Diabetes, DM1, and “Fortuitous” Drug Effects
An important downstream consequence of the DM1 mutation is aberrant splicing of the insulin receptor (INSR) transcript, glucose intolerance, insulin resistance, and development of type 2 diabetes (T2D). Metformin, an established anti-diabetic drug, has been used for symptomatic treatment of T2D in DM1. For reasons that are, as yet, unclear, metformin may be valuable in addressing other consequences of DM1, including improving patient mobility in a randomized, placebo-controlled clinical trial (Bassez et al., 2018). Since DM1 is without an approved therapy that is targeted to the primary disease mechanism, understanding of such multi-systems drug effects is of vital importance to the management of those living with DM1.
Cancer and DM1
Patients with DM1 are at elevated risk of cancer (Gadalla et al., 2011; Alsaggaf et al., 2018). In the general population, epidemiological studies have suggested that use of metformin for T2D also has beneficial effects for cancer prevention and treatment.
Connecting the dots—the common use of metformin in T2D in DM1, its potential anti-cancer activity, and the prevalence of cancer in DM1—Dr. Shahinaz Gadalla (National Cancer Institute/NIH) and colleagues explored putative cancer-preventative effects in DM1 patients receiving the drug for diabetes (Alsaggaf et al., 2019).
This study took advantage of a large UK National Health System medical record cohort with a substantial DM1 population—the completeness of this database allowed for control of multiple potentially confounding variables. In the cohort of 913 DM1 subjects, plus over 12,000 randomized, matched controls, the research team assessed cancer risk in T2D patients prescribed metformin versus those not receiving the drug. Cox regression modeling generated hazard ratios that established a higher prevalence of T2D in DM1 versus controls (8% vs. 3%); of note, those DM1 patients with T2D were more likely to have late-onset DM1 than those without T2D. Moreover, DM1 patients who also had T2D were at three-fold higher risk to develop cancer—this risk was reversed when DM1/T2D patients were treated with metformin. By contrast, in the control cohort, metformin use was not associated with decreased cancer risk.
Understanding, but Still Many Known Unknowns
This study makes clear that DM1 patients are at nearly three-fold enhanced risk of developing T2D, and suggests that those who do develop T2D are also at greater risk for cancer. Finally, the data raise the possibility that metformin significantly reduces cancer risk in DM1/T2D patients. This information may stimulate further research to asses T2D and cancer risk in DM1.
Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial.
Bassez G, Audureau E, Hogrel JY, Arrouasse R, Baghdoyan S, Bhugaloo H, Gourlay-Chu ML, Le Corvoisier P, Peschanski M.
Brain. 2018 Oct 1;141(10):2855-2865. doi: 10.1093/brain/awy231.
Cancer risk among patients with myotonic muscular dystrophy.
Gadalla SM, Lund M, Pfeiffer RM, Gørtz S, Mueller CM, Moxley RT 3rd, Kristinsson SY, Björkholm M, Shebl FM, Hilbert JE, Landgren O, Wohlfahrt J, Melbye M, Greene MH.
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Cancer Risk in Myotonic Dystrophy Type I: Evidence of a Role for Disease Severity.
Alsaggaf R, St George DMM, Zhan M, Pfeiffer RM, Wang Y, Wagner KR, Greene MH, Amr S, Gadalla SM.
JNCI Cancer Spectr. 2018 Nov;2(4):pky052. doi: 10.1093/jncics/pky052. Epub 2018 Dec 10.
Diabetes, Metformin, and Cancer Risk in Myotonic Dystrophy Type I.
Alsaggaf R, Pfeiffer RM, Wang Y, St George DMM, Zhan M, Wagner KR, Amr S, Greene MH, Gadalla SM.
Int J Cancer. 2019 Nov 20. doi: 10.1002/ijc.32801. [Epub ahead of print]