C-Reactive Protein and 5-Year Survival in Type 2 Diabetes: The Casale Monferrato Study

Graziella Bruno; Paolo Fornengo; Giulia Novelli; Francesco Panero; Massimo Perotto; Olivia Segre; Chiara Zucco; PierCarlo Deambrogio; Giuseppe Bargero; Paolo Cavallo Perin

doi:10.2337/db08-0900

Original Article

C-Reactive Protein and 5-Year Survival in Type 2 Diabetes

The Casale Monferrato Study

Graziella Bruno¹,
Paolo Fornengo¹,
Giulia Novelli¹,
Francesco Panero¹,
Massimo Perotto¹,
Olivia Segre¹,
Chiara Zucco¹,
PierCarlo Deambrogio²,
Giuseppe Bargero² and
Paolo Cavallo Perin¹

¹Department of Internal Medicine, University of Torino, Torino, Italy; and
²Santo Spirito Hospital, Casale Monferrato, Alessandria, Italy.

Corresponding author: Graziella Bruno, graziella.bruno{at}unito.it.

Diabetes 2009 Apr; 58(4): 926-933. https://doi.org/10.2337/db08-0900

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FIG. 1.
Kaplan-Meier curves depicting the survival curves of the cohort by CRP levels (dotted line CRP ≤3 mg/l, solid line >3 mg/ml). Log-rank test P < 0.001.

Tables

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TABLE 1

Baseline characteristics of subjects with type 2 diabetes of the Casale Monferrato Study, by CRP values

	CRP tertiles			P
	<1.6 mg/l	1.6–4.4 mg/l	>4.4 mg/l	P
n	759	834	788
Men	434 (57.2)	422 (50.6)	328 (41.6)	<0.0001
Age (years)	67.1 ± 10.6	68.1 ± 9.9	67.7 ± 10.7	0.16
Duration of diabetes (years)	11.2 ± 8.4	10.3 ± 7.4	10.5 ± 8.0	0.06
BMI (kg/m²)	26.7 ± 4.0	28.7 ± 4.5	30.6 ± 6.0	<0.0001
Waist circumference (cm)	93.9 ± 11.0	98.8 ± 11.6	101.9 ± 12.5	<0.0001
Systolic blood pressure (mmHg)	143.2 ± 15.9	146.7 ± 15.9	147.1 ± 17.0	<0.0001
Diastolic blood pressure (mmHg)	81.8 ± 7.9	82.2 ± 8.1	83.4 ± 8.5	<0.0001
Hypertension	653 (86.3)	740 (89.1)	718 (91.1)	0.01
Glucose (mg/dl)	163.0 ± 48.7	172.9 ± 52.9	182.6 ± 61.0	<0.0001
A1C (%)	6.8 ± 1.7	6.9 ± 1.7	7.3 ± 1.9	<0.0001
Total cholesterol (mg/dl)	205.6 ± 40.6	213.8 ± 38.7	215.4 ± 40.6	<0.0001
LDL cholesterol (mg/dl)	123.0 ± 35.5	128.7 ± 31.9	130.9 ± 35.0	<0.0001
HDL cholesterol (mg/dl)	57.2 ± 16.1	54.5 ± 14.8	52.7 ± 14.2	<0.0001
Triglycerides (mg/dl)	113 (79–155)	134 (96–178)	141 (101–192)	<0.0001
ApoA1 (mg/dl)	160.5 ± 39.5	154.7 ± 37.8	147.1 ± 38.4	<0.0001
ApoB (mg/dl)	96.1 ± 26.0	103.5 ± 25.9	106.7 ± 27.4	<0.0001
ApoB/apoA1	0.65 ± 0.31	0.72 ± 0.31	0.79 ± 0.37	<0.0001
Creatinine (mg/dl)	0.84 (0.70–0.97)	0.84 (0.71–0.98)	0.86 (0.69–1.02)	0.16
Fibrinogen (g/l)	353.5 ± 66.5	371.8 ± 68.9	413.1 ± 96.2	<0.0001
Uric acid (mg/dl)	5.22 ± 1.44	5.57 ± 1.55	6.08 ± 2.53	<0.0001
AER (μg/min)	10.9 (4.0–22.6)	13.1 (4.6–27.7)	16.3 (4.9–40.7)	<0.0001
20–200	137 (22.9)	169 (25.7)	184 (29.8)	<0.0001
>200	24 (4.0)	31 (4.7)	46 (7.5)
CVD	136 (17.9)	180 (21.6)	194 (24.6)	0.006
Smoking
Former smoker	243 (32.9)	236 (29.7)	221 (28.9)	0.28
Smoker	112 (15.2)	130 (16.3)	109 (14.2)
Glucose-lowering treatment
Diet	128 (17.0)	135 (16.4)	102 (13.1)	0.21
Oral drugs	549 (73.0)	605 (73.7)	585 (75.4)
Insulin	75 (10.0)	81 (9.9)	89 (11.5)
Statins	163 (21.5)	163 (19.5)	151 (19.2)	0.77

Data are means ± SD, n (%), or geometric means (95% CI).

TABLE 2

Baseline characteristics of people with type 2 diabetes of the Casale Monferrato Study, by living status on 31 December 2006

	Survived	Deceased	P
n	1,885	496
Men	922 (48.9)	262 (52.8)	0.12
Age (years)	65.9 ± 10.2	74.1 ± 8.5	<0.0001
Duration of diabetes (years)	10.2 ± 7.8	12.6 ± 8.4	<0.0001
CRP (mg/dl)	2.5 (1.2–5.3)	3.7 (1.6–9.1)	<0.0001
<1.6	642 (34.1)	117 (23.6)	<0.0001
1.6–4.4	671 (35.6)	163 (32.8)
>4.4	572 (30.3)	216 (43.6)
BMI (kg/m²)	28.9 ± 5.0	28.0 ± 5.4	0.0009
Waist circumference (cm)	98.2 ± 12.2	98.3 ± 12.8	0.82
Systolic blood pressure (mmHg)	145.5 ± 16.2	146.7 ± 17.1	0.14
Diastolic blood pressure (mmHg)	83.0 ± 8.2	82.3 ± 8.4	0.10
Hypertension	1,653 (87.9)	458 (92.3)	0.005
Glucose (mg/dl)	171.5 ± 53.5	178.3 ± 60.0	0.014
A1C (%)	7.0 ± 1.7	7.3 ± 1.9	0.0003
Total cholesterol (mg/dl)	213.1 ± 40.0	206.3 ± 40.2	0.001
LDL cholesterol (mg/dl)	129.0 ± 34.2	122.3 ± 33.9	0.0002
HDL cholesterol (mg/dl)	54.7 ± 14.8	55.0 ± 16.6	0.70
Triglycerides (mg/dl)	129.6 (92–177)	127.7 (87–175)	0.57
ApoA1 (mg/dl)	154.9 ± 38.8	150.7 ± 39.1	0.03
ApoB (mg/dl)	102.8 ± 26.3	100.0 ± 28.3	0.04
ApoB/apoA1	0.72 ± 0.33	0.72 ± 0.34	0.99
Creatinine (mg/dl)	0.83 (0.69–0.97)	0.93 (0.73–1.11)	<0.001
Fibrinogen (g/l)	372.1 ± 68.5	406.9 ± 110.4	<0.0001
Uric acid (mg/dl)	5.52 ± 1.73	6.04 ± 2.51	<0.0001
AER (μg/min)	12.1 (4.2–25.5)	21.3 (6.4–49.3)	<0.0001
20–200	377 (24.3)	113 (35.3)
>200	73 (4.7)	28 (8.8)
CVD	353 (18.7)	157 (31.6)	0.0001
Smoking
Former smoker	534 (29.3)	166 (34.9)	0.03
Smoker	291 (16.0)	60 (12.6)
Glucose-lowering treatment
Diet	303 (71.0)	62 (12.7)	<0.0001
Oral drugs	1,402 (75.4)	337 (68.9)
Insulin	155 (8.3)	90 (18.4)
Statins	379 (20.1)	98 (19.8)	0.98

Data are means ± SD, n (%), or geometric means (95% CI).

TABLE 3

HRs (95% CI) of 5-year mortality in people with type 2 diabetes of the Casale Monferrato Study

	All-cause mortality			Cardiovascular mortality
	Model 1	Model 2	Model 3	Model 1	Model 2	Model 3
CRP tertiles (mg/dl)
<1.6	1.00	1.00	1.00	1.00	1.00	1.00
1.6–4.4	1.27 (1.00–1.62)	1.27 (0.98–1.64)	1.35 (0.98–1.87)	1.18 (0.82–1.68)	1.07 (0.73–1.56)	1.22 (0.74–2.00)
>4.4	1.99 (1.58–2.49)	1.81 (1.41–2.32)	1.65 (1.20–2.28)	1.94 (1.39–2.71)	1.62 (1.13–2.33)	1.76 (1.09–2.82)
P for trend	<0.0001	<0.0001	<0.0001	<0.0001	0.006	0.015
CRP (mg/l)
≤3 mg/l	1.00	1.00	1.00	1.00	1.00	1.00
>3 mg/l	1.64 (1.37–1.96)	1.49 (1.22–1.82)	1.51 (1.18–1.92)	1.53 (1.17–1.99)	1.32 (0.99–1.77)	1.44 (0.99–2.08)
AER
<20 μg/min			1.00			1.00
≥20 μg/min			1.47 (1.15–1.87)			1.47 (1.01–2.14)
Hypertension			1.02 (0.64–1.63)			0.69 (0.36–1.34)
LDL cholesterol (1 SD)			0.89 (0.79–1.01)			1.07 (0.89–1.28)
HDL cholesterol (1 SD)			0.99 (0.88–1.13)			0.92 (0.76–1.12)
A1C (1 SD)			1.10 (0.97–1.26)			1.19 (0.97–1.44)
CVD			1.70 (1.31–2.22)			2.56 (1.74–3.76)
Antidiabetes treatment
Diet			1.00			1.00
Oral drugs			1.09 (0.76–1.57)			1.24 (0.68–2.24)
Insulin			1.81 (1.12–2.94)			2.29 (1.08–4.84)
Smoking
Never			1.00			1.00
Former smoker			1.34 (0.96–1.86)			1.24 (0.74–2.06)
Current smoker			1.42 (0.94–2.15)			0.74 (0.33–1.65)
Central obesity			0.87 (0.67–1.12)			0.92 (0.62–1.37)
Statins			1.02 (0.75–1.37)			1.31 (0.86–1.99)

Model 1: adjusted for age, sex, diabetes duration. Model 2: model 1 adjustments plus hypertension, LDL and HDL cholesterol, A1C, smoking status, CVD, diabetes treatment, waist circumference, and statins. Model 3: model 2 adjustments plus AER.

TABLE 4

HRs (95% CI) of 5-year mortality in people with type 2 diabetes of the Casale Monferrato Study

	All-cause mortality		Cardiovascular mortality
	Number of deaths	HR (95% CI) for CRP >3.0 mg/l	Number of deaths	HR (95% CI) for CRP >3.0 mg/l
Men	262	1.41 (1.02–1.96)	105	1.61 (0.94–2.74)
Women	234	1.66 (1.14–2.41)	118	1.51 (0.88–2.57)
Subjects without CVD at baseline
All cohort	339	1.67 (1.24–2.24)	133	1.36 (0.83–2.24)
Men	171	1.55 (1.03–2.32)	57	1.11 (0.52–2.37)
Women	168	1.71 (1.09–2.69)	76	1.62 (0.82–3.22)
A1C (%)
≤6.7	216	1.54 (1.08–2.19)	89	1.20 (0.67–2.14)
>6.7	268	1.51 (1.07–2.11)	128	1.56 (0.94–2.57)
Diabetes duration (years)
≤8.7	202	1.60 (1.11–2.32)	76	1.29 (0.70–2.40)
>8.7	291	1.48 (1.06–2.06)	144	1.54 (0.94–2.51)
LDL cholesterol (mg/dl)
≤126	265	1.38 (1.00–1.90)	95	1.41 (0.80–2.50)
>128	199	1.72 (1.18–2.50)	110	1.49 (0.91–2.46)
HDL cholesterol (mg/dl)
≤51	237	1.55 (1.09–2.21)	109	1.50 (0.88–2.54)
>51	242	1.52 (1.08–2.14)	106	1.45 (0.84–2.49)
Central obesity
No	241	1.40 (0.98–1.99)	102	1.46 (0.83–2.58)
Yes	255	1.71 (1.20–2.43)	121	1.48 (0.88–2.50)

HRs adjusted for age, sex, diabetes duration, LDL and HDL cholesterol, A1C, smoking status, CVD, AER, diabetes treatment, waist circumference, and statins, apart from the stratification variable.

TABLE 5

HR (95% CI) of 5-year mortality in people with type 2 diabetes of the Casale Monferrato Study

	All-cause mortality		Cardiovascular mortality
	HR (95% CI)		HR (95% CI)
	AER <20 μg/min	AER ≥20 μg/min	AER <20 μg/min	AER ≥20 μg/min
CRP ≤3 mg/l	1.00	1.48 (1.03–2.13)	1.00	1.74 (1.00–3.04)
CRP >3 mg/l	1.52 (1.11–2.09)	2.22 (1.60–3.09)	1.64 (1.00–2.69)	2.13 (1.26–3.61)

HRs adjusted for age, sex, diabetes duration, LDL and HDL cholesterol, A1C, smoking status, CVD, diabetes treatment, waist circumference, and statins.

TABLE 6

Measures of discrimination and calibration in the Casale Monferrato Study, by selected variables

	All-causes mortality	Cardiovascular mortality
Discrimination
C statistic
Nonmodifiable risk factors (age, sex, and diabetes duration) (model 1)	0.706	0.717
Established risk factors (model 2)	0.744	0.793
Established risk factors plus AER	0.750	0.799
Established risk factors plus AER and CRP	0.756	0.802
LR test
Established risk factors (model 2)	LR = 66, df = 11, P < 0.0001	LR = 61.85, df = 11, P < 0.0001
Established risk factors plus AER	LR = 10.76, df = 1, P = 0.001	LR = 4.69, df = 1, P = 0.03
Established risk factors plus AER and CRP	LR = 9.94, df = 1, P = 0.002	LR = 3.03, df = 1, P = 0.08
Bayes information criterion
Nonmodifiable risk factors (age, sex, and diabetes duration) (model 1)	4,021.24	1,693.40
Established risk factors	4,036.78	1,713.18
Established risk factors plus AER	4,033.45	1,715.90
Established risk factors plus AER and CRP	4,030.93	1,720.29
Calibration
Grønnesby and Borgan test
Nonmodifiable risk factors (age, sex, and diabetes duration) (model 1)	P = 0.28	P = 0.10
Established risk factors	P = 0.44	P = 0.21
Established risk factors plus AER	P = 0.42	P = 0.27
Established risk factors plus AER and CRP	P = 0.10	P = 0.28