Abstract
Background
Parkinson’s disease (PD) is a progressive disorder characterised by both motor and non‐motor problems. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP‐1 receptors in the pancreas, which triggers the release of insulin. GLP‐1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP‐1 receptor agonists in neurodegenerative disorders such as PD.
Objectives
To evaluate the effectiveness and safety of GLP‐1 receptor agonists for Parkinson’s disease.
Search methods
We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020.
Selection criteria
We included randomised controlled trials (RCTs) of adults with PD that compared GLP‐1 receptor agonists with conventional PD treatment, placebo, or no treatment.
Data collection and analysis
Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author.
Main results
Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double‐blind study of exenatide versus placebo randomised 62 participants, who self‐administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12‐week washout. One single‐blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self‐administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles‐Olmos 2013.
Exenatide versus placebo
Primary outcomes
We found low‐certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) Part III in the off‐medication state (mean difference (MD) ‐3.10, 95% confidence interval (CI) ‐6.11 to ‐0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD ‐3.5, 95% CI ‐6.7 to ‐0.3), exceeding the minimum clinically important difference (MCID).
We found low‐certainty evidence suggesting that exenatide has little or no effect on health‐related quality of life (HRQoL) as assessed by the Parkinson’s Disease Questionnaire (PDQ)‐39 Summary Index (SI) (MD ‐1.80, 95% CI ‐6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI ‐0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI ‐3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low‐certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76).
Exenatide versus no treatment
Primary outcomes at 14 months
We found very low‐certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS‐UPDRS Part III off medication (MD ‐4.50, 95% CI ‐8.64 to ‐0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ‐39 SI (MD 3.50, 95% CI ‐2.75 to 9.75; very low‐quality evidence). We found very low‐certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low‐certainty evidence suggesting that exenatide may lead to weight loss (MD ‐2.40 kg, 95% CI ‐4.56 to ‐0.24).
Primary outcomes at 24 months
We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS‐UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ‐39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8).
Authors’ conclusions
Low‐ or very low‐certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease‐modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non‐motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP‐1 receptor agonists.
Plain language summary
Can exenatide, a diabetes drug, be used to treat Parkinson’s disease?
Review question
To evaluate the effectiveness and safety of GLP‐1 receptor agonists for Parkinson’s disease.
Background
People with Parkinson’s disease (PD) have problems with movement, such as slow movement and shaking at rest. They may also have other problems such as depression, difficulty swallowing, and gastrointestinal dysfunction. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are used for treatment of type 2 diabetes. They work by stimulating GLP‐1 receptors in the pancreas, which causes the release of insulin. GLP‐1 receptors have also been found in the brain. Neurones in the brain send signals to and from the brain and the rest of the body. Insulin signalling in the brain is important for keeping neurones healthy, but it has been shown that insulin signalling does not work well in the brain of people with PD. Researchers are interested in finding out about the protective effects of GLP‐1 receptor agonists on neurones, and how these agonists might help people with disease affecting the brain, such as PD.
Study characteristics
We found two studies that provided data for a total of 104 patients (following dropout of three patients). One study compared exenatide (a GLP‐1 receptor agonist) versus placebo (a pretend medicine), and the other study compared exenatide versus no treatment (other than the usual treatment that people received). Evidence is current to June 2020.
Key results
We found low‐certainty evidence suggesting that people who took exenatide had better improvement in motor symptoms than people who took placebo. Movement was measured 12 weeks after patients had stopped taking exenatide. We found low‐certainty evidence suggesting that for people taking exenatide, there may be little or no difference in health‐related quality of life (HRQoL). Six serious adverse events (SAEs) were seen in people taking exenatide and two in people taking placebo, but all were considered by the study authors to be not related to the drug.
We found very low‐certainty evidence suggesting that people who took exenatide had better improvement in motor symptoms than people who received no treatment other than their usual care. Movement was measured two months after patients stopped taking exenatide. We found very low‐certainty evidence suggesting that exenatide compared to no treatment had little or no effect on HRQoL, and we found very low‐certainty evidence suggesting little or no difference in the number of SAEs among people taking exenatide.
Quality of evidence
The quality of evidence was low or very low. In one study, people not taking exenatide received their usual treatment only; thus, people in the study knew whether they were given extra treatment, and this may have changed the study results.
Conclusions
We are uncertain whether exenatide may improve motor symptoms for people with PD. The improvement in symptoms found in two small studies persisted for several weeks after people stopped taking the drug. This might mean that the drug has modified the disease process in some way. More studies with more people are needed so that we can be more sure whether GLP‐1 receptor agonists do help people with PD.
