Online-Only Supplemental Material

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to:

The Excess Risk of Lower Extremity Amputations in Persons with Type 1 Diabetes compared to the General Population.

Arndís Finna Ólafsdóttir R.N., Pg.D., Department of Medicine, NU Hospital Group, Uddevalla, Sweden and Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

Ann-Marie Svensson Ph.D., Center of Registers in Region Västra Götaland

Aldina Pivodic MSc, Statistiska Konsultgruppen, Gothenburg, Sweden

Soffía Gudbjörnsdottir M.D., Ph.D.,Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

Thomas Nyström M.D., Ph.D., Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

Hans Wedel Ph.D., Health Metrics Sahlgrenska Academy at University of Gothenburg, Sweden

Annika Rosengren M.D., Ph.D., Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

Marcus Lind M.D., Ph.D., Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden and Department of Medicine, NU-Hospital Group, Uddevalla, Sweden

1.   Table of contents

 

1.      Table of contents. 2

2.      Supplement Figure 1 - Patient Flow Chart 2

3.      ICD codes. 2

4.      The SAS code for a time-updated Cox regression: 2

5.      Supplement Table 1. Baseline characteristics of persons with type 1 diabetes and their controls with no prior amputation by categories of HbA1c at first inclusion in the register in 1998-2013. 2

6 Supplemental Table 2. Distribution of age by gender and calendar periods. 2

7 Supplemental Table 3. Standardized (for age and sex in first period) event rates with 95% CI per 1000 patient years for any amputation, below ankle and above ankle for diabetes patients and controls, by calendar periods. 2

8 Supplemental Table 4. Adjusted HR (95% CI) for time to first amputation for T1D vs Controls by calendar period and within diabetes cohort, analysis done from model 3 and evaluated by Cox regression. 2

9 Supplement Table 5. All models - Hazard ratios for all amputations and 95% confidence intervals for Type 1DM versus the reference group, time-updated mean HbA1c categories, albuminuria categories and eGFR categories examined by Cox regression. 2

10 Supplement Table 6. All models Adjusted hazard ratios for all Amputation and 95% confidence intervals for time-updated mean HbA1c categories and Normoalbuminuria versus the reference group examined by Cox regression  2

11.    Supplement Table 7. All models Adjusted hazard ratio of all amputations for persons with type 1DM versus controls and 95% confidence intervals for time-updated mean HbA1c categories and coexisting normoalbuminuria and eGFR>60 ml/min. 2

12.    Supplement Table 8. All models - Hazard ratios for minor amputations and 95% confidence intervals for people with type 1DM versus controls, time-updated mean HbA1c categories, albuminuria categories and eGFR categories examined by Cox regression. 2

13.    Supplement Table 9. All models - Hazard ratios for major amputations and 95% confidence intervals for people with Type 1DM versus controls, time-updated mean HbA1c categories, albuminuria categories and eGFR categories examined by Cox regression. 2

14.    Supplement Table 10. Adjusted hazard ratios for minor amputation and 95% confidence intervals for time-updated mean HbA1c categories and Normoalbuminuria versus controls examined by Cox regression  2

15.    Supplement Table 11. Adjusted hazard ratios for Minor amputation and 95% confidence intervals for time-updated mean HbA1c categories and eGFR<60/>=60 categories versus controls examined by Cox regression  2

16.    Supplement Table 12. Adjusted hazard ratios for Major amputation and 95% confidence intervals for time-updated mean HbA1c categories and Normoalbuminuria versus controls examined by Cox regression  2

17.    Supplement Table 13. Adjusted hazard ratios for Major amputation and 95% confidence intervals for time-updated mean HbA1c categories and eGFR<60/>=60 categories versus the reference group examined by Cox regression. 2

 

2.   Supplement Figure 1 - Patient Flow Chart

 

 

Type 1 DM

 

 

Controls

 

Total number of Patients from NDR

 

36,872

 

Matched Controls

184,360

 

 

 

Death before study start

237

 

 

184,123

Death before study start

4

 

36,868

 

Their controls

20

 

184,103

 

 

 

Amputation before study start

38

 

 

184,065

Amputations before study start

291

 

 

36,577

 

Their controls

1448

 

182,617

 

Total

 

36,577

 

 

Total

 

182,617

 

 

 

 

 

 

3.   ICD codes

The following ICD-9 and ICD-10 codes were collected:

coronary heart disease: 410-414 (ICD-9), I20-I25 (ICD-10) (including acute myocardial infarction: 410, I21);

stroke (431-434, 436; I61-I64);

hospitalization for heart failure (428; I50);

atrial fibrillation (427D; I48);

valve disease (394-396, 424, 746; I05-I09, I34-I37, Q22-Q23);

foot ulcer (operation code 250G; ICD10 E10.5, E11.5, E12.5, E13.5, E14.5); and cancer (140-208; C00-C97).

For renal dialysis and transplantation, the following codes were used: V42A, V45B, V56A, V56W (ICD-9) and Z94.0, Z49, Z99.2 (ICD-10).

All events were collected from the inpatient register except for atrial fibrillation that was collected both from inpatient and outpatient register.

4.   The SAS code for a time-updated Cox regression:

PROC PHREG DATA = data;

CLASS mainvar / REF = LAST;

MODEL (startyr,stopyr)*endpsplit(0) = mainvar &covars. / RL;

RUN;

The dataset data is split up for each patient by consecutive time periods between startyr-stopyr given in years from start of study (first visit date in NDR). For each new value of any variable that is studied as time-updated in the model, there is a new observation for that patient starting with startyr and stopping with stopyr that is either a new updated value or the last updated timepoint ending up in an amputation event or a censoring event. Endpsplit is 0 for all consecutive observations unless it is the last observation, i.e. the last time period, where it is either 0 if censoring or 1 if the studied event has occurred at the end of that time interval (stopyr). Mainvar is for example time-updated HbA1c category with last category corresponding to controls. &covars. is a macro-variable including all adjustment variables, e.g. ageupd sex with time-updated age and sex in model 1.

SAS software link with an example: http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/viewer.htm#statug_phreg_sect038.htm

5.    Supplement Table 1. Baseline characteristics of persons with type 1 diabetes and their controls with no prior amputation by categories of HbA1c at first inclusion in the register in 1998-2013

 

 

HbA1c categories at baseline (NGSP % / IFCC mmol/mol)

 

Controls
n=182617

All Type I diabetes
n=36577

≤6.9%
(≤52 mmol/mol)
n=5867

7.0-7.8%
(53-62 mmol/mol)
n=9687

7.9-8.7%
(63-72 mmol/mol)
n=10414

8.8-9.6%
(73-82 mmol/mol)
n=6005

≥9.7%
(≥83 mmol/mol)
n=4367

Missing value
n=237

Women

82738 (45.3%)

16567 (45.3%)

2603 (44.4%)

4286 (44.2%)

4714 (45.3%)

2733 (45.5%)

2130 (48.8%)

101 (42.6%)

Age (years)

35.2 (14.6)
n=182617

35.2 (14.6)
n=36577

35.3 (15.2)
n=5867

36.1 (14.8)
n=9687

35.8 (14.5)
n=10414

34.9 (14.1)
n=6005

32.3 (13.5)
n=4367

30.4 (14.4)
n=237

Age category

 

 

 

 

 

 

 

 

18-34

102427 (56.1%)

20495 (56.0%)

3444 (58.7%)

5200 (53.7%)

5600 (53.8%)

3307 (55.1%)

2774 (63.5%)

170 (71.7%)

35-49

45377 (24.8%)

9083 (24.8%)

1161 (19.8%)

2412 (24.9%)

2717 (26.1%)

1679 (28.0%)

1074 (24.6%)

40 (16.9%)

50-64

27588 (15.1%)

5533 (15.1%)

977 (16.7%)

1646 (17.0%)

1676 (16.1%)

819 (13.6%)

397 (9.1%)

18 (7.6%)

65+ 

7225 (4.0%)

1466 (4.0%)

285 (4.9%)

429 (4.4%)

421 (4.0%)

200 (3.3%)

122 (2.8%)

9 (3.8%)

Born in Sweden

158353 (86.7%)

34028 (93.0%)

5433 (92.6%)

9065 (93.6%)

9776 (93.9%)

5570 (92.8%)

3997 (91.5%)

187 (78.9%)

Education category

 

 

 

 

 

 

 

 

Low

38640 (21.5%)

8091 (22.4%)

1069 (18.5%)

1833 (19.2%)

2229 (21.6%)

1515 (25.6%)

1357 (31.6%)

88 (39.1%)

Mid

92477 (51.6%)

19378 (53.7%)

2916 (50.3%)

4995 (52.2%)

5656 (54.9%)

3306 (55.9%)

2398 (55.9%)

107 (47.6%)

High

48234 (26.9%)

8629 (23.9%)

1807 (31.2%)

2738 (28.6%)

2420 (23.5%)

1097 (18.5%)

537 (12.5%)

30 (13.3%)

Variables in the National Diabetes Regiser only

 

 

 

 

 

 

 

 

HbA1c (mmol/mol, IFCC)

 

66.1 (14.7)
n=36340

46.7 (4.9)
n=5867

57.7 (2.7)
n=9687

67.1 (2.8)
n=10414

76.9 (2.8)
n=6005

94.1 (10.9)
n=4367

 

HbA1c (%, NGSP)

 

8.20 (1.35)
n=36340

6.42 (0.45)
n=5867

7.43 (0.24)
n=9687

8.29 (0.26)
n=10414

9.18 (0.26)
n=6005

10.8 (1.0)
n=4367

 

Diabetes duration (years)

 

19.9 (14.7)
n=36577

18.6 (16.2)
n=5867

20.8 (15.0)
n=9687

20.8 (14.3)
n=10414

19.9 (13.7)
n=6005

17.7 (13.1)
n=4367

13.4 (14.5)
n=237

Insulin method

 

 

 

 

 

 

 

 

Injection

 

27972 (80.3%)

4693 (84.1%)

7430 (79.4%)

7837 (78.8%)

4519 (79.5%)

3352 (82.2%)

141 (83.4%)

Pump    

 

6841 (19.7%)

886 (15.9%)

1928 (20.6%)

2108 (21.2%)

1163 (20.5%)

728 (17.8%)

28 (16.6%)

BMI (kg/m2)

 

25.9 (4.6)
n=35343

25.2 (4.4)
n=5639

25.7 (4.2)
n=9460

26.2 (4.5)
n=10149

26.5 (4.7)
n=5838

25.8 (5.2)
n=4149

26.0 (4.9)
n=108

LDL (mmol/L)

 

2.63 (0.82)
n=33009

2.52 (0.78)
n=5265

2.57 (0.77)
n=9015

2.62 (0.80)
n=9571

2.70 (0.83)
n=5405

2.83 (0.94)
n=3721

2.71 (0.99)
n=32

Systolic BP (mmHg)

 

126.1 (15.7)
n=36121

124.7 (15.4)
n=5786

125.7 (15.3)
n=9618

126.6 (15.6)
n=10324

127.3 (15.9)
n=5965

126.2 (16.8)
n=4287

123.4 (17.9)
n=141

Diastolic BP (mmHg)

 

72.6 (9.3)
n=36121

71.7 (9.0)
n=5786

71.7 (9.2)
n=9618

72.6 (9.1)
n=10324

73.5 (9.4)
n=5965

74.4 (9.7)
n=4287

73.2 (10.1)
n=141

Smoking

 

4435 (12.3%)

468 (8.1%)

880 (9.2%)

1194 (11.6%)

915 (15.4%)

945 (22.2%)

33 (21.6%)

Blood pressure lowering medication

 

14171 (39.3%)

1950 (33.9%)

3791 (39.6%)

4222 (41.0%)

2535 (42.7%)

1644 (38.4%)

29 (15.1%)

Lipid lowering medication

 

12978 (35.9%)

1645 (28.5%)

3506 (36.5%)

3997 (38.7%)

2397 (40.3%)

1416 (32.9%)

17 (8.7%)

eGFR

 

93.5 (31.6)
n=34328

91.0 (32.9)
n=5513

91.2 (29.9)
n=9283

92.8 (28.0)
n=9881

94.9 (33.3)
n=5629

101.5 (37.3)
n=3973

101.9 (42.8)
n=49

Albuminuria

 

 

 

 

 

 

 

 

Normoalbuminuria   

 

26797 (80.0%)

4597 (85.4%)

7582 (83.0%)

7841 (80.9%)

4137 (75.3%)

2613 (69.3%)

27 (71.1%)

Microalbuminuria   

 

3796 (11.3%)

366 (6.8%)

860 (9.4%)

1110 (11.5%)

795 (14.5%)

664 (17.6%)

1 (2.6%)

Macroalbuminuria   

 

2117 (6.3%)

249 (4.6%)

473 (5.2%)

551 (5.7%)

451 (8.2%)

390 (10.3%)

3 (7.9%)

CKD stage 5        

 

794 (2.4%)

172 (3.2%)

215 (2.4%)

186 (1.9%)

108 (2.0%)

106 (2.8%)

7 (18.4%)

Registrations in the InPatient Register prior to baseline

 

 

 

 

 

 

 

 

Acute Myocardial Infarction (I21)

835 (0.5%)

808 (2.2%)

99 (1.7%)

223 (2.3%)

232 (2.2%)

150 (2.5%)

102 (2.3%)

2 (0.8%)

Atrial Fibrillation (I48)

811 (0.4%)

215 (0.6%)

38 (0.6%)

57 (0.6%)

73 (0.7%)

26 (0.4%)

18 (0.4%)

3 (1.3%)

Coronary Heart Disease (I20-I25)

1667 (0.9%)

1605 (4.4%)

229 (3.9%)

435 (4.5%)

449 (4.3%)

275 (4.6%)

209 (4.8%)

8 (3.4%)

Heart Failure (I50)

438 (0.2%)

491 (1.3%)

74 (1.3%)

124 (1.3%)

143 (1.4%)

83 (1.4%)

60 (1.4%)

7 (3.0%)

Valve disease (I05-I09,I34-I36)

359 (0.2%)

134 (0.4%)

16 (0.3%)

24 (0.2%)

42 (0.4%)

26 (0.4%)

20 (0.5%)

6 (2.5%)

Stroke (I61-I64)

726 (0.4%)

548 (1.5%)

80 (1.4%)

132 (1.4%)

168 (1.6%)

88 (1.5%)

77 (1.8%)

3 (1.3%)

Cancer (C00-C97)

2093 (1.1%)

515 (1.4%)

100 (1.7%)

143 (1.5%)

153 (1.5%)

69 (1.1%)

48 (1.1%)

2 (0.8%)

Foot ulcer (circulatory complications) (E10.5,E11.5,E12.5,E13.5,E14.5)

17 (0.0%)

1349 (3.7%)

182 (3.1%)

318 (3.3%)

384 (3.7%)

264 (4.4%)

195 (4.5%)

6 (2.5%)

For categorical variables n (%) is presented. For continuous variables Mean (SD) is presented.

 

6 Supplemental Table 2. Distribution of age by gender and calendar periods

 

Gender

Calendar period

Mean (SD)
at risk n=

Men

1998-2001

39·9 (13·0)
n=8350

2002-2004

40·5 (13·5)
n=11738

2005-2007

41·0 (14·0)
n=14386

2008-2010

40·8 (14·8)
n=16548

2011-2013

41·3 (15·2)
n=18245

Women

1998-2001

40·3 (13·3)
n=7071

2002-2004

41·1 (13·8)
n=9868

2005-2007

41·6 (14·5)
n=12190

2008-2010

41·6 (15·2)
n=14022

2011-2013

42·3 (15·6)
n=15369

 

7 Supplemental Table 3. Standardized (for age and sex in first period) event rates with 95% CI per 1000 patient years for any amputation, below ankle and above ankle for diabetes patients and controls, by calendar periods.

 

Event

Population

1998-2001

2002-2004

2005-2007

2008-2010

2011-2013

All amputations

All diabetes patients

3.09 (2.56-3.62)

3.31 (2.85-3.77)

3.04 (2.65-3.42)

2.50 (2.19-2.82)

2.64 (2.31-2.98)

 

diabetes patients, Men

3.82 (3.02-4.63)

3.74 (3.08-4.41)

3.79 (3.21-4.38)

3.24 (2.75-3.74)

3.23 (2.72-3.74)

 

diabetes patients, Women

2.24 (1.58-2.90)

2.80 (2.17-3.43)

2.16 (1.68-2.64)

1.65 (1.27-2.02)

1.97 (1.54-2.39)

 

Controls

0.05 (0.02-0.09)

0.06 (0.03-0.08)

0.05 (0.03-0.07)

0.05 (0.03-0.07)

0.04 (0.02-0.06)

Minor amputations

All diabetes patients

1.62 (1.23-2.00)

1.93 (1.58-2.28)

1.87 (1.57-2.17)

1.58 (1.32-1.83)

1.79 (1.51-2.07)

 

diabetes patients, Men

2.00 (1.42-2.58)

2.29 (1.76-2.81)

2.44 (1.97-2.91)

2.16 (1.75-2.57)

2.47 (2.02-2.92)

 

diabetes patients, Women

1.16 (0.69-1.64)

1.52 (1.05-1.98)

1.21 (0.85-1.57)

0.90 (0.62-1.19)

1.00 (0.69-1.30)

 

Controls

0.01 (-0.00-0.03)

0.01 (0.00-0.02)

0.01 (0.00-0.02)

0.02 (0.01-0.03)

0.01 (0.00-0.02)

Major amputations

All diabetes patients

1.84 (1.43-2.25)

1.92 (1.57-2.26)

1.65 (1.37-1.93)

1.40 (1.17-1.63)

1.50 (1.25-1.74)

 

diabetes patients, Men

2.29 (1.66-2.91)

2.16 (1.65-2.66)

1.99 (1.57-2.41)

1.71 (1.36-2.06)

1.66 (1.31-2.01)

 

diabetes patients, Women

1.32 (0.81-1.83)

1.64 (1.16-2.11)

1.27 (0.90-1.63)

1.04 (0.75-1.34)

1.31 (0.97-1.65)

 

Controls

0.05 (0.02-0.07)

0.05 (0.02-0.07)

0.04 (0.02-0.05)

0.03 (0.02-0.04)

0.03 (0.01-0.04)

 

8 Supplemental Table 4. Adjusted HR (95% CI) for time to first amputation for T1D vs Controls by calendar period and within diabetes cohort, analysis done from model 3 and evaluated by Cox regression.

 

Cohort

Calendar period/Comparison

HR (95% CI)
p-value

p-value for interaction Group*Calendar period

 

Any amputations

 

Type 1DM vs Controls

1998-2001

34·8 (17·5-69·3)

0.74

 

 

2002-2004

30·4 (18·6-49·7)

 

 

 

2005-2007

24·1 (15·9-36·5)

 

 

 

2008-2010

27·1 (18·0-40·9)

 

 

 

2011-2013

22·4 (15·6-32·0)

 

 

Type 1DM cohort

2002-2004 vs 1998-2001

1·03 (0·79-1·34)
p=0·83

 

 

 

2005-2007 vs 1998-2001

0·87 (0·66-1·14)
p=0·31

 

 

 

2008-2010 vs 1998-2001

0·81 (0·61-1·08)
p=0·15

 

 

 

2011-2013 vs 1998-2001

0·75 (0·56-1·01)
p=0·060

 

 

Type 1DM vs Controls

1998-2003

39·1 (24·3-63·0)

0.46

 

 

2004-2008

28·4 (20·5-39·3)

 

 

 

2009-2013

28·0 (20·9-37·7)

 

 

Type 1DM cohort

2004-2008 vs 1998-2003

0·87 (0·72-1·06)
p=0·17

 

 

 

2009-2013 vs 1998-2003

0·75 (0·61-0·94)
p=0·011

 

 

Minor Amputations

 

 

Type 1DM vs Controls

1998-2001

51.7 (16.0-167.2)

0.65

 

 

2002-2004

113.4 (35.8-359.4)

 

 

 

2005-2007

50.8 (24.7-104.5)

 

 

 

2008-2010

71.5 (31.4-162.9)

 

 

 

2011-2013

44.4 (24.5-80.4)

 

 

Type 1DM cohort

2002-2004 vs 1998-2001

1.29 (0.89-1.87)
p=0.18

 

 

 

2005-2007 vs 1998-2001

1.12 (0.77-1.63)
p=0.56

 

 

 

2008-2010 vs 1998-2001

0.96 (0.65-1.42)
p=0.84

 

 

 

2011-2013 vs 1998-2001

0.96 (0.66-1.48)
p=0.96

 

 

Type 1DM vs Controls

1998-2003

67.2 (29.3-154.1)

0.62

 

 

 

 

2004-2008

84.5 (43.0-165.9)

 

 

 

 

 

2009-2013

56.1 (34.0-92.4)

 

 

 

 

Type 1DM cohort

2004-2008 vs 1998-2003

0.98 (0.76-1.27)
p=0.89

 

 

 

2009-2013 vs 1998-2003

0.88 (0.66-1.17)
p=0.37

 

 

Major Amputations

 

Type 1DM vs Controls

1998-2001

26.0 (11.8-57.3)

0.85

 

 

2002-2004

17.9 (10.3-31.1)

 

 

 

2005-2007

15.4 (9.4-25.3)

 

 

 

2008-2010

16.5 (10.4-26.5)

 

 

 

2011-2013

16.3 (10.4-25.6)

 

 

Type 1DM cohort

2002-2004 vs 1998-2001

0.83 (0.59-1.18)
p=0.29

 

 

 

2005-2007 vs 1998-2001

0.67 (0.47-0.96)
p=0.028

 

 

 

2008-2010 vs 1998-2001

0.66 (0.46-0.94)
p=0.023

 

 

 

2011-2013 vs 1998-2001

0.57 (0.39-0.84)
p=0.0045

 

 

Type 1DM vs Controls

1998-2003

30.6 (17.5-53.5)

0.18

 

 

 

 

2004-2008

16.6 (11.5-23.9)

 

 

 

 

 

2009-2013

21.4 (14.8-30.8)

 

 

 

 

Type 1DM cohort

2004-2008 vs 1998-2003

0.72 (0.55-0.92)
p=0.010

 

 

 

2009-2013 vs 1998-2003

0.62 (0.46-0.82)
p=0.0010

 

 

 

9 Supplement Table 5. All models - Hazard ratios for all amputations and 95% confidence intervals for Type 1DM versus the reference group, time-updated mean HbA1c categories, albuminuria categories and eGFR categories examined by Cox regression

 

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

 

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Group All Type I diabetes with no prior amputation

53.6 (44.3 - 64.8)
<.0001

39.3 (32.1 - 48.1)
<.0001

51.7 (42.7 - 62.5)
<.0001

67.9 (55.5 - 83.2)
<.0001

89.3 (70.7 - 112.9)
<.0001

31.5 (25.6 - 38.8)
<.0001

38.0 (31.1 - 46.3)
<.0001

45.7 (37.0 - 56.6)
<.0001

55.1 (43.1 - 70.5)
<.0001

 

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%)

19.5 (14.4 - 26.6)
<.0001

13.0 (9.5 - 17.9)
<.0001

17.8 (13.0 - 24.2)
<.0001

24.2 (17.7 - 33.1)
<.0001

33.0 (23.6 - 45.9)
<.0001

11.8 (8.5 - 16.3)
<.0001

14.8 (10.8 - 20.2)
<.0001

18.5 (13.4 - 25.5)
<.0001

23.2 (16.4 - 32.6)
<.0001

53-62 mmol/mol (7.0-7.8%)

32.8 (26.2 - 41.1)
<.0001

21.8 (17.1 - 27.7)
<.0001

29.7 (23.7 - 37.3)
<.0001

40.5 (32.1 - 51.1)
<.0001

55.1 (42.6 - 71.3)
<.0001

18.6 (14.6 - 23.7)
<.0001

23.3 (18.5 - 29.4)
<.0001

29.2 (22.9 - 37.1)
<.0001

36.5 (28.0 - 47.8)
<.0001

63-72 mmol/mol (7.9-8.7%)

50.0 (40.5 - 61.9)
<.0001

34.0 (27.1 - 42.6)
<.0001

46.3 (37.4 - 57.3)
<.0001

63.1 (50.6 - 78.7)
<.0001

86.0 (67.1 - 110.1)
<.0001

28.1 (22.3 - 35.4)
<.0001

35.2 (28.3 - 43.8)
<.0001

44.1 (35.1 - 55.5)
<.0001

55.3 (42.6 - 71.6)
<.0001

73-82 mmol/mol (8.8-9.6%)

92.8 (74.5 - 115.7)
<.0001

64.2 (50.9 - 80.8)
<.0001

87.4 (70.2 - 108.9)
<.0001

119.1 (94.8 - 149.7)
<.0001

162.3 (125.7 - 209.5)
<.0001

49.1 (38.8 - 62.1)
<.0001

61.5 (49.0 - 77.1)
<.0001

77.0 (60.7 - 97.7)
<.0001

96.5 (73.8 - 126.1)
<.0001

>=83 mmol/mol (>=9.7%)

232.4 (185.2 - 291.6)
<.0001

161.5 (127.5 - 204.4)
<.0001

220.0 (175.8 - 275.4)
<.0001

299.8 (237.4 - 378.5)
<.0001

408.5 (315.1 - 529.6)
<.0001

116.9 (91.8 - 148.9)
<.0001

146.5 (116.0 - 185.0)
<.0001

183.5 (143.6 - 234.5)
<.0001

229.9 (174.6 - 302.6)
<.0001

 

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Normoalbuminuria

27.0 (21.8 - 33.4)
<.0001

23.1 (18.5 - 29.0)
<.0001

27.0 (21.8 - 33.5)
<.0001

31.5 (25.1 - 39.6)
<.0001

36.7 (28.2 - 47.8)
<.0001

20.6 (16.4 - 25.9)
<.0001

23.1 (18.5 - 28.7)
<.0001

25.8 (20.4 - 32.7)
<.0001

28.9 (22.0 - 37.9)
<.0001

Microalbuminuria

72.5 (57.8 - 91.0)
<.0001

59.8 (46.8 - 76.5)
<.0001

69.8 (55.5 - 87.8)
<.0001

81.4 (64.3 - 103.1)
<.0001

95.0 (72.9 - 123.8)
<.0001

48.0 (37.4 - 61.7)
<.0001

53.7 (42.4 - 68.0)
<.0001

60.1 (47.0 - 76.8)
<.0001

67.2 (51.0 - 88.6)
<.0001

Macroalbuminuria

148.5 (118.7 - 185.7)
<.0001

122.7 (96.4 - 156.2)
<.0001

143.2 (114.3 - 179.3)
<.0001

167.0 (132.3 - 210.7)
<.0001

194.8 (149.9 - 253.1)
<.0001

89.2 (69.5 - 114.5)
<.0001

99.8 (78.9 - 126.3)
<.0001

111.6 (87.4 - 142.6)
<.0001

124.9 (94.8 - 164.5)
<.0001

CKD stage 5

505.1 (397.6 - 641.6)
<.0001

411.4 (318.0 - 532.3)
<.0001

479.9 (377.4 - 610.3)
<.0001

559.9 (438.0 - 715.6)
<.0001

653.0 (497.7 - 856.9)
<.0001

273.7 (209.6 - 357.3)
<.0001

306.1 (237.7 - 394.2)
<.0001

342.4 (263.7 - 444.5)
<.0001

383.0 (286.7 - 511.7)
<.0001

 

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

CKD stage 1 (eGFR >=90)

27.3 (21.4 - 34.8)
<.0001

24.2 (18.8 - 31.0)
<.0001

27.9 (21.9 - 35.5)
<.0001

32.2 (24.9 - 41.7)
<.0001

37.3 (27.8 - 49.9)
<.0001

21.6 (16.8 - 27.7)
<.0001

24.1 (18.8 - 30.8)
<.0001

26.8 (20.6 - 34.9)
<.0001

29.9 (22.2 - 40.4)
<.0001

CKD stage 2 (eGFR 60-89)

37.6 (30.3 - 46.7)
<.0001

32.3 (25.7 - 40.7)
<.0001

37.4 (30.1 - 46.4)
<.0001

43.2 (34.3 - 54.4)
<.0001

49.9 (38.3 - 65.0)
<.0001

29.9 (22.2 - 40.4)
<.0001

31.3 (25.0 - 39.1)
<.0001

34.9 (27.5 - 44.2)
<.0001

38.9 (29.6 - 51.2)
<.0001

CKD stage 3 (eGFR 30-59)

87.2 (69.3 - 109.8)
<.0001

72.0 (56.0 - 92.7)
<.0001

83.2 (65.9 - 105.1)
<.0001

96.2 (75.7 - 122.1)
<.0001

111.1 (85.1 - 145.1)
<.0001

53.5 (41.3 - 69.4)
<.0001

59.7 (46.8 - 76.2)
<.0001

66.6 (51.9 - 85.6)
<.0001

74.3 (56.2 - 98.2)
<.0001

CKD stage 4 (eGFR 15-29)

152.3 (109.5 - 211.7)
<.0001

126.3 (89.5 - 178.1)
<.0001

145.9 (104.8 - 203.2)
<.0001

168.6 (120.6 - 235.8)
<.0001

194.8 (136.5 - 278.1)
<.0001

84.5 (59.4 - 120.1)
<.0001

94.3 (67.0 - 132.6)
<.0001

105.1 (74.3 - 148.8)
<.0001

117.3 (81.0 - 169.7)
<.0001

CKD stage 5 (eGFR <15, dialysis or transplantation)

496.3 (390.6 - 630.5)
<.0001

411.9 (318.4 - 532.7)
<.0001

475.9 (374.3 - 605.1)
<.0001

549.9 (429.9 - 703.4)
<.0001

635.4 (483.1 - 835.6)
<.0001

267.9 (204.9 - 350.1)
<.0001

298.8 (231.8 - 385.1)
<.0001

333.3 (256.3 - 433.2)
<.0001

371.7 (277.6 - 497.7)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

10 Supplement Table 6. All models Adjusted hazard ratios for all Amputation and 95% confidence intervals for time-updated mean HbA1c categories and Normoalbuminuria versus the reference group examined by Cox regression

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Time updated mean HbA1c categories and Albuminuria

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%) – Normoalbuminuria

9.3 (5.7 - 15.1)
<.0001

7.1 (4.3 - 11.6)
<.0001

9.0 (5.6 - 14.7)
<.0001

11.5 (7.1 - 18.8)
<.0001

14.7 (8.9 - 24.4)
<.0001

6.2 (3.7 - 10.4)
<.0001

7.5 (4.5 - 12.4)
<.0001

9.0 (5.3 - 15.0)
<.0001

10.8 (6.3 - 18.3)
<.0001

53-62 mmol/mol (7.0-7.8%) – Normoalbuminuria

19.0 (14.2 - 25.5)
<.0001

14.3 (10.6 - 19.4)
<.0001

18.3 (13.7 - 24.5)
<.0001

23.4 (17.3 - 31.5)
<.0001

29.8 (21.6 - 41.3)
<.0001

13.0 (9.6 - 17.7)
<.0001

15.7 (11.7 - 21.1)
<.0001

18.8 (13.9 - 25.5)
<.0001

22.6 (16.2 - 31.5)
<.0001

63-72 mmol/mol (7.9-8.7%) – Normoalbuminuria

28.7 (22.0 - 37.5)
<.0001

22.0 (16.6 - 29.0)
<.0001

28.1 (21.5 - 36.7)
<.0001

35.9 (27.2 - 47.3)
<.0001

45.8 (33.7 - 62.2)
<.0001

19.7 (14.9 - 26.1)
<.0001

23.7 (18.0 - 31.1)
<.0001

28.4 (21.4 - 37.7)
<.0001

34.1 (24.9 - 46.7)
<.0001

73-82 mmol/mol (8.8-9.6%) – Normoalbuminuria

40.2 (28.8 - 56.2)
<.0001

31.3 (22.2 - 44.0)
<.0001

39.9 (28.6 - 55.8)
<.0001

51.0 (36.2 - 71.9)
<.0001

65.2 (45.2 - 94.1)
<.0001

26.4 (18.7 - 37.3)
<.0001

31.8 (22.7 - 44.5)
<.0001

38.1 (26.9 - 54.0)
<.0001

45.8 (31.5 - 66.5)
<.0001

>=83 mmol/mol (>=9.7%) – Normoalbuminuria

160.7 (116.1 - 222.3)
<.0001

129.3 (93.2 - 179.5)
<.0001

165.4 (119.8 - 228.2)
<.0001

211.1 (151.2 - 294.8)
<.0001

269.7 (188.0 - 386.9)
<.0001

106.7 (76.5 - 148.8)
<.0001

128.1 (92.3 - 178.0)
<.0001

153.9 (109.4 - 216.5)
<.0001

184.8 (127.6 - 267.5)
<.0001

<=52 mmol/mol (<=6.9%) - Not Normoalbuminuria

58.2 (39.1 - 86.5)
<.0001

40.0 (26.4 - 60.5)
<.0001

51.1 (34.2 - 76.3)
<.0001

65.3 (43.7 - 97.5)
<.0001

83.4 (55.1 - 126.3)
<.0001

32.6 (21.5 - 49.4)
<.0001

39.2 (26.1 - 58.7)
<.0001

47.0 (31.3 - 70.6)
<.0001

56.5 (37.0 - 86.2)
<.0001

53-62 mmol/mol (7.0-7.8%)- Not Normoalbuminuria

71.5 (54.7 - 93.4)
<.0001

49.5 (37.0 - 66.1)
<.0001

63.2 (48.2 - 82.9)
<.0001

80.8 (61.4 - 106.1)
<.0001

103.1 (76.9 - 138.4)
<.0001

38.7 (28.8 - 52.0)
<.0001

46.5 (35.2 - 61.5)
<.0001

55.8 (42.1 - 74.1)
<.0001

67.0 (49.4 - 91.1)
<.0001

63-72 mmol/mol (7.9-8.7%) - Not Normoalbuminuria

106.6 (84.2 - 134.9)
<.0001

77.4 (60.0 - 99.8)
<.0001

98.9 (78.0 - 125.5)
<.0001

126.4 (99.0 - 161.3)
<.0001

161.4 (123.1 - 211.8)
<.0001

60.2 (46.5 - 78.1)
<.0001

72.3 (56.6 - 92.4)
<.0001

86.8 (67.4 - 111.9)
<.0001

104.3 (78.6 - 138.4)
<.0001

73-82 mmol/mol (8.8-9.6% ) - Not Normoalbuminuria

173.7 (136.6 - 220.9)
<.0001

129.0 (99.9 - 166.5)
<.0001

164.8 (129.5 - 209.7)
<.0001

210.6 (164.1 - 270.2)
<.0001

268.9 (203.7 - 355.1)
<.0001

96.6 (74.4 - 125.4)
<.0001

116.0 (90.4 - 148.8)
<.0001

139.3 (107.4 - 180.7)
<.0001

167.2 (125.0 - 223.7)
<.0001

>=83 mmol/mol (>=9.7%) - Not Normoalbuminuria

385.0 (299.8 - 494.3)
<.0001

292.3 (225.3 - 379.3)
<.0001

373.5 (291.4 - 478.8)
<.0001

477.3 (368.7 - 617.8)
<.0001

609.6 (457.2 - 812.6)
<.0001

207.3 (158.5 - 271.2)
<.0001

249.0 (192.3 - 322.4)
<.0001

299.0 (228.3 - 391.6)
<.0001

359.0 (265.8 - 485.0)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

11.  Supplement Table 7. All models Adjusted hazard ratio of all amputations for persons with type 1DM versus controls and 95% confidence intervals for time-updated mean HbA1c categories and coexisting normoalbuminuria and eGFR>60 ml/min.

 

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Time updated mean HbA1c categories and eGFR

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%) - eGFR>=60

11.1 (7.1 - 17.2)
<.0001

8.9 (5.7 - 13.8)
<.0001

11.0 (7.1 - 17.0)
<.0001

13.6 (8.7 - 21.2)
<.0001

16.8 (10.6 - 26.7)
<.0001

7.8 (4.9 - 12.4)
<.0001

9.1 (5.8 - 14.5)
<.0001

10.8 (6.8 - 17.1)
<.0001

12.7 (7.8 - 20.6)
<.0001

53-62 mmol/mol (7.0-7.8%) - eGFR>=60

19.4 (14.7 - 25.6)
<.0001

15.3 (11.4 - 20.4)
<.0001

18.9 (14.3 - 25.0)
<.0001

23.4 (17.5 - 31.2)
<.0001

29.0 (21.1 - 39.7)
<.0001

13.5 (10.1 - 18.1)
<.0001

15.9 (12.0 - 21.1)
<.0001

18.7 (13.9 - 25.1)
<.0001

22.0 (15.9 - 30.4)
<.0001

63-72 mmol/mol (7.9-8.7%) - eGFR>=60

33.8 (26.4 - 43.2)
<.0001

27.0 (20.9 - 34.9)
<.0001

33.4 (26.1 - 42.7)
<.0001

41.4 (32.0 - 53.5)
<.0001

51.2 (38.4 - 68.4)
<.0001

24.1 (18.6 - 31.2)
<.0001

28.3 (22.1 - 36.3)
<.0001

33.4 (25.7 - 43.3)
<.0001

39.2 (29.2 - 52.7)
<.0001

73-82 mmol/mol (8.8-9.6%) - eGFR>=60

53.5 (40.7 - 70.5)
<.0001

43.4 (32.7 - 57.6)
<.0001

53.7 (40.8 - 70.7)
<.0001

66.5 (50.0 - 88.5)
<.0001

82.4 (60.1 - 113.0)
<.0001

36.4 (27.3 - 48.5)
<.0001

42.8 (32.4 - 56.6)
<.0001

50.4 (37.7 - 67.5)
<.0001

59.3 (42.9 - 82.0)
<.0001

>=83 mmol/mol (>=9.7%) - eGFR>=60

170.5 (128.5 - 226.3)
<.0001

142.9 (107.4 - 190.2)
<.0001

177.0 (133.7 - 234.2)
<.0001

219.0 (163.1 - 294.2)
<.0001

271.3 (195.7 - 376.2)
<.0001

117.6 (87.9 - 157.3)
<.0001

138.4 (104.0 - 184.3)
<.0001

162.9 (120.5 - 220.3)
<.0001

191.6 (137.1 - 267.8)
<.0001

<=52 mmol/mol (<=6.9%) - eGFR<60

56.1 (36.6 - 86.0)
<.0001

40.3 (25.9 - 62.9)
<.0001

49.9 (32.4 - 76.8)
<.0001

61.8 (40.1 - 95.1)
<.0001

76.5 (49.1 - 119.4)
<.0001

32.7 (20.9 - 51.1)
<.0001

38.5 (24.9 - 59.5)
<.0001

45.3 (29.3 - 70.1)
<.0001

53.3 (33.9 - 83.7)
<.0001

53-62 mmol/mol (7.0-7.8%) - eGFR<60

78.0 (58.6 - 103.8)
<.0001

56.8 (41.7 - 77.3)
<.0001

70.3 (52.6 - 94.0)
<.0001

87.0 (65.0 - 116.5)
<.0001

107.8 (78.9 - 147.3)
<.0001

43.4 (31.8 - 59.4)
<.0001

51.1 (38.0 - 68.8)
<.0001

60.2 (44.6 - 81.3)
<.0001

70.8 (51.3 - 97.7)
<.0001

63-72 mmol/mol (7.9-8.7%) - eGFR<60

123.6 (95.8 - 159.6)
<.0001

92.5 (70.2 - 121.9)
<.0001

114.6 (88.5 - 148.5)
<.0001

141.8 (109.0 - 184.6)
<.0001

175.7 (131.7 - 234.4)
<.0001

67.2 (50.6 - 89.2)
<.0001

79.1 (60.5 - 103.4)
<.0001

93.1 (70.7 - 122.5)
<.0001

109.5 (81.0 - 148.0)
<.0001

73-82 mmol/mol (8.8-9.6%) - eGFR<60

220.9 (169.4 - 288.1)
<.0001

167.5 (126.3 - 222.2)
<.0001

207.5 (158.8 - 271.1)
<.0001

256.8 (195.4 - 337.4)
<.0001

318.1 (236.0 - 428.7)
<.0001

117.2 (87.5 - 157.0)
<.0001

137.9 (104.4 - 182.3)
<.0001

162.3 (122.0 - 216.0)
<.0001

190.9 (139.8 - 260.9)
<.0001

>=83 mmol/mol (>=9.7%) - eGFR<60

462.1 (350.2 - 609.8)
<.0001

355.4 (265.6 - 475.6)
<.0001

440.1 (333.4 - 581.0)
<.0001

544.7 (409.9 - 723.8)
<.0001

674.8 (495.1 - 919.7)
<.0001

248.5 (184.1 - 335.5)
<.0001

292.5 (219.3 - 390.1)
<.0001

344.3 (256.2 - 462.9)
<.0001

405.0 (293.4 - 559.1)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

12.  Supplement Table 8. All models - Hazard ratios for minor amputations and 95% confidence intervals for people with type 1DM versus controls, time-updated mean HbA1c categories, albuminuria categories and eGFR categories examined by Cox regression

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation below ankle

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Overall, n events=689, data used = 100.0%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Group All Type I diabetes with no prior amputation

112.3 (79.2 - 159.4)
<.0001

90.3 (63.2 - 129.2)
<.0001

114.2 (80.5 - 162.2)
<.0001

144.3 (99.9 - 208.3)
<.0001

182.4 (121.7 - 273.4)
<.0001

75.7 (52.6 - 109.0)
<.0001

86.3 (60.2 - 123.8)
<.0001

98.4 (67.3 - 143.9)
<.0001

112.3 (73.7 - 171.0)
<.0001

Time updated mean HbA1c categories, n events=686, data used = 99.9%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%)

39.1 (24.3 - 62.9)
<.0001

29.5 (18.2 - 47.9)
<.0001

38.2 (23.7 - 61.5)
<.0001

49.4 (30.4 - 80.4)
<.0001

64.0 (38.4 - 106.8)
<.0001

27.3 (16.7 - 44.7)
<.0001

32.0 (19.7 - 52.0)
<.0001

37.4 (22.8 - 61.5)
<.0001

43.7 (25.9 - 74.0)
<.0001

53-62 mmol/mol (7.0-7.8%)

67.7 (46.1 - 99.2)
<.0001

50.4 (34.0 - 74.9)
<.0001

65.3 (44.5 - 95.8)
<.0001

84.5 (56.9 - 125.4)
<.0001

109.3 (71.5 - 167.3)
<.0001

45.0 (30.2 - 67.2)
<.0001

52.7 (35.6 - 77.9)
<.0001

61.6 (41.1 - 92.4)
<.0001

72.0 (46.5 - 111.7)
<.0001

63-72 mmol/mol (7.9-8.7%)

100.6 (69.5 - 145.8)
<.0001

76.2 (52.0 - 111.5)
<.0001

98.6 (68.0 - 142.8)
<.0001

127.6 (87.0 - 187.1)
<.0001

165.1 (108.9 - 250.3)
<.0001

65.6 (44.6 - 96.7)
<.0001

76.8 (52.5 - 112.2)
<.0001

89.8 (60.5 - 133.2)
<.0001

105.0 (68.3 - 161.5)
<.0001

73-82 mmol/mol (8.8-9.6%)

197.5 (135.6 - 287.5)
<.0001

150.9 (102.7 - 221.6)
<.0001

195.3 (134.2 - 284.1)
<.0001

252.7 (171.5 - 372.6)
<.0001

327.1 (214.6 - 498.4)
<.0001

123.4 (83.4 - 182.6)
<.0001

144.4 (98.3 - 212.1)
<.0001

168.9 (113.1 - 252.0)
<.0001

197.5 (127.6 - 305.6)
<.0001

>=83 mmol/mol (>=9.7%)

504.1 (344.4 - 738.0)
<.0001

386.7 (262.4 - 569.9)
<.0001

500.4 (342.6 - 730.9)
<.0001

647.6 (437.7 - 958.3)
<.0001

838.1 (548.0 - 1281.9)
<.0001

299.7 (201.5 - 445.6)
<.0001

350.5 (237.2 - 517.8)
<.0001

409.9 (273.0 - 615.4)
<.0001

479.4 (308.0 - 746.3)
<.0001

Time updated albuminuria categories, n events=589, data used = 98.6%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Normoalbuminuria

57.7 (39.8 - 83.6)
<.0001

53.3 (36.5 - 77.7)
<.0001

58.9 (40.6 - 85.4)
<.0001

65.3 (44.1 - 96.6)
<.0001

72.2 (46.7 - 111.7)
<.0001

48.6 (33.1 - 71.4)
<.0001

50.4 (34.5 - 73.7)
<.0001

52.4 (35.1 - 78.2)
<.0001

54.3 (34.8 - 85.0)
<.0001

Microalbuminuria

170.5 (116.5 - 249.5)
<.0001

153.8 (103.7 - 228.1)
<.0001

170.1 (116.1 - 249.1)
<.0001

188.4 (126.8 - 280.0)
<.0001

208.6 (135.2 - 321.9)
<.0001

130.6 (87.5 - 195.1)
<.0001

135.5 (91.7 - 200.2)
<.0001

140.6 (93.6 - 211.2)
<.0001

145.9 (93.3 - 228.1)
<.0001

Macroalbuminuria

301.9 (206.2 - 442.2)
<.0001

271.6 (183.0 - 403.2)
<.0001

300.4 (205.0 - 440.1)
<.0001

332.8 (224.1 - 494.3)
<.0001

368.4 (239.0 - 567.9)
<.0001

209.2 (139.4 - 314.1)
<.0001

217.0 (146.2 - 322.0)
<.0001

225.2 (149.5 - 339.4)
<.0001

233.7 (149.2 - 366.2)
<.0001

CKD stage 5

974.7 (655.5 - 1449.2)
<.0001

868.5 (575.3 - 1311.0)
<.0001

960.5 (645.8 - 1428.5)
<.0001

1064.3 (707.9 - 1600.0)
<.0001

1178.0 (757.2 - 1832.5)
<.0001

623.7 (408.4 - 952.6)
<.0001

646.8 (428.6 - 975.9)
<.0001

671.5 (439.1 - 1026.8)
<.0001

696.7 (439.2 - 1105.2)
<.0001

Time updated eGFR categories, n events=571, data used = 99.0%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

CKD stage 1 (eGFR >=90)

53.0 (35.6 - 78.8)
<.0001

50.1 (33.5 - 74.8)
<.0001

54.6 (36.7 - 81.3)
<.0001

59.6 (39.1 - 90.8)
<.0001

65.0 (40.8 - 103.6)
<.0001

45.9 (30.6 - 69.0)
<.0001

47.2 (31.5 - 70.7)
<.0001

48.5 (31.6 - 74.5)
<.0001

49.8 (31.0 - 80.2)
<.0001

CKD stage 2 (eGFR 60-89)

89.6 (61.8 - 129.8)
<.0001

83.7 (57.3 - 122.3)
<.0001

91.3 (62.9 - 132.6)
<.0001

99.6 (67.2 - 147.7)
<.0001

108.6 (70.1 - 168.4)
<.0001

75.3 (51.2 - 110.8)
<.0001

77.3 (52.9 - 113.2)
<.0001

79.5 (53.1 - 118.9)
<.0001

81.7 (52.1 - 128.0)
<.0001

CKD stage 3 (eGFR 30-59)

221.6 (150.6 - 326.2)
<.0001

202.8 (135.8 - 302.9)
<.0001

221.2 (150.0 - 326.2)
<.0001

241.3 (161.4 - 360.8)
<.0001

263.1 (169.4 - 408.7)
<.0001

160.5 (106.4 - 242.1)
<.0001

164.9 (110.6 - 245.9)
<.0001

169.5 (111.9 - 256.7)
<.0001

174.2 (110.6 - 274.5)
<.0001

CKD stage 4 (eGFR 15-29)

287.0 (171.5 - 480.5)
<.0001

262.8 (155.4 - 444.5)
<.0001

286.7 (171.2 - 480.3)
<.0001

312.8 (184.7 - 529.5)
<.0001

341.1 (195.6 - 594.9)
<.0001

190.8 (111.7 - 325.9)
<.0001

196.0 (115.7 - 332.2)
<.0001

201.5 (117.4 - 345.7)
<.0001

207.2 (117.0 - 366.8)
<.0001

CKD stage 5 (eGFR <15, dialysis or transplantation)

958.2 (644.4 - 1424.9)
<.0001

874.6 (580.3 - 1318.3)
<.0001

953.9 (641.2 - 1418.9)
<.0001

1040.4 (690.5 - 1567.7)
<.0001

1134.7 (726.0 - 1773.4)
<.0001

623.1 (408.2 - 950.9)
<.0001

640.1 (424.0 - 966.4)
<.0001

658.0 (429.3 - 1008.5)
<.0001

676.2 (424.5 - 1077.1)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

13.  Supplement Table 9. All models - Hazard ratios for major amputations and 95% confidence intervals for people with Type 1DM versus controls, time-updated mean HbA1c categories, albuminuria categories and eGFR categories examined by Cox regression

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation above ankle

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Overall, n events=725, data used = 100.0%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Group All Type I diabetes with no prior amputation

42.6 (34.0 - 53.2)
<.0001

27.8 (21.7 - 35.6)
<.0001

38.4 (30.6 - 48.1)
<.0001

53.1 (41.9 - 67.2)
<.0001

73.3 (55.8 - 96.3)
<.0001

21.4 (16.6 - 27.5)
<.0001

27.3 (21.5 - 34.5)
<.0001

34.8 (27.1 - 44.7)
<.0001

44.4 (33.2 - 59.4)
<.0001

Time updated mean HbA1c categories, n events=716, data used = 99.9%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%)

15.6 (10.6 - 22.9)
<.0001

9.0 (6.0 - 13.5)
<.0001

13.0 (8.8 - 19.1)
<.0001

18.6 (12.6 - 27.5)
<.0001

26.7 (17.7 - 40.3)
<.0001

8.1 (5.3 - 12.2)
<.0001

10.8 (7.3 - 16.0)
<.0001

14.4 (9.7 - 21.5)
<.0001

19.3 (12.6 - 29.4)
<.0001

53-62 mmol/mol (7.0-7.8%)

28.0 (21.4 - 36.6)
<.0001

16.3 (12.1 - 21.9)
<.0001

23.4 (17.8 - 30.7)
<.0001

33.6 (25.5 - 44.3)
<.0001

48.2 (35.6 - 65.4)
<.0001

13.2 (9.8 - 17.8)
<.0001

17.6 (13.3 - 23.3)
<.0001

23.5 (17.7 - 31.4)
<.0001

31.5 (22.8 - 43.3)
<.0001

63-72 mmol/mol (7.9-8.7%)

39.3 (30.5 - 50.8)
<.0001

23.6 (17.9 - 31.2)
<.0001

33.9 (26.2 - 43.8)
<.0001

48.6 (37.4 - 63.2)
<.0001

69.8 (52.0 - 93.8)
<.0001

18.6 (14.0 - 24.8)
<.0001

24.9 (19.1 - 32.5)
<.0001

33.3 (25.3 - 43.8)
<.0001

44.5 (32.6 - 60.7)
<.0001

73-82 mmol/mol (8.8-9.6%)

69.8 (53.3 - 91.3)
<.0001

42.8 (32.1 - 57.2)
<.0001

61.5 (46.9 - 80.4)
<.0001

88.2 (66.9 - 116.3)
<.0001

126.6 (93.0 - 172.5)
<.0001

30.6 (22.8 - 41.1)
<.0001

40.9 (30.9 - 54.0)
<.0001

54.6 (40.9 - 73.0)
<.0001

73.0 (52.7 - 101.2)
<.0001

>=83 mmol/mol (>=9.7%)

190.1 (144.3 - 250.5)
<.0001

117.0 (87.3 - 156.8)
<.0001

167.9 (127.8 - 220.6)
<.0001

241.0 (182.1 - 318.8)
<.0001

346.0 (253.4 - 472.5)
<.0001

78.4 (58.1 - 105.9)
<.0001

104.8 (78.8 - 139.4)
<.0001

140.0 (104.0 - 188.5)
<.0001

187.1 (134.1 - 261.1)
<.0001

Time updated albuminuria categories, n events=608, data used = 98.6%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Normoalbuminuria

20.6 (15.9 - 26.7)
<.0001

15.7 (11.8 - 20.8)
<.0001

19.6 (15.1 - 25.4)
<.0001

24.4 (18.6 - 32.0)
<.0001

30.5 (22.3 - 41.6)
<.0001

13.6 (10.2 - 18.1)
<.0001

16.5 (12.6 - 21.6)
<.0001

20.1 (15.2 - 26.6)
<.0001

24.4 (17.6 - 33.7)
<.0001

Microalbuminuria

48.1 (36.2 - 63.8)
<.0001

34.7 (25.3 - 47.6)
<.0001

43.3 (32.4 - 57.8)
<.0001

54.0 (40.4 - 72.2)
<.0001

67.4 (48.8 - 93.1)
<.0001

26.2 (19.0 - 36.2)
<.0001

31.8 (23.6 - 42.9)
<.0001

38.7 (28.5 - 52.4)
<.0001

47.0 (33.5 - 65.9)
<.0001

Macroalbuminuria

118.5 (90.6 - 155.1)
<.0001

86.1 (63.8 - 116.4)
<.0001

107.5 (81.8 - 141.2)
<.0001

134.0 (101.7 - 176.7)
<.0001

167.3 (122.6 - 228.3)
<.0001

59.3 (43.4 - 80.9)
<.0001

72.0 (54.1 - 95.9)
<.0001

87.6 (65.3 - 117.4)
<.0001

106.4 (76.5 - 148.0)
<.0001

CKD stage 5

427.5 (321.4 - 568.5)
<.0001

305.7 (222.7 - 419.6)
<.0001

381.4 (285.9 - 508.8)
<.0001

475.6 (356.0 - 635.3)
<.0001

593.8 (430.9 - 818.4)
<.0001

194.1 (139.8 - 269.5)
<.0001

235.9 (173.9 - 320.0)
<.0001

286.7 (210.1 - 391.4)
<.0001

348.5 (246.7 - 492.3)
<.0001

Time updated eGFR categories, n events=580, data used = 99.0%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

CKD stage 1 (eGFR >=90)

22.8 (16.8 - 30.8)
<.0001

17.8 (13.0 - 24.4)
<.0001

22.2 (16.5 - 30.0)
<.0001

27.8 (20.3 - 38.0)
<.0001

34.8 (24.4 - 49.6)
<.0001

15.4 (11.2 - 21.2)
<.0001

19.0 (14.0 - 25.7)
<.0001

23.3 (16.9 - 32.1)
<.0001

28.6 (19.9 - 41.1)
<.0001

CKD stage 2 (eGFR 60-89)

26.9 (20.6 - 35.0)
<.0001

20.0 (14.9 - 26.9)
<.0001

25.1 (19.2 - 32.8)
<.0001

31.3 (23.8 - 41.3)
<.0001

39.2 (28.6 - 53.8)
<.0001

16.7 (12.4 - 22.6)
<.0001

20.6 (15.6 - 27.1)
<.0001

25.2 (19.0 - 33.6)
<.0001

31.0 (22.4 - 43.0)
<.0001

CKD stage 3 (eGFR 30-59)

55.0 (41.5 - 72.9)
<.0001

38.4 (27.8 - 53.2)
<.0001

48.1 (35.9 - 64.4)
<.0001

60.1 (45.0 - 80.4)
<.0001

75.2 (54.6 - 103.5)
<.0001

26.7 (19.1 - 37.3)
<.0001

32.8 (24.1 - 44.5)
<.0001

40.2 (29.6 - 54.7)
<.0001

49.5 (35.3 - 69.3)
<.0001

CKD stage 4 (eGFR 15-29)

122.0 (81.7 - 182.3)
<.0001

86.1 (56.1 - 132.3)
<.0001

107.7 (71.8 - 161.7)
<.0001

134.7 (89.7 - 202.1)
<.0001

168.5 (109.8 - 258.7)
<.0001

55.0 (35.5 - 85.4)
<.0001

67.6 (44.5 - 102.8)
<.0001

83.1 (54.5 - 126.6)
<.0001

102.1 (65.3 - 159.6)
<.0001

CKD stage 5 (eGFR <15, dialysis or transplantation)

421.5 (316.9 - 560.6)
<.0001

300.3 (218.4 - 412.9)
<.0001

375.6 (281.5 - 501.1)
<.0001

469.5 (351.4 - 627.2)
<.0001

587.5 (425.8 - 810.6)
<.0001

185.3 (132.9 - 258.5)
<.0001

227.7 (167.5 - 309.6)
<.0001

279.6 (204.6 - 382.2)
<.0001

343.7 (242.9 - 486.3)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

14.  Supplement Table 10. Adjusted hazard ratios for minor amputation and 95% confidence intervals for time-updated mean HbA1c categories and Normoalbuminuria versus controls examined by Cox regression

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation below ankle

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Time updated mean HbA1c categories and Albuminuria

 

 

 

 

 

 

 

 

 

 

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%) – Normoalbuminuria

15.4 (7.4 - 32.1)
<.0001

13.0 (6.2 - 27.3)
<.0001

15.6 (7.5 - 32.7)
<.0001

18.9 (8.9 - 39.8)
<.0001

22.7 (10.5 - 49.0)
<.0001

11.3 (5.2 - 24.6)
<.0001

12.5 (5.8 - 27.2)
<.0001

13.9 (6.3 - 30.5)
<.0001

15.4 (6.8 - 34.6)
<.0001

53-62 mmol/mol (7.0-7.8%) – Normoalbuminuria

45.4 (29.3 - 70.3)
<.0001

37.8 (24.2 - 59.1)
<.0001

45.6 (29.4 - 70.6)
<.0001

54.9 (35.0 - 86.2)
<.0001

66.2 (40.7 - 107.6)
<.0001

34.9 (22.2 - 54.9)
<.0001

38.7 (24.8 - 60.4)
<.0001

43.0 (27.1 - 68.1)
<.0001

47.6 (29.0 - 78.3)
<.0001

63-72 mmol/mol (7.9-8.7%) – Normoalbuminuria

63.6 (41.8 - 96.8)
<.0001

53.5 (34.9 - 82.2)
<.0001

64.5 (42.4 - 98.2)
<.0001

77.8 (50.3 - 120.3)
<.0001

93.8 (58.4 - 150.5)
<.0001

49.6 (32.2 - 76.5)
<.0001

55.0 (35.9 - 84.2)
<.0001

61.0 (39.2 - 95.1)
<.0001

67.7 (41.7 - 109.7)
<.0001

73-82 mmol/mol (8.8-9.6%) – Normoalbuminuria

82.2 (50.1 - 135.0)
<.0001

69.8 (42.3 - 115.2)
<.0001

84.1 (51.3 - 138.1)
<.0001

101.4 (60.9 - 168.8)
<.0001

122.3 (71.1 - 210.3)
<.0001

61.8 (37.2 - 102.6)
<.0001

68.5 (41.5 - 113.1)
<.0001

76.0 (45.3 - 127.5)
<.0001

84.3 (48.6 - 146.3)
<.0001

>=83 mmol/mol (>=9.7%) – Normoalbuminuria

290.3 (177.0 - 476.2)
<.0001

251.3 (152.9 - 413.2)
<.0001

303.0 (185.0 - 496.2)
<.0001

365.3 (219.4 - 608.0)
<.0001

440.3 (255.5 - 759.1)
<.0001

221.8 (134.0 - 367.0)
<.0001

245.8 (149.0 - 405.3)
<.0001

272.8 (162.5 - 457.8)
<.0001

302.4 (173.8 - 526.3)
<.0001

<=52 mmol/mol (<=6.9%) - Not Normoalbuminuria

130.5 (74.1 - 229.8)
<.0001

102.3 (57.2 - 183.0)
<.0001

123.4 (69.9 - 217.8)
<.0001

148.8 (83.9 - 263.9)
<.0001

179.3 (98.9 - 325.2)
<.0001

87.9 (48.9 - 157.9)
<.0001

97.4 (54.8 - 173.0)
<.0001

108.1 (60.4 - 193.4)
<.0001

119.9 (65.4 - 219.7)
<.0001

53-62 mmol/mol (7.0-7.8%)- Not Normoalbuminuria

139.4 (90.5 - 214.6)
<.0001

109.4 (69.7 - 171.7)
<.0001

131.9 (85.4 - 203.7)
<.0001

159.0 (102.3 - 247.2)
<.0001

191.7 (119.8 - 306.7)
<.0001

91.7 (58.0 - 144.9)
<.0001

101.6 (65.2 - 158.2)
<.0001

112.7 (71.7 - 177.2)
<.0001

125.0 (77.1 - 202.7)
<.0001

63-72 mmol/mol (7.9-8.7%) - Not Normoalbuminuria

209.3 (141.0 - 310.7)
<.0001

169.3 (112.3 - 255.2)
<.0001

204.1 (137.3 - 303.5)
<.0001

246.1 (163.7 - 370.0)
<.0001

296.7 (190.6 - 461.9)
<.0001

139.2 (91.5 - 211.5)
<.0001

154.2 (102.7 - 231.5)
<.0001

171.1 (112.5 - 260.4)
<.0001

189.8 (120.2 - 299.5)
<.0001

73-82 mmol/mol (8.8-9.6% ) - Not Normoalbuminuria

379.6 (256.2 - 562.3)
<.0001

310.9 (207.2 - 466.4)
<.0001

374.8 (252.9 - 555.4)
<.0001

451.8 (300.9 - 678.4)
<.0001

544.7 (349.8 - 848.0)
<.0001

252.0 (166.4 - 381.5)
<.0001

279.2 (186.4 - 418.2)
<.0001

309.9 (203.8 - 471.4)
<.0001

343.6 (217.4 - 543.1)
<.0001

>=83 mmol/mol (>=9.7%) - Not Normoalbuminuria

862.2 (578.2 - 1285.8)
<.0001

715.3 (475.3 - 1076.6)
<.0001

862.4 (579.1 - 1284.2)
<.0001

1039.7 (688.1 - 1570.8)
<.0001

1253.4 (799.3 - 1965.4)
<.0001

547.9 (359.9 - 834.1)
<.0001

607.1 (402.6 - 915.6)
<.0001

673.8 (439.6 - 1032.8)
<.0001

747.1 (468.9 - 1190.4)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

15.  Supplement Table 11. Adjusted hazard ratios for Minor amputation and 95% confidence intervals for time-updated mean HbA1c categories and eGFR<60/>=60 categories versus controls examined by Cox regression

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation below ankle

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Time updated mean HbA1c categories and eGFR, n events=570, data used = 98.9%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%) - eGFR>=60

19.0 (9.8 - 36.8)
<.0001

16.7 (8.6 - 32.6)
<.0001

19.5 (10.1 - 37.9)
<.0001

22.8 (11.7 - 44.7)
<.0001

26.6 (13.2 - 53.6)
<.0001

14.7 (7.4 - 29.4)
<.0001

16.0 (8.0 - 31.8)
<.0001

17.3 (8.6 - 34.9)
<.0001

18.8 (9.1 - 38.9)
<.0001

53-62 mmol/mol (7.0-7.8%) - eGFR>=60

43.5 (28.3 - 66.9)
<.0001

37.7 (24.3 - 58.4)
<.0001

44.0 (28.6 - 67.6)
<.0001

51.3 (32.9 - 80.1)
<.0001

59.9 (37.0 - 97.0)
<.0001

34.7 (22.2 - 54.1)
<.0001

37.6 (24.3 - 58.3)
<.0001

40.9 (26.0 - 64.3)
<.0001

44.4 (27.2 - 72.5)
<.0001

63-72 mmol/mol (7.9-8.7%) - eGFR>=60

69.3 (46.4 - 103.5)
<.0001

60.4 (40.1 - 91.1)
<.0001

70.5 (47.2 - 105.4)
<.0001

82.3 (54.1 - 125.2)
<.0001

96.1 (60.7 - 152.1)
<.0001

55.7 (36.7 - 84.4)
<.0001

60.5 (40.2 - 90.9)
<.0001

65.6 (42.8 - 100.5)
<.0001

71.2 (44.6 - 113.8)
<.0001

73-82 mmol/mol (8.8-9.6%) - eGFR>=60

125.2 (82.2 - 190.6)
<.0001

110.0 (71.8 - 168.5)
<.0001

128.3 (84.3 - 195.3)
<.0001

149.8 (96.7 - 232.0)
<.0001

174.8 (108.5 - 281.7)
<.0001

98.1 (63.6 - 151.3)
<.0001

106.5 (69.5 - 163.2)
<.0001

115.6 (74.0 - 180.5)
<.0001

125.5 (77.2 - 204.1)
<.0001

>=83 mmol/mol (>=9.7%) - eGFR>=60

377.1 (245.5 - 579.2)
<.0001

337.1 (218.9 - 519.1)
<.0001

393.4 (256.4 - 603.6)
<.0001

459.2 (293.4 - 718.7)
<.0001

536.0 (328.8 - 873.8)
<.0001

297.7 (191.8 - 462.2)
<.0001

323.2 (209.0 - 499.8)
<.0001

350.8 (222.3 - 553.6)
<.0001

380.9 (231.5 - 626.6)
<.0001

<=52 mmol/mol (<=6.9%) - eGFR<60

128.5 (69.6 - 237.4)
<.0001

105.1 (56.0 - 197.1)
<.0001

122.7 (66.2 - 227.2)
<.0001

143.2 (77.0 - 266.4)
<.0001

167.1 (88.0 - 317.4)
<.0001

91.1 (48.4 - 171.6)
<.0001

98.9 (53.1 - 184.2)
<.0001

107.4 (57.3 - 201.1)
<.0001

116.6 (60.8 - 223.4)
<.0001

53-62 mmol/mol (7.0-7.8%) - eGFR<60

175.5 (112.2 - 274.5)
<.0001

144.6 (90.7 - 230.5)
<.0001

168.8 (107.6 - 264.9)
<.0001

197.0 (124.6 - 311.4)
<.0001

230.0 (141.3 - 374.2)
<.0001

117.3 (73.0 - 188.5)
<.0001

127.3 (80.4 - 201.6)
<.0001

138.2 (86.5 - 220.8)
<.0001

150.0 (91.1 - 247.1)
<.0001

63-72 mmol/mol (7.9-8.7%) - eGFR<60

270.3 (178.5 - 409.3)
<.0001

226.4 (147.1 - 348.5)
<.0001

264.3 (174.1 - 401.1)
<.0001

308.5 (201.1 - 473.0)
<.0001

360.0 (227.1 - 570.7)
<.0001

178.2 (114.6 - 276.9)
<.0001

193.4 (126.0 - 296.8)
<.0001

209.9 (135.2 - 326.0)
<.0001

227.9 (141.7 - 366.5)
<.0001

73-82 mmol/mol (8.8-9.6%) - eGFR<60

460.9 (301.4 - 704.6)
<.0001

387.9 (250.1 - 601.7)
<.0001

452.8 (295.8 - 693.1)
<.0001

528.5 (341.5 - 817.8)
<.0001

616.9 (385.6 - 986.8)
<.0001

299.9 (191.0 - 471.0)
<.0001

325.6 (209.9 - 505.0)
<.0001

353.4 (225.2 - 554.7)
<.0001

383.7 (236.2 - 623.3)
<.0001

>=83 mmol/mol (>=9.7%) - eGFR<60

1057.9 (690.5 - 1620.7)
<.0001

898.2 (579.2 - 1392.9)
<.0001

1048.3 (684.2 - 1606.4)
<.0001

1223.6 (789.0 - 1897.6)
<.0001

1428.2 (890.0 - 2291.8)
<.0001

693.3 (442.0 - 1087.5)
<.0001

752.6 (485.0 - 1167.8)
<.0001

816.9 (519.4 - 1284.8)
<.0001

886.9 (544.1 - 1445.5)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

16.  Supplement Table 12. Adjusted hazard ratios for Major amputation and 95% confidence intervals for time-updated mean HbA1c categories and Normoalbuminuria versus controls examined by Cox regression

 

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation above ankle

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Time updated mean HbA1c categories and Albuminuria

 

 

 

 

 

 

 

 

 

 

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%) – Normoalbuminuria

9.3 (5.3 - 16.3)
<.0001

6.1 (3.4 - 10.9)
<.0001

8.3 (4.7 - 14.6)
<.0001

11.3 (6.4 - 20.0)
<.0001

15.4 (8.6 - 27.7)
<.0001

5.6 (3.1 - 10.2)
<.0001

7.3 (4.1 - 13.2)
<.0001

9.5 (5.3 - 17.2)
<.0001

12.4 (6.7 - 22.8)
<.0001

53-62 mmol/mol (7.0-7.8%) – Normoalbuminuria

15.3 (10.7 - 22.0)
<.0001

10.1 (6.9 - 14.8)
<.0001

13.7 (9.5 - 19.7)
<.0001

18.7 (12.9 - 27.0)
<.0001

25.4 (17.1 - 37.8)
<.0001

8.9 (6.0 - 13.1)
<.0001

11.6 (8.0 - 16.7)
<.0001

15.0 (10.3 - 21.9)
<.0001

19.5 (13.0 - 29.3)
<.0001

63-72 mmol/mol (7.9-8.7%) – Normoalbuminuria

19.0 (13.4 - 27.0)
<.0001

12.8 (8.9 - 18.6)
<.0001

17.5 (12.3 - 24.9)
<.0001

23.8 (16.6 - 34.1)
<.0001

32.4 (21.9 - 48.0)
<.0001

11.1 (7.7 - 16.2)
<.0001

14.5 (10.1 - 20.7)
<.0001

18.8 (13.0 - 27.1)
<.0001

24.4 (16.3 - 36.5)
<.0001

73-82 mmol/mol (8.8-9.6%) – Normoalbuminuria

32.0 (20.8 - 49.0)
<.0001

22.0 (14.2 - 34.2)
<.0001

30.0 (19.6 - 46.0)
<.0001

40.9 (26.5 - 63.1)
<.0001

55.6 (35.1 - 88.3)
<.0001

17.6 (11.3 - 27.4)
<.0001

22.9 (14.9 - 35.2)
<.0001

29.7 (19.1 - 46.1)
<.0001

38.6 (24.1 - 61.7)
<.0001

>=83 mmol/mol (>=9.7%) – Normoalbuminuria

131.2 (86.6 - 198.8)
<.0001

94.5 (62.0 - 144.2)
<.0001

128.7 (85.3 - 194.2)
<.0001

175.2 (114.9 - 267.3)
<.0001

238.6 (151.6 - 375.4)
<.0001

71.7 (46.6 - 110.3)
<.0001

93.2 (61.1 - 142.1)
<.0001

121.0 (78.3 - 186.9)
<.0001

157.2 (98.5 - 251.1)
<.0001

<=52 mmol/mol (<=6.9%) - Not Normoalbuminuria

37.6 (22.1 - 64.2)
<.0001

22.0 (12.6 - 38.6)
<.0001

30.0 (17.5 - 51.5)
<.0001

40.8 (23.8 - 69.9)
<.0001

55.6 (32.0 - 96.5)
<.0001

17.1 (9.7 - 30.1)
<.0001

22.2 (12.9 - 38.4)
<.0001

28.9 (16.7 - 49.8)
<.0001

37.5 (21.4 - 65.8)
<.0001

53-62 mmol/mol (7.0-7.8%)- Not Normoalbuminuria

59.5 (43.1 - 82.1)
<.0001

35.4 (24.7 - 50.7)
<.0001

48.2 (34.6 - 67.1)
<.0001

65.6 (47.3 - 91.1)
<.0001

89.3 (62.9 - 126.9)
<.0001

25.9 (18.0 - 37.4)
<.0001

33.7 (23.9 - 47.4)
<.0001

43.7 (31.1 - 61.5)
<.0001

56.8 (39.3 - 82.2)
<.0001

63-72 mmol/mol (7.9-8.7%) - Not Normoalbuminuria

88.4 (66.7 - 117.1)
<.0001

56.0 (40.9 - 76.7)
<.0001

76.3 (57.3 - 101.6)
<.0001

103.9 (77.8 - 138.8)
<.0001

141.4 (102.5 - 195.3)
<.0001

41.2 (29.9 - 56.8)
<.0001

53.5 (39.7 - 72.0)
<.0001

69.5 (51.3 - 94.1)
<.0001

90.3 (64.3 - 126.7)
<.0001

73-82 mmol/mol (8.8-9.6% ) - Not Normoalbuminuria

119.0 (87.9 - 161.2)
<.0001

77.9 (56.1 - 108.1)
<.0001

106.1 (78.2 - 143.9)
<.0001

144.4 (105.8 - 197.1)
<.0001

196.6 (139.3 - 277.5)
<.0001

55.0 (39.4 - 76.9)
<.0001

71.5 (52.1 - 98.1)
<.0001

92.8 (67.0 - 128.6)
<.0001

120.7 (84.0 - 173.3)
<.0001

>=83 mmol/mol (>=9.7%) - Not Normoalbuminuria

312.4 (229.7 - 424.9)
<.0001

210.7 (152.1 - 291.8)
<.0001

286.9 (211.3 - 389.4)
<.0001

390.6 (285.3 - 534.7)
<.0001

531.8 (375.0 - 754.0)
<.0001

139.2 (99.4 - 195.0)
<.0001

180.9 (131.4 - 248.9)
<.0001

234.8 (168.7 - 326.7)
<.0001

305.2 (211.4 - 440.7)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.

 

17.  Supplement Table 13. Adjusted hazard ratios for Major amputation and 95% confidence intervals for time-updated mean HbA1c categories and eGFR<60/>=60 categories versus the reference group examined by Cox regression

 

Hazard ratio (95% CI)
p-value

 

Model 1

Model 2

Model 3

Amputation above ankle

All

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Diabetes duration 30 years

Diabetes duration 40 years

Diabetes duration 50 years

Diabetes duration 60 years

Time updated mean HbA1c categories and eGFR, n events=578, data used = 98.9%

 

 

 

 

 

 

 

 

 

Controls (reference)

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

<=52 mmol/mol (<=6.9%) - eGFR>=60

10.7 (6.4 - 18.0)
<.0001

7.5 (4.4 - 12.8)
<.0001

9.9 (5.9 - 16.7)
<.0001

13.1 (7.7 - 22.1)
<.0001

17.3 (10.0 - 29.9)
<.0001

6.8 (3.9 - 11.7)
<.0001

8.6 (5.0 - 14.8)
<.0001

11.0 (6.4 - 19.0)
<.0001

14.1 (8.0 - 24.8)
<.0001

53-62 mmol/mol (7.0-7.8%) - eGFR>=60

17.5 (12.5 - 24.5)
<.0001

12.1 (8.5 - 17.4)
<.0001

16.0 (11.4 - 22.4)
<.0001

21.2 (15.0 - 29.8)
<.0001

27.9 (19.2 - 40.7)
<.0001

10.3 (7.1 - 14.8)
<.0001

13.1 (9.3 - 18.5)
<.0001

16.8 (11.8 - 23.9)
<.0001

21.4 (14.5 - 31.5)
<.0001

63-72 mmol/mol (7.9-8.7%) - eGFR>=60

26.1 (19.2 - 35.4)
<.0001

18.5 (13.4 - 25.6)
<.0001

24.4 (18.0 - 33.1)
<.0001

32.2 (23.5 - 44.1)
<.0001

42.5 (29.9 - 60.5)
<.0001

16.0 (11.5 - 22.2)
<.0001

20.4 (15.0 - 27.9)
<.0001

26.1 (18.9 - 36.0)
<.0001

33.3 (23.2 - 47.8)
<.0001

73-82 mmol/mol (8.8-9.6%) - eGFR>=60

34.0 (23.4 - 49.3)
<.0001

24.6 (16.7 - 36.3)
<.0001

32.5 (22.4 - 47.2)
<.0001

42.9 (29.3 - 62.9)
<.0001

56.7 (37.5 - 85.9)
<.0001

19.4 (13.1 - 28.7)
<.0001

24.8 (17.0 - 36.2)
<.0001

31.7 (21.5 - 46.7)
<.0001

40.4 (26.5 - 61.8)
<.0001

>=83 mmol/mol (>=9.7%) - eGFR>=60

115.9 (79.2 - 169.7)
<.0001

88.2 (59.9 - 129.8)
<.0001

116.4 (79.9 - 169.7)
<.0001

153.7 (104.0 - 227.2)
<.0001

202.9 (132.4 - 311.0)
<.0001

67.3 (45.3 - 99.8)
<.0001

85.9 (58.4 - 126.3)
<.0001

109.6 (73.4 - 163.8)
<.0001

140.0 (90.2 - 217.2)
<.0001

<=52 mmol/mol (<=6.9%) - eGFR<60

35.8 (20.3 - 63.1)
<.0001

21.9 (12.1 - 39.8)
<.0001

29.0 (16.3 - 51.5)
<.0001

38.3 (21.6 - 67.7)
<.0001

50.5 (28.2 - 90.6)
<.0001

17.2 (9.4 - 31.2)
<.0001

21.9 (12.3 - 39.1)
<.0001

28.0 (15.7 - 49.8)
<.0001

35.7 (19.7 - 64.6)
<.0001

53-62 mmol/mol (7.0-7.8%) - eGFR<60

54.9 (38.6 - 78.3)
<.0001

34.4 (23.2 - 50.9)
<.0001

45.4 (31.6 - 65.4)
<.0001

60.0 (41.8 - 86.0)
<.0001

79.2 (54.0 - 116.1)
<.0001

24.6 (16.5 - 36.7)
<.0001

31.4 (21.6 - 45.7)
<.0001

40.1 (27.6 - 58.3)
<.0001

51.2 (34.5 - 76.2)
<.0001

63-72 mmol/mol (7.9-8.7%) - eGFR<60

90.0 (65.9 - 122.9)
<.0001

58.8 (41.6 - 83.1)
<.0001

77.6 (56.4 - 106.8)
<.0001

102.5 (74.4 - 141.1)
<.0001

135.3 (95.5 - 191.7)
<.0001

39.4 (27.6 - 56.4)
<.0001

50.4 (36.1 - 70.2)
<.0001

64.3 (45.9 - 90.0)
<.0001

82.1 (56.8 - 118.5)
<.0001

73-82 mmol/mol (8.8-9.6%) - eGFR<60

158.8 (114.4 - 220.5)
<.0001

105.4 (73.7 - 150.7)
<.0001

139.2 (99.8 - 194.1)
<.0001

183.7 (131.4 - 256.9)
<.0001

242.6 (168.5 - 349.3)
<.0001

69.0 (47.7 - 99.9)
<.0001

88.1 (62.3 - 124.8)
<.0001

112.5 (79.1 - 160.0)
<.0001

143.6 (97.9 - 210.7)
<.0001

>=83 mmol/mol (>=9.7%) - eGFR<60

381.8 (273.1 - 533.7)
<.0001

257.6 (179.6 - 369.5)
<.0001

340.1 (242.7 - 476.6)
<.0001

448.9 (319.2 - 631.3)
<.0001

592.8 (409.2 - 858.8)
<.0001

166.2 (114.5 - 241.4)
<.0001

212.3 (149.3 - 301.9)
<.0001

271.0 (189.4 - 387.6)
<.0001

346.0 (234.3 - 510.8)
<.0001

Model 1: Adjusted for time-updated age and sex.
Model 2: Adjusted for time-updated age, sex and time-updated diabetes duration centered at 30, 40, 50 and 60 years.
Model 3: Adjusted for time-updated age, sex, born in Sweden, maximum education level, baseline comorbidities and time-updated diabetes duration centered at 30, 40, 50 and 60 years.