The Effects of Type 1 Diabetes on Cognitive Performance: A meta-analysis

Augustina M.A. Brands; Geert Jan Biessels; Edward H.F. de Haan; L. Jaap Kappelle; Roy P.C. Kessels

doi:10.2337/diacare.28.3.726

Reviews/Commentaries/ADA Statements

The Effects of Type 1 Diabetes on Cognitive Performance

A meta-analysis

Augustina M.A. Brands, MSC1 2 3,
Geert Jan Biessels, PHD, MD1,
Edward H.F. de Haan, PHD1 3,
L. Jaap Kappelle, PHD, MD1 and
Roy P.C. Kessels, PHD1 3

¹Department of Neurology, University Medical Center, Utrecht, the Netherlands
²Department of Neuropsychology, Hofpoort Hospital/Regional Psychiatrisch Centrum, Woerden, the Netherlands
³Helmholtz Instituut, Utrecht University, the Netherlands

Address correspondence and reprint requests to Augustina M.A. Brands, MSc, Department of Neuropsychology, Hofpoort Hospital, Blekerijlaan 3, 3447 AC Woerden, Netherlands. E-mail: i.brands{at}altrecht.nl

Diabetes Care 2005 Mar; 28(3): 726-735. https://doi.org/10.2337/diacare.28.3.726

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Figure 1—
Standardized effect sizes (Cohen’s d) and 95% CIs for the cognitive domains in patients with type 1 diabetes compared with nondiabetic control subjects. Number of patients included in each domain is listed between brackets. Nonsignificant P values are not shown. Refs.: a = (1,3,18,19,20–32), b = (18,19,22,27,29, c = (6,18,19,25), d = (3,6,18,20,22,23,25,31), e = (6,18,22,25,29), f = (3,6,18,22,25), g = (6,22,25,29), h = (3,22,25), i = (3,6,18,19,21,22,25,30), j = (20,24,28,29,32), k = (20,27), l = (2,3,21,25,29), m = (18,27,29), n = (25,26,29), o = (25,29,31), p = (3,18,19,20–22,25,27,29), q = (6,18,19,27,29), and r = (2,19,22,25).
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Figure 2—
Standardized effect sizes (Cohen’s d) and 95% CIs for the cognitive domains in patients with compared with patients without recurrent episodes of severe hypoglycemia. Number of patients with recurrent episodes of severe hypoglycemia in each domain is listed between brackets. Nonsignificant P values are not shown. Refs.: a = (4,29–31,36,37,39,41), b = (29,30,36,41), c = (4,31,37,39,41), d = (29,36,37,39), e = (29,37,39), f = (30,37,39,41), g = (29,36), h = (4,39,41), i = (29,31,37,39,41), j = (4,29,36,37,39), and k = (29,39)

Tables

Figures

Table 1—

Characteristics of studies that have assessed cognitive functioning in patients with type 1 diabetes and nondiabetic control subjects

First author (ref.)	n (grp 1)/(grp 2)	% Males (grp 1)/(grp 2)	Age (grp 1)/(grp 2) (years)	Subjects matched for	HbA_1c or HbA₁ (%)	Duration (years)	Calculated age at onset (years)	Included complications and characteristics	Exclusion criteria or absent characteristics
Meuter et al. 1980 (17)	112/112	50/50	38 ± 14.3/ND	E	ND	10.5 ± 9.3	17	H,Hy,N,R,Ne	ND
Franceschi et al. 1984 (18)	37/26	43/42	25.8 ± 5/26.4 ± 5	E,O,SES	12.7 ± 2.5	7.7 ± 5.5	18	Hy,N,R	H,Ne,CI,DL,P
Skenazy et al. 1984 (19)
Visually impaired	20/24	70/67	28 ± 6.1/22.6 ± 5.6	ND	ND	18.7 ± 5.9	9	H,Hy,N,R,Ne	ND
Nonvisually impaired	19/24	53/67	32.1 ± 6.2/22.6 ± 5.6	ND	ND	15.3 ± 7.8	17	H,Hy,N,R,Ne	ND
Lawson et al. 1984 (5)	48/40	54/48	38.3 ± 14.6/38.8 ± 12.8	ND	9.1	13 ± 10.8	15	Hy,N	P
Grill et al. 1990 (20)	6/5	ND	37.1 ± 6.9/30.3 ± 4.5	ND	6.9 ± 0.7	19.4 ± 5.1	18	Hy,R	CV,Ne,H,CI,N
Widom et al. 1990 (21)
Poor metabolic control	9/10	44/60	22 ± 3/27 ± 3.2	ND	11.8 ± 1.2	12 ± 6	10	R	N,Ne,
Good metabolic control	8/10	50/60	27 ± 5.7/27 ± 3.2	ND	8 ± 0.6	7 ± 2.8	20	ND	N,Ne,R
Dejgaard et al. 1991 (22)	20/120	ND/ND	44 ± 9/ND	ND	9.1 ± 1.4	26 ± 9	18	Hy,N,R,Ne	P
Pozzessere et al. 1991 (23)	16/16	70/70	33.2 ± 12.6/33.4 ± 12.5	E	7 ± 1.6	9 ± 7.7	24	H	Hy,NA,P,DL
Blackman et al. 1992 (24)	14/10	43/50	29.5 ± 6/26.7 ± 6	ND	11 ± 1.9	ND	ND	ND	Hy,N
Ryan et al. 1992 (2)	75/75	45/25	35.5 ± 5.6/36.2 ± 6.8	E,SES	10.3	26.6 ± 6.7	9	Hy,N,R,	ND
Sachon et al. 1992 (3)
Severe hypoglycemia	30/25	77/48	41 ± 13/38 ± 15	O,SES	7.4 ± 1.2	18 ± 13	23	Hy,N,Ne,R	ND
No hypoglycemia	25/25	60/48	34 ± 10/38 ± 15	O,SES	8.6 ± 1.9	15 ± 11	18	N,Ne,R	Hy,ND
Wirsen et al. 1992 (25)	10/12	100/100	R 20–43/R 18–32	E,	7.9 ± 0.6	ND	ND	Hy	N
Cox et al. 1993 (26)	10/10	40/ND	34/ND	E,O	9.8	18	16	ND	ND
Deary et al. 1993 (1)	100/100	ND/ND	40.9 ± 8.8/40.2 ± 6.7	E	ND	>5	>19	Hy,R,N,Ne	P
Ryan et al. 1993 (6)
Females	41/41	0/0	33.4 ± 5.5/35.2 ± 8.4	E,SES	10.9 ± 1.8	25.3 ± 6.6	8	Hy,N,Ne,R	ND
Males	41/41	100/100	33.4 ± 5.2/34.7 ± 7.5	E,SES	10.6 ± 2	27.1 ± 5.5	6	Hy,N,Ne,R	ND
Ryan et al. 1993 (27)	142/100	51/47	33.5 ± 5.6/34.1 ± 6.7	E,SES	10.6 ± 1.8	24.8 ± 6.1	8	Hy,N,Ne,R	ND
Maran et al. 1995 (28)
Good metabolic control	8/8	75/63	36 ± 3/31 ± 2	ND	7.7 ± 0.3	16 ± 2	20	Hy	ND
Poor metabolic control	10/8	60/63	32 ± 4/31 ± 2	ND	10.1 ± 0.2	17 ± 3	15	ND	ND
Hershey et al. 1997 (29)
Severe hypoglycemia	26/21	ND/ND	26.2 ± 6.6/27.8 ± 8.1	E	ND	>5	<14	Hy	R,N
No hypoglycemia	12/21	ND/ND	22.8 ± 7.7/27.8 ± 8.1	E	ND	>5	<14	—	Hy,R,N
Kramer et al. 1998 (30)	108/108	45/ND	36 ± 13/36 ± 13	ND	ND	>1	>16	H,Hy,N,R,	P,Ne
Snoek et al. 1998 (31)
Severe hypoglycemia	9/9	100/100	36.9 ± 6.7/ND	ND	7.4	13.4	24	Hy	P,
No hypoglycemia	9/9	100/100	36.9 ± 6.7/ND	ND	7.4	13.4	24	—	Hy,P,
Lobmann et al. 2000 (32)	12/12	33/58	31 ± 7/27 ± 3	ND	7.4 ± 1.8	7.8 ± 8.6	23	Hy	N,R,H,CI,Ne,

Data are means ± SD, unless otherwise indicated. CI, cardiac insufficiency; DL, dyslipidemia; E, education; H, hypertension or hypertensive treatment; Hy, severe hypoglycemic episodes; N, neuropathy; ND, not specifically defined; Ne, nephropathy and/or microalbuminuria; O, occupation; P, psychiatric problems and/or use of psychoactive drugs and/or addiction to alcohol or other substances; R, retinopathy; SES, socioeconomic status.

Table 2—

Characteristics of studies that have assessed cognitive functioning in patients with type 1 diabetes, comparing different diabetic characteristics

First author (ref.)	Type (grp 1/grp 2)	n (grp 1/grp 2)	% Males (grp 1/grp 2)	Age (grp 1/grp 2)	HbA₁ (grp 1/grp 2)	Duration (grp 1/grp 2)	Calculated age at onset (grp 1/grp 2)	Included complications and characteristics	Exclusion criteria or absent characteristics	Subjects matched for
Hung et al. 1984 (33)	Poor MC/good MC	12/20	67/65	35.1/34.15	13 ± 0.9/10 ± 0.8	20.2/22.8	15/14	R,N	Ne	ND
Skenazy et al. 1984 (19)	Vis imp/non-vis imp	20/19	70/53	28 ± 6.1/32.1 ± 6	ND/ND	18.7 ± 5.9/15.3 ± 7.8	9/17	H,N,R,Ne	ND	ND
Holmes 1986 (7)	Poor MC/good MC	8/19	100/100	20.9 ± 2.4/23.4 ± 5.4	12.4 ± 0.7/8.2 ± 1.6	7.8 ± 4.1/8.4 ± 5.7	13/15	ND	P	E,SES
Holmes et al. 1988 (34)	Poor MC/good MC	6/10	100/100	22.2 ± 4.3/24 ± 5.3	10.1 ± 1/6.9 ± 0.8	7.5 ± 3.8/6.7 ± 4.4	15/14	ND	R	ND
Prescott et al. 1990 (35)	Poor MC/good MC	20/20	50/50	40.3 ± 11.6/39.8 ± 10	13.1 ± 1.6/8.9 ± 1	15.2 ± 10.5/14 ± 10.3	25/26	ND	ND	SES
Widom et al. 1990 (21)	Poor MC/good MC	9/8	44/50	22 ± 3/27 ± 5.7	11.8 ± 1.2/8 ± 0.6	12 ± 6/7 ± 2.8	10/20	R,ND	N,Ne	ND
Wredling et al. 1990 (4)	Sev hy/no sev hy	17/17	ND/ND	49 ± 18/48 ± 17	7.9 ± 1.6/8.8 ± 1.6	28 ± 18/29 ± 13	21/19	N,R,P	ND	E
Langan et al. 1991 (36)	Sev hy/no sev hy	24/23	58/48	37.9 ± 6.4/38.5 ± 5.3	10 ± 2.3/10.2 ± 1.8	10.7 ± 4/13 ± 4	27/25	R,N,Ne,H	CV,P,PD	ND
Sachon et al. 1992 (3)	IHA/NHA	30/25	77/60	41 ± 13/34 ± 10	7.4 ± 1.2/8.6 ± 1.9	18 ± 13/15 ± 11	24/19	N,Ne,R	ND	O,SES
Ryan et al. 1993 (27)	Compl/no compl	113/29	49/55	34.3 ± 5.4/30.7 ± 5.6	10.6 ± 1.7/10.7 ± 1.9	25.9 ± 5.6/20.5 ± 5.8	8/10	N,Ne,R	ND	E,SES
Chabriat et al. 1994 (37)	Sev hy/no sev hy	15/6	ND/ND	47.6 ± 17/42.8 ± 19	7.2 ± 1.7/7.1 ± 0.8	19.6 ± 16/11.3 ± 7	28/32		H,R,M,N,CV	E
Gold et al. 1995 (38)	IHA/NHA	10/10	ND/ND	35 ± 7.7/37.4 ± 5.1	9.7 ± 1/10.3 ± 2.2	12.8 ± 4.4/17.9 ± 7.8	23/19	H	P,R,N	ND
Maran et al. 1995 (28)	Poor MC/good MC	10/8	60/75	32 ± 4/36 ± 3	10.1 ± 0.2/7.7 ± 0.3	17 ± 3/16 ± 2	15/20	ND	ND	ND
DCCT 1996 (39)
>5 episodes	Sev hy/no sev hy	23/1,045	ND/ND	<50/<50	ND/ND	>6/>6	ND	—	R,Ne,N,P	ND
1–5 episodes	Sev hy/no sev hy	314/1,045	ND/ND	<50/<50	ND/ND	>6/>6	ND	—	R,Ne,N,P	ND
Reichard et al. 1996 (40)	Poor MC/good MC	48/43	ND	ND/ND	8.3 ± 1/7.2 ± 0.6	ND/ND	ND	R	ND
Hershey et al. 1997 (29)	Sev hy/no sev hy	26/12	ND/ND	26.2 ± 6.6/22.8 ± 7.7	ND/ND	>5/>5	<14	—	R,N	E
Kramer et al. 1998 (30)
Hypoglycemia	Sev hy/no sev hy	55/53	35/57	38 ± 14/34 ± 12	7 ± 1.6/6.9 ± 1.3	17.6 ± 11.6/10.8 ± 10.6	20/23	H,N,R	P,Ne	A
MC	HbA_1c >6.5/HbA_1c <6.5	ND/ND	ND/ND	ND/ND	ND/ND	ND/ND	>16	H,N,R	P,Ne	A
Snoek et al. 1998 (31)	Sev hy/no sev hy	9/9		36.9 ± 6.7/36.9 ± 6.7	7.4/7.4	13.4/13.4	24/27	—	P	A,S
Howorka et al. 2000 (41)	Sev hy/no sev hy	13/14	46/36	36.1 ± 10.2/36.1 ± 10	7.6 ± 1/7.3 ± 1.2	16.7 ± 7.4/15.6 ± 8.6	19/20	R	P,CV,N,CI	A,S
Strachan et al. 2000 (42)	IHA/NHA	20/20	65/60	36.4 ± 14.7/34 ± 12.5	8.3 ± 1.3/10 ± 1.7	15.5 ± 7.6/13 ± 8.2	20/21	ND	P	A,S
Ferguson et al. 2003 (8)	R/no R	25/46	50/40	31.5 ± 6/26.4 ± 4.6	8.9 ± 1.3/8.4 ± 1.2	21.6 ± 5.9/17 ± 4.6	10/9	Hy	N,Ne,H,P	ND

Data are means ± SD, unless otherwise indicated. A, age; CI, cardiac insufficiency; Compl, diabetes complications; DL, dyslipidemia; E, education; Gluc, hypoglycemia prevented during testing; H, hypertension or hypertensive treatment; Hy, severe hypoglycemic episodes; IHA, impaired awareness of hypoglycemia; MC, metabolic control; N, neuropathy; ND, not specifically defined; Ne, nephropathy and/or microalbuminuria; NHA, normal awareness of hypoglycemia; O, occupation; P, psychiatric problems and/or use of psychoactive drugs and/or addiction to alcohol or other substances; R, retinopathy; S, sex; SES, socioeconomic status; Sev hy, episodes of severe hypoglycemia; Vis imp, visually impaired.

Table 3—

Domain scores from studies that could not be explored further meta-analytically

Cognitive domains
First author (ref.)	Group 1	Group 2	Overall intelligence	Working memory	Learning immediate memory	Delayed memory	Psychomotor efficiency	Speed of information process	Motor speed	Attention	Cognitive flexibility	Visual perception	Language
Hung et al. (33)	Poor MC	Good MC	—	0.18	−0.71	—	—	—	—	—	0.17	—	—
Skenazy et al. (19)	Vis imp	Non vis imp	0.23	—	—	—	—	—	—	—	—	—	0.29
Holmes (7)	Poor MC	Good MC	−0.31	—	—	—	—	−0.53	0.38	—	—	—	—
Holmes et al. (34)	Poor MC	Good MC	−0.10	—	—	—	0.14	−0.73	0.64	—	—	—	—
Prescott et al. (35)	Good MC	Good MC	—	—	0	—	—	—	—	—	—	—	—
Widom et al. (21)	Poor MC	Good MC	—	—	—	—	−0.33	—	—	0.17	0.89	—	—
Ryan et al. (27)	Compl	No compl	0.23	—	−0.24	—	—	—	−0.80	−0.28	0.10	−0.35	—
Gold et al. (38)	IHA	NHA	−0.33	—	—	—	0	—	—	—	—	—	—
Maran et al. (28)	Poor MC	Good MC	—	—	—	—	—	0.45	—	—	—	—	—
Kramer et al. (30)	Poor MC	Good MC	0.28	—	—	—	0	—	—	—	—	—	—
Strachan et al. (42)	IHA	NHA	—	—	−0.10	−0.13	−0.77	0	—	−0.63	−0.54	—	—
Ferguson et al. (8)	R	No R	−0.31	—	—	—	−0.48	−0.59	—	−0.40	−0.34	—	—

Data are Cohen’s d. Negative effects sizes reflect worse performance in group 1. Compl, diabetes complications; IHA, impaired awareness of hypoglycemia; MC, metabolic control; NHA, normal awareness of hypoglycemia; Vis imp, visually impaired; R, retinopathy.