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OBJECTIVE
To study the ability of lipid variables to predict incident coronary artery disease
(CAD) events in patients with type 1 diabetes at different stages of nephropathy.
Patients (n = 3,520) with type 1 diabetes and available lipid proles participating in
the Finnish Diabetic Nephropathy Study (FinnDiane) were included in the study.
During a follow-up period of 10.2 years (8.612.0), 310 patients suffered an incident CAD event.
RESULTS
Apolipoprotein B (ApoB)/ApoA-I ratio was the strongest predictor of CAD in normoalbuminuric patients (hazard ratio 1.43 [95% CI 1.171.76] per one SD
increase), and ApoB was the strongest in macroalbuminuric patients (1.47
[1.191.81]). Similar results were seen when patients were stratied by sex or
glycemic control. LDL cholesterol was a poor predictor of CAD in women, normoalbuminuric patients, and patients with HbA1c below the median (8.3%, 67
mmol/L). The current recommended triglyceride cutoff of 1.7 mmol/L failed to
predict CAD in normoalbuminuric patients, whereas the cohort median 0.94
mmol/L predicted incident CAD events.
CONCLUSIONS
In patients with type 1 diabetes, the predictive ability of the lipid variables differed substantially depending on the patients sex, renal status, and glycemic
control. In normoalbuminuric patients, the ratios of atherogenic and antiatherogenic lipoproteins and lipids were the strongest predictors of an incident CAD
event, whereas in macroalbuminuric patients, no added benet was gained from
the ratios. Current treatment recommendations may need to be revised to capture residual CAD risk in patients with type 1 diabetes.
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of AER in at least two out of three consecutive 24-h or overnight urine collections. AER ,20 mg/min or ,30 mg/24 h
was dened as normal AER, 20#
AER ,200 mg/min or 30# AER ,300
mg/24 h as microalbuminuria, and AER
$200 mg/min or AER $300 mg/24 h as
macroalbuminuria. ESRD was dened as
requirement of dialysis or renal transplantation. In addition to the urine collections used for the classication of the
renal status, 24-h AER was also measured centrally from a single sample
with an immunoturbidimetric method.
The result of this measurement was
used in the multivariate analyses. Estimated glucose disposal rate (eGDR)
was calculated with an equation developed by Williams et al. (14) modied for
use with HbA1c instead of HbA1 (12). Serum lipid and lipoprotein concentrations
were all measured centrally from serum
samples using earlier described methods
(11). LDL-C was calculated with the
Friedewald formula if triglycerides were
,4.0 mmol/L (15).
At baseline, patients underwent a
thorough clinical investigation at a regular visit to their attending physician.
The baseline data were collected between 1994 and 2008. Complete baseline data including centrally measured
lipid proles were available for 3,872
patients. Follow-up data were obtained
from the Finnish Hospital Discharge
Register (HDR) based on hospital discharge records and the Finnish Cause
of Death Registry (CDR) through to 31
December 2010 and available for all patients. An incident CAD event was dened as myocardial infarction given as
ICD-10 code I21 (ICD-9, 410), coronary
artery bypass graft surgery or coronary
angioplasty. Researcher N.T. from the
FinnDiane study group veried the Finnish HDR data by double-checking the
hospital records of 28% of patients. In
this sample, no classication errors
were found, and only four borderline
cases of acute myocardial infarction
were identied. Otherwise all cases
were in accordance with the universal
denition of myocardial infarction (16)
or underwent either coronary artery
bypass graft surgery or coronary angioplasty. Fatal CAD events were identied
from a search of the Finnish CDR and
established when the immediate or underlying cause of death was from CAD,
i.e., given as ICD-10 codes I2025 (ICD-9,
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Table 1Clinical characteristics at baseline of patients with type 1 diabetes stratied by an incident CAD event and non-CAD
death
No CAD event
Incident CAD event
Non-CAD death
P value*
n
3,037
310
173
Men (%)
50.3
55.8
60.1
0.09
35.4 6 10.8
47.6 6 9.6
42.5 6 11.2
,0.001
Age (years)
Age at onset (years)
15.5 6 8.5
14.4 6 8.0
14.9 6 8.9
0.02
19.9 6 11.3
33.2 6 9.1
27.6 6 9.7
,0.001
SBP (mmHg)
DBP (mmHg)
131 6 16
79 6 9
148 6 20
81 6 11
143 6 23
82 6 12
,0.001
0.007
BMI (kg/m2)
25.0 6 3.4
25.1 6 3.7
24.6 6 4.8
0.55
WHR
Men
Women
0.90 6 0.07
0.81 6 0.06
0.95 6 0.07
0.84 6 0.07
0.93 6 0.07
0.85 6 0.08
,0.001
,0.001
HbA1c (%)
HbA1c (mmol/mol)
8.4 6 1.5
68 6 16.4
8.6 6 1.6
70 6 17.5
8.9 6 1.6
74 6 17.5
0.008
AER (mg/24 h)
10 (529)
51 (8495)
77 (11601)
,0.001
100 6 23
68 6 33
66 6 38
,0.001
,0.001
eGDR (mg/kg/min)
6.90 (4.758.74)
4.49 (3.335.51)
4.54 (3.186.10)
24.1
25.8
33.1
0.52
44.2
53.2
59.6
0.007
29.2
75.1
65.1
,0.001
7.3
69.5
25.1
31.4
17.4
22.5
,0.001
,0.001
Microalbuminuria (%)
12.7
13.9
13.3
0.57
Macroalbuminuria (%)
10.4
28.5
31.2
,0.001
ESRD (%)
2.5
23.0
28.3
,0.001
25.5
73.5
69.4
,0.001
4.86 6 0.92
5.42 6 1.20
5.28 6 1.09
,0.001
NonHDL-C (mmol/L)
3.51 6 0.96
4.20 6 1.23
3.97 6 1.15
,0.001
LDL-C (mmol/L)
2.97 6 0.83
3.45 6 1.00
3.25 6 1.00
,0.001
0.98 (0.741.39)
1.30 (0.971.89)
1.35 (0.972.03)
,0.001
1.24 6 0.34
1.46 6 0.39
1.14 6 0.34
1.33 6 0.41
1.24 6 0.44
1.40 6 0.52
,0.001
,0.001
0.47 6 0.24
0.64 6 0.28
0.44 6 0.23
0.57 6 0.28
0.50 6 0.30
0.64 6 0.35
,0.001
,0.001
0.78 6 0.19
0.83 6 0.22
0.70 6 0.18
0.76 6 0.22
0.74 6 0.22
0.78 6 0.26
,0.001
0.002
1.32 6 0.20
1.46 6 0.23
1.32 6 0.20
1.41 6 0.23
1.37 6 0.24
1.49 6 0.31
0.002
ApoB (g/L)
0.86 6 0.22
1.00 6 0.25
0.95 6 0.25
,0.001
ApoB/A-I
0.63 6 0.20
0.75 6 0.23
0.70 6 0.23
,0.001
0.76 (0.511.17)
3.58 (2.914.46)
1.06 (0.731.90)
4.30 (3.555.60)
1.11 (0.701.80)
4.20 (3.195.30)
,0.001
,0.001
Triglycerides (mmol/L)
HDL-C (mmol/L)
Men
Women
HDL2-C (mmol/L)
Men
Women
HDL3-C (mmol/L)
Men
Women
ApoA-I (g/L)
Men
Women
Triglyceride/HDL-C
Total cholesterol/HDL-C
Data are means 6 SD, median (IQR), or %. DBP, diastolic blood pressure. *P values indicate differences between incident CAD event and no CAD
event groups. P values for lipid variables are adjusted for age, BMI, and sex (if not already stratied by sex). The BMI- and age-corrected ApoA-I
levels in men were 1.27 and 1.33 g/L in no CAD and CAD event groups, respectively, and the difference between these was signicant.
CONCLUSIONS
This study is the rst report on a complete panel of both antiatherogenic and
atherogenic lipid parameters as predictors of incident CAD outcomes in patients with type 1 diabetes. In this
study we have shown that in patients
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Table 2Cox regression analyses with risk factors for a CAD event
Variable
HR (95% CI)
P value
LR x2
AUC
AIC
1.22 (1.071.40)
0.003
350
0.854
2,684
2.2 (P = 0.30)
1.27 (1.121.46)
,0.001
353
0.857
2,680
4.7 (P = 0.06)
1.21 (1.051.39)
0.009
340
0.854
2,625
3.2 (P = 0.22)
Ln triglycerides
1.34 (1.141.58)
,0.001
354
0.859
2,680
6.2 (P = 0.03)
0.86 (0.731.00)
0.05
345
0.857
2,688
2.1 (P = 0.45)
0.85 (0.721.01)
0.06
338
0.855
2,630
3.9 (P = 0.14)
0.88 (0.761.03)
0.12
336
0.854
2,631
20.2 (P = 0.92)
0.85 (0.730.98)
1.40 (1.211.62)
0.03
,0.001
346
361
0.857
0.859
2,688
2,673
4.6 (P = 0.05)
7.7 (P = 0.01)
ApoB/A-I (0.21)
1.24 (1.131.37)
,0.001
356
0.860
2,678
7.1 (P = 0.02)
Ln triglyceride/HDL-C
1.28 (1.111.49)
0.001
352
0.860
2,682
5.2 (P = 0.10)
Ln total C/HDL-C
1.22 (1.061.39)
0.004
349
0.858
2,684
6.1 (P = 0.04)
The model also included the following: duration of diabetes, eGFR, SBP, retinal laser treatment, sex, HbA1c, WHR, ln AER, and history of smoking.
N = 2,521 (events = 198). Results are presented as HRs per one SD increase with 95% CI. AUC of the receiver operating characteristics indicates
discrimination. LR x2 statistics from the Cox model, higher values indicate better global t. Lower values of AIC indicate better tradeoff between the
likelihood of the model against its complexity. NRI indicates the sum of correctly reclassied individuals with and without CAD events after the
inclusion of the lipid variable to the model when patients were divided into the risk groups ,5, 510, 1020, and $20%. Total C, total cholesterol.
Table 3Cox regression analyses with risk factors for a CAD event in patients stratied by renal status
Normal AER
Microalbuminuria
Macroalbuminuria
ESRD
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
1.04 (0.841.30)
0.72
1.12 (0.801.59)
0.50
1.32 (1.111.58)
0.002
1.28 (1.011.63)
0.04
1.16 (0.941.44)
0.17
1.18 (0.851.66)
0.32
1.34 (1.121.60)
0.001
1.34 (1.031.73)
0.03
1.10 (0.891.35)
0.38
1.19 (0.861.64)
0.30
1.33 (1.091.63)
0.005
1.23 (0.981.54)
0.07
Ln triglycerides
1.40 (1.111.77)
0.005
1.13 (0.811.58)
0.48
1.22 (0.961.56)
0.10
1.25 (0.891.74)
0.19
0.74 (0.590.94)
0.01
0.85 (0.601.20)
0.36
0.87 (0.681.11)
0.26
0.93 (0.701.23)
0.61
0.75 (0.590.96)
0.82 (0.651.02)
0.02
0.07
0.90 (0.631.29)
0.88 (0.631.24)
0.58
0.47
0.87 (0.661.14)
0.80 (0.611.05)
0.32
0.10
0.81 (0.601.08)
1.12 (0.871.45)
0.15
0.39
0.72 (0.570.91)
0.006
0.77 (0.531.12)
0.17
0.98 (0.791.23)
0.88
0.90 (0.671.21)
0.48
1.35 (1.081.70)
0.01
1.31 (0.931.83)
0.12
1.47 (1.191.81)
,0.001
1.24 (0.921.67)
0.15
ApoB/A-I (0.21)
1.43 (1.171.76)
,0.001
1.32 (0.971.78)
0.08
1.21 (1.051.39)
0.007
1.33 (1.001.77)
0.048
Ln triglyceride/HDL-C
1.44 (1.151.81)
0.002
1.15 (0.831.61)
0.41
1.20 (0.961.49)
0.10
1.18 (0.871.61)
0.29
Ln total C/HDL-C
1.29 (1.041.61)
0.02
1.18 (0.861.63)
0.30
1.23 (1.031.48)
0.02
1.17 (0.921.50)
0.21
Variable
The model also included the following: duration of diabetes, eGFR, SBP, retinal laser treatment, sex, HbA1c, WHR, and history of smoking. Results are
presented as HRs per one SD increase of the study cohort with 95% CI. Total C, total cholesterol.
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Figure 1The cumulative incidence of CAD in normoalbuminuric patients stratied by the group median of LDL-C subdistribution HR (subHR) 1.07
(95% CI 0.701.64), P = 0.74 (A); macroalbuminuric patients stratied by the group median of LDL-C subHR 1.63 (0.992.67), P = 0.06 (B);
normoalbuminuric patients stratied by the group median of triglycerides (TG) subHR 1.74 (1.132.69), P = 0.01 (C); macroalbuminuric patients
stratied by the group median of TG subHR 1.26 (0.762.08), P = 0.38 (D); normoalbuminuric patients stratied by the recommended cutoff 1.7
mmol/L for TG subHR 0.88 (0.421.85), P = 0.74 (E); and macroalbuminuric patients stratied by the recommended cutoff 1.7 mmol/L for TG subHR
1.69 (1.002.85), P = 0.05 (F). The competing risk regression model also included the following: duration of diabetes, eGFR, SBP, retinal laser
treatment, sex, HbA1c, WHR, and history of smoking.
lipid disturbances associated with nephropathy than with cardiovascular disease (CVD) (25). To the best of our
knowledge, other prospective studies
have not taken into account the renal
status when evaluating the prediction
of lipid variables for an incident CAD
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References
1. Lozano R, Naghavi M, Foreman K, et al.
Global and regional mortality from 235 causes
of death for 20 age groups in 1990 and 2010:
a systematic analysis for the Global Burden of
Disease Study 2010 [published correction appears in Lancet 2013;381:628]. Lancet 2012;
380:20952128
2. Haffner SM, Lehto S, Ronnemaa T, Pyorala K,
Laakso M. Mortality from coronary heart disease
in subjects with type 2 diabetes and in nondiabetic
subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229234
3. Soedamah-Muthu SS, Fuller JH, Mulnier HE,
Raleigh VS, Lawrenson RA, Colhoun HM. High
risk of cardiovascular disease in patients with
type 1 diabetes in the U.K.: a cohort study using
the general practice research database. Diabetes Care 2006;29:798804
4. Groop PH, Thomas MC, Moran JL, et al.;
FinnDiane Study Group. The presence and severity of chronic kidney disease predicts allcause mortality in type 1 diabetes. Diabetes
2009;58:16511658
5. Orchard TJ, Secrest AM, Miller RG, Costacou
T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to
that of the general population: a report from
the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 2010;53:2312
2319
6. Mattock MB, Cronin N, Cavallo-Perin P, et al.;
EURODIAB IDDM Complications Study. Plasma
lipids and urinary albumin excretion rate in
Type 1 diabetes mellitus: the EURODIAB
IDDM Complications Study. Diabet Med 2001;
18:5967
7. Jensen T, Borch-Johnsen K, KofoedEnevoldsen A, Deckert T. Coronary heart disease
in young type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia 1987;30:
144148
8. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of
premature death from coronary heart disease
continuous and graded? Findings in 356,222
primary screenees of the Multiple Risk Factor
Intervention Trial (MRFIT). JAMA 1986;256:
28232828
9. American Diabetes Association. Standards of
medical care in diabetesd2013. Diabetes Care
2013;36(Suppl. 1):S11S66
10. Taskinen MR. Quantitative and qualitative
lipoprotein abnormalities in diabetes mellitus.
Diabetes 1992;41(Suppl. 2):1217
11. Tolonen N, Forsblom C, Thorn L, et al.;
FinnDiane Study Group. Relationship between
lipid proles and kidney function in patients
with type 1 diabetes. Diabetologia 2008;51:
1220
12. Tolonen N, Hietala K, Forsblom C, et al.;
FinnDiane Study Group. Associations and interactions between lipid proles, retinopathy and
nephropathy in patients with type 1 diabetes:
the FinnDiane Study. J Intern Med 2013;274:
469479
13. Levey AS, Stevens LA, Schmid CH, et al.;
CKD-EPI (Chronic Kidney Disease Epidemiology
Collaboration). A new equation to estimate glomerular ltration rate. Ann Intern Med 2009;
150:604612
14. Williams KV, Erbey JR, Becker D, Arslanian S,
Orchard TJ. Can clinical factors estimate insulin
resistance in type 1 diabetes? Diabetes 2000;49:
626632
15. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of
the preparative ultracentrifuge. Clin Chem
1972;18:499502
16. Thygesen K, Alpert JS, Jaffe AS, et al.;
Joint ESC/ACCF/AHA/WHF Task Force for Universal Denition of Myocardial Infarction.
Third universal denition of myocardial infarction. J Am Coll Cardiol 2012;60:1581
1598
17. Sundstr o m J, Byberg L, Gedeborg R,
Michaelsson K, Berglund L. Useful tests of usefulness of new risk factors: tools for assessing
reclassication and discrimination. Scand J Public Health 2011;39:439441
18. Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease risk assessment
in asymptomatic people: role of traditional risk
factors and noninvasive cardiovascular tests.
Circulation 2001;104:18631867
19. National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). Third report
of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III) nal report.
Circulation 2002;106:31433421
20. Fine JP, Gray RJ. A proportional hazards
model for the subdistribution of a competing
risk. J Am Stat Assoc 1999;94:496509
21. Orchard TJ, Olson JC, Erbey JR, et al. Insulin
resistance-related factors, but not glycemia,
predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh
Epidemiology of Diabetes Complications Study.
Diabetes Care 2003;26:13741379
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