Current Clinical Pharmacology, 2006, 1, 21-33 21

Recommendations for the Treatment of Hypertension in Patients with

DM: Critical Evaluation Based on Clinical Trials

Giuseppe Derosa1,*, Sibilla Salvadeo and Arrigo F.G. Cicero2

1
Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy and 2“G. Descovich”
Atherosclerosis Study Center, “D. Campanacci” Department of Clinical Medicine and Applied Biotechnology,
University of Bologna, Bologna, Italy

Abstract: Hypertension (blood pressure (BP) >140/90 mmHg) is a common comorbidity of type 2 DM (DM) and a major
risk factor for macro- and microvascular complications.
To review the effectiveness of different antihypertensive drugs in reducing BP, and diabetic complications in patients with
DM, we analysed clinical trials, reviews and reports, published in Cochrane Library and PubMed from 1991 to 2004.
Evidences suggest that optimal control of hypertension complications is obtained in diabetic patients when BP values are
<130/80 mmHg.
Different drug classes result useful to obtain this target BP, but their effects on different metabolic and non-metabolic
aspects have to be taken in account and a flexible approach according to individual response to different regimens is
essential.
Keywords: Hypertension, DM, ACE-inhibitor, Diuretic, Calcium-channel blocker, Angiotensin-receptor blocker.

INTRODUCTION Randomised clinical trials have demonstrated the benefit

(reduction of CHD events, stroke, and nephropathy) of
As stated by the last guidelines of the American Diabetes
lowering BP to <140 mmHg systolic and <80 mmHg
Association for Diabetes management, diabetes is a chronic
diastolic in persons with diabetes [5-7].
illness that requires continuing medical care and patient self-
management education to prevent acute complications and to Epidemiologic analyses show that BP values >115/75
reduce the risk of long-term complications. Diabetes care is mmHg are associated with increased CV events rates and
in fact complex and requires that many issues, beyond mortality in persons with diabetes [8,9].
glycemic control, be addressed. A large body of evidence
Therefore, a target BP goal of <130/80 mmHg is
exists that supports a range of interventions to improve
reasonable if it can be safely achieved.
diabetes outcomes [1].
Among patients with type 2 diabetes, cardiovascular NON PHARMACOLOGICAL TREATMENT OF
disease (CVD) accounts for 70–80% of mortality, with HYPERTENSION
around 15% of patients dying from stroke. Coronary heart
disease (CHD) rates are 2–6 fold higher than in the non- Although there are no well-controlled long-term studies
diabetic population and there is a loss of pre-menopausal of diet and exercise in the treatment of hypertension in
protection among diabetic women. The strength of the persons with diabetes, reducing sodium intake and body
relation between CV risk factors and CHD is similar to non- weight (when indicated), increasing consumption of
diabetics but is at a higher level [2]. vegetables, and low-fat dairy products, avoiding excessive
alcohol consumption, and increasing activity levels have
Hypertension (blood pressure (BP) >140/90 mmHg) is a been shown to be effective in reducing BP in non-diabetic
common comorbidity of diabetes, affecting the majority of individuals. In particular, even when pharmacologic agents
people with diabetes, depending on type of diabetes, age, are used, there is often a better response when there is
obesity, and ethnicity. [3] Hypertension is also a major risk concomitant salt restriction due to the volume component of
factor for CVD and microvascular complications such as the hypertension that is almost always present [10].
retinopathy and nephropathy. In type 1 diabetes, hypertension
is often the result of underlying nephropathy [4]. These non pharmacological strategies may also positively
affect glycemia and lipid control. However, their effects on
In type 2 diabetes, hypertension may be present as part of CV events have not been well measured yet.
the metabolic syndrome (i.e., obesity, hyperglycemia,
dyslipidemia) that is accompanied by high rates of CVD. Weight reduction can reduce BP independently of
sodium intake and also can improve blood glucose and lipid
levels. The loss of one kilogram of body weight has resulted
*Address correspondence to this author at the Department of in a decrease in mean 1 mmHg of BP [11]. Moderately
Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; E- intense physical activity, such as 30–45 min of brisk walking
mail: giuderosa@tin.it
most days of the week, has been shown to lower BP, in

1574-8847/06 $50.00+.00 ©2006 Bentham Science Publishers Ltd.

22 Current Clinical Pharmacology, 2006, Vol. 1, No. 1 Derosa et al.

diabetic patients as well [12]. Smoke quitting and In the 583 type 2 diabetic patients enrolled in SHEP,
moderation of alcohol intake are also recommended by JNC antihypertensive regimen resulted effective in lowering BP
VII and are clearly appropriate for all patients with diabetes. with few adverse effects. Based on the 5-year cumulative
events rates for all major CV events, SHEP treatment
THE PHARMACOLOGICAL CLASSES OF ANTI- prevented 101 diabetic participants per 1000 from having
HYPERTENSIVE AGENTS CVD event, compared to 51 per 1000 non-diabetic patients.
Moreover, SHEP treatment demonstrated a similar
In recent years, adequate data from well designed favourable influence on relative risk (RR) and absolute risk
randomized clinical trials, have demonstrated the effective- for diabetic as well as non-diabetic patients.
ness of aggressive treatment of hypertension with one or
more drugs in reducing both microvascular and macro- These results suggest that low-dose diuretic therapy
vascular diabetes complications. Moreover, an adequate should be strongly considered as a first choice treatment of
treatment of hypertension is linked to a reduced risk of renal systolic hypertension in the presence of non-insulin treated
failure in diabetic patients [13]. diabetes and glucose intolerance [16].
However, there is a lack of data derived from direct A retrospective analysis evaluated the development of
comparison of different antihypertensive drugs on main DM in all 4736 participants in the SHEP. New cases of
outcomes. Thus, the choice of drugs to be used is often taken diabetes were reported by 8.6% of the participants in the
from the metabolic effect of the antihypertensive drug, from active treatment group and 7.5% of the participants in the
its safety profile and from the patient comorbidities [14]. placebo group (p=0.25). Small effects of active treatment
compared to placebo were observed with fasting levels of
In Table 1 are resumed the antihypertensive drug classes glucose, total cholesterol, HDL cholesterol and creatinine.
that have shown to be somewhat useful in the treatment of Larger effects were seen with fasting levels of triglycerides,
diabetic hypertension: it is easy to note that the table uric acid, and potassium. In conclusion, antihypertensive
includes the major part of available antihypertensive drugs. therapy with low-dose chlorthalidone for ISH showed to be
In the past, the drug choice was primarily derived from the effective in lowering BP and CV complications and has
metabolic neutrality of drugs and from the absolute relatively mild effects on other CVD risk factors [17].
antihypertensive effect. Today, our choice has been made
more evidence-based by the results of many large long-term SYST-EUR (SYSTolic Hypertension in EURrope)
clinical trials on microvascular and macrovascular
complication rate of diabetic patients (hard outcomes). Active treatmentwith nitrendipine lowered the global
incidence of stroke by 42%, of non fatal stroke by 44%, of
Table 1. Antihypertensive Drug Classes that have Shown to total CV events (sudden death included) of 26%, of CV
Effectively Reduce Blood Pressure in Diabetic death by 27%, of HF by 29%, of myocardial infarction (MI)
Patients; the Major Molecules Available in Italian by 30%, of total mortality by 14%. In conclusion,
Market nitrendipine showed to be effective in reducing the rate of
CV complications and cerebrovascular events in patients 60
- Angiotensin-converting enzyme (ACE) inhibitors: Ramipril, years old with ISH [18].
captopril, enalapril, lisinopril,quinapril In the 492 diabetic patients (10.5%) of the randomized
- Angiotensin receptor blockers (ARBs): losartan, valsartan,
patients in SYST-EUR treatment with nitredipine (if
necessary replaced or combined with enalapril) decreased
irbesartan, telmisartan, olmesartan, candesartan mortality by 55%, CVD by 76%, strokes by 73% and cardiac
events by 63%. Treatment reduction in overall mortality,
- Beta-blockers: Atenolol, carvedilol, bisoprolol, metoprolol mortality from CVD, and all CV events was greater among
diabetic patients compared to non-diabetic patients (p=0.04,
- Dihydropyridine calcium channel blockers (CCBs): Nifedipine,
p=0.02, and p=0.01, respectively).
amlodipine, nicardipine, isradipine, lercanidipine, felodipine, Antihypertensive therapy based on the long acting
dihydropiridine calcium channel blocker (CCB) nitrendipine
nisoldipine.
was beneficial in older patients with hypertension and
- Diuretics: Chlorthalidone, hydrochlorothiazide, furosemide, diabetes and failed to support the notion that long acting
CCBs are harmful in diabetics [19].
spironolactone, amiloryde
HOT (Hypertension Optimal Treatment Randomized
Trial)
LARGE LONG-TERM CLINICAL TRIALS CARRIED
OUT ON HYPERTENSIVE DIABETICS This multicenter, international, prospective, randomized,
open blinded end-point study aimed at evaluating the optimal
SHEP (Systolic Hypertension in the Elderly Program) target DBP in treated hypertensive patients.
In patients 60 years old with isolated systolic hyper- The rate of major CV events was 9.9 events per 1000
tension (ISH) stepped care therapy based on chlorthalidone patient-years in the
90 mmHg group, 10.0 events per 1000
showed a reduction the incidence of major CV events and patient-years in the
85 mmHg and 9.3 events per 1000
stroke [15]. patient-years in the
80 mmHg.
Recommendations for the Treatment of Hypertension Current Clinical Pharmacology, 2006, Vol. 1, No. 1 23

The lowest risk of major CV events was achieved at a clearance, throughout the follow up period, of 5-6
mean DBP of 82.6 mmHg and SBP of 138.8 mmHg and the ml/min/1.73m2/year, whether they were in moderate or
lowest risk of CV mortality was at a mean DBP 86.5 mmHg intensive BP control group.
and SBP 138.8 mmHg.
No difference was found between the intervention with
In patients with DM (1501) major CV events occurred at regard to individuals progressing from normoalbuminuria to
a rate of 24.4, 18.6 and 11.9 events per 1000 patient-years in microalbuminuria (25% with intensive therapy vs 18% with
the three groups (
90 mmHg,
85 mmHg,
80 mmHg) moderate therapy, p=0.20) or microalbuminuria to overt
(p=0.005), respectively. In diabetic patients total mortality albuminuria (16% with intensive therapy vs 23% moderate
was 15.9, 15.5, and 9.0 per 1000 patient-years, (p=0.068), therapy, p=0.28). The intensive therapy was associated with
respectively; CV mortality was 11.1, 11.2, and 3.7 per 1000 lower overall incidence of deaths (5.5% vs 10.7%, p=0.037).
person-years, (p=0.016), respectively. These results Over a follow up of 5 years, there was no difference between
demonstrate the benefit of lowering BP (DBP down to 82.6 the intensive and moderate groups in the progression of
mmHg) in patients with hypertension to 140 mmHg systolic diabetic retinopathy and neuropathy. Moreover, the effects of
and 85 diastolic or lower with particular benefit for the nisoldipine and enalapril on diabetic retinopathy and
subgroups of patients with DM. The rate of CV events neuropathy were similar.
observed with treatment initiated with felodipine was much
lower than that observed in previous trials with diuretic or The ABCD trial suggests that creatinine clearance in
beta-blockers initiated treatment. This is probably due to a hypertensive type 2 diabetic patients can be stabilized over 5
more effective lowering of BP in HOT. Moreover, years, for BP values 132/78-138/86 mmHg, if therapy is
association with small dose of acetylsalicylic acid with started before the onset of albuminuria. These effects result
antihypertensive treatment can be recommended: it shows to independent on the use of nisoldipine or enalapril as the
be effective in reducing the risk of MI without exaggerating initial antihypertensive medication. There was no difference
the risk of central bleeding [6]. in the progression of diabetic retinopathy and neuropathy
over 5 years between moderate vs intensive BP control and
ABCD TRIAL (Appropriate Blood Pressure Control in enalapril vs nisoldipine. In conclusion, the more intensive BP
Diabetes) control resulted effective in decreasing all cause mortality
[21].
The purpose of this randomized, double-blind, placebo
controlled (normotensive cohort) study were to determine the
FACET (Fosinopril Versus Amlodipine Cardiovascular
effectiveness of intensive vs moderate BP control on the
Events Randomized Trial)
outcome of type 2 diabetic end-organ complications in
normotensive and hypertensive population and to compare This was an open-label, randomized prospective clinical
enalapril and nisoldipine as first line antihypertensive drugs trial comparing fosinopril to amlodipine in hypertensive
in terms of prevention and progression of diabetes people with type 2 DM. The primary aim was to compare the
complications. effect of fosinopril and amlodipine on serum lipids and
diabetes control in type 2 diabetic patients with hypertension.
A similar control in BP and no differences in glucose
Prospectively defined CV events were assessed as secondary
levels, glycosylated haemoglobin (HbA1c) and cholesterol
were observed both in nisoldipine and enalapril treated outcomes.
groups. There was a lower incidence of fatal and non fatal Both fosinopril and amlodipine resulted effective in
MI in patients on enalapril (5 events) compared to nisoldipine lowering BP: at the last visit, SBP was 4 mmHg lower in the
(25 events) (risk ratio 9.5; 95% CI, 2.3-21.4). These results amlodipine group compared tp fosinopril (p<0.01). Patients
were similar also in patients with hypertension and type 2 treated with fosinopril had significantly lower risk of the
DM, while infarction occurrence was lower in patients combined outcome of the acute MI, stroke, or hospitalized
treated with enalapril [20]. angina than those receiving amlodipine (14/189 vs 27/191;
A subsequent study investigated the effects of intensive HR 0.49, 95% CI, 0.26-0.95, p=0.030).
vs moderate BP control on type 2 diabetic complications
Fosinopril and amlodipine demonstrated similar effects
(nephropathy, retinopathy and neuropathy) in hypertensive
on biochemical measures, but the patients randomized to
type 2 diabetic patients enrolled in ABCD.
fosinopril had a significantly lower risk of major CV events
The mean BP achieved was 132/78 mmHg in the compared to the patients randomized to amlodipine [22].
intensive group and 138/86 mmHg in the moderate control
group. During the follow up period, no difference in the UKPDS (United Kingdom Prospective Diabetes Study)
change of creatinine clearance was observed between
intensive vs moderate BP control and between enalapril vs It was the largest and the longest clinical trial conducted
nisoldipine treatment. After 1 year of antihypertensive in the context of DM. It started in 1977 and interested 5000
treatment creatinine clearance was stabilized in both the patients enrolled in 503 centers of the United Kingdom. It
intensive and moderate BP control group in patients with was divided into two arms: UKPDS 38 and UKPDS 39.
baseline normo- or microalbuminuria. UKPDS 38 was designed to determine whether tight BP
In contrast, patients starting with overt albuminuria control could reduce micro- and macrovascular complications
(>300 mg/day) showed a steady decline in creatinine in patients with type 2 DM.
24 Current Clinical Pharmacology, 2006, Vol. 1, No. 1 Derosa et al.

Table 2. Main Features of the All Clinical Trials Included in the Text

NAME (References) DRUGS SAMPLES INCLUSION BP Changes FOLLOW- UP EFFECTS ON

CRITERIA PRIMARY
AND BASELINE OUTCOME
PARAMETERS

SHEP[15-16] Chlorthalidone 4736 60 years old Baseline(average) 4.5 years Treatment effective vs
(SHEP Cooperative Atenolol ISH SBP 170 mmHg (average) placebo in lowering
Research group, Reserpine SBP 160-219 mmHg DBP 77 mmHg BP and CV
JAMA 1991) DBP < 90 mmHg complications
Final
SBP 144 mmHg
DBP 68 mmHg
(J.D. Curb et al. As above 583 As above 5 years Treatment effective vs
JAMA 1996) (diabetic placebo in preventing
patients) CV events both in
diabetic and non-
diabetic patients and
more favourable for
diabetic patients (CHD
end-points).

SYST-EUR[18-19] Nitrendipine 4695  60 years old Reduction in 2 years (average) Treatment effective in
(Staessen JA et al. Placebo ISH SBP/DBP: reducing the rate of CV
Lancet 1997) -23/-7 mmHg complications and
(active treatment) cerebrovascular events.
-13/-2 mmHg Reduction in total
(placebo) mortality statistically
significant.
2 years (average)
(Tuomilheto J et al. The same 492 The same Reduction in Treatment reduction in
N Engl J Med) (diabetic SBP/DBP: overall mortality,
patients) -8.6/-3.9mmHg mortality from CVD,
(active treatment) and all CV events was
-13/-2mmHg greater among diabetic
(placebo) patients compared to
-10.3/-4.6 mmHg non-diabetic patients.
(non diabetics)

HOT[6] Felodipine 18790 50-80 years old Reduction in the 3 3.8 years For major CV events
( Hansson L et al. Aspirin 1501 type DBP100-115 mmHg target groups the lowest point of risk
Lancet 1998) 2 diabetics -26.2/-20.3mmHg was at a mean achieved
patients (
90mmHg) DBP 82.6 mmHg and a
-28.0/-22.3mmHg mean achieved SBP
(
85 mmHg) 138.5 mmHg. Among
-29.9/-24.3mmHg diabetic patients, in the
(
80 mmHg) group randomized to
DBP
80mmHg an
approxiamate halving
of the risk was
observed for the major
CV endpoints in
comparison with the
group randomized to
DBP
90mmHg.
Recommendations for the Treatment of Hypertension Current Clinical Pharmacology, 2006, Vol. 1, No. 1 25

(Table 2. Contd….)

NAME (References) DRUGS SAMPLES INCLUSION BP Changes FOLLOW- EFFECTS ON

CRITERIA UP PRIMARY OUTCOME
AND BASELINE
PARAMETERS

ABCD [20-21] Nisoldipine 470 40-74 years old Predefined targets of 5.3 years Lisinopril lowered
Enalapril hypertension DBP: incidence of MI.
(DBP90 mmHg) DBP
90mmHg Creatinine clearance
type 2 DM (WHO DBP<75 mmHg stabilized over 5 years with
diagnostic criteria) the obtained values of BP
Final BP: (when therapy is started
before the onset of overt
132/78mmHg(tight albuminuria).The more
BP control) intensive BP control
reduced all cause
138/86mmHg(less mortality.
tight BP control)

FACET [22] Fosinopril 380 Hypertension Baseline BP: 2.5-3.5 years Both treatments resulted
(Tatti et al. Diabetes Amlodipine SBP>150mmHg 170±1/95±1mmHg effective in lowering BP
Care 1998) DBP>90mmHg (fosinopril) and led to a similar effect
Type 2 DM 171±1/94±1mmHg on metabolic parameters
(amlodipine) in diabetic hypertensive
Final BP: patients.
157±1/88±1mmHg
153±1/86±1mmHg
Difference:
13mmHg (fosinopril)
19mmHg(amlodipine)

UKPDS [23] Tight BP vs 1148 25-65 years old Baseline mean BP: 8.4 years BP<150/85 mmHg resulted
(The UKPDS study less tight BP BP160/90mmHg 160/90 mmHg associated with reduction of
group. BMJ 1998) 5 control with BP150/85mmHg on the risk of death and
captopril and antihypertensive Final BP: complications in type 2 DM.
atenolol therapy 144±14/82±7 mmHg
(tight BP control)
154±16/87±7mmHg
(less tight BP control) Captopril and aenolol were
equally effective in reducing
(The UKPDS study 1148 56.4 years old Baseline mean BP the risk of fatal and non fatal
group. BMJ 1998) As UKPDS 38 160/94mmHg macrovascular and
(average)
Final BP microvascular complications
144/83mmHg(captopril) of type 2 DM:
143/81mmHg(atenolol)

CAPPP [24-25-26] Captopril 10985 25-65 years old Baseline BP in 6.1 years An antihypertensive
(Hansson et al. Lancet Beta-blockers Treated or untreated previously untreated regimen based on ACE-
1999)27 Diuretics primary hypertension: patients inhibitors is effective as a
(Niklason A et al. J DBP100mmHg, no 166/103mmHg conventional treatment
Hypertens 2004) upper limits 163/101mmHg with diuretics and beta-
For previously blockers in prevention of
treated: NA CV morbidity and
mortality., and most
probably more effective in
prevention of diabetes.
Primary CV end-point was
As above lower in captopril group
(Niskanen L et al. As above Diabetics Baseline BP in 5 years than in conventional
Diabetes Care 2001) 309 diabetics. treatment group.
captopril 163/97 Patients with impaired
263 metabolic control seemed
convention to benefit the most from
al ACE-inhibitors treatment.
treatment
26 Current Clinical Pharmacology, 2006, Vol. 1, No. 1 Derosa et al.

(Table 2. Contd….)

NAME (References) DRUGS SAMPLES INCLUSION BP Changes FOLLOW- EFFECTS ON

CRITERIA UP PRIMARY OUTCOME
AND BASELINE
PARAMETERS

CALM [27] Candesartan 199 30-74 years old Baseline 24 weeks At the used dosage,
cilexetil candesartan is as effective
(Mogensen CE et al. Lisinopril DBP 90-110 DBP: 90-110 mmHg as lisinopril in reducing BP
BMJ 2000) mmHg
and microalbuminuria in
type 2 diabetes Final reduction hypertensive type 2
urinary 16.3mmHg(combined
diabetic patients,
albumine/creatinine treatment)
combination treatment
ratio 2.5-25 mg/mmol 10.4mmHg(candesartan) resulting more effective in
10.7mmHg(lisinopril) reducing BP.

IRMA [28] Irbesartan 590 30-70 years old Baseline BP: 2 years Irbesartan resulted
(Parving HH et al. Type 2 diabetics 153±15mmHg renoprotective
N Engl J Med 2001) Persistent 90±9 mmHg independently of its BP-
microalbuminuria lowering effects in patients
Serum creatinine BP thoughtout the with type 2 DM and

1.5mg/dl study: microalbuminuria.
(men) 144/83mmHg

1.1mg/dl 143/83mmHg
(women) 141/83mmHg

IDNT [29-30] Irbesartan 1715 30-70 years old Baseline BP 2.6 years Irbesartan effective in
(Lewis EJ et al. Amlodipine Type 2 DM SBP 159±20 mmHg protecting against the
N Engl J Med 2001) Hypertension DBP 87±11 mmHg prgression of nephropathy
SBP135mmHg due to type 2 DM.
DBP85mmHg BP at subsequent
or antihypertensive visits:
treatment 140/77 mmHg
protein excretion at 141/77 mmHg
least 900 mg/dl 144/80 mmHg
serum creatinine: 1.0-
3.0 mg/dl

RENAAL [31] Losartan 1513 31-70 years old Baseline BP 3-4 years Losartan conferred
(Brenner BM et al. Type 2 DM significant renal benefit in
N Engl J Med 2001) Nephropathy SBP162±19 mmHg patients with type 2 DM
DBP82±10 mmHg and nephropathy

140/74 mmHg
(irbesartan)
142/74 mmHg
(placebo)

ALLHAT [32-33] Lisinopril Baseline BP: 4-8 years Chlorthalidone

(Davis BR et al. Amlodipine 15297 66 years (average) NA resulted more effective in
JAMA 2002) Chlorthalidone diabetics reducing CV end-points,
(Berecek KH et al. Doxazosin Final BP: but seemed to worsen
Curr Hypertens Rep NA insulin resistance and
2004) incidence of new on-set
DM.

LIFE [34-35-36] Losartan 9193 55-80 years old Baseline BP: 4.8 years Losartan prevents more
(Dahlof B et al. Atenolol 1195 previously treated or 174.4/97.8 mmHg CV morbidity and
Lancet 2002) diabetics untreated (average) mortality than atenolol for
(Lindholm LH et al. 7998 non hypertension a similar reduction in BP.
2002) diabetics at ECG signs of LVH Final BP: New-onset DM seemed to
(Lindholm LH et al. baseline 144.1/81.3mmHg be less frequent among
J Hypertens 2002) (losartan) patients treated losartan.
145.4/80.9 mmHg
(atenolol)
Recommendations for the Treatment of Hypertension Current Clinical Pharmacology, 2006, Vol. 1, No. 1 27

(Table 2. Contd….)

NAME (References) DRUGS SAMPLES INCLUSION BP Changes FOLLOW- EFFECTS ON

CRITERIA UP PRIMARY OUTCOME
AND BASELINE
PARAMETERS

MARVAL [37] Valsartan 332 35-75 years old Baseline BP: 24 weeks A statistically significant
(Viberti G et al. Amlodipine Normo or NA decrease in AER with
Circulation 2002) hypertensive valsartan compared with
Persistent Final BP reductions: amlodipine.
microalbuminuria -11.2/6.(valsartan)
-11.6/6.5
(amlodipine)

GEMINI [38] Carvedilol 1253 36-85 years old Baseline BP: 35 weeks Carvedilol in addition to a
(Bakris GL et al. Metoprolol Hypertension (>n NA RAS blocker did not affect
JAMA 2004) tartrate 130/80 mmHg) glycemic control and
Type 2 DM Final BP seemed to improve some
(HbA 1c 6.5-8.5%) components of metabolic
control.

VALUE [39] Valsartan 15245
50 years old Baseline BP: 4.2 years The main outcome of
(Julius S et al. Lancet Amlodipine Hypertension (treated 154.6/87.5 mmHg cardiac disease did not
2004) or untreated) differ between the
High risk for CV Final BP: treatment groups:
events (DM included) 139.3/79.2 mmHg
These findings underline
(valsartan)
the importance of a prompt
137.5/77.7 mmHg
BP control in hypertensive
(amlodipine)
patients at high CV risk.

DETAIL [40] Enalapril 250 Type 2 DM NA 5 years Telmisartan resulted not

(Barnett AH et al. Early nephropathy inferior to enalapril in
Telmisartan
N Engl J Med 2004) providing long-term
renoprotection in type 2
diabetic patients.This
support the clicnical
equivalence of ARBs and
ACE-inhibitors in high risk
persons.

The absolute risk for any diabetes related end-point was UKPDS 39 was a protocol derived from a subanalysis of
50.9 and 67.4 events per 1000 patient-years in the tight and UKPDS 38. It was conducted to compare the effect of
less tight control groups (RR 0.76; 95% CI, 0.62-0.92, intensive lowering of BP with captopril vs atenolol on
p=0.0046). Diabetes related death occurred at a rate of 13.7 prevention of micro- and macrovascular complications in
and 20.3 per 1000 patient- years, respectively (RR 0.68, 95% patients with type 2 DM.
CI, 0.49-0.94, p=0.019). Total mortality occurred at a rate of The incidence of any end-point related to diabetes
22.4 and 27.2 in the tight and less tight BP control group resulted similar in both treatment groups (53.3 vs 48.4 events
(RR 0.82,95% CI, 0.63-1.08, p=0.17). Risk of stroke (RR per 1000 patient-years in the captopril and atenolol groups,
0.56, 95% CI, 0.35-0.89, p =0.013), HF (RR 0.44, 95% CI, respectively; RR for captopril 1.10; 95% CI, 0.86-1.41,
0.20-0.94, p =0.0043) and risk of microvascular compli- p=0.43). UKPDS 39 demonstrated that captopril and atenolol
cations resulted reduced by the tight BP regimen (RR 0.63, were equally effective in reducing BP and the complications
95%, CI 0.44-0.89, p=0.0092). The reduction in of DM in hypertensive patients. So the study suggests that
microvascular end-points was predo-minantly due to a BP reduction might be more important than the specific
reduction in the risk of deterioration of retinopathy therapy used for prevention of diabetes complications [23].
(p=0.004) and retinal photocoagulation.
UKPDS 38 results demonstrated that tight BP control CAPPP (CAptopril Prevention Project Preventing Trial)
was associated to reduction in the risk of diabetes related
It was a randomized, open-label, parallel group, blinded
mortality and morbidity in hypertensive patients with type 2
end-point trial conducted in order to establish whether
DM [5].
antihypertensive treatment with captopril reduces CV
28 Current Clinical Pharmacology, 2006, Vol. 1, No. 1 Derosa et al.

mortality and morbidity more than a therapeutic regimen that more effective than either monotherapy, with a total
does not include an ACE-inhibitor. Secondary end-points reduction of SBP by 25.3 mmHg and 16.3 mmHg from
were to compare total mortality, development or deterioration baseline. Albumin/creatinine ratio was reduced by 24% in
of a heart disease, LV failure (LVF), atrial fibrillation, DM the candesartan cilexetil group, by 39% in the lisinopril
and possible differences in renal function in the 2 groups. group and by 50% with the combination.
The incidence of fatal and non fatal MI, stroke and other Creatinine clearance resulted slightly decreased over 24
CV deaths was similar in the captopril and conventional weeks in the groups treated with lisinopril (adjusted mean
groups (11.1 per 1000 patient-years vs 10.2 per 1000 patient- decrease 0.0835 ml/sec, p=0.04) and the combination
years; RR 1.05, p=0.52). Cardiovascular mortality resulted treatment (0.0735 ml/sec, p=0.05) but it was not affected in
lower with captopril than with conventional treatment (76 vs the group treated with candesartan.
95 events; RR 0.77, 95% CI, 0.90-1.22, p=0.092), the Dual blockade of the renin_angiotensin system (RAS),
incidence of fatal and non fatal MI was similar (162 vs 161), both at the level of ACE and at the level of the AII receptor,
while the incidence of stroke resulted higher in the captopril was associated with more effective reduction in BP than
group (189 vs 148 events, RR 1.25, 95% CI, 1.01-1.55, observed with a single agent.
p=0.044) [24].
The present study could not determine if these further
A recent subanalysis of the CAPPP, focusing on the effects on urinary albumin excretion relate to RAS provided
onset of DM in cohorts of patients enrolled in the study. A additional evidence for a role of agents which interrupt the in
lower incidence of DM during captopril treatment was conferring renoprotective effects in patients with incipient
observed in the whole CAPPP cohort that was non-diabetic diabetic nephropathy [27].
at baseline (n = 10413) as well as in such CAPPP patients
that were previously untreated (n = 5033). IRMA (IRbesartan Micro Albuminuria Type 2 DM in
Hypertensive Patients)
A captopril-based antihypertensive treatment regimen is
associated with a lower risk of DM development, compared In this randomized, double-blind, placebo-controlled
to conventional therapy based on diuretics and/or beta- trial, conducted in 96 centers worldwide, the renoprotective
blockers [25]. effect of irbesartan was evaluated in patients with type 2 DM
and persistent albuminuria. The primary outcome was the
In a successive study, CV mortality and morbidity in the time to the onset of diabetic nephropathy.
diabetic subpopulation of CAPPP was further analysed. In
patients with DM, captopril was associated to less primary Ten of the 194 patients in the 300 mg group (5.2%) and
end-point event rate (RR 0.59, 95% CI, 0.38-0.91, p=0.019). 19 of the 195 patients in the irbesartan 150 mg group (9,7%;
Specifically, CV mortality tended to be lower in the captopril RR 0.30, 95% CI, 0.14-0.61, p<0.001) reached the primary
group (RR 0.48, 95% CI, 0.21-1.10, p=0.084), and no end-point, as compared tp 30 of the 201 patients in the
difference was observed between the study groups for fatal placebo group (14,9%, 95% CI, 0.34-1.08, p=0.08).
and non fatal stroke (RR 1.02, 95% CI, 0.55-1.87, p=0.96). Irbesartan reduced the level of AER throughout the study
Fatal and non fatal MIs were less frequent in the captopril (24% reduction in irbesartan 300 mg and 38% reduction in
group than in the conventional therapy group (RR 0.34 95% the 300 mg group) vs 2% in the placebo group (p<0.001).
CI, 0.17-0.67, p=0.002). Total mortality was lower in the High dose irbesartan restored normoalbuminuria. Serious
captopril compared to the conventional therapy group (RR adverse events were less frequent among the patients treated
0.54, 95% CI, 0.31-0.95, p=0.034) and all cardiac events with irbesartan (p=0.02). Non fatal CV events occurred in
were lower in the captopril than in the conventional therapy 4.5% of the irbesartan 300 mg group vs 8.7% in the placebo
group (RR 0.67, 95% CI, 0.46-0.96, p=0.029). Patients with group (p=0.11).
impaired metabolic control (with fasting blood glucose
8.1
Irbesartan resulted renoprotective independently of its BP
mmol/L) seemed to benefit the most from ACE-inhibitor-
lowering effect in patients with type 2 DM and micro-
based therapy (p=0.033). albuminuria [28].
These results suggest that captopril is an obvious first-
choice drug for preventing CV events in hypertensive patients IDNT (Irbesartan Diabetic Nephropathy Trial)
with DM, especially in those with metabolic decompensation
This prospective, randomized, double-blind clinical trial
(poor glycemic control, lipid abnormalities) [26].
was conducted in 210 clinical centers. The purpose was to
determine whether either irbesartan (ARB) or amlodipine
CALM (Candesartan And Lisinopril Microalbuminuria
(CCB) slows the progression of nephropathy independently
Study) of the antihypertensive effect.
This randomized, parallel-group controlled trial was
The primary end-point was the composite of a doubled
designed to asses and compare the effectiveness of
baseline serum creatinine concentration, the onset of end-
candesartan cilexetil, lisinopril and their combination on
stage renal disease (indicated by initiation of dialysis, renal
DBP and albuminuria in hypertensive patients with type 2
transplantation, or a serum creatinine concentration of at
DM and microalbuminuria. Both SBP and DBP resulted
least 6.0 mg/dl) or death from any cause.
significantly reduced with candesartan cilexetil and lisinopril
with no significant differences between the two treatments. The secondary CV end-point was the composite of death
The combination of candesartan cilexetil and lisinopril was for CV causes, non fatal MI, HF resulted in hospitalization, a
Recommendations for the Treatment of Hypertension Current Clinical Pharmacology, 2006, Vol. 1, No. 1 29

permanent neurologic deficit caused by cerebrovascular of morbidity and mortality from CV causes, proteinuria, and
events, or lower limb amputation above the ankle. the rate of progression of renal disease.
The risk of the primary composite end-point was lowered The primary end-point was reached by 327 patients in the
by 20% in the irbesartan group compared to placebo group of losartan (43.5%) and by 359 patients (47.1%) in the
(p=0.02) group and by 23% in the irbesartan group compared placebo group: treatment with losartan resulted in a 16%
to amlodipine group (p=0.006). The risk of a doubling of the reduction in the risk (p=0.02) of the primary composite end-
serum creatinine concentration was 33% lower in the point. The decrease in risk did not change after adjustment
irbesartan group than in the placebo group (p=0.003) and for BP. There were no significant differences in the rates of
37% lowered in the irbesartan group than in the amlodipine most CV end-points. The level of proteinuria declined by
group (p<0.001). Treatment with irbesartan was associated 35% with losartan (p<0.001 for the comparison with
to a RR of end-stage renal disease that was 23% lower than placebo).
that in both other groups (p=0.07 for both comparisons).
Losartan was well tolerated and conferred renal benefits
Differences achieved in the BP could not explain these
results. The serum creatinine concentration increased in the in patients with type 2 DM and nephropathy [31].
irbesartan group 24% slower than in the placebo group
(p=0.008) and 21% slower than in the amlodipine group ALLHAT (Antihypertensive and Lipid-Lowering
(p=0.02). There were no significant differences in the rates Treatment to Prevent Heart Attack Trial)
of death from any cause or in the CV composite end-point. This randomized, double blind, active-control, multicenter
The trial demonstrated that irbesartan is effective in trial had the purpose to assess the incidence of fatal coronary
protecting against the progression of nephropathy in type 2 heart disease and non fatal MI in patients treated with 4 types
DM independently of its antihypertensive effect [29]. of antihypertensive drugs: chlorthalidone, doxazosin,
amlodipine, or lisinopril. The primary outcome measure was
The effectiveness of the irbesartan in hypertensive in fatal CHD or nonfatal MI, analyzed by intent to treat;
delaying or preventing diabetic nephropathy in patients with secondary outcome measures included all-cause mortality,
type 2 DM, hypertension and persistent microalbuminuria stroke, and combined CVD (CHD death, nonfatal MI, stroke,
was also evaluated. angina, coronary revascularization, CHF, and peripheral
Onset of diabetic nephropathy (defined by persistent arterial disease); compared to the chlorthalidone group vs the
doxazosin group.
albuminuria in overnight specimens, with a AER that was
greater than 200
g/min and at least 30% higher than the Some key messages on the results of ALLHAT are
baseline level) was reached by 10 of the 194 patients in the available: the lowering of BP and not the drug used to
300 mg group (5.2%) and 19 of the 195 patients in the 150 achieve this, remains the key variable in preventing future
mg group (9.7%) compared to 30 of the 201 patients in the CV events. The rates of CHF were higher among patients
placebo group (14.9%). HR for diabetic nephropathy was receiving either amlodipine or lisinopril compared to those
0.30 (95% CI, 0.14-0.61, p<0.001) and 0.61 (95% CI, 0.34- treated with chlorthalidone. A small increase in fasting blood
1.08, p=0.08) for the two irbesartan groups, respectively in glucose levels of 0.2 mmol/L and therefore modestly higher
comparison with placebo. The level of AER decreased by rates of new onset diabetes in the chlorthalidone group
24% and 38% in the 150 and 300 mg irbesartan vs 2% in the compared to the ACE-inhibitor and CCBs groups were
placebo group (p<0.001 for the comparison between the observed [32].
placebo and the combined irbesartan groups). Serious
adverse events resulted less frequent in patients treated with The ALLHAT was not designed to prospectively assess
irbesartan (15.4% vs 22.8% in the placebo group, p=0.02) the treatment effect in diabetic patients. However the
[30]. diabetic cohort was predesigned for subgroup analysis. Post
hoc power analysis revealed a lower degree of confidence for
the detection of a difference between the chlorthalidone and
RENAAL (Reduction of End-Points in NIDDM (Non-
the other treatment arms for the primary outcome of the
Insulin Dependent DM) with Angiotensin II Antagonist
Losartan) study (fatal and non fatal CHD). However this analysis
showed a higher power of detection of a difference in the
It was an investigator initiated, multinational, double- secondary outcome of the study (combined CVD) among the
blind, placebo-controlled trial designed to evaluate the diabetic subgroup.
renoprotective effects of losartan in patients with type 2
A significant higher six-years rate of HF was observed
diabetes and nephropathy. Nephropathy was defined by the
with amlodipine compared to chlorthalidone (10.2 vs 7.7
presence of two occasions of a ratio of urinary albumin
(measured in mg/L) to urinary creatinine (measured in g/L) respectively, RR 1.38). The lisinopril group had a higher 6-
years rate of combined CVD (stroke and CHF), compared to
from a first morning specimen of at least 300 (or a rate of
chlorthalidone (33.3% vs 30.9%, respectively).
urinary excretion of at least 0.5 g/day) and serum creatinine
values between 1.3 and 3.0 mg/dl with a lower limit of 1.5 Optimal control of BP in people with diabetes resulted
mg/dl for male patients weighing more than 60 Kg. difficult to achieve and required multiple medications. In a
large diabetic cohort with a mean age of 64.5 years
The primary outcome was a composite of a doubling of a
baseline serum creatinine concentration, end-stage renal (comparable with ALLHAT 66.6 mean age of the diabetic
subgroup), a BP goal was achieved in only 25% of patients.
disease, or death. Secondary end-points included a composite
30 Current Clinical Pharmacology, 2006, Vol. 1, No. 1 Derosa et al.

Furthermore an average of 3.1 medications was required to Independently of the calculated risk score, fewer
achieve such a BP goal. hypertensive patients with LVH developed DM if they were
treated with losartan than if they were treated with atenolol
Insulin resistance and incidence of new-onset DM
[36].
resulted worsened in the group treated with diuretics. On the
other hand, diuretics demonstrated the reduction of CV
MARVAL (Micro Albuminuria Reduction with
mortality, even in higher risk patients (particularly patients
VALsartan)
with diabetes and/or chronic kidney disease). These
contrasting results might be due to an inadeguate period of This multicenter, randomized, double-blind active
follow up, not long enough to evaluate the effect of diuretics control, parallel group study was conducted to investigate
on the development of new diabetes and the long term CVD whether the effect of valsartan on AER was independent of
morbidity and mortality. its BP-lowering properties. The primary end-point was the
percentage change in AER from baseline to week 24. The
Moreover, ALLHAT did not offer relevant information
secondary end-point was the proportion of patients returning
for the diabetic population such as the use of antidiabetic
agents, glucose control or microalbuminuria. to normoalbuminuria status.
Valsartan compared to amlodipine determined a
Compared to doxazosin, chlorthalidone yields essentially
statistically significant decrease in AER (95% CI, 0.539-
equal risk of CHD death/nonfatal MI but significantly
0.729, p<0.001). Valsartan, in contrast to amlodipine,
reduces the risk of combined CVD events, particularly CHF,
lowered AER progressively over time to a nadir at 24 weeks.
in high-risk hypertensive patients [33].
The AER at 24 weeks with valsartan was 56% (95% CI,
49.6-63.0) of baseline, equivalent to a 44% reduction. The
LIFE (Losartan Intervention For End-Point Reduction) AER for amlodipine at week 24 was 92% (95% CI, 81.7 -
This double-blind, randomized, parallel-group trial 103.7) of baseline, with a reduction of only 8%. The
compared the long term effects of atenolol and losartan on treatment effect was highly significant (95% CI, 0.520-
CV mortality and morbidity in hypertensive patients with LV 0.710, p<0.001). These results did not change after the
hypertrophy. adjustment for baseline hypertensive status.
Losartan showed to be more effective than atenolol in Subgroup analysis for patients who were hypertensive or
preventing the combined end-point of CV death, stroke and normotensive at entry produced a similar pattern of results
MI. Losartan significantly reduced the rates of stroke for change in AER (hypertensive subgroup: 95% CI, 0.482-
compared to atenolol and tended to reduce CV mortality and 0.737, p<0.001; normotensive subgroup: 95% CI, 0.486-
total mortality [34]. 0.772, p<0.001). The mean reductions in trough BP from
baseline to week 24 were similar in both treatment groups. In
A substudy of LIFE compared the long term effect of normotensive patients there were small decreases in BP with
atenolol and losartan on CV mortality and morbidity in both treatments (valsartan: SBP/DBP, -2.8/-2.7 mm Hg;
hypertensive patients with DM enrolled in LIFE. amlodipine, -1.9/-2.1 mm Hg) and no significant differences
Cardiovascular mortality resulted in 6% in the losartan between the 2 treatments (DBP, p=0.246; SBP, p=0.329).
group and 10% in the atenolol group (adjusted HR 0.63; 95% True equivalence of BP reduction was thus obtained between
CI, 0.42-0.95, p=0.028). Stroke occurred in 9% and 11% of the two antihypertensive regimens, and this applied
patients, respectively (HR 0.79; 95% CI, 0.55-1.14, p=0.204) irrespective of normotensive or hypertensive status. The
and MI in 7% and 8%, respectively (HR 0.83; 95% CI, 0.55- results of the analysis to assess whether changes in BP might
1.25, p=0.373). The composite end-point of CV death, stroke explain the differences in AER between treatments showed
or MI occurred in 18% of patients in the losartan group vs that both change in DBP and SBP were statistically
23% in the atenolol group (adjusted HR 0.76, 95% CI, 0.58- significant covariates (p=0.03 and p<0.001, respectively).
0.98, p=0.031). Total mortality was 11% v s 17%, However, the treatment effect remained significant
respectively (0.61, 95% CI, 0.45-0.84, p=0.002). Albuminuria (p<0.001) in both models, indicating that the observed
was noted in 7% vs 13% (p=0.002), respectively. Chest pain changes in AER were independent of differences in BP
was reported by 12% vs 8% of patients, (p=0.036), reduction. The proportion of patients achieving target BP
respectively. was similar in the two groups (valsartan, 53%; amlodipine,
45%) and not significantly different (difference 8.3%, 95%
Losartan demonstrated to be more effective than atenolol CI, (-7%)-20.1%, p=0.196).
in reducing total and CV mortality as well the composite
end-point of CV morbidity and mortality, hospitalization for The secondary end-point analysis showed a significantly
HF and the risk of developing albuminuria in hypertensive greater percentage of patients returning to normoalbuminuria
patients with diabetes and ECG signs of LVH [35]. status by week 24 with valsartan (29.9%; n=49) than with
amlodipine (14.5%; n=23) (between-treatment difference
A subanalysis was conducted to study the risk of new- 15.4%, 95% CI, 5.6-25.8, p<0.001). There was no significant
onset diabetes in hypertensive individuals who were at risk difference in mean change in absolute values of HbA1c from
of developing DM in the LIFE study. New-onset DM baseline to week 24 between valsartan (0.04%) and
occurred in 242 patients receiving losartan (13.0 per 1000 amlodipine (0.16%) (95% CI, (-0.34)-0.15, p=0.427). HbA1c
person-years) and 320 receiving atenolol (17.5 per 1000 remained stable and did not differ throughout the study with
person-years) (RR 0.75, 95% CI, 0.63 -0.88, p<0.001). either treatment. Eighty five percent of patients received oral
Recommendations for the Treatment of Hypertension Current Clinical Pharmacology, 2006, Vol. 1, No. 1 31

hypoglycemic agents in both treatment groups. Total effect of ARBs and ACE-inhibitors. The primary end-point
cholesterol, serum potassium, and serum creatinine were was the change in the glomerular filtration rate (determined
similar at baseline between the two groups and did not by measuring the plasma clearance of iohexol) between the
change significantly during follow-up [37]. baseline value and the last available value during the 5 years
treatment period. The change in the glomerular filtration rate
GEMINI (Glycemic Effects in DM: Carvedilol- was -17.9 ml per minute per 1.73 m2 of body-surface area
Metoprolol Comparison in Hypertensives) (where the minus sign denotes a decrement) with telmisartan
(in 103 subjects), as compared to enalapril -14.9 ml per
In large clinical trials, beta-blockers have been shown to
minute per 1.73 m2 with enalapril (in 113 subjects), for a
decrease CV risk in patients with hypertension and type 2
treatment difference of -3.0 ml per minute per 1.73 m2 (95 %
DM, but some components of metabolic syndrome were
CI, -7.6 to 1.6 ml per minute per 1.73 m2). The lower
observed to be worsened by some beta-blockers.
boundary of the CI, in favour of enalapril, was greater than
In GEMINI the carvedilol and metoprolol treatment the predefined margin of -10.0 ml per minute per 1.73 m2,
produced different mean change in HbA1c from baseline indicating that telmisartan was not inferior to enalapril.
(0,13%; 95% CI, (-0.22%)-0.04%, p=0.004) for the modified Telmisartan resulted not inferior to enalapril in providing
intention to treat analysis. The mean HbA1c (0.02% vs long-term renoprotection in persons with type 2 DM.
0.04%, p=0.65) increased with metoprolol and not with
carvedilol (0.15% vs 0.04%, p<0.001). Carvedilol improved These findings do not necessarily apply to persons with
insulin-sensitivity (-9.1%, p=0.004), but not metoprolol (- more advanced nephropathy, but they support the clinical
2.0%, p=0.48), the between-group difference being -7.2% equivalence of ARBs and ACE-inhibitors in persons with
(95% CI, (-13.8%)-(-0.2%), p=0.004). Achievements in BP conditions that place them at high risk for CV events [40].
values were similar in the two groups. Progression to
microalbuminuria resulted less frequent in the carvedilol COMMENTS AND DISCUSSION
group then in metoprolol group (6.4% vs 10.3%, OR 0.60; As explained above the major part of the studies
95% CI, 0.36-0.97, p=0.04). regarding hypertension treatment in diabetic patients have
Both beta-blockers resulted to be well tolerated; use of absolutely demonstrate that the reduction of BP values
carvedilol in addiction to a RAS blocker did not affect significantly diminish CV events and act as a protective
glycemic control and showed to be more effective than agent for targeted organs. On the other hand, many issues
metoprolol in improving some components of the metabolic regarding the optimal target BP are still partially unsolved as
syndrome in participants with DM and hypertension [38]. well as the comparison between the efficiency between the
different drug classes.
VALUE (Valsartan Antihypertensive Long Term-Use In the UKPDS a tight control in BP clearly resulted in a
Evaluation)
better control macro and microvascular complications while
This randomized, double-blind, parallel-group trial was the SHEP and the SYST-EUR have provided strong
designed to test the hypothesis that, for the same BP control, evidence of the utility of reducing pure systolic hypertension.
valsartan would reduce cardiac morbidity and mortality more In the diabetics patients randomized in HOT the best
than amlodipine in hypertensive patients at high CV risk. results in terms of CV reduction have been obtained with
Both valsartan and amlodipine resulted effective in DBP<80 mmHg.
reducing blood pressure, but the effects of the amlodipine- On the other hand, in the UKPDS treatment with ACE-
based regimen were more relevant, especially in the early inhibitor ramipril resulted effective in reducing by 25% the
period. The primary composite end-point occurred in 810 different primary combined end-points, despite of a minimal
patients in the valsartan group (10.6%, 25.5 per 1000 patient- effect on BP. Among the main studies evaluating ACE-
years) and 789 in the amlodipine group (10.4%, 24.7 per inhibitors, the UKPDS and the CAPPP, only CAPPP has
1000 patient years; HR 1.04, 95% CI, 0.94-1.15, p=0.49). demonstrated a significantly major reduction of CV events
The main outcome of cardiac disease did not differ and mortality with captopril.
between the treatment groups. Unequal reductions in BP Finally, the LIFE has recently showed a more favourable
might be responsible for differences between the groups in effect of losartan vs atenolol on CV events and mortality.
cause-specific outcomes.
Moreover, prevention and slowing progression to
New onset DM rate was lowered by 23% in the valsartan diabetic nephropathy is a fundamental target in the treatment
group (p<0.0001). This significant reduction of incidence of of type 2 DM: IDNT, IRMA, RENAAL, MARVAL have
new onset diabetes, according to the results obtained in the suggested that reduction in BP values in diabetic patients has
ALLHAT in lisinopril group, suggests that a positive effect a beneficial effect on poteinuria and diabetic nephropathy
on long term glucose metabolism might be related to progression indipendently of the drug used.
blockade of biological effects of angiotensin II [39].
Another issue emerging from literature is the charming
DETAIL (Diabetics Exposed to Telmisartan and possibility that some antihypertensive drugs might be useful
Enalapril Study) in preventing type 2 DM. The major part of evidence
supporting this interesting concept come from experiences
This prospective, multicenter, double-blind, 5-years with drugs active on RAAS system as ACE-inhibitors and
study was assessed to directly compare the renoprotective ARBs.
32 Current Clinical Pharmacology, 2006, Vol. 1, No. 1 Derosa et al.

In the UKPDS and in the CAPPP patients treated with Diabetic patient with blood pressure >130/80
ACE-inhibitors had lower levels of HbA1c or less ¢
development of DM compared to those taking beta-blockers 1- Non pharmacological treatment associated to first-line pharmacological treatment
or diuretics. Anyway, it is not clear if the difference in - No microalbuminuria -> Low-dose diuretic
development of diabetes observed in these studies is due to a - Microalbuminuria -> ACE inhibitors, Angiotensin receptor blockers (ARBs)
protective effect of ACE-inhibitors or to an adverse effect of ¢
beta-blockers or diuretics. Different mechanism could 2- Goal not achieved
explain and support a possible beneficial effect of ACE- - Increase dosage of first drug employed
inhibition in preventing DM. First of all hypokaliemia - Add a new agent
impairs the insulin secretory response to glucose, which may ¢
be favourably affected by ACE- inhibitors. Ace-inhibitors 3- Goal not achieved
also lower aldosteone secretion and renal potassium - Add a third agent
waisting, thus probably preserving beta-cell functions.
Moreover, ACE-inhibitors may reduce insulin resistance in Fig. (1). Practical flow-chart for the approach to the hypertensive
skeletal muscles, by determining an increase in insulin- diabetic patient.
mediate glucose uptake in this tissue. The increased insulin-
As it regards the molecule choice in a drug class, it is
mediated glucose uptake is due to increased bradykinin-
more difficult to give strong suggestions, especially because
mediated nitric oxide production and not to reductions in
of lack of data of long-term direct comparison of their
angyotensin 2 production or action. These concepts are
suggested by several observations. Finally ACE-inhibitors efficacy in monotherapy. Of course, a priority should be
given to molecules that have clearly showed their efficacy in
may also reduce insulin resistance at the liver and fat cells
diabetic patients. Large trials teach us that almost all ACE
[41].
inhibitors and ARBs appear to be equally effective, when
The CALM has demonstrate that the more benefit in used at adequate dosage.
diabetic patients has been obtained with dual blockade of Some preliminary data from preclinical studies and small
RAA system, while the LIFE and the VALUE have clinical studies suggest some interesting properties of single
suggested that losartan and valsartan could be associated molecules that could have a positive impact on the metabolic
with less incidence of new-onset DM, but systematic control of diabetic patients and consequently on their CV
investigations are required to well estabilish a statistically risk. Among them, we would like to remember perindopril
significant relation between ARBs and prevention of DM. and telmisartan [42,43] that appear to have a some regulating
In conclusion, more studies are needed, and particularly activities on the Peroxisome Proliferator Activator Receptor
prospective trials with prevention of DM in hypertensive (PPARs). We have yet to wait for specific data about
patients as primary end-point. molecules more recently entered in the market, such as
olmesartan.
PRACTICAL SUGGESTIONS
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Received: 15 June, 2005 Revised: 08 August, 2005 Accepted: 20 September, 2005