Impact of Age of Onset, Puberty, and Glycemic Control Followed From Diagnosis on Incidence of Retinopathy in Type 1 Diabetes: The VISS Study

Maria Nordwall; Mats Fredriksson; Johnny Ludvigsson; Hans J. Arnqvist

doi:10.2337/dc18-1950

Pathophysiology/Complications

Impact of Age of Onset, Puberty, and Glycemic Control Followed From Diagnosis on Incidence of Retinopathy in Type 1 Diabetes: The VISS Study

Maria Nordwall¹,²,
Mats Fredriksson³,⁴,
Johnny Ludvigsson¹,⁵ and
Hans J. Arnqvist⁶ ⇑

¹Division of Paediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Östergötland, Sweden
²Vrinnevi Hospital, Norrköping, Östergötland, Sweden
³Division of Occupational and Environmental Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Östergötland, Sweden
⁴Forum Östergötland, Linköping University, Linköping, Östergötland, Sweden
⁵Division of Paediatrics, Department of Clinical and Experimental Medicine, Crown Princess Victoria Children’s Hospital, Linköping University, Linköping, Östergötland, Sweden
⁶Departments of Endocrinology and Clinical and Experimental Medicine, Linköping University, Linköping, Östergötland, Sweden

Corresponding author: Hans J. Arnqvist, hans.arnqvist{at}liu.se

Diabetes Care 2019 Apr; 42(4): 609-616. https://doi.org/10.2337/dc18-1950

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Figure 1
A: Incidence of simplex retinopathy in different long-term wHbA_1c categories in an unselected population with type 1 diabetes followed for 18–24 years. Overall significance P < 0.001. P = 0.02 for 7.7–8.6% (61–70 mmol/mol) and P < 0.01 for 8.7–9.5% (71–80 mmol/mol) and for >9.5% (80 mmol/mol) in comparison with <50 mmol/mol. B: Incidence of simplex retinopathy in relation to onset before, during, and after puberty. Overall significance P = 0.03, before and during puberty P = 0.04, and before and after puberty P = 0.01. Puberty defined as age 10.4–14.9 years for girls and 12.0–16.9 years for boys. C: Incidence of simplex retinopathy in relation to age of onset in an unselected population of type 1 diabetes followed for 18–24 years. Overall significance P = 0.024. P = 0.003–0.022 for 0–4 years age-group in comparison with older age-groups, while there were no significant differences between the other age-groups.

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Table 1

Long-term mean wHbA_1c during whole follow-up of 18–24 years in an unselected population with type 1 diabetes with onset before, during, or after puberty

	Subgroup evaluated for incidence of simplex retinopathy				All patients evaluated for incidence of proliferative retinopathy
	All	Female	Male	P^*	All	Female	Male	P
Diabetes onset
Before puberty	68 (12) [8.4 (1.1)], 104	71 (10) [8.6 (0.9)], 40	67 (13) [8.3 (1.2)], 64	0.04	68 (12) [8.4 (1.1)], 160^†	71 (10) [8.6 (0.9)], 68^‡	66 (13) [8.2 (1.2)], 92	0.02
During puberty	69 (16) [8.5 (1.5)], 51	76 (15) [9.1 (1.4)], 22	64 (15) [8.0 (1.4)], 29	0.01	68 (13) [8.4 (1.2)], 88^§	72 (15) [8.7 (1.4)], 37^‡	65 (10) [8.1 (0.9)], 51	0.01
After puberty	64 (15) [8.0 (1.4)], 126	68 (18) [8.4 (1.7)], 53	62 (12) [7.8 (1.1)], 73	0.06	64 (13) [8.0 (1.2)], 183	63 (14) [7.9 (1.3)], 81	64 (12) [8.0 (1.2)], 102	0.47
Age at onset (years)
0–4.9	67 (10) [8.3 (0.9)], 32	68 (8) [8.4 (0.7)], 14	65 (12) [8.1 (1.1)], 18	0.38	67 (10) [8.3 (0.9)], 51	68 (8) [8.4 (0.7)], 25	67 (12) [8.3 (1.1)], 26	0.61
5–9.9	69 (13) [8.5 (1.2)], 64	73 (11) [8.8 (1.0)], 26	67 (14) [8.3 (1.3)], 38	0.07	69 (12) [8.5 (1.1)], 94	72 (10) [8.7 (0.9)], 43^‖	66 (13) [8.2 (1.2)], 51	0.02
10–14.9	71 (16) [8.6 (1.5)], 50^¶	76 (15) [9.1 (1.4)], 22^¶	67 (15) [8.3 (1.4)], 28	0.05	68 (14) [8.4 (1.3)], 90	71 (16) [8.6 (1.5)], 39^‖	65 (11) [8.1 (1.0)], 51	0.04
15–19.9	64 (16) [8.0 (1.5)], 32	63 (19) [7.9 (1.7)], 13	65 (15) [8.1 (1.4)], 19	0.75	63 (13) [7.9 (1.2)], 56	60 (11) [7.6 (1.0)], 24	66 (13) [8.2 (1.2)], 32	0.05
20–24.9	60 (15) [7.6 (1.4)], 34	59 (19) [7.5 (1.7)], 12	61 (11) [7.7 (1.0)], 22	0.64	63 (12) [7.9 (1.1)], 47	61 (15) [7.7 (1.4)], 18	64 (9) [8.0 (0.8)], 29	0.52
25–29.9	67 (17) [8.3 (1.6)], 37	74 (18) [8.9 (1.7)], 18	60 (12) [7.6 (1.1)], 19	0.01	63 (13) [7.9 (1.1)], 51	65 (15) [8.1 (1.4)], 24	62 (11) [7.8 (1.0)], 26	0.45
30–34	65 (10) [8.1 (0.9)], 32	73 (10) [8.8 (0.9)], 10	62 (9) [7.8 (0.8)], 22	<0.01	66 (12) [8.2 (1.1)], 43	69 (11) [8.5 (1.0)], 13	65 (12) [8.1 (1.1)], 30	0.310
Total	67 (14) [8.3 (1.3)], 281	70 (15) [8.6 (1.4)], 115	64 (13) [8.0 (1.2)], 166	<0.001	66 (12) [8.2 (1.1)], 431	68 (13) [8.4 (1.2)], 186	65 (12) [8.1 (1.1)], 245	0.04

Puberty defined as age 10.0–14.9 years for girls and 12.0–16.9 years for boys. Mean (SD) wHbA_1c data are expressed as mmol/mol [%], number of individuals.
↵*P value for the difference between female and male, t test;
↵†P = 0.002 compared with after puberty;
↵‡P = 0.001 compared with after puberty;
↵§P = 0.021 compared with after puberty;
↵‖P < 0.02 compared with age 15–19.9 years;
↵¶P < 0.05 compared with age 20–24.9 years. ANOVA with Bonferroni post hoc test.

Table 2

Long-term wHbA_1c calculated for different time periods, i.e., ≤5 years after onset, >5 years after onset, and also before, during, and after puberty

	Subgroup evaluated for incidence of simplex retinopathy				All patients evaluated for incidence of proliferative retinopathy
	All	Female	Male	P^*	All	Female	Male	P^*
wHbA_1c after ≤5 years’ duration	61 (15) [7.7 (1.4)], 265	64 (17) [8.0 (1.6)], 107	59 (14) [7.5 (1.3)], (158)	0.05	61 (16) [7.7 (1.5)], 427	63 (16) [7.9 (1.5)], 185	60 (15) [7.6 (1.4)], 242	0.08
wHbA_1c after >5 years’ duration	71 (16) [8.6 (1.5)]	75 (17) [9.0 (1.6)]	68 (14) [8.4 (1.3)]	0.01	68 (13) [8.4 (1.2)]	70 (14) [8.6 (1.3)]	67 (12) [8.3 (1.1)]	0.04
P^†	<0.001	<0.001	<0.001		<0.001	<0.001	<0.001
wHbA_1c before puberty	60 (14) [7.6 (1.3)], 87^‡	60 (13) [7.6 (1.2)], 34^‡	61 (14) [7.7 (1.3)], 53^‡	0.88	60 (13) [7.6 (1.2)], 143^§	60 (11) [7.6 (1.0)], 56^§	60 (14) [7.6 (1.3)], 87^§	0.93
wHbA_1c during puberty	70 (14) [8.6 (1.3)]^‖	70 (11) [8.6 (1.0)]^¶	69 (16) [8.5 (1.5)]	0.86	71 (14) [8.6 (1.3)]	72 (12) [8.7 (1.1)]	70 (15) [8.6 (1.4)]	0.50
wHbA_1c after puberty	73 (16) [8.8 (1.5)]	79 (16) [9.4 (1.5)]	70 (15) [8.6 (1.4)]	0.01	71 (14) [8.6 (1.3)]	74 (11) [89 (1.0)]	68 (14) [8.4 (1.3)]	<0.01
P^#	<0.001	<0.001	<0.001		<0.001	<0.001	<0.001

Mean (SD) wHbA_1c data expressed as mmol/mol [%], number of individuals.
↵*P value for the difference between female and male, t test;
↵†P value for the difference between wHbA_1c ≤5 years’ duration and >5 years’ duration, paired t test;
↵‡P < 0.001 compared with during and after puberty, GLM;
↵§P < 0.001 compared with during and after puberty, GLM;
↵‖P = 0.033 compared with after puberty;
↵¶P = 0.01 compared with after puberty, GLM;
↵#P value for the difference between wHbA_1c before, during, and after puberty, GLM.

Table 3

Cox regression models of risk factors for simplex and proliferative retinopathy

Model	Risk factor	Simplex retinopathy			Proliferative retinopathy
Model	Risk factor	P	Hazard ratio	95% CI	P	Hazard ratio	95% CI
A	Sex (women/men)	0.55	0.92	0.71–1.20	0.84	0.95	0.55–1.62
	Onset before puberty	<0.001	0.57	0.43–0.77	0.92	1.03	0.57–1.89
	Onset during puberty	0.38	0.85	0.60–1.22	0.47	1.28	0.65–2.50
	Onset after puberty		Reference			Reference
	wHbA_1c	<0.001	1.05	1.03–1.06	<0.001	1.10	1.08–1.12
B	Sex (women/men)	0.73	0.95	0.74–1.24	0.89	0.96	0.56–1.65
	Onset 0.0–4.9 years	0.001	0.38	0.22–0.66	0.69	0.77	0.22–2.77
	Onset 5.0–9.9 years	0.08	0.66	0.42–1.06	0.92	1.06	0.35–3.21
	Onset 10.0–14.9 years	0.50	0.85	0.52–1.38	0.64	1.30	0.43–3.91
	Onset 15.0–19.9 years	0.94	0.98	0.57–1.67	0.98	0.99	0.28–3.52
	Onset 20.0–24.9 years	0.50	0.83	0.49–1.42	0.83	0.86	0.23–3.26
	Onset 25.0–29.9 years	0.96	0.99	0.59–1.66	0.58	0.69	0.18–2.61
	Onset 30.0–34.9 years		Reference			Reference
	wHbA_1c	<0.001	1.05	1.04–1.06	<0.001	1.10	1.08–1.12
C	Sex (women/men)	0.57	0.93	0.71–1.21	0.95	1.02	0.60–1.74
	Age at onset	<0.001	1.03	1.01–1.04	0.48	1.01	0.98–1.04
	wHbA_1c ≤5 years	0.03	1.01	1.00–1.02	0.31	0.99	0.97–1.01
	wHbA_1c >5 years	<0.001	1.04	1.03–1.05	<0.001	1.12	1.09–1.14
D	Sex (women/men)	0.74	0.92	0.56–1.51	0.06	2.54	0.98–6.56
	Age at onset	<0.001	1.24	1.14–1.36	0.04	1.22	1.01–1.47
	wHbA_1c before puberty	0.69	1.01	0.98–1.03	0.69	0.99	0.95–1.03
	wHbA_1c during puberty	0.32	1.01	0.99–1.04	0.68	1.01	0.97–1.05
	wHbA_1c after puberty	0.02	1.03	1.01–1.05	<0.001	1.12	1.06–1.18