Trials of Antidiabetic Drugs in Amyotrophic Lateral Sclerosis: Proceed with Caution?

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited therapeutic options. Clinical trials of several drugs shown to be effective in the superoxide dismutase (SOD1) model of ALS have shown no or negative effects when tested in humans. Here we discuss the role of pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, which failed to show efficacy in a recently published phase II clinical trial of ALS patients. The antioxidant and anti-inflammatory properties of pioglitazone make it an attractive therapeutic candidate for neurodegenerative disorders. However, its antidiabetic and antidyslipidemic effects might be detrimental, as emerging evidence suggests that some features of the metabolic syndrome may be protective in ALS. A number of clinical studies show that dyslipidemia, high body mass index, and possibly diabetes mellitus type 2 are associated with better clinical outcomes in ALS. This is further corroborated by studies on transgenic animal models and immortalized neuronal cell lines. Finally, the intricate interplay between glucose/lipid metabolism and susceptibility to oxidative damage in neurons warrants a judicious approach in further trials of antidiabetic drugs in ALS.

Pre‐morbid type 2 diabetes mellitus as a prognostic factor in amyotrophic lateral sclerosis

“…After considering the methodologic differences, it appears that the Paganoni et al . study may actually be in agreement with studies supporting a “protective” effect of DM2 on ALS . Future studies on this important topic should employ stringent statistical analyses, include all ALS patients, and compare their findings to the full body of existing literature on the subject while reaching a conclusion regarding the prognostic value of DM2 in ALS.…”

Systemic metabolism in frontotemporal dementia

“…9 A recent phase II clinical trial in MND with pioglitazone, an antidiabetic medication, resulted in an increase in mortality. 30 The mechanisms underlying changes in lipid levels and insulin resistance and how these may be protective in MND are not understood. 6 One hypothesis is that patients with MND increase their energy intake in order to compensate for a state of hypermetabolism, 5,31-34 which then results in increased lipid levels and a state of insulin resistance.…”

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

“…The anti-diabetic drug pioglitazone improved motor performance, delayed weight loss, attenuated motor neuron loss, and extended survival in a SOD 1 mouse model [158]; however, pioglitazone failed to show efficacy in a phase II clinical trial of ALS patients [159]. Furthermore, it has been suggested that anti-diabetic drugs are detrimental in ALS in light of emerging evidence that some features of the metabolic syndrome may be protective in ALS [160]. Since pioglitazone, no further diabetic agents have been studied in ALS, and therefore the uncertainty of benefit from anti-diabetic drugs remains.…”