Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 20, No. 3, pp. 355e367, 2006

doi:10.1016/j.beem.2006.07.002
available online at http://www.sciencedirect.com

Insulin resistance in hypertension

and cardiovascular disease

Valéria Lamounier-Zepter* MD

Monika Ehrhart-Bornstein PhD

Department of Endocrinology, Diabetes and Metabolism, University Medical Center,
University of Dresden, 01307 Dresden, Germany

Stefan R. Bornstein MD, PhD

Department of Internal Medicine III, University Medical Center, University of Dresden,
01307 Dresden, Germany

Insulin resistance is not simply a problem of decreased glucose uptake in response to insulin, but
a multifaceted syndrome that significantly increases the risk for cardiovascular disease. Insulin
resistance is strongly associated with arterial hypertension and a pathogenetic role in the devel-
opment of arterial hypertension has been suggested. One question that remains open concerns
the clinical approach to insulin-resistant patients. Observational and clinical trial data suggest
that lifestyle changes including weight reduction and regular physical activity can improve insulin
sensitivity and reduce the incidence and mortality of cardiovascular disease. Daily physical activ-
ity of moderate intensity for 30 min has a cardioprotective effect and reduces insulin resistance,
independent of the effect on body weight. A pharmacological therapy for insulin resistance
reducing cardiovascular disease remains to be defined. Concerning the antihypertensive therapy
of insulin-resistant hypertensive patients, most hypertensive guidelines fail to provide specific
advice.

Key words: insulin resistance; obesity; hypertension; cardiovascular disease.

INTRODUCTION

Insulin resistance refers to a decrease in the biological and physiological response to

insulin, resulting in an oversecretion of insulin to compensate for this impairment in

* Corresponding author. Tel.: þ49 351 458 6605; Fax: þ49 351 458 6336.
E-mail address: valeria.zepter@uniklinikum-dresden.de (V. Lamounier-Zepter).
1521-690X/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
356 V. Lamounier-Zepter et al

the glucose transport in skeletal muscle and fat cells.1 Insulin resistance is a common
state, associated with genetic predisposition, ageing, sedentary lifestyle and, mainly,
obesity. Indeed, insulin resistance seems to directly result from obesity.2 Basal and
total 24-hours rates of insulin secretion are 3e4 times higher in obese subjects.3 Insulin
resistance increases with weight gain and decreases with weight loss, suggesting
a causal role for obesity in the development of insulin resistance.4 Indeed, increased
formation of fatty acids in obesity may interfere with the mobilisation of the glucose
transport enzyme 4, thus decreasing insulin sensitivity.5 Others possible molecules
suggested to be involved in the development of insulin resistance in obesity are
tumour necrosis factor-a (TNF-a), adiponectin, resistin and leptin.2
Insulin resistance resulting in hyperinsulinaemia and hyperglycaemia is an indepen-
dent predictor of cardiovascular disease.6e8 Insulin resistance is strongly related to
visceral obesity, hypertension, atherogenic dyslipidaemia, microalbuminuria, pro-
thrombotic and proinflammatory states. The clustering of these risk factors has
been named ‘metabolic syndrome’ or ‘Syndrome X’. In the early 1990s, Ferrannini
suggested that the underlying cause of this syndrome was insulin resistance and pro-
posed the term ‘insulin resistance syndrome.’9 Today it seems to be clear that insulin
resistance is not, itself, the only cause of the metabolic syndrome, but fat accumu-
lation, especially in the visceral compartment plays a central role. Nevertheless insu-
lin resistance, even in the absence of diabetes, is an important component of this
syndrome having a causative role for the development of cardiovascular disease
and it should therefore be taken into consideration in the development of strategies
towards the metabolic syndrome.

INSULIN RESISTANCE AND HYPERTENSION

Epidemiological evidence supports a link between insulin resistance and hypertension.

How can this link be explained? One possibility would be the coincidence of two com-
mon diseases. However, several lines of evidence suggest that the two conditions are
closely related. Hypertension is associated with insulin resistance independently of
others factors, even in individuals with normal as well as those with elevated blood
pressure.10,11 Fasting insulin levels correlate with systolic and diastolic blood pressure
independent of age, weight and serum glucose levels.12 Blood pressure reduction fol-
lowing weight loss is related to an improvement in insulin sensitivity.13 Thus, a further
possible explanation is a causal relationship between both abnormalities, or a common
underlying factor.
A causal role for hypertension in the development of insulin resistance has been
discussed. Supporting this hypothesis, Mondon & Reaven showed an impairment in
insulin-mediated glucose metabolism in spontaneously hypertensive rats in comparison
with normotensive control rats.14 These data, however, could not be confirmed sub-
sequently in spontaneously hypertensive rats as well as in other experimental models
of hypertension.15,16 Clinical observations also do not support this hypothesis: lower-
ing blood pressure in hypertensive subjects is not necessarily accompanied by an im-
provement in insulin sensitivity. Thus, it appears to be unlikely that hypertension may
be a cause of insulin resistance.
But may insulin resistance cause hypertension? Insulin per se has a direct vasodila-
tory effect through the stimulation of endothelial nitric oxide synthase. In insulin-
resistant states, however, this insulin-mediated endothelial vasodilatation is greatly
diminished or abolished.10,17 Based on the observations that short-term insulin
 Insulin resistance, hypertension and cardiovascular disease 357

infusion and overfeeding may induce increased sympathetic activity, it has been postu-
lated that hyperinsulinaemia, as a consequence of insulin resistance, would mediate the
increase in arterial pressure in obesity via central activation of the sympathetic ner-
vous system.18,19 Increased basal sympathetic activity has been reported in
obesity20,21, which seems to be correlated with the degree of insulin resistance.22
As suggested by Landsberg, the central effect of insulin on sympathetic activity may
be a compensatory mechanism in obesity, recruited in order to increase the metabolic
rate and restore energy balance, thus limiting further weight gain, but leading to an
undesired consequence of hypertension.19 The hypertensive effect of increased sym-
pathetic activity is mainly mediated by the renal sympathetic efferent nerves, leading
to increased sodium reabsorption and, consequently, to hypertension.23 In accordance
with this idea, studies with obese dogs fed a high-fat diet show that renal denervation
markedly attenuated sodium retention and hypertension in those dogs.24 Increased renal
sympathetic nerve activity promotes tubular reabsorption, both by a direct action on
proximal and distal tubules and indirectly via stimulation of renin release and angiotensine
aldosterone production.
The role of hyperinsulinaemia in the pathogenesis of arterial hypertension has also
been suggested by Lind et al, who observed insulin resistance in approximately 25% of
their essentially hypertensive subjects when using the euglycaemic hyperinsulinaemic
clamp method.25 Furthermore, salt-sensitive hypertensive subjects are relatively
insulin-resistant compared to those with low salt-sensitivity.26 Interestingly, insulin
sensitisers, such as metformin27 and glitazones28 decrease blood pressure in parallel
with an improvement in glucose metabolism.
Otherwise, besides an acute effect of insulin on sympathetic activity, neither chronic
systemic insulin infusion nor infusion into the cerebral circulation has been shown to
cause increased arterial pressure.29e31 The failure to show a hypertensive effect in
chronic hyperinsulinaemia is not dependent on an insulin-resistant state, since chronic
infusion of insulin has no haemodynamic effect even in obese insulin-resistant dogs.32
Chronic hyperinsulinaemia in subjects with insulinoma does not appear to be associated
with increased blood pressure.33 Furthermore, in dogs with high-fat diet-induced hyper-
tension the improvement in insulin resistance of high-dose aspirin has no lowering effect
on blood pressure.34 All these data together suggest that hyperinsulinaemia does not
appear to be the major cause of obesity-related hypertension, but other additional fac-
tors seem to be involved, such as leptin, which increases sympathetic activity, the adi-
pose rennin-angiotensin system (RAS) and direct and indirect adrenal stimulation by
mineralocorticoid-stimulating factors and oxidised fatty acids, respectively.35
Does a common pathogenetic factor exist for insulin resistance and hypertension?
Some authors have suggested that the link between hypertension and insulin sensitivity
may be mediated by the RAS. Adipose tissue expresses a complete RAS, which seems
to be regulated by nutritional factors.36 A paracrine role for adipose angiotensin II in
adipose tissue metabolism is well established, influencing both adipogenesis and lipol-
ysis.37 Interestingly, in rat models of insulin resistance, RAS blockade with either
angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor
(AT1-R) blockers reduce insulin levels, triglycerides, free fatty acids and blood pres-
sure.38 Moreover, both in vitro as well in vivo experiments have shown that angioten-
sin II enhances insulin sensitivity.39 Thus, it has been suggested that angiotensin II has
a crucial role in the regulation of insulin sensitivity in adipose tissue. Regarding the
effect on blood pressure, some authors have suggested a functional importance for
the adipose RAS in obesity-related hypertension. A systemic role for adipose RAS
in blood pressure regulation is mainly supported by an experimental study with
358 V. Lamounier-Zepter et al

transgenic mice, showing that adipocyte-derived angiotensinogen (AGT) can be

released into the circulation.40 Furthermore, they found increased systolic blood pres-
sure in mice that overexpress adipose AGT, associated with increased plasma AGT
levels. Thus, angiotensin II may be the common pathogenic factor of insulin resistance
and hypertension.

INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

Several lines of evidence suggest that hyperinsulinemia is associated with increased risk of
cardiovascular disease. The San Antonio Heart Study, for example, correlated high insu-
lin resistance to a 2.5-fold increase in cardiovascular risk.41 Despres et al followed more
than 2000 men for 12 years. They observed that higher levels of insulin were associated
with increased risk of cardiovascular disease, even after controlling for blood pressure,
medication use, family history, age, body mass index (BMI), plasma lipid levels, tobacco
and alcohol use.6 An association between plasma insulin levels and coronary heart dis-
ease endpoints was also observed in the Helsinki Policemen Study, which included nearly
1000 men followed for a period of 9½ years.8 Similar associations were observed by
Ducimetiere et al following more than 7000 non-diabetic middle-aged men.7
In the insulin-resistant state, vascular endothelial dysfunction may play a key role in
the development of atherogenesis and, consequently, increase the risk for cardiovas-
cular events.42 Insulin, in addition to its metabolic functions, has important vascular
actions that involve the stimulation of endothelial nitric oxide (NO) production.
NO release mediates vasodilation and increases blood flow.43 In addition, insulin reg-
ulates the secretion of the vasoconstrictor endothelin-1 (ET-1). Insulin resistance may,
therefore, cause imbalance between endothelial vasodilators and vasoconstrictors,
leading to endothelial dysfunction and hypertension, as has been shown in spontane-
ously hypertensive rats (SHR), which are hypertensive and insulin-resistant.44
Three major mechanisms are thought to be involved in the development of endo-
thelial dysfunction as a consequence of insulin resistance: glucotoxicity, lipotoxicity and
inflammation. These three mechanisms interact in their pathological influence on en-
dothelial function. A central, initiating role in the development of these dysfunctions is
attributed to the increased production of the mitochondrial superoxide, reactive
oxygen species (ROS).45

Glucotoxicity

Hyperglycaemia causes insulin resistance and endothelial dysfunction by inducing oxi-

dative stress due to the increased production of the mitochondrial superoxide, ROS;
by the formation of glycation endproducts, which damage cells by intracellular and ex-
tracellular mechanisms46; by increased hexosamine pathway activity, resulting in the
UDP-N-acetylglucosamine which, by insertion into transcription factors, will result
in pathological changes in gene expression; and by protein kinase C-activation via
intracellular diacylglycerol, with diverse intracellular and extracellular consequences
(for a review, see Kim et al).47

Lipotoxicity

Elevated levels of free fatty acids (FFAs) are another major factor contributing to
insulin resistance and endothelial dysfunction. The association between insulin
 Insulin resistance, hypertension and cardiovascular disease 359

resistance and dyslipidaemia is initiated by increased FFA release from, or defective

uptake of FFAs into, adipocytes. Insulin resistance at the level of the adipocyte is
seen as the initiating disturbance, leading to an increased intracellular hydrolysis of
triglycerides and release of FFA.48 Like glucotoxicity, increased levels of FFA induce
oxidative stress via increased FFA flux into, and increased oxidation and ROS produc-
tion, in endothelial cells.45

Inflammation

Glucotoxicity, as well as lipotoxicity, induces proinflammatory signalling in endothelial

cells by the activation of nuclear factor kappa-B (NF-kB)49,50 and, consequently, the
increase of proinflammatory cytokines such as TNF-a and interleukin-6 (IL-6). These
proinflammatory cytokines may contribute to insulin resistance by modulating insulin
signalling and transcription.47 In addition, NF-kB inhibits insulin-stimulated activation
of endothelial nitric oxide synthase51,52 thus inhibiting the production of the endothe-
lial vasodilator NO.

CLINICAL IMPLICATIONS

Diagnosis of insulin resistance

The currently accepted gold-standard for the assessment of insulin resistance is the
hyperinsulinaemiceeuglycaemic clamp technique. In this technique the individual re-
sponse to insulin is analysed by carrying out a simultaneous infusion of fixed doses of
insulin and variable glucose infusions to maintain constant glucose levels
(5.0e5.6 mmol/l). A well-accepted alternative for the assessment of insulin resistance
is an intravenous glucose tolerance test.53 However, both methods are expensive,
complex to perform and are not applicable for routine clinical practice. They should
be reserved for research studies. Mathematical models have been developed for es-
timating insulin resistance by using fasting insulin and glucose levels. The most well
accepted model is the homeostasis model assessment of insulin resistance (HOMA-
IR) proposed by Matthews et al54 Recently, a new model has been proposed, the
quantitative insulin-sensitivity check index (QUICKI)55, which is derived from the
logarithmic transformation of fasting insulin and glucose (Table 1). Both are well cor-
related with in vivo measures of insulin sensitivity (hyperinsulinaemic-euglycaemic
clamp), are widely available and have predictive value in the development of type
2 diabetes. Neither model is routinely used in clinical practice, since there is still
no evidence-based data supporting a clinical approach for an individual patient based
on these models for insulin resistance assessment. The authors of the National Cho-
lesterol Education Program’s Adult Treatment Panel III report suggested a fasting

Table 1. Mathematical models for insulin resistance assessment.

HOMA-IR Fasting insulin (mM/ml)

(homeostasis model assessment of insulin resistance) fasting glucose (mmol/l)/22.5
QUICKI 1/[log fasting insulin þ log fasting
(quantitative insulin-sensitivity check index) glucose (mg/dl)]
360 V. Lamounier-Zepter et al

blood glucose level of 110 mg/dl or more as evidence of insulin resistance.56 Others
suggest that a combination of increased triglyceride and fasting insulin levels was
more effective in identifying insulin resistance.57 Recently, Stern & colleagues have
suggested diagnostic criteria for insulin resistance based on routine clinical measure-
ments. By using euglycaemic clamp data from more than 2300 individuals, they sug-
gested that insulin resistance may be diagnosed if BMI > 28.9 kg/m2. If they added
HOMA-IR to the diagnostic criteria, insulin resistance can be diagnosed if
BMI > 27.5 kg/m2 and HOMA-IR > 3.60. Addition of other clinical characteristics, in-
cluding a family history of diabetes and elevated triglyceride levels increases the sensi-
tivity and specificity of insulin resistance predictions.58

Practice points

HOMA-IR and QUICKI are well established models for the assessment of
insulin resistance using routine clinical measurements. The validity of their
routine use in clinical practice remains to be proved.
Body mass index (BMI) is a strong predictor of insulin resistance. Data support
the diagnosis of insulin resistance if BMI > 28.9 kg/m2, or if BMI > 27.5 kg/m2
and HOMA-IR > 3.60.
Reduced high density lipoprotein (HDL) cholesterol, increased triglyceride,
arterial hypertension and family history of diabetes further support the diag-
nosis of insulin resistance.

TREATMENT OF INSULIN RESISTANCE

Do we need to target and treat insulin-resistant subjects? Insulin resistance seems to

be an independent risk factor for cardiovascular disease. Hu et al have shown that the
risk of developing cardiovascular disease in prediabetic subjects is increased even be-
fore the clinical diagnosis of diabetes.59 Interestingly, it has been shown that proinflam-
matory proteins predictive for cardiovascular disease are predominantly elevated in
prediabetic subjects with insulin resistance but not in those with a primary defect in
beta-cell function.60 Similarly, atherogenic changes in the prediabetic state are mainly
seen in insulin-resistant subjects, rather than in those with insulin secretion impair-
ment61, providing additional evidence that the increased cardiovascular risk in predia-
betic subjects seems to be related to a high insulin-resistant state.60 Therefore,
targeting patients with insulin resistance seems to be valuable for interventions aimed
at preventing cardiovascular disease.
The most effective approach to improve insulin resistance and to reduce cardio-
vascular risk is appropriate changes in lifestyle (Table 2). Moderate levels of excessive
weight loss (5e10%) with a daily caloric intake reduction with a balanced diet and
increased physical activity improve glucose tolerance and have proven effective in de-
creasing the risk for cardiovascular events. Weight loss improves blood pressure con-
trol, plasma lipid levels and insulin resistance and reduces levels of inflammatory
markers.62,63 Furthermore, weight loss associated with regular physical activity may
prevent the development of diabetes mellitus: the Diabetes Prevention Program
 Insulin resistance, hypertension and cardiovascular disease 361

Table 2. Recommended lifestyle changes to reduce insulin resistance and cardiovascular risk.
Diet Low intake of saturated fat and simple sugars,
increased intake of vegetables, fruits and whole grains
Physical activity, 30 min daily, Reduces cardiovascular risk, blood pressure, improves
moderate-intensity (3.5e7 kcal/min) insulin resistance and plasma lipids
Weight reduction Reduces cardiovascular risk, blood pressure,
(5e10% of body weight) lipids, improves insulin resistance
Ideal BMI 18.5e24.9 kg/m2
Waist circumference <88 cm in female, <102 cm in male
Waist-to-hip ratio <0.85 in female, <0.90 in male
Total body fat <22% in females, <16% in males
Increase lean muscle mass
Smoking Cessation
Alcohol restriction <20 g per day
Caffeine restriction <100 mg/day

showed a 58% reduction in the incidence of diabetes in insulin-resistant individuals

submitted to a lifestyle modification programme, including weight loss of 7% or
more and 150 min of moderate-intensity exercise per week.64 Daily physical activity
is not only important in assisting weight loss but also improves insulin sensitivity, gly-
caemic and dyslipidaemia control, hypertension, inflammation and endothelial dysfunc-
tion.65 The metabolic effect of regular physical activity on insulin sensitivity is
observed among both diabetic and non-diabetic subjects.66 All these beneficial effects
of regular exercise result in the reduction of cardiovascular risk, which is independent
of the effect on body weight.65 Diverse clinical studies have shown an effective reduc-
tion in cardiovascular disease incidence and mortality with regular physical activity.
Cardiovascular mortality correlates inversely with the distance of walking.67 Most in-
vestigations have examined the effect of physical activity, rather than physical fitness.
However, cardiorespiratory fitness is also inversely correlated with cardiovascular
mortality.68 Physical activity must not be as vigorous as previously thought. The
World Health Organization recommends a daily moderate-intensity activity (brisk
walking) of 30 min in its guideline for the prevention of cardiovascular disease and
other chronic diseases; a recommendation endorsed by the American Diabetes
Association in a joint statement with the American Heart Association and American
Cancer Society.69
The recommendations regarding the treatment of patients with a concomitant
manifestation of hypertension and diabetes mellitus are already generally accepted;
however, those for patients with increased insulin resistance, but who are not yet
diabetic, remain to be established. Both the guidelines from the American Diabetes
Association and the JNC 7 (Seventh report of the Joint National Committee on Pre-
vention, Detection, Evaluation, and Treatment of High Blood Pressure) agree that it is
important to control blood pressure levels to 130/80 mmHg or lower in the diabetic
patient.70 The treatment goals for insulin-resistant hypertensive subjects are still
not established, although it may be argued that similar goals (130/80 mmHg) should
be recommended for them.
Regarding antihypertensive therapy, diverse clinical trials have shown advantages in
inhibiting the renineangiotensin system in patients with hypertension and type 2 di-
abetes mellitus. Again, no clear recommendations exist for patients with insulin resis-
tance without manifestation of diabetes. Some studies have shown that therapy with
362 V. Lamounier-Zepter et al

ACE inhibitor and AT1-R blockers has been associated with a reduction in new-onset
type 2 diabetes mellitus among hypertensive patients, compared with beta-blockers
and thiazide diuretics.71e75 Since patients with insulin resistance have an increased
risk for developing diabetes mellitus, an initial antihypertensive therapy with ACE inhib-
itor or AT1-R blockers should be preferred, unless there are contraindications or
concomitant diseases with compelling indications for other drugs.
Long-term antihypertensive treatment with beta-blockers and thiazide diuretics can
impair glycaemic control, in comparison to AT1-R and calcium-channels blockers
(CCBs). Beta-blockers and thiazide diuretics further worsen insulin resistance and dys-
lipidaemia.76,77 Furthermore, beta-blockers can cause weight gain, which potentially
would aggravate insulin resistance.78 The adverse metabolic effect of diuretics and
beta-blockers has been proven in different clinical trials. In the ALLHAT study, the
absolute risk of developing diabetes was 11.6%, 9.8% and 8.1% for chlorthalidone,
amlodipine and lisinopril, respectively.73 In the Alpine study, antihypertensive treat-
ment with a diuretic, combined with beta-blockers if necessary, was correlated with
a worsened metabolic outcome in comparison to patients treated with a combination
of AT1-R blockers and CCB.75 Regarding the effect of antihypertensives on cardiovas-
cular mortality the results of the ALLHAT trial showed no difference in the frequency
of fatal and non-fatal coronary artery disease among the groups treated with chlortha-
lidone, amlodipine and lisinopril. Thus, even with more adverse metabolic effects the
treatment with chlorthalidone was not associated with increased cardiovascular mor-
tality, which led the authors to recommend the use of thiazide diuretics as a first-step
therapy for most hypertensive patients.73 However, the increased risk of developing
diabetes mellitus in the diuretic group raises the question of a potentially increased
incidence of diabetes in the long-term and, consequently, cardiovascular disease, espe-
cially in high-risk insulin-resistant subjects. Thus, the use of beta-blockers and thiazide
diuretics as a first-step antihypertensive therapy in obese patients with insulin resistance
should be questioned, unless there are compelling clinical indications for their use.
For several patients a combination of more than one antihypertensive treatment
may be necessary. However, evidence-based data comparing different combinations
of antihypertensive therapies for insulin-resistant patients are still insufficient,
especially regarding the reduction in cardiovascular mortality. A CCB seems to be
an attractive combination therapy with an ACE inhibitor or AT1-R blockers. Amlodipin
has positive effects on insulin resistance and endothelial function that are additive
to the beneficial therapeutic effects of ACE inhibitor, suggesting that an ACE
inhibitoreCCB combination therapy may be a good option for the treatment of insu-
lin-resistant patients.79,80 A thiazide diuretic is also a reasonable secondary antihyper-
tensive therapy after optimal inhibition of the RAS, since hypertensive patients with
insulin resistance are frequently obese and, in these patients, sodium and volume
retention play an important role in the development of hypertension.35 The adverse
effects of thiazide diuretics on glucose, lipid and electrolyte metabolism can be mini-
mised by using low-dose therapy.81
In addition to antihypertensive therapy, growing evidence exists on the positive
effect of pharmacological interventions in improving insulin sensitivity and preventing
new-onset diabetes mellitus. The thiazolidinediones (TZDs) are antidiabetic agents
that improve glycaemic control by improving insulin sensitivity in target tissues in-
cluding skeletal muscles, adipose tissue and liver.82 Furthermore, TZDs promote de-
creases in blood pressure, improve lipid control and exert direct anti-atherogenic
effects on the vasculature, by decreasing medial thickness and inhibiting endothelial
migration of monocytes. The use of TZDs in the treatment of type 2 diabetes is
 Insulin resistance, hypertension and cardiovascular disease 363

well established. A place for TZDs in the prevention of diabetes in high-risk popu-
lations has also been discussed. In a recent clinical trial, a preventative effect of
TZDs on the development of type 2 diabetes in a high-risk population was ob-
served.83 In the Troglitazone in Prevention of Diabetes (TRIPOD) study, troglitazone
was associated with a 56% reduction in progression to diabetes in women with
previous gestational diabetes. The protective effect persisted long after the medica-
tion was stopped, suggesting a true protective action for troglitazone.84 For patients
at high risk of developing diabetes, the preventive use of other antidiabetic drugs
has also been suggested. In the STOP-NIDDM trial, a 25% relative risk reduction
in the progression to diabetes was observed in patients with impaired glucose tol-
erance treated with acarbose.85 In the Diabetes Prevention Program metformin
therapy reduced the risk of type 2 diabetes by 31% in patients with increased insulin re-
sistance, but was less effective than lifestyle changes in delaying the onset of diabetes
(58% risk reduction with diet and exercise).64 However, data showing that pharmaco-
logical therapy of insulin resistance is capable of reducing the risk of cardiovascular
morbidity and mortality is still insufficient. Therefore, the routine use of pharmacolog-
ical agents in the therapy of insulin resistance is still not indicated.

Practice points

 Lifestyle modifications including daily sport activity and weight loss are essen-
tial for the treatment of patients with insulin resistance.
 Some pharmacological agents such as acarbose, thiazolidinediones (TZDs) and
metformin may improve insulin sensitivity and reduce the risk of new-onset
diabetes. However, the routine use of these agents in insulin-resistant patients
is not indicated, at least until there are studies showing the cost-effectiveness
of this therapy, especially with regard to the reduction in cardiovascular disease.
 Initial antihypertensive therapy for hypertensive patients with insulin resistance
should be with angiotensin converting enzyme (ACE) inhibitors or angiotensin
II type 1 receptor (AT1-R) blockers, unless there are contraindications or com-
pelling indications for other drugs.
 Appropriate combination antihypertensive therapy should be ACE inhibitor or
AT1-R blockers with calcium-channels blocker (CCB) or low-dose thiazide
diuretic.

Research agenda

 The pathophysiological mechanism linking insulin resistance, arterial hyperten-

sion and cardiovascular disease is still unclear.
 There is still no consensus about diagnostic criteria and the clinical approach to
patients with insulin resistance for the routine practical clinic.
 Clinical trials for hypertensive therapy for patients with insulin resistance, but
who are still not diabetic, are needed.
 The place of pharmacological interventions in insulin resistance with regard to
the cost-effectiveness of the therapy and cardiovascular disease and mortality
reduction, remain to be defined.
364 V. Lamounier-Zepter et al

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