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. Author manuscript; available in PMC: 2016 Oct 28.
Published in final edited form as: Curr Diab Rep. 2014;14(9):528. doi: 10.1007/s11892-014-0528-7

Table 2.

Summary of Trials Reporting Impact of Glucose Control on CAN measures

Type 1 Diabetes Observational Studies
Study Name Author/year CAN Measures Study Population N/age Intervention Follow-up HbA1c Outcomes
Ziegler et al./1991(36) Heart rate variation at rest and during deep breathing N=32
Group 1=13
Group 2=19
Mean age 20 years
N/A 5 years Baseline
Group 1: 10.6 %
Group 2: 11.6 %
Follow-up
Group 1:< 8.3 %
Group 2: >8.3 %
Prevalence of CAN
Group 1 Group2
Baseline 0 3 %
24 month 0 17 %
48 months 0 8.3 %
60 months 5 23.3 %
P <0.05
EURODIAB IDDM Complications Study
Tesfaye S et al./1996 (57) Witte et al. 2005 (34)
Changes in R–R and systolic blood pressure with standing
Changes in R–R and systolic blood pressure with standing
N=3250
Mean age 33 years
N=956
Mean age 31 years
N/A
N/A
7.3 years
7.3 years
Baseline : 6.7 %
Follow- up : 8.3 %
CAN+ : 6.9 %
CAN -: 6.4 %
OR CAN per % A1c increase
1.20 (1.09–1.32)
P<0.001
20 % increase in risk of CAN per percentage point increase in HbA1c.
P <0.001
Randomized Controlled Trials
Study Name Author/year CAN Measures Study Population N/age Intervention Follow-up HbA1c Outcomes
Oslo study
Amthor et al./1994(62)
Cardiovascular reflex tests obtained only at follow-up N=45
Mean age 26 years
INT N=33
continuous insulin infusion, multiple injections (4–6 daily)
CON N=12
twice daily insulin therapy
8 years Baseline : 11.2 %
Follow-up : 9.5 %
RR Variation
A1c>10 %=19.4
A1c<10 %=27.4
P=0.03
Diabetes Control and Complications Trial (DCCT) DCCT study group/1993(5; 29) Cardiovascular reflex tests.
One of the following conditions: R-R variation<15; R-R variation <20 in combination with Valsalva ratio =1.5 or postural hypotension
N =1441
Mean age 26 years
INT N=711
either external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring
CON N=730
one or two daily insulin injections
6.5 years Baseline
INT : 9.1 %
CON: 9.1 %
End of DCCT
INT : 7.2 %
CON: 9. 1 %
CAN Prevalence
INT : 4 %
CON: 5 %
CAN Prevalence
INT: 3 %
CON: 10 %
P =0.001
45 % risk reduction in incident CAN with INT
Epidemiology of Diabetes Interventions and Complications (EDIC)
Pop-Busui et al./ 2009(31)
Cardiovascular reflex tests.
One of the following conditions: R-R variation<15; R-R variation <20 in combination with Valsalva ratio =1.5 or postural hypotension
N=1211
Mean age 48 years
N/A
Former INT N=620
Former CON N =591
13–14 years EDIC year 13/14
INT : 8.0 %
CON: 8. 0 %
CAN Prevalence and Incidence Prevalence
INT: 29 %
CON: 35 %
P <0.05
Incidence 30 % risk reduction in incident CAN at year 13–14 with INT
Type 2 diabetes
Study Name Author/year CAN Measures Study Population N/age Intervention Follow-up HbA1c Outcomes
KUMAMOTO Trial
Ohkubo et al./ 1995(12)
Coefficient of variation (CV) of R-R interval and postural hypotension N=110
Mean age 49 years
INT N=50
3 or more injections of insulin daily
CON N=52
1or 2 daily injections of insulin
6 years Baseline
INT: ~9.2 %
CON : ~9 %
Follow-up HbA1c
INT: 7.1 %
CON : 9.4 %
CV of R-R interval
Baseline
INT : 5.3 %
CON : 5.2 %
Follow-up
INT : 5.7
CON : 4.9
P=NS
United Kingdome Prospective
Diabetes Study (UKPDS)
UKPDS study Group/1998(22)
R-R interval and postural hypotension N=3867
Mean Age 53±9 years
INT N=2729
Oral agents or with insulin
CON N=1138
Diet or oral agents or with insulin
10 years Baseline
INT : 7.05 %
CONV : 7.09 %
Follow-up
INT : 7.0 %
CONV : 7.9 %
No differences between groups
P=NS
VA Cooperative Study on Type II
Diabetes Mellitus (VA CSDM)
Azad et al./1999(18)
Valsalva ratio<1.2
R-R variation <10
N =153
Mean age 60 years
INT N=75
four-step plan, daily self-monitoring CON N =78
1 morning injection/ day
2 years Baseline
INT: 9.3 %
CON : 9.5 %
Follow-up
INT =7.3 %
CON =9.5 %
Prevalence abnormal Valsalva ratio and/ or R-R variation
Baseline
INT : 31 %
CON: 38 %
Follow-up
INT : 48 %
CON: 55 %
P=NS
Veteran Affairs Diabetes Trial (VADT)
Duckworth et al. /2009(24)
Self-reported symptomatic orthostatic hypotension, gastroparesis, neurogenic bladder, or diabetic diarrhea N =1791
Mean age 60 years
INT N=892
started on oral drugs, or insulin if HbA1c>6 %
CON N=899
started on half the maximal doses, insulin if HbA1c>9 %
5.6 years Baseline
INT: 9.4 %
CON: 9.4 %
Follow-up
INT: 6.9 %
CON: 8.4 %
Prevalence of self-reported autonomic symptoms at follow-up
INT: 8.2 %
CON: 5.2 %
P=NS
STENO 2
Gaede et al./2003(23)
R-R interval during deep breathing and orthostatic hypotension N =160
Mean age 55 years
INT N=80
stepwise behavior modification and pharmacologic therapy
CON N =80
Denmark national guidelines
7.8 years Baseline
INT: 8.4 %
CON: 8.8 %
Follow-up
INT :7.9 %
CON: 8.6 %
Relative Risk for CAN at follow-up
OR 0.37 (0.18–0.79) with INT
P=0.002

Footnotes: T1D –type 1 diabetes, T2D- type 2 diabetes, HbA1c- hemoglobin A1c; INT-intensive treatment, CON-conventional treatment, CAN- cardiovascular autonomic neuropathy, RCT-randomized control trial, OR-odds ratio, N-number, N/A-not applicable, HR-hazard ratio, CI-confident interval, NS-non significant, VR- Valsalva ratio

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