The primary goal in the treatment of hypertensive patients is to achieve the maximum possible reduction in the long-term total risk of cardiovascular (CV) and renal morbidity and mortality. In addition to the lowering of blood pressure (BP) per se, successful realisation of the primary goal of treatment also requires appropriate consideration of co-morbidities.1–3 Although there is some controversy surrounding the benefits of ancillary effects of different classes of antihypertensive agents on the underlying mechanisms of vascular disease,4,5 it is also acknowledged that specific drug classes may have benefits that extend beyond their BP-lowering effects, and specific antihypertensive drug classes are increasingly being recommended as particularly beneficial in groups of patients with different CV risk factors.1,3
Recent results from large randomised studies have shown reductions in CV mortality and morbidity in patients with hypertension treated with calcium antagonists,6–13 with overall CV benefits comparable to those seen with older drug classes such as β-adrenoceptor antagonists (β-blockers) and diuretics, and potential additional benefit in terms of stroke prevention.14 The addition of a calcium antagonist (amlodipine) to an angiotensin-converting enzyme (ACE) inhibitor reduced the risk of combined major CV events in patients with diabetes mellitus to a greater extent than the combination of a β-blocker with a thiazide diuretic (hazard ratio 0.87; p=0.0283) in the large Anglo-Scandinavian Cardiac Outcomes Trial- Blood Pressure Lowering Arm (ASCOT-BPLA) in 19,257 patients with hypertension.8 Notably, in this context meta-analytical data are available to show that newer antihypertensive agents, including calcium antagonists, have a greater beneficial effect on intima-media thickness (IMT) than older agents such as thiazide diuretics and β-adrenoceptor blockers.15
Further analysis has yielded other information of interest: antihypertensive therapy based on a second-generation long-acting calcium antagonist has been shown to be particularly beneficial in older patients with isolated systolic hypertension (ISH) and diabetes mellitus.16 Of 4,695 patients aged 60 years or over in the Systolic Hypertension in Europe (Syst-Eur) trial,6 492 (10.5%) had diabetes mellitus. Reductions in overall mortality, mortality from CV disease and all CV events were significantly greater among patients with diabetes mellitus than among those without.
Dihydropyridine calcium antagonists (DHPs) are very effective antihypertensive agents that are widely used for the treatment of hypertension, both as first-choice treatment and in combination with other antihypertensive drugs.17–19 However, just as differences exist between various classes of antihypertensive agents with regard to ancillary effects, differences also exist within classes, including the DHPs. Evolution of DHPs from relatively short-acting first-generation agents to slow-onset, long-acting latest-generation agents has been aimed at maintaining antihypertensive efficacy while improving tolerability.18 Manidipine is a lipophilic, highly vasoselective third-generation DHP that has sustained 24-hour antihypertensive activity and is well tolerated during once-daily dosing with the recommended doses (10 or 20mg/day).20,21 Compared with the second-generation DHP amlodipine, which is one of the most extensively studied and widely used DHPs, manidipine is at least as effective an antihypertensive agent, but with more favourable tolerability, in patients with mild to moderate hypertension.20–23
Manidipine in Isolated Systolic Hypertension Patients
Progressive increases in systolic BP (SBP) related to structural and functional modifications of the arterial tree during the ageing process contribute to the high incidence of ISH in elderly patients.24 In general, landmark trials specifically addressing the treatment of ISH have used DHPs with good effect.6,25 The antihypertensive effect of manidipine has recently been compared with that of amlodipine in a study in elderly patients with ISH.26 At the end of this three-month trial, a response (≥15% reduction in sitting SBP) was achieved in similar proportions of patients in the two treatment groups, as was normalisation of sitting SBP to ≤140mmHg (see Figure 1). Relative to the significant 19.5 and 18.4mmHg reductions in SBP reported in association with manidipine and amlodipine, respectively (p<0.001), potentially harmful, clinically significant alterations in diastolic BP did not occur in either treatment group (reductions of approximately 5mmHg). Although both DHPs exhibited a good safety profile in these elderly patients, the incidence of ankle oedema, which is typical of DHPs and, expectedly, the most common adverse event, was more than double in the amlodipine than in the manidipine group (9 versus 4%) (see Table 1).
Manidipine in Patients with Type 2 Diabetes and Metabolic Syndrome
As shown by a retrospective analysis of the literature, the co-existence of diabetes mellitus with hypertension roughly doubles the risk of CV events. Moreover, calcium antagonists were found to reduce the risk of cardiac end-points in elderly patients with diabetes mellitus by 63% (stroke by 73%).27 The improved CV protection seen with calcium antagonists may be linked to the absence of metabolic side effects such as glucose intolerance and disturbance of serum lipid profiles, to which patients treated with thiazide diuretics may be vulnerable.28 The metabolic ‘neutrality’ of newer agents such as calcium antagonists is in practice more than welcomed since, in contrast to calcium antagonists, diuretics – particularly in association with β-blockers – amplify a natural time-dependent tendency predisposing to the development of diabetes mellitus in certain hypertensive persons at risk of diabetes mellitus.29
Combination therapy with thiazides and β-blockers has been called into question by the results of a meta-analysis of randomised and controlled trials that has suggested that patients exposed to this older style of treatment may be at elevated risk of developing diabetes mellitus, particularly if predisposing factors (e.g. obesity) are already present.30 The major issue appears to be that essential hypertension is associated in many patients with a decrease in insulin sensitivity while glycaemic control appears to be normal. Differential effects of various treatments on CV end-points may be linked to concomitant risk factors such as impaired glucose tolerance, diabetes mellitus and dyslipidaemia. These may be ineffectively controlled or may even be worsened by some treatments. Diuretics and β-blockers may decrease insulin sensitivity and worsen dyslipidaemia, with non-selective β-blockers having the most pronounced effect, although β1-selective adrenergic receptor antagonism still has significant detrimental effects on lipid profiles.31
The mechanisms by which these older drugs modify insulin sensitivity and cardiovascular risk remain under investigation. Mancia et al. suggest a haemodynamic cause whereby the diabetogenic effects of diuretics and β-blockers may originate from effects on blood flow to skeletal muscle via reductions in blood volume and cardiac output, or by β2-adrenoceptor inactivation;32 however, other factors may also be of significance.
Recently, a network meta-analysis (which accounts for both direct and indirect comparisons) has examined 22 clinical trials in 143,153 patients, most of whom had hypertension (17 trials) but who did not have diabetes mellitus at study entry. Calcium antagonists were associated with an odds ratio for development of diabetes mellitus of 0.75, which was compared with 0.77 for placebo, and with ratios of 0.57, 0.67 and 0.9 for angiotensin receptor blockers (ARBs), ACE inhibitors and β-blockers, respectively.33 Thus, calcium antagonists are neutral, diuretics and β-blockers accelerate and renin–angiotensin system (RAS) blockers reduce the development of new-onset diabetes.
The metabolic syndrome, which is a cluster of metabolic disturbances that includes various combinations of abnormalities in glucose metabolism, lipid metabolism and BP, results in a high risk of CV disease, including a high risk of new-onset diabetes and subclinical organ damage such as microalbuminuria and reduced glomerular filtration rate (GFR). The attention that has been given to the differential effects of various antihypertensive agents in hypertensive patients with diabetes and/or renal disease should therefore be extended to hypertensive patients with the metabolic syndrome.
The effects of manidipine and amlodipine on metabolic parameters have indeed been compared in hypertensive non-diabetic patients with metabolic syndrome and impaired fasting glucose during a three-month study.34 Despite similar reductions in BP, manidipine, but not amlodipine, significantly (p<0.01) increased both insulin sensitivity and plasma adiponectin levels in these patients (p=0.01 for the between-group difference) (see Figure 2). Adiponectin is one of a series of so-called ‘adipokines’, a group of compounds expressed by adipose tissue that includes leptin, resistin and visfatin and that has been linked to a chronic inflammatory state and to the development of insulin resistance.35
The manidipine-induced increase in plasma adiponectin was significantly correlated with the decrease in the homeostasis model assessment (HOMA) insulin resistance index (R=0.58; p<0.001). Enhanced insulin sensitivity has also been reported in association with manidipine in small studies of hypertensive patients with type 2 diabetes.36,37 The stimulation of adiponectin secretion and insulin sensitisation with manidipine has been linked in an in vitro model to peroxisome proliferator-activated receptor (PPAR)-γ activation.38
PPAR-γ is an orphan nuclear receptor that is highly expressed in adipose tissue. Its ligands include the thiazolidinediones, a group of drugs that induce adipogenesis and improve insulin sensitivity. According to preliminary data, adiponectin expression and insulin sensitisation depend on PPAR-γ activation, but not on T-type calcium channel blockade, and other calcium antagonists including mibefradil, benidipine, efonidipine, amlodipine and lercanidipine lack these actions.39 This effect of manidipine was found to be approximately two-thirds that of the thiazolidinedione pioglitazone (see Figure 3) and was blocked by the PPAR-γ antagonist GW9662. Manidipine has also been shown in vitro to be as effective as pioglitazone in the prevention of expression of specific hepatic receptors for advanced glycation end-products (RAGEs) that generate reactive oxygen species, which in turn elicit C-reactive protein expression, a process that is inhibited by PPAR-γ.40
Analyses of subgroups of diabetic patients in landmark studies attest 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 to manidipine, significant and similar reductions in BP have been observed in clinical trials comparing the antihypertensive efficacy of manidipine monotherapy with the ACE inhibitor enalapril,41,42 and trials comparing manidipine–delapril combination therapy with ARB–hydrochlorothiazide (HCTZ) fixed combinations, in patients with hypertension and type 2 diabetes.43,44
Deterioration of glucose or lipid metabolism were not observed in association with manidipine monotherapy or combination therapy 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 indicated by significant reductions in glycated haemoglobin (HbA1c) and blood glucose concentration during a six-month treatment period (p<0.05) (see Figure 4).41 In contrast to the maintenance of metabolic control observed with manidipine–delapril over a three-month treatment period in the combination therapy trials,43,44 HbA1c and fasting insulin deteriorated in patients treated with olmesartan–HCTZ (p<0.05 versus manidipine–delapril),43 and relatively high proportions of patients treated with losartan–HCTZ experienced increases in blood glucose and/or HbA1c.44
Nephroprotective Action of Manidipine
Prevention of renal damage is an important aim of antihypertensive therapy. Small increases in serum creatinine levels, reduced GFR, microalbuminuria and/or proteinuria are all indicative of likely increases in risk of CV events and death, are frequent in patients with hypertension and are related to both inadequate BP control and the metabolic risk factors previously discussed.45–48
A meta-analysis published in the mid-1990s showed no apparent effect of dihydropyridine calcium antagonists on proteinuria, whereas the pooled results of three trials with non-dihydropyridines showed reductions in proteinuria.49 These effects could not be accounted for by changes in GFR, plasma flow or filtration fraction alone. Since that time, however, other data have shown apparent renal protection with calcium antagonist therapy, in particular with manidipine.
Mainly because of their predominant effects on L-type calcium-channel-containing afferent arterioles, older DHPs, such as amlodipine, do not reduce glomerular capillary pressure, can impair renal autoregulation mechanisms of the pre-glomerular vasculature and may aggravate glomerular hypertension.50,51 Unlike older DHPs, manidipine is able to block both L- and T-type calcium channels and dilate both L-type channel-containing afferent and T-type channel-containing efferent arterioles, thereby preserving autoregulation and potentially exerting additional renal-protective effects to those that occur in association with systemic antihypertensive activity.50,51
Clinical trials have compared the effects of manidipine on indicators of renal damage with those of earlier-generation DHPs in patients with chronic renal disease, and in diabetic patients with incipient nephropathy.52,53 In a three-month trial involving hypertensive patients with chronic renal failure, manidipine was not associated with significant alterations in proteinuria, whereas a significant increase was observed in association with nifedipine (p<0.05).52 After six months of add-on therapy with manidipine in patients with type 2 diabetes, uncontrolled hypertension and microalbuminuria despite ≥6 months of therapy with an ACE inhibitor or an ARB, manidipine was associated with a significantly greater reduction in albumin excretion than amlodipine (p<0.001) (see Figure 5).53 Manidipine exhibited similar antihypertensive activity to nifedipine and amlodipine in these trials.
Tolerability
Although ankle oedema, which is considered to be the most common adverse effect of DHP therapy, is generally relatively mild, it can still lead to discontinuation of therapy and poor patient compliance.54 In studies in which manidipine has been compared with amlodipine, the incidence of ankle oedema has been consistently low in patients treated with manidipine (see Table 1).22,26,53 Furthermore, when measured during a three-month study in which hypertensive patients received manidipine or lercanidipine, ankle-plus-foot volume increased significantly with lercanidipine (+6.6%; p<0.05), but was not significantly changed in patients treated with manidipine (+4.4%).55
The stimulated release of renin and increased sympathetic outflow that occurs with DHPs is blunted by the addition of an RAS-blocking agent, such as an ACE inhibitor or an ARB, resulting in additive antihypertensive efficacy.56 As well as augmenting the BP response, combining a DHP with an RAS inhibitor can reduce the potential for ankle oedema by counterbalancing unopposed sympathetic activation and arterial vasodilation with blunted sympathetic outflow and dilation of the venous circulation.54,56 For example, as well as resulting in significantly greater reductions in BP than either agent alone (p<0.01) in a six-week cross-over trial in patients with mild to moderate hypertension, combination therapy with manidipine and delapril produced significant reductions in changes in ankle–foot volume and pre-tibial subcutaneous pressure observed with manidipine alone (p<0.01).57
Conclusions
It has become clear that calcium antagonists have beneficial effects that accompany their ability to lower BP in patients with hypertension. Large trials have shown reductions in CV risk and rates of onset of new cases of diabetes mellitus in patients receiving these agents. The association between hypertension and a range of metabolic abnormalities – including insulin resistance – is well known, and newer antihypertensive agents such as the calcium antagonists are characterised by a metabolic neutrality that distinguishes them from older drugs (e.g. thiazide diuretics and β-blockers) that may worsen dyslipidaemia and reduce insulin sensitivity. The cellular mechanisms underlying these effects have been only poorly understood for many years, but emerging data are now clarifying some of these issues. Of particular interest are the studies with manidipine described in the current review that show effects of this agent on PPAR-γ activation, adiponectin secretion and insulin sensitivity, together with other data pertaining to differential calcium channel effects.
Together with results indicating improvements in other clinical outcomes, including renal function and atherosclerotic changes, these findings suggest potential for increasing emphasis on the treatment of hypertension with calcium antagonists in order to capture metabolic benefits beyond those occurring from blood pressure reduction. Further study is required to clarify the mechanisms underlying these beneficial effects at a cellular level, and there is a need for further and longer-term follow-up in patients with hypertension, particularly those with impaired glucose tolerance or frank diabetes mellitus. In the meantime, it is clear that the pharmacological management of hypertension should focus on the selection of drugs that confer metabolic benefit in addition to BP control.
Judging from its beneficial effects on metabolic parameters and renal function relative to other DHPs such as amlodipine, manidipine is one of the most appropriate choices of DHP for inclusion in RAS-based antihypertensive regimens in hypertensive patients with metabolic syndrome, diabetes and/or renal disease. Equivalent antihypertensive activity and a reduced risk of ankle oedema also contribute to positioning manidipine as a more rational treatment choice than amlodipine in patient populations ranging from relatively young patients with mild to moderate essential hypertension to elderly patients with ISH. Finally, in practice, combining manidipine with an RAS inhibitor meets all of the theoretical requirements for combination therapy, including complementary mechanisms of action, a favourable metabolic profile, excellent antihypertensive efficacy and enhanced tolerability, characterised by an even more marked reduction in the incidence of ankle oedema. In summary, powerful BP-lowering properties, organ-protective potential and an excellent tolerability profile all contribute to making manidipine a rational choice for inclusion in antihypertensive regimens that ultimately aim to reduce the long-term risk of cardiovascular and renal morbidity and mortality in high-risk patients with hypertension.