Levodopa Efficacy and GLP‐1 Receptor Agonists

We report the case of a 62‐year‐old female with a 14‐year history of Parkinson's disease (PD) well controlled on 2 carbidopa/levodopa (L‐dopa) (Rytary) extended‐release capsules (36.25–145 mg) 5–6 times per day for the prior year. In May 2025, she began taking semaglutide (Ozempic) 0.25 mg subcutaneously once weekly to lose weight. She reported an immediate, severe delay of 3–6 hours (worse after food intake) in L‐dopa “ON” time, compared to a 1 hour delay prior to starting semaglutide. In response, the patient took multiple additional doses of the extended‐release capsules on her own, leading to “ON” time with severe dyskinesia at night. She chose to continue weekly semaglutide because it lowered her cholesterol levels and resulted in approximately 5.44 kg of weight loss. In a second similar case, a 56‐year‐old woman whose Parkinsonian tremor had previously responded to L‐dopa (Sinemet CR 25/100 TID) reported that her tremor no longer responded to L‐dopa after starting tirzepatide (Zepbound). Other antiparkinson medications tried after starting Zepbound included rasagiline 1 mg daily, carbidopa (Lodosyn) 25 mg three times a day, and carbidopa‐ L‐dopa (Rytary)23.75/95 mg ER capsule three times a day. She did report improved tremor by switching to the rotigotine patch after increasing to 6 mg daily; however, this caused severe hypotension.

We wished to examine whether delayed “ON” time had been previously reported with glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) and were surprised to find no previous case reports, despite the fact that GLP‐1RA drugs are reported to delay the absorption of other oral medications. A systematic review of injectable GLP‐1RAs and oral medications found that, due to delayed gastric emptying, the GLP‐1RAs reduce the Cmax and delay the Tmax of multiple orally administered drugs (including warfarin, contraceptive pills, and digoxin), although they do not affect the overall area under curve (AUC). ¹ The interaction with oral Parkinson's medications has not been specifically studied. A 2013 study of an older GLP‐1RA, exenatide, in PD reported that one participant “withdrew due to worsening PD (recurrent L‐dopa dose failures).” ² However, the total number of dose failures was higher in the control arm of two published trials of Exenatide ^{2 , 3} and was not different between the treatment arms of the Phase III trial of extended release exenatide (Table 1). ⁴

TABLE 1.

Reported L‐dopa failures and disease progression in participants of the EXPD1, EXPD2, and EXPD3 trials. [unpublished data from Drs. Girges and Foltynie]

Trial	Formulation	N	Levodopa dose failures		Worsening of Parkinson's disease		Reference
			Exenatide	Control	Exenatide	Control
EXPD1 (open label)	Exenatide short‐acting	44	4	12	Not reported	Not reported	2
EXPD2	Exenatide extended release	60	8	12	0	1	3
EXPD3	Exenatide extended release	194	4	3	20	18	4

We hypothesize that semaglutide and tirzepatide may be associated with greater delays in L‐dopa “ON” time compared to exenatide because semaglutide is reported to cause the greatest number of gastrointestinal side effects, whereas exenatide ER causes the fewest. ⁵ With the dramatic increase in GLP‐1RA consumption and a projected expansion of its use across populations and indications in the near future, the impact of GLP‐1RA on oral PD medications should be studied.

Author Roles

(1) Manuscript: A. Conceptualization, B. Drafting, C. Revision; (2) Data Analysis: A. Data acquisition, B. Analysis and interpretation.

C.M.: 1B, 1C, 2B.

C.G.: 1C, 2A, 2B.

T.F.: 1C, 2A, 2B.

A.W.: 1A, 1B, 1C, 2B.

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Patient informed consent was obtained for this manuscript. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors declare that there are no conflicts of interest relevant to this work. Catherine Martinez: No specific funding was received for this work. Dr. Christine Girges: No specific funding was received for this work. Dr. Thomas Foltynie: Dr. Foltynie has received grants from National Institute of Health Research, Michael J. Fox Foundation, Cure Parkinson's, for work related to Exenatide. Dr. Anne‐Marie Wills: No specific funding was received for this work.

Financial Disclosures for the Previous 12 Months: Catherine Martinez: The author declares that there are no additional disclosures to report. Dr. Christine Girges: The author declares that there are no additional disclosures to report. Dr. Thomas Foltynie: Advisory boards, Advisory Boards for AbbVie, Lilly & Bial. Honoraria, honoraria for talks sponsored by Bial. Grants, Grants from National Institute of Health Research, Edmond J Safra Foundation, Michael J. Fox Foundation. Dr. Anne‐Marie Wills: Consulting fees, Novartis—Steering Committee Member, Ono Pharmaceuticals—Steering Committee Member, Amylyx Pharmaceuticals—Consulting agreement, Roche/Genentech—Steering Committee Member. Support for attending meetings and/or travel, Movement Disorders Society. Participation in clinical trials, Has participated in clinical trials sponsored by Biohaven, Bial, Ferrer, Amylyx, Ono, Roche/Genentech, and Biogen. Additional funding, Has received funding from the NIA/NIH and the Parkinson's Foundation.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.