Schmieder.qxp 30/7/08 3:57 pm Page 72
Hypertension
Figure 3: Effects of Pioglitazone, Manidipine, Amlodipine
not on T-type calcium channel blockade, and other calcium antagonists
and Lercanidipine
including mibefradil, benidipine, efonidipine, amlodipine and
lercanidipine lack these actions.
39
This effect of manidipine was found to
500
be approximately two-thirds that of the thiazolidinedione pioglitazone
400
(see Figure 3) and was blocked by the PPAR-γ antagonist GW9662.
Manidipine has also been shown in vitro to be as effective as
300
pioglitazone in the prevention of expression of specific hepatic receptors
% for advanced glycation end-products (RAGEs) that generate reactive
200 oxygen species, which in turn elicit C-reactive protein expression, a
process that is inhibited by PPAR-γ.
40
100
Analyses of subgroups of diabetic patients in landmark studies attest
0
abc
to the general benefits of an intensive DHP-based approach to BP
control in this high-risk group of patients.
6,9,16
Specifically with regard
Pioglitazone Manidipine Amlodipine Lercanidipine
to manidipine, significant and similar reductions in BP have been
observed in clinical trials comparing the antihypertensive efficacy of
Effects of pioglitazone, manidipine, amlodipine and lercanidipine on (a) peroxisome proliferator activated
manidipine monotherapy with the ACE inhibitor enalapril,
41,42
and
receptor (PPAR)-γ activation, (b) adiponectin expression and (c) insulin-induced deoxyglucose uptake. Results of
experiments with mouse adipocytes incubated with drugs (10mol/l) for 72 hours (effect of neutral vehicle=0).
38 trials comparing manidipine–delapril combination therapy with
ARB–hydrochlorothiazide (HCTZ) fixed combinations, in patients
Figure 4: Changes from Baseline in Glycated Haemoglobin
with hypertension and type 2 diabetes.
43,44
7
Deterioration of glucose or lipid metabolism were not observed in
association with manidipine monotherapy or combination therapy
6.6
in these trials.
16–19
In fact, as reported by Luque Otero and colleagues,
manidipine may even have a positive effect on glucose metabolism, as
*
6.2
indicated by significant reductions in glycated haemoglobin (HbA
1c
)
(%)
1c
and blood glucose concentration during a six-month treatment period
HbA
5.8 (p<0.05) (see Figure 4).
41
In contrast to the maintenance of metabolic
control observed with manidipine–delapril over a three-month
5.4 treatment period in the combination therapy trials,
43,44
HbA
1c
and
fasting insulin deteriorated in patients treated with olmesartan–HCTZ
5
(p<0.05 versus manidipine–delapril),
43
and relatively high proportions
Manidipine Enalapril
of patients treated with losartan–HCTZ experienced increases in blood
Baseline Final
glucose and/or HbA
1c
.
44
Changes from baseline in glycated haemoglobin (HbA1c) after six months of treatment with manidipine (n=37)
Nephroprotective Action of Manidipine
or enalapril (n=40) 10–20mg/day in a parallel, randomised, double-blind study in patients with hypertension and
type 2 diabetes.
41 Prevention of renal damage is an important aim of antihypertensive
*p<0.06 versus baseline.
therapy. Small increases in serum creatinine levels, reduced GFR,
Adapted from Luque Otero, et al., Clin Ther, 2005:27:166.
42
microalbuminuria and/or proteinuria are all indicative of likely
plasma adiponectin levels in these patients (p=0.01 for the between- increases in risk of CV events and death, are frequent in patients with
group difference) (see Figure 2). Adiponectin is one of a series of hypertension and are related to both inadequate BP control and the
so-called ‘adipokines’, a group of compounds expressed by adipose metabolic risk factors previously discussed.
45–48
tissue that includes leptin, resistin and visfatin and that has been
linked to a chronic inflammatory state and to the development of A meta-analysis published in the mid-1990s showed no apparent
insulin resistance.
35
effect of dihydropyridine calcium antagonists on proteinuria, whereas
the pooled results of three trials with non-dihydropyridines showed
The manidipine-induced increase in plasma adiponectin was significantly reductions in proteinuria.
49
These effects could not be accounted for
correlated with the decrease in the homeostasis model assessment by changes in GFR, plasma flow or filtration fraction alone. Since that
(HOMA) insulin resistance index (R=0.58; p<0.001). Enhanced insulin time, however, other data have shown apparent renal protection with
sensitivity has also been reported in association with manidipine in small calcium antagonist therapy, in particular with manidipine.
studies of hypertensive patients with type 2 diabetes.
36,37
The stimulation
of adiponectin secretion and insulin sensitisation with manidipine has Mainly because of their predominant effects on L-type calcium-channel-
been linked in an in vitro model to peroxisome proliferator-activated containing afferent arterioles, older DHPs, such as amlodipine, do not
receptor (PPAR)-γ activation.
38
PPAR-γ is an orphan nuclear receptor that reduce glomerular capillary pressure, can impair renal autoregulation
is highly expressed in adipose tissue. Its ligands include the mechanisms of the pre-glomerular vasculature and may aggravate
thiazolidinediones, a group of drugs that induce adipogenesis and glomerular hypertension.
50,51
Unlike older DHPs, manidipine is able to block
improve insulin sensitivity. According to preliminary data, adiponectin both L- and T-type calcium channels and dilate both L-type channel-
expression and insulin sensitisation depend on PPAR-γ activation, but containing afferent and T-type channel-containing efferent arterioles,
72 EUROPEAN CARDIOLOGY
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