On 2014 Feb 14, David Keller commented:

Were the benefits due to lower glucose levels, pleiotropic effects of exenatide, or lack of a placebo control?

The possible beneficial effect of exenatide on the progression of Parkinson disease might have been due to the mild sustained decrease in blood glucose levels which is the usual intended effect of this medication in diabetics, or to the pleiotropic neuroprotective effects hypothesized by the investigators, or to a combination of effects, including the placebo effect. Self-injection is a powerful placebo procedure, especially in a condition like Parkinson's disease, in which the magnitude of the patient's symptoms are affected by their psychological state and mood. Because the comparison group did not self-inject daily, the placebo effect was not controlled for in this study. Some of these questions could be addressed by comparing exenatide to self-injected basal insulin in future studies, dosed to produce an equivalent degree of glucose-lowering but without frank hypoglycemia. A slight lowering of blood glucose (within the normal range) might be neuroprotective by means of decreasing metabolism, and thereby decreasing the oxidative stress and the free radicals generated by metabolic reactions. Any benefit due to reduced metabolism caused by lowered blood glucose should be equivalent for equipotent doses of exenatide and basal insulin. Any additional benefit of exenatide over equipotent basal insulin could be ascribed to pleiotropic neuroprotective effects of the former.

A recent meta-analysis found that Parkinson patients treated with active drug had significantly less objectively measured motor response to the same intervention if they knew there was a chance that they were receiving placebo, even with effective double blinding (1). This decreased response, dubbed "the lessebo effect", could account for up to 4.1 UPDRS units of motor improvement for patients in studies lacking double-blinded placebo controls.

Reference

1) Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE. Another face of placebo: The lessebo effect in Parkinson disease: Meta-analyses. Neurology. 2014 Apr 22;82(16):1402-9. doi: 10.1212/WNL.0000000000000340. Epub 2014 Mar 21. PubMed PMID: 24658930; PubMed Central PMCID: PMC4001195.

On 2014 Feb 14, David Keller commented:

Were the benefits due to lower glucose levels, pleiotropic effects of exenatide, or lack of a placebo control?

The possible beneficial effect of exenatide on the progression of Parkinson disease might have been due to the mild sustained decrease in blood glucose levels which is the usual intended effect of this medication in diabetics, or to the pleiotropic neuroprotective effects hypothesized by the investigators, or to a combination of effects, including the placebo effect. Self-injection is a powerful placebo procedure, especially in a condition like Parkinson's disease, in which the magnitude of the patient's symptoms are affected by their psychological state and mood. Because the comparison group did not self-inject daily, the placebo effect was not controlled for in this study. Some of these questions could be addressed by comparing exenatide to self-injected basal insulin in future studies, dosed to produce an equivalent degree of glucose-lowering but without frank hypoglycemia. A slight lowering of blood glucose (within the normal range) might be neuroprotective by means of decreasing metabolism, and thereby decreasing the oxidative stress and the free radicals generated by metabolic reactions. Any benefit due to reduced metabolism caused by lowered blood glucose should be equivalent for equipotent doses of exenatide and basal insulin. Any additional benefit of exenatide over equipotent basal insulin could be ascribed to pleiotropic neuroprotective effects of the former.

A recent meta-analysis found that Parkinson patients treated with active drug had significantly less objectively measured motor response to the same intervention if they knew there was a chance that they were receiving placebo, even with effective double blinding (1). This decreased response, dubbed "the lessebo effect", could account for up to 4.1 UPDRS units of motor improvement for patients in studies lacking double-blinded placebo controls.

Reference

1) Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE. Another face of placebo: The lessebo effect in Parkinson disease: Meta-analyses. Neurology. 2014 Apr 22;82(16):1402-9. doi: 10.1212/WNL.0000000000000340. Epub 2014 Mar 21. PubMed PMID: 24658930; PubMed Central PMCID: PMC4001195.