Greater daily glucose variability and lower time in range assessed with continuous glucose monitoring are associated with greater aortic stiffness: The Maastricht Study

Aims CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis. Methods We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) (n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SDCGM] and CGM-assessed CV [CVCGM]) and time in range (TIRCGM) with carotid–femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima–media thickness, ankle–brachial index and circumferential wall stress via multiple linear regression. Results Higher SDCGM was associated with higher cf-PWV after adjusting for demographics, cardiovascular risk factors and lifestyle factors (regression coefficient [B] per 1 mmol/l SDCGM [and corresponding 95% CI]: 0.413 m/s [0.147, 0.679], p = 0.002). In the model additionally adjusted for CGM-assessed mean sensor glucose (MSGCGM), SDCGM and MSGCGM contributed similarly to cf-PWV (respective standardised regression coefficients [st.βs] and 95% CIs of 0.065 [−0.018, 0.167], p = 0.160; and 0.059 [−0.043, 0.164], p = 0.272). In the fully adjusted models, both higher CVCGM (B [95% CI] per 10% CVCGM: 0.303 m/s [0.046, 0.559], p = 0.021) and lower TIRCGM (B [95% CI] per 10% TIRCGM: −0.145 m/s [−0.252, −0.038] p = 0.008) were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures. Conclusions Our findings show that greater daily glucose variability and lower TIRCGM are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIRCGM to prevent CVD. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00125-021-05474-8.


ESM Table 5. Multivariable-adjusted associations of time in range (TIRCGM) with arterial outcome variables
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated with 10% increase in TIRCGM. Crude: TIRCGM. Model 1: adjusted for age, sex, and education level. Model 2: additionally adjusted for mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs.

ESM Table 7. P values for interaction for sex, age, and type 2 diabetes status for the associations between SDCGM and arterial outcome variables
All models were adjusted for age, education level, mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs.
a For the associations with 'SDCGM*diabetes status' as interaction term, the associations were additionally adjusted for diabetes status. Bold denotes statistical significance; b For the associations with 'SDCGM*type 2 diabetes status' as interaction term, the associations were additionally adjusted for type 2 diabetes status. Bold denotes statistical significance.

ESM Table 8. Sex-stratified associations of daily glucose variability (expressed as SDCGM) with carotid intima-media thickness
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated with 1 unit (mmol/L) increase of SDCGM. Crude: SDCGM. Model 1: adjusted for age and education level. Model 2: additionally adjusted for office systolic blood pressure, body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs. Model 2 + MSGCGM: additionally adjusted for mean sensor glucose.

variables, additionally adjusted for physical activity and Dutch healthy diet adherence
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated 1 unit (mmol/L) increase of SDCGM. Crude: SDCGM. Model 1: adjusted for age, sex, and education level. Model 2: additionally adjusted for mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs. Model 3: additionally adjusted for physical activity and Dutch healthy diet adherence. Model 3 + MSGCGM: additionally adjusted for mean sensor glucose.
Of note, the alcohol component of the Dutch healthy diet adherence index was subtracted from the sum score prior to performing the regression analyses to avoid multicollinearity.

ESM Table 14. Multivariable-adjusted associations of SDCGM with arterial outcome variables after exclusion of individuals with type 1 diabetes
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated with 1 unit (mmol/L) increase of SDCGM. Crude: SDCGM. Model 1: adjusted for age, sex, and education level. Model 2: additionally adjusted for mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs. Model 2 + MSGCGM: additionally adjusted for mean sensor glucose.

ESM Table 15. Multivariable-adjusted associations of daily glucose variability (expressed as SDCGM) with arterial outcome variables after exclusion of individuals with CGM data gaps
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated with 1 unit (mmol/L) increase of SDCGM. Crude: SDCGM. Model 1: adjusted for age, sex, and education level. Model 2: additionally adjusted for mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs. Model 2 + MSGCGM: additionally adjusted for mean sensor glucose.

ESM Table 16. Multivariable-adjusted associations of daily glucose variability (expressed as SDCGM) with arterial outcome variables after exclusion of individuals with a suboptimal CGM recording period
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated with 1 unit (mmol/L) increase of SDCGM. Crude: SDCGM. Model 1: adjusted for age, sex, and education level. Model 2: additionally adjusted for mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs. Model 2 + MSGCGM: additionally adjusted for mean sensor glucose.

ESM Table 17. Multivariable-adjusted associations of daily glucose variability (expressed as SDCGM) with arterial outcome variables after exclusion of individuals who underwent CGM as part of a 'catch-up visit'
Regression coefficients (B) indicate the mean difference (95% confidence interval) associated with 1 unit (mmol/L) increase of SDCGM. Crude: SDCGM. Model 1: adjusted for age, sex, and education level. Model 2: additionally adjusted for mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, and use of antihypertensive and lipid-modifying drugs. Model 2 + MSGCGM: additionally adjusted for mean sensor glucose.  Regression coefficients (B) indicate the median difference (95% confidence interval) associated with 1 unit (mmol/L) increase of SDCGM. Standardized regression coefficients (st.β) indicate the median difference (95% confidence interval) associated with 1 SD higher SDCGM or MSGCGM. All coefficients were estimated by use of ridge regression. We pragmatically chose the level of penalization based on the λ required to reduce the variance inflation factor (VIF) of Model 2 + MSGCGM back to the VIF of Model 2 (or halfway back). Point estimates and 95% confidence intervals were calculated by use of 1,000 bootstrap estimates.
The associations were adjusted for age, sex, educational level, mean arterial pressure (*), office systolic blood pressure ( †) or brachial pulse pressure ( ‡), heart rate (in case of cf-PWV and ABI only), body mass index, smoking status, alcohol use, total-to-HDL cholesterol levels, use of antihypertensive and lipid-modifying drugs, and the other CGM-assessed index.