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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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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