A retrospective evaluation of glucagon-like peptide-1 receptor agonists in systemic lupus erythematosus patients

Abstract

Objectives

Glucagon-like peptide-1 receptor agonists (GLP1-RA) are an emerging class of medications with demonstrated promise in improving cardiometabolic outcomes. Whether these drugs may be useful in mitigating the cardiac risk associated with SLE remains unknown, and a recent case of drug-induced lupus secondary to GLP1-RA use calls the safety of GLP1-RAs in SLE patients into question. Accordingly, this retrospective analysis was initiated to evaluate outcomes of GLP1-RAs in SLE.

Methods

All patients in the NYU Lupus Cohort who had used a GLP1-RA were eligible for inclusion. Patient characteristics were assessed at baseline (most recent rheumatology visit prior to starting GLP1-RA), 1–4 months and 6–10 months after GLP1-RA initiation.

Results

Of the 1211 patients in the cohort, only 24 had received a GLP1-RA. Six were excluded due to insufficient documentation regarding duration of medication use. Of the remaining 18 (median age 50), 17 (94%) were female and nine (50%) were White. There was one mild-to-moderate flare at 6–10 months, but no patients accumulated new SLE criteria during the follow-up period. Compared with baseline, median BMI was reduced by 3% at 1–4 months (P = 0.002) and 13% at 6–10 months (P = 0.001). Nine (50%) patients were initially denied insurance coverage for a GLP1-RA.

Conclusion

While limited by a small sample size, this descriptive study showed that GLP1-RAs did not trigger flares above expected background rates and were associated with significantly decreased BMI. Future studies exploring the potential benefits of GLP1-RAs in patients with SLE are warranted.

Rheumatology key messages.

• GLP1-RAs were rarely used in SLE patients and were not associated with increased disease flares.

• GLP1-RAs were associated with a significant reduction in BMI after 1–4 months and 6–10 months of use.

• GLP1-RAs may be useful adjunctive agents for cardiovascular risk modification in SLE patients.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by heterogeneous clinical manifestations and can affect nearly any organ in the body [1]. The profound immune dysregulation resulting from SLE is associated with metabolic dysfunction and poor cardiac outcomes. For example, SLE patients suffer from higher rates of premature subclinical coronary artery disease and vascular inflammation and have up to a 50-fold increase in their risk of myocardial infarction [2–4]. This risk is likely exacerbated by glucocorticoids, which remain a mainstay of treatment for SLE [5]. Therefore, controlling traditional cardiovascular risk factors is a critical aspect of SLE management.

Glucagon-like peptide-1 receptor agonists (GLP1-RA) are an emerging class of medications that have shown significant promise in improving cardiometabolic outcomes [6]. While initially approved for glucose control, these agents have shown pleiotropic benefits, including cardiovascular risk reduction, weight loss, renal protection and anti-inflammatory effects, among others [6]. However, the rheumatology community has not systematically investigated a role for GLP1-RAs in reducing the cardiovascular risk associated with inflammatory diseases. As such, whether these drugs may be useful adjunctive agents to mitigate the metabolic dysfunction associated with corticosteroid use and the pathogenesis of SLE remains unknown, and the safety of GLP1-RAs in SLE patients has yet to be established. A recent case report describing drug-induced lupus, characterized by anti-double stranded DNA (anti-dsDNA) and anti-histone antibodies, secondary to GLP1-RA administration underscores these uncertainties and may cause some providers to limit the use of these drugs in SLE patients [7]. The impressive weight loss associated with GLP1-RAs has led to a recent surge in their popularity for this indication, which makes understanding their effect in SLE even more pressing [8]. Accordingly, this study utilized the NYU Lupus Cohort to retrospectively evaluate outcomes of SLE patients treated with GLP1-RAs.

Methods

Study design and patient population

The NYU Lupus Cohort is a prospective longitudinal convenience cohort initiated in 2014 that includes stored biospecimens from multiracial/multiethnic SLE patients with matched phenotypic data. Patients fulfilling either the American College of Rheumatology (ACR) [9], Systemic Lupus Erythematosus International Cooperating Clinics (SLICC) [10] and/or the European League Against Rheumatism (EULAR)/ACR classification criteria [11] for SLE, speaking English, Spanish or Mandarin, and willing to participate in research, are enrolled in the NYU Lupus Cohort at a routine rheumatology visit with a lupus specialist. Comprehensive clinical data including medications, lupus-related laboratory values and disease activity measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) – Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-Hybrid) are recorded at baseline and each visit thereafter [12]. All patients enrolled in the NYU Lupus Cohort as of June 2024 were eligible for inclusion. Patients were excluded if the timing of GLP1-RA initiation could not be verified in the medical chart. The cohort database was queried for all GLP1-RAs (both generic and brand names) and combined GLP1-RA/gastrin inhibitory peptide (GIP) agonists to identify relevant cases. Additional information not captured by the database including body mass index (BMI), duration of GLP1-RA use, the specialty prescribing a GLP1-RA, and insurance coverage for GLP1-RAs were retrospectively collected through chart review. The attainment of the definition of remission in SLE (DORIS) [13] and the SELENA-SLEDAI flare index [12] were also assessed. Clinical characteristics were evaluated at baseline (most recent rheumatology visit prior to starting GLP1-RA), and at 1–4 months and 6–10 months after GLP1-RA initiation. These timepoints were chosen based on the available follow-up data. The NYU Lupus Cohort study protocol was approved by the NYU and Bellevue Hospital Institutional Review Boards. All patients provided informed consent to be included in the NYU Lupus Cohort.

Statistics

Due to the small sample size, this was largely a descriptive analysis. Descriptive statistics are represented as N (%) for categorical variables and median (interquartile range) for continuous variables. A paired Wilcoxon signed-rank test was used to compare BMI at baseline and follow-up.

Results

Among the 1211 patients enrolled in the cohort, only 24 had received a GLP1-RA, with the first prescription recorded in the year 2019. Six patients were excluded from the analysis due to insufficient documentation regarding the duration of GLP1-RA use. Of the remaining 18 (median age 50, interquartile range: 37–55), 17 (94%) were female, nine (50%) were White, seven (39%) were Black and two (11%) were Hispanic. All patients were on GLP1-RAs for weight loss and only one had type 2 diabetes. In no case was the prescription written by rheumatology but rather six (33%) weight management, seven (39%) endocrinology, two (11%) bariatrics, two (11%) primary care and one (6%) unknown. Nine (50%) patients were initially denied insurance coverage for a GLP1-RA, but all received coverage after appealing or switching to a different agent in the same class.

At baseline, all but four patients were in DORIS remission. Of these four, two patients had alopecia, one had arthritis and one had both arthritis and a rash. None of the patients included had active nephritis (Table 1). There was follow-up data available for 16 patients at 1–4 months and 11 patients at 6–10 months. The SLEDAI manifestations present at baseline and follow-up for each patient are shown in Fig. 1. The patient with type 2 diabetes was patient number 12 in Fig. 1. This patient did not have any signs of clinically active lupus at the start of GLP1-RA therapy and remained clinically quiescent throughout the follow-up period. At 1–4 months, one patient developed recurrent leukopenia, but disease activity either improved or remained the same for all others (Table 1 and Fig. 1). There was one mild-to-moderate flare assessed by the SELENA-SLEDAI flare index at 8 months (Fig. 1). This was observed in a 36-year-old female diagnosed with SLE five years prior to starting a GLP1-RA. Her clinical SLE activity, which included relapsing and remitting alopecia, arthritis, pleuritis and rash, had been well controlled for approximately one year before this documented flare. The flare resolved after increasing her mycophenolate dose and her treating physician did not identify a specific clinical trigger. No other flares were observed during the follow-up period (Fig. 1). In total, three (27%) patients developed low complement and/or anti-dsDNA antibodies at 6–10 months and two (18%) patients developed alopecia (Table 1 and Fig. 1). While this activity was not present at baseline, in each case these laboratory or clinical abnormalities occurred previously and represented recurrent activity. Their rheumatologists did not note any apparent cause for the recurrent manifestations, and none of these patients required medication changes as a result. No patients accumulated new SLE criteria during the follow-up period. There was a significant reduction in median BMI of 3% from baseline at 1–4 months (P = 0.002) and 13% at 6–10 months (P = 0.001) (Table 1).

Table 1.

Clinical characteristics prior to and at 1–4 months or 6–10 months after GLP1-RA initiation

	All patients	Patients with 1–4 months of follow-up data		Patients with 6–10 months of follow-up data
Clinical characteristic	Pre GLP1-RA	Pre GLP1-RA	1–4 months on GLP1-RA	Pre GLP1-RA	6–10 months on GLP1-RA
	N = 18	N = 16	N = 16	N = 11	N = 11
Months prior to or after GLP1-RA initiation	2 (1–5)	3 (1–5)	2 (2–3)	4 (1–6)	8 (7–9)
SLEDAI scoreb	2 (0–2)	2 (0–2)	1 (0–2)	2 (0–2)	2 (2–3)
In DORIS remission	14 (78%)	13 (81%)	14 (88%)	8 (73%)	7 (64%)
Anti-dsDNA positivity	8 (47%) N = 17	8 (53%) N = 15	7 (47%) N = 15	4 (40%) N = 10	6 (55%)
Low complement	1 (6%)	1 (6%)	0 (0%) N = 14	0 (0%)	2 (18%)
C3 (mg/dL)	121 (113–132)	119 (113–134)	120 (103–147) N = 14	121 (113–131)	124 (98–135)
C4 (mg/dL)	24 (18–33)	24 (18–34)	28 (20–39) N = 14	24 (20–33)	22 (18–32)
Thrombocytopenia	0 (0%)	0 (0%)	0 (0%) N = 15	0 (0%)	0 (0%)
Leukopenia	0 (0%)	0 (0%)	1 (7%) N = 15	0 (0%)	0 (0%)
Serum creatinine (mg/dL)	0.82 (0.75–0.86)	0.82 (0.75–0.87)	0.81 (0.73–0.87) N = 15	0.75 (0.74–0.83)	0.85 (0.79–0.91)
UPCR (g/g)	0 (0–0.08) N = 17	0 (0–0.16) N = 15	0.03 (0–0.08) N = 15	0.02 (0–0.08) N = 10	0.03 (0–0.06)
Hydroxychloroquine	14 (78%)	13 (81%)	13 (81%)	8 (73%)	8 (73%)
Prednisone or equivalent	1 (6%)	1 (6%)	1 (6%)	0 (0%)	0 (0%)
Immunosuppressiona	9 (50%)	8 (50%)	8 (50%)	5 (45%)	5 (45%)
BMI kg/m2	35.2 (31.8–36.8)	35.8 (32.0–37.3)	34.2 (29.4–36.3)	35.7 (33.5–36.5)	30.1 (28.2–33.5)
BMI percent change from baseline			–3.3 (–0.9–7.7)		–13.2 (–8.0–17.4)
Wegovy (Semaglutide)			7 (44%)		5 (45%)
Ozempic (Semaglutide)			4 (25%)		4 (36%)
Mounjaro (Tirzepatide)			2 (13%)		1 (9%)
Zepbound (Tirzepatide)			2 (13%)		0 (0%)
Trulicity (Dulaglutide)			1 (6%)		1 (9%)

Data represented as median (IQR) or N (%). N is specified where it differs from the overall sample size due to missing data.

^aImmunosuppression included azathioprine, methotrexate, belimumab, mycophenolate and/or rituximab.

^bSLEDAI was calculated even when laboratory studies were not available, where blood and/or urine was missing is noted in Table 1.

BMI: body mass index; DORIS: definition of remission in SLE; SLEDAI: systemic lupus erythematosus disease activity index; UPCR: urine protein : creatinine ratio.

Figure 1.

Map of SLEDAI domains affecting patients at each visit. Only those SLEDAI components present at any timepoint were included. Each row represents one patient. Green = presence of that manifestation; white = absence of that manifestation; grey = missing data. Patient 12 had type 2 diabetes

Discussion

In this retrospective analysis, GLP1-RAs were rarely used by SLE patients in the cohort. For those few who did receive them, these agents did not trigger any new clinical SLE manifestations, and only one mild-to-moderate flare was observed during the follow-up period. Significant weight loss was observed at 1–4 months and 6–10 months after starting a GLP1-RA and half of patients faced insurance rejections for these medications.

Studies evaluating the impact of GLP1-RAs in inflammatory arthritic conditions are severely lacking. A recent scoping review of the existing literature by Karacabeyli and Lacaille found only limited data on the use of these agents in rheumatoid arthritis, psoriatic arthritis and gout [14]. These authors identified no studies on ankylosing spondylitis, systemic sclerosis or SLE [14]. The absence of established safety data in patients with pre-existing autoimmunity is particularly problematic in light of a recent report describing a case of apparent semaglutide-induced lupus [7]. In that case report, Castellanos and colleagues present an elderly woman who was found to have liver injury along with low complement and autoantibodies including anti-dsDNA, anti-histone, anti-mitochondrial M2 and anti-smooth muscle antibodies three months after initiating semaglutide [7]. This raises serious questions about the potential effects of these medications in patients who have already broken immune tolerance. In our study, there was only one observed mild-to-moderate flare and no severe flares during the follow-up period. This was not above the expected background flare rates previously observed in longitudinal SLE cohorts and clinical trials, which should be reassuring to physicians and their SLE patients considering starting a GLP1-RA [12, 15, 16]. For example, in the oral contraceptive (OC)-SELENA and hormone replacement therapy (HRT)-SELENA studies, 60% and 50% of patients receiving a placebo, respectively, experienced at least one mild or moderate flare during the 12 month follow-up periods [12, 17].

GLP1-RAs offer significant cardiac and renal protection and promote weight loss [6]. In SLE, the risk of cardiovascular disease is increased likely by the inflammatory milieu associated with disease pathogenesis and treatment with corticosteroids [3, 5]. In addition, SLE patients with obesity report lower health-related quality of life and, in some studies, obesity is associated with more severe SLE disease activity [14]. Consequently, GLP1-RAs are potentially attractive adjunctive agents for modifying cardiovascular risk and improving patient-reported outcomes. In this study GLP1-RAs were associated with significant weight loss with a reduction in median BMI of 5.6 kg/m² 6–10 months after starting the medication. This is a promising observation and warrants prospective longitudinal studies to determine whether this translates to improvement in other markers of cardiovascular health and quality of life. GLP1-RAs also have demonstrated efficacy in protecting diabetic kidneys by reducing albuminuria [6, 18]. Up to 60% of SLE patients develop lupus nephritis which is characterized by proteinuria and can lead to end-stage renal disease requiring dialysis or transplant [19]. Though no patients in this study had active lupus nephritis, future investigations should evaluate a possible role for GLP1-RAs in reducing the proteinuria and resultant kidney injury associated with lupus nephritis.

Despite the potential benefits of GLP1-RAs, their use in SLE patients at our institution was rare with no rheumatologists prescribing them. This suggests that rheumatologists have not yet adopted these agents as risk modifiers. The reason for this is unclear, but it may be due to the absence of data on the efficacy of GLP1-RAs in this patient population, as well as a lack of familiarity and comfort among rheumatologists with these medications. In addition, half of patients were initially denied insurance coverage for these drugs. If prospective studies confirm the benefits suggested by this study, these challenges need to be addressed to facilitate appropriate implementation by rheumatologists. GLP1-RAs are now part of guideline-directed therapy for patients with type 2 diabetes to reduce cardiovascular risk and to slow chronic kidney disease progression [20]. Yet, these medications are still underutilized by cardiologists because of similar barriers [20]. A systems-based multidisciplinary educational approach has recently been shown to overcome these challenges associated with GLP1-RAs and could be used as a model to increase prescriptions in SLE patients should efficacy be proven in this population [20].

This study had several limitations. It was representative of real-world GLP1-RA use but was limited by its retrospective nature and small sample size. The population included had relatively quiescent baseline disease activity and were mostly middle-aged females. In addition, while minority patients were significantly represented, no Asians were included, and all patients were treated by rheumatologists with expertise in SLE, which limits the generalizability of the findings. As a retrospective study, follow-up time and medication dosing was not standardized and varied between patients. Only medications that patients are currently taking at each visit are recorded in the NYU Lupus Cohort database. Therefore, any patients who were prescribed a GLP1-RA but never started the drug likely were not captured.

In summary, while limited by a small sample size, this retrospective study showed that GLP1-RAs did not trigger new clinical SLE manifestations and were associated with significantly decreased BMI. Future studies exploring the potential benefits of GLP1-RAs in patients with SLE are warranted.

Data availability

Data underlying this article are not publicly available to preserve the privacy of patients included. Data can be shared upon reasonable request to the corresponding author.

Funding

The NYU Lupus Cohort and this project were supported by the Centers for Disease Control and Prevention (CDC) of the US Department of Health and Human Services (HHS) under grant U01 DP006700 and grant 6U48DP006396-03-01. The Cohort was also supported by the National Institutes of Health, Bethesda, MD under grant P50 AR07059.

Disclosure statement: P.I. has declared consulting for Hansoh Bio. All other authors have no disclosures.