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Meta-Analysis
. 2020 Jul 23;7(7):CD012990.
doi: 10.1002/14651858.CD012990.pub2.

GLP-1 receptor agonists for Parkinson's disease

Caroline A Mulvaney  1 , Gonçalo S Duarte  2   3 , Joel Handley  1   4 , David Jw Evans  1 , Suresh Menon  5 , Richard Wyse  6 , Hedley Ca Emsley  1   7
Affiliations
Meta-Analysis

GLP-1 receptor agonists for Parkinson's disease

Caroline A Mulvaney et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

CAM: none known.

GSD: none known.

JH: none known.

DE: none known.

SM: none known.

RW: none known.

HCAE: none known.

Figures

1
1
2 Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 1: PD motor impairment ‐ MDS‐UPDRS Part III (off medication)
1.2
1.2. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 2: HRQoL ‐ PDQ‐39 SI
1.3
1.3. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 3: HRQoL ‐ EQ5D
1.4
1.4. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 4: HRQoL ‐ EQ5D‐VAS
1.5
1.5. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 5: Adverse events ‐ weight loss (kg) (assessed at 48 weeks post baseline)
1.6
1.6. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 6: PD motor impairment ‐ MDS‐UPDRS Part III
1.7
1.7. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 7: PD motor impairment ‐ UDysRS
1.8
1.8. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 8: Non‐motor impairment ‐ MDS‐UPDRS Part I
1.9
1.9. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 9: Non‐motor impairment ‐ NMSQuest
1.10
1.10. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 10: Activities of daily living ‐ MDS‐UPDRS Part II
1.11
1.11. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 11: Psychological outcomes ‐ Mattis DRS
1.12
1.12. Analysis
Comparison 1: Exenatide vs placebo (60 weeks post‐baseline), Outcome 12: Psychological outcomes ‐ MADRS
2.1
2.1. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 1: PD motor impairment ‐ MDS‐UPDRS Part III (off medication)
2.2
2.2. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 2: HRQoL ‐ PDQ‐39 SI
2.3
2.3. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 3: Serious adverse events
2.4
2.4. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 4: Adverse events ‐ weight loss (kg) (assessed at 12 months (52 weeks))
2.5
2.5. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 5: PD motor impairment ‐ MDS‐UPDRS Part III
2.6
2.6. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 6: PD motor impairment ‐ Rush Dyskinesia Rating Scale
2.7
2.7. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 7: Non‐motor impairment ‐ MDS‐UPDRS Part I
2.8
2.8. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 8: Activities of daily living ‐ MDS‐UPDRS Part II
2.9
2.9. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 9: Psychological outcomes ‐ Mattis DRS
2.10
2.10. Analysis
Comparison 2: Exenatide vs no treatment (14 months (60.8 weeks) post baseline), Outcome 10: Psychological outcomes ‐ MADRS
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Update of

  • doi: 10.1002/14651858.CD012990

References

References to studies included in this review

Athauda 2017 {published data only}
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References to ongoing studies

Clinicaltrials.gov identifier: NCT02953665 {published data only}
    1. A phase II, randomized, double-blinded, placebo-controlled trial of liraglutide in Parkinson’s disease. Ongoing study. April 2017. Contact author for more information.
ClinicalTrials.gov Identifier: NCT03439943 {published data only}
    1. Study to evaluate the effect of lixisenatide in patients with Parkinson's disease (LixiPark). Ongoing study. June 2018. Contact author for more information.
ClinicalTrials.gov Identifier: NCT03659682 {published data only}
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Clinicaltrials.gov identifier: NCT04154072 {published data only}
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