Use of semaglutide and tirzepatide among people with multiple sclerosis

Abstract

Background and Objectives:

Little is known about glucagon-like peptide-1 receptor agonists (GLP1RAs) use in multiple sclerosis. We described the frequency and characteristics associated with use.

Methods:

A cross-sectional survey of NARCOMS Registry participants captured use of GLP1RAs semaglutide and tirzepatide. Multivariable logistic regression explored factors associated with use.

Results:

Among 4181 eligible participants, 7.4% had ever and 5.5% currently used these GLP1RAs. Ever users were younger and had more cardiometabolic conditions. 37.3% of never users had an indication for GLP1RAs.

Discussion:

Despite 40% having an indication for taking GLP1RAs, a small percentage of surveyed persons with multiple sclerosis used them.

Keywords

Multiple sclerosis glucagon-like peptide-1 receptor agonists pharmacoepidemiology

Introduction

About 12% of adults in the United States use glucagon-like peptide-1 receptor agonists (GLP1RAs), a new class of medications which improve glycemic control in type 2 diabetes and cardiovascular outcomes.¹ Although interest in the potential benefits of GLP1RAs in multiple sclerosis (MS) is rising, we know little about their use in people with MS (PwMS). Two small, single-site retrospective studies in PwMS reported they were safe and tolerable.^2,3 Yet, further information would guide future studies seeking to understand their risks and benefits in PwMS. The study aimed to describe the frequency with which PwMS in the NARCOMS Registry have used GLP1RAs and their characteristics.

Methods

The NARCOMS Registry, a self-report registry for PwMS described elsewhere,⁴ investigated the utilization of the most commonly prescribed GLP1RAs among participants in our Fall 2024 survey in addition to sociodemographic and clinical questions. Participants indicated whether they had ever taken or were currently taking either semaglutide and/or tirzepatide (GLP1RAs herein). Based on their responses, we categorized participants as ever users, current users, and never users.

Covariates

Enrollment questionnaires capture birthdate, race, ethnicity, educational attainment, sex, and age of MS symptom onset. The fall 2024 questionnaire captured sociodemographic factors (e.g. annual household income, health insurance, employment, marital status), health behaviors, disability (measured using Patient-Determined Disease Steps [PDDS]),⁵ height, weight, and comorbidities. We determined body mass index (BMI) from height and weight. BMI was categorized as underweight (< 18.5 kg/m²), normal (18.5–25 kg/m²), overweight (>25–29.9 kg/m²), and obese (>30 kg/m²). Comorbidities (present/absent) captured were acne rosacea, anxiety, autoimmune thyroid disease, cancer, depression, diabetes mellitus, fibromyalgia, heart attack, hypertension, high cholesterol, heart trouble, irritable bowel syndrome, lung trouble, osteoporosis, polycystic ovary syndrome, psoriasis, sleep apnea, and stroke using a validated questionnaire.⁶ Obesity (BMI > 30 kg/m²) was included as a comorbidity. The number of total comorbidities and cardiometabolic comorbidities (diabetes mellitus, heart attack, hypertension, high cholesterol, heart trouble, obesity, stroke) were summed and categorized as 0, 1, 2, or ⩾3.

Statistical analysis

Responders missing age or sex (n = 9), reporting unconfirmed MS diagnoses (n = 14), living outside the United States (n = 88), and who did not answer the GLP1RAs questions (n = 405) were excluded. Participants considered as meeting the criteria for the FDA-approved indication (Supplemental Table 1) were defined as having either a BMI ⩾ 30, a BMI ⩾ 27 and at least one cardiometabolic condition (including diabetes) or sleep apnea. We used analysis of variance, chi-square, and logistic regression to examine factors associated with ever and current use. Multivariable logistic regression models used a stepwise selection method with BIC indices to select covariates for inclusion from those described above. We report adjusted odds ratios (OR), 95% confidence interval [95% CI], and Hosmer–Lemeshow goodness-of-fit test (HLGOF).

Results

Of 6582 participants invited to participate, 4697 (71.4%) responded, of whom 4181 (89.0%) met eligibility criteria. Non-responders were more likely to identify as Black, had less education, and more disability than responders (Supplemental Table 2).

Overall, 301 (7.4%) participants reported ever using these medications and 222 (5.5%) were currently users. Ever users were more likely to have shorter MS disease duration, identify as Black, have a relapsing disease course, be employed, have more comorbidities, and lower alcohol intake (Table 1). Characteristics of current and ever users were similar as were their differences from never users (Table 1).

Table 1.

Characteristics of study participants by glucagon-like peptide-1 receptor agonist use status.

	Ever(N = 301)	Current(N = 222)	Never(N = 3765)	Ever versus neverp-value	Current versus neverp-value
Age	62.6 (9.4)	61.1 (8.8)	64.7 (9.9)	<0.01 ^a	<0.01 ^a
Female, n (%)	257 (85.4)	189 (85.1)	3092 (82.1)	0.15^b	0.25^b
Race, n (%)				<0.01 ^b	<0.01 ^b
White	248 (82.4)	183 (82.4)	3329 (88.4)
Black/African American	14 (4.7)	11 (5.0)	72 (1.9)
Other	39 (13.0)	28 (12.6)	363 (9.6)
BMI	32.8 (7.8)	32.5 (7.5)	27.3 (17.6)	<0.01 ^a	<0.01 ^a
BMI categories, n (%)				<0.01 ^b	<0.01 ^b
Normal weight	38 (12.6)	27 (12.2)	1524 (40.5)
Underweight	5 (1.7)	2 (0.9)	249 (6.6)
Overweight	84 (27.9)	70 (31.5)	1088 (28.9)
Obese	174 (57.8)	123 (55.4)	904 (24.0)
Education level at enrollment, n (%)				0.21^b	0.23^b
High school/GED or less	123 (43.3)	91 (43.8)	1418 (39.5)
>Post-secondary	161 (56.7)	117 (56.3)	2168 (60.5)
Missing	17	14	179
Annual household income, n (%)				0.07^b	0.02 ^b
Less than $50,000	85 (28.6)	51 (23.3)	1014 (27.1)
$50,0001-$100,000	74 (24.9)	61 (27.9)	920 (24.6)
Over $100,000	87 (29.3)	70 (32.0)	927 (24.8)
I do not wish to answer	51 (17.2)	37 (16.9)	878 (23.5)
Missing	4	3	26
Has health insurance, n (%)	282 (97.9)	211 (98.1)	3577 (99.3)	<0.01 ^b	0.05^b
Single, n (%)	99 (33.0)	70 (31.7)	1239 (33.1)	0.98^b	0.67^b
Not employed, n (%)	194 (64.5)	135 (60.8)	2839 (75.4)	<0.01 ^b	<0.01 ^b
Age at MS symptom onset	31.2 (9.60)	31.0 (9.46)	31.6 (9.98)	0.59^a	0.39^a
Age at MS diagnosis	38.7 (9.06)	38.3 (8.89)	38.8 (9.87)	0.82^a	0.45^a
Disease Duration	24.5 (9.03)	24.6 (8.57)	27.1 (9.59)	<0.01 ^a	<0.01 ^a
Clinical course, n (%)				<0.01 ^b	<0.01 ^b
CIS/RRMS	196 (66.2)	148 (68.2)	1994 (54.7)
Primary or secondary progressive	85 (28.7)	59 (27.2)	1369 (37.5)
PDDS, median (25th, 75th)	3.0 (1.0, 5.0)	3.0 (1.0, 5.0)	3.0 (1.0, 6.0)	0.16^a	0.09^a
Number of comorbidities, n (%)				<0.01 ^b	<0.01 ^b
0	10 (3.3)	9 (4.1)	416 (11.1)
1	28 (9.3)	19 (8.6)	675 (18.0)
2	38 (12.6)	28 (12.6)	830 (22.1)
⩾3	225 (74.8)	166 (74.8)	1830 (48.8)
Missing	0	0	14
Number of cardiometabolic comorbidities, n (%)				<0.01 ^b	<0.01 ^b
0	64 (21.3)	50 (22.6)	1490 (39.9)
1	78 (26.0)	50 (22.6)	1223 (32.7)
2	67 (22.3)	50 (22.6)	735 (19.7)
⩾3	91 (30.3)	71 (32.1)	289 (7.7)
Missing	1	1	28
Diabetes, n (%)	135 (45.6)	103 (47.2)	237 (6.5)	<0.01 ^b	<0.01 ^b
Obesity, n (%)	174 (57.8)	123 (55.4)	904 (24.0)	<0.01 ^b	<0.01 ^b
Current smoker, n (%)	11 (3.7)	9 (4.1)	191 (5.1)	0.28^b	0.52^b
Alcohol intake, n (%)				<0.01 ^b	0.01 ^b
Never	129 (42.9)	92 (41.4)	1483 (39.4)
Monthly or less	102 (33.9)	73 (32.9)	958 (25.5)
Two to four times per month	39 (13.0)	31 (14.0)	571 (15.2)
Two to three times per week	17 (5.6)	14 (6.3)	356 (9.5)
Four or more times per week	14 (4.7)	12 (5.4)	393 (10.5)
Missing	0	0	4
Physically active, n (%)	154 (51.7)	118 (53.6)	2301 (61.9)	<0.01 ^b	0.01 ^b
Currently taking DMT, n (%)	154 (52.7)	115 (53.0)	1647 (44.9)	<0.01 ^b	0.02 ^b

CIS = clinically isolated syndrome; RRMS = relapsing-remitting MS; PDDS = patient-determined disease steps; DMT = disease-modifying therapy.

ANOVA F-test p-value.

Chi-square p-value.

Of participants, 40.4% (n = 1644) met the FDA-approved indication for GLP1RA use; 14.6% of whom were ever users. Users had an average age of 63 (8.7) and 37.2% had ⩾ 3 cardiometabolic comorbidities (Supplemental Table 3). Figure 1 displays the overlap in the presence of specific cardiometabolic comorbidities, obesity and those reporting no physical activity among those meeting the indication by group. In those who met the indication for GLP1RA use, older age was associated with lower odds of ever using these medications (0.66 [0.57–0.77]) whereas having 2 or ⩾ 3 cardiometabolic conditions was associated with elevated odds of use (1 vs 0: 1.3 [0.78–2.00]; 2 vs 0: 2.1 [1.26–3.34]; ⩾ 3 vs 0: 5.6 [3.48–9.12]; HLGOF: $χ_{8}^{2}$ = 8.7, p = 0.36).

Figure 1.

Number of participants with health conditions and no physical activity among those meeting the indication for a glucagon-like peptide-1 receptor agonist by use status (a. ever, b. never).

Discussion

Overall, about 1 in 14 PwMS reported ever using GLP1RAs. Although 40% of individuals had an indication for use, only 14.6% had ever taken a GLP1RA. Over one-third of PwMS with diabetes and 16% of those with obesity were taking GLP1RAs. Limited data on the relative prevalence of indications for and uptake of GLP1RAs exists, but one study at a large Midwest health system in 2023–2024 found that over 60% had an indication for use; uptake was approximately 30% for those with diabetes or obesity.⁷

GLP1RAs have safety and tolerability issues, primarily gastrointestinal. Bowel dysfunction is a frequent and early symptom in PwMS; this could reduce tolerability and dissuade people from considering them.⁸ There are other contraindications and precautions which vary across GLP1RAs. Other potential concerns could include visual complications, cost, concerns around polypharmacy, and unknown impact on MS disease. We could not investigate the effect of these medications on these areas as we did not ask details on duration, adherence, side effects and studied only two commonly prescribed GLP1RAs in 2024 which could underestimate their contraindications and barriers to use. Other study limitations include the voluntary nature of NARCOMS participants, response rate of 71.4%, cross-sectional and self-report nature of the study and potential lack of generalizability to young MS populations.

GLP1RAs have benefits on obesity and cardiovascular disease which is important as these conditions have been associated with adverse outcomes in PwMS,⁹ suggesting there could be secondary benefits on MS. Calorie restriction has improved cognition and produced beneficial changes in metabolic and immunological markers among PwMS.¹⁰ However, in one single-center retrospective study, PwMS treated with GLP1RAs lost an average of 3.7% (10.6%) in BMI and had increased vitamin D levels, but no changes in disability were observed.³ Yet, these medications have the potential to address a modifiable risk factor more efficiently than behavioral approaches alone.

Our findings show that while PwMS use GLP1RAs, over half of never users in our population have an indication for use. The widespread use of GLP1RAs in PwMS supports intervention studies exploring if these therapies might be beneficial in MS.

Supplemental Material

sj-docx-1-msj-10.1177_13524585261442033 – Supplemental material for Use of semaglutide and tirzepatide among people with multiple sclerosis

Supplemental material, sj-docx-1-msj-10.1177_13524585261442033 for Use of semaglutide and tirzepatide among people with multiple sclerosis by Amber Salter, Alexis Novak, Samantha Lancia, Gary R Cutter, Robert J Fox and Ruth Ann Marrie in Multiple Sclerosis Journal

Footnotes

Acknowledgements

NARCOMS is a project of the Consortium of Multiple Sclerosis Centers (CMSC). NARCOMS is funded in part by the CMSC and the Foundation of the CMSC. The study was also supported in part by the Multiple Sclerosis Clinical Research Chair (to R.A.M.). The funding source(s) had no role in the study design, collection, analysis or interpretation of the data, nor in the decision to submit the article for publication.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.S. receives research funding from the National Multiple Sclerosis Society, CMSC, and the Department of Defense Congressionally Directed Medical Research Program, is a member of editorial board for Neurology, she serves as a consultant for Gryphon Bio, LLC, Abata Therapeutics and Sora Neuroscience and has equity in Owl Therapeutics, is a member of the Data and Safety Monitoring Board for Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), Video Telehealth Pulmonary Rehabilitation to Reduce Hospital Readmission in Chronic Obstructive Pulmonary Disease (Tele-COPD), P3 EQUATE Health Equity Research Network and Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH), and holds the Kenney Marie Dixon-Pickens Distinguished Professorship in Multiple Sclerosis Research. A.N. reports no disclosures relevant to the manuscript. G.R.C. serves on Data and Safety Monitoring Boards for Applied Therapeutics, AI therapeutics, AMO Pharma, Argenx, Astra-Zeneca, Avexis Pharmaceuticals, Bristol Meyers Squibb, CSL Behring, Cynata Therapeutics, DiamedicaTherapeutics, Horizon Pharmaceuticals, Immunic, Inhibrix, Karuna Therapeutics, Kezar Life Sciences, Medtronic, Merck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma Holdings, Prothena Biosciences, Novartis, Pipeline Therapeutics (Contineum), Regeneron, Sanofi-Aventis, Teva Pharmaceuticals, United BioSource LLC, and University of Texas Southwestern. He serves on Consulting or Advisory Boards for Alexion, Antisense Therapeutics/Percheron, Avotres, Biogen, Clene Nanomedicine, Clinical Trial Solutions LLC, Endra Life Sciences, Cognito Therapeutics, Genzyme, Genentech, Immunic, Klein-Buendel Incorporated, Kyverna Therapeutics, Inc., Linical, Merck/Serono, Noema, Neurogenesis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Revelstone Consulting, Roche, SAB Biotherapeutics, Sapience Therapeutics, Scott&Scott LLP, and Tenmile. G.R.C. is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. R.J.F. receives personal consulting fees from Astoria Biologica, Biogen, Bristol Myers Squibb, Cognito, EMD Serono, Galvani, Immunic, INmune Bio, Kiniksa, Novartis, Sanofi, Siemens, TG Therapeutics, and Viracta, has served on advisory committees for AB Science, Biogen, Immunic, Novartis, and Sanofi, and received clinical trial contract and research grant funding from Biogen, Novartis, Sanofi, and Synaptogenix. R.A.M. receives research funding from CIHR, MS Canada, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society, Public Health Agency of Canada, MMSF, CHRIM, Pfizer Foundation, and the US Department of Defense, is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada, holds the Multiple Sclerosis Clinical Research Chair (Dalhousie University), and serves on the editorial board of Neurology. S.L. reports no disclosures relevant to the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Amber Salter

Alexis Novak

Samantha Lancia

Gary R Cutter

Robert J Fox

Ruth Ann Marrie

Data Availability Statement

The data sets generated and analyzed during this study are held by the NARCOMS Registry (narcoms.org).

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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