Anti-Diabetic Medications and the Risk of Hepatocellular Cancer: A Systematic Review and Meta-Analysis
01 Jun 2013-The American Journal of Gastroenterology (Nature Publishing Group)-Vol. 108, Iss: 6, pp 881-891
TL;DR: ADMs may modify the risk of HCC in patients with DM, especially in the Western population, however, the effect of each individual agent should be interpreted with caution owing to inherent cancer-modifying effect of the comparator group.
About: This article is published in The American Journal of Gastroenterology.The article was published on 2013-06-01. It has received 250 citations till now. The article focuses on the topics: Odds ratio & Relative risk.
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TL;DR: While several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed to help explain the failure of prior studies.
Abstract: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies.
1,144 citations
TL;DR: The major risk factors for hepatocellular carcinoma (HCC) in contemporary clinical practice are becoming increasingly related to sustained virological response after hepatitis C, suppressed hepatitis B virus during treatment, and alcoholic and nonalcoholic fatty liver disease.
958 citations
TL;DR: Primary prevention efforts aimed at decreasing the prevalence of obesity and diabetes and controlling mycotoxin growth, are just as urgently required for HCC.
748 citations
TL;DR: Urgent measures that increase global awareness and tackle the metabolic risk factors are necessary to reduce the impending burden of NAFLD-related HCC and propose preventive strategies to tackle this growing problem.
Abstract: One quarter of the global population is estimated to have nonalcoholic fatty liver disease (NAFLD). The incidence of nonalcoholic steatohepatitis (NASH) is projected to increase by up to 56% in the next 10 years. NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC) in the USA, France and the UK. Globally, the prevalence of NAFLD-related HCC is likely to increase concomitantly with the growing obesity epidemic. The estimated annual incidence of HCC ranges from 0.5% to 2.6% among patients with NASH cirrhosis. The incidence of HCC among patients with non-cirrhotic NAFLD is lower, approximately 0.1 to 1.3 per 1,000 patient-years. Although the incidence of NAFLD-related HCC is lower than that of HCC of other aetiologies such as hepatitis C, more people have NAFLD than other liver diseases. Urgent measures that increase global awareness and tackle the metabolic risk factors are necessary to reduce the impending burden of NAFLD-related HCC. Emerging evidence indicates that reduced immune surveillance, increased gut inflammation and gut dysbiosis are potential key steps in tumorigenesis. In this Review, we discuss the global epidemiology, projections and risk factors for NAFLD-related HCC, and propose preventive strategies to tackle this growing problem.
696 citations
TL;DR: A rapidly expanding body of clinical evidence is critically discussed that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NA FLD and CVD morbidity and mortality.
470 citations
Cites background from "Anti-Diabetic Medications and the R..."
...JOURNAL OF HEPATOLOGY morpho-functional changes, occurring in a variety of organ systems that are potentially involved in the development of T2DM....
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...161 Qualitative and quantitative changes in amino acid plasma composition, e.g. increased branched chain amino acids, may result not only from gluconeogenesis leading to muscle depletion, but also from their synthesis by gut microbiota, with Prevotella copri and Bacteroides vulgatus being the main producers of branched chain amino acids.164 Gut Experimental bariatric surgery has shown that the proximal bowel plays an important role in the pathophysiology of T2DM.165 Moreover, agonists of the innate immune receptors, toll-like receptor Please cite this article in press as: Lonardo A et al. Hypertension, diabetes, a Journal of (TLR)2 and TLR4, may trigger the development of T2DM and other cardiometabolic diseases....
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...2).24 Similarly, in a cohort study of nearly 4,000 nondiabetic Japanese individuals, who were followed-up for 10 years, the authors showed that improvement of NAFLD on ultrasonography was independently associated with an approximately 70% risk reduction of incident T2DM.26 However, these Please cite this article in press as: Lonardo A et al. Hypertension, diabetes, a Journal of two studies are not randomised controlled trials of NAFLD management, so caution should be exercised when interpreting these results....
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...that hypoglycaemic agents modulate the risk of incident HCC in patients with T2DM.(73) However, the effect of each individual hypoglycaemic agent...
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...166 By affecting gut microbiota, high-fat diet increases intestinal permeability and induces metabolic endotoxaemia, leading to chronic inflammation in the post-prandial phases.167,168 Therefore, glucagon-like peptide-2 may drive improved gut permeability in obese mice.169 Finally, short-chain fatty acids, such as butyrate and propionate, which are mainly synthesised by gut microbiota, may also contribute to modulating hepatic/peripheral IR and the risk of developing incident T2DM.164 Adipose tissue Peripheral IR develops because of an energy surplus, leading to ectopic intramuscular lipid accumulation and reduced muscle glucose uptake.170 IR within the skeletal muscles redirects dietary glucose to the liver, resulting in increased hepatic de novo lipogenesis and dyslipidaemia.170,171 Chronic inflammatory changes within the white therosclerosis and NASH: Cause or consequence?....
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References
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TL;DR: A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination, and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake.
Abstract: The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
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TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
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Abstract: Flaws in the design, conduct, analysis, and reporting of randomised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurate
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