|
1
|
Lee HM, Wong WKK, Fan B, Lau ES, Hou Y, O CK, Luk AOY, Chow EYK, Ma RCW, Chan JCN, Kong APS. Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes. Sci Rep 2021; 11:23756. [PMID: 34887498 PMCID: PMC8660865 DOI: 10.1038/s41598-021-03222-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/30/2021] [Indexed: 12/14/2022] Open
Abstract
People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.
Collapse
Affiliation(s)
- Heung Man Lee
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Willy Kwun Kiu Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Baoqi Fan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Eric Siu Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Yong Hou
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Chun Kwan O
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Andrea On Yan Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Elaine Yee Kwan Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Juliana Chung Ngor Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Alice Pik Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China. .,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. .,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
| |
Collapse
|
|
2
|
Zhang AM, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in Obesity, Inflammation, and Cancer. Diabetes Metab J 2021; 45:285-311. [PMID: 33775061 PMCID: PMC8164941 DOI: 10.4093/dmj.2020.0250] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.
Collapse
Affiliation(s)
- Anni M.Y. Zhang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth A. Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Janel L. Kopp
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
3
|
Fujita K, Iwama H, Miyoshi H, Tani J, Oura K, Tadokoro T, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Masaki T. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6100-13. [PMID: 27468203 PMCID: PMC4945972 DOI: 10.3748/wjg.v22.i27.6100] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.
Collapse
|
|
4
|
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.
Collapse
|
|
5
|
Raz I, Riddle MC, Rosenstock J, Buse JB, Inzucchi SE, Home PD, Del Prato S, Ferrannini E, Chan JC, Leiter LA, LeRoith D, DeFronzo R, Cefalu WT. Personalized management of hyperglycemia in type 2 diabetes: reflections from a Diabetes Care Editors' Expert Forum. Diabetes Care 2013; 36:1779-88. [PMID: 23704680 PMCID: PMC3661796 DOI: 10.2337/dc13-0512] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In June 2012, 13 thought leaders convened in a Diabetes Care Editors' Expert Forum to discuss the concept of personalized medicine in the wake of a recently published American Diabetes Association/European Association for the Study of Diabetes position statement calling for a patient-centered approach to hyperglycemia management in type 2 diabetes. This article, an outgrowth of that forum, offers a clinical translation of the underlying issues that need to be considered for effectively personalizing diabetes care. The medical management of type 2 diabetes has become increasingly complex, and its complications remain a great burden to individual patients and the larger society. The burgeoning armamentarium of pharmacological agents for hyperglycemia management should aid clinicians in providing early treatment to delay or prevent these complications. However, trial evidence is limited for the optimal use of these agents, especially in dual or triple combinations. In the distant future, genotyping and testing for metabolomic markers may help us to better phenotype patients and predict their responses to antihyperglycemic drugs. For now, a personalized ("n of 1") approach in which drugs are tested in a trial-and-error manner in each patient may be the most practical strategy for achieving therapeutic targets. Patient-centered care and standardized algorithmic management are conflicting approaches, but they can be made more compatible by recognizing instances in which personalized A1C targets are warranted and clinical circumstances that may call for comanagement by primary care and specialty clinicians.
Collapse
Affiliation(s)
- Itamar Raz
- Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | | | - Julio Rosenstock
- Dallas Diabetes and Endocrine Center at Medical City and University of Texas Southwestern Medical Center, Dallas, Texas
| | - John B. Buse
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Silvio E. Inzucchi
- Yale University School of Medicine and Yale-New Haven Hospital, New Haven, Connecticut
| | | | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy
| | - Ele Ferrannini
- Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy
| | - Juliana C.N. Chan
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Prince of Wales Hospital, China
| | - Lawrence A. Leiter
- Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, and Departments of Medicine and Nutritional Sciences, University of Toronto, Toronto, Canada
| | - Derek LeRoith
- Mount Sinai Medical School, New York, New York, and Rambam Technion Hospital, Haifa, Israel
| | - Ralph DeFronzo
- University of Texas Health Science Center, San Antonio, Texas
| | - William T. Cefalu
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
| |
Collapse
|
|
6
|
Walraven I, van 't Riet E, Stehouwer CDA, Polak BCP, Moll AC, Dekker JM, Nijpels G. Fasting proinsulin levels are significantly associated with 20 year cancer mortality rates. The Hoorn Study. Diabetologia 2013; 56:1148-54. [PMID: 23460020 DOI: 10.1007/s00125-013-2864-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 01/24/2013] [Indexed: 11/30/2022]
Abstract
AIMS/HYPOTHESIS Proinsulin is possibly associated with cancer through activation of insulin receptor isoform A. We sought to investigate the associations between proinsulin and 20 year cancer mortality rates. METHODS The study was performed within the Hoorn Study, a population-based study of glucose metabolism in individuals aged 50-75 years in the Dutch population. Fasting proinsulin levels were measured twice by a double-antibody radioimmunoassay. Participants were continuously followed to register mortality; causes of death were derived from medical records. Cox survival analyses were performed to assess the 20 year risk of death from cancer in relation to proinsulin. All analyses were adjusted for age and sex, with additional adjustments for traditional risk factors. The effect modification of glucose metabolism and sex was tested. RESULTS Proinsulin levels were measured in 438 individuals (41% normal glucose tolerance, 35.7% impaired glucose metabolism, 23.3% type 2 diabetes). Of these participants, 53 died from cancer. After adjustment for age and sex, proinsulin >16.5 pmol/l (the upper tertile) was significantly associated with a twofold risk of cancer mortality (HR 2.01, 95% CI 1.16, 3.46) compared with individuals with lower proinsulin levels. Additional adjustment for glucose metabolism, BMI and smoking did not substantially change the results (HR 1.91, 95% CI 1.04, 3.52). No interaction with glucose metabolism or sex was observed. CONCLUSIONS/INTERPRETATION Individuals with fasting proinsulin levels >16.5 pmol/l have a twofold risk of cancer mortality over a 20 year time span. These findings provide population-based evidence for the independent association between high proinsulin levels and cancer mortality rates.
Collapse
Affiliation(s)
- I Walraven
- EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.
| | | | | | | | | | | | | |
Collapse
|
|
7
|
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.
Collapse
Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Sheen YJ, Sheu WHH. Links among type 2 diabetes, cancer and metformin use: what have we learned? Diabetes Res Clin Pract 2012; 97:169-71. [PMID: 22497968 DOI: 10.1016/j.diabres.2012.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 03/19/2012] [Indexed: 10/28/2022]
|
|
9
|
Yang XL, Ma RCW, So WY, Kong APS, Xu G, Chan JCN. Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings--what, why and how? Diabetes Obes Metab 2012; 14:579-85. [PMID: 22171706 DOI: 10.1111/j.1463-1326.2011.01551.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that 'immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for 'immortal time bias' using time-dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non-drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non-clinical trial settings.
Collapse
Affiliation(s)
- X L Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | | | | | | | | | | |
Collapse
|
|
10
|
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.
Collapse
Affiliation(s)
- Xilin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China.
| | | | | | | | | | | |
Collapse
|