Characteristics of the study sample at baseline were similar between the intensive treatment group and routine-care group (Table
1). Our study sample had a mean age of 58 years at inclusion and included 35% women. The percentage of participants receiving antihypertensive medication and lipid lowering medication at baseline were 34% and 14%, respectively. The percentage of participants receiving antihypertensive medication and lipid lowering medication was much higher at 13 years follow-up in both randomization-groups. The level of HbA
1c, BMI, and waist circumference were comparable at baseline and at follow-up. After 13 years of follow-up, cholesterol levels, systolic and diastolic blood pressure and weekly alcohol consumption decreased in both randomization-groups as did the percentages of current smokers. Overall, the intensive treatment group and the routine care groups were similar with regard to medication and levels of observed clinical variables at 13 years follow-up (Table
1).
Table 1
Characteristics of the study sample at baseline and 13 years follow-up
n | 169 | 242 | | 169 | 242 | |
Female sex | 59 (34.9) | 84 (34.7) | 411 | 59 (34.9) | 84 (34.7) | 411 |
Age at inclusion (years) | 58 (6.8) | 58 (6.5) | 411 | 58 (6.8) | 58 (6.5) | 411 |
Age at follow-up (years) | | | | 71 (6.72) | 70 (6.63) | 411 |
Follow-up time (years) | | | | 12.6 (1.41) | 12.5 (1.42) | 411 |
BMI (kg/m2) | 31 (4.9) | 30 (5.3) | 399 | 30 (5.2) | 30 (5.8) | 410 |
Waist (cm) | 104.7 (12.2) | 104 (12.8) | 399 | 105 (13.2) | 106 (14.2) | 407 |
Systolic blood pressure (mmHg) | 148.3 (19.3) | 145.6 (16.8) | 399 | 141.2 (16.3) | 137.4 (15.5) | 410 |
Diastolic blood pressure (mmHg) | 88.1 (10.6) | 87.6 (9.6) | 399 | 83.6 (9.9) | 82.0 (9.3) | 410 |
HbA1c (%) | 6.7 (1.4) | 6.9 (1.6) | 395 | 6.7 (0.9) | 6.9 (0.9) | 410 |
HbA1c (mmol/mol) | 50 (15) | 52 (17) | 395 | 50 (10) | 52 (10) | 410 |
Total cholesterol (mmol/L) | 5.8 (1.2) | 5.7 (1.1) | 384 | 4.4 (1.0) | 4.3 (1.0) | 410 |
Triglycerides (mmol/L) | 1.97 (1.3) | 1.95 (1.3) | 377 | 1.69 (0.7) | 1.82 (0.9) | 410 |
HDL cholesterol (mmol/L) | 1.39 (0.3) | 1.38 (0.4) | 374 | 1.38 (0.4) | 1.37 (0.4) | 410 |
LDL cholesterol (mmol/L) | 3.45 (1.0) | 3.45 (1.0) | 362 | 2.26 (0.8) | 2.16 (0.8) | 398 |
Albumine Creatinine ratio (mg/g) | 2.95 (10.5) | 1.88 (4.2) | 372 | 8.31 (37.1) | 5.89 (20.3) | 406 |
Any glucose-lowering drug | s | – | 411 | 106 (72.6) | 149 (77.6) | 338 |
Metformin | – | – | 411 | 91 (62.3) | 131 (68.2) | 338 |
Insulin | – | – | 411 | 24 (16.4) | 36 (18.8) | 338 |
Sulphonylurea | – | – | 411 | 10 (6.8) | 16 (8.3) | 338 |
Antihypertensives | 62 (36.7) | 79 (32.6) | 411 | 120 (82.2) | 165 (85.9) | 338 |
ACE/ARB blockers | 25 (14.8) | 37 (15.3) | 411 | 101 (69.2) | 147 (76.6) | 338 |
Betablockers | 24 (14.2) | 32 (13.2) | 411 | 39 (26.7) | 50 (26.0) | 338 |
Calcium antagonists | 17 (10.1) | 21 (8.7) | 411 | 57 (39.0) | 69 (35.9) | 338 |
Diuretics | 35 (20.7) | 41 (16.9) | 411 | 66 (45.2) | 105 (54.7) | 338 |
Statins | 21 (12.4) | 35 (14.5) | 411 | 113 (77.4) | 155 (80.7) | 338 |
Aspirin | 15 (8.9) | 24 (9.9) | 411 | 66 (45.2) | 119 (62.0) | 338 |
Smoking | | | 407 | | | 379 |
Non-smoker | 56 (33.7) | 101 (41.9) | | 54 (34.2) | 90 (40.7) | |
Former smoker | 63 (38.0) | 81 (33.6) | | 79 (50.0) | 104 (47.1) | |
Current smoker | 47 (28.3) | 59 (24.5) | | 25 (15.8) | 27 (12.2) | |
Alcohol use * | 47 (29.2) | 66 (29.9) | 382 | 7.7 (8.9) | 7.7 (9.0) | 308 |
At follow-up, mean cfPWV was 10.5 m/s and 9.9 m/s in the routine care group and intensive treatment group, respectively (Table
2). Differences between the intensive treatment group and the routine care group in brachial systolic blood pressure, brachial mean blood pressure, central systolic blood pressure, and central mean blood pressure were not statistically significant (Table
2).
Table 2
Hemodynamic characteristics at 13 years follow-up by treatment group
N | 169 | 242 |
Brachial systolic blood pressure (mmHg) | 141.2 (16) | 137.4 (15) |
Brachial diastolic blood pressure (mmHg) | 83.6 (10) | 82.0 (9) |
Brachial pulse pressure (mmHg) | 57.6 (13) | 55.4 (13) |
Mean brachial blood pressure (mmHg) | 106.4 (12) | 103.7 (11) |
Central systolic blood pressure (mmHg) | 131.0 (17) | 127.5 (16) |
Central diastolic blood pressure (mmHg) | 83.5 (10) | 81.8 (9) |
Mean central blood pressure (mmHg) | 103.1 (12) | 100.7 (11) |
Central pulse pressure (mmHg) | 47,5 (13) | 45.7 (14) |
Central augmentation index (%) | 28.5 (10.2) | 27.7 (9.4) |
Aortic pulse wave velocity (m/s) | 10.5 (2.6) | 9.9 (2.2) |
We found that the intensive treatment group had 0.58 m/s lower cfPWV (95% CI − 1.09 to − 0.06 m/s) compared with the routine care group after adjustment for cluster randomization and heart rate. With further adjustment for age and sex, the cfPWV difference was 0.48 m/s (95% CI − 0.97 to 0.01 m/s) in favor of intensive treatment. Accounting for the effects of mean blood pressure the cfPWV difference between treatment groups attenuated further to 0.35 m/s lower (95% CI − 0.84 to 0.14 m/s) in the intensive treatment group. With adjustment for heart rate and cluster randomization, central mean arterial pressure was 2.14 mmHg lower (95% CI − 4.87 to 0.59 mmHg) and central augmentation index was 1.25% lower (95% CI − 3.28 to 0.78%) in the intensive treatment compared with the routine care group. In line with this, we found no statistically significant differences between treatment arms in other central or peripheral hemodynamic indices. After adjustment for age and sex, the associations attenuated, but all hemodynamic estimates still pointed in favor of intensive treatment (Table
3). We found no effect modification by sex.
Table 3
Effect of intensive treatment compared with routine care on hemodynamic indices
Peripheral systolic blood pressure (mmHg) | − 3.38 (− 7.14 to 0.38) | − 3.34 (− 7.12 to 0.43) |
Peripheral diasolic blood pressure (mmHg) | − 1.23 (− 3.21 to 0.76) | − 1.47 (− 3.4 to 0.45) |
Peripheral pulse pressure (mmHg) | − 2.33 (− 5.28 to 0.62) | − 1.97 (− 4.83 to 0.89) |
Central systolic blood pressure (mmHg) | − 3.06 (− 7.08 to 0.96) | − 2.85 (− 6.82 to 1.12) |
Central diastolic blood pressure (mmHg) | − 1.70 (− 3.74 to 0.34) | − 1.85 (− 3.85 to 0.16) |
Central pulse pressure (mmHg) | − 1.74 (− 4.79 to 1.31) | − 1.28 (− 4.11 to 1.55) |
Central mean arterial pressure (mmHg) | − 2.14 (− 4.87 to 0.59) | − 2.19 (− 4.94 to 0.56) |
Central augmentation index (%) | − 1.25 (− 3.28 to 0.78) | − 1.03 (− 2.85 to 0.79) |
Pulse wave velocity (m/s) | − 0.58 (− 1.09 to − 0.06) † | − 0.48 (− 0.97 to 0.01) |
Pulse wave velocity (m/s)* | − 0.47 (− 0.99 to 0.06) | − 0.35 (− 0.84 to 0.14) |
We assessed characteristics of the study sample by trial-end (5 years after inclusion) (Additional file
1: Table S1). Overall, characteristics were broadly similar in the randomization groups. However, glycose-lowering medication overall, ACE inhibitors or ARB, lipid-lowering drugs and aspirin were more often prescribed in the intensive treatment group than in the routine care group. Also, levels of total cholesterol and LDL cholesterol were lower in the intensive treatment group. (Additional file
1: Table S1).
Baseline characteristics and follow-up characteristics of participants attending the 13 year clinical follow-up examination without assessments of cfPWV and central hemodynamic indices (n = 176) were highly similar to the characteristics of the study sample (those with measures of hemodynamic indices). However, participants in the study sample were a few years younger and were more often prescribed antihypertensive medications at inclusion (Additional file
1: Table S2). After adjustment for cluster randomization and heart rate the cfPWV at 5 year was 0.65 m/s (95% CI − 1.04 to − 0.26 m/s) lower in those who attended the 13 years follow-up compared with those who did not attend the 13 years follow-up. We found that the intensive treatment group had 0.56 m/s lower cfPWV (95% CI − 1.23 to 0.12 m/s) compared with the routine care group in those who did not attend the 13 years follow-up and 0.50 m/s lower cfPWV (95% CI − 1.00 to − 0.00 m/s) in those who did attend the 13 years follow-up.
Discussion
In this analysis of 411 persons with screen-detected type 2 diabetes, we found that participants who attended general practices randomized to provide multifactorial target driven intensive treatment during the 5-year trial period had lower cfPWV 13 years post-randomization compared to individuals who attended general practices randomized to provide routine care during the trial. In addition, our results indicate a favorable statistically non-significant effect of intensive treatment on the other central and peripheral hemodynamic indices included in this study.
During the ADDITON trial, the care for people with diabetes improved due to a change in the national guidelines for diabetes care. The changes included more aggressive treatment with very similar treatment goals to those used for the intensive treatment group of the ADDITON trial. The changes of the clinical guidelines were largely driven by the results of the Danish STENO-2 trial [
4]. Results from STENO-2 pointed towards a clear beneficial effect on CVD risk of multifactorial treatment, including formalized goals for blood pressure using ACE/ inhibitors or ARB and formalized goal for LDL-cholesterol by statin treatment in type 2 diabetes patients with persistent microalbuminuria [
24].
It is likely and arguable that changes in clinical recommendations during the trial period affected the intensity of cardiovascular risk factor management in both arms of the ADDITION trial, reducing the difference between the two groups and thus attenuate the intervention effect that we observe. In this light, it is interesting that even the relatively small differences in cardiometabolic risk factors in the intensive treatment arm, against a background of over-all tighter management led to lower arterial stiffness. This observation affirms the role that intermediate end-points, and particularly cfPWV can play in the monitoring of the impact of cardiovascular risk management strategies. We have previously published data on peripheral and central hemodynamic indices at trial-end using data from the ADDITION-Denmark trial [
20]. We reported that participants attending practices randomized to deliver intensive treatment had 0.51 m/s lower (95% CI − 0.96–0.05 m/s) cfPWV compared with those attending practices that provided routine care [
20]. In the present analysis 13 years after inclusion, we found a sustained effect in individuals attending practices randomized to provide intensive treatment i.e. cfPWV was 0.58 m/s lower compared with individuals attending practices that provided routine care. This persistent effect could conceptually be explained by either a sustained difference in cardiovascular risk factors post-intervention, or by an early effect on arterial stiffness during the trial period which persists after the end of the intervention.
Overall, there was a reduction of most risk factors by the end of the ADDITION trial (at five year follow-up) with some differences between randomization groups [
8]. At 10 years follow-up in the international ADDITION trial, the reduction of most CVD risk factors (bodyweight, HbA
1c, cholesterols and blood pressure) was sustained, but the difference between treatment arms was attenuated or lost [
7]. In line with these results, we observed that lipid lowering medication, aspirin, and ACE inhibitors or ARB were more frequently used by the intensive treatment group at trial-end in the sub-sample of the Danish arm of ADDITION included in this analysis. However, except for aspirin, these differences diminished at 13 years follow-up. We do not know when the difference in treatment and risk factors leveled out between the intervention groups, but our results do not support the notion that the lower arterial stiffness observed 5 years after the end of the trial period is due to a sustained difference in risk factor levels, which in turn maintain the difference in cfPWV. Rather, our results are consistent with an early effect of intensive risk factor management on arterial stiffness, which is maintained even when the risk factor differences diminish i.e. we may observe a carryover effect founded during the intervention period. Results from STENO-2 and other clinical trials also report a sustained effect of intervention on diabetes related complications even years after the active intervention has stopped, which corroborates this hypothesis [
5,
25].
Our study points towards a small positive effect of multifactorial intervention on all hemodynamic indices. The marked attenuation of the difference in cfPWV observed in the study by further adjustment for the mediating effect of mean brachial blood pressure, supports the notion that blood pressure changes partly mediate the lower cfPWV, although, we did not have power to detect a marked difference between randomization groups in mean arterial blood pressure.
The first line drugs for the management of peripheral hypertension both during the trial period and now are ACE inhibitors or ARBs [
26]. They affect the elasticity of the arterial wall by modulation of the kidney function and through direct effects on the wall, which in turn may lead to reduced cfPWV [
17,
27]. In line with this, other studies have shown that people both with and without diabetes but treated with an ACE inhibitor or ARB have reduced cfPWV [
16,
17]. However, the long-term effect by ACE or ARBs on pulse wave velocity is not clear. Similarly, studies have suggested, that statin treatment lowers aortic stiffness [
18,
19]. The exact mechanisms is not clear but reduction of the vascular remodeling and vascular tone in combination with reduced oxidative stress have been suggested [
28,
29]. New glucose lowering drugs may decrease pulse wave velocity directly [
30]. However, in the ADDITION trial, metformin was the first line drug and there seems to be no direct effect by metformin on pulse wave velocity [
31]. Our results corroborates that differences in the use of antihypertensive medication and lipid-lowering medication may reduce pulse wave velocity as the difference in aortic stiffness first observed at the end of the trial period, have now been observed to be sustained.