Table 2.
Summary of the RCTs on various drug treatment options for diabetic patients with CAN
| First Author, Publication year, Location of study |
Study design | Experimenta /Comparator | Inclusion (I) and exclusion (E) criteria | Number of patients | Key findings* | ||||
|---|---|---|---|---|---|---|---|---|---|
| HRV, CARTs (excluding OH) | BP (including OH) | HR | Symptoms of CAN | QT Interval | |||||
| Antihypertensives–ACEI, ARB, BB | |||||||||
| Athyros et al. 1998, Greece [19] | NR, parallel-group RCT for 1 year | Quinapril 20 mg daily / Placebo |
(I) T1DM or T2DM, CAN (E) History of cardiovascular disease |
30/30 |
Significant difference in LF/HF between the 2 groups from 7:00–15:00 h, 15:00–23:00 h, 23:00–7:00 h (p < 0.001) Significant changes in all indices from baseline (quinapril): From 7:00–15:00 h: increase in HF (p < 0.05), decrease in LF/HF (p < 0.05) From 23:00- 7:00 h: increase in HF, decrease in LF and LF/HF (p < 0.001 for all three indices) Significant changes in all indices from baseline (placebo): From 7:00–15:00 h: decrease in HF (p < 0.05), increase in LF (p < 0.01) and LF/HF (p < 0.01) From 15:00–23:00 h: increase in LF/HF (p < 0.05) |
No significant changes in SBP and DBP from baseline in both groups (p ≥ 0.05) |
Significant decrease in HR (quinapril) (p < 0.01), significant increase in HR (placebo) (p < 0.05) from baseline HR was significantly lower in quinapril than placebo group (p < 0.001) |
Not studied | Not studied |
| Didangelos et al. 2006, Greece [20] | Open, parallel-group RCT for 1 year |
Quinapril 20 mg daily / Losartan 100 mg daily/ Quinapril 20 mg daily + losartan 100 mg daily |
(I) T1DM or T2DM, CAN (E) History of cardiovascular disease |
20/22/20 | Significant changes in the indices with abnormal values at baseline for all groups: increase in E/I, MCR, SDRR (all groups), Valsalva ratio (quinapril only), 30:15 (losartan only, losartan + quinapril) (p < 0.05 for all indices) | No significant change in OH, SBP and DBP from baseline in all groups (p ≥ 0.05) | Significant decrease in HR in all groups (p < 0.05) | Not studied | Not studied |
| Didangelos et al. 2017, Greece [30] | Open, parallel-group RCT for 2 years | Quinapril 20 mg daily/Placebo |
(I) T1DM or T2DM, CAN (E) Coronary artery disease |
31/32 |
Significant difference between the 2 groups for all indices except Valsalva ratio (p < 0.001 for E/I, MCR, SDRR, 30:15, p ≥ 0.05 for Valsalva ratio) Significant increase in E/I (p = 0.011), MCR (p = 0.006), SDRR (p = 0.004) from baseline (quinapril), no notable changes in Valsalva ratio, 30:15 (p ≥ 0.05 for both indices) Significant decrease in E/I (p = 0.007), MCR (p = 0.01), SDRR (p < 0.05), 30:15 (p < 0.05) from baseline (placebo), no notable changes in Valsalva ratio (p ≥ 0.05) |
Significant difference in OH between the two groups (p < 0.001) No notable changes in OH (p ≥ 0.05) from baseline (quinapril); significant increase in OH (p = 0.018) from baseline (placebo) |
Not studied | Not studied | Not studied |
| Hjortkjær et al. 2016, Denmark [21] | Double-blind crossover RCT with 12 weeks of one intervention before switching for 12 more weeks | Enalapril 20 mg in the morning and placebo at bedtime/Placebo in the morning and 20 mg enalapril at bedtime |
(I) T1DM, CAN, nocturnal BP dipping of < 10% (E) T2DM, Cardiovascular disease, kidney disease, hypersensitivity to ACEI |
13/11 | Not studied |
Significant difference in SBP dipping between the 2 groups: Mean dipping at bedtime 2.4% greater than morning (95% CI 0.03 to 4.9%, p = 0.048) Notable but not significant difference in DBP dipping between the 2 groups: mean dipping at bedtime 1.7% greater than morning (95% CI − 0.7 to 4.1%, p = 0.07) No significant difference in MAP dipping between the 2 groups: mean dipping at bedtime 2.2% greater than morning (95% CI − 0.1 to 4.5%, p = 0.17) |
No significant difference in daytime HR (p = 0.15) and nighttime HR (p = 0.34) between the 2 groups | Not studied | Not studied |
| Kontopoulos et al. 1997, Greece [25] | Double-blind, parallel-group RCT for 6 months | Quinapril 20 mg daily/Placebo |
(I) T1DM or T2DM, CAN (E) Cardiovascular disease, concurrent treatment with beta blocker or ACEI |
20/20 |
Significant difference between the 2 groups for SDNN, RMSSD, TP (p < 0.05 for three indices) and HF, LF/HF (p < 0.01 for both indices); no notable difference for LF (p ≥ 0.05); increase (quinapril) and decrease (placebo) in SDNN, RMSSD Significant increase in TP from baseline (p < 0.05) (quinapril), no notable changes in TP from baseline (p ≥ 0.05) (placebo) Significantly greater HF, RMSSD, pNN50, significantly lower LF in moderate than severe CAN (baseline: p < 0.05, at 6 months: p < 0.01) |
No significant changes in BP from baseline in both groups (p ≥ 0.05) | Not studied | Not studied | Not studied |
| Reid et al. 1987, NR [22] | Double-blind, crossover RCT with single dose interventions given in a randomised order at weekly intervals | Epanolol 200 mg/atenolol 50 mg/pindolol 5 mg/Placebo |
(I) T2DM, CAN (E) NR |
8 patients undergo all interventions in randomize-d order | Not studied | Not studied |
Significantly lower HR from 08.00–13.00 h, 14.00–23.00 h for epanolol (p < 0.05) and atenolol (p < 0.001) and from 23.00–08.00 h for atenolol (p < 0.01) than placebo Significantly higher HR for pindolol (p < 0.05) than placebo |
Not studied | Not studied |
| Antioxidants | |||||||||
| Didangelos et al. 2020, Greece [42] | Double-blind, parallel-group RCT for 1 year | SOD 10 mg, ALA 570 mg, ALC 300 mg, Vitamin B12 250mcg daily/Placebo |
(I) T2DM, CAN, DPN (E) History of cardiovascular disease including arrhythmias |
43/42 |
No significant differences in MCR (p = 0.220) and Valsalva ratio (p = 0.393) between the 2 groups Significant decrease in the MCR from baseline in the placebo group (p = 0.01) |
Significant difference in OH between the 2 groups (p = 0.001); significant decrease in OH from baseline (p = 0.001) (ALA), no notable change in OH from baseline (p = 0.06) (placebo) No significant difference in SBP (p = 0.369) and DBP (p = 0.258) between the 2 groups |
Not studied | Not studied | Not studied |
| Didangelos et al. 2021, Greece [43] | Double-blind, parallel-group RCT for 1 year | Oral dispersible tablet containing 1000 μg of methylcobala-min / Placebo |
(I) T2DM, CAN, DPN, low vitamin B12, metformin for ≥ 4 years (E) Cardiovascu-lar events, kidney disease |
44/46 |
No significant differences in MCR (p = 0.452) and Valsalva ratio (p = 0.761) between the 2 groups Significant decrease in MCR from baseline in the placebo group (p = 0.025) |
No significant difference in OH (p = 0.929), SBP (p = 0.547) and DBP (p = 0.350) between the 2 groups | Not studied | Not studied | Not studied |
|
Lee et al 2017, Korea [23] |
Double-blind, parallel-group RCT for 24 weeks | ALA 600 mg daily (12 weeks) then 1200 mg daily (12 weeks)/Placebo |
(I) T2DM, CAN (E) kidney or liver disease, cardiovascular disease including arrhythmias |
46/45 |
Notable but not significant difference in 3 indices between the 2 groups: SDNN (p = 0.06), LF/HF (p = 0.06), LF (p = 0.08) SDNN, LF/HF, LF increased in ALA group (p ≥ 0.05) but decreased in placebo group (p ≥ 0.05) |
Significant difference between the 2 groups in orthostatic SBP (p = 0.048), but no significant difference in orthostatic DBP (p = 0.286) | No significant differences between the 2 groups (p = 0.591) | Not studied | Not studied |
| Manzella et al. 2001, NR [26] | Double-blind, parallel-group RCT for 4 months | Vitamin E 600 mg daily/Placebo |
(I) T2DM, CAN (E) Respiratory rate < 10 breaths/min |
25/25 |
Near significant increase in RR interval length, TP and HF, significant decrease in LF and LF/HF (p = 0.05 for all indices) from baseline (vitamin E) No significant changes in all 5 indices from baseline (placebo) (p > 0.05) Significant negative correlation between the LF/HF and the plasma vitamin E concentration (r = –0.43, p < 0.04) |
No significant difference in MAP between the two groups (p > 0.05) | Not studied | Not studied | Not studied |
| Serhiyenko et. al 2018, Ukraine [27] | NR, parallel-group RCT for 3 months | One 1 g capsule daily (containing 90% omega-3 PUFA and 4 mg α-tocopherol acetate) with hypoglycemic treatment/ Hypoglycemic treatment |
(I) T2DM, CAN (E) NR |
21/15 |
Significant increase in SDNN, SDANNi, RMSSD, pNN50, HF, LF/HF (p < 0.05 for the five indices), LF (p < 0.01) from baseline (omega-3 PUFA and hypoglycemic treatment), no notable change in VLF (p > 0.05) No significant changes in any indices from baseline in patients given hypoglycemic treatment only (p > 0.05) |
Not studied | Not studied | Not studied | Not studied |
| Serhiyenko et al. 2019, Ukraine [44] | Open, parallel-group RCT for 3 months | One 1 g capsule daily (containing 90% omega-3 PUFA and 4 mg α-tocopherol acetate) with hypoglycemic treatment/ Hypoglycemic treatment |
(I) T2DM, CAN (E) Taken omega-3 PUFAs for 6mths before study, other causes of neuropathy, cardiovascular disease |
21/21 | Not studied |
Significant decrease in DBP, time index of DBP, standard deviation of DBP (p < 0.001 for the three indices) and load of DBP (p < 0.05) from baseline (omega-3 PUFAs and hypoglycemic treatment), no notable change in diurnal DBP index (p ≥ 0.05) No significant changes in DBP parameters from baseline at night for hypoglycemic treatment only (p ≥ 0.05) No significant changes in SBP in both groups at night (p ≥ 0.05) |
Not studied | Not studied | Not studied |
| Ziegler et al. 1997, Germany [28] | Double-blind, parallel-group RCT for 4 months | ALA 800 mg daily/Placebo |
(I) T2DM, CAN (E) Taken ALA 3 months before study, other causes of neuropathy, cardiovascular disease |
39/34 |
Significant difference in LF and RMSSD between the 2 groups (p < 0.05): both indices increased in ALA group but decreased in placebo group Notable but not significant difference in HF (p = 0.094) and CV (p = 0.097) between the 2 groups: increase in HF in ALA group but decreased in placebo group No significant difference in LF/HF between the 2 groups (p ≥ 0.05) |
No significant difference in SBP and DBP between the 2 groups (p ≥ 0.05 for both indices) | No significant difference in heart rate between the 2 groups (p ≥ 0.05) | No significant difference in the rates of CAN symptoms between the 2 groups; the rate decreased by 6.9% in ALA group, increased by 3.6% in placebo group (p ≥ 0.05) | Not studied |
HRV heart rate variability, BP blood pressure, HR heart rate, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, NR not reported by the study, RCT randomised controlled trial, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, CAN cardiovascular autonomic neuropathy, DPN diabetic peripheral neuropathy, SOD superoxide dismutase, ALA alpha-lipoic acid, ALC acetyl L-carnitine, PUFAs polyunsaturated fatty acids, ECG electrocardiogram, mL millilitres, min minute, m metre squared, TP total power of HRV, VLF very low frequency power of HRV, LF low frequency power of HRV, HF high frequency power of HRV, LF/HF low-to-high frequency ratio, OH orthostatic hypotension, DBP diastolic blood pressure, SBP systolic blood pressure, MAP mean arterial pressure, E/I expiration-to-inspiration ratio, MCR mean circular resultant of vector analysis, SDRR standard deviation of RR intervals, 30:15 ratio of RR intervals at 15th and 30th heartbeats after standing, SDNN standard deviation of NN intervals, SDANNi standard deviation of the means of all NN intervals in all 5 min segments, RMSSD root mean square of successive differences between NN intervals, pNN50 percentage of differences > 50 ms between adjacent NN intervals, CV coefficient of variation in HRV
*Significance level of 5% was used by the studies