Introduction
Methods
Search strategy
Prediabetes or the metabolic syndrome related terms | CAN related terms |
---|---|
‘Pre-diabetes or prediabetes’ | ‘Cardiac autonomic neuropathy’ |
‘Impaired glucose tolerance’ | ‘Cardiovascular autonomic dysfunction’ |
‘IGT’ | ‘Autonomic neuropathy’ |
‘Impaired fasting glucose’ | ‘Abnormal heart rate variability’ |
‘IFG’ | ‘Autonomic Function Tests’ |
‘Metabolic syndrome’ | ‘Cardiac autonomic function tests’, |
‘MS’ | ‘Cardiovascular autonomic reflex tests’, |
‘Insulin resistance syndrome’ | ‘Borderline autonomic function tests’ |
‘Metabolic syndrome X’ | ‘Definite CAN’ |
‘Dysmetabolic syndrome’ | ‘Mild cardiac autonomic neuropathy’, |
‘Syndrome X’ | ‘Moderate cardiac autonomic neuropathy’, |
‘Severe cardiac autonomic neuropathy’ | |
‘30:15 ratio’ | |
‘E/I’ | |
‘E:I’ | |
‘Orthostatic hypotension’ | |
‘Postural hypotension’ | |
‘Neuropathy’ | |
‘Diabetic neuropathy’ | |
‘Valsalva ratio’ | |
‘Heart rate response to deep breathing’ | |
‘Heart rate response to Valsalva manoeuvre’ | |
‘Resting heart rate variability’ | |
‘Heart rate response to standing’ | |
‘Prolonged QT interval’ | |
‘Sympathetic nervous system’ | |
‘SNS overactivity’ | |
‘Parasympathetic nervous system denervation’ | |
‘PNS denervation’ | |
‘Vagus nerve denervation’ | |
‘Resting tachycardia’ | |
‘Palpitations’ | |
‘Syncope’ | |
‘Sudomotor function’ |
Inclusion/exclusion criteria
Data extraction and quality assessment
Controls and comparators
Critical appraisal
Definition of CAN and analysis of subgroups
Data analysis
Results
Search results
Study | Country | Primary care or hospital based | Sample size | Study group | Group size | Age, years | Sex, n female/n male | Male, % |
---|---|---|---|---|---|---|---|---|
Ziegler et al, 2015 [25] | Germany | Primary care/ population based | 1332 | iIFG | 336 | 63 (58–68) | 128/208 | 62 |
iIGT | 72 | 65 (62–69) | 44/28 | 39 | ||||
IFG+IGT | 151 | 65 (61–70) | 61/90 | 60 | ||||
NGT | 565 | 63 (58–68) | 328/237 | 42 | ||||
kDM | 130 | 65 (61–69) | 60/70 | 54 | ||||
nDM | 78 | 66 (61–71) | 33/45 | 58 | ||||
Dimova et al, 2020 [41] | Bulgaria | Primary care/population based | 87 | PreDM | 35 | 44.8 ± 10.2 | 19/16 | 46 |
NGT | 35 | 45.5 ± 14.1 | 19/16 | 46 | ||||
nDM | 17 | 48.0 ± 8.5 | 10/7 | 41 | ||||
Laitinen et al, 2011 [38] | Finland | Primary care/population based | 268 | IGT | 268 | 62 ± 7 | 177/91 | 34 |
Wu et al, 2009 [42] | China | Primary care/population based | 1638 | PreDM | 412 | 49.5 ± 14.2 | 218/194 | 47 |
NGT | 1069 | 39.4 ± 14.0 | 568/501 | 47 | ||||
DM | 157 | 57.7 ± 12.8 | 67/90 | 57 | ||||
Zimmerman et al, 2018 [40]a | Sweden | Primary care/population based | 119 | IGT | 29 | NA | 9/20 | 69 |
NGT | 39 | NA | 18/21 | 54 | ||||
(T2)DM | 51 | NA | 15/36 | 71 | ||||
Dimova et al, 2017 [36] | Bulgaria | Primary care and hospital based | 478 | PreDM | 227 | NA | NA | NA |
IFG | 125 | 51.7 ± 12.1 | 71/54 | 43 | ||||
IGT | 102 | 49.2 ± 13.5 | 71/31 | 30 | ||||
NGT | 130 | 46.6 ± 11.4 | 82/48 | 37 | ||||
(T2)DM | 121 | 54.4 ± 11.5 | 54/67 | 55 | ||||
Balbinot et al, 2012 [43] | Brazil | Hospital based | 79 | PreDM | 13 | 56.8 ± 12.6 | 10/3 | 23 |
NGT | 37 | 45.1 ± 14 | 21/16 | 43 | ||||
(T2)DM | 29 | 59.9 ± 9.4 | 10/9 | 31 | ||||
Dinh et al, 2011 [37] | Germany | Hospital based | 145 | IGT | 48 | NA | NA | NA |
NGT | 45b | 57 ± 11 | NA | NA | ||||
(T2)DM | 51 | NA | NA | NA | ||||
Callaghan et al, 2020 [44] | USA | Hospital based | 184 | Obese PreDM | 56 | 44.7 ± 11.4 | 46/10 | 18 |
Lean NGT | 46 | 44.1 ± 12.1 | 38/8 | 17 | ||||
Obese NGT | 33 | 40.2 ± 10.7 | 25/8 | 24 | ||||
Obese DM | 49 | 48.9 ± 10.4 | 34/15 | 31 | ||||
Putz et al, 2013 [39] | Hungary | Hospital based/primary care | 115 | IGT | 75 | 58.7 ± 11.1 | 41/34 | 45 |
NGT | 40 | 55.1 ± 10.0 | 23/17 | 43 | ||||
Kamel et al, 2014 [45] | Australia | NA | 52 | IGT | 8 | NA | NA | NA |
NGT | 26b | 49 | 13/13 | 50 | ||||
DM | 18 | NA | NA | NA |
Study | Subgroup | FPG, mmol/l (mg/dl) | OGTT, mmol/l | HbA1c, % (mmol/mol) | Systolic BP, mmHg | Diastolic BP, mmHg | Triacylglycerols, mmol/l (mg/dl) | Cholesterol, mmol/l | BMI, kg/m2 |
---|---|---|---|---|---|---|---|---|---|
Ziegler et al, 2015 [25] | iIFG | NA | NA | 5.6 (5.4–5.8) (37.7 [35.5–39.9]) | NA | NA | 1.33 (0.98–1.81) | NA | 28.2 (25.8–30.8) |
iIGT | NA | NA | 5.5 (5.3–5.8) (36.6 [34.4–39.9]) | NA | NA | 1.30 (1.03–1.85) | NA | 29.4 (26.1–32.0) | |
IFG+IGT | NA | NA | 5.7 (5.5–6.0) (38.8 [36.6–42.1]) | NA | NA | 1.45 (1.16–2.11) | NA | 29.1 (27.4–31.9) | |
NGT | NA | NA | 5.5 (5.3–5.8) (36.6 [34.4–39.9]) | NA | NA | 1.16 (0.84–1.62) | NA | 26.9 (24.7–29.5) | |
kDM | NA | NA | 6.8 (6.2–7.9) (50.8 [44.3–62.8]) | NA | NA | 2.23 (1.53–3.15) | NA | 31.2 (28.1–34.3) | |
nDM | NA | NA | 6.1 (5.7–6.4) (53.2 [38.8–46.4]) | NA | NA | 1.65 (1.30–2.25) | NA | 29.9 (27.9–33.0) | |
Dimova et al, 2020 [41] | PreDM | 6.4 ± 0.5 | 7.6 ± 1.9 | 5.7 ± 0.7 (39 ± 6) | 125 ± 12 | 79 ± 9 | 1.7 (0.9–2.4) | 5.3 ± 1.0 | 33.3 ± 5.9 |
NGT | 5.5 ± 0.4 | 5.2 ± 1.2 | 5.6 ± 0.3 (38 ± 3) | 122 ± 14 | 78 ± 11 | 1.5 (1.0–2.2) | 5.6 ± 1.3 | 28.7 ± 6.5 | |
nDM | 9.3 ± 2.6 | 14.6 ± 4.9 | 7.7 ± 1.4 (61 ± 15) | 127 ± 19 | 81 ± 13 | 1.9 (1.6–2.7) | 5.6 ± 0.9 | 33.2 ± 6.8 | |
Laitinen et al, 2011 [38] | IGT | 6.1 ± 0.7 | 8.2 ± 2.3 | 5.5 ± 0.4 (36.6 ± 4.4) | 133 ± 18 | 79 ± 10 | 1.5 ± 0.6 | 5.4 ± 0.9 | 30.3 ± 5.4 |
Wu et al, 2009 [42] | PreDM | 5.6 ± 0.5 | NA | 5.1 ± 0.6 (32.2 ± 6.6) | 124.5 ± 21.0 | 74.7 ± 10.9 | 1.5 ± 0.9 | 5.2 ± 1.0 | 24.7 ± 3.8 |
NGT | 4.9 ± 0.4 | NA | 4.9 ± 0.5 (30.1 ± 5.5) | 114.4 ± 17.5 | 69.7 ± 9.6 | 1.3 ± 1.0 | 4.9 ± 1.1 | 23.0 ± 3.3 | |
DM | 8.7 ± 3.4 | NA | 7.5 ± 2.3 (58.5 ± 25.3) | 135.8 ± 24.9 | 78.7 ± 11.1 | 2.3 ± 3.6 | 5.3 ± 1.4 | 25.8 ± 3.5 | |
Zimmerman et al, 2018 [40]a | IGT | NA | NA | 5.5 (5.3–5.6) (36.6 [34.4–37.7]) | NA | NA | 1.35 (0.85–1.65) | 5.1 (4.3–5.9) | 27.1 ± 5.4 |
NGT: | NA | NA | 5.4 (5.2–5.5) (35.5 [33.3–36.6]) | NA | NA | 1.09 (0.82–1.52) | 5.9 (5.2–6.4) | 25.8 ± 3.6 | |
(T2)DM | NA | NA | 7.2 (6.5–7.9) (55.2 [47.5–62.8]) | NA | NA | 1.47 (1.08–1.99) | 4.7 (4.3–5.1) | 29.7 ± 4.3 | |
Dimova et al, 2017 [36] | IFG | 6.5 ± 0.3 | 6.1 ± 1.1 | 5.9 ± 0.4 (41.0 ± 4.4) | 126 ± 14 | 77 ± 11 | 1.6 ± 1.4 | 5.2 ± 1.2 | 31.3 ± 5.8 |
IGT | 6.2 ± 0.8 | 9.1 ± 1.1 | 5.9 ± 0.4 (41.0 ± 4.4) | 125 ± 14 | 77 ± 11 | 1.9 ± 1.2 | 5.4 ± 1.2 | 31.6 ± 6.1 | |
NGT | 5.4 ± 0.4 | 5.3 ± 1.3 | 5.6 ± 0.3 (37.7 ± 3.3) | 121 ± 14 | 76 ± 10 | 1.3 ± 0.8 | 5.2 ± 1.2 | 29.1 ± 6.2 | |
(T2)DM | 10.1 ± 4.4 | 15.2 ± 6 | 8.2 ± 2.4 (66.1 ± 26.4) | 129 ± 18 | 80 ± 11 | 2.2 ± 1.8 | 5.5 ± 1.2 | 32.5 ± 6.2 | |
Balbinot et al, 2012 [43] | PreDM | NA | NA | NA | 130.5 ± 6.2 | 83.5 ± 6.3 | NA | NA | 30.0 ± 2.8 |
NGT | NA | NA | NA | 121.7 ± 9.0 | 79.7 ± 8.8 | NA | NA | 25.3 ± 3.8 | |
(T2)DM | NA | NA | NA | 131.7 ± 8.0 | 85.9 ± 7.9 | NA | NA | 27.1 ± 4.0 | |
Dinh et al, 2011 [37] | NA | NA | NA | NA | NA | NA | NA | NA | |
Callaghan et al, 2020 [44] | Obese PreDM | 5.4 ± 0.6 (98.5 ± 10.3) | 7.0 ± 1.7 (126.6 ± 31.4) | 5.7 ± 0.3 (39.1 ± 3.6) | 131.5 ± 15.6 | 74.2 ± 13.3 | 1.4 ± 0.6 (122.7 ± 48.2) | NA | 46.8 ± 7.1 |
Lean NGT: | 4.7 ± 0.4 (84.9 ± 6.3) | 4.9 ± 1.1 (89.0 ± 19.5) | NA | 108.7 ± 10.2 | 66.2 ± 9.5 | 0.8 ± 0.3 (71.2 ± 22.7) | NA | 23.0 ± 2.0 | |
Obese NGT | 4.9 ± 0.3 (88.2 ± 5.7) | 5.3 ± 1.0 (96.3 ± 17.8) | 5.3 ± 0.3 (34.4 ± 2.9) | 126.2 ± 16.0 | 72.9 ± 12.5 | 1.2 ± 0.5 (104.5 ± 42.8) | NA | 48.5 ± 8.3 | |
Obese DM | 7.2 ± 2.4 (129.5 ± 43.4) | 8.7 ± 3.6 (156.5 ± 64.3) | 7.4 ± 1.5 (57.7 ± 16.5) | 131.2 ± 12.8 | 72.9 ± 88 | 1.9 ± 1.5 (160 ± 129.9) | NA | 45.0 ± 6.8 | |
Putz et al, 2013 [39] | IGT | 5.6 ± 0.6 | 8.7 ± 1.0 | 6.0 ± 0.3 (42.1 ± 2.0) | 126 ± 12 | 75 ± 7 | 1.3 (1.0–1.7) | 5.0 ± 1.1 | 29.9 ± 4.7 |
NGT | 4.9 ± 0.5 | 4.9 ± 0.5 | 5.0 ± 0.5 (31.1 ± 3.1) | 117 ± 10 | 71 ± 6 | 1.3 (0.9–1.8) | 5.1 ± 1.0 | 25.1 ± 3.9 | |
Kamel et al, 2014 [45] | IGT | NA | NA | NA | NA | NA | NA | NA | NA |
NGT | NA | NA | NA | NA | NA | NA | NA | NA | |
DM | NA | NA | NA | NA | NA | NA | NA | NA |
Author | Country | Sample size | Study group | Group size | Age, years | Sex, n female/ n male | No. of AFTs used for diagnosis | AFT tests | No. of participants with CAN | Prevalence, % |
---|---|---|---|---|---|---|---|---|---|---|
Ziegler et al, 2015 [25] | Germany | 1332 | iIFG | 336 | 63 (58–68) | 128/208 | ≥2 | Linear HRV analysis (time and frequency domain) and non-linear HRV analysis derived from non-linear dynamics | 27 | 8.1 |
iIGT | 72 | 65 (62–69) | 44/28 | 4 | 5.9 | |||||
IFG+IGT | 151 | 65 (61–70) | 61/90 | 17 | 11.4 | |||||
NGT | 565 | 63 (58–68) | 328/237 | 25 | 4.5 | |||||
kDM | 130 | 65 (61–69) | 60/70 | 23 | 17.5 | |||||
nDM | 78 | 66 (61–71) | 33/45 | 9 | 11.7 | |||||
DM | NA | NA | NA | 32 | 15.4 | |||||
Dimova et al, 2020 [41] | Bulgaria | 87 | PreDM | 35 | 44.8 ± 10.2 | 19/16 | ≥2 | АNX-3.0 method that computes sympathetic and parasympathetic activity non-invasively, separately and simultaneously based on cardiorespiratory synchronisation at rest and Ewing testsa: deep breathing challenge, Valsalva challenge and stand-up challenge | 3 | 8.6 |
NGT | 35 | 45.5 ± 14.1 | 19/16 | 2 | 5.7 | |||||
nDM | 17 | 48.0 ± 8.5 | 10/7 | 4 | 23.5 | |||||
Laitinen et al, 2011 [38] | Finland | 268 | IGT | 268 | 62 ± 7 | 177/91 | 1 | Deep breathing test; active orthostatic test; expiration/inspiration (E/I) ratioa | 67 | 25 |
Wu et al, 2009 [42] | China | 1638 | PreDM | 412 | 49.5 ± 14.2 | 218/194 | 1 | Orthostatic hypotension, BP and heart rate variability after standinga | 73 | 17.7 |
NGT | 1069 | 39.4 ± 14.0 | 568/501 | 148 | 13.8 | |||||
DM | 157 | 57.7 ± 12.8 | 67/90 | 40 | 25.5 | |||||
Zimmerman et al, 2018 [40] | Sweden | 119 | IGT | 29 | NA | 18/15 | 1 | Expiration/inspiration (E/I) ratio | 0 | 0 |
NGT | 39 | NA | 9/11 | 0 | 0 | |||||
(T2)DM | 51 | NA | 15/19 | 0 | 0 | |||||
Dimova et al, 2017 [36] | Bulgaria | 478 | PreDM | 227 | NA | NA | ≥2 | HRV at rest and during deep breathing, Valsalva challenge, standing challengea | NA | 19.8 |
IFG | 125 | 51.7 ± 12.1 | 71/54 | 17 | 13.2 | |||||
IGT | 102 | 49.2 ± 13.5 | 71/31 | 21 | 20.6 | |||||
NGT | 130 | 46.6 ± 11.4 | 82/48 | 16 | 12.3 | |||||
(T2)DM | 121 | 54.4 ± 11.5 | 54/67 | 39 | 32.2 | |||||
Balbinot et al, 2012 [43] | Brazil | 79 | PreDM | 13 | 56.8 ± 12.6 | 10/3 | ≥2 | HRV tests comprised three spectral indices (in the frequency domain) and four Ewing tests; including the Valsalva manoeuvre, orthostatic test, deep breathing testa and orthostatic hypotension test | 5 | 38.5 |
NGT | 37 | 45.1 ± 14 | 21/16 | 3 | 8.1 | |||||
(T2)DM | 29 | 59.9 ± 9.4 | 10/9 | 16 | 55.2 | |||||
Dinh et al, 2011 [37] | Germany | 145 | IGT | 48 | NA | NA | ≥2 | HRV at rest; spectral power in the very low-frequency band; spectral power in the low-frequency band; HRV during deep breathing; maximum/minimum 30:15 ratio; Valsalva ratio; postural change in systolic blood pressurea | 6 | 12.5 |
NGT | 45c | 57 ± 11 | NA | NA | ||||||
(T2)DM | 51 | NA | 15 | 29 | ||||||
Callaghan et al, 2020 [44] | USA | 184 | Obese PreDM | 56 | 44.7 ± 11.4 | 46/10 | 1 | Expiration/inspiration (E/I) ratio | 12 | 21.4 |
Lean NGT | 46 | 44.1 ± 12.1 | 38/8 | 2 | 4.4 | |||||
Obese NGT | 33 | 40.2 ± 10.7 | 25/8 | 6 | 18.2 | |||||
Obese DM | 49 | 48.9 ± 10.4 | 34/15 | 16 | 31.9 | |||||
Putz et al, 2013 [39] | Hungary | 115 | IGT | 75 | 58.7 ± 11.1 | 41/34 | 1 or ≥2 | HRV during deep | 43 | 57.3 |
NGT | 40 | 55.1 ± 10.0 | 23/17 | Breathing, standing (30/15 ratio) and Valsalva manoeuvre (Valsalva ratio), BP response to standing and sustained handgripc | 0 | 0 | ||||
Kamel et al, 2014 [45] | Australia | 52 | IGT | 8 | NA | NA | ≥2 | HRV response to Valsalva manoeuvre. Heart rate variation during deep breathing. BP response to standing, BP response to sustained handgrip was performed by first determining the maximum voluntary contraction using a handgrip dynamometerc | 2 | 25 |
NGT | 26b | 49 | 13/13 | NA | NA | |||||
DM | 18 | NA | NA | 5 | 27.8 |