Lercanidipine – Effective and Well Tolerated
Cardiovascular diseases are the most common cause of morbidity and mortality worldwide (1). More than 70% of patients do not achieve adequate control of elevated blood pressure (BP) (2, 3), and even a slight increase above optimal values increases the risk of target-organ damage and cardiovascular mortality (4, 5). The kidneys are among the organs frequently damaged by elevated BP.
Calcium channel blockers (CCBs) are important medications for reducing BP and cardiovascular risk. They bind to L-type calcium channels, block the movement of calcium ions into cells, induce smooth muscle relaxation and vascular dilation. This reduces peripheral vascular resistance and BP (6, 7). The BP-lowering effect of CCBs has been demonstrated in numerous clinical trials. In addition, in patients with hypertension or atherosclerosis, dihydropyridine CCBs improve endothelial function and reduce the risk of cardiovascular events. CCBs improve renal blood flow, increase the glomerular filtration rate and have a natriuretic effect.
Lercanidipine is a third-generation vasoselective dihydropyridine CCB that effectively reduces BP (8–10). Its high lipophilicity results in a slower onset of action, a more gradual and prolonged effect, and good tolerability compared with other dihydropyridine CCBs (11).
Lercanidipine Protects Against Kidney Damage
Primary arterial hypertension is quite often associated with kidney damage, including thickening of the renal arterioles, fibrinoid deposits in the glomeruli and proteinuria. Hypertension and proteinuria are among the most important factors determining the progression of chronic kidney disease (CKD), as well as mortality and morbidity among patients undergoing dialysis (17). Kidney damage occurs when autoregulatory mechanisms within the glomeruli are unable to maintain renal blood flow and pressure (3, 4).
CCBs reduce systemic BP while preserving or even increasing renal blood flow (18), and are therefore considered to have a relatively selective effect on the kidneys. Kestenbaum and colleagues (12) found that, among patients undergoing dialysis, treatment with CCBs reduced the risk of all-cause mortality by 21% and the risk of cardiovascular mortality by 26%.
Lercanidipine slows glomerular damage and the development of glomerulosclerosis (2, 6). It dilates both afferent arterioles, through which blood enters the glomerulus, and efferent arterioles, through which blood leaves the glomerulus, and therefore has less effect on renal autoregulation (19). The renoprotective effects of lercanidipine have been demonstrated in clinical and experimental studies.
The nephroprotective properties of lercanidipine were investigated in a double-transgenic rat (dTGR) model with overexpression of the human renin and angiotensinogen genes (14–16). Mortality was statistically significantly lower in rats treated with lercanidipine than in untreated rats (p<0.001). Blood pressure recorded at the end of the study was also lower, and treatment with lercanidipine significantly reduced serum creatinine concentration (p<0.05) and albuminuria (p<0.01). Histological examination showed that lercanidipine treatment protected against damage to small renal blood vessels and monocytic infiltration.
The ZAFRA clinical study (13) evaluated the safety of lercanidipine in patients with chronic renal failure (CRF), as well as its nephroprotective effects in these patients. The study included 203 patients with CRF: blood creatinine concentration was >124 μmol/l in men and >106 μmol/l in women, or creatinine clearance...
All patients were treated with angiotensin-converting enzyme inhibitors (ACEIs; 63.4%) or angiotensin receptor blockers (ARBs; 36.6%), but their BP remained above the level recommended for patients with CRF (<130/85 mm Hg). None of the patients were taking diuretics. Lercanidipine was added to the treatment regimen of all study participants. The study lasted 6 months.
The ZAFRA study found that BP decreased in 89.2% of patients, from 162±17/93±8.3 mm Hg to 132±12/78±6 mm Hg. Optimal BP (<130/85 mm Hg) was achieved in 58.1% of patients. No cases of ankle edema occurred during the study, while vasodilation-related adverse effects were reported in only 3 patients (1.48%).
Serum creatinine concentration remained unchanged, but creatinine clearance increased from 41.8±16 to 45.8±18 ml/min (p=0.019), while proteinuria decreased, with the reduction reaching statistical significance after 6 months (p=0.015). Plasma cholesterol concentration also decreased from 5.72±1.19 mmol/l to 5.46±0.90 mmol/l (p=0.001).
Lercanidipine Causes Ankle Edema Less Frequently
Peripheral (ankle) edema is one of the specific adverse effects of CCBs and one of the reasons for discontinuing these medications. Ankle edema depends on the dose and duration of treatment but is not associated with fluid retention and therefore is not relieved by treatment with diuretics.
Because of its specific vasodilatory properties, lercanidipine causes ankle edema particularly rarely. Studies have shown that it reduces BP as effectively as other antihypertensive medications and is well tolerated. It can therefore be used either as monotherapy for mild to moderate hypertension or in combination with other BP-lowering medications when hypertension is more severe and requires several medications.
An analysis of clinical trials—14 placebo-controlled, double-blind studies involving 1,850 patients with arterial hypertension or stable angina who were treated for up to 18 weeks—showed that the incidence of peripheral edema with lercanidipine (10–20 mg/day) was 2.4% (11), whereas studies of other dihydropyridine CCBs reported peripheral edema rates of 6–29% (11, 12).
Lercanidipine was well tolerated in both uncontrolled and controlled studies. Objective assessments showed that lercanidipine causes ankle edema less frequently than modified-release nifedipine (23) and amlodipine (24–26). The rate of discontinuation of lercanidipine is low and similar to that of placebo (27–29). This characteristic is likely related to the drug's good tolerability: treatment with lercanidipine is discontinued because of peripheral edema less frequently than treatment with amlodipine (24, 25) or modified-release nifedipine (30).
Effectiveness of Lercanidipine in Older Patients
Various randomized clinical trials have evaluated the safety and effectiveness of lercanidipine in different patient populations. The effectiveness and safety of amlodipine, lercanidipine and lacidipine were evaluated in 828 older patients with arterial hypertension (>60 years) in a 1-year clinical trial (31). The study showed that the antihypertensive effect of lercanidipine was similar to that of other dihydropyridine CCBs, while peripheral edema occurred less frequently.
Another study, ELLE (Elderly and Lercanidipine), included 324 patients older than 65 years (32). They were treated for 6 months with lercanidipine 5 mg/day, lacidipine 2 mg/day, or modified-release nifedipine 30 mg/day.
The results showed that lercanidipine had a BP-lowering effect in older patients similar to that of modified-release nifedipine but greater than that of lacidipine. Microalbuminuria and hypertension are risk factors for diabetic nephropathy in patients with type 2 diabetes mellitus (DM), which is a cause of end-stage renal failure.
It has been demonstrated that blockade of the renin-angiotensin system slows the progression of diabetic nephropathy. The DIAL study (22) compared the effects of lercanidipine and ramipril on albumin excretion in patients with mild to moderate hypertension and type 2 DM. The study included 277 patients and was a multicenter, randomized, double-blind trial.
After 9–12 months of treatment, albumin excretion decreased statistically significantly in both groups: by 17.4±65 μg/min in the lercanidipine group (p<0.05) and by 19.7±52.5 μg/min in the ramipril group (p<0.05). No statistically significant difference was observed between the groups. BP also decreased statistically significantly in both groups (p<0.0001 in both groups).
The DIAL study therefore demonstrated that lercanidipine does not increase albuminuria in patients with hypertension and type 2 DM who have microalbuminuria.
In clinical trials, lercanidipine demonstrated antihypertensive efficacy similar to that of other dihydropyridine CCBs in patients with mild to moderate arterial hypertension. In a multicenter, randomized, double-blind, parallel-group study, 130 patients aged 18–70 years with mild to moderate arterial hypertension (supine diastolic BP ≤115 mm Hg) were randomly assigned to receive lercanidipine 10 mg/day or prolonged-release nifedipine 20 mg twice daily. These doses were administered for 4 weeks (33). If the response was inadequate, the drug doses were increased by half or hydrochlorothiazide was added.
After 4 weeks, systolic and diastolic BP decreased similarly in both treatment groups. Increasing the drug doses by half or adding another medication enabled an even greater proportion of patients to achieve target BP.
Another study compared the effects of three dihydropyridine CCBs on BP and heart rate in 250 patients with mild to moderate arterial hypertension (34). The patients were 31–74 years old and were randomly assigned to lercanidipine 10 mg/day, felodipine 10 mg/day, or nifedipine GITS 30 mg/day. After 4 weeks, if the response was inadequate, the doses were increased by half.
All groups showed a significant reduction in systolic and diastolic BP compared with baseline. The proportion of patients who achieved target BP was similar across all treatment groups. Thus, the study showed that the effectiveness of lercanidipine was comparable to that of the other CCBs.
To evaluate the effectiveness of lercanidipine, it was compared not only with other CCBs but also with medications from other classes. In a multicenter, double-blind, randomized study involving 217 patients with mild to moderate arterial hypertension, participants received lercanidipine 10 mg/day or atenolol 50 mg/day (35). After 4 weeks, significant reductions in systolic and diastolic BP were observed in both groups (p<0.01). BP was normal after 4 weeks in 65% of patients in the lercanidipine group and 75% of patients in the atenolol group. Both medications were well tolerated, with adverse effects occurring in 10.2% of patients receiving lercanidipine and 7.2% of those receiving atenolol. As expected, heart rate decreased significantly in the atenolol group. Lercanidipine had no effect on heart rate.
In another study with a similar design, lercanidipine (10 mg/day) was compared with captopril (50 mg/day divided into two doses) (36). If the response was inadequate, the doses were increased to 30 mg/day of lercanidipine and 100 mg/day of captopril, respectively. Similar reductions in systolic and diastolic BP were observed in both groups (p<0.01), while heart rate remained unchanged. Both treatment regimens were also well tolerated.
Similar results were observed in a comparative study of lercanidipine and losartan (37). During treatment, the target diastolic blood pressure (
Lercanidipine Pharmacokinetics
Lercanidipine is rapidly and completely absorbed from the gastrointestinal tract. More than 98% of the drug binds to plasma proteins. Its plasma elimination half-life is 2–5 hours. Lercanidipine is recommended to be taken before meals because a high-fat meal increases its bioavailability by up to threefold.
Clinical studies have demonstrated that, in patients with mild to moderate hypertension, a well-tolerated and effective dose of lercanidipine is 10–30 mg/day. Treatment is recommended to begin at 10 mg/day. The dose should be taken at least 15 minutes before a meal. If the response is inadequate, the dose may be increased by half after 2 weeks.
Summary
Based on the study results, the following conclusions can be drawn:
– lercanidipine effectively reduces BP and can therefore be used either as monotherapy in patients with mild to moderate hypertension or in combination with other BP-lowering medications when hypertension is more severe and requires several medications;
– lercanidipine effectively reduces systolic BP in patients with chronic renal failure. A beneficial effect of lercanidipine on renal function was observed, with increased creatinine clearance and reduced proteinuria;
– lercanidipine is well tolerated. Because of its vasodilatory effect on different arterioles, it reduces hydrostatic pressure at the arteriocapillary junction and causes less ankle edema than other CCBs. The rate of lercanidipine discontinuation is low and similar to that of placebo;
– lercanidipine is well tolerated in older patients and in patients with chronic kidney disease;
– lercanidipine reduces albuminuria in patients with hypertension and diabetes mellitus who have microalbuminuria.
Prepared by Dr. Rasa Geigalienė
Source: Internistas
