The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma

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Abstract

Background:

Insulin/insulin-like growth factor-1 signalling may underlie the promoting effect of type 2 diabetes on cancer. This study examined the association of diabetes, including steroid-induced diabetes (SID), and the impact of anti-diabetic medication on clinical outcomes of multiple myeloma (MM).

Methods:

A retrospective review was conducted of 1240 MM patients. Overall survival (OS) and MM disease status prior to death were analysed.

Results:

Diabetic patients had a significantly shorter OS than non-diabetic patients (median: 65.4 vs 98.7 months). In multivariate analysis, SID was a significant predictor of decreased OS, along with age, comorbidity, MM stage, and cytogenetic abnormalities. Analyzing only the diabetic MM patients, Cox regression showed that metformin predicted an increased OS, whereas use of insulin/analogues predicted a decreased OS. Competing risk analysis showed that DM was associated with increased cumulative incidence of death with progressive MM. Among the diabetics, multivariate regression showed that insulin/analogues were associated with increased, but metformin with decreased death with progressive MM. Potential immortal time bias was evaluated by landmark analyses.

Conclusions:

DM, SID in particular, is associated with poor clinical outcomes in MM. Insulin/analogues are associated with poor outcomes, whereas metformin is associated with improved outcomes. No conclusion about causal relationships can be made at this time. Managing hyperglycaemia with non-insulin regimens should be investigated in randomised trials.

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Most cited references 26

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Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults.

Steven S Coughlin, Eugenia E Calle, Lauren Teras … (2004)

Several studies have suggested that diabetes mellitus may alter the risk of developing a variety of cancers, and the associations are biologically plausible. To learn more about the relation between diabetes and cancer mortality, the authors examined associations with selected cancers in a large, prospective US cohort of 467,922 men and 588,321 women who had no reported history of cancer at enrollment in 1982. After 16 years of mortality follow-up, diabetes was significantly associated with fatal colon cancer in men (multivariate relative risk (RR) = 1.20, 95% confidence interval (CI): 1.06, 1.37) and women (RR = 1.24, 95% CI: 1.07, 1.43) and with pancreatic cancer in men (RR = 1.48, 95% CI: 1.27, 1.73) and women (RR = 1.44, 95% CI: 1.21, 1.72). For men, diabetes was significantly associated with liver cancer (RR = 2.19, 95% CI: 1.76, 2.72) and bladder cancer (RR = 1.43, 95% CI: 1.14, 1.80). In addition, diabetes was significantly associated with breast cancer in women (RR = 1.27, 95% CI: 1.11, 1.45). These associations were not explained by high body mass. Our findings suggest that diabetes is an independent predictor of mortality from cancer of the colon, pancreas, female breast, and, in men, of the liver and bladder.

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Metformin use is associated with better survival of diabetic patients with pancreatic cancer.

Sai-Ching J. Yeung, Donghui Li, J L Abbruzzese … (2012)

Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer. We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan-Meier plot, log-rank test, and Cox proportional hazards regression models. Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ(2) test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52-0.89) in a univariate model (P = 0.004), 0.64 (0.48-0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44-0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only. Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population. ©2012 AACR.

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Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

D. Kuhn, Chad C. Bjorklund, Hua Wang … (2012)

Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.

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Author and article information

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 29 July 2014

Publication date (Electronic): 12 June 2014

Volume: 111

Issue: 3

Pages: 628-636

Affiliations

[1 ]Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[2 ]Zhongshan Hospital, Xiamen University , Xiamen, Fujian, People's Republic of China

[3 ]Department of Biostatistics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[4 ]Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[5 ]Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[6 ]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[7 ]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[8 ]Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

Author notes

[* ]E-mail: syeung@ 123456mdanderson.org

[9]

These authors contributed equally to this work.

Article

Publisher Item ID: bjc2014307

DOI: 10.1038/bjc.2014.307

PMC ID: 4119980

PubMed ID: 24921909

SO-VID: 0cf0f080-f496-4442-b07a-5e6bc3bc1e9e

License:

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

History

Date received : 07 February 2014

Date revision received : 10 May 2014

Date accepted : 12 May 2014

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The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma

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Abstract

Background:

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Results:

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Karger: Oncology

Most cited references 26

Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults.

Metformin use is associated with better survival of diabetic patients with pancreatic cancer.

Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

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Cited by 27

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