Statin use and cognitive function in middle-aged adults with type 1 diabetes

Table 1 Adults with type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study, by participation status in the ancillary neurocognitive study

	Non-participant (n = 154)	Participant (n = 108)	P value
Demographic and lifestyle factors, data are n (%), mean ± SD, or median (IQR)
Age (yr)	51.17 ± 7.74	49.52 ± 7.04	0.08
Female	86/136 (63%)	55 (51%)	0.07
Years of education	14 ± 2	15 ± 3	0.05
Ever smoking 100 + cigarettes1	57/136 (42%)	41 (38%)	0.60
ApoE4 (24, 34, 44)	34/151 (23%)	34 (32%)	0.12
BMI (kg/m2)	27.52 ± 4.88	26.74 ± 4.26	0.20
Depressive symptoms2	45/128 (35%)	23/100 (23%)	0.06
Physical activity (Kcal)3	729 (308-1663)	1009 (448-1966)	0.05
Type 1 diabetes-related factors
T1D duration (yr)	37.14 ± 7.20	35.50 ± 6.32	0.07
Age at diagnosis (yr)	8.62 ± 4.10	8.28 ± 4.11	0.51
HbA1c (%)	7.69 ± 1.69	7.85 ± 1.85	0.51
A1c months (AU)	1036.38 ± 481.55	966.82 ± 382.02	0.21
Insulin sensitivity (eGDR, mg/kg per minute)	7.65 ± 2.11	7.68 ± 2.47	0.94
eGFR (mL/min per 1.73 m2)	77.49 ± 24.41	83.31 ± 24.06	0.09
Proliferative retinopathy	85/131 (65%)	51/107 (48%)	0.009
Microalbuminuria	98/133 (74%)	54/92 (59%)	0.02
Coronary artery disease	48 (31%)	18 (17%)	0.009
Cardiac autonomic neuropathy	89/125 (71%)	48/97 (49%)	0.001
Distal symmetric polyneuropathy	86/128 (67%)	52/100 (52%)	0.02
Cardio-metabolic factors
Systolic blood pressure (mmHg)	116 ± 17	114 ± 16	0.28
Diastolic blood pressure (mmHg)	65 ± 10	66 ± 11	0.42
History of high blood pressure4	71 (46%)	39 (36%)	0.13
Total cholesterol (mg/dL)	174.07 ± 34.92	174.79 ± 35.85	0.88
LDL cholesterol (mg/dL)	98.15 ± 28.44	98.48 ± 33.72	0.94
HDL cholesterol (mg/dL)	59.89 ± 16.31	60.63 ± 16.68	0.74
Serum creatinine (mg/dL)	1.12 ± 0.67	1.07 ± 0.61	0.57
Ever used statins1	97 (63%)	57 (53%)	0.13
Years of statin use1	3 (0-6)	2 (0-8)	0.44
Study average LDLc (mg/dL)1	109.95 ± 23.28	107.65 ± 25.96	0.45
Inflammatory markers
WBC × 103/mm2	6.2 (4.9-7.8)	6.1 (5.2-6.9)	0.30
Adiponectin (μg/mL)	21.1 (15.2-31.0)	22.2 (15.2-30.1)	0.83
IL-6 (ng/mL)	1.4 (0.8-2.3)	1.3 (0.8-1.8)	0.42
TNFα (pg/mL)	1.3 (1.0-1.9)	1.3 (1.0-1.8)	0.92
C-reactive protein (mg/L)	1.7 (0.9-3.3)	1.1 (0.6-2.5)	0.03

¹Assessed repeatedly from 1986-88 (baseline) through 2004-2006;

²Beck Depression Inventory score ≥ 10;

³Estimated self-reported weekly activity per modified Paffenbarger questionnaire;

⁴Blood pressure > 140/80 at any physical exam as part of the parent study and/or any self-reported use of anti-hypertensive medication (1986-2006). Factors assessed in 2004-2006 unless otherwise specified. T1D: Type 1 diabetes; LDLc: Low density lipoprotein cholesterol; BMI: Body mass index; eGDR: Estimated glucose disposal rate; WBC: White blood cell count; IL-6: Interleukin-6; TNFα: Tumor necrosis factor alpha.

Table 2 Comparison of middle-aged adults with type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study by duration of statin use

	Never used (n = 51)	1-6 yr (n = 25)	7-12 yr (n = 32)	P value1
Demographic and lifestyle factors, data are n (%), mean ± SD, or median (IQR)
Age at cognitive testing (yr)	47.5 ± 7.3	51.8 ± 6.1	51.0 ± 6.7	0.02
Female	27 (53%)	16 (64%)	12 (38%)	0.10
Years of education	15 ± 2	16 ± 3	14 ± 3	0.52
Ever smoking 100+ cigarettes5	22 (43%)	11 (44%)	8 (25%)	0.05
Apo E4 (24, 34, 44)	16 (31%)	7 (28%)	11 (34%)	0.66
BMI (kg/m2)	26.0 ± 4.3	27.6 ± 5.1	29.8 ± 4.7	0.002
Cognitive function
Cognitively impaired	7 (14%)	8 (32%)	15 (47%)	0.003
Estimated verbal IQ	108.6 ± 8.2	107.7 ± 10.0	106.5 ± 6.9	0.24
Memory domain z-score	0.24 ± 0.75	-0.23 ± 0.64	-0.25 ± 0.78	0.004
Executive function z-score	0.18 ± 0.56	-0.10 ± 0.82	-0.30 ± 0.79	0.06
Psychomotor speed z-score	0.29 ± 0.66	-0.33 ± 1.10	-0.28 ± 0.89	0.01
Visuo- construction z-score	0.21 ± 0.64	-0.16 ± 0.82	-0.21 ± 1.45	0.13
Type 1 diabetes-related factors
Diabetes duration (yr)	39.6 ± 5.8	43.4 ± 6.9	42.1 ± 6.5	0.03
Serum glucose (mg/dL)	188.6 ± 90.5	151.1 ± 73.6	173.0 ± 81.8	0.56
A1c > 7.5%, 14-yr average	27 (53%)	17 (68%)	25 (78%)	0.02
Glucose disposal rate (mg/kg per minutr)2	8.1 ± 2.0	7.5 ± 1.8	5.8 ± 2.9	< 0.001
Proliferative retinopathy2	17 (33%)	14 (58%)	20 (63%)	0.03
eGFR (mL/min per 1.73 m2)24	91.3 ± 21.1	79.7 ± 20.1	74.7 ± 27.5	0.02
Coronary artery disease2	5 (10%)	3 (12%)	10 (31%)	0.02
Cardiac autonomic neuropathy2	21 (47%)	14 (58%)	13 (46%)	0.36
Distal symmetric polyneuropathy2	22 (49%)	13 (57%)	17 (53%)	0.61
Cardio-metabolic factors
History of stroke5	1 (2%)	2 (8%)	2 (6%)	0.99
Systolic blood pressure (mmHg)	117.6 ± 12.0	119.6 ± 15.5	123.2 ± 19.3	0.44
Diastolic blood pressure (mmHg)	65.0 ± 9.5	64.6 ± 9.1	67.5 ± 10.6	0.18
History of high blood pressure3	13 (25%)	10 (40%)	16 (50%)	0.04
Study average LDLc (mg/dL)5	100.3 ± 25.6	112.2 ± 24.9	115.9 ± 24.7	0.02
Inflammatory markers
2WBC × 103/ mm2	5.9 (5.0-6.7)	6.2 (5.2-6.9)	6.2 (5.2-7.1)	0.29
Adiponectin (μg/mL)2	22.0 (15.7-30.7)	21.8 (14.2-31.4)	22.3 (15.2-28.3)	0.75
IL-6 (ng/mL)2	1.4 (0.7-1.9)	1.2 (0.8-1.7)	1.2 (1.0-1.6)	0.28
TNFα (pg/mL)2	1.3 (1.0-2.3)	1.2 (1.0-1.8)	1.3 (1.0-1.6)	0.07
C-reactive protein (mg/L)2	0.9 (0.6-2.3)	0.9 (0.2-1.6)	1.9 (0.6-4.1)	0.08

¹P values are adjusted for age and education;

²Assessed in 2004-2006;

³Defined as any EDC assessed SBP > 140 mmHg or DBP > 90, or ever self-reported use of anti-hypertensive medication from 1986-1988 through 2010-2013;

⁴Estimated per the Chronic Kidney Disease - Epidemiology (CKD-EPI) formula;

⁵Assessed from EDC baseline (1986-1988) through time of cognitive testing (2010-2013). Factors assessed at time of cognitive testing (2010-2013) unless otherwise specified. T1D: Type 1 diabetes; LDLc: Low density lipoprotein cholesterol; BMI: Body mass index; eGDR: Estimated glucose disposal rate; WBC: White blood cell count; IL-6: Interleukin-6; TNFα: Tumor necrosis factor alpha.

Table 3 Select characteristics¹ of middle-aged adults with childhood-onset type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study, by cognitive impairment status

	Cognitively normal (n = 78)	Cognitively impaired (n = 30)	P value
Data are n (%), mean ± SD, or median (IQR)
Coronary artery disease2	9 (12%)	9 (30%)	0.02
Cardio-metabolic risk factors
Ever using statins (1986-2013)3	34 (44%)	23 (77%)	0.003
Duration of statin use (statin years)3	0 (0-6)	7 (2-8)	0.002
If statin use, only used lipophilic statin3	30 (88%)	21 (91%)	0.99
Study average LDLc (mg/dL)3	104.5 ± 25.8	115.9 ± 24.8	0.06
History of high blood pressure4	26 (33%)	13 (43%)	0.24
Brain imaging
Severe White Matter Hyperintensities5	17 (26%)	11 (46%)	0.09
Left hippocampal volume6	0.31 ± 0.03	0.31 ± 0.03	0.31

Reported P value is adjusted for education. ¹Relationships between other factors and cognitive impairment in this type 1 diabetes cohort have been previously described and published elsewhere (for details, see Nunley et al[18], 2015);

²Assessed in 2004-2006;

³Assessed since EDC baseline (1986-1988) through time of cognitive testing (2010-2013);

⁴Defined as any EDC assessed SBP > 140 mmHg or DBP > 90, or ever self-reported use of anti-hypertensive medication from 1986-1988 through 2010-2013;

⁵Fazekas rating 2-3 vs Fazekas rating 1; data on n = 89 (for details, see Nunley et al[28], 2015);

⁶Hippocampal volume as a percentage of total intracranial volume, data on n = 88 (for details, see Hughes et al[26], 2013). Measures assessed 2010-2013 unless otherwise noted. LDLc: Low density lipoprotein cholesterol.

Table 4 Results of logistic regression models assessing the association between duration of statin use and cognitive impairment in middle-aged adults with type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study

	Variables in Model	Cognitive impairment OR (95%CI) P value
Model 1	Never used statins	Referent group
	1-6 yr statins	3.16 (0.93-10.72), P = 0.064
	7-12 yr statins	4.84 (1.63-14.44), P = 0.005
Model 2	Never used statins	Referent group
	1-6 yr statins	2.86 (0.83-9.86), P = 0.095
	7-12 yr statins	4.26 (1.40-13.00), P = 0.011
	Average LDLc	1.01 (0.99-1.03), P = 0.24
Model 3	Never used statins	Referent group
	1-6 yr statins	3.29 (0.95-11.40), P = 0.061
	7-12 yr statins	4.13 (1.35-12.60), P = 0.013
	CAD	2.88 (0.88-9.44), P = 0.081
Model 4	Never used statins	Referent group
	1-6 yr statins	3.14 (0.93-10.64), P = 0.066
	7-12 yr statins	4.95 (1.65-14.82), P = 0.004
	Apo E4 allele	0.73 (0.26-2.02), P = 0.55
Model 5	Never used statins	Referent group
	1-6 yr statins	2.90 (0.82-10.29), P = 0.099
	7-12 yr statins	3.69 (1.17-11.68), P = 0.026
	Average LDLc	1.01 (0.99-1.03), P = 0.24
	CAD	2.72 (0.81-9.13), P = 0.11
	Apo E4 allele	0.75 (0.26-2.15), P = 0.59

Statin use groups: Never used n = 51; 1-6 years n = 25; 7+ years n = 32. Binary outcome: Cognitive impairment present/absent. Model 1: Statin use groups, controlling for age and education; Model 2: Model 1, further controlling for average long-term LDLc (1986-1988 through 2010-2013); Model 3: Model 1, further controlling for prevalent coronary artery disease (CAD); Model 4: Model 1, further controlling for Apo E4 allele status (24, 34, or 44); Model 5: Model 1, further controlling for LDLc, CAD, and Apo E4 allele. LDLc: Low density lipoprotein cholesterol.

Table 5 Results of linear regression models assessing the association between duration of statin use and memory domain function in middle-aged adults with type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study

	Variables in Model	Memory domain standardized β, P value
Model 1	Never used statins	Referent group
	1-6 yr statins	-0.284, P = 0.003
	7-12 yr statins	-0.232, P = 0.01
Model 2	Never used statins	Referent group
	1-6 yr statins	-0.267, P = 0.006
	7-12 yr statins	-0.209, P = 0.031
	Average LDLc	-0.084, P = 0.34
Model 3	Never used statins	Referent group
	1-6 yr statins	-0.267, P = 0.006
	7-12 yr statins	-0.213, P = 0.032
	CAD	0.02, P = 0.86
Model 4	Never used statins	Referent group
	1-6 yr statins	-0.284, P = 0.003
	7-12 yr statins	-0.231, P = 0.014
	Apo E4 allele	-0.01, P = 0.92
Model 5	Never used statins	Referent group
	1-6 yr statins	-0.267, P = 0.007
	7-12 yr statins	-0.213, P = 0.034
	Average LDLc	-0.084, P = 0.35
	CAD	0.02, P = 0.86
	Apo E4 allele	-0.001, P = 0.99

Statin use groups: Never used n = 51; 1-6 years n = 25; 7-12 years n = 32. Outcome: Standardized score of seven tasks assessing memory domain (z-score, in SD units). Model 1: Statin use groups, controlling for age and education; Model 2: Model 1, further controlling for average long-term LDLc (1986-88 through 2010-2013); Model 3: Model 1, further controlling for prevalent coronary artery disease (CAD) as of 2004-2006; Model 4: Model 1, further controlling for Apo E4 allele status (24, 34, or 44); Model 5: Model 1, further controlling for LDLc, CAD, and Apo E4 allele. LDLc: Low density lipoprotein cholesterol.