Biomedical Research Center, Baton Rouge, LA Beijing University of Traditional Chinese Medicine, Beijing, China
| | | | - Weiqin Li
- Pennington Biomedical Research Center, Baton Rouge, LA Tianjin Women's and Children's Health Center, Tianjin, China
| | - Yujie Wang
- Pennington Biomedical Research Center, Baton Rouge, LA
| | - Xiaocheng Wu
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Gang Hu
- Pennington Biomedical Research Center, Baton Rouge, LA
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Abstract
AIMS This review is aimed at highlighting the potential mitogenic/tumour growth-promoting or antimitogenic/tumour growth-inhibiting effects of the main antihyperglycaemic drug classes. METHODS We review and discuss the most current studies evaluating the association between antidiabetic medications used in clinical practice and malignancies as described so far. RESULTS Metformin seems to be the only antidiabetic drug to exert protective effects both on monotherapy and also when combined with other oral antidiabetic drugs or insulins in several site-specific cancers. In contrast, several other drug classes may increase cancer risk. Some reason for concern remains regarding sulphonylureas and also the incretin-based therapies regarding pancreas and thyroid cancers and the sodium glucose cotransporter-2 inhibitors as well as pioglitazone regarding bladder cancer. The majority of meta-analyses suggest that there is no evidence for a causal relationship between insulin glargine and elevated cancer risk, although the studies have been controversially discussed. For α-glucosidase inhibitors and glinides, neutral or only few data upon cancer risk exist. CONCLUSION Although the molecular mechanisms are not fully understood, a potential risk of mitogenicity and tumour growth promotion cannot be excluded in case of several antidiabetic drug classes. However, more large-scale, randomized, well-designed clinical studies with especially long follow-up time periods are needed to get reliable answers to these safety issues.
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Affiliation(s)
- Stefan Z Lutz
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Harald Staiger
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany Division of Nutritional and Preventive Medicine, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany German Centre for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
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Yang X, Chan JC. Metformin and the risk of cancer in type 2 diabetes: methodological challenges and perspectives. ANNALS OF TRANSLATIONAL MEDICINE 2014; 2:52. [PMID: 25333027 DOI: 10.3978/j.issn.2305-5839.2014.06.07] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 06/10/2014] [Indexed: 12/22/2022]
Affiliation(s)
- Xilin Yang
- 1 Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China ; 2 Department of Medicine and Therapeutics, 3 Hong Kong Institute of Diabetes and Obesity, 4 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Juliana Cn Chan
- 1 Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China ; 2 Department of Medicine and Therapeutics, 3 Hong Kong Institute of Diabetes and Obesity, 4 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
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Yang X, Ma RCW, So WY, Wang Y, Kong APS, Ozaki R, Xu G, Chan JCN. Renin angiotensin system inhibitors may attenuate low LDL cholesterol-related cancer risk in type 2 diabetes. Diabetes Metab Res Rev 2014; 30:415-23. [PMID: 24677790 DOI: 10.1002/dmrr.2504] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 01/31/2013] [Accepted: 02/23/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND In type 2 diabetes (T2D), copresence of low-density lipoprotein cholesterol (LDL-C) < 2.8 mmol/L with triglyceride < 1.7 mmol/L or with albuminuria synergistically increased cancer risk. We tested whether use of renin angiotensin system inhibitors attenuated the increased cancer risk associated with these two risk subphenotypes. METHODS A prospective cohort of 4307 patients with T2D enrolled from December 1996 to January 2005 was analysed using a new user cohort design. Cox model analysis was used to obtain hazard ratios and 95% confidence intervals. The study measured additive interactions between nonuse of renin angiotensin system inhibitors and low LDL-C plus low triglyceride or albuminuria for the risk of cancer. A positive interaction suggests a specific drug effect on the low LDL-C-related cancer risk. RESULTS During 18 769 person years of follow-up (median follow-up years: 4.44), 4.48% (n = 193) of patients developed cancer. Use of renin angiotensin system inhibitors was associated with reduced cancer risk among patients with copresence of low LDL-C plus low triglyceride or low LDL-C plus albuminuria but not in patients without these subphenotypes. In multivariable analysis, renin angiotensin system inhibitor usage attenuated the hazard ratio of copresence of low LDL-C plus low triglyceride versus lack of this subphenotype for cancer from 2.08 (95% CI: 1.25-3.47) to 1.13 (0.61-2.11) with significant additive interaction (p = 0.0225). Similarly, RAS inhibitor usage attenuated the hazard ratio of copresence of low LDL-C plus albuminuria versus lack of this subphenotype for cancer from 1.99 (95% CI: 1.12-3.56) to 0.82 (0.43-1.54) with significant additive interaction (p = 0.0009). CONCLUSION In T2D, renin angiotensin system inhibitor usage may specifically attenuate the low LDL-C-related cancer risk.
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Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Breast Cancer Res Treat 2014; 148:81-90. [PMID: 25253174 PMCID: PMC4196136 DOI: 10.1007/s10549-014-3141-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 09/17/2014] [Indexed: 12/16/2022]
Abstract
Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
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Affiliation(s)
- Sara Gandini
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Matteo Puntoni
- Clinical Trials Office, Office of the Scientific Director, E.O. Ospedali Galliera, Genoa, Italy
| | - Brandy M Heckman-Stoddard
- Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Barbara K Dunn
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Leslie Ford
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Andrea DeCensi
- Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy
| | - Eva Szabo
- Lung and Upper Aerodigestive Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
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Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila) 2014; 7:867-85. [PMID: 24985407 DOI: 10.1158/1940-6207.capr-13-0424] [Citation(s) in RCA: 317] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52-0.90], although between-study heterogeneity was considerable (I(2) = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54-0.81; I(2) = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70-0.96 with I(2) = 76% and SRR, 0.90; 95% CI, 0.89-0.91 with I(2) = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites.
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Affiliation(s)
- Sara Gandini
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Matteo Puntoni
- Clinical Trials Office, Office of the Scientific Director, E.O. Ospedali Galliera, Genoa, Italy
| | - Brandy M Heckman-Stoddard
- Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Barbara K Dunn
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Leslie Ford
- Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Andrea DeCensi
- Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy
| | - Eva Szabo
- Lung and Upper Aerodigestive Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
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Kong APS, Yang X, So WY, Luk A, Ma RCW, Ozaki R, Cheung KKT, Lee HM, Yu L, Xu G, Chow CC, Chan JCN. Additive effects of blood glucose lowering drugs, statins and renin-angiotensin system blockers on all-site cancer risk in patients with type 2 diabetes. BMC Med 2014; 12:76. [PMID: 24886453 PMCID: PMC4046510 DOI: 10.1186/1741-7015-12-76] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/25/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hyperglycemia is associated with increased risk of all-site cancer that may be mediated through activation of the renin-angiotensin-system (RAS) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMGCR) pathways. We examined the joint associations of optimal glycemic control (HbA1c <7%), RAS inhibitors and HMGCR inhibitors on cancer incidence in patients with type 2 diabetes. METHODS Patients with type 2 diabetes, with or without a history of cancer or prior exposure to RAS or HMGCR inhibitors at baseline were observed between 1996 and 2005. All patients underwent a comprehensive assessment at baseline and were followed until the censored date at 2005 or their death. RESULTS After a median follow-up period of 4.91 years (interquartile range, 2.81 to 6.98), 271 out of 6,103 patients developed all-site cancer. At baseline, patients with incident cancers were older, had longer disease duration of diabetes, higher alcohol and tobacco use, and higher systolic blood pressure and albuminuria, but lower triglyceride levels and estimated glomerular filtration rate (P <0.05). Patients who developed cancers during follow-up were less likely to have started using statins (22.5% versus 38.6%, P <0.001), fibrates (5.9% versus 10.2%, P = 0.02), metformin (63.8% versus 74.5%, P <0.001) or thiazolidinedione (0.7% versus 6.8%, P <0.001) than those who remained cancer-free. After adjusting for co-variables, new treatment with metformin (hazard ratio: 0.39; 95% confidence interval: 0.25, 0.61; P <0.001), thiazolidinedione (0.18; 0.04, 0.72; P = 0.015), sulphonylurea (0.44; 0.27, 0.73; P = 0.014), insulin (0.58; 0.38, 0.89; P = 0.01), statins (0.47; 0.31, 0.70; P <0.001) and RAS inhibitors (0.55; 0.39, 0.78; P <0.001) were associated with reduced cancer risk. Patients with all three risk factors of HbA1c ≥7%, non-use of RAS inhibitors and non-use of statins had four-fold adjusted higher risk of cancer than those without any risk factors (incidence per 1,000-person-years for no risk factors: 3.40 (0.07, 6.72); one risk factor: 6.34 (4.19, 8.50); two risk factors: 8.40 (6.60, 10.20); three risk factors: 13.08 (9.82, 16.34); P <0.001). CONCLUSIONS Hyperglycemia may promote cancer growth that can be attenuated by optimal glycemic control and inhibition of the RAS and HMGCR pathways.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, China.
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Kong APS, Yang X, Luk A, Ma RCW, So WY, Ozaki R, Ting R, Cheung K, Ho CS, Chan MHM, Chow CC, Chan JCN. Severe hypoglycemia identifies vulnerable patients with type 2 diabetes at risk for premature death and all-site cancer: the Hong Kong diabetes registry. Diabetes Care 2014; 37:1024-31. [PMID: 24513587 DOI: 10.2337/dc13-2507] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We examined the associations of clinical profiles in type 2 diabetic patients who developed severe hypoglycemia and their clinical outcomes, including death and all-site cancer. RESEARCH DESIGN AND METHODS A consecutive cohort of 8,767 type 2 diabetic patients with and without severe hypoglycemia in the 12 months before enrollment were recruited between 1995 and 2007, with follow-up until 2009. Severe hypoglycemia was defined by ICD-9 codes as hospitalizations resulting from hypoglycemia. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% CIs of clinical factors collected at enrollment for severe hypoglycemia. RESULTS In this cohort, mean age was 57.4 (SD 13.2) years and median disease duration of diabetes was 5 (interquartile range [IQR] 1-11) years. During a median follow-up of 6.71 (IQR 3.47-10.38) years, 235 patients had severe hypoglycemia (incidence 3.96 [95% CI 3.45-4.46] per 1,000 patient-years). At enrollment, patients with and without severe hypoglycemia had similar cancer rates. During follow-up, patients with severe hypoglycemia had a higher incidence of all-site cancer (13.4 vs. 6.4%, P < 0.0001) and mortality (32.8 vs. 11.2%, P < 0.0001) than those without severe hypoglycemia. After adjusting for confounders, old age, low BMI, high glycated hemoglobin, low triglyceride (TG), low LDL cholesterol (LDL-C), albuminuria, and chronic kidney disease were independent predictors for severe hypoglycemia. CONCLUSIONS In type 2 diabetes, severe hypoglycemia is associated with advanced age, renal dysfunction, poor glycemic control, and cancer subphenotypes (low BMI, low LDL-C, and low TG).
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Yang X, Kong APS, Luk AOY, Ozaki R, Ko GTC, Ma RCW, Chan JCN, So WY. Validation of Methods to Control for Immortal Time Bias in a Pharmacoepidemiologic Analysis of Renin^|^ndash;Angiotensin System Inhibitors in Type 2 Diabetes. J Epidemiol 2014; 24:267-73. [PMID: 24747198 PMCID: PMC4074630 DOI: 10.2188/jea.je20130164] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin–angiotensin system (RAS) inhibitors as the reference cardioprotective drug. Methods We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs. Results During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68–1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs. Conclusions In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes.
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Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Alice PS Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Andrea OY Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Risa Ozaki
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Gary TC Ko
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Ronald CW Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Juliana CN Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Wing Yee So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
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Vílchez JA, Martínez-Ruiz A, Sancho-Rodríguez N, Martínez-Hernández P, Noguera-Velasco JA. The real role of prediagnostic high-density lipoprotein cholesterol and the cancer risk: a concise review. Eur J Clin Invest 2014; 44:103-14. [PMID: 24111547 DOI: 10.1111/eci.12185] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 09/24/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND In several observational and clinical studies, the association between serum cholesterol levels and cancer is still unsettled although serum total cholesterol has been associated with increased mortality from cancer. Moreover, the importance of abnormal levels of serum lipid components as the main features of dyslipidemia and the risk of individual cancers is unclear. The prevalence of dyslipidemia is increasing worldwide but, the precise aetiology of the link between risk of cancer and the behaviour of lipid profile, prior diagnosis, has yet to be determinated. Low levels of high-density lipoprotein cholesterol (HDL) at baseline of many of the studies analyzed has to be taken into account, and continued low levels of HDL without explanation should be considered by clinicians. AIMS The main aim of this review was to undertake the assessment of the most recent studies implying the lipid profile and cancer risk, and focused on low HDL levels at baseline and follow up, and also analyzing this behaviour on the different cancer types. MATERIAL AND METHODS A literature search was performed to identify publications. The most recent prospective and case-control studies with multivariate Cox models were analyzed and also were considered some recent meta-analyses. RESULTS AND CONCLUSIONS The findings exposed in this review suggest that the association with low HDL levels at baseline of different studies of cancer risk is shared among many types of cancer, and it is mainly linked to obesity and inflammation, suggesting a common pathway.
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Affiliation(s)
- Juan A Vílchez
- Department of Clinical Analysis, University Hospital Virgen de la Arrixaca, Murcia, Spain; Department of Cardiology, University Hospital Virgen de la Arrixaca, Murcia, Spain
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Takahashi K, Ohkuchi A, Suzuki H, Usui R, Kuwata T, Shirasuna K, Matsubara S, Suzuki M. Biophysical interaction between blood pressure and uterine artery Doppler for the occurrence of early-onset preeclampsia: A prospective cohort study. Pregnancy Hypertens 2013; 3:270-7. [DOI: 10.1016/j.preghy.2013.07.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/25/2013] [Indexed: 02/04/2023]
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Abrahamowicz M, Beauchamp ME, Fournier P, Dumont A. Evidence of subgroup-specific treatment effect in the absence of an overall effect: is there really a contradiction? Pharmacoepidemiol Drug Saf 2013; 22:1178-88. [PMID: 23939947 DOI: 10.1002/pds.3485] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 05/29/2013] [Accepted: 06/24/2013] [Indexed: 11/12/2022]
Abstract
PURPOSE Interaction and subgroup analyses remain controversial topics in epidemiology. A recent theoretical paper suggested that a combination of no overall treatment-outcome association and treatment effect limited to a single subgroup would imply a clinically implausible interaction, with opposite treatment effects in the two subgroups. However, this argument was based entirely on point estimates and ignored sampling error and statistical inference. METHODS We simulated hypothetical studies in which treatment truly affected the outcome in only one subgroup, with no effect in the other subgroup. We generated 1000 random samples for three study designs (small clinical study, case-control, and large cohort), and different values of total sample size (N), relative size of the affected subgroup, and treatment effect. We estimated the frequency of significant results for tests of overall and subgroup-specific treatment effects, and treatment-by-subgroup interaction. RESULTS Combination of statistically non-significant overall treatment effect and significant treatment-by-subgroup interaction occurred frequently, especially if the affected subgroup was proportionally smaller, even in studies with high power to detect the overall effect (e.g. in 37.1% of samples with N = 20 000, with 600 outcomes, and an effect (odds ratio of 1.5) limited to 30% of subjects). Furthermore, in most samples with a significant interaction, subgroup analyses correctly indicated that the significant effect was limited to one subgroup. CONCLUSION In studies where the treatment truly affects the risks in only one subgroup, a non-significant overall effect will often coincide with a statistically significant treatment-by-subgroup interaction. Thus, a non-significant overall effect should not prevent testing plausible interactions.
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Affiliation(s)
- Michal Abrahamowicz
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada; Division of Clinical Epidemiology, McGill University Health Centre, Montreal, QC, Canada
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Franciosi M, Lucisano G, Lapice E, Strippoli GFM, Pellegrini F, Nicolucci A. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One 2013; 8:e71583. [PMID: 23936520 PMCID: PMC3732236 DOI: 10.1371/journal.pone.0071583] [Citation(s) in RCA: 336] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 07/01/2013] [Indexed: 12/20/2022] Open
Abstract
Aims/Hypothesis Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association between metformin and risk of cancer and cancer mortality in patients with diabetes. Methods Data source: MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers. Results Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death [6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80], all malignancies [18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88], liver [8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60] colorectal [12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74–0.92], pancreas [9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36–0.86], stomach [2 studies, 100701 patients, OR:0.83, 95%CI: 0.76–0.91], and esophagus cancer [2 studies, 100694 patients, OR:0.90, 95%CI: 0.83–0.98]. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma. Conclusions/Interpretation Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted.
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Affiliation(s)
- Monica Franciosi
- Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro (CH), Chieti, Italy.
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Thakkar B, Aronis KN, Vamvini MT, Shields K, Mantzoros CS. Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metabolism 2013; 62:922-34. [PMID: 23419783 DOI: 10.1016/j.metabol.2013.01.014] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 01/12/2013] [Accepted: 01/14/2013] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Accumulating evidence suggests that patients with type 2 diabetes mellitus (T2DM) and hyperinsulinemia are at increased risk for developing malignancies. It remains to be fully elucidated whether use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affect cancer incidence in subjects with T2DM. MATERIAL & METHODS We performed a meta-analysis using PubMed, of randomized control trials (RCTs), cohorts, and case-control studies published through July 2012 that assess effects of metformin and/or sulfonylurea sulfonylureas on cancer risk at any site, in subjects with T2DM. Fixed and random effects meta-analysis models were used, and the effect size was summarized as relative risk (RR) for RCTs/cohorts and as odds ratio (OR) for the case-control studies. RESULTS Analysis of 24 metformin studies in subjects with T2DM showed that metformin use is associated with reduced risk for the development of cancer, in both cohort (RR=0.70 [95% CI=0.67-0.73]) and case-control studies (OR=0.90 [95% CI=0.84-0.98]), but this finding was not supported by RCTs (RR=1.01[95% CI=0.81-1.26]). Data from 18 sulfonylurea studies in subjects with T2DM showed that sulfonylurea use is associated with an increase in all-cancer risk, in cohort studies (RR=1.55 [95% CI=1.48 -1.63]), though data from RCTs (RR=1.17 [95% CI=0.95-1.45]) and case-control studies (OR=1.02 [95% CI=0.93-1.13]) failed to demonstrate a statistically significant effect. CONCLUSIONS This analysis using pooled primary data demonstrates that metformin use reduces, while sulfonylurea use may be associated with an increased cancer risk in subjects with T2DM. These findings need to be confirmed in large-scale RCTs before they are translated into clinical practice.
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Affiliation(s)
- Bindiya Thakkar
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA.
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Yang X, Chan JC. Comment on: Suissa and Azoulay. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 2012;35:2665-2673. Diabetes Care 2013; 36:e87. [PMID: 23704695 PMCID: PMC3661801 DOI: 10.2337/dc12-2561] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Xilin Yang
- Department of Epidemiology and Biostatistics School of Public Health, Tianjin Medical University, Tianjin, China
| | - Juliana C.N. Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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Yang X, Wang Y, Luk AOY, So WY, Ma RCW, Kong APS, Xu G, Chan JCN. Enhancers and attenuators of risk associations of chronic hepatitis B virus infection with hepatocellular carcinoma in type 2 diabetes. Endocr Relat Cancer 2013; 20:161-71. [PMID: 23250907 DOI: 10.1530/erc-12-0290] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection promotes hepatocellular carcinoma (HCC) risk. In type 2 diabetes (T2D), use of insulin and statins was associated with reduced cancer risk while co-presence of low LDL cholesterol (LDLC <2.8 mmol/l) plus low triglyceride (TG; <1.7 mmol/l) increased cancer risk. There is experimental evidence showing that insulin insufficiency might promote HCC. In this study, we examined whether this lipid subphenotype and use of insulin or statins might modify the promoting effect of chronic HBV infection (indicated by the presence of hepatitis B surface antigen) on HCC. We analyzed data of 1319 T2D patients enrolled into the Hong Kong Diabetes Registry from December 1996 to January 2005 and followed up to 2005. Additive interaction was estimated using relative excess risk due to interaction and attributable proportion due to interaction. During 5782 person-years of follow-up, 1.74% (n=23) of patients developed HCC (incidence, 3.98; 95% confidence interval, 2.36-5.60/1000 person-years). HbA1c ≥7.0% and the lipid phenotype (LDLC <2.8 mmol/l plus TG <1.7 mmol/l) increased the hazard ratios (HRs) of chronic HBV infection for HCC from 3.74 to 74.96 and from 11.01 to 89.82 respectively with significant interactions. Use of insulin or statins decreased the HRs from 37.51 to 5.87 and from 64.94 to 16.99 respectively with significant interactions (all P values <0.05). These findings support our hypothesis that hyperglycemia and co-presence of low LDLC plus low TG might enhance, while insulin or statin usage might attenuate the promoting effect of chronic HBV infection on HCC in T2D.
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Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
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Yang X, So WY, Ma RCW, Kong APS, Lee HM, Xu G, Ozaki R, Chan JCN. Synergistic effects of low LDL cholesterol with other factors for the risk of cancer in type 2 diabetes: the Hong Kong Diabetes Registry. Acta Diabetol 2012; 49 Suppl 1:S185-93. [PMID: 22722949 DOI: 10.1007/s00592-012-0409-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 05/29/2012] [Indexed: 12/23/2022]
Abstract
We have reported associations of cancer with low triglyceride and high high-density lipoprotein cholesterol (HDL-C) as well as co-presence of low low-density lipoprotein cholesterol (LDL-C) and albuminuria in type 2 diabetes (T2D). This analysis aims to test (1) whether low LDL-C and low triglyceride have synergistic effects to increase cancer risk in T2D and (2) whether high HDL-C enhances the effect of co-presence of low LDL-C and albuminuria on cancer risk. A prospective cohort of patients with T2D, established within the Prince of Wales Hospital, was used in the analysis. A total of 3,476 T2D patients in Hong Kong enrolled between 1996 and 2005, free of cancer at enrolment and not using statins or fibrates within 2.5 years before enrolment and during follow-up, were followed until 2005. The study measured additive interactions of low LDL-C with other factors for cancer using relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP). A statistically significant RERI > 0 or AP > 0 indicates additive interaction. During 5.11 years of follow-up, 199 patients developed cancer. Co-presence of triglyceride <1.70 mmol/L and LDL-C < 2.80 mmol/L was associated with increased cancer risk (multivariable hazard ratio [HR]:2.13, P = 0.0008) with significant interaction. Co-presence of HDL-C ≥ 1.30 mmol/L and LDL-C < 2.80 mmol/L plus albuminuria was also associated with increased cancer risk (HR: 3.84, P < 0.0001) with significant interaction. In T2D, low triglyceride may potentiate cancer risk associated with low LDL-C while high HDL-C enhances the synergistic effect of low LDL-C with albuminuria towards increased cancer risk.
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Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.
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Abstract
OBJECTIVE Time-related biases in observational studies of drug effects have been described extensively in different therapeutic areas but less so in diabetes. Immortal time bias, time-window bias, and time-lag bias all tend to greatly exaggerate the benefits observed with a drug. RESEARCH DESIGN AND METHODS These time-related biases are described and shown to be prominent in observational studies that have associated metformin with impressive reductions in the incidence of and mortality from cancer. As a consequence, metformin received much attention as a potential anticancer agent; these observational studies sparked the conduction of randomized, controlled trials of metformin as cancer treatment. However, the spectacular effects reported in these studies are compatible with time-related biases. RESULTS We found that 13 observational studies suffered from immortal time bias; 9 studies had not considered time-window bias, whereas other studies did not consider inherent time-lagging issues when comparing the first-line treatment metformin with second- or third-line treatments. These studies, subject to time-related biases that are avoidable with proper study design and data analysis, led to illusory extraordinarily significant effects, with reductions in cancer risk with metformin ranging from 20 to 94%. Three studies that avoided these biases reported no effect of metformin use on cancer incidence. CONCLUSIONS Although observational studies are important to better understand the effects of drugs, their proper design and analysis is essential to avoid major time-related biases. With respect to metformin, the scientific evidence of its potential beneficial effects on cancer would need to be reassessed critically before embarking on further long and expensive trials.
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Affiliation(s)
- Samy Suissa
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada.
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Younis NN, Durrington PN. HDL functionality in diabetes mellitus: potential importance of glycation. ACTA ACUST UNITED AC 2012. [DOI: 10.2217/clp.12.60] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Affiliation(s)
- Alice P S Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, SAR, China.
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Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat 2012; 135:639-46. [PMID: 22847511 DOI: 10.1007/s10549-012-2170-x] [Citation(s) in RCA: 156] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 07/13/2012] [Indexed: 12/29/2022]
Abstract
Observational studies have suggested that metformin decreases the incidence of several common cancers. However, findings regarding breast cancer have been mixed. In order to explore this issue, a systematic literature review and meta-analysis were performed with a focus on potential biases. We conducted a comprehensive literature search for all pertinent studies addressing metformin use and breast cancer risk by searching PubMed, Cochrane Library, and Scopus (which includes Embase, ISI Web of Science) using the Mesh terms: "metformin" or "biguanides" or "diabetes mellitus, type 2/therapy" and "cancer" or "neoplasms." When multiple hazard ratios (HR) or odds ratio (OR) were reported, the most adjusted estimate was used in the base-case analysis. We pooled the adjusted HR and performed sensitivity analyses on duration of metformin use (> or ≤3 years use), study quality (assessed using the GRADE system), and initial observation year of the cohort (before vs after 1997). From a total of 443 citations, 18 full-text articles were considered, and seven independent studies were included. All were observational (four cohort and three case control). Our combined OR of all seven studies was 0.83 (0.71-0.97). Stronger associations were found when analyses were limited to studies estimating the impact of longer metformin use (OR = 0.75. 95 % CI 0.62, 0.91) or among studies that began observing their cohort before 1997 (OR = 0.68. 95 % CI 0.55-0.084). Stratification according to study quality did not affect the combined OR but higher quality studies had smaller CI and achieved statistical significance. Interpretation is limited by the observational nature of reports and different comparison groups. Our analyses support a protective effect of metformin on breast cancer risk among postmenopausal women with diabetes. Clinical trials are needed for definitive determination of the role of metformin in breast cancer risk reduction.
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Affiliation(s)
- Nananda F Col
- College of Osteopathic Medicine, University of New England, Biddeford, ME, USA.
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Yang X, So WY, Ma RCW, Yu LWL, Kong APS, Lee HM, Xu G, Ozaki R, Ko GTC, Chan JCN. Use of thiazolidinedione and cancer risk in Type 2 diabetes: the Hong Kong diabetes registry. Diabetes Res Clin Pract 2012; 97:e13-7. [PMID: 22502769 DOI: 10.1016/j.diabres.2012.03.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 03/04/2012] [Accepted: 03/13/2012] [Indexed: 11/17/2022]
Abstract
We examined possible anticancer effects of thiazolidinediones (TZDs) in 6074 Chinese with Type 2 diabetes free of cancer at enrolment. During a median follow-up of 4.93 years, 270 patients developed cancer. Use of TZDs was associated with reduced risk of cancer in a dose-response manner in multivariable analysis.
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Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
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Yang X, So WY, Ma RCW, Kong APS, Xu G, Chan JCN. Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry. Diabetes Metab Res Rev 2012; 28:379-87. [PMID: 22318884 DOI: 10.1002/dmrr.2287] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Diabetes is a disorder of energy metabolism associated with increased cancer risk, but the underlying mechanism is poorly understood. In a prospective cohort of patients enrolled in the Hong Kong Diabetes Registry, we explored risk factors for cancer including drug usage in type 2 diabetes. In a series of published papers, we reported a linear risk association of cancer with glycated haemoglobin with a threshold at 6.0%-6.5% and non-linear risk associations of body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and white blood cell (WBC) count in V-shaped or A-shaped manners. Detailed pharmacoepidemiological analysis revealed markedly attenuated cancer risk in patients treated with insulin and oral anti-diabetic drugs compared with non-users of these drugs. We further observed significant drug-subphenotype interactions with attenuated cancer risk in metformin users with low high-density lipoprotein cholesterol, renin-angiotensin system (RAS) inhibitor users with high WBC count and statin users with co-presence of low low-density lipoprotein cholesterol plus albuminuria or low triglyceride. These novel observations corroborate with experimental findings of possible consequences of hyperglycaemia on dysregulation of cholesterol metabolism, renin-angiotensin system and adenosine 5'-monophosphate-activated protein kinase pathways, all of which may be implicated in carcinogenesis. On the basis of these epidemiological and experimental findings, we argue for the strong need to strengthen the health care system to ensure that type 2 diabetes subjects receive appropriate drugs to optimize internal milieu to reduce all events including cancer. Apart from mechanistic studies, large-scale, randomized clinical trials using medications such as statin, renin-angiotensin system inhibitors and metformin in patients with risk-conferring subphenotypes are needed to confirm their anti-cancer effects.
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Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.
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Soranna D, Scotti L, Zambon A, Bosetti C, Grassi G, Catapano A, La Vecchia C, Mancia G, Corrao G. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 2012; 17:813-22. [PMID: 22643536 DOI: 10.1634/theoncologist.2011-0462] [Citation(s) in RCA: 207] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Oral antidiabetic drugs (including metformin and sulfonylurea) may play a role in the relationship between type 2 diabetes and cancer. To quantify the association between metformin and sulfonylurea and the risk of cancer, we performed a meta-analysis of available studies on the issue. MATERIALS AND METHODS We performed a MEDLINE search for observational studies that investigated the risk of all cancers and specific cancer sites in relation to use of metformin and/or sulfonylurea among patients with type 2 diabetes mellitus. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR). Between-study heterogeneity was tested using χ(2) statistics and measured with the I(2) statistic. Publication bias was evaluated using funnel plot and Egger's regression asymmetry test. RESULTS Seventeen studies satisfying inclusion criteria and including 37,632 cancers were evaluated after reviewing 401 citations. Use of metformin was associated with significantly decreased RR of all cancers (summary RR 0.61, 95% confidence interval [CI] 0.54-0.70), colorectal cancer (0.64, 95% CI 0.54-0.76), and pancreatic cancer (0.38, 95% CI 0.14-0.91). With the exception of colorectal cancer, significant between-study heterogeneity was observed. Evidence of publication bias for metformin-cancer association was also observed. There was no evidence that metformin affects the risk of breast and prostate cancers, nor that sulfonylurea affects the risk of cancer at any site. CONCLUSIONS Metformin, but not sulfonylurea, appears to reduce subsequent cancer risk. This has relevant implications in light of the exploding global epidemic of diabetes.
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Affiliation(s)
- Davide Soranna
- Dipartimento di Epidemiologia, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy
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Yang XL, Chan JC. Diabetes, insulin and cancer risk. World J Diabetes 2012; 3:60-4. [PMID: 22532884 PMCID: PMC3334387 DOI: 10.4239/wjd.v3.i4.60] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 03/03/2012] [Accepted: 04/10/2012] [Indexed: 02/05/2023] Open
Abstract
There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown. On the other hand, there are ongoing debates about the risk association of insulin use with cancer. We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer, as well as the current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth. Based on the novel findings from the Hong Kong Diabetes Registry and consistent experimental evidence, we argue that use of insulin to control hyperglycemia is unlikely to contribute to increased cancer risk and that dysregulations in the AMP-activated protein kinase pathway due to reduced insulin action and insulin resistance, the insulin-like growth factor-1 (IGF-1)-cholesterol synthesis pathway and renin-angiotensin system, presumably due to reduced insulin secretion and hyperglycemia, may play causal roles in the increased risk of cancer in diabetes. Further exploration into the possible causal relationships between abnormalities of these pathways and the risk of cancer in diabetes is warranted.
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Affiliation(s)
- Xi-Lin Yang
- Xi-Lin Yang, Department of Epidemiology, Public Health College, Tianjin Medical University, Tianjin 300070, China
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Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 2012; 7:e33411. [PMID: 22448244 PMCID: PMC3308971 DOI: 10.1371/journal.pone.0033411] [Citation(s) in RCA: 440] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2011] [Accepted: 02/14/2012] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. Our objective was to enhance the precision of estimates of the effect of metformin on the risk of any-site and site-specific cancers in patients with diabetes. METHODS/PRINCIPAL FINDINGS We performed a search of MEDLINE, EMBASE, ISI Web of Science, Cochrane Library, and ClinicalTrials.gov for pertinent articles published as of October 12, 2011, and included them in a systematic review and meta-analysis. We calculated pooled risk ratios (RRs) for overall cancer mortality and cancer incidence. Of the 21,195 diabetic patients reported in 6 studies (4 cohort studies, 2 RCTs), 991 (4.5%) cases of death from cancer were reported. A total of 11,117 (5.3%) cases of incident cancer at any site were reported among 210,892 patients in 10 studies (2 RCTs, 6 cohort studies, 2 case-control studies). The risks of cancer among metformin users were significantly lower than those among non-metformin users: the pooled RRs (95% confidence interval) were 0.66 (0.49-0.88) for cancer mortality, 0.67 (0.53-0.85) for all-cancer incidence, 0.68 (0.53-0.88) for colorectal cancer (n = 6), 0.20 (0.07-0.59) for hepatocellular cancer (n = 4), 0.67 (0.45-0.99) for lung cancer (n = 3). CONCLUSION/SIGNIFICANCE The use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence. However, this analysis is mainly based on observational studies and our findings underscore the more need for long-term RCTs to confirm this potential benefit for individuals with diabetes.
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Affiliation(s)
- Hiroshi Noto
- Department of Diabetes and Metabolic Medicine, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.
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