Use of Antidiabetic Agents and the Risk of Pancreatic Cancer: A Case–Control Analysis

Bodmer, Michael; Becker, Claudia; Meier, Christian; Jick, Susan S.; Meier, Christoph

doi:10.1038/ajg.2011.483

Cited by 122 publications

(98 citation statements)

References 29 publications

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“…In the latter study, there were interactions between metformin and glibenclamide use towards lower cancer risk; after adjusting for the interaction terms, the use of glibenclamide provided no protective effect (HRZ1.27; 95% CI 0.76-2.11) (24). Some studies have not found an imbalance in cancer types among glibenclamide users (40), but others have found increased risks of pancreatic or hepatocellular carcinoma among sulphonylurea users (22,41,42). A recent meta-analysis, however, found no evidence that sulphonylureas affected the risk of cancer at any site (43).…”

Section: Glibenclamidementioning

confidence: 99%

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients

Castiglione

Ghigo

et al. 2013

European Journal of Endocrinology

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Objective: Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory. Design: We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic. Methods: All 1277 patients treated with sulphonylureas during 1996-1997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause-specific mortality), including several potential confounders. Results: Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HRZ0.30; 95% CI 0.16-0.55, and HRZ0.48; 95% CI 0.29-0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HRZ0.40; 95% CI 0.22-0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrolment. Conclusions: Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucoselowering effect and strongly advocate for further investigation.

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Section: Glibenclamidementioning

confidence: 99%

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients

Castiglione

Ghigo

et al. 2013

European Journal of Endocrinology

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“…Table 1A summarizes epidemiological studies that show pancreatic cancer risk and cancer mortality associated with metformin use while Table 1B presents observational studies and clinical trials on overall cancer risk and mortality in relation to metformin use. While some studies show a reduction in pancreatic cancer [35][36][37][38][39] and overall cancer risk [37,[39][40][41][42][43][44][45] among diabetic metformin users, there are also studies that report no significant difference in cancer risk among diabetics who take metformin compared to patients who take other anti-diabetic treatments [36,[46][47][48][49][50][51]. These conflicting results may be explained by differences in the study population, the confounding factors accounted for during statistical analysis and the selected study design (e.g., cohort versus case-control).…”

Section: Chemopreventive Properties Of Metforminmentioning

confidence: 61%

Metformin and Pancreatic Cancer Metabolism

Cantoria¹,

Hitendra²,

Boros³

et al. 2014

Pancreatic Cancer - Insights Into Molecular Mechanisms and Novel Approaches to Early Detection and Treatment

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“…Many studies support the notion that the use of metformin results in lower incidence of cancer [71][72][73][74][75]. Lung, pancreatic, prostate, breast, ovarian, and hepatocellular cancer incidence has been found to be lower among patients receiving metformin [76][77][78][79][80][81][82]. Moreover, the mortality from cancer was lower in diabetes patients taking metformin as part of their anti-diabetic medication compared with those not taking metformin [83][84][85][86].…”

Section: Metformin Cancer Prevention and Mortalitymentioning

confidence: 77%

Metformin and Cancer

Vallianou¹,

Evangelopoulos²,

Kazazis³

2013

Rev Diabet Stud

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■ AbstractMetformin is well-known as an anti-diabetic drug, but it seems to possess anti-cancerous properties as well. Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved regulator of the cellular response to the presence of low energy in all eukaryotic cells. It is considered a key sensor of the balance of cellular ATP and AMP concentrations. LKB1 serine/threonine kinase is a divergent yet evolutionarily well-conserved kinase, biochemically sufficient to activate AMPK in vitro and genetically required for AMPK activation. Because of this potent connection to AMPK, LKB1 may act as a central regulator of metabolism in vivo. Once activated, AMP kinase phosphorylates the transcriptional activator TorC2, thereby blocking its nuclear translocation and inhibiting the expression of genes involved in gluconeogenesis. Data suggest that LKB1/AMPK signaling plays a role in protection from apoptosis, specifically in response to agents that increase the cellular AMP/ATP ratio. Active AMPK signaling offers a protective effect by providing the cell with time to reverse the aberrantly high ratio of AMP/ATP. If unable to reverse this ratio, the cell will eventually undergo cell death. These observations offer the provocative suggestion of a potential therapeutic window in which LKB1-deficient tumor cells may be acutely sensitive to AMP analogues or sensitized to cell death by other stimuli when treated in combination with agents that increase the AMP/ATP ratio. LKB1 therefore is a classical tumor suppressor. AMPK is a direct LKB1 substrate. A consequence of AMPK activation by LKB1 is the inhibition of the mammalian target of rapamycin (mTOR) C1 pathway. Metformin's anti-cancerous properties have been demonstrated in various cancer cells in vitro, such as lung, pancreatic, colon, ovarian, breast, prostate, renal cancer cells, melanoma, and even in acute lymphoblastic leukemia cells. To test metformin's action in vivo, mice were implanted with transformed mammary epithelial cells and treated with three cycles of metformin and with the anthracycline doxorubicin. When combined with doxorubicin, metformin wiped out tumors and prevented recurrence. Metformin alone had no effect, and doxorubicin as a single agent initially shrank tumors, but they regrew later. Virtually no cancer stem cells were recovered immediately after treatment and the complete response was sustained for nearly two months. Further studies are needed to assess the anti-cancerous potentials of metformin in vivo. This article reviews the current knowledge on the actions of LKB1/AMPK and the effectiveness of metformin in cancer, specifically in diabetes patients.

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Use of Antidiabetic Agents and the Risk of Pancreatic Cancer: A Case–Control Analysis

Abstract: Use of metformin was associated with a decreased risk of pancreatic cancer in women only, whereas use of sulfonylureas and of insulin was associated with an increased risk of pancreatic cancer.

Cited by 122 publications

References 29 publications

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients

Metformin and Pancreatic Cancer Metabolism

Metformin and Cancer

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