Introduction:

Monoclonal gammopathy of undetermined significance (MGUS) is associated with increased risk of cardiovascular disease (CVD) (Liu et al., Blood 2023), while type 2 diabetes (T2D) is associated with increased likelihood of hematologic disorders (e.g., MGUS) (Gkalea et al., Cancers, 2023; Chang et al., Blood 2024). The underlying association between MGUS and CVD can be plausibly explained by chronic inflammation, genetic abnormalities, vascular calcification, cryoproteins, autoantibodies, and the direct or indirect effects of monoclonal proteins on the vascular endothelium. Existing evidence on these associations were observed using data collected from western populations (Schwartz et al., Cardio Oncology 2022), with limited data available from Asian cohorts. Moreover, little is known regarding how the MGUS-CVD relationship manifests in Asian individuals with T2D. We aim to examine the coexistence and the association between MGUS and the risk of CVD in Asian populations.

Methods:

We analyzed data from the Taiwan National Health Insurance (NHI) database. As enrollment in the NHI system is mandatory, the database covers approximately 99% of Taiwan's population, over 95% of whom are of Asian descent (Hsing et al., JAMA Intern Med 2015). We included individuals diagnosed with T2D, identified using ICD-9/10-CM codes (250.X0, 250.X2/E11), from 2001-2021, who were older than 16 years by the end of 2021 and had complete birth year information. We excluded individuals without any recorded clinical visits. The exposure¾MGUS status¾ and the outcome of interest¾CVD events¾ were identified using ICD-9/10-CM codes (MGUS: 273.1/D47.2; CVD: 410, 411, 412, 414 (exclude 414.1), 428, 433, 434.10, 434.11, 434.91, 435, 440, 441, V45.81, V45.82/ I20, I21, I22, I24, I25, I65, I63, I50, I70, Z95.5, Z98.61, G45.9).

To ensure sufficient observation time, we excluded individuals with less than one year of observation time post-MGUS diagnosis prior to matching. Individuals with MGUS were matched 1:5 with non-MGUS individuals based on birth year and observation time. For MUGS individuals, observation time was defined as the period from the index age¾defined as the age at MGUS diagnosis¾to the earlies occurrence of a CVD event, death without CVD, or censoring. For non-MGUS individuals, observation time was defined as the period from the first clinical visit to the last, with the index age defined as the age at the first clinical visit. Multivariable logistic regression model was used to estimate the multivariable-adjusted odds ratio (aOR) of the incident CVD event. Covariates included ages at T2D and MGUS diagnosis, respectively, use of antidiabetic medications within 1 year before MGUS diagnosis (metformin, GLP-1 receptor agonists, SGLT2 inhibitors, insulin, and sulfonylureas), and the Charlson Comorbidity index (CCI) within ±1 year of MGUS diagnosis.

Results:

The final analytic sample contained 7,464 individuals¾1,244 with MGUS and 6,220 without. Median age at T2D diagnosis was 65 (interquartile range [IQR]: 56-73) years and 70 (IQR: 61-78) years at MGUS diagnosis. The incidence of CVD was higher among T2D individuals with MGUS compared to those without (75% vs. 66% had CVD; p <0.001).

The multivariable analysis shows that MGUS was associated with an increased risk of CVD (aOR=1.19; 95% CI: 1.01-1.39). Moreover, older age at T2D diagnosis (aOR: 1.05; 95% CI: 1.05-1.06), higher CCI (aOR: 1.19; 95% CI: 1.16-1.22), and insulin use (aOR: 1.36; 95% CI: 1.01-1.82) were associated with a higher risk of CVD. Conversely, metformin use was associated with reduced risk of CVD (aOR: 0.85; 95% CI: 0.73-0.99). There was no evidence showing that the other covariates were associated with an increased risk of CVD.

Conclusions:

In this predominantly Asian population, the incidence of MGUS and CVD was highly correlated. Furthermore, consistent with evidence from western countries, MGUS is associated with an elevated risk of developing CVD. Both MGUS and CVD contribute to multimorbidity in individuals with T2D. These findings highlight the importance of integrating CVD risk factor monitoring and prevention strategies into the routine care of individuals with T2D and MGUS. Such strategies should go beyond standard diabetes management measures¾such as glycemic control, medication adherence, and lifestyle modification¾as part of their multimorbidity management and by applied across all racial and ethnic populations, including Asian populations.

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2025
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