Chapter 13

Hypertension and Dyslipidemia in

Patients with Pre-Diabetes: Dietary and
Other Therapies
V. Tsimihodimos, MD, PhD and M. Florentin, MD
Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece

Chapter Outline
Introduction 157 Effects of Antihypertensive Drugs Other Than Those
Dyslipidemia in Pre-Diabetes: Mechanisms and Clinical Acting on RAAS on Glucose Metabolism 166
Characteristics 158 Thiazide Diuretics 166
Clinical Significance of Dyslipidemia in Pre-Diabetes 159 β-Blockers 166
Targets of Lipid-Lowering Interventions in Pre-Diabetic Calcium Channel Blockers 167
Subjects 160 Other Antihypertensive Drugs 167
Therapeutic Options 161 Development of New-Onset T2DM with Different
Lifestyle Modification 161 Antihypertensive Drug Classes 167
Antidiabetic Agents 162 Diuretics and/or β-Blockers Versus Placebo 167
Lipid-Lowering Agents 162 Thiazide Diuretics Versus β-Blockers 167
Statins 162 RAAS Inhibitors Versus Placebo 167
Fibrates 163 CCBs Versus Diuretics and/or β-Blockers 168
Drugs Inhibiting Intestinal Cholesterol Absorption 163 CCB/HCTZ Versus HCTZ 168
Omega-3 Fatty Acids 164 RAAS Inhibitors Versus Diuretics and/or β-Blockers 168
The Role of RAAS in BP and Glucose Metabolism 164 Studies Assessing DM Incidence with RAAS Inhibitors,
Angiotensin II 164 CCBs, Diuretics, and/or β-Blockers or Other Drugs
Oxidative Stress 164 (in Various Combinations) 169
Insulin Signaling 165 New-Onset T2DM and Cardiovascular Outcomes 170
Inflammation 165 Antihypertensive Treatment in Patients with Pre-Diabetes 171
Fibrinolytic Balance 165 Lifestyle Modification 171
Aldosterone 165 Pharmacotherapy 171
Hypokalemia 166 ARBs with Peroxisome Proliferator-Activated Receptor-γ
Effects of Aldosterone in Adipose Tissue and Skeletal Properties 172
Muscle 166 Conclusions 173
Effects of Insulin on Aldosterone Production 166 References 173

INTRODUCTION complications that adversely affect the quality of life and

Type 2 diabetes mellitus (T2DM) is a public health prob-
lem of epidemic proportions in both developed and devel-
oping countries [1,2]. The clinical significance of this
metabolic disorder is mainly attributed to its detrimental
effects on vascular physiology and anatomy. Indeed,
T2DM is characterized by micro- and macrovascular
Glucose Intake and Utilization in Pre-Diabetes and Diabetes.
© 2015 Elsevier Inc. All rights reserved.
life expectancy of patients. Impaired glucose metabolism
is the main culprit of the microvascular features of
T2DM. However, the progression to cardiovascular dis-
ease (CVD) is influenced by the presence of additional
risk factors, such as smoking, hypertension, and dyslipide-
mia [1,2]. In support of this concept are the results of
157
158 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
interventional studies showing that the modification of
these “classic” risk factors results in a substantial reduc-
tion of cardiovascular morbidity and mortality in diabetic
patients [3].
Dyslipidemia is a primary component of T2DM, most
frequently characterized by increased concentrations of
triglyceride-rich lipoproteins and reduced levels of the ather-
oprotective high-density lipoprotein-cholesterol (HDL-C).
Low-density lipoprotein-cholesterol (LDL-C) levels are usu-
ally not elevated, but the LDL particle distribution is shifted
toward the more atherogenic small, dense LDL particles
[4,5]. The contribution of lipid abnormalities in the develop-
ment of CVD in diabetic individuals is supported by several
studies showing that the administration of lipid-lowering
therapy in this population results in significant reduction in
cardiovascular morbidity and mortality [6 9]. Thus, dysli-
pidemia in patients with T2DM should be aggressively trea-
ted with a high-intensity statin [10].
The activation of the renin angiotensin aldosterone
system (RAAS) not only plays a key role in the pathogen-
esis of hypertension but also impairs insulin sensitivity
and glucose metabolism. Indeed, hypertensive patients are
at high risk of developing T2DM [11]. Both angiotensin
II (Ang II) and aldosterone seem to be implicated in the
development of insulin resistance. Therefore, the choice
of treatment for hypertension may need to differ in
patients with T2DM or altered glucose metabolism.
Regimens that improve insulin sensitivity must represent
the first line of antihypertensive therapy in these patient
groups, whereas drugs with neutral effects on glucose
homeostasis should be added if first-line treatment fails to
achieve the blood pressure (BP) goals. The term pre-
diabetes is used to describe an intermediate stage between
normal glucose metabolism and overt T2DM. As such, it
consists of two potentially overlapping groups of indivi-
duals: those with impaired fasting glucose (IFG, defined
as serum fasting glucose concentrations between 100 and
126 mg/dL) and those with impaired glucose tolerance
(IGT, defined as a 2-h post-challenge serum glucose
between 140 and 200 mg/dL). It should be noted that IFG
and IGT represent two heterogeneous conditions with dif-
ferent underlying pathophysiological mechanisms. In fact,
subjects with IGT present mainly with muscle insulin
resistance, while those with IFG have severe hepatic insu-
lin resistance and mild muscle insulin resistance. Both
IFG and IGT are characterized by a reduction in early-
phase insulin secretion, while IGT is distinguished by
impairment in late-phase insulin secretion [12 15]. In the
last few years it has been proposed that glycated hemo-
globin (HbA1c) levels between 5.7% and 6.4% may also
be sufficient for the diagnosis of pre-diabetes [16,17].
Several lines of evidence suggest that pre-diabetic
individuals carry a high risk for CVD [18]. Whether
IGT represents a stronger predictor of macrovascular
complications than IFG remains a subject of debate. In
this context, it has been proposed that the therapeutic
approach to pre-diabetes should be identical to that used in
patients with established T2DM and aim at the restoration
of normoglycemia as well as aggressive modification of
the co-existing cardiovascular risk factors. In the following
sections, we discuss the pathophysiology and clinical char-
acteristics of dyslipidemia and hypertension encountered
in the pre-diabetic state. The potential contribution of lipid
abnormalities and BP elevation in the determination of the
future cardiovascular risk of pre-diabetic subjects, as well
as the currently available therapeutic options for these
patients, will be discussed in detail.
DYSLIPIDEMIA IN PRE-DIABETES:
MECHANISMS AND CLINICAL
CHARACTERISTICS
The dyslipidemia of pre-diabetes mirrors the effects of
insulin resistance on the mechanisms that regulate lipid
metabolism [19]. However, the characteristics of this
abnormality are not uniform in all individuals with pre-
diabetes. Thus, it has been proposed that patients with
IGT exhibit a more severe form of dyslipidemia charac-
terized by hypertriglyceridemia, low HDL-C concentra-
tions, an abundance of large very low-density lipoprotein
(VLDL) particles, and a predominance of small, dense
LDL and HDL particles [20 22]. On the other hand,
patients with IFG have different, and possibly milder,
alterations in lipid metabolism, mainly expressed as
increased concentrations of apolipoprotein B, high VLDL,
LDL and intermediate density lipoprotein (IDL) particle
numbers as well as decreased HDL particle size [20].
Finally, patients with both IFG and IGT exhibit a combi-
nation of the abnormalities described for patients with iso-
lated IGT and IFG, which is identical to the atherogenic
dyslipidemia of individuals with overt T2DM [20].
Whether these differences contribute, at least in part, to
the differences observed in the cardiovascular risk of
patients with IFG and IGT remains to be established.
The diversity in the characteristics of dyslipidemia in
patients with IFG and IGT seems to depend largely on the
site of insulin resistance. As described above, patients
with IFG are characterized predominantly by hepatic insu-
lin resistance, whereas the peripheral tissues usually retain
their sensitivity to insulin. The increased concentrations
of the apolipoprotein B-containing lipoproteins in this
case reflect the inability of insulin to suppress the assem-
bly and secretion of VLDL by liver cells [19].
On the other hand, in patients with IGT, the increased
activity of peripheral tissue triglyceride lipase results in
an increased delivery of free fatty acids to liver cells.
This results in an overproduction of triglyceride-enriched
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 159
large VLDL particles, which is clinically expressed as
hypertriglyceridemia. Another mechanism that may con-
tribute to the accumulation of VLDLs in individuals with
IGT is their defective catabolism by lipoprotein lipase, an
endothelial-bound enzyme that hydrolyzes the triglyceride
content of triglyceride-rich lipoproteins. Indeed, it has
been shown that insulin resistance is characterized by
decreased activity of adipose tissue lipoprotein lipase,
whereas its effect on the skeletal muscle enzyme remains
controversial [19]. The diminished activity of lipoprotein
lipase, along with its saturation by the increased number
of VLDL particles, may explain, at least in part, the
defective catabolism of chylomicrons and the postprandial
lipemia that has been observed in individuals with pre-
diabetes [23]. The expansion of the pool of triglyceride-
rich lipoproteins along with the increased activity of the
cholesteryl ester transfer protein (CETP) in IGT patients
results in increased exchange of triglycerides for choles-
teryl esters among HDL, LDL, and triglyceride-rich lipo-
proteins. The triglyceride content of the triglyceride-
enriched LDL and HDL particles is subsequently hydro-
lyzed by hepatic lipase, thus resulting in the production of
small, dense LDL and HDL particles [24,25]. These dense
LDL particles are considered more atherogenic than the
large, buoyant ones, whereas the predominance of small,
dense HDL particles is associated with impaired reverse
cholesterol transport. In addition, HDL metabolism in
patients with IGT is also adversely affected by the
decreased production and accelerated renal catabolism of
apolipoprotein AI, which represents the main apolipopro-
tein constituent of HDLs [26].
It must be noted that the abnormalities in lipid metab-
olism in patients with pre-diabetes show a linear relation-
ship with glucose and insulin concentrations in most of
the studies and persist even after the adjustment of poten-
tial confounders such as body mass index (BMI) and mea-
surements of adiposity.
CLINICAL SIGNIFICANCE OF
DYSLIPIDEMIA IN PRE-DIABETES
Epidemiological studies have revealed increased cardio-
vascular morbidity and mortality long before the diagnosis
of overt T2DM. A meta-analysis that included 96,000
non-diabetic subjects found that compared with a glucose
level of 75 mg/dL, fasting and 2-h glucose levels of 110
and 140 mg/dL, respectively, were associated with a rela-
tive cardiovascular event risk of 1.33 (95% CI 1.06 1.67)
and 1.58 (95% CI 1.19 2.10), respectively [27]. However,
although the significance of IGT as an important determi-
nant of cardiovascular risk is more than clear, the role of
IFG remains indeterminate. Thus, it has been proposed
that IFG may represent a more benign condition in terms
of cardiovascular complications, at least until the transition
to overt T2DM [28 30].
Data from both observational and interventional stud-
ies have shown that dyslipidemia may play an important
role in the pathogenesis of atherosclerosis in diabetic sub-
jects [2]. Although pre-diabetes shares many pathophysio-
logical and clinical similarities with overt T2DM,
currently it is less clear whether the disturbances in lipid
metabolism participate actively in the acceleration of ath-
erogenesis in pre-diabetic patients. In 1997, Yanagi et al.
[31] reported that the coexistence of IGT with heterozy-
gous familial hypercholesterolemia (FH) increases the
prevalence of coronary heart disease (CHD) by almost
50% (from 43% to 59%) compared with patients with FH
and normal glucose tolerance. This finding underlines the
deleterious effects of the combination of disturbed carbo-
hydrate and lipid metabolism on human vasculature. In
line with this observation, Alexander et al. [32], in the
Third National Health and Nutrition Examination Survey
(1988 1994), found that IFG carries an increased risk for
CVD (rate ratio 1.47 compared with normal glucose toler-
ance) that was mainly attributed to classic cardiovascular
risk factors such as dyslipidemia (especially low HDL-C
values) and hypertension. Similarly, St. Pierre et al. [33]
in a cross-sectional study found that pre-diabetes is char-
acterized by increased cardiovascular risk only in the
presence of “hypertriglyceridemic waist” i.e., waist cir-
cumference $ 90 cm and serum triglyceride concentra-
tion $ 177 mg/dL, while according to Drexel et al. [34]
the low HDL-C/high triglyceride ratio and not the high
LDL-C phenotype more accurately predicts the incidence
of vascular events in patients with pre-diabetes. On the
contrary, the Nateglinide and Valsartan in the Impaired
Glucose Tolerance Outcomes Research (NAVIGATOR)
trial revealed that LDL-C levels represent an important
predictor of both CHD and stroke in patients with IGT
[35,36]. (This study will be presented in detail in one of
the next sections.) On the other hand, the role of the qual-
itative lipid abnormalities observed in pre-diabetic sub-
jects remains ill defined. Thus, although in the multi-
ethnic study of atherosclerosis Tsai et al. [37] failed to
find an association between small, dense LDL-C and
small, dense LDL particle number with cardiovascular
outcomes in patients with IFG, Gerber et al. [38] revealed
a significant relationship between sdLDL and carotid
intima media thickness in a population with identical
characteristics. Finally, according to Qiao et al. [39], dis-
turbed carbohydrate metabolism is the most significant
determinant of cardiovascular risk in pre-diabetic indivi-
duals, whereas conventional risk factors (including lipids)
account for only 23% of the increment in cardiovascular
risk associated with IGT.
The contribution of dyslipidemia in the determina-
tion of future cardiovascular risk in individuals with
160 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
pre-diabetes is also supported by interventional studies
showing that dyslipidemia treatment results in a huge
decline in the incidence of vascular events in this
patient population. In the Scandinavian Simvastatin
Survival Study (4S), simvastatin administration in
patients with IFG significantly reduced total and cardio-
vascular mortality by 43% and 55%, respectively [40].
Similarly, in a subgroup analysis in the cholesterol and
recurrent events (CARE) trial, pravastatin reduced the
recurrence rate of cardiovascular events by 50% in
patients with IFG and a history of CVD [41].
It has been proposed that in addition to its detrimental
effects on vascular physiology and anatomy, dyslipidemia
in pre-diabetic subjects may impair insulin action and
predispose to the development of overt T2DM [42].
Furthermore, the increased concentrations of triglycerides
and non-esterified fatty acids observed in situations of
disturbed carbohydrate homeostasis may participate in the
development of disabling peripheral neuropathy [43].
The above-mentioned data suggest that the correction
of lipid abnormalities should represent a therapeutic prior-
ity in individuals with pre-diabetes.
TARGETS OF LIPID-LOWERING
INTERVENTIONS IN PRE-DIABETIC
SUBJECTS
It has been proposed that the lipid abnormalities in pre-
diabetic individuals should be treated in a manner identical
to that used in patients with established T2DM [44].
Although this suggestion is not based on prospective data,
the similarities in the cardiovascular risk of patients with
pre-diabetes (especially IGT) and overt diabetes makes
this approach reasonable. On the other hand, despite the
abundance of data from prospective trials and post hoc
analyses of large-scale interventional studies, the treatment
of diabetic dyslipidemia remains puzzling. What is gener-
ally accepted is that LDLs represent the most atherogenic
lipoprotein particles and that the reduction in the concen-
tration of LDL-C is the primary target of lipid-lowering
intervention in both diabetic and normoglycemic subjects.
However, the value of the utilization of specific LDL-C
targets in diabetic and pre-diabetic subjects with and with-
out CVD remains a subject of debate. In their 2011 recom-
mendation, the European Society of Cardiology (ESC) and
the European Atherosclerosis Society (EAS) suggest that
in all patients with T2DM the LDL-C concentration should
be lowered to less than 70 mg/dL, independent of the pres-
ence of established CVD [45]. If this target cannot be
reached, a reduction of LDL-C greater than 50% is consid-
ered a reasonable alternative goal [45]. On the other hand,
the American Diabetes Association (ADA) suggests the
target of 70 mg/dL only for type 2 diabetics with a history
of CVD [46]. In patients without CVD the target was set
at 100 mg/dL and statin therapy is proposed only for those
who are over the age of 40 years and have one or more
other CVD risk factors (family history of CVD, hyperten-
sion, smoking, dyslipidemia, or albuminuria) [46]. In con-
trast to the above-mentioned strategies, the American
Heart Association (AHA) and the American College of
Cardiology (ACC) in their 2013 guidelines noted that there
is no evidence to support titrating cholesterol-lowering
drug therapy to achieve specific LDL-C targets [10].
According to this recommendation all type 2 diabetics
with established CVD or an estimated 10-year CVD risk
greater than 7.5% (calculated with the Pooled Cohort
Equations developed specifically for this guideline) and
LDL-C 70 189 mg/dL should receive high-intensity
statin therapy aiming at an LDL-C reduction greater than
50% [10].
Moderate-intensity statin therapy (reducing LDL-C
by 30 50%) should be initiated in adults 40 75 years
of age with T2DM and CVD risk lower than 7.5%.
Finally, in adults with T2DM who are younger than 40 or
older than 75 years of age, it is reasonable to evaluate
the potential for CVD benefits, adverse effects, and
drug drug interactions, and to consider patient prefer-
ences when deciding to initiate, continue, or intensify
statin therapy [10].
Greater controversy exists on the utility of secondary
lipid targets in patients who have already achieved their
pre-specified LDL-C goal. Non-HDL-C represents the
sum of all apolipoprotein B-containing lipoprotein parti-
cles and in addition to LDL-C takes into account the
concentrations of VLDLs, lipoprotein remnants, and lipo-
protein (a) [Lp(a)]. Since the levels of these particles are
elevated in insulin-resistant states it has been proposed
that non-HDL-C may provide a more precise estimator of
future cardiovascular risk than LDL-C. Thus, in European
guidelines non-HDL-C is now recognized as a secondary
target in diabetic and pre-diabetic patients. The specific
target for non-HDL-C should be 30 mg/dL higher than
the corresponding LDL-C target; this corresponds to the
LDL-C level augmented by the cholesterol fraction con-
tained in 150 mg/dL of triglycerides, which is the upper
limit of what is recommended [45].
A significant proportion of diabetic and pre-diabetic
subjects have LDL-C levels within normal limits and their
dyslipidemia is mainly characterized by hypertriglyceride-
mia and low HDL-C values. Although the ADA proposed
triglyceride values ,150 mg/dL and HDL-C values .40
or 50 mg/dL for men and women, respectively, as second-
ary targets of lipid-modifying therapy [46], the evidence
that supports this approach is less robust than that for
LDL-C reduction. Several clinical trials have shown that
the concentrations of triglyceride and HDL-C are impor-
tant determinants of future cardiovascular risk in patients
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 161
with atherogenic dyslipidemia. However, whether the cor-
rection of these abnormalities translates into a consider-
able reduction in vascular events is far from clear. In this
context, the Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Trial (VA-HIT), a secondary pre-
vention study, demonstrated that CVD events were signif-
icantly reduced by treating patients with gemfibrozil
when the predominant lipid abnormality was low HDL-C
[47]. In this trial, for every 5 mg/dL increase in HDL-C
concentration a modest reduction (11%) in ischemic
events was observed [47]. On the other hand, the adminis-
tration of fenofibrate (a drug that decreases triglyceride
levels and increases HDL-C concentrations) in diabetic
subjects, either as monotherapy or in combination with
simvastatin, failed to decrease total and cardiovascular
mortality [48,49]. However, it must be noted that sub-
group analyses in these studies suggested that in patients
with high triglyceride and low HDL-C concentrations at
baseline, fenofibrate significantly reduced the incidence
of cardiovascular events [48,49]. This subgroup of dia-
betic patients was mostly benefited by the administration
of gemfibrozil in the Helsinki Heart Study (HHS) [50].
Similarly, in the secondary prevention Bezafibrate
Infarction Prevention (BIP) trial, bezafibrate was more
effective in reducing cardiovascular morbidity and mortal-
ity in the subpopulations of participants with high triglyc-
eride values ( . 200 mg/dL) and/or augmented features of
metabolic syndrome [51]. These findings support the con-
cept that dyslipidemia treatment in pre-diabetic indivi-
duals must include the correction of all abnormalities in
lipid metabolism whenever possible. Although the reduc-
tion of LDL-C remains the primary target of lipid-
lowering therapy, the decrease in triglyceride values and
the increase in HDL-C concentration may provide addi-
tional cardiovascular benefit in this patient population.
On the other hand, the AHA/ACC guideline concluded
that there is no sufficient evidence supporting the use of
lipid targets other than LDL-C and proposed that the con-
cept of goals should be abandoned [10]. In addition, their
suggestion against the use of lipid-lowering drugs other
than statins makes the correction of triglyceride and
HDL-C abnormalities in diabetic and pre-diabetic subjects
very difficult, if not impossible [10].
THERAPEUTIC OPTIONS
Lifestyle Modification
During the previous decade, two studies showed that the
progression from IGT to overt T2DM can be halted or
even be reversed. Indeed, the results of the Diabetes
Prevention Program (DPP) and the Finnish Diabetes
Prevention Study (DPS) revealed that intensive lifestyle
modification (including changes in dietary habits, weight
loss, and an increase in aerobic physical activity) can
reduce the incidence of diabetes mellitus in high-
risk individuals with IGT by about 60% [52,53]. These
findings were in line with a previous Asian study
showing that diet, exercise, or their combination can pre-
vent diabetes evolution in individuals with IGT [54].
Interestingly, the intensive lifestyle modification group in
the DPP exhibited a significant improvement in serum
lipid values. More specifically, triglycerides were reduced
by almost 25 mg/dL, HDL-C concentration was increased
by 1 mg/dL, and the proportion of patients with the type
B LDL subfraction phenotype (which is characterized
by a preponderance of small, dense LDL subfractions)
decreased significantly [55]. At the end of the study, the
proportion of patients receiving hypolipidemic treatment
for LDL-C and/or triglyceride reduction was 12% in
the intensive lifestyle modification group and 16% in the
placebo group [55]. A recently published analysis of the
DPP data revealed a decrease in the concentration and
diameter of VLDL particles as well as reduction in the
number of small, dense LDL and HDL particles in the
intensive lifestyle modification group [56]. These changes
were mainly attributed to the concomitant changes in the
insulin sensitivity, BMI values, and adiponectin concen-
trations in this patient group [56]. On the other hand, in
the Finnish DPS only triglyceride levels were reduced
significantly (by 18 mg/dL) with lifestyle modification,
whereas the increase in HDL-C values did not reach sta-
tistical significance [53]. Although these changes may not
be sufficient to completely correct the lipid abnormalities
in pre-diabetic subjects, they can decrease the number or
the doses of lipid-lowering agents needed, whereas the
changes in dietary habits and the increase in physical
activity may provide additional cardiovascular benefits in
this patient group.
Orlistat is an intestinal lipase inhibitor currently used
in the treatment of obesity. The XENical in the
Prevention of Diabetes in Obese Subjects (XENDOS)
study was a randomized, double-blind, placebo-controlled
trial, which evaluated the effects of lifestyle intervention
with orlistat or placebo in 3305 obese subjects [57]. In
this study, after 4 years orlistat reduced the progression to
diabetes by 40 52% in obese people with IGT. Studies
from our group have demonstrated that orlistat signifi-
cantly reduces the levels of LDL-C and triglycerides (by
almost 12%), whereas it normalizes the distribution of
HDL and LDL particles by reducing the concentrations of
their small, dense subfractions [58,59]. Thus, orlistat may
be an interesting therapeutic option for the management
of hyperlipidemia in obese, pre-diabetic patients.
More recently, a study evaluating the effects of phen-
termine/topiramate combination on the incidence of new-
onset diabetes mellitus in patients with pre-diabetes and/or
metabolic syndrome revealed that different doses of this
162 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
preparation may reduce the incidence rate of diabetes by
70 80% over 2 years [60]. These impressive decreases
were directly related to the degree of weight loss and were
accompanied by important decreases in triglycerides
(10 20%) and increases in HDL-C values (10 15%)
[60]. Thus, the phentermine/topiramate combination can
be a useful option for the treatment of dysglycemia, obe-
sity, and dyslipidemia in patients with pre-diabetes.
Antidiabetic Agents
Although lifestyle modification significantly retards or
reverses the development of T2DM within the context of
clinical trials, its efficiency in the real world remains
problematic due to poor compliance. Thus, drug adminis-
tration may represent an alternative approach, although
less effective, for the prevention of T2DM in subjects
with pre-diabetes. Three different glucose-lowering drugs
have been proven effective in reducing the incidence of
diabetes in high-risk individuals, namely metformin, acar-
bose, and pioglitazone [55,61,62]. Between them pioglita-
zone increases the levels of HDL-C by 4 6 mg/dL;
metformin modestly decreases small, dense LDL particles
and increases small and large HDL particle numbers; and
acarbose has a neutral effect on serum lipids [56,63].
However, it must be noted that although ADA recom-
mends the use of metformin in high-risk individuals with
IGT or an HbA1c of 5.7 6.4% (age ,60 years, BMI
.35 kg/m2, and in women with a history of gestational
diabetes mellitus), none of the above-mentioned drugs has
been approved by the Food and Drug Administration
(FDA) for use with pre-diabetic patients.
Lipid-Lowering Agents
Statins
Statins represent the mainstay of lipid-lowering therapy in
high-risk patients. They reduce the concentration of LDL-
C, and this reduction shows a significant correlation with
the decrease in cardiovascular morbidity and mortality.
On the other hand, most statins do not substantially affect
the concentrations of HDL-C: only the most potent mem-
bers of this class (atorvastatin and rosuvastatin) signifi-
cantly reduce serum triglycerides when given at high
doses [64]. Triglyceride reduction in this later case is usu-
ally accompanied by a shift towards larger and more
buoyant LDL particles [65,66]. In addition, the use of sta-
tins in pre-diabetic individuals may also have various
other cardioprotective, pleiotropic effects such as a reduc-
tion in the intensity of inflammation of the vascular wall.
Although no statin trial has been specifically con-
ducted in individuals with pre-diabetes, subgroup analyses
in large studies have shown that the statin-induced
decrease in the incidence of cardiovascular events in this
population is the same as or greater than that observed in
the general population. Thus, as mentioned before, in the
4S trial simvastatin administration in patients with IFG
significantly reduced the number of major coronary events
by 38% as well as total and cardiovascular mortality by
43% and 55%, respectively [40]. Similarly, pravastatin
administration in patients with pre-diabetes significantly
reduced the recurrence rate of cardiovascular events (by
50%) in the CARE trial [41] as well as the risk of any car-
diovascular event or stroke (by 37% and 42%, respec-
tively) in the primary prevention Long-Term Intervention
with Pravastatin in Ischemic Disease (LIPID) trial [67].
These results suggest that statins represent the hypolipi-
demic therapy of choice in patients with pre-diabetes.
However, data suggesting that statins may adversely affect
carbohydrate metabolism recently raised questions about
the safety of these drugs in patients predisposed to T2DM.
Thus, in the Justification for the Use of Statins in
Prevention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) study, rosuvastatin increased the incidence of
physician-diagnosed new-onset diabetes by almost 25%
compared with placebo [68]. A subsequent meta-analysis
of 13 statin trials revealed that statin therapy was associ-
ated with a modest increase of 9% (95% confidence inter-
val [CI] 2 17%) in new-onset T2DM [69], a finding that
was later confirmed by two other studies. Specifically, in
the Stroke Prevention by Aggressive Reduction in
Cholesterol Levels (SPARCL) trial, which compared ator-
vastatin 80 mg with placebo in individuals with a history
of stroke or a transient ischemic attack but no CHD, a
44% increase in the risk of T2DM was observed in the
atorvastatin group during a follow-up period of approxi-
mately 5 years [70]. Similarly, the Women’s Health
Initiative (WHI) revealed that statin use is associated with
a 71% increase in the risk of T2DM, an association that
remained significant even after adjustment for potential
confounders (multivariate adjusted hazard ratio 1.48; 95%
CI 1.38 1.59) [71]. This adverse effect on carbohydrate
metabolism was similar for all statins studied. A subse-
quent meta-analysis, including five recent statin trials, pro-
vided convincing evidence of a dose-dependent effect
[72]. Indeed, high doses of statins in these trials were
associated with a 12% greater risk for the development of
T2DM compared with moderate doses. On the other hand,
high doses of statins were significantly more efficient in
the reduction of cardiovascular events compared with
lower doses [72]. In absolute terms, treating 498 patients
with intensive-dose therapy for one year led to one addi-
tional case of T2DM, whereas treating 155 patients for 1
year prevented one from experiencing a cardiovascular
event, a finding clearly indicating that the observed car-
diovascular benefit outweighs the risk for the development
of diabetes. However, a recently published analysis of
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 163
three statin trials revealed that the risk for statin-induced
new-onset diabetes is significantly affected by the
patient’s baseline fasting glucose level and the presence of
features of metabolic syndrome (such as obesity, hyperten-
sion, and triglycerides) [70]. These data indicate that pre-
diabetic individuals may be more prone to the develop-
ment of T2DM after statin administration and that in this
population the ratio of harm to benefit (i.e., the ratio of
the number of new cases of T2DM to the number of car-
diovascular events prevented by statin administration)
may be greater than that in the general population.
So far it is unclear whether the observed relationship
between statins and T2DM implies causality. Several
mechanisms have been proposed to explain the adverse
effects of statins’ carbohydrate homeostasis. Thus, it has
been proposed that statins may induce hepatic insulin
resistance, interfere with insulin signaling, or impair the
production of insulin by the β-cells [73]. More studies are
needed to define the safety of this class of hypolipidemic
drugs in individuals at risk of developing T2DM. In addi-
tion, important questions on the reversibility of the
adverse effects on glucose homeostasis after drug discon-
tinuation and on the potential exacerbation of these
effects by the coadministration of potentially diabetogenic
drugs such as diuretics and beta blockers remain to be
answered [74].
Fibrates
Fibrates represent a class of lipid-lowering drugs that
exert their effects through the modification of the expres-
sion of various genes involved in lipoprotein metabolism.
In general, these drugs significantly reduce serum trigly-
cerides, increase HDL-C, and induce a shift in LDL and
HDL subfractions towards larger particles. On the other
hand, their effect on LDL-C is usually negligible. Thus,
these drugs represent a pathophysiologically appropriate
approach for the management of dyslipidemia in diabetic
and pre-diabetic subjects which is usually characterized
by hypertriglyceridemia, low HDL-C values, and a pre-
ponderance of small LDL and HDL subspecies [75]. This
opinion is strengthened by the results of recent trials
showing that fibrates may also decrease the incidence of
microvascular complications in diabetic subjects [76,77].
However, the evidence that supports the beneficial effects
of fibrates in cardiovascular morbidity and mortality in
individuals with disturbed carbohydrate metabolism is
less convincing compared with that for statins.
The VA-HIT compared gemfibrozil with placebo in
2531 men with CHD, an HDL-C level of # 40 mg/dL,
and an LDL-C level of # 140 mg/dL. The primary study
outcome was nonfatal myocardial infarction or death from
coronary causes. After a median follow-up period of 5.1
years, gemfibrozil reduced the incidence of the composite
primary endpoint by 24% [78]. Subsequent analysis
revealed that the reduction in cardiovascular events with
gemfibrozil was greater in subjects with insulin resistance
than without (28% vs. 20%), despite the finding that the
gemfibrozil-induced increase in HDL-C and the decrease
in triglycerides was smaller in those with insulin resistance
than in those without [47]. According to these results,
gemfibrozil is an interesting therapeutic option for pre-
diabetic subjects with dyslipidemia that is characterized by
high triglycerides and low HDL-C concentration. A poten-
tial disadvantage of this drug is the high rate of muscular
toxicity when combined with statins.
Fenofibrate is the most commonly prescribed fibrate
and, compared to gemfibrozil, has an excellent safety pro-
file. The Diabetes Atherosclerosis Intervention Study
(DAIS) was designed to assess the effects of correcting
lipoprotein abnormalities with fenofibrate on coronary ath-
erosclerosis in T2DM. In this trial, fenofibrate significantly
reduced the angiographic progression of coronary artery
disease, thus suggesting that the drug could reduce the
incidence of cardiovascular events in individuals with dis-
turbed carbohydrate metabolism [79]. Surprisingly, in the
Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) and the Action to Control Cardiovascular Risk in
Diabetes (ACCORD) trials, fenofibrate failed to decrease
cardiovascular mortality in patients with diabetes either
when used as monotherapy or in combination with simva-
statin, although it significantly decreased the rates of
microvascular complications (retinopathy, nephropathy,
and microvascular lower-limb disease) [48,49]. However,
subgroup analyses in these studies revealed that fenofi-
brate significantly reduces cardiovascular risk in diabetic
individuals with dyslipidemia characterized by high trigly-
ceride low HDL-C concentrations [48,49]. Since this type
of dyslipidemia is found in the majority of patients with
T2DM and pre-diabetes, it seems reasonable to conclude
that fenofibrate is a very useful option in these patient
groups. The drug can be used either as monotherapy in
individuals with low LDL-C and abnormal concentrations
of triglycerides and HDL-C, or as an adjunct to statin ther-
apy in order to correct the residual abnormalities in trigly-
cerides and HDL-C that remain after the reduction of
LDL-C. Obviously, the presence of microvascular compli-
cations in these patients represents an additional indication
supporting the use of fenofibrate.
Drugs Inhibiting Intestinal Cholesterol
Absorption
Ezetimibe exerts its lipid-lowering effects by inhibiting
the absorption of cholesterol at the brush border of the
intestinal wall. Various clinical studies have confirmed
the efficacy of ezetimibe as an LDL-C-lowering agent
when used either as monotherapy or in combination with
164 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
other hypolipidemic compounds, such as statins or
fibrates [80 82]. In addition, small studies in individuals
with abnormal carbohydrate tolerance have shown that
ezetimibe may normalize the distribution of LDL particles
and decrease the fasting and postprandial levels of
triglyceride-rich lipoproteins [82,83]. However, since no
study with clinical cardiovascular endpoints has been con-
ducted to date in individuals with pre-diabetes, this drug
may have a role in this population only when statin mono-
therapy fails to achieve the pre-specified LDL-C targets.
Bile acid sequestrants are the oldest lipid-lowering
agents. Despite their efficiency in reducing the levels of
LDL-C as well as the incidence of CVD in patients with
hypercholesterolemia, cholestyramine, and colestipol are
used rarely because of their important gastrointestinal
side effects. Colesevelam is a newer member of this class
with a more favorable side-effect profile. An interesting
finding in many small studies is that in addition to its
LDL-C-lowering effects, colesevelam may also favorably
affect carbohydrate metabolism in both diabetic and pre-
diabetic subjects [84,85]. Although the mechanism that
underlies this phenomenon remains indeterminate, the
glucose-lowering properties of colesevelam make it ideal
for administration in pre-diabetic subjects either as mono-
therapy or in combination with statins. Whether coleseve-
lam can reduce or completely reverse the statin-induced
increase in the incidence of new-onset diabetes as well as
the cardiovascular benefit of this approach remain to be
established.
Omega-3 Fatty Acids
Despite their effects on lipid metabolism (reduction in
LDL-C and triglycerides and an increase in HDL-C), the
effects of omega-3 fatty acids on cardiovascular risk
remain unknown [86]. Of note, in 12,536 high-risk patients
with dysglycemia ω-3 fatty acids (1 g/day) did not reduce
vascular morbidity and mortality compared with placebo
after a median of 6.2 years [87]. Thus, the use of these
drugs is justified only in pre-diabetic subjects with severe
hypertriglyceridemia, possibly in combination with
fibrates, to reduce the risk of acute pancreatitis.
THE ROLE OF RAAS IN BP AND GLUCOSE
METABOLISM
The RAAS is activated in states of intravascular volume
contraction, where the renal filtrate flow rate and/or the
filtrate NaCl concentration in the kidneys decrease [88].
Subsequently, the juxtaglomerular cells in the kidneys
secrete renin directly into the circulation. Renin performs
the conversion of angiotensinogen, which is primarily
synthesized in the liver and adipose tissue, to angiotensin
I [88]. The latter is converted to Ang II by the angiotensin
converting enzyme (ACE), which is released from the
lungs. Finally, Ang II stimulates aldosterone production
by the adrenal cortex of the adrenal glands [88].
The activation of the RAAS has a well-established
role in the pathogenesis of hypertension [11]. In addition,
RAAS signaling represents a potential pathway for the
development of vascular insulin resistance and impaired
endothelial-mediated vasodilatation [89]. Both Ang II and
aldosterone promote the development of insulin resistance
with various different mechanisms. The former is impli-
cated in insulin signaling pathways, tissue blood flow,
vasculature remodeling, oxidative stress, sympathetic ner-
vous system activity, coagulation balance, inflammation,
and adipogenesis [3 10]. Most of its actions are mediated
through Ang II type I receptors; however, Ang II also
exerts direct effects on endothelial cells and vascular
smooth muscle cells (VSMCs) [1,11]. Aldosterone influ-
ences insulin sensitivity by being involved in insulin pro-
duction, secretion, and signaling. The actions of Ang II
and aldosterone and their role in glucose homeostasis will
be reviewed herein.
ANGIOTENSIN II
Oxidative Stress
The cell redox balance, inflammatory state, and vasomo-
tion are regulated by the balance between nitric oxide
(NO) and reactive oxygen species (ROS; i.e., superperox-
ide anion and hydrogen peroxide) [1,11]. Abnormalities
in vascular NO production and transport result in endothe-
lial dysfunction, a feature of CVD. Importantly, apart
from its known role in endothelial-derived relaxation
[90], NO inhibits the growth and migration of VSMCs
[1,12] and reduces the expression of proinflammatory
molecules and the transcription of nuclear factor-κB (NF-
κB) and activator protein-1 (AP-1) [1]. NF-κB is a protein
complex that controls the transcription of DNA. It is
found in almost all animal cell types and is involved in
cellular responses to several stimuli, including cytokines,
free radicals, ROS, oxidized LDL, and bacterial or viral
antigens [91 93]. As NF-κB controls many genes
involved in inflammation, it is chronically active in many
inflammatory states, including atherosclerosis [94].
AP-1 (Fos/Jun) is a transcriptional regulator composed
of members of the Fos and Jun families of DNA binding
proteins [95], which play an important role in inflamma-
tion, as the induction with AP-1 is essential for several
genes expressing cytokines [95].
Ang II enhances the generation of ROS [88], which
leads to NO destruction, while it opposes NO properties.
Furthermore, it induces cardiovascular tissue remodeling,
proliferation, migration, and hypertrophy through activation
of several small G proteins including Ras, Rho, and Rac
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 165
[96]. RAAS-mediated oxidative stress activates the JAK/
STAT, Akt (protein kinase B), and P38 MAPK pathways,
which are implicated in the regulation of gene transcrip-
tion and cell migration [97]. RAAS activation also leads
to increased signaling through the Rho and Rho kinase
pathways, which participate in VSMC migration and the
development of hypertrophy, inflammation, and hyperpla-
sia in cardiovascular tissue [98]. Overall, in states of
RAAS activation the beneficial vascular actions of NO
are restrained and the balance between ROS and NO
favors ROS [14,15].
Several observations are in agreement with the afore-
mentioned mechanisms. In overweight and obese persons,
as well as in patients with hypertension, systemic and vas-
cular insulin resistance and cardiovascular tissue RAAS
activation usually coexist [89]. Moreover, T2DM is asso-
ciated with increased ROS production and nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase activ-
ity, along with low levels of endogenous antioxidants
(e.g., glutathione) [99]. Finally, impaired vascular vasodi-
latation and abnormal VSMC function have been demon-
strated in insulin-resistant states, contributing to the
macro- and microvascular complications of T2DM [99].
Insulin Signaling
Glucose metabolism is regulated at multiple sites, with
transmembrane glucose transport being the rate-limiting
step in healthy and diabetic subjects [15]. The primary
insulin responsive glucose transporter (GLUT) in skeletal
muscle and adipose tissue is GLUT-4. Glucose transport in
the skeletal muscle accounts for approximately 70% of
whole-body insulin-mediated glucose uptake [100]. Insulin
binds its plasma membrane receptor, leading to phosphory-
lation of the receptor and insulin receptor substrates
(IRS-1), stimulation of phosphatidylinositol-3-kinase (PI-3
kinase), and, subsequently, translocation of GLUT-4 to the
cell surface from intracellular vesicles [101]. Diminished
translocation of GLUT-4 to the plasma membrane due to
defective intracellular signaling may account for insulin
resistance mainly in the skeletal muscle [101].
The insulin signaling pathway overlaps those of Ang II,
bradykinin, and NO at multiple levels, suggesting a role of
RAAS activation in impaired glucose metabolism. Indeed,
insulin-mediated glucose uptake and intracellular glucose
metabolism are diminished in patients with essential hyper-
tension and normal glucose tolerance independent of the
presence of obesity [100], whereas hypertension has been
associated with obesity, IGT, and T2DM [8,11]. Of note,
Ang II has been shown to reduce IRS-1 phosphorylation,
PI-3 kinase activity, and thus GLUT-4 translocation in adi-
pose tissue and skeletal muscle [20,21], as well as glucose
utilization in VSMCs [18]. In contrast, bradykinin, which
is reduced during RAAS activation, has been found to
activate IRS-1 and PI-3 kinase in skeletal and cardiac mus-
cle [102]. It also enhances NO release via activation of NO
synthase, resulting in NO-induced activation of glucose
transport [103]; importantly, this effect is independent of
the insulin signaling pathway [104].
Inflammation
Ang II stimulates the local production of metalloproteins
and the expression of cellular adhesion molecules, mono-
cytes, and VSMC chemotactic protein-1 [14,15,24]. This
enhances the adhesion of monocytes, leukocytes, and pla-
telets to the endothelium, thus propagating vascular
inflammation [1,11]. Importantly, activated inflammatory
cells release enzymes that lead to Ang II generation (e.g.,
ACE) [90], further augmenting the deleterious effects of
Ang II.
As already mentioned, insulin resistance, endothelial
dysfunction, inflammation, and atherosclerosis are interre-
lated; specifically, insulin resistance and associated endo-
thelial dysfunction contribute to the initiation and
progression of atherothrombosis [105].
Fibrinolytic Balance
Fibrinolysis is a normal process that prevents blood clot
formation and growth. The first key molecule in the cas-
cade of the fibrinolytic system is plasmin, which is pro-
duced in an inactive form, plasminogen, in the liver.
Tissue plasminogen activator (tpA) and urokinase convert
plasminogen to plasmin and, thus, are essential for fibrino-
lysis [106]. Interestingly, plasmin itself further stimulates
its own generation by producing more active forms of tPA
and urokinase [106]. These two molecules are inhibited by
plasminogen activator inhibitor-1 and plasminogen activa-
tor inhibitor-2 (PAI-1 and PAI-2) [106]. Tissue ACE also
downregulates tPA production by degrading bradykinin
[27]. The latter is a potent stimulator of plasminogen acti-
vator production by endothelial cells [27].
Coagulability is particularly enhanced in the presence
of diabetes and hypertension [88], due to decreased tPA
[24 27] and enhanced Ang II-mediated PAI-1 formation
[1,28,29]. Apart from its role in fibrinolysis, PAI-1 impairs
matrix degradation and increases fibrosis in vascular tis-
sues [24 27]. Accordingly, increased levels of PAI-1
have been associated with atherosclerosis progression [27].
ALDOSTERONE
The impact of aldosterone on the development of hyper-
tension has been classically attributed to sodium retention
and intravascular volume expansion. Signaling through the
mineralocorticoid receptor also appears to be involved in
the development of hypertension and the pathogenesis of
166 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
CVD overall [34]. In fact, patients with primary aldoste-
ronism have increased cardiac mass and fibrosis, which is
not the case in individuals with essential hypertension and
comparable BPs [107]. Furthermore, primary aldosteron-
ism has been associated with IGT and T2DM in several
epidemiological studies [14,29]. The possible mechanisms
associating aldosterone with impaired glucose metabolism
and insulin resistance will be discussed herein.
Hypokalemia
Potassium is involved in the regulation of insulin receptor
function and glucose-mediated insulin secretion by β-cells
[108]. Insulin release from β-cells is stimulated by their
depolarization, i.e., a reduction in the transmembrane
charge difference [109]. The molecule that links membrane
polarization to insulin release is an ATP-dependent potas-
sium (KATP) channel which is located at β-cells’ outer
membranes [109]. Under normal conditions, these channels
are spontaneously active, allowing potassium ions to flow
out of the cell [110]. When the membrane is polarized,
insulin remains trapped in secretory vesicles in β-cells,
while the uptake of glucose by β-cells leads to ATP-
induced closing of the potassium channels [109]. The ensu-
ing membrane depolarization causes a massive influx of
calcium inside the cells, promoting insulin release [110].
In this context, aldosterone-induced hypokalemia may
have a deleterious effect on insulin secretion. A signifi-
cant correlation between diuretic-induced hypokalemia
and increased glucose levels further supports this assump-
tion [111]. Aldosterone-induced hypokalemia may affect
glucose/insulin homeostasis via the adipose tissue as well.
Specifically, adiponectin, an adipokine with insulin-
sensitizing properties, has been directly correlated with
potassium levels in patients with primary aldosteronism
and low renin essential hypertension [112]. In contrast,
this association was weaker in patients with low renin
hypertension but without primary aldosteronism, suggest-
ing that chronic hypokalemia in primary aldosteronism
may contribute to low adiponectin levels and thus to insu-
lin resistance [33].
Effects of Aldosterone in Adipose Tissue and
Skeletal Muscle
Aldosterone inhibits the production of insulin receptors in
adipose tissue and skeletal muscle [113] and diminishes
the affinity of these receptors for insulin in adipose tissue
[99]. Furthermore, it downregulates glucose transporters
and increases fibrosis in target tissues (i.e., pancreas, adi-
pose tissue, and skeletal muscle) [99]. As is the case with
Ang II, aldosterone also enhances the degradation of IRS-
1 in VSMCs, an effect mediated by ROS and c-Src; the
latter is a tyrosine kinase protein encoded by the SRC
gene [114]. In addition, mineralocorticoid-induced stimu-
lation of c-Src promotes the activation of MAPKs (P38
MAPK, JNK, ERK1/2) associated with cellular growth,
apoptosis, and collagen deposition [105].
Effects of Insulin on Aldosterone Production
The relationship between aldosterone and insulin/glucose
homeostasis seems to be bidirectional. Indeed, apart from
the aforementioned effects of aldosterone in insulin func-
tion, increased insulin secretion in insulin-resistant states
promotes aldosterone production and secretion, further
deteriorating insulin sensitivity [99]. Particularly, a dose-
dependent enhancement in insulin-mediated aldosterone
production has been reported in rodents [115]. Furthermore,
complement-C1q TNF-related protein 1 (CTRP1), an adi-
pokine with structural homology with adiponectin, was
found to stimulate aldosterone production in Zucker dia-
betic fatty rats [116]. Overall, there appears to be a compli-
cated interaction between insulin and aldosterone, which
probably contributes to impaired glucose homeostasis in
cases of RAAS activation.
Taking into consideration the impact of RAAS inhibi-
tion in insulin sensitivity, we should probably consider
thoroughly the choice of antihypertensive treatment in
patients with pre-diabetes in order not to deteriorate insu-
lin sensitivity—and perhaps to improve it. At this point
we will discuss the effects of antihypertensive drugs other
than those acting on the RAAS in insulin/glucose homeo-
stasis, as well as the impact of different drug classes in
the development of new-onset T2DM.
EFFECTS OF ANTIHYPERTENSIVE DRUGS
OTHER THAN THOSE ACTING ON RAAS
ON GLUCOSE METABOLISM
Thiazide Diuretics
Thiazide diuretics reduce insulin secretion and peripheral
insulin sensitivity and, thus, worsen glycemic control in a
dose-dependent manner [40 42]. Thiazide-induced hypo-
kalemia may blunt insulin release; accordingly, potassium
supplementation has been found to moderate the occur-
rence of glucose intolerance associated with thiazide
use [49 51].
β-Blockers
Conventional β-blockers reduce blood flow to the skeletal
muscle due to reduced cardiac output or unopposed α1-
adrenergic vasoconstrictor activity [52,53] and decrease
the first phase of insulin secretion [54,55]. Weight gain
associated with the use of these drugs may potently deteri-
orate glucose metabolism, but this effect has not been
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 167
consistently demonstrated. Indeed, decreased insulin sensi-
tivity has been observed in patients who did not gain
weight on β-blockers [2,55 58]. On the other hand,
β-blockers with vasodilator properties may favorably
affect glycemic control [117]. For example, carvedilol
(α 1 β-blocker) significantly improved insulin sensitivity
and HbA1c levels compared with metoprolol (50 200 mg/
day) (both P , 0.05) in patients with hypertension and
T2DM currently treated with an ACE inhibitor or an
angiotensin receptor blocker (ARB) (n 5 1235) in the
Glycemic Effects in Diabetes Mellitus: Carvedilol-
Metoprolol Comparison in Hypertensives (GEMINI) trial
[47]. We should note that both treatments conferred simi-
lar reductions in BP.
Calcium Channel Blockers
Calcium channel blockers (CCBs) seem to have beneficial
effects on insulin sensitivity and secretion [50,51].
Dihydropyridines and long-acting non-dihydropyridine
CCBs may improve insulin sensitivity by inducing vaso-
dilatation in insulin-sensitive tissues [118], by preventing
the inhibition of GLUT and glycogen synthase by calcium
[119] as well as via antioxidant effects [120].
Other Antihypertensive Drugs
Other classes of antihypertensive agents are not broadly
used due to their adverse effects and the lack of large clin-
ical trials. Moxonidine and α-adrenergic blockers seem to
improve insulin sensitivity [121 124]. In contrast, α2-ago-
nists (e.g., clonidine) may inhibit pancreatic β-cell insulin
secretion, thus impairing glucose metabolism [125].
DEVELOPMENT OF NEW-ONSET T2DM
WITH DIFFERENT ANTIHYPERTENSIVE
DRUG CLASSES
Several prospective randomized trials evaluated the devel-
opment of T2DM with antihypertensive therapy. However,
their results should be interpreted with caution as the inci-
dence of new-onset T2DM was a secondary endpoint.
Furthermore, in most studies the agent under investigation
was given on top of other antihypertensive drugs, making
it difficult to distinguish the effects among different drugs
or drug classes.
Diuretics and/or β-Blockers Versus Placebo
In the European Working Party on High blood pressure in
the Elderly (EWPHE) study (n 5 840) new-onset T2DM
was more frequent with triamterene 50 mg/day plus
hydrochlorothiazide (HCTZ) 25 mg/day (with a potential
for both doses to be doubled during the study) compared
with placebo; however, this difference was not significant
(relative risk [RR] 1.5, 95% confidence interval [CI]
0.85 2.6) [126].
In the Systolic Hypertension in the Elderly Program
(SHEP), 4736 patients with isolated systolic hypertension
were randomized to chlorthalidone (12.5 25 mg/day) or
placebo; if BP remained above target, atenolol or a
matching placebo was added [127]. A non-significant
excess in the incidence of new-onset T2DM was observed
with chlorthalidone compared with placebo (8.6% vs.
7.5%, respectively) [49]. However, this difference reached
significance (13% vs. 8.7%, P , 0.0001) when the current
definition of DM was used [i.e., fasting plasma glucose
.126 mg/dL instead of .140 mg/dL which was used in
the initial SHEP analysis]. Importantly, patients treated
with both chlorthalidone and atenolol were more likely to
develop T2DM compared with those on chlorthalidone
monotherapy (16.4% vs. 11.8%, P , 0.007) [128].
As already mentioned, some of the vasodilating
β-blockers, such as celiprolol, carvedilol, and nebivolol
seem to lack the diabetogenic effects of traditional
β-blockers, as they affect insulin sensitivity less than met-
oprolol [129,130]. Nebivolol has recently been shown not
to worsen glucose tolerance compared with placebo and
when added to HCTZ [131].
Thiazide Diuretics Versus β-Blockers
In the Heart Attack Primary Prevention in Hypertension
(HAPPHY) trial, there was no difference in the incidence
of T2DM between thiazide diuretics (bendroflumethiazide
5 mg/day or HCTZ 50 mg/day) and β-blockers (atenolol
100 mg/day or metoprolol 200 mg/day) (RR 0.88, 95%
CI 0.65 1.19) in Caucasian men with hypertension
(n 5 6569) [71].
RAAS Inhibitors Versus Placebo
In the Heart Outcomes Prevention Evaluation (HOPE)
trial, the RR for developing T2DM with ramipril (up to
10 mg/day) was 0.66 compared with placebo (95% CI
0.51 0.85, P , 0.001) in 5720 patients with vascular dis-
ease but without DM [132].
In the Prevention of Events with Angiotensin
Converting Enzyme Inhibition (PEACE) trial, trandolapril
(target dose 4 mg/day) reduced the risk for developing new-
onset T2DM by 17% compared with placebo (95% CI
0.72 0.96, P , 0.01) in patients with stable CHD and nor-
mal or slightly reduced left ventricular function (n 5 8290)
[59]. Similarly, in a retrospective study of 291 non-diabetic
patients with left ventricular dysfunction enrolled in the
Studies Of Left Ventricular Dysfunction (SOLVD), a signif-
icant reduction in the incidence of new-onset T2DM was
observed with enalapril (5 20 mg/day) compared with
168 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
placebo (P , 0.0001); this reduction was more pronounced
in patients with IFG (P , 0.0001) [133].
In the Candesartan in Heart failure Assessment of
Reduction in Mortality and Morbidity (CHARM) trial, the
RR for developing T2DM among 7601 patients with
chronic heart failure was lower with candesartan (titrated
to 32 mg/day) compared with placebo (RR 0.78, 95% CI
0.64 0.96, P , 0.001) [4]. In contrast, in the Study on
Cognition and Prognosis in the Elderly (SCOPE), cande-
sartan (8 16 mg/day) did not decrease the incidence of
T2DM compared with placebo in 4964 hypertensive
patients [134]. Of note, the majority of patients (84%) in
the control group received active antihypertensive ther-
apy, with approximately two-thirds of them being on
β-blockers or diuretics [134].
The first prospective, double-blind, randomized study
to assess the development of new-onset T2DM in indivi-
duals with impaired glucose metabolism was the Diabetes
Reduction Assessment with Ramipril and Rosiglitazone
Medication (DREAM) study [132]. The administration of
ramipril (up to 15 mg/day) for 3 years did not reduce the
incidence of DM in patients with IFG or IGT without vas-
cular disease (n 5 5269); however, it increased regression
to normoglycemia. We should stress that approximately
43% of patients in both groups were hypertensive and
many among them were treated with various other antihy-
pertensive drugs [132].
In contrast, the more recent NAVIGATOR study dem-
onstrated more favorable findings with another RAAS
inhibitor. NAVIGATOR was a multinational, randomized,
double-blind, placebo-controlled trial assessing the effects
of valsartan and nateglinide in the development of T2DM
and cardiovascular outcomes in patients with IGT and
established CVD or cardiovascular risk factors (n 5 9306)
[135]. Overall, 78% of participants had hypertension.
Patients were randomized to valsartan (up to 160 mg
daily) or placebo and nateglinide or placebo and were fol-
lowed for a median of 5 years. The cumulative incidence
of diabetes was 33.1% in the valsartan group compared
with 36.8% in the placebo group (HR 0.86; 95% CI
0.80 0.92; P , 0.001). However, valsartan did not reduce
the rate of cardiovascular events [135]. Several study lim-
itations may have accounted for the absence of beneficial
effects in terms of CVD lowering. First of all, off-study
ACE inhibitors and ARBs were used in the placebo
group. Furthermore, there was a 13% rate of loss to fol-
low-up, a high non-adherence rate (34% by the end of the
study), as well as a small percentage of participants with
established CVD (24%). Finally, the BP was generally
well controlled at baseline [136]. Nevertheless,
NAVIGATOR was the only randomized study that specif-
ically addressed new-onset T2DM development with a
RAAS inhibitor and demonstrated positive findings.
However, the lack of benefit in terms of hard outcomes
should be taken into account when choosing antihyperten-
sive therapy.
CCBs Versus Diuretics and/or β-Blockers
In the International Verapamil-Trandolapril (INVEST)
study, which included 16,176 patients with hypertension
and CHD, verapamil-based treatment (verapamil sus-
tained release 240 mg/day 6 trandolapril) was associated
with a lower incidence of T2DM compared with atenolol-
based treatment (atenolol 50 mg/day 6 HCTZ; RR 0.85,
95% CI 0.77 0.95, P , 0.005) [74].
In contrast, in the Nordic Diltiazem (NORDIL) study,
diltiazem (180 360 mg/day) did not reduce the incidence
of T2DM compared with diuretic and/or β-blocker-based
treatment in 10,881 hypertensive patients (RR 0.87, 95%
CI 0.73 1.04) [72].
Finally, in the Intervention as a Goal in Hypertension
(INSIGHT) trial, the incidence of T2DM was lower with
nifedipine (30 mg/day) compared with amiloride/HCTZ
(2.5/25 mg/day) in patients with hypertension and at least
one additional vascular risk factor (n 5 5019) (RR 0.77,
95% CI 0.62 0.96, P 5 0.023) [75].
CCB/HCTZ Versus HCTZ
The Felodipine Event Reduction (FEVER) study com-
pared the effects of HCTZ (12.5 mg/day) plus felodipine
(5 mg/day) and HCTZ alone on the incidence of new-
onset T2DM in Chinese patients with hypertension and
one or two additional vascular risk factors or established
CVD (n 5 9800). No significant difference was demon-
strated between the two groups [61].
RAAS Inhibitors Versus Diuretics and/or
β-Blockers
In the Losartan Intervention For Endpoint reduction
(LIFE) in Hypertension study, 9193 patients with hyper-
tension and left ventricular hypertrophy were randomized
to losartan (50 mg plus HCTZ 12.5 mg/day up-titrated to
100/12.5 25 mg/day if systolic BP was $ 140 mmHg or
diastolic BP $ 90 mmHg) or atenolol (50 mg plus HCTZ
12.5 mg/day up-titrated to 100/12.5 25 mg/day as
required) [77]. A 25% lower incidence of T2DM was
observed in the losartan-based treatment group (RR 0.75,
95% CI 0.63 0.88, P , 0.001) [62].
Similarly, in the Captopril Prevention Project (CAPPP),
the incidence of T2DM was lower with captopril (50 mg/
day) compared with diuretic and/or β-blocker-based ther-
apy (bendroflumethiazide 2.5 mg/day or HCTZ 25 mg/day
and/or atenolol or metoprolol 50 100 mg/day; RR 0.86,
95% CI 0.74 0.99, P 5 0.039) [76].
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 169
In the Antihypertensive treatment and Lipid Profile In
a North of Sweden Evaluation (ALPINE) study, there was
a lower incidence of T2DM in patients treated with can-
desartan (16 mg/day) compared with those taking HCTZ
(25 mg/day) (RR 0.13, 95% CI 0.02 0.99, P , 0.03). We
should mention that almost 71% of patients in the cande-
sartan group received felodipine (2.5 5 mg/day) as well,
while 84% of patients in the HCTZ group were taking
atenolol (50 100 mg/day); these drugs may have further
increased the difference in the development of new-onset
T2DM between the two treatment arms [63]. The results
of this study should be interpreted with great caution, as it
was a small study (n 5 392) and new-onset T2DM was
diagnosed in eight patients overall in the HCTZ group
and only one patient in the candesartan group.
The ADaPT study, an open, prospective, parallel
group study (n 5 1507), compared the effect of ramipril
versus diuretic-based treatment in the development of
new-onset T2DM in subjects with pre-diabetes [137].
Patients in one group received ramipril as monotherapy or
in combination with felodipine or another CCB, while
patients in the other group were treated with any diuretic
with or without β-blocker-based therapy but without drugs
blocking RAAS. Incidence rates of T2DM were consis-
tently higher in the diuretic group through years 1 4.
The prevalence rose continuously during follow-up,
reaching statistical significance at a median treatment
duration of 3 years (24.3% vs. 29%, P , 0.05). The differ-
ence at 4 years was largely preserved, but became
non-significant. Both treatments were equally effective in
reducing BP [137].
Studies Assessing DM Incidence with RAAS
Inhibitors, CCBs, Diuretics, and/or
β-Blockers or Other Drugs (in Various
Combinations)
In the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT), conducted in
14,816 high-risk hypertensive patients without DM, the
incidence of new-onset T2DM at 4 years was 11.6% with
chlorthalidone (12.5 25 mg/day) compared with 9.8%
(P 5 0.04) with amlodipine (2.5 10 mg/day) and 8.1%
(P , 0.001) with lisinopril (10 40 mg/day) [138]. We
should bear in mind, though, that only 38% of patients
with a baseline plasma glucose measurement had a repeat
measurement at 4 years [138].
Similarly, in the African American Study of Kidney
disease and hypertension (AASK), treatment with ramipril
was associated with a lower incidence of T2DM compared
with amlodipine (RR 0.49, 95% CI 0.31 0.79, P 5 0.003)
and metoprolol (RR 0.53, 95% CI 0.36 0.78, P 5 0.001)
in 1017 African American patients with hypertensive
chronic kidney disease without DM at baseline [139]. No
significant difference in the incidence of T2DM was
observed between amlodipine and metoprolol.
In the Valsartan Antihypertensive Long-term Use
Evaluation (VALUE) trial, 15,245 patients with treated or
untreated hypertension and high risk of cardiac events
were randomized to treatment with valsartan (80 mg) or
amlodipine (5 mg) [140]. Further antihypertensive drugs
apart from ARBs were allowed to achieve BP control.
ACE inhibitors and CCBs were allowed only if they were
clinically indicated for reasons other than hypertension.
New-onset diabetes arose in significantly fewer patients
in the valsartan group (HR 0.77; 95% CI 0.69 0.86,
P , 0.0001) [140].
In the Anglo-Scandinavian Cardiac Outcomes Trial-
Blood Pressure Lowering Arm (ASCOT-BPLA), 19,257
patients with hypertension and at least three other cardio-
vascular risk factors were randomly assigned to amlodi-
pine (5 10 mg) plus perindopril (4 8 mg) as required
(amlodipine-based regimen; n 5 9639) or atenolol
(50 100 mg) plus bendroflumethiazide (1.25 2.5 mg)
and potassium as required (atenolol-based regimen;
n 5 9618) [141]. The study was stopped prematurely after
a median of 5.5 years as fewer individuals on the
amlodipine-based regimen had a primary endpoint (nonfa-
tal myocardial infarction and fatal CHD). The incidence
of developing diabetes was smaller in the amlodipine
group compared with the atenolol group (RR 0.70, 95%
CI 0.63 0.78, P , 0.0001) [141]. The extent to which the
addition of perindopril in the amlodipine group and of
bendroflumethiazide to the atenolol group affected this
outcome remains unknown. Nevertheless, treatment with
a CCB plus an ACE inhibitor would actually be expected
to have a more favorable effect in glucose/insulin homeo-
stasis compared with the combination of a diuretic plus a
conventional β-blocker.
In contrast, in the Swedish Trial in Old Patients with
Hypertension-2 (STOP-Hypertension) study, ACE inhibi-
tors (enalapril 10 mg/day or lisinopril 10 mg/day) and
CCBs (felodipine 2.5 mg/day or isradipine 2 5 mg/day)
did not decrease the incidence of T2DM compared with
diuretics (HCTZ 25 mg plus amiloride 2.5 mg/day) and/or
β-blockers (atenolol 50 mg, metoprolol 100 mg, or pindo-
lol 5 mg/day) in hypertensive patients 70 84 years old
(n 5 6614) [142].
A re-analysis of the data of the NAVIGATOR study
assessed the development of T2DM in participants who
were treatment naı̈ve to β-blockers (n 5 5640), diuretics
(n 5 6346), statins (n 5 6146), and CCBs (n 5 6294) at
baseline [143]. Use of CCBs was used as a metabolically
neutral control. During a median 5 years of follow-up,
β-blockers were started in 915 (16.2%) patients, diuretics
in 1316 (20.7%), statins in 1353 (22%), and CCBs in
1171 (18.6%). After adjustment for baseline characteristics
170 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
and time-varying confounders, diuretics and statins were
both associated with an increased risk of new-onset
T2DM (HR 1.23, 95% CI 1.06 1.44 and 1.32, CI
1.14 1.48, respectively), whereas β-blockers and CCBs
were not (1.10, 0.92 1.31, and 0.95, 0.79 1.13, respec-
tively) [143]. This study agrees with previous data regard-
ing the diabetogenic effects of diuretics but contradicts
previous studies with respect to the effect of β-blockers on
glucose metabolism.
Apart from the aforementioned data, which were based
on individual clinical trials, it would be worth mentioning
the risk of developing T2DM with different antihyperten-
sive drug classes as demonstrated in large observational
studies, a systematic review, and a meta-analysis.
In the prospective Atherosclerosis Risk in Communities
(ARIC) cohort study, patients (n 5 3804) taking β-blockers
had a 28% higher risk of developing T2DM compared
with untreated patients with hypertension (RR 1.28, 95%
CI 1.04 1.57). In contrast, patients treated with thiazide
diuretics, ACE inhibitors, or CCBs were not at greater risk
compared with those taking no treatment [6].
Of interest are the results of a long-term observational
study including 41,193 older women from the Nurses’
Health Study (NHS) I, 14,151 younger women from the
NHS II and 19,472 men from the Health Professionals’
Follow-up Study (HPFS) [144]. The RR for developing
T2DM in patients taking thiazide diuretics was 1.20 (95%
CI 1.08 1.33) in older women, 1.45 (95% CI 1.17 1.79)
in younger women, and 1.36 (95% CI 1.17 1.58) in men.
The respective RR in participants treated with β-blockers
were 1.32 (95% CI 1.20 1.46) in older women and 1.20
(95% CI 1.05 1.38) in men [144]. In contrast, ACE inhi-
bitors and CCBs did not affect the risk for new-onset
T2DM [144].
A network meta-analysis of 22 trials with more than
160,000 participants demonstrated that the association of
antihypertensive agents with the development of new-
onset T2DM is lowest for ARBs and ACE inhibitors, fol-
lowed by CCBs and placebo, β-blockers, and diuretics in
rank order [145].
Similarly, a more recent systematic review of 25 ran-
domized controlled trials with antihypertensive agents
demonstrated that the risk of T2DM was increased with
diuretics compared with ACE inhibitors (RR 1.43;
1.12 1.83) and CCBs (RR 1.27; 1.05 1.57) [146].
Overall, ACE inhibitors and ARBs exert more benefi-
cial effects on glucose/insulin homeostasis compared with
diuretics and β-blockers, something that translates into a
lower incidence of new-onset T2DM. Whether the differ-
ence between these drug classes is due to a protective
effect of ACEs or ARBs, an adverse effect of diuretics
and/or β-blockers, or both is not clear. On the other hand,
the exact role of CCBs is not so apparent. These drugs
seem to have either a neutral or a beneficial effect in
insulin sensitivity. Probably RAAS inhibitors and CCBs
should be preferred over diuretics and β-blockers in
patients at risk of developing DM if there is no clear indi-
cation for their use.
NEW-ONSET T2DM AND
CARDIOVASCULAR OUTCOMES
At this point it would be worth summarizing the associa-
tion between new-onset T2DM and cardiovascular burden
and outcomes. In most clinical trials the increased inci-
dence of new-onset T2DM was not associated with
increased vascular morbidity and mortality. In fact, in the
Hypertension Detection and Follow-Up Program (HDPF)
[147] and the SHEP trial [127], thiazide diuretics induced
beneficial vascular outcomes despite their association with
increased incidence of new-onset T2DM. Furthermore, in
the ALLHAT, the greater prevalence of new-onset T2DM
with chlorthalidone did not result in more adverse cardio-
vascular outcomes or higher all-cause mortality [138]. The
findings of this study suggest that drug-induced develop-
ment of T2DM may not have the same deleterious effects
with “innate” DM. We should stress, though, that possible
adverse vascular effects related to T2DM may have not
been observed in these trials due to the relatively short
duration of follow-up after developing T2DM. In a long-
term study which followed 795 initially untreated hyper-
tensive patients for up to 16 years (median 6 years), those
who developed T2DM after antihypertensive treatment
initiation had comparable vascular risk with those who
were diabetic at baseline [148]. However, only a small
percentage of patients developed T2DM (5.8%); therefore,
the conclusions of this study should be interpreted with
circumspection.
In contrast to ALLHAT, diuretic-induced hyperglyce-
mia was associated with higher incidence of vascular dis-
ease during 6.3 years of follow-up in 6886 hypertensive
patients [149]. Furthermore, the increase in blood glucose
levels was an independent risk factor for myocardial
infarction (P 5 0.0001) in men treated with antihyperten-
sive agents (mainly β-blockers and thiazide diuretics)
compared with those taking no therapy [150]. In the
Multiple Risk Factor Intervention Trial (MRFIT), which
followed up 11,645 subjects for 18 years, patients who
developed T2DM, most of whom had received diuretics,
often at high doses, had higher mortality rates compared
with those who did not [151]. The aforementioned results
(which come from larger and longer-term studies com-
pared with the individual clinical trials previously pre-
sented) suggest that antihypertensive drug-related T2DM
may lead to greater long-term vascular risk.
However, in a recent study, ramipril was found to
reduce both the incidence of new-onset T2DM and
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 171
cardiovascular morbidity and mortality compared with
diuretic-based therapy in individuals with pre-diabetes
[137]. Furthermore, an analysis of the SHEP trial with
14.3 years of follow-up did not report adverse cardiovas-
cular effects of antihypertensive drug-induced T2DM
[128]. Specifically, new-onset T2DM in the placebo
group was associated with increased vascular and total
mortality (RR 1.56, 95% CI 1.11 2.18 and 1.34, 95% CI
1.05 1.72, respectively), whereas such effects were not
observed in the diuretic group (RR 1.04, 95% CI
0.74 1.45 and 1.15, 95% CI 0.92 1.43, respectively).
Patients who developed T2DM with chlorthalidone treat-
ment not only did not have a significant increase in vascu-
lar events but also had a better prognosis compared with
those who were diabetic at baseline.
In conclusion, it has not been clarified whether antihy-
pertensive treatment-induced new-onset T2DM poses a
greater vascular burden and if this risk differs among the
various drugs that impair glucose metabolism. Taking
into account that patients with hypertension and pre-
diabetes are already at increased vascular risk due to the
coexistence of several risk factors and excessive activa-
tion of the RAAS, it would be prudent not to accelerate
their progression to overt T2DM and to try to improve
insulin resistance instead. In this context, the choice of
antihypertensive treatment may play a critical role in
these patients.
ANTIHYPERTENSIVE TREATMENT IN
PATIENTS WITH PRE-DIABETES
As no randomized control trials or prospective studies
have been specifically conducted in patients with pre-
diabetes and hypertension, the goals of BP in this group
do not differ from those of other hypertensive individuals,
i.e., below 140/90 mmHg. In contrast, so far the target
levels of BP in patients with overt DM were lower; i.e.,
below 130/80 mmHg [152]. However, the recently pub-
lished guidelines of the European Society of Hypertension
(ESH) and the ESC for the management of hypertension
recommend that the goal in diabetic patients should be
below 140/85 mmHg [153]. This change occurred, at least
in part, due to the futility of large clinical trials, such as
the ACCORD trial [154], to decrease cardiovascular mor-
bidity and mortality with lower BP targets than those
recommended by guidelines in patients with T2DM.
An interesting meta-analysis compared the effects of
systolic BP # 135 versus # 140 mmHg on macro- or
microvascular events in patients with T2DM or IFG/IGT
[155]. The more intensive BP control was associated with
a 10% reduction in all-cause mortality (odds ratio [OR]
0.90; 95% CI 0.83 to 0.98) and a 17% reduction in stroke,
but also a 20% increase in serious adverse effects. Of
note, similar outcomes for other macro- and microvascular
(cardiac, renal, and retinal) events were observed in both
groups [155]. An even stricter BP control (#130 mmHg)
was associated with a further reduction in stroke, but did
not reduce other events. Although risk reduction for stroke
continued at levels of systolic BP ,120 mmHg, a 40%
increase in serious adverse events with no benefit for other
outcomes was observed at levels ,130 mmHg [155].
Lifestyle Modification
Treatment always begins with lifestyle measures, which
both prevent and treat hypertension, and should be main-
tained for life independent of pharmacotherapy. These
include salt restriction, moderation of alcohol intake, adop-
tion of certain eating habits, weight reduction, regular
exercise, and abstinence from smoking [153]. Specifically,
sodium consumption should not exceed 5 6 g/day and
alcohol 20 30 g ethanol/day in men and 20 30 g ethanol/
day in women. Diets should be rich in vegetables, low-fat
dairy products, dietary and soluble fiber, whole grains, and
protein from plant sources, and low in saturated fat and
cholesterol. Fresh fruits are also recommended, although
with caution in overweight patients because sometimes
fruits’ carbohydrate content is high and may promote
weight gain. Weight should be maintained at normal levels
(i.e., BMI between 18.5 and 24.9 kg/m2) and waist circum-
ference ,102 cm in men and ,88 cm in women.
Furthermore, lifestyle modification recommendations
include moderate dynamic exercise (walking, jogging,
swimming, or cycling) of at least 30 min/day, 5 7 days
per week [153]. We should note that even regular physical
activity of lower intensity and duration has been shown to
be associated with about a 20% decrease in mortality in
cohort studies [156,157]. Importantly, modest lifestyle
changes including healthful nutrition and increased physi-
cal activity may reduce the development of diabetes by
nearly 60% in high-risk individuals [158].
Pharmacotherapy
In the 2003 and 2007 versions, the ESH/ESC guidelines
reviewed a large number of randomized trials with antihy-
pertensive treatment and concluded that the main benefits
of therapy are attributed to BP lowering per se and are
largely independent of the drugs employed [159,160].
Sporadically, though, meta-analyses have claimed superi-
ority of one drug class over another for some outcomes
[161 163], but this mainly depended on the selection
bias of trials included, while the largest available meta-
analyses did not show clinically relevant differences
between drug classes [164 166]. In this context, the cur-
rent guidelines reconfirm that diuretics (including thia-
zides, chlorthalidone, and indapamide), β-blockers, CCBs,
172 Glucose Intake and Utilization in Pre-Diabetes and Diabetes
ACE inhibitors, and ARBs are all suitable for the initia-
tion and maintenance of antihypertensive treatment, either
as monotherapy or in various combinations with one
another [153]. Of course, if the initial selected drug is
intolerable or contraindicated then it should be substituted
with a drug from one of the other classes. Some agents
should be considered the preferential choice in specific
conditions either because they have been used in clinical
trials in those conditions or due to greater effectiveness in
certain types of organ damage [153]. One of these “spe-
cific conditions” is DM, where an ARB or an ACE inhibi-
tor is preferred as initial treatment. In contrast, pre-
diabetes is not considered a specific clinical condition
requiring therapy with a certain drug class. Initiation of
antihypertensive treatment with a two-drug combination
may be considered in patients with markedly high base-
line BP or at high cardiovascular risk [153].
When one or two antihypertensive drugs are initiated
and the BP goal is not achieved, doses can be stepped up;
if the target is still not achieved with a two-drug combina-
tion at full doses, then switching to another two-drug com-
bination can be considered or a third drug added [153].
Regarding antihypertensive therapy in diabetic
patients, initiation of drug treatment in those whose sys-
tolic BP is $ 160 mmHg is mandatory; it is strongly
recommended to start drug treatment when systolic BP is
$ 140 mmHg. As previously mentioned, the target BP
levels in these patients is ,140/85 mmHg [153].
All classes of antihypertensive agents are recommended
and can be used in patients with diabetes; RAAS blockers
may be preferred, especially in the presence of proteinuria
or microalbuminuria [153]. It is recommended that
individual drug choice take comorbidities into account.
Importantly, simultaneous administration of two RAAS
blockers is not recommended and should be avoided due to
increased incidence of adverse effects [153].
Supportive evidence against lowering systolic BP
,130 mmHg comes from the ACCORD trial [167], a
post hoc analysis of randomized, controlled trials, and a
nationwide register-based observational study in Sweden,
which suggest that benefits do not increase below
130 mmHg [168,169].
Since no data from large outcome trials exist for
patients with pre-diabetes, it would be useful to overview
the effects of different antihypertensive drugs both in
“healthy” hypertensive individuals as well as in patients
with DM to guide us in the choice of proper antihyperten-
sive therapy in this population.
A meta-analysis in healthy people at risk of CVD
including 25 trials demonstrated the following findings:
ACE inhibitors were inferior to CCBs in terms of stroke
risk (RR 1.19; 95% CI 1.03 1.38), but superior regarding
the risk of heart failure (RR 0.82; 95% CI 0.69 0.94)
[146]. Diuretics reduced the risk of myocardial infarction
compared with β-blockers (RR 0.82; 95% CI 0.68 0.98)
and that of heart failure compared with CCBs (RR 0.73;
95% CI 0.62 0.84), β-blockers (RR 0.73; 95% CI
0.54 0.96), and α-blockers (RR 0.51; 95% CI 0.40 0.64)
[146]. As expected, the risk of T2DM increased with
diuretics compared with ACE inhibitors (RR 1.43;
1.12 1.83) and CCBs (RR 1.27; 1.05 1.57) [146].
Thiazide diuretics are beneficial in DM, either as
monotherapy or as part of a combined treatment regimen.
In the pre-specified diabetic subgroup of ALLHAT,
chlorthalidone reduced the primary endpoint of fatal CHD
and myocardial infarction to the same degree as therapy
with lisinopril or amlodipine [138].
RAAS inhibitors are also an important component of
most treatment regimens to control BP in diabetic patients
[11,170 172]. These drugs may be used as monotherapy
but have been proved more effective when combined with
thiazide diuretics or other antihypertensive drugs. In the
Micro-Hope subanalysis of the HOPE Study, which
included both hypertensive and normotensive individuals,
the addition of an ACE inhibitor to conventional therapy
resulted in a B25% reduction in combined myocardial
infarction, stroke, and cardiovascular death and a B33%
reduction in stroke compared with placebo plus conven-
tional therapy in high-risk diabetic patients [173]. ACE
inhibitors and ARBs have been shown to delay renal func-
tion deterioration and albuminuria progression in patients
with DM and are, thus, recommended by the ADA in dia-
betic patients with chronic kidney disease [174 176].
β-blockers, particularly β1-selective agents, may be
beneficial in diabetics, particularly as part of multidrug
therapy. Their deleterious effects on glucose homeostasis
should be taken into account. Of course, these agents are
definitely indicated in diabetic patients with CHD [152].
CCBs may be useful in DM, mainly as part of combi-
nation antihypertensive treatment, as they have been dem-
onstrated to reduce cardiovascular events in diabetics
compared with placebo in several clinical outcome trials
[177 180]. As previously mentioned, in the diabetic
cohort of ALLHAT, amlodipine was as effective as
chlorthalidone in all categories with the exception of heart
failure, where it was significantly inferior [138].
In conclusion, it seems that the choice of treatment
should be individualized, taking into account the baseline
BP values, comorbidities, age, preferences, and tolerance
of each patient.
ARBs WITH PEROXISOME PROLIFERATOR-
ACTIVATED RECEPTOR-γ PROPERTIES
Apart from the more favorable effects of RAAS inhibitors
compared with other antihypertensive drug classes on glu-
cose homeostasis, evidence suggests that certain ARBs
 Chapter | 13 Hypertension and Dyslipidemia in Patients with Pre-Diabetes: Dietary and Other Therapies 173
with peroxisome proliferator-activated receptor-γ (PPAR-
γ) properties may improve insulin sensitivity even more.
By modulating the expression of several metabolic genes,
PPAR-γ play a role in glucose metabolism [181].
Specifically, PPAR-γ activation leads to the differentiation
of preadipocytes into small fat cells in the subcutaneous
adipose tissue and promotes the apoptosis of differentiated
large adipocytes in the subcutaneous and visceral fat
[181]. This results in a reduction in visceral fat and an
increase in subcutaneous fat, leading to greater insulin
sensitivity and improved glucose metabolism [181].
Among ARBs, telmisartan partially activates PPAR-γ.
Indeed, in an experimental model telmisartan functioned
as a moderately potent selective PPAR-γ partial agonist,
activating the receptor by 25 30% of the maximum level
achieved by the full agonists pioglitazone and rosiglita-
zone [182]. Irbesartan also has this slight capacity,
whereas other ARBs do not [182]. The greater PPAR-γ
activation capacity of telmisartan has been associated
with improvements in insulin sensitivity and glucose
metabolism compared with other ARBs [183]. However,
the ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial (ONTARGET) study dis-
proved the hypothesis that the PPAR-γ activity of telmi-
sartan may render this compound more effective in
preventing or delaying new-onset T2DM, as the incidence
of new-onset T2DM did not differ significantly between
telmisartan and ramipril [184]. Therefore, it seems that
RAAS inhibition with any drug may potently prevent the
onset of T2DM.
CONCLUSIONS
The prevention of T2DM is imperative due to its great
burden in terms of cost and cardiovascular morbidity and
mortality. Many individuals have impaired glucose
metabolism in the form of either IFG or IGT, and are
thus very likely to develop overt T2DM in the future.
Moreover, these subjects frequently have other cardiovas-
cular risk factors, such as hypertension and dyslipidemia.
All therapeutic interventions should be made with great
caution in this group of patients so as to avoid or delay
the development of T2DM. In this context, it would be
prudent to choose among antihypertensive drugs with a
favorable impact in insulin sensitivity, such as RAAS
inhibitors. Regarding lipid abnormalities, these should be
treated with a statin to achieve target LDL-C goals, while
the addition of other lipid-lowering drugs to improve
parameters of atherogenic dyslipidemia may be consid-
ered. We should stress, though, that statins are the only
drug class that has consistently been associated with ben-
eficial effects in CVD morbidity and mortality in all
patient populations. On the other hand, the deleterious
effect of statins in glucose metabolism is problematic.
Overall, it appears that the observed cardiovascular bene-
fit from these agents outweighs the risk of DM develop-
ment. However, as this risk is affected by the patient’s
baseline fasting glucose level and other features of meta-
bolic syndrome, subjects with pre-diabetes are probably
more prone to develop T2DM after statin administration.
These are frequent and important considerations that
should be taken into account when treating patients with
pre-diabetes. In this context, the intensification of life-
style measures and individualization of treatment choices
appear sensible.
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