Asymmetric Dimethylarginine and Adverse CV Events in T2D
Asymmetric Dimethylarginine and Adverse CV Events in T2D
The mean age of the 270 patients was 67 ± 12 years, and most of the patients were male (n = 213, 78.9%) and had concomitant CAD (n = 211, 78.1%). The mean plasma ADMA level, SDMA level and L-arginine level were 0.46 ± 0.09 μmol/l, 0.76 ± 0.42μmol/l and 87.5 ± 29.4 μmol/l, respectively, and the mean HbA1c level was 7.8 ± 1.6%. Significant correlations were observed between plasma ADMA level and age (r = 0.21, p < 0.01), creatinine (r = 0.34, p < 0.01), SDMA (r = 0.44, p < 0.01), L-arginine (r = 0.22, p < 0.01) and eGFR (r = −0.28, p < 0.01), respectively. In contrast, there was no significant correlation between plasma ADMA level and HbA1c concentration (r = −0.09, p = 0.13). Notably, the plasma ADMA levels of patients receiving metformin were significantly lower than those without (0.45 ± 0.08 μmol/l vs 0.48 ± 0.09 μmol/l, p < 0.01). Furthermore, there was a trend toward higher plasma ADMA level in patients receiving insulin therapy (p = 0.07). The baseline characteristics of patients grouped according to ADMA tertiles are shown in Table 1. There were no significant differences in baseline clinical parameters among the three groups, with the exception that the patients in higher ADMA tertiles were older and had worse renal function (Table 1).
All patients were followed up completely for a median period of 5.7 years (inter-quartile range: 5.0 − 7.3 years). During the follow-up period, MACE was observed in 55 patients (20.4%), which included 36 cardiovascular death (13.3%), 16 non-fatal MI (6.0%) and 7 stroke (2.6%). The plasma ADMA levels in patients who developed MACE were significantly higher than in those who did not (0.49 ± 0.09 μmol/l versus 0.45 ± 0.09 μmol/l, p = 0.006). By Kaplan-Meier analysis, event-free survival from MACE was significantly associated with ADMA tertiles (p < 0.005), with outcome being the worst in those patients with the highest plasma ADMA levels (Figure 1).
(Enlarge Image)
Figure 1.
Kaplan-Meier survival analyses for major adverse cardiovascular event during follow-up according to the plasma ADMA tertiles. P values by log-rank test are shown.
In multivariate Cox regression analysis adjusted for age, sex, BMI, HbA1c, L-arginine, hypertension and serum creatinine level, patients in the highest ADMA tertile was independently associated with a 2.31-fold increased risk for MACE when compared with patients with the lowest ADMA tertile (p = 0.026, HR: 2.31, 95% CI: 1.10 − 4.81). When considering the plasma ADMA level as a continuous variable, the plasma ADMA level remained a significant independent predictor for the occurrence of MACE, and the relative risk of MACE increased by 30% when plasma ADMA level increased by 1 SD of value (p = 0.04, HR: 1.30, 95% CI: 1.01 − 1.68).
The plasma SDMA level was significantly associated with long-term MACE in uni-variate analysis (p < 0.01, HR: 1.30, 95% CI: 1.14 − 1.48). However, when we put both ADMA and SDMA into the multivariate Cox regression analysis, the significance of SDMA disappeared (p = 0.21).
To investigate the relationship of diabetic control and ADMA, we divided all patients into those with plasma HbA1c level ≤6.5% (n = 50) and >6.5% (n = 220). The baseline characteristics of both groups are shown in Table 2. The plasma ADMA level of both groups were similar, and there were no significant differences in baseline clinical parameters between the two groups, with the exception that the patients with better diabetic control received less sulfaurea and insulin treatment, and had higher HDL and lower triglyceride levels (Table 2).
Table 3 showed the MACE rate stratified according to the ADMA tertiles and HbA1c level. By Kaplan-Meier analysis, the higher plasma ADMA tertiles were still associated with increased risk of MACE in subgroup with serum HbA1c >6.5%, but not in subgroup with HbA1c ≤6.5% (Figure 2A, B). In multivariate analysis, ADMA remained an independent significant predictor for MACE in subgroup with HbA1c >6.5% (tertile III versus tertile I: p = 0.02, HR: 3.0, 95% CI: 1.2 − 7.7; ADMA as a continuous variable: p = 0.04; HR per increase of 1 SD: 1.38, 95% CI: 1.0 − 1.9), but not in patients with HbA1c ≤6.5% (Table 4). There was a significant interaction between the predictive power of ADMA tertiles for the MACE risk and diabetic control (interaction p = 0.01). In contrast, glycemic control was not associated with long-term cardiovascular outcomes (HbA1c ≤6.5% versus HbA1c >6.5%: p = 0.57 by log-rank test).
(Enlarge Image)
Figure 2.
Kaplan-Meier survival analyses for major adverse cardiovascular event during follow-up according to the plasma ADMA tertiles in subgroup with HbA1c >6.5% (A) and subgroup with HbA1c ≤6.5% (B). P values by log-rank test are shown.
Results
Baseline Characteristics of the Study Population
The mean age of the 270 patients was 67 ± 12 years, and most of the patients were male (n = 213, 78.9%) and had concomitant CAD (n = 211, 78.1%). The mean plasma ADMA level, SDMA level and L-arginine level were 0.46 ± 0.09 μmol/l, 0.76 ± 0.42μmol/l and 87.5 ± 29.4 μmol/l, respectively, and the mean HbA1c level was 7.8 ± 1.6%. Significant correlations were observed between plasma ADMA level and age (r = 0.21, p < 0.01), creatinine (r = 0.34, p < 0.01), SDMA (r = 0.44, p < 0.01), L-arginine (r = 0.22, p < 0.01) and eGFR (r = −0.28, p < 0.01), respectively. In contrast, there was no significant correlation between plasma ADMA level and HbA1c concentration (r = −0.09, p = 0.13). Notably, the plasma ADMA levels of patients receiving metformin were significantly lower than those without (0.45 ± 0.08 μmol/l vs 0.48 ± 0.09 μmol/l, p < 0.01). Furthermore, there was a trend toward higher plasma ADMA level in patients receiving insulin therapy (p = 0.07). The baseline characteristics of patients grouped according to ADMA tertiles are shown in Table 1. There were no significant differences in baseline clinical parameters among the three groups, with the exception that the patients in higher ADMA tertiles were older and had worse renal function (Table 1).
Long-term Outcome and Dimethylarginines
All patients were followed up completely for a median period of 5.7 years (inter-quartile range: 5.0 − 7.3 years). During the follow-up period, MACE was observed in 55 patients (20.4%), which included 36 cardiovascular death (13.3%), 16 non-fatal MI (6.0%) and 7 stroke (2.6%). The plasma ADMA levels in patients who developed MACE were significantly higher than in those who did not (0.49 ± 0.09 μmol/l versus 0.45 ± 0.09 μmol/l, p = 0.006). By Kaplan-Meier analysis, event-free survival from MACE was significantly associated with ADMA tertiles (p < 0.005), with outcome being the worst in those patients with the highest plasma ADMA levels (Figure 1).
(Enlarge Image)
Figure 1.
Kaplan-Meier survival analyses for major adverse cardiovascular event during follow-up according to the plasma ADMA tertiles. P values by log-rank test are shown.
In multivariate Cox regression analysis adjusted for age, sex, BMI, HbA1c, L-arginine, hypertension and serum creatinine level, patients in the highest ADMA tertile was independently associated with a 2.31-fold increased risk for MACE when compared with patients with the lowest ADMA tertile (p = 0.026, HR: 2.31, 95% CI: 1.10 − 4.81). When considering the plasma ADMA level as a continuous variable, the plasma ADMA level remained a significant independent predictor for the occurrence of MACE, and the relative risk of MACE increased by 30% when plasma ADMA level increased by 1 SD of value (p = 0.04, HR: 1.30, 95% CI: 1.01 − 1.68).
The plasma SDMA level was significantly associated with long-term MACE in uni-variate analysis (p < 0.01, HR: 1.30, 95% CI: 1.14 − 1.48). However, when we put both ADMA and SDMA into the multivariate Cox regression analysis, the significance of SDMA disappeared (p = 0.21).
The Relationship Between ADMA and the Control of DM
To investigate the relationship of diabetic control and ADMA, we divided all patients into those with plasma HbA1c level ≤6.5% (n = 50) and >6.5% (n = 220). The baseline characteristics of both groups are shown in Table 2. The plasma ADMA level of both groups were similar, and there were no significant differences in baseline clinical parameters between the two groups, with the exception that the patients with better diabetic control received less sulfaurea and insulin treatment, and had higher HDL and lower triglyceride levels (Table 2).
Table 3 showed the MACE rate stratified according to the ADMA tertiles and HbA1c level. By Kaplan-Meier analysis, the higher plasma ADMA tertiles were still associated with increased risk of MACE in subgroup with serum HbA1c >6.5%, but not in subgroup with HbA1c ≤6.5% (Figure 2A, B). In multivariate analysis, ADMA remained an independent significant predictor for MACE in subgroup with HbA1c >6.5% (tertile III versus tertile I: p = 0.02, HR: 3.0, 95% CI: 1.2 − 7.7; ADMA as a continuous variable: p = 0.04; HR per increase of 1 SD: 1.38, 95% CI: 1.0 − 1.9), but not in patients with HbA1c ≤6.5% (Table 4). There was a significant interaction between the predictive power of ADMA tertiles for the MACE risk and diabetic control (interaction p = 0.01). In contrast, glycemic control was not associated with long-term cardiovascular outcomes (HbA1c ≤6.5% versus HbA1c >6.5%: p = 0.57 by log-rank test).
(Enlarge Image)
Figure 2.
Kaplan-Meier survival analyses for major adverse cardiovascular event during follow-up according to the plasma ADMA tertiles in subgroup with HbA1c >6.5% (A) and subgroup with HbA1c ≤6.5% (B). P values by log-rank test are shown.
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