Improved Mobility With Metformin in Patients With Myotonic Dystrophy Type 1

A Randomized Controlled Trial

Guillaume Bassez; Etienne Audureau; Jean-Yves Hogrel; Raphaëlle Arrouasse; Sandrine Baghdoyan; Hamza Bhugaloo; Marie-Laurence Gourlay-Chu; Philippe Le Corvoisier; Marc Peschanski


Brain. 2018;141(10):2855-2865. 

In This Article

Abstract and Introduction


Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose-escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 ± 32.7 m, while the placebo group (n = 14) gained 3.7 ± 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.


Myotonic dystrophy type 1 (DM1; OMIM #160900), an autosomal dominant monogenic disease caused by an unstable CTG expansion, is the most common form of muscular dystrophy in adults. DM1 phenotype is characterized by a multi-systemic array of symptoms, among which is altered mobility secondary to major muscle weakness, wasting and myotonia, which represents the main disease burden (De Antonio et al., 2016). Beside recent advances in symptomatic treatments for sleepiness (Puymirat et al., 2012) or myotonia (Logigian et al., 2010), DM1 has remained essentially an unmet medical need.

Over recent years, we have assessed pathological mechanisms associated with DM1 using cells differentiated from human pluripotent stem cell lines derived from DM1 mutated gene-carrying embryos and from affected adult DM1 patients (Marteyn et al., 2011; Gauthier et al., 2013). During this research programme, we have identified that the compound metformin—the most widely used anti-diabetic drug—can induce changes toward normalization in ratios of protein isoforms, the alteration of which is associated to various DM1 clinical symptoms (Laustriat et al., 2015). Subsequently, we showed that similar metformin-induced biological effects on alternate RNA splicing changes occurred in vivo in diabetic patients exposed to the drug. These effects are, therefore, not specific to DM1. While non-DM1 specific, metformin counteracts alternative splicing deregulation of a subset of genes known to be affected in DM1, similar to other compounds reported by others [e.g. manumycin (Oana et al., 2013), chromomycin (Ketley et al., 2014), pentamidine (Warf et al., 2009), furamidine (Siboni et al., 2015), resveratrol (Takarada et al., 2015)]. These beneficial effects were observed at relatively high concentrations of the drug. A complementary study using the DMSXL mouse model of the disease revealed a statistically significant functional benefit on motor testing after metformin treatment. However, the link with a biological effect on alternate splicing of specific genes was not established and metformin may have induced that behavioural benefit via other molecular mechanisms, e.g. autophagia (Brockhoff et al., 2017), glycogen synthesis (Scalzo et al., 2017) or insulin sensitivity (for review see Dial et al., 2018; Kjobsted et al., 2018).

Altogether, despite this uncertainty on the mode of action, these positive experimental results and the very good safety profile of metformin led us to undertake the present clinical trial designed to explore the effects of the drug on mobility in non-diabetic adult DM1 patients. The 6-minute walk test (6MWT), a robust functional test to assess mobility, was selected as the primary endpoint of functional capacity outcome measures, in agreement with the recommendations of the Outcome Measures in Myotonic Dystrophy type 1 (OMMYD-2) expert consensus (Gagnon et al., 2015). A series of secondary outcomes explored concomitant changes in muscle strength, myotonia, gait variables, biological parameters and quality of life.