485250

2013
DVR10510.1177/1479164113485250Diabetes & Vascular Disease ResearchPatel and Mehta

Review Article
Diabetes & Vascular Disease Research

Choice of anti-hypertensive agents in 10(5) 385­–396

© The Author(s) 2013
Reprints and permissions:
diabetic subjects sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1479164113485250
dvr.sagepub.com

Bhoomika M Patel1,2 and Anita A Mehta1

Abstract
Hypertension is an extremely common co-morbid condition in diabetes leading to acceleration in micro-vascular and
macro-vascular complications. The use of anti-hypertensives in diabetic patients should be considered in the context
of preventing the development of complications. Various factors contribute to the pathophysiology of diabetes in
hypertension. With the advancements in technology, the understanding of the pathophysiological mechanisms has
increased, and this can contribute in providing evidence for beneficial role of certain anti-hypertensives. Many clinical
trials have been carried out for use of diuretics, beta blockers, calcium channel blockers, angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers. The present review gives an overview of pathophysiological mechanisms of
hypertension and diabetes in addition to the details of clinical trials of anti-hypertensives in diabetic patients. This is an
attempt to provide some evidences for the clinicians, which may serve as a guide for use of anti-hypertensives in clinical
practice.

Keywords
Anti-hypertensives, diabetes mellitus, pathophysiology, treatment algorithm

Introduction
Diabetes mellitus (DM) and hypertension are two of the diabetes, reduction of diastolic BP to about 80 mmHg and
most common diseases, and the frequency of both diseases of systolic BP to about 130 mmHg is accompanied by a
increases with the advancing age.1 Hypertension is an further reduction in CV events or diabetes-related micro-
extremely common co-morbid condition in diabetes, affect- vascular complications, in comparison with patients with
ing approximately 20%–60% of patients with diabetes, less stringent BP control.10–14 Furthermore, in the UK
depending on obesity, ethnicity and age.2 Furthermore, the Prospective Diabetes Study (UKPDS) epidemiological
usual finding in long-term survivors of diabetes is the study, each 10-mmHg reduction in mean systolic BP was
absence of hypertension.3 Hypertension leads to a two- to found to be associated with reductions in risk of 12% for
threefold increase in major cardiovascular (CV) events in any complication related to diabetes, 11% for myocardial
both type 1 and type 2 diabetes. In type 1 diabetes, hyper- infarction (MI) and 13% for micro-vascular complica-
tension may reflect the onset of diabetic nephropathy,4 tions.13 BP treatment versus placebo has been effective in
while in type 2 diabetes, hypertension is often present as a reducing complications of diabetes15,16 and has helped to
part of the metabolic syndrome of insulin resistance, define the optimal level of BP control.11,13,17 An aggressive
including central obesity and dyslipidaemia.5 Hypertensive approach to the diagnosis and treatment of hypertension in
diabetic patients are at increased risk of diabetes-specific patients with diabetes is required in order to substantially
complication including retinopathy and nephropathy.6 reduce the incidence of both macro-vascular and micro-
Despite the benefit of blood pressure (BP) lowering and vascular complications. The objective of the current review
glycaemic control, rates of detection and control of the con- is to give a brief account of the pathophysiological
ditions have been suboptimal. Since both DM and hyper-
tension are important risk factors for cardiovascular 1Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad,
diseases (CVDs),7,8 management of hypertension and DM Gujarat, India
is therefore essential for the reduction of CV events and 2Department of Pharmacology, Institute of Pharmacy, Nirma University,

mortality. Up to 75% of CVDs in diabetes may be attribut- Ahmedabad, Gujarat, India

able to hypertension, leading to recommendations for more
Corresponding author:
aggressive treatment (i.e. reducing BP to <130/85 mmHg) Anita A Mehta, Department of Pharmacology, L. M. College of
in persons with coexistent diabetes and hypertension.9 It Pharmacy, Ahmedabad 380 009, Gujarat, India.
has been demonstrated by several trials that in patients with Email: [email protected]
386 Diabetes & Vascular Disease Research 10(5)

mechanisms underlying hypertension and diabetes and to In diabetic–hypertensive individuals, premature athero-
familiarize the readers with the choice of anti-hypertensives sclerosis probably contributes to premature ageing
in diabetic patients with reference to clinical trials being changes of the vasculature,28,29 which plays a key role in
carried out for the same. This is an attempt to provide some the relatively high prevalence of isolated systolic hyper-
evidences for the clinicians, which may serve as a guide for tension and decreased baroreceptor sensitivity in young
use of anti-hypertensives in clinical practice. diabetic individuals.30 The decreased baroreceptor sensi-
tivity is followed by the development of clinical neuro-
logical disease in young diabetic pateints.30 Decreased
Prevalence baroreceptor reflex sensitivity as well as altered cardiac
Approximately 50% of people with diabetes are hyperten- innervation may partially explain the marked variability
sive, and 35%–75% of complications of diabetes are of BP.28,30,31 These latter characteristics suggest prema-
thought to be due to hypertension.18,19 When hypertension ture ageing of the CV system in diabetic individuals with
coexists with diabetes, the risk of CVDs is increased by coexistent hypertension.27 In addition to premature vas-
75%, which further contributes to the overall morbidity cular ageing and its effect on vascular rigidity and resist-
and mortality of an already high-risk population.9,20 ance, other factors contribute to the pathophysiology of
Extensive epidemiological evidence indicates that dia- hypertension in diabetes (Figure 1). Moreover, sodium
betic individuals with hypertension have greatly increased retention, hyperglycaemia, hyperinsulinaemia (Figure 2),
risks of CVD, renal insufficiency and diabetic retinopa- enhanced vascular smooth muscle contractility and
thy.6,21 In both the type 1 diabetic and non-diabetic popu- renin–angiotensin system are major pathological mecha-
lations, hypertension is underdiagnosed,22 and the timing nisms responsible for hypertension in diabetic patients
and presentation of hypertension differs between type 1 (Table 1).
and type 2 diabetes. In type 1 diabetes, hypertension
develops after several years of the disease and usually
reflects the development of diabetic nephropathy ulti- Choice of anti-hypertensives
mately affecting ~30% of individuals with type 1 diabe- At the doses available for clinical use, most anti-hyperten-
tes.4,23 In type 2 diabetes, hypertension may be present at sives will produce a reduction in systolic or diastolic BP of
the time of diagnosis or even before the development of 5%–10% in patients with mild or moderate hypertension.2
hyperglycaemia.24 Approximately 20%–60% of patients Most patients require more than one agent to control BP.
with type 2 diabetes will develop hypertension, depending Several factors are important in selecting anti-hypertensive
on age, ethnicity and obesity. In some ethnic groups, dia- agents for use in hypertensive patients with diabetes.
betic nephropathy may be the primary determinant of
hypertension in type 2 diabetes. This has been documented
in Pima Indians.25 About 25%–47% of persons with Diuretics
hypertension have insulin resistance or impaired glucose
Thiazide diuretics
tolerance.26 Several confounding factors, present in type 2
diabetes, make the assessment of the prevalence of hyper- Thiazide diuretics are the first choice of agents in non-
tension attributable to diabetes difficult. Type 2 diabetic diabetic patients, but there has been a tendency to avoid
patients are older and have a greater degree of adiposity their use in patients with diabetes due to concerns over
than non-diabetic patients. The clustering of hyperten- adverse metabolic effects, despite evidence that these are
sion, glucose intolerance or frank type 2 diabetes, hyper- minimal when lower dose agents are used.32 Diuretics
lipidaemia, central obesity and insulin resistance has been reduce total body sodium through their natriuretic action
documented in several populations.5 Thus, increased BP and have also been shown to have vasodilatory effects.33
in these individuals may represent the ageing or obesity of Evidence from retrospective studies suggests increased
the population. However, after adjusting for age and CV mortality in diabetic patients receiving diuretics.34,35
weight, the prevalence of hypertension is still 1.5 times These studies were not randomized, and significant base-
higher in diabetic groups.24 The relationship between dia- line differences between patients receiving diuretics and
betic neuropathy and arterial hypertension is less clear. the patients not receiving them may have existed. In addi-
However, some epidemiological studies suggest that tion, these studies were based on data collected in the
hypertension may also be a contributory factor for this 1970s when high-dose diuretic treatment was the norm.2
condition.6 High-dose diuretics have detrimental effects on serum glu-
cose and HbA1c levels as well as on triglyceride and cho-
lesterol.19 However, low-dose diuretics are now more
Pathophysiology commonly prescribed and rarely cause clinically signifi-
Hypertension in diabetic individuals has certain charac- cant problems. Trials based on thiazide therapy, such as
teristics similar to hypertension in the elderly persons.27 Systolic Hypertension in the Elderly Program (SHEP),
Patel and Mehta 387

Figure 1. Relationship between diabetes and hypertension.

Figure 2. Co-relation between insulin and exchange pumps.

have shown a substantial benefit in hypertensive patients captopril-treated group and no difference in the primary
with diabetes.36 The Captopril Prevention Project (CAPPP) end point of combined MI, stroke and death from CV
trial showed a lower incidence of stroke in the convention- causes.37 The results of Antihypertensive and Lipid-
ally treated group (diuretics and beta blockers) than in the Lowering Treatment to Prevent Heart Attack Trial
388 Diabetes & Vascular Disease Research 10(5)

Table 1. Pathophysiological mechanisms of hypertension in diabetics.

Mechanisms Effect
Sodium retention Increased plasma volume
Enhanced vascular smooth muscle contractility Exaggerated vasoconstrictor responses
Altered vascular smooth muscle cation transport
Increased vascular free intracellular calcium
Renin–angiotensin system Increased plasma inactive renin levels
Altered plasma renin activity
Hyperglycaemia Increased vascular rigidity
Direct toxic effect of glucose on endothelial cells
Hyperinsulinaemia Sodium reabsorption and retention
Attenuation of vascular smooth muscle calcium influx

(ALLHAT), comparing chlorthalidone, lisinopril and Adrenergic blockers

amlodipine, favoured thiazide diuretics as first-line agents
due to their efficacy, safety and low cost (including for the Centrally acting agents
36% of participants who had diabetes). No significant dif- These drugs effectively lower BP by decreasing central
ference was seen between these three agents in the primary sympathetic outflow.41 However, studies on their effects on
end point of fatal or non-fatal MI, although significantly the progression or development of micro-vascular compli-
fewer patients randomized to chlorthalidone developed cations or CVD have not been carried out. Their major side
heart failure.38 Another arm of the study examining the use effects are orthostatic hypotension, drowsiness, impotence
of doxazosin was terminated early due to an increase in and dry mouth, and minor side effects are depression and
combined CV disease (mainly heart failure) with respect to Coombs-positive anaemia (with α-methyldopa).44 They
diuretic therapy.39 should be used with caution in patients with CV autonomic
In diabetic patients receiving thiazides, insulin sensitiv- neuropathy.
ity has been measured.33,40,41 Hydrochlorothiazide at a
daily dose of 25 mg or bendrofluazide at 1.25 mg daily
does not significantly decrease insulin sensitivity. Beta blockers
However, bendrofluazide at a daily dose of 5 mg caused a Beta blockers are competitive inhibitors of the β-adrenergic
significant reduction of in vivo insulin sensitivity.33 Low- receptors. Beta blockers have also been avoided due to a
dose chlorthalidone in combination with atenolol was theoretical adverse effect on insulin sensitivity and lipid
associated with low insulin sensitivity and increased tri- profiles, as well as a detrimental effect on hypoglycaemic
glyceride levels.41 The clinical significance of these meta- awareness. Cardioselective and non-selective beta blockers
bolic findings is unknown. In diuretic-based therapy, a differ in this regard, and fewer problems are seen with low-
low-dose thiazide diuretic has been shown to reduce the dose cardioselective drugs.19,45 Small effects on insulin sen-
CV event rate by 34% compared with placebo; the abso- sitivity and the lipid profile are rarely relevant in the clinical
lute risk reduction was twice as great for diabetic patients management of hypertension, but beta blockers are contra-
versus non-diabetic patients.15 indicated in patients with frequent hypoglycaemia or hypo-
glycaemic unawareness.
In UKPDS, atenolol was at least as effective as captopril
Non-thiazide diuretics
as a first-line agent,46 but the drug treatment comparison
A significant decrease in total body sodium and mild vaso- was inadequately powered to provide a definite conclusion,
dilation is the anti-hypertensive mechanism of loop diuret- that is, formal ‘equivalence’. No significant differences
ics.42 In the treatment of patients with diabetic nephropathy, were seen between the two groups’ lipid profiles.
furosemide in combination with β-adrenergic blockers was Differences were seen in HbA1c in the first 4 years of fol-
used as the mainstay anti-hypertensive regime in a study low-up but not in the second 4 years. In the atenolol groups,
reported by Parving et al.,43 and there was a significant 81% of patients were receiving an additional oral hypogly-
reduction in the rate of deterioration of the glomerular fil- caemic agent after 8 years compared to 71% in the captopril
tration rate (GFR) in patients with type 1 diabetes treated groups. It is notable that the patients randomized to atenolol
with an aggressive anti-hypertensive regimen. The major gained more weight over the follow-up period. Compliance
adverse effects of loop diuretics are hypokalaemia, was initially similar between the groups, but over time,
hyponatraemia and volume depletion.41 Their use is recom- fewer patients continued to take atenolol. There was no dif-
mended for patients with decreased renal function (GFR < ference in rates of hypoglycaemia between the groups, and
60 mL/min). no comment was made on hypoglycaemic awareness.
Patel and Mehta 389

Non-selective β-blockers are associated with decreased CCBs

counter-regulatory responses to hypoglycaemia, particu-
larly in patients taking insulin.47 However, it is unknown CCBs inhibit calcium influx through membrane-bound
whether this effect is clinically important; the UKPDS voltage-dependent calcium channels, resulting in decreased
study did not show an increased incidence of hypoglycae- intracellular calcium levels and vasodilation.41 The use of
mic episodes in the group treated with β-blockers. CCBs in high-risk groups has been the subject of debate, as
Following this, several trials were carried out for use of some retrospective cohort studies have shown adverse
metoprolol and carvedilol in diabetic patients. Carvedilol effects on cardiac disease. Initial concerns were raised by
has more favourable metabolic effects in diabetic patients studies in non-diabetic populations using short-acting dihy-
than traditional β-blockers.48,49 The Carvedilol Or dropyridines, which suggested that they may increase the
Metoprolol European Trial (COMET) demonstrated that incidence of MI. The main concerns for patients with dia-
carvedilol at a target dose of 50 mg daily reduced mortality betes came from the Appropriate Blood Pressure Control
in patients with heart failure compared with metoprolol tar- in Diabetes (ABCD)18,60 trial and Fosinopril versus
trate at a target dose of 100 mg daily in patients with chronic Amlodipine Cardiovascular Events Randomized Trial
heart failure.50,51 The subsequent analysis of COMET (FACET).61 These were small, underpowered trials with
revealed that treatment with carvedilol is associated with non-CV primary end points. In contrast, large well-designed
less development of new onset diabetes in patients with trials, which have included patients with diabetes, support
heart failure compared with treatment with metoprolol tar- the use and safety of calcium channel antagonists. ALLHAT
trate.52 The possible mechanism behind this could be that showed that amlodipine was not significantly different
insulin-stimulated endothelial function remained preserved from chlorthalidone in preventing MI.38 Supporting evi-
during treatment with carvedilol and blunted during treat- dence comes from the Hypertension Optimal Treatment
ment with metoprolol.53 (HOT) study, which used step-wise therapy based on
felodipine.11 The Systemic hypertension in Europe (SYST-
EUR) study also used a regime based on the calcium chan-
α-Adrenergic blockers nel antagonist nitrendipine. This study showed a reduction
α-Adrenergic blockers are inhibitors of the α-post- in stroke and CV events against placebo in older patients
sympathetic adrenergic receptors.54 α-Blockers have been with isolated systolic hypertension. A further subanalysis
recommended for the treatment of diabetic hypertension was performed on the subgroup of patients with diabetes
on the basis of their efficacy, lack of adverse effects on (492 of 4695).16 However, in both HOT and SYST-EUR
glucose or insulin metabolism and neutral or perhaps ben- trials, most patients were also receiving a β-blocker or an
eficial effect on the lipid profile.55 The anti-hypertensive ACE inhibitor in order to achieve the goals of therapy.
effects of these medications at the doses approved for clin- Therefore, it is difficult to judge the effectiveness of mono-
ical use are similar to other groups of agents. α-Adrenergic therapy with these drugs in reducing CV end points.2
blockers have been associated with improved insulin sen- Benefit was again seen in this group, which was at least as
sitivity in patients with insulin resistance associated with great as that shown in SHEP.36 Swedish Trial in Old Patients
essential hypertension.56 A slight decrease in low-density (STOP) examined three groups of patients given conven-
lipoprotein (LDL) cholesterol has been reported with tional therapy (diuretic or beta blocker), ACE inhibitor or
α-adrenergic blockers in small short-term clinical studies, calcium channel antagonist.62 It was originally reported
all involving <25 patients per group.57 The clinical signifi- that all three agents conferred equal benefit; however, in a
cance of these findings is unclear. Initial doses of these post-trial diabetes subgroup analysis (719 of 6614 patients),
agents, particularly prazosin,54 have been associated with there were more MIs in the calcium channel group (although
orthostatic hypotension; therefore, this agent should be there was no difference in mortality).62 A recent meta-anal-
used with caution in patients with diabetic autonomic neu- ysis has confirmed a trend for stroke outcomes to be better
ropathy. The ALLHAT study had an arm comparing an for CCBs, although in this analysis, they were inferior to
α-blocker, doxazosin, with a β-blocker, a calcium channel other anti-hypertensives in terms of preventing MI.63 In
blocker (CCB) and an angiotensin-converting enzyme conclusion, long-acting CCBs appear safe in people with
(ACE) inhibitor versus a diuretic.58 There are both advan- hypertension and diabetes.
tages and disadvantages to the use of central sympatholytic
anti-hypertensive agents (e.g. clonidine, guanabenz,
methyldopa and guanfacine) in the diabetic patient.
ACE inhibitors
Advantages include their lipid-neutral and minimal-to- ACE inhibitors have been promoted as first-line agents in
absent hyperglycaemic effects. However, centrally acting diabetes since they appear to have actions over and above
sympatholytic medications may worsen or unmask both BP-lowering alone. They have beneficial effects in heart
orthostatic hypotension and sexual dysfunction in diabetic failure and appear to be beneficial in left ventricular hyper-
patients.59 trophy (LVH) and in non-diabetic renal disease.
390 Diabetes & Vascular Disease Research 10(5)

Additionally, ACE inhibitors are not thought to affect glu- were also seen in the treatment group. BP was 12/5 mmHg
cose or lipid levels adversely. Although there are data dem- lower in the combination group and 5/3 mmHg lower in the
onstrating the efficacy of ACE inhibitors in lowering BP, perindopril group. This suggests that the effect seen may
there are as yet few data showing a reduction in CV mortal- have been attributable to BP-lowering rather than a specific
ity. Most of the available data are from the Heart Outcomes effect of the agent or class; however, it does provide hard
Prevention Evaluation (HOPE) study.64 This trial recruited outcome data for ACE inhibition in this context.
9541 patients aged over 55 years with a history of coronary
artery disease or diabetes and one or more other CV risk
factors. It examined ramipril against placebo with a com- Angiotensin receptor blockers
posite primary end point of MI, stroke and death from CV Fewer side effects is the major benefit of angiotensin
causes. In those randomized to ramipril, the incidence of receptor blockers (ARBs). With the exception of the
MI was reduced by 20%, stroke by 32% and death from CV Losartan Intervention for Endpoint reduction in hyperten-
causes by 26%. This was achieved with a mean BP reduc- sion (LIFE) study, scant CV morbidity and mortality data
tion of 3/2 mmHg in a population that was mainly normo- are available.70 This was a double-masked, randomized,
tensive. Importantly, in this context, 3577 of the patients in parallel-group trial comparing losartan and atenolol in
the HOPE study had diabetes. This subgroup was deliber- patients with hypertension and LVH, which showed a
ately recruited with the intention of having a cohort large 25% reduction in stroke, but not in MI, with losartan. A
enough to look at CV outcomes as well as the progression of difference in the rate of development of diabetes was also
diabetes. The results in the subgroup with diabetes were seen between the groups (four additional cases with aten-
similar to those in the overall study. The benefits observed olol per 1000 patient years). A pre-specified diabetes sub-
in association with active treatment in HOPE were calcu- group analysis was published at the same time.71 A total of
lated by the investigators to be around 3 times greater than 1195 patients with diabetes (both types 1 and 2) were ran-
those predicted from BP-related risk estimates (from the domized to receive atenolol or losartan and followed up
placebo group of HOPE and other studies). Therefore, they for a mean of 4.7 years. Additional therapy with hydro-
hypothesized that ACE inhibition confers benefits beyond chlorothiazide was added to achieve BPs of 146/79 (losar-
BP-lowering.65 However, a subsequent substudy, which tan) and 148/79 (atenolol). At the end of the trial, more
measured 24-h ambulatory BP, suggested that BP-lowering than 60% of participants were taking more than just the
was indeed the mechanism of end point reduction in patients study medication. The primary end point was a composite
randomized to ramipril. There were large differences in BP of CV mortality, stroke and MI and occurred in 103 (18%)
between patients taking placebo and those taking ramipril patients allocated to losartan and in 139 (23%) allocated
(especially at nighttime) compared to the small differences to atenolol, giving an adjusted hazard ratio of 0.76, p =
in office BP readings reported in the main study. Thus, 0.031. Confidence intervals were wide, and MI and stroke
BP-lowering may explain the benefits seen with rami- as individual end points were not significantly reduced,
pril.66,67 The UKPDS–Hypertension in Diabetic Study although there were significant reductions in CV (losartan
(UKPDS-HDS) showed similar beneficial effects of the 6%, atenolol 10%) and total mortality (losartan 11%, ate-
ACE inhibitor captopril and the β-blocker atenolol on diabe- nolol 17%). In the absence of other morbidity and mortal-
tes-related mortality and micro-vascular and CV complica- ity data from the ARB class, it is difficult to draw definitive
tions in patients with type 2 diabetes.13,66 Similarly, the conclusions from this trial, but it seems that losartan has
CAPPP trial compared captopril to conventional anti-hyper- advantages over atenolol for some patients at least. In the
tensive agents (diuretics and beta blockers) in 11,018 Candesartan in Heart Failure: Assessment of Reduction in
patients with hypertension of whom 572 also had diabetes. Mortality and Morbidity (CHARM) study, which involved
The results showed no significant difference in the primary patients who had symptomatic heart failure and had been
end point of combined MI and stroke (whether fatal or not) hospitalized in the previous 6 months, candesartan, when
and other CV deaths.37 In the diabetic subgroup, fewer added to existing therapy with any ACE inhibitor used at
patients randomized to captopril reached the primary end variable doses (with less than half the patients receiving
point than those randomized to conventional therapy (rela- full doses), was superior to placebo in reducing death or
tive risk: 0.59, p = 0.018).68 Further information on the hospitalization for heart failure.72 Another study on
effects of ACE inhibition in stroke disease comes from the Valsartan in Acute Myocardial Infarction Trial (VALIANT)
PROGRESS (perindopril protection against recurrent established the non-inferiority of valsartan, as compared
stroke) study which examined perindopril-based treatment with captopril, in patients with left ventricular (LV) dys-
in hypertensive and normotensive patients with a history of function or heart failure after MI since the combination of
stroke disease.69 A significant reduction in recurrent stroke a full dose of captopril plus valsartan did not significantly
was seen in patients given a combination of indapamide and reduce the occurrence of the primary outcome.73
perindopril, although interestingly not in those on perindo- Telmisartan was equivalent to ramipril in patients with
pril alone. Benefits in terms of mortality and CV events vascular disease or high-risk diabetes and was associated
Patel and Mehta 391

with less angioedema.74 Telmisartan was well tolerated in LV remodelling in patients with essential hypertension,
patients unable to tolerate ACE inhibitors and modestly and the addition of spironolactone during candesartan
reduced the risk of the composite outcome of CV death, treatment is clinically efficacious in reducing the LVH,
MI or stroke.75 A meta-analysis of randomized controlled which has been already developed.83 Furthermore, Naruse
trials indicates that telmisartan provides a superior BP et al.84 have reported that endothelin-1 messenger RNA
control over ACE inhibitors (enalapril, ramipril and perin- (mRNA) expression increases after a longer period of
dopril) and has fewer drug-related adverse events and bet- candesartan administration in spontaneously hypertensive
ter tolerability in hypertensive patients.76 stroke prone rats but was decreased by co-administration
of spironolactone. Exploring further, the combination
therapy for long-term studies may be beneficial for hyper-
Combination therapy tensive diabetic patients.
Low-dose combination therapy may resolve some of the
dilemmas in hypertensive patients with diabetes, although
Newer agents
it is not without its problems. In UKPDS, after 9 years of
follow-up, 29% of patients in the ‘tight BP control’ group Aliskiren is an orally active renin inhibitor, which became
needed three or more therapies to meet target BP.13 In the first drug in its class to receive regulatory approval for
clinical practice, most hypertensive patients with diabetes the treatment of hypertension. Aliskiren inhibits the first
will not have their BP controlled on one therapy alone, rate-limiting step in the renin–angiotensin–aldosterone
rendering the argument over the best single agent less rel- system (RAAS) cascade, the conversion of angiotensino-
evant. There has been some examination of the most gen to angiotensin I and thereby reducing synthesis of all
effective therapeutic combinations. Low-dose diuretics subsequent components of the cascade.85 Aliskiren Trial
are noted to augment the anti-hypertensive effects of other in Type 2 Diabetes Using Cardio-Renal Endpoints
major classes and therefore work well in combinations.77 (ALTITUDE), an international, randomized, double-
They may have a particular role in combination with drugs blind, placebo-controlled, parallel-group trial, was initi-
that block the renin–angiotensin system. CCBs and ACE ated to determine the effect of aliskiren on CV and renal
inhibitors in combination may be beneficial as they have morbidity and mortality compared with placebo when
different mechanisms of decreasing BP and have been added to conventional treatment (including ACE inhibitor
shown to be effective together. In a small study, dual or ARB) in three categories of high-risk patients with type
blockade of the renin–angiotensin system using candesar- 2 diabetes. Initially, they aimed to randomize 8600
tan and lisinopril [the Candesartan and Lisinopril patients with a planned follow-up time of 48 months.86
Microalbuminuria (CALM) study] found that the combi- However, ALTITUDE trial was stopped prematurely in
nation of both agents reduced BP and urinary albumin lev- December 2011 on recommendation of the data monitor-
els to a greater extent than either medication alone.78 In ing committee after it found an increased occurrence of
general, combination therapy may help to improve com- side effects, and continuation of the study was deemed
pliance, as one drug may antagonize the adverse effects of ‘futile’. Patients in the aliskiren group experienced sig-
another.79 Fixed-dose combinations of many drugs are nificantly increased serum potassium of ≥6 mmol/L and
available and may be appropriate when the patient requires reported hypotension.87 It was further reported that the
more than one drug, the dosages in the product are appro- addition of aliskiren to standard therapy with renin–angi-
priate for the patient, and the costs are not greatly otensin system blockade in patients with type 2 diabetes
increased. A morbidity–mortality double-blind trial, who are at high risk for CV and renal events is not sup-
ADVANCE (Action in Diabetes and Vascular disease: ported by these data and may even be harmful.88
PreterAx and DiamicroN MR Controlled Evaluation) Alagebrium (4,5-dimethylthiazolium) is a novel breaker
study in normotensive or hypertensive patients with type of cross-links in advanced glycation end products (AGEs)
2 diabetes, used a fixed-dose combination tablet contain- and has been studied mainly for its chronic effects on
ing perindopril and indapamide. Significant reductions in AGEs.89 A randomized, double-blind, parallel-group trial
the relative risk of death from CVD, total coronary events of assessment of safety and efficacy was initiated for
and total renal events were observed.80 Combination of an alagebrium in 2007.90 However, the study was terminated
ACE inhibitor and an ARB was used in Randomized early due to financial constraints.91 Thus, with new anti-
Evaluation of Strategies for Left Ventricular Dysfunction hypertensives coming into the market, there seems still a
(RESOLVD) pilot study, which depicted no sustained long way to go for use of the same in diabetes.
aldosterone reduction.81 In heart, the combination of vals-
artan and spironolactone has been shown to suppress car-
diac remodelling, such as myocyte hypertrophy and Treatment plan
perivascular fibrosis, in hypertensive rats.82 In another The choice of anti-hypertensives to be used in diabetic
study, candesartan treatment improves the early stage of patients should not only aim at controlling hypertension but
392 Diabetes & Vascular Disease Research 10(5)

Figure 3. Treatment algorithm for anti-hypertensives in diabetics.

DM: diabetes mellitus; ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; ISA: intrinsic sympa-
thomimetic action.
Patel and Mehta 393

also in preventing/delaying the development of complica- 3. Borch-Johnson K, Nissen RN and Nerup J. Blood pressure
tions. In such patients, initially, the BP should be monitored after 40 years of insulin-dependent diabetes. Nephron 1985;
for 1 month to confirm the presence of hypertension. The 4: 11–12.
confirmed hypertensive diabetic patients should be given 4. Mathiesen ER, Ronn B, Jensen T, et al. Relationship
between blood pressure and urinary albumin excretion
the treatment as per the algorithm (Figure 3). Patients hav-
in development of microalbuminuria. Diabetes 1990; 39:
ing BP between 130/80 mmHg and 140/90 mmHg should
245–249.
be first started with lifestyle modification and monitored 5. Eriksson H, Welim L, Wilhelmsen L, et al. Metabolic dis-
regularly. For patients with BP ≥ 140/90 mmHg, the first- turbances in hypertension: results from the population study
line therapy consists of ACE inhibitor or ARBs. ACE inhib- ‘Men born in 1913’. J Intern Med 1992; 232: 389–395.
itor should be started for type 1 diabetics and ARBs for type 6. Knuiman MW, Welborn TA, McCann VJ, et al. Prevalence
2 diabetics; however, ACE inhibitor should be the choice of of diabetic complications in relation to risk factors. Diabetes
agent for patients with micro-albuminuria for both type 1 1986; 35: 1332–1339.
and type 2 diabetic patients. For patients with micro-albu- 7. Chobanian AV, Bakris GL, Black HR, et al.; National Heart,
minuria who are unable to tolerate ACE inhibitors or ARBs, Lung, and Blood Institute Joint National Committee on
CCBs should be considered. If the BP control is not Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure; National High Blood Pressure Education
obtained with the first-line treatment, the doses can be
Program Coordinating Committee. The seventh report of
increased, and if BP is not controlled even with increased
the Joint National Committee on Prevention, Detection,
doses, second-line therapy should be initiated with diuretic, Evaluation, and Treatment of High Blood Pressure: the JNC
β-blocker or CCB, depending on compelling indication 7 report. JAMA 2003; 289: 2560–2572.
present. Despite this, if BP is not under control, other agents 8. Woodward M, Zhang X, Barzi F, et al.; Asia Pacific Cohort
can be added or a specialist should be consulted. Although Studies Collaboration. The effects of diabetes on the risks of
the algorithm present gives an overview of the anti-hyper- major cardiovascular diseases and death in the Asia-Pacific
tensive to be given for diabetic patients, the treatment deci- region. Diabetes Care 2003; 26: 360–366.
sions should be individualized. 9. Sowers JR, Epstein M and Frohlich ED. Diabetes, hyperten-
sion, and cardiovascular disease. Hypertension 2001; 37:
1053–1059.
Conclusions 10. Brenner BM, Cooper ME, de Zeeuw D, et al.; RENAAL
Study Investigators. Effects of losartan on renal and car-
Hypertension patients with diabetes are at considerably diovascular outcomes in patients with type 2 diabetes and
greater risk for diabetes-specific complications and an nephropathy. N Engl J Med 2001; 345: 861–869.
aggressive approach for the diagnosis and treatment is 11. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of
required to substantially reduce the incidence of both intensive blood-pressure lowering and low-dose aspi-
macro-vascular and micro-vascular complications. The rin on patients with hypertension: principal results of the
choice of anti-hypertensives to be used in diabetic patients Hypertension Optimal Treatment (HOT) randomized trial.
should not only aim at controlling hypertension but also in Lancet 1998; 351: 1755–1762.
preventing/delaying the development of complications. 12. Parving HH, Lehnert H, Bröchner-Mortensen J, et al. The
effect of irbesartan on the development of diabetic nephropa-
Most of the patients do not respond to single drug, and
thy in patients with type 2 diabetes. N Engl J Med 2001; 345:
hence, multiple drugs are required. When more than one
870–878.
anti-hypertensive is given, patient should be closely moni- 13. UK Prospective Diabetes Study Group. Tight blood pressure
tored for major adverse effects. Furthermore, there is a dire control and risk of macrovascular and microvascular com-
need for conducting more long-term clinical trials to sub- plications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:
stantiate the current literature. 703–713.
14. Zanchetti A and Ruilope LM. Antihypertensive treatment in
Declaration of conflicting interests patients with type-2 diabetes mellitus: what guidance from
recent controlled randomized trials? J Hypertens 2002; 20:
The authors declare that there is no conflict of interest.
2099–2110.
15. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based
Funding antihypertensive treatment on cardiovascular disease risk in
This research received no specific grant from any funding agency older diabetic patients with isolated systolic hypertension:
in the public, commercial, or not-for-profit sectors. Systolic Hypertension in the Elderly Program Cooperative
Research Group. JAMA 1996; 276: 1886–1892.
16. Tuomilehto J, Rastenyte D, Birkenhager WH, et al.
References Effects of calcium-channel blockade in older patients with
1. Sowers JR and Zemel MB. Clinical implications of hyperten- diabetes and systolic hypertension. N Engl J Med 1999;
sion in the diabetic patient: a review. Am J Hypertens 1990; 340: 677–684.
3: 415–424. 17. Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood
2. Arauz-Pacheco C, Parrott MA and Raskin P. The treatment pressure control on diabetic microvascular complications
of hypertension in adult patients with diabetes. Diabetes in patients with hypertension and type 2 diabetes. Diabetes
Care 2002; 25: 134–147. Care 2000; 23: B54–B64.
394 Diabetes & Vascular Disease Research 10(5)

18. Estacio RO and Schrier RW. Antihypertensive therapy Hypertension in the Elderly Program (SHEP). JAMA 1991;
in type 2 diabetes: implications of the Appropriate Blood 265: 3255–3264.
Pressure Control in Diabetes (ABCD) trial. Am J Cardiol 37. Hansson L, Lindholm LH, Niskanen L, et al. Effect of
1998; 82: 9R–14R. angiotensin-converting-enzyme inhibition compared with
19. MacLeod MJ and McLay J. Drug treatment of hypertension conventional therapy on cardiovascular morbidity and
complicating diabetes mellitus. Drugs 1998; 56: 189–202. mortality in hypertension: the Captopril Prevention Project
20. Adler AI, Stratton IM, Neil HA, et al. Association of sys- (CAPPP) randomised trial. Lancet 1999; 353: 611–616.
tolic blood pressure with macrovascular and microvascular 38. ALLHAT Officers and Coordinators for the ALLHAT
complications of type 2 diabetes (UKPDS 36): prospective Collaborative Research Group. Major outcomes in high-
observational study. BMJ 2000; 321: 412–419. risk hypertensive patients randomized to angiotensin-
21. Hasslacher C, Sted W, Wahl P, et al. Blood pressure and converting enzyme inhibitor or calcium channel blocker
metabolic control as risk factors for nephropathy in type I vs diuretic: the Antihypertensive and Lipid-Lowering
(insulin-dependent) diabetes. Diabetologia 1985; 28: 6–11. Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
22. Maahs DM, Kinney GL, Wadwa P, et al. Hypertension prev- 2002; 288: 2981–2997.
alence, awareness, treatment, and control in an adult type 1 39. ALLHAT Officers and Coordinators for the ALLHAT
diabetes population and a comparable general population. Collaborative Research Group. Major cardiovascular events
Diabetes Care 2005; 28: 301–306. in hypertensive patients randomised to doxazosin vs chlo-
23. Nishimura R, LaPorte RE, Dorman JS, et al. Mortality trends rthalidone: the Antihypertensive and Lipid-Lowering
in type 1 diabetes: the Allegheny County (Pennsylvania) Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
Registry 1965–1999. Diabetes Care 2001; 24: 823–827. 2000; 283: 1967–1975.
24. Hypertension in Diabetic Study (HDS): prevalence of hyper- 40. Prince MJ, Stuart CA, Padia M, et al. Metabolic effects of
tension in newly presenting type 2 diabetic patients and the hydrochlorothiazide and enalapril during treatment of the
association with risk factors for cardiovascular and diabetic hypertensive diabetic patient. Arch Intern Med 1988; 148:
complications. J Hypertens 1993; 11: 309–317. 2363–2368.
25. Nelson RG, Bennett PH, Beck GJ, et al. Development and 41. Schneider M, Lerch M, Papiri M, et al. Metabolic neutrality
progression of renal disease in Pima Indians with non-insu- of combined verapamil-trandolapril treatment in contrast to
lin-dependent diabetes mellitus. N Engl J Med 1996; 335: beta-blocker-low-dose chlortalidone treatment in hyperten-
1636–1642. sive type 2 diabetes. J Hypertens 1996; 14: 669–677.
26. Lind L, Berne C and Lithell H. Prevalence of insulin resistance 42. Henning M. Pharmacology of antihypertensive drugs in
in essential hypertension. J Hypertens 1995; 13: 1457–1462. Amsterdam. In: Van Zwiten PA (ed.) Hard-book of hyper-
27. Sowers JR. Hypertension in the elderly. Am J Med 1987; tension, vol. 3. Elsevier, 1984, pp. 154–193.
82: 1–8. 43. Parving HH, Andersen AR, Smidt UM, et al. Effect of
28. Sowers JR, Levy J and Zemel MB. Hypertension and diabe- antihypertensive treatment on kidney function in diabetic
tes. Med Clin North Am 1988; 72: 1399–1414. nephropathy. BMJ 1987; 294: 1443–1447.
29. Schonfeld G. Diabetes, lipoproteins, and atherosclerosis. 44. Webster J and Koch HF. Aspects of tolerability of centrally
Metabolism 1985; 34: 45–50. acting antihypertensive drugs. J Cardiovasc Pharmacol
30. Eckberg DL, Harkins SW, Fritsch JM, et al. Baroreflex 1996; 27: S49–S54.
control of plasma norepinephrine and heart period in 45. White WB, Prisant LM and Wright JT. Management of
healthy subjects and diabetic patients. J Clin Invest 1986; patients with hypertension and diabetes: advances in the
78: 366–374. evidence for intensive treatment. Am J Med 2000; 108:
31. Wiegmann TB, Herron KG, Chonko AM, et al. Recognition 238–245.
of hypertension and abnormal blood pressure burdened with 46. UK Prospective Diabetes Study Group. Efficacy of ateno-
ambulatory blood pressure recordings in type I diabetes mel- lol and captopril in reducing the risk of macrovascular and
litus. Diabetes 1990; 39: 1556–1560. microvascular complications in type 2 diabetes: UKPDS 39.
32. Harper R, Ennis CN, Heaney AP, et al. A comparison of BMJ 1998; 317: 713–720.
the effects of low- and conventional-dose thiazide diuretic 47. Clausen-Sjobom N, Lins PE, Adamson U, et al. Effects of
on insulin action in hypertensive patients with NIDDM. metoprolol on the counter-regulation and recognition of pro-
Diabetologia 1995; 38: 853–859. longed hypoglycemia in insulin-dependent diabetics. Acta
33. Lant A. Diuretic drugs: progress in clinical pharmacology. Med Scand 1987; 222: 57–63.
Drugs 1986; 31: 40–55. 48. Jacob S, Rett K, Wicklmayr M, et al. Differential effect of
34. Klein R, Moss SE, Klein BE, et al. Relation of ocular and chronic treatment with two beta-blocking agents on insulin
systemic factors to survival in diabetes. Arch Intern Med sensitivity: the carvedilol-metoprolol study. J Hypertens
1989; 149: 266–272. 1996; 14: 489–494.
35. Warram JH, Laffel LM, Valsania P, et al. Excess mortality 49. Bakris GL, Fonseca V, Katholi RE, et al.; GEMINI
associated with diuretic therapy in diabetes mellitus. Arch Investigators. Metabolic effects of carvedilol vs metoprolol
Intern Med 1991; 151: 1350–1356. in patients with type 2 diabetes mellitus and hypertension: a
36. SHEP Cooperative Research Group. Prevention of stroke randomized controlled trial. JAMA 2004; 292: 2227–2236.
by antihypertensive drug treatment in older persons with 50. Poole-Wilson PA, Cleland JG, Di Lenarda A, et al. Rationale
isolated systolic hypertension: final results of the Systolic and design of the Carvedilol Or Metoprolol European Trial
Patel and Mehta 395

in patients with chronic heart failure: COMET. Eur J Heart reduction and cardiovascular risk in HOPE study. Lancet
Fail 2002; 4: 321–329. 2001; 358: 2130–2131.
51. Poole-Wilson PA, Swedberg K, Cleland JG, et al.; Carvedilol 66. Kurtz TW. False claims of blood pressure-independent pro-
Or Metoprolol European Trial Investigators. Comparison of tection by blockade of the renin angiotensin aldosterone sys-
carvedilol and metoprolol on clinical outcomes in patients tem? Hypertension 2003; 41: 193–196.
with chronic heart failure in the Carvedilol Or Metoprolol 67. Svensson P, De Faire U, Sleight P, et al. Comparative effects
European Trial (COMET): randomised controlled trial. of ramipril on ambulatory and office blood pressures: a
Lancet 2003; 362: 7–13. HOPE substudy. Hypertension 2001; 38: e28–e32.
52. Torp-Pedersen C, Metra M, Charlesworth A, et al.; COMET 68. Niskanen L, Hedner T, Hansson L, et al. Reduced cardio-
Investigators. Effects of metoprolol and carvedilol on pre- vascular morbidity and mortality in hypertensive diabetic
existing and new onset diabetes in patients with chronic heart patients on first-line therapy with an ACE inhibitor com-
failure: data from the Carvedilol Or Metoprolol European pared with a diuretic/beta-blocker-based treatment regimen:
Trial (COMET). Heart 2007; 93: 968–973. a subanalysis of the Captopril Prevention Project. Diabetes
53. Kveiborg B, Hermann TS, Major-Pedersen A, et al. Care 2001; 24: 2091–2096.
Metoprolol compared to carvedilol deteriorates insulin-stim- 69. PROGRESS Collaborative Group. Randomised trial of a
ulated endothelial function in patients with type 2 diabetes perindopril-based blood-pressure-lowering regimen among
– a randomized study. Cardiovasc Diabetol 2010; 9: 21. 6,105 individuals with previous stroke or transient ischaemic
54. Van Zwieten PA, Timmermans PB and Van Brummelen P. attack. Lancet 2001; 358: 1033–1041.
Role of alpha adrenoceptors in hypertension and in antihy- 70. Dahlöf B, Devereux RB, Kjeldsen SE, et al.; LIFE Study
pertensive drug treatment. Am J Med 1984; 77: 17–25. Group. Cardiovascular morbidity and mortality in the
55. Sowers JR and Epstein M. Diabetes mellitus and associated Losartan Intervention for Endpoint reduction in hypertension
hypertension, vascular disease, and nephropathy. An update. study (LIFE): a randomised trial against atenolol. Lancet
Hypertension 1995; 26: 869–879. 2002; 359: 995–1003.
56. Pollare T, Sithell H, Selnius J, et al. Application of prazo- 71. Lindholm LH, Ibsen H, Dahlöf B, et al.; LIFE Study Group.
sin is associated with an increase of insulin sensitivity in Cardiovascular morbidity and mortality in patients with dia-
obese patients with hypertension. Diabetologia 1988; 31: betes in the Losartan Intervention for Endpoint reduction in
415–420. hypertension study (LIFE): a randomised trial against ateno-
57. Kwan CM, Shepherd AM, Johnson J, et al. Forearm and fin- lol. Lancet 2002; 359: 1004–1010.
ger hemodynamics, blood pressure control, and lipid changes 72. McMurray JJ, Ostergren J, Swedberg K, et al.; CHARM
in diabetic hypertensive patients treated with atenolol and Investigators and Committees. Effects of candesartan in
prazosin: a brief report. Am J Med 1989; 86: 55–58. patients with chronic heart failure and reduced left-ventricu-
58. Messerli FH. Implications of discontinuation of doxa- lar systolic function taking angiotensin-converting-enzyme
zosin arm of ALLHAT: the Antihypertensive and Lipid- inhibitors: the CHARM-Added trial. Lancet 2003; 362:
Lowering Treatment to Prevent Heart Attack Trial. Lancet 767–771.
2000; 355: 863–864. 73. Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan,
59. National High Blood Pressure Education Program Working captopril, or both in myocardial infarction complicated by
Group. National high blood pressure education pro- heart failure, left ventricular dysfunction, or both. N Engl J
gram working group report on hypertension in diabetes. Med 2003; 349: 1893–1906.
Hypertension 1994; 23: 145–158. 74. ONTARGET Investigators. Telmisartan, ramipril, or both in
60. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisol- patients at high risk for vascular events. N Engl J Med 2008;
dipine as compared with enalapril on cardiovascular out- 358: 1547–1559.
comes in patients with non-insulin-dependent diabetes and 75. Telmisartan Randomised Assessment Study in ACE Intolerant
hypertension. N Engl J Med 1998; 338: 645–654. Subjects with Cardiovascular Disease (TRANSCEND)
61. Tatti P, Pahor M, Byington RP, et al. Outcome results of Investigators. Effects of the angiotensin-receptor blocker
the Fosinopril versus Amlodipine Cardiovascular Events telmisartan on cardiovascular events in high-risk patients
Randomised Trial (FACET) in patients with hypertension intolerant to angiotensin-converting enzyme inhibitors: a
and NIDDM. Diabetes Care 1998; 21: 597–603. randomised controlled trial. Lancet 2008; 372: 1174–1183.
62. Lindholm LH, Hansson L, Ekbom T, et al. Comparison of 76. Zou Z, Xi GL, Yuan HB, et al. Telmisartan versus angioten-
antihypertensive treatments in preventing cardiovascular sion-converting enzyme inhibitors in the treatment of hyper-
events in elderly diabetic patients: results from the Swedish tension: a meta-analysis of randomized controlled trials. J
Trial in Old Patients with Hypertension – 2. J Hypertens Hum Hypertens 2009; 23: 339–349.
2000; 18: 1671–1675. 77. Brown MJ, Cruickshank JK, Dominiczak AF, et al.;
63. Staessen JA, Wang J and Thijs L. Cardiovascular protection Executive Committee, British Hypertension Society. Better
and blood pressure reduction: a meta-analysis. Lancet 2001; blood pressure control: how to combine drugs. J Hum
358: 1305–1315. Hypertens 2003; 17: 81–86.
64. Heart Outcomes Prevention Evaluation (HOPE) Study 78. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised
Investigators. Effects of ramipril on cardiovascular and controlled trial of dual blockade of renin-angiotensin
microvascular outcomes in people with diabetes mellitus. system in patients with hypertension, microalbuminuria,
Lancet 2000; 355: 253–259. and non-insulin dependent diabetes: the Candesartan and
65. Sleight P, Yusuf S, Pogue J, et al.; Heart Outcomes Lisinopril Microalbuminuria (CALM) study. BMJ 2000;
Prevention Evaluation (HOPE) Study. Blood-pressure 321: 1440–1444.
396 Diabetes & Vascular Disease Research 10(5)

79. Epstein M and Bakris G. New approaches to antihyperten- of ET-1 mRNA in SHR-SP/Izm. J Cardiovasc Pharmacol
sive therapy: use of fixed-dose combination therapy. Arch 2004; 44: S1–S3.
Intern Med 1996; 156: 1969–1978. 85. Staessen JA, Li Y and Richart T. Oral renin inhibitors.
80. Heim A, Feihl F and Waeber B. ADVANCE: a morbidity Lancet 2006; 368: 1449–1456.
mortality study of diabetes and hypertension. Rev Méd Suisse 86. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren
2008; 4: 28, 30, 32–33. Trial in Type 2 Diabetes Using Cardio-Renal Endpoints
81. McKelvie R, Usuf S, Pericak D, et al. Comparison of candesar- (ALTITUDE): rationale and study design. Nephrol Dial
tan, enalapril, and their combination in congestive heart fail- Transplant 2009; 24: 1663–1671.
ure: Randomized Evaluation of Strategies for Left Ventricular 87. http://www.sciencedaily.com/releases/2012/08/120826142958.
Dysfunction (RESOLVD) Pilot Study: the RESOLVD Pilot htm (accessed 22 December 2012).
Study Investigators. Circulation 1999; 100: 1056–1064. 88. Parving HH, Brenner BM, McMurray JJ, et al.;
82. Okada T, Nagai M, Taniguchi I, et al. Combined treatment ALTITUDE Investigators. Cardiorenal end points in a
with valsartan and spironolactone prevents cardiovascular trial of aliskiren for type 2 diabetes. N Engl J Med 2012;
remodeling in renovascular hypertensive rats. Int Heart J 367: 2204–2213.
2006; 47: 783–793. 89. Guo Y, Lu M, Qian J, et al. Alagebrium chloride protects the
83. Taniguchi I, Kawai M, Date T, et al. Effects of spironolac- heart against oxidative stress in aging rats. J Gerontol A Biol
tone during an angiotensin II receptor blocker treatment on Sci Med Sci 2009; 64: 629–635.
the left ventricular mass reduction in hypertensive patients 90. http://clinical-trials.findthedata.org/l/21018/Study-of-
with concentric left ventricular hypertrophy. Circ J 2006; 70: Alagebrium-in-Patients-With-Insulin-Dependent-Type-1-
995–1000. Diabetes-and-Microalbuminuria (accessed 22 January 2013).
84. Naruse M, Tanabe A, Hara Y, et al. Effects of AT1 recep- 91. http://clinicaltrials.gov/ct2/show/results/NCT00557518
tor antagonist and spironolactone on cardiac expression (accessed 22 January 2013).