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      Diabetes Medication Use in Association with Survival among Patients of Breast, Colorectal, Lung, or Gastric Cancer

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          Abstract

          Purpose

          Studies suggest that regular use of metformin may decrease cancer mortality. We investigated the association between diabetes medication use and cancer survival.

          Materials and Methods

          The current study includes 633 breast, 890 colorectal, 824 lung, and 543 gastric cancer cases identified from participants of two population-based cohort studies in Shanghai. Information on diabetes medication use was obtained by linking to electronic medical records. The associations between diabetes medication use (metformin, sulfonylureas, and insulin) and overall and cancer-specific survival were evaluated using time-dependent Cox proportional hazards models.

          Results

          After adjustment for clinical characteristics and treatment factors, use of metformin was associated with better overall survival among colorectal cancer patients (hazards ratio [HR], 0.55; 95% confidence interval [CI], 0.34 to 0.88) and for all four types of cancer combined (HR, 0.75; 95% CI, 0.57 to 0.98). Ever use of insulin was associated with worse survival for all cancer types combined (HR, 1.89; 95% CI, 1.57 to 2.29) and for the four cancer types individually. Similar associations were seen for diabetic patients. Sulfonylureas use was associated with worse overall survival for breast or gastric cancer (HR, 2.87; 95% CI, 1.22 to 6.80 and HR, 2.05; 95% CI, 1.09 to 3.84, respectively) among diabetic patients. Similar association patterns were observed between diabetes medication use and cancer-specific survival.

          Conclusion

          Metformin was associated with improved survival among colorectal cancer cases, while insulin use was associated with worse survival among patients of four major cancers. Further investigation on the topic is needed given the potential translational impact of these findings.

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          Most cited references30

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          Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

          In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.
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            Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis.

            Diabetes mellitus appears to be a risk factor for some cancers, but the effect of preexisting diabetes on all-cause mortality in newly diagnosed cancer patients is less clear. To perform a systematic review and meta-analysis comparing overall survival in cancer patients with and without preexisting diabetes. We searched MEDLINE and EMBASE through May 15, 2008, including references of qualifying articles. English-language, original investigations in humans with at least 3 months of follow-up were included. Titles, abstracts, and articles were reviewed by at least 2 independent readers. Of 7858 titles identified in our original search, 48 articles met our criteria. One reviewer performed a full abstraction and other reviewers verified accuracy. We contacted authors and obtained additional information for 3 articles with insufficient reported data. Studies reporting cumulative survival rates were summarized qualitatively. Studies reporting Cox proportional hazard ratios (HRs) or Poisson relative risks were combined in a meta-analysis. A random-effects model meta-analysis of 23 articles showed that diabetes was associated with an increased mortality HR of 1.41 (95% confidence interval [CI], 1.28-1.55) compared with normoglycemic individuals across all cancer types. Subgroup analyses by type of cancer showed increased risk for cancers of the endometrium (HR, 1.76; 95% CI, 1.34-2.31), breast (HR, 1.61; 95% CI, 1.46-1.78), and colorectum (HR, 1.32; 95% CI, 1.24-1.41). Patients diagnosed with cancer who have preexisting diabetes are at increased risk for long-term, all-cause mortality compared with those without diabetes.
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              Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin.

              Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer. This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided. We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 +/- 1.9 years (means +/- SD). The mean age for the cohort was 63.4 +/- 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1-1.6]; P = 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5-2.4; P < 0.0001). Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk.
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                Author and article information

                Journal
                Cancer Res Treat
                Cancer Res Treat
                CRT
                Cancer Research and Treatment : Official Journal of Korean Cancer Association
                Korean Cancer Association
                1598-2998
                2005-9256
                April 2019
                2 July 2018
                : 51
                : 2
                : 538-546
                Affiliations
                [1 ]Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
                [2 ]Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China
                [3 ]Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China
                [4 ]Division of General Internal Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA
                Author notes
                Correspondence: Xiao-Ou Shu, MD, PhD Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 600 (IMPH), Nashville, TN 37203-1738, USA Tel: 1-615-936-0713 Fax: 1-615-936-8291 E-mail: xiao-ou.shu@ 123456vanderbilt.edu
                Article
                crt-2017-591
                10.4143/crt.2017.591
                6473299
                29986576
                1b7e213c-1377-4be5-9d04-cb25535b8016
                Copyright © 2019 by the Korean Cancer Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 December 2017
                : 25 June 2018
                Categories
                Original Article

                Oncology & Radiotherapy
                cancer survival,diabetes medication,metformin
                Oncology & Radiotherapy
                cancer survival, diabetes medication, metformin

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