The Association between Glucagon-like Peptide-1 Receptor Agonist and Major Adverse Cardiac and Cerebrovascular Events in Monoclonal Gammopathy of Undetermined Significance: A Propensity-Score Analysis
Authors: Song Junmin , Deshpande Shweta Ravindra , Chang Yu-Cheng , Chiang Cho-Han , Ahn Jaeun , Caceres Lessa Ana Yasmin , Soni Anushri , Gonzales Anthony , Lee Pei-Lun , Chang Yu , Parker Terri L. , Kwan Jennifer , Chi Kuan-Yu , Nanna Michael G. 
Published: December 2024

Background
Recent studies have demonstrated a significant burden of cardiovascular risk factors and major adverse cardiac and cerebrovascular events (MACCE) among patients with monoclonal gammopathy of undetermined significance (MGUS), though the safety and efficacy of available cardiovascular treatments in this patient population are relatively unknown. We set out to investigate the association of glucagon-like peptide-1 receptor agonists (GLP-1 RA) use with future MACCE in MGUS patients with diabetes mellitus (DM).
Methods
A retrospective propensity score-matching analysis (PSM) was conducted using aggregate data from the TriNetX Global database, comprising over 120 million individuals from 126 healthcare organizations, to establish the comparative effectiveness of GLP-1 RA use versus non-use for the hazard of future MACCE. Adult patients diagnosed with MGUS between January 1st, 2019, and July 15th, 2022, were identified. Patients with a prior or current diagnosis of multiple myeloma (serum M protein ≥3g/dL or bone marrow clonal plasma cells ≥10%), a history of polyclonal gammopathy, or amyloidosis were excluded. Patients were subsequently subdivided into two arms: GLP-1 RA users and non-users. GLP-1 RA users were defined as those carrying the diagnosis of type 2 DM and having at least one prescription of GLP-1 RA within 1 year before the MGUS diagnosis. GLP-1 RA non-users were diabetic patients who were treated with any non-GLP-1 RA anti-DM medications, including metformin, dipeptidyl peptidase 4 inhibitors (DPP4i), insulin, sulfonylureas, sodium-glucose co-transporter 2 inhibitors (SGLT2i), thiazolidinediones, or alpha-glucosidase inhibitors within 1 year before the MGUS diagnosis. Those who had any record of GLP-1RA use before the MGUS diagnosis were excluded from the GLP-1 RA non-user arm. The date of the first MGUS diagnosis was set as the study index date. The primary endpoint was MACCEs, defined as a composite of all-cause mortality, acute decompensated heart failure (HF), myocardial infarction (MI), or ischemic stroke/transient ischemic attack (TIA). Secondary endpoints were individual components of the MACCE composite. Urinary tract infection (UTI) and a composite of femoral, lumbar, and pelvic fractures were set as falsification endpoints. The two cohorts were matched in a 1:1 ratio utilizing the greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standard deviations. Differences in baseline characteristics between the two groups were compared using standardized mean differences (SMD) after PSM, with an SMD &lt;0.10 indicating balanced characteristics. The outcomes were compared within 2 years of the index date between GLP-1 RA users and non-users.
Results
Over the study period, a total of 89,091 MGUS patients were identified, including 1,063 GLP-1 RA users and 8,039 non-users. After PSM, both GLP-1 RA users and non-users were matched into 1,039 patients, respectively. The two matched cohorts were characterized by a similar mean age (66.2 vs 66.1 years), race (black patients 22.9% vs 23.0%), sex (females 47.4% vs 47.7%), BMI (34.9 vs 33.9), and hemoglobin A1c level (7.7% vs 7.6%). Co-morbidities between the two cohorts including hypertension (85.6% vs 83.8%), chronic kidney disease (49.6% vs 46.0%), ischemic heart disease (38.0% vs 37.2%), atrial fibrillation/flutter (14.2% vs 13.0%) and HF (24.4% vs 22.9%) were also similar. Baseline use of guideline-directed medical therapy for HF, loop diuretics (39.4% vs 38.1%), statins (76.8% vs 78.2%), and anticoagulants (44.2% vs 43.2%) were also balanced between the two cohorts. Baseline GLP-1 RA use was associated with significantly lower 2-year MACEs (HR, 0.81; 95% CI, 0.70 to 0.94) compared with non-use. Secondary endpoints revealed that GLP-1 RA use was associated with significant reductions in all-cause mortality (HR, 0.69; 95% CI, 0.52 to 0.92) and decompensated HF (HR, 0.75; 95% CI, 0.62 to 0.92), but not MI (HR, 0.83; 95% CI, 0.63 to 1.10) and ischemic stroke/TIA (HR, 1.08; 95% CI, 0.82 to 1.44) when compared to non-users. Two falsification endpoints, UTI (HR, 0.98; 95% CI, 0.78 to 1.23) and fractures (HR, 1.07; 95% CI, 0.75 to 1.53), were comparable between the two arms.
Conclusions
GLP-1 RA use was associated with significant reductions in 2-year MACEs, primarily driven by reductions in all-cause mortality and decompensated HF in MGUS patients with type 2 DM.