Pre-Diabetes, Insulin Resistance, Inflammation and CVD Risk

7/28/2019 Pre-Diabetes, Insulin Resistance, Inflammation and CVD Risk

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Pre-diabetes, insulin resistance, inflammation and CVD risk

Steven M. Haffner *

Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, DTL, Room

5.606U, Mail code 7873, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA

Abstract

There is accumulating evidence that insulin resistance in the pre-diabetic state is associated with the presence of

additional cardiovascular risk factors and increased incidence of cardiovascular disease (CVD). There is also

accumulating evidence indicating that chronic sub-clinical inflammation as measured by such inflammatory markers as

C-reactive protein (CRP) is associated with insulin resistance and other features of the insulin resistance syndrome,

increased risk of development of type 2 diabetes and increased cardiovascular event risk. Insulin-sensitizing agents may

have greater effects in reducing cardiovascular risk than secretagogues in the pre-diabetic state, and glitazones have

been found to decrease CRP levels in patients with diabetes. Statins also reduce CRP levels. Efforts to reduce CVD

should include increased emphasis on improving glycaemic control, preventing development of diabetes and addressing

cardiovascular risk factors in the pre-diabetic state.

# 2003 Elsevier Ireland Ltd. All rights reserved.

Keywords: Insulin resistance; C-reactive protein; Pre-diabetes; Diabetes; Statins

1. Introduction

Patients with type 2 diabetes are at increased

risk of coronary heart disease (CHD) and in-

creased risk of mortality from CHD [1,2]. Further,

patients with diabetes are at increased risk of pre-

hospitalization mortality from CHD [3]. Such datahave motivated recommendations for more ag-

gressive lipid-lowering therapy in patients with

diabetes [4] and indicate that more intensive

primary and secondary prevention measures

should be part of routine medical care for these

patients.

Additional data indicate that a large proportion

of patients with myocardial infarction (MI) with-

out previously recognized diabetes have impaired

glucose tolerance (IGT) or frank diabetes at the

time of MI. In a study of 181 consecutive patients

with MI, no diagnosis of diabetes and a blood

glucose concentration ofB/11.1 mmol/l, 35% hadIGT and 31% were diagnosed with new diabetes at

hospital discharge; at 3 months after discharge,

40% had IGT and 25% had a diagnosis of diabetes

[5]. Such findings suggest an even stronger rela-

tionship between diabetes and its risk factors and

cardiovascular disease (CVD) than is commonly

acknowledged and re-emphasize the importance of

earlier identification of diabetes as a way of

reducing CHD risk for the individual patient as

well as overall prevalence of CHD. Such findings* Tel.: '/1-210-567-4729; fax: '/1-210-567-6955.

E-mail address: [email protected] (S.M. Haffner).

Diabetes Research and Clinical Practice 61 (2003) S9 /S18

www.elsevier.com/locate/diabres

0168-8227/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/S0168-8227(03)00122-0
mailto:[email protected]:[email protected]


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have also prompted considerable interest in iden-

tifying elements of the pre-diabetic state that

would appear to modulate the atherosclerotic

process such that increased risk of cardiovascularevents becomes strikingly evident in the popula-

tion with frank diabetes.

2. Insulin resistance

In an early analysis of data from participants in

the population-based San Antonio Heart Study

[6], significant differences were found in baseline

values for cardiovascular risk factors (e.g. lipidlevels, blood pressure, glucose and insulin levels

and obesity measures) in individuals without

diabetes in whom type 2 diabetes developed over

8 years of follow-up, compared with those in

whom diabetes did not develop, with these find-

ings indicating a more atherogenic pattern of risk

factors among pre-diabetic subjects. Analysis re-

stricted to subjects with normal glucose tolerance

at baseline showed that significant differences

persisted for levels of triglycerides and high-

density lipoprotein (HDL)/cholesterol, systolicblood pressure and fasting glucose and insulin

levels (Table 1). It was noteworthy that while the

subjects in whom diabetes developed had much

higher fasting insulin levels at baseline, they also

had significantly elevated fasting blood glucose

levels, suggesting a role of decreased insulin

secretion in the pre-diabetic state.

In a subsequent study in the San Antonio Heart

Study population [7], the relative contributions of

insulin resistance and decreased insulin secretion

to the development of diabetes were assessed, as

well as the association of these defects with other

atherogenic risk factors. Over 7 years of follow-up,

195 of 1734 initially non-diabetic subjects con-

verted to type 2 diabetes. Converters had signifi-

cantly greater body mass index (BMI), waist

circumference, triglyceride concentration and

blood pressure and significantly lower HDL-cho-

lesterol levels than non-converters at baseline.

Insulin resistance was measured with the ho-

meostasis model assessment for insulin resistance

(HOMA-IR), and insulin secretion was measuredby ratio of insulin increment to glucose increment

during the first 30 min of glucose challenge (DI30-0

min/DG30-0 m in). High or low values on these

measures were those above or below median

values in the study population at baseline.

As shown in Fig. 1, risk of conversion to type 2

diabetes was highest among subjects with both

insulin resistance and low insulin secretion and

lowest among those with neither defect, with risk

among those with isolated insulin resistance being

greater than in those with isolated low insulinsecretory capacity. Among the subjects converting

to diabetes, 54% had both insulin resistance and

low insulin secretion, 28.7% had insulin resistance

and good insulin secretion, 15.9% had low insulin

secretion and insulin sensitivity, and 1.5% had

neither defect. Each of these four subgroups had

similar values for fasting glucose levels and

Table 1

Age- and sex-adjusted cardiovascular risk factors at baseline in subjects with normal glucose tolerance according to conversion to type

2 diabetes or not over 8 years of follow-up in the San Antonio Heart Study

Conversion status P value

Diabetes (n0/18) Non-converter (n0/490)

BMI (kg/m2) 28.2 27.2 0.472

Centrality ratio 1.38 1.16 0.078

Triglycerides (mmol/l) 1.83 1.28 0.006

HDL-cholesterol (mmol/l) 1.14 1.28 0.045

Systolic blood pressure (mmHg) 116.8 108.8 0.004

Fasting glucose (mmol/l) 5.28 5.00 0.032

Fasting insulin (pmol/l) 157 81 0.006

From [6].

S.M. Haffner / Diabetes Research and Clinical Practice 61 (2003) S9/S18S10


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levels at 30, 60, and 120 min after glucose

challenge.

Assessment for differences in other CHD risk

factors by stratification for insulin resistance/good

insulin secretion versus insulin sensitivity/low in-

sulin secretion among subjects converting todiabetes showed that baseline triglyceride levels

were significantly higher and HDL-cholesterol

levels significantly lower in those with insulin

resistance, compared with those with insulin

sensitivity and subjects not converting to diabetes.

No significant differences were observed between

converters with insulin sensitivity and non-

converters (Fig. 2). Similarly, systolic blood

pressure was significantly higher in the

insulin-resistant/good insulin secretion group

compared with the insulin-sensitive convertergroup and the non-converters, with no

difference being observed between the latter

two groups. These differences remained after

adjustment for BMI. These data thus

indicate that while there are increased CHD risk

factors in the pre-diabetic state, there is also

heterogeneity among individuals with this condi-

tion, with the presence of insulin resistance

appearing to be associated with a more athero-

genic risk profile.

The increase in cardiovascular risk factors in the

pre-diabetic state is accompanied by increased

frequency of CVD. A recently reported 20-year

follow-up of women in the Nurses Health Study

cohort [8] showed that when type 2 diabetes

developed during follow-up, a dramatically in-creased risk of non-fatal MI or stroke prior to

diagnosis of diabetes was present (by definition,

fatal events could not occur prior to diabetes

diagnosis). In total, 1508 women had type 2

diabetes at baseline, 110 227 remained free of

diabetes during follow-up, and diabetes developed

in 5894 patients during follow-up. On multi-

variate analysis (including age, time period, BMI,

cigarette smoking, menopausal and hormone re-

placement therapy status and parental history of

premature MI), relative risk of non-fatal MI orstroke was 2.82 among eventual converters prior

to the diagnosis of diabetes (Fig. 3). Although risk

was higher after conversion to diabetes and among

subjects with diabetes at baseline, these data

indicate a substantially elevated risk of CVD in

the pre-diabetic state. Analysis of risk for non-

fatal MI or stroke among subjects converting to

diabetes according to time from baseline to

diagnosis of diabetes showed relative risks, com-

pared with subjects remaining free of diabetes, of

Fig. 1. Percentages of subjects converting to type 2 diabetes over 7 years of follow-up in the San Antonio Heart Study according to low

or high (below or above median values) insulin resistance (HOMA-IR) and insulin secretion (DI30-0 min/DG30-0 min). Reproduced with

permission from [7].

S.M. Haffner / Diabetes Research and Clinical Practice 61 (2003) S9/S18 S11


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2.40 for those diagnosed at ]/15 years, 3.19 for

those diagnosed at 10/14.9 years and 3.64 for

those diagnosed within 10 years. Thus, these data

also suggest that there is a relationship between

duration of the pre-diabetic state and cardiovas-

cular risk, with risk increasing during progressionto overt diabetes.

In another study in the San Antonio Heart

Study population, 2569 subjects without diabetes

or CVD at baseline were followed for 8 years, with

197 having a cardiovascular event (MI, stroke,

heart surgery, angina or CVD death) during

follow-up [9]. In the total population, there was

a significant trend across quintiles of baseline

HOMA-IR for worsening of cardiovascular risk

factor variables, including levels of HDL-choles-

terol, low-density lipoprotein (LDL)/cholesterol,

total cholesterol, triglycerides and systolic and

diastolic blood pressure (Table 2). As shown in

Fig. 4, there was a significant association between

baseline HOMA-IR quintile and risk of cardio-

vascular events on analysis adjusted for age, sexand ethnicity. This association was attenuated

somewhat but remained significant when analysis

was also adjusted for levels of LDL-cholesterol,

triglycerides, HDL-cholesterol and systolic blood

pressure; smoking; alcohol consumption; and

leisure time exercise.

Such findings elucidate the elevated risk of CVD

in the pre-diabetic state and emphasize the need to

prevent diabetes and to intervene to reduce risk

during this period. The findings in the San

Fig. 2. Mean triglyceride (top) and HDL-cholesterol (bottom) levels by insulin resistance/secretion category among San Antonio

Heart Study subjects converting to type 2 diabetes and non-converters. High HOMA-IR0/high insulin resistance; high DI30-0 min/DG30-

0 min0/good insulin secretion. Reproduced with permission from [7].



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Antonio Heart Study populations suggest that

insulin resistance in the pre-diabetic state is

associated with increased cardiovascular risk at

least partially independent of other established riskfactors. One implication of these findings for

management may be that although both insulin

sensitizers and insulin secretagogues may be

equally effective in preventing diabetes, insulin

sensitizers may have superior effects in preventing

CVD in the pre-diabetic state.

3. Sub-clinical inflammation

There is accumulating evidence of a relationship

between levels of C-reactive protein (CRP) andrisk of CHD [10/12], and elevated levels of CRP

and other systemic markers of inflammation found

in patients with type 2 diabetes [13]. Many of the

analyses of insulin resistance and other CHD risk

factors in the pre-diabetic state have not included

or been adjusted for CRP or other inflammatory

Fig. 3. Risk of non-fatal MI or stroke prior to diagnosis of type 2 diabetes or after diagnosis in subjects converting to diabetes during

follow-up, subjects remaining without diabetes during follow-up and subjects with diabetes at baseline in the Nurses Health Study.

Reproduced with permission from [8].

Table 2

Values for cardiovascular risk factors according to HOMA-IR quintile at baseline in subjects in the San Antonio Heart Study without

diabetes or CVD (adjusted for age, sex, ethnicity)

HOMA-IR quintilea

1 2 3 4 5

HDL-cholesterol (mg/dl) 51.7 49.3 47.8 45.0 41.2

LDL-cholesterol (mg/dl) 115.7 119.3 125.0 128.1 124.8

Total cholesterol (mg/dl) 188.0 191.6 197.9 200.8 199.0

Triglycerides (mg/dl) 105.7 116.6 129.7 145.4 187.2

Systolic blood pressure (mmHg) 114.9 116.5 118.3 119.3 123.0

Diastolic blood pressure (mmHg) 69.0 70.4 71.9 73.1 75.4

P (trend) for all B/0.0001. From [9].a Quintile cut points: 1.0, 1.6, 2.5, 4.8.



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markers. However, recently reported data, includ-

ing those from the Insulin Resistance Athero-sclerosis Study, indicate that chronic sub-clinical

inflammation is a component of the pre-diabetic

state and is associated with insulin resistance.

In a study of 1008 subjects from the Insulin

Resistance Atherosclerosis Study who did not

have diabetes or clinical coronary artery disease

(one third with IGT) [14], investigators studied the

relationships between the inflammatory markers

CRP, white blood cell count and fibrinogen and

the variables commonly considered to be part of

the insulin resistance syndrome. All three inflam-matory markers were found to be significantly

correlated with measures of obesity, systolic blood

pressure, HDL-cholesterol, fasting glucose, fasting

insulin and insulin sensitivity (measured by fre-

quently sampled intravenous glucose tolerance

tests) (Table 3). The correlations of CRP with

measures of obesity, fasting insulin and insulin

sensitivity were particularly strong (correlation

coefficients /0.3). Insulin sensitivity, systolic

blood pressure and BMI were independently

related to CRP levels in a multi-variate linear

regression analysis. As shown in Fig. 5, there was alinear increase in mean log CRP values according

to the number of metabolic disorders present in

Fig. 4. Association of baseline quintiles of insulin resistance (HOMA-IR) with risk for cardiovascular events over 8 years of follow-up

in the San Antonio Heart Study. A, analysis adjusted for age, sex and ethnicity; B, analysis adjusted for age, sex, ethnicity, LDL-

cholesterol, triglycerides, HDL-cholesterol, systolic blood pressure, fasting glucose, smoking, alcohol consumption and waist

circumference; CI, confidence interval. Reproduced with permission from [9].

Table 3

Partial Spearman correlation analysis of inflammatory markers

with insulin resistance syndrome variables (adjusted for age,

sex, clinic, ethnicity and smoking) in Insulin Resistance

Atherosclerosis Study subjects without diabetes and cardiovas-

cular disease (only variables with significant correlation with all

three markers are shown)

Correlation coefficients

CRP White blood

cell count

Fibrinogen

BMI 0.40* 0.17* 0.22*

Waist circumference 0.43* 0.18* 0.27*

Systolic blood pressure 0.20* 0.08% 0.11$

HDL-cholesterol (/0.11$ (/0.12$ (/0.15*

Fasting glucose 0.18* 0.13* 0.07%

Fasting insulin 0.33* 0.24* 0.18*

Insulin sensitivity (/0.37* (/0.24* (/0.18*

*PB/0.0001, $PB/0.005, %PB/0.05. From [14].



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each patient, with metabolic disorders consisting

of dyslipidaemia (elevated triglyceride and/or lowHDL-cholesterol levels), upper body adiposity,

insulin resistance and hypertension.

In a prospective study in the Insulin Resistance

Atherosclerosis Study population [15], the rela-

tionship of baseline levels of CRP, fibrinogen and

plasminogen activator inhbitor-1 (PAI-1) to new

diabetes was assessed in 1047 subjects without

diabetes at baseline who were followed for 5 years.

Levels of all three inflammatory markers in the

144 subjects diagnosed with diabetes during fol-

low-up were significantly greater than those innon-converters. As shown in Fig. 6, there was a

significant linear increase in incidence of new

diabetes with increasing quartiles of both CRP

and PAI-1. In this study, PAI-1 was actually a

stronger predictor of diabetes, since it remained a

significant predictor after adjustment for insulin

sensitivity, whereas the relationship for CRP was

attenuated; however, practical considerations in

measuring PAI-1 make it unlikely that it will be

used as a marker for predicting diabetes.

Insulin-sensitizing agents may decrease sub-

clinical inflammation. There is evidence thatperoxisome proliferator activated receptor-g

(PPAR-g) agonists may affect inflammatory path-

ways through transcriptional mechanisms. In a

recently reported study [16], the effects of the

PPAR-g agonist rosiglitazone on levels of CRP

and matrix metalloproteinase-9 (MMP-9) were

examined. MMP-9 is implicated in the pathogen-

esis of plaque rupture in patients with type 2

diabetes. As shown in Fig. 7, 26 weeks of treat-

ment with rosiglitazone resulted in significant

decreases in levels of CRP (although there wasno apparent dose response) and MMP-9. The

change in CRP levels from baseline to week 26

were positively correlated with changes in HOMA-

IR and MMP-9 and inversely correlated with

changes in HDL-cholesterol levels.

Statin therapy is widely used in patients with

diabetes, because of the aggressive LDL-

cholesterol/lowering goals in these patients in

accordance with elevated risk of CHD. There is

evidence that statins as a class also lower levels of

Fig. 5. Mean log CRP values according to number of metabolic disorders present in non-diabetic subjects in the Insulin Resistance

Atherosclerosis Study. Metabolic disorders are dyslipidaemia (triglycerides /200 mg/dl and/or HDL 5/35 mg/dl in men, 5/45 mg/dl

in women), upper body adiposity (]/75th percentile for waist circumference for men and women), insulin resistance (B/25th percentile

on insulin sensitivity testing) and hypertension (systolic pressure ]/140 mmHg and/or diastolic pressure ]/90 mmHg or use of anti-

hypertensive medication). All comparisons among subgroups were significant at P0/0.0001, except for 2 vs. 4 (PB/0.005) and 3 vs. 4,

which was not significant. Reproduced with permission from [14].



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CRP. For example, a recent crossover study [17] of

patients with combined hyperlipidaemia (elevated

LDL-cholesterol and triglyceride levels) showed

that CRP levels were significantly reduced by 6

weeks of treatment with pravastatin 40 mg (20.3%

reduction), simvastatin 20 mg (22.8% reduction)

and atorvastatin 10 mg (28.3% reduction), with no

significant differences among the statins in this

regard. These decreases are similar in magnitude to

those that have been observed with glitazone

treatment. Overall, 72.7/81.8% of patients had

reductions in CRP levels with the individual

statins, and 54.6% responded to all three. The

effects in reducing CRP levels were independent of

effects in reducing levels of LDL-cholesterol. It

bears noting that in the study of rosiglitazone in

patients with type 2 diabetes, approximately one

quarter of patients were receiving statin therapy,and decreases in CRP levels in these patients were

similar in magnitude to those in patients not

receiving statins [unpublished observation]; this

finding suggests the possibility that decreases in

CRP with glitazones and statins are complement-

ary.

Overall, the findings for CRP and other inflam-

matory markers suggest that chronic sub-clinical

inflammation is associated with insulin resistance,

increased risk for diabetes and increased CHD

risk. Insulin-sensitizing treatment with glitazones

may reduce such inflammation, and there is

evidence to indicate that statin therapy also

reduces such inflammation independent of LDL-

cholesterol/lowering effects.

4. Conclusion

Insulin resistance is a pronounced defect in the

pre-diabetic state and is associated with the pres-

ence of atherosclerosis risk factors and increased

risk of CVD. Chronic sub-clinical inflammation as

measured by inflammatory markers is associated

with increased CHD risk and appears to be

associated with insulin resistance and other fea-

tures of the insulin resistance syndrome in the pre-

diabetic state. These findings highlight the impor-tance of intervention in the pre-diabetic state both

to reduce the excess CVD already present and to

prevent progression to diabetes and the even

greater CHD risk associated with diabetes.

Although diabetes develops in only about one

third of those with IGT in normal-risk popula-

tions, the high levels of cardiovascular risk in

people with pre-diabetes suggest that risk reduc-

tion and diabetes prevention in these patients may

do more to reduce the CHD epidemic than

Fig. 6. Incidence of type 2 diabetes over a 5-year follow-up by baseline quartile of fibrinogen, CRP and PAI-1 in initially non-diabetic

subjects in the Insulin Resistance Atherosclerosis Study. Reproduced with permission from [15].



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aggressive treatment of CHD risk factors once

diabetes has been diagnosed. Thus, a multi-factor-

ial approach to the prevention of CHD in the

context of metabolic abnormalities should include

increased efforts to improve glycaemic control and

aggressive treatment of cardiovascular risk factors.There is some evidence that insulin-sensitizing

agents may be preferable for use in reducing

cardiovascular risk associated with insulin resis-

tance in patients with pre-diabetes, and there is

some evidence to indicate that use of insulin

sensitizers and statins may also be useful by

reducing sub-clinical inflammation. Optimal use

should be made of currently available therapies,

and efforts should be directed to the development

of innovative agents and strategies that can

demonstrably reduce the risk of CVD and diabetes

in the pre-diabetic state.

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Pre-Diabetes, Insulin Resistance, Inflammation and CVD Risk