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

Disclosures

Brain. 2018;141(10):2855-2865. 

In This Article

Discussion

This randomized placebo-controlled double-blind phase II study failed, possibly marred by the large number of patients who were lost to follow-up, to demonstrate a significant improvement after metformin in the ITT population for the walking distance over 6 min, which was the primary outcome of the study. However, a statistically significant increase in 6MWT distance was identified in the per protocol population of patients who fully completed the study, suggesting promising effects of metformin on the mobility of patients with myotonic dystrophy type 1. The more precise analysis of the various secondary outcomes that may have contributed to this functional effect points to positive changes in gait whereas muscle strength and myotonia did not improve in a statistically significant manner. Metformin may thus have an original target mechanism and be a complement to current candidate therapies. However, our study has limitations, in particular because its results are considered encouraging based only on the analysis of a reduced per protocol population of patients. This calls for confirmation in a high-powered multicentre phase III trial.

The primary endpoint of this study was the 6MWT, according to the recommendation of the international consensus workshop OMMYD-2 (Gagnon et al., 2015). There is a general agreement on the difficulty in finding a reliable and feasible test that would be fully informative on the progressive decline of patients with myotonic dystrophy type 1. This is especially due to the multi-systemic nature of the disease where the different symptoms develop according to different time schedules, as well as to their slow and non-uniform rate of progression. Within that general framework, the 6MWT was selected by the international committee in a large part because it has been very widely used over the years and facilitates a standard comparison of results. The test has also been shown to be reliable from one session to another when repeated in the same DM1 patients and feasible for most of them (Kierkegaard and Tollback, 2007). Nevertheless, one main challenge for our study was the reported lack of a statistically significant decline of the DM1 patients' performance over 1 year for that test. This was indeed clearly the case in the control group in the present study. This did not allow us to reveal a potential preservation of performance under treatment, and only the potentially more challenging detection of a statistically significant improvement in mobility was to be pertinent. A meaningful change had been calculated by previous authors to 6% of baseline value, i.e. over 27 m in the present study (Kierkegaard and Tollback, 2007). The performance of the treated group indeed outperformed that theoretical success threshold at all time points in the per protocol population. It is worth mentioning that a statistically significant improvement of mobility was already observed at 16 weeks in the same per protocol population. A limited weight loss also evolved in a statistically significant manner in parallel to the 6MWT in the treated group but the two features have been shown to evolve independently in previous studies dealing with non-DM1 patients affected by heart failure (Wong et al., 2012). Interestingly, the difference observed in mobility performance between the two studies suggests that the effects of metformin recorded in the present study may bear some specificity for the DM1 disease process.

Among the main symptoms associated with DM1 that may impact mobility, metformin did not appear to have visible effects either on myotonia or on muscle strength. In contrast, there was a statistically significant improvement in some gait parameters, as revealed functionally by an increased mechanical power. It has been shown that the distance performed at the 6MWT is correlated with muscle strength, particularly ankle flexion and extension and knee extension but also in other muscle groups not involved in locomotion (Bachasson et al., 2016). In the absence of a gain in muscle strength, the increase in 6MWT distance may be due to an improvement in motor strategy or coordination. Accelerometry was used to get more information on the gait quality in addition to the gait quantity during the 6MWT. The mechanical power can be deduced from Newton's second law, where it is said that the acceleration of an object equals the sum of the forces applied to its centre of gravity divided by its mass. The body mass being constant, we can speculate that the increased power reflects increased force acting upon the device. The increase of the power in the cranio-caudal and antero-posterior directions thus suggests a better efficiency in gait biomechanics possibly due to a slightly relative decrease of the rolling and waddling components. Gait disorders are one of the main functional impairments in myotonic dystrophy. During the progression of muscle atrophy, patients first maintain an autonomous gait for some time. However, gait defects will eventually couple with limited walking perimeter, and gait speed, as well as falls, contribute to the burden of the disease. As previously described by our group (Bachasson et al., 2016), lower trunk accelerometry analysis during walking at a self-selected pace reveals impairments in all spatiotemporal gait variables (i.e. slower walking speed, lower stride frequency, and smaller stride length) in patients with DM1 compared to controls. Patients with DM1 are unstable during standing and walking, which contributes to a restriction of their walking distance. Significant correlations have been observed between postural instability and muscle weakness. Therefore, metformin may have promoted an increased walking distance by improving gait parameters.

Metformin has not been shown in preclinical studies to affect specific DM1 molecular targets as do other drugs that were specifically designed for either decreasing expression of DMPK (Pandey et al., 2015), or else releasing MBNL1 from the expanded CUG repeats (Rzuczek et al., 2015). However, a deregulation of the AMPK/mTORC1 has additionally been recently identified in DM1 cells, and metformin is a well-known activator of AMPK (Brockhoff et al., 2017). One may rather consider more general metabolic effects, such as the well-known effects of metformin in partially stimulating autophagy (Jagannathan et al., 2015) and inhibiting the UPR transcription programme (Saito et al., 2009; Theriault et al., 2011), increasing glycogen synthesis (Scalzo et al., 2017) or improving insulin sensitivity in skeletal muscles (for review see Dial et al., 2018; Kjobsted et al., 2018). It is not possible to determine whether those hypothetical mechanisms may play a role in the observed clinical effects, in the absence of biological samples of skeletal muscles from patients. However, one conclusion can be drawn from this list of mechanisms, namely that they may well be very different from those of drugs that are currently tested in DM1 patients and, therefore, may point to metformin as an interesting add on treatment, whatever drug is used for targeting molecular mechanisms more directly related to DM1 (Konieczny et al., 2017).

Our phase II clinical study has, however, obvious limitations that need to be addressed before metformin may be widely prescribed to patients with DM1. The most important one is the general setting of our study, which was limited both in sample size and in the number of clinical centres involved. In addition, there was a substantial dropout rate in both groups, but more pronounced in the group receiving metformin. Mild to moderate drug side effects and imperfect compliance have obviously played a significant role in our observations. As a result, a potential loss in statistical power cannot be ruled out, as well as a possible, albeit limited, selection bias due to differential attrition. This large loss of patients to follow-up during the study may have participated to the lack of statistical significance between groups in the ITT analysis, despite an apparent systematic difference in values. Of note, statistically significant trends were nonetheless identified in the per protocol population in favour of the experimental group, confirming the appropriateness of the sample size calculations made before the conduct of the study. The results obtained in this monocentric study with just a handful of patients seem to us sufficiently encouraging to stimulate the planning of a larger-scale multicentre multi-national well-powered phase III clinical trial to provide definite proof of efficacy. In such a study, specific analysis of gait and balance parameters should definitely be added, although it is our contention that the 6MWT should be confirmed as the primary endpoint, in the absence of another test that would receive a similar consensus. In addition, the results on the mechanical power must only be considered as potential clues for the interpretation of the 6MWT improvement. As such, they should be assumed as hypotheses rather than definitive causal explanations.

Organizing a costly phase III clinical trial may, however, be a concern because a sufficient return on investment is difficult to foresee with such an old and cheap drug, accessible to patients as a generic. Another limitation of our study that calls for attention is the fact that a number of patients treated with metformin exhibited gastrointestinal adverse effects. In four cases, they were strong enough to cause the patients to withdraw. These gastrointestinal adverse effects were better tolerated under appropriate symptomatic treatment, but remained uncomfortable to many. Such adverse effects are well known with metformin treatment (Bonnet and Scheen, 2017). They require, however, particular attention and care in DM1 patients who suffer from disease-related gastrointestinal manifestations.

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