Lercanidipine was first assessed in dose finding studies where single doses of 10 to 20 mg as well as 20 to 40 mg daily showed a significant BP-lowering effect in patients with mild to moderate 567, and severe HTN respectively 8. In the ELYPSE trial (Eficacia de Lercanidipino y su Perfil de Seguridad), a large non-comparative observational study that enrolled 9059 patients with mild to moderate HTN 9, 10 mg once daily administration of Lercanidipine decreased significant BP levels after 3 months of treatment (from 160.1 +/- 10.2/95.6 +/- 6.6 mmHg to 141.4 +/- 11.3/ 83.1 +/- 6.9 mmHg p < 0.001 versus baseline). In addition, a BP < 140/90 mmHg) was achieved in 32% of the patients. Moreover, in a large observational phase IV study that enrolled 2199 HTN patients, treatment with the over mentioned drug (10 to 20 mg as monotherapy, substitution of another drug because of adverse effects, or as add-on therapy) significantly decreased BP levels, with 63% of the patients reaching BP levels < 140/90 mmHg 10. Similar results were obtained in an open study that enrolled 756 hypertensive patients. The addition of lercanidipine (10 mg/day) as monotherapy effectively reduced BP levels after 8 weeks of follow up 11.

As expected, the combination of Lercanidipine with another antihypertensive drug led to a more marked decrease in BP levels when compared to monotherapy, regardless of the initial drug used (ACEi, ARB, a ß-blocker, or diuretic) 12131415. In a randomized double-blind control study that enrolled 854 HTN patients, the combination of Lercanidipine with enalapril decreased home BP levels to a greater extent than the corresponding monotherapies and placebo (fall with monotherapies (-8.8/-5.9 mmHg, P < 0.001/<0.001 vs. placebo) with combination treatment (11.6/-7.6 mmHg, P < 0.001/< 0.001 vs. placebo and P < 0.01/< 0.05 vs. monotherapy) 14.

Similar findings were observed with Fixed-Dose Single-Pill Combinations (SPC) containing lercanidipine 161718. In a double-blind, placebo-controlled trial, 1039 HTN patients were randomized to receive placebo, monotherapy with Lercanidipine (LE) (10 or 20 mg daily), monotherapy with Enalapril (E) 10 or 20 mg daily, or LE/E combination at the following daily doses: LE10/E10, LE10/E 20, LE20/10 mg and LE20/E20. As expected, combination therapy was superior to placebo at all doses for both office and home BP 17. Likewise, in an open-label, prospective interventional study, the authors administered Lercanidipine (LE) 10 mg in treatment naïve patients with stage I hypertension and LE 10 mg/enalapril (E) 10 mg in hypertensive patients with stage II hypertension 18. After a period of 6 weeks, if patients didn’t reach BP levels<140/90 mmHg were up-titrated to LE 10 mg/E 10 mg or LE 10 mg/E 20 mg, respectively, for a further 6 weeks. After 12 weeks of treatment, BP levels decreased significantly by 16/7 mmHg for day time (systolic and diastolic BP levels respectively) (p<0.0001) and 13/7 mmHg for night time (P<0.009) in the ambulatory BP measurement 18. Lastly, in a meta-analysis that evaluated the efficacy and safety of lercanidipine/enalapril SPC in 9565 patients with mild to moderate essential hypertension, four observational studies treated with lercanidipine/enalapril SPC, were analyzed. Lercanidipine/enalapril SPC decreased SBP by 26 mmHg (95% CI, 23–29), and DBP by 13 mmHg (12–15), p < 0.05 16.

Current ESH guidelines recommend the use of combination therapy in the majority of HTN patients since BP control with monotherapy is low 4. In addition, the use if SPC combinations decrease the number of pills to be taken, increasing thus patient’s adherence to treatment 4. Especially ACEi and CCB combination was extendedly assessed by many randomized controlled trials 19202122, with significant results. The combination of these drugs decreases significantly BP levels and on the same time presents several significant pleiotropic effects that go beyond BP reduction 419202122. Moreover, the use of this combination decreases the rate of adverse events such as ankle edema while is metabolically neutral 419202122.

Lercanidipine was compared in randomized controlled trials with all the major antihypertensive drug classes. In a double-blind controlled study, 217 patients with mild to moderate essential hypertension were divided in two groups receiving either lercanidipine 10 mg or atenolol 50 mg once daily 23. Βoth drugs showed similar BP-lowering efficacy. Similar results were observed when lercanidipine was compared with different angiotensin II receptor blockers (ARBs). In three different randomized controlled trials, Lercanidipine was compared against Losartan 2425, and Telmisartan 26. Once again, BP reduction was similar for both groups of drugs. Likewise, the comparison of lercanidipine with captopril 27, as well as with hydrochlorothiazide 2829, in three more randomized controlled studies showed that practically, the magnitude of BP reduction of lercanidipine in monotherapy is similar to that of the other major antihypertensive drug classes (Figure 2).

Lercanidipine was also compared with other CCBs such as amlodipine, lacidipine, and nifedipine gastrointestinal therapeutic systems (GITS). In a multicenter, double-blind, parallel study, 828 HTN patients ≥60 years, were randomized to receive lercanidipine 10 mg/day, amlodipine 5 mg/day, or lacidipine 2 mg/day in a ratio 2:1:1 30. In this study, there were no significant differences in SBP and DBP reductions obtained by the three treatment regimens. Likewise, in another controlled study, 324 HTN patients were randomized to receive lercanidipine 5 mg, lacidipine 2 mg, or nifedipine 30 mg for 24 weeks. All three treatment regiments decreased similarly systolic blood pressure, while the decrease in diastolic blood pressure in the lercanidipine group (-18.3 mmHg) and in the nifedipine group (-17.7 mmHg) surpassed that in the lacidipine group (-16.6 mmHg) 31. Moreover, in the TOLERANCE study, the authors compared the effectiveness and tolerability of high doses of lercanidipine (20 mg) with amlodipine (10 mg) and nifedipine GITS (60 mg), in 650 patients with essential hypertension 32. Although the antihypertensive effect of all drugs was similar, signs and symptoms related to vasodilation were significantly higher (P < 0.001) in the amlodipine/nifedipine GITS group (76.8%, CI 95% ^{70.7; 82.9}) than in lercanidipine group (60.8%, ^56.1;65.5). Lastly, in a recent multicenter, retrospective observational study with 47,640 hypertensive patients, patients treated with amlodipine or lercanidipine were assessed. Both drugs demonstrated comparable effectiveness in terms of major adverse cardiac events prevention (2.8% vs. 4.1%, P = 0.11) 33.

The majority of HTN patients usually present overlapping comorbidities and risk factors. Several studies have addressed this issue, assessing the therapeutic efficacy of lercanidipine in patients with insulin-independent diabetes, chronic kidney disease, obesity, and high-risk patients.

As expected, apart from the significant BP-lowering effect, lercanidipine in monotherapy or add-on therapy in patients with insulin-independent diabetes doesn’t affect glucose homeostasis parameters 34. Several randomized controlled studies affirm that combination treatment of a renin-angiotensin-system (RAS) blocker with lercanidipine is superior in terms of metabolic control when compared to diuretics 4. Moreover, the antihypertensive efficacy of lercanidipine is not affected by the body mass index or excess body fat. Several observational studies 3536, demonstrate the significant antihypertensive effect of this drug in this challenging population.

It’s well known that glomerular pressure regulation is impaired in patients with HTN. The vast majority of the CCBs vasodilate only afferent arterioles of the glomerulus affecting glomerular pressure and increasing the risk of time-dependent glomerular damage. According to studies in animal models, lercanidipine vasodilates both afferent and efferent arterioles, effect that may be beneficial in patients with hypertension and renal disease 37. Moreover, in the DIAL study (diabete, ipertensione, albuminuria, lercanidipina) 38, a multicenter, double-blind, active- controlled, parallel-group trial, 277 HTN patients were randomized to receive 10-20 mg/day of lercanidipine or 5-10 mg/day of ramipril and followed up for 9-12 months. In both groups, there was a significant reduction in albumin excretion rate (-17.4+/-65 microg/min for lercanidipine (p<0.05) and -19.7+/-52.5 for ramipril (p<0.05)). Likewise, there are several studies affirming that lercanidipine decreases proteinuria in patients with proteinuric renal disease 3940. Finally, in the RED LEVEL study, the authors compared the effects of lercanidipine + enalapril and amlodipine + enalapril combinations on renal parameters in HTN patients 41. In this study, apart from the BP reduction, albuminuria was significantly decreased with the lercanidipine + enalapril combination at 3, 6 and 12 months (changes from baseline were: -162.5 (p-value = 0.0439), -425.8 (p-value = 0.0010), -329.0 (p-value = 0.0011) mg/24 h), respectively). This effect was not observed with enalapril + amlodipine administration.

The efficacy of lercanidipine was also assessed in patients with high CV risk 42. In this study, the magnitude of BP reduction was related to CV risk levels. The higher the CV risk, the more pronounced the BP reduction.

Apart from the renoprotective effects mentioned above, several studies affirm that lercanidipine decreases not only peripheral BP but also central BP levels, aortic pulse pressure, and pulse wave velocity 43. When lercanidipine was compared with an ACEi (perindopril), a β- blocker (atenolol), or a diuretic (bendrofluazide) in a randomized study with elder patients with isolated systolic hypertension, all 4 classes of drugs reduced peripheral pulse pressure to the same extend however only perindopril, lercanidipine, and bendrofluazide significantly reduced central pulse pressure. In addition lercanidipine showed a more pronounced reduction of augmentation index 43. In addition, this drug exerts a significant vascular endothelial protective effect 44, since it increases the number of circulating endothelial progenitor cells ((CD34+/CD133+/VEGFR-2 + cells: 78.3 ± 64.5 vs 46.6 ± 32.8; CD34+/VEGFR-2+: 87996 ± 165116 vs 1026 ± 1559, respectively, p < 0.05, after 4 weeks of treatment). Moreover, in a pilot study, lercanidipine administration was associated with an improvement of peripheral, microcirculation, retinal circulation, and vasa vasorum networks 45. The presence of left ventricle hypertrophy (LVH) practically reflects the hypertensive burden of the patient and is associated with an increased risk of CV morbidity and mortality 4. Regression of LVH is translated into an improvement in CV prognosis since it reflects the decrease not only of the hypertensive burden but also reduces the harmful effects of LVH per se.3 Several randomized controlled studies have shown that lercanidipine decreases not only LVH, but also improves diastolic function 464748.

Several studies affirm that lercanidipine exerts a neutral or even favorable effect on lipid and glycemic profile 32354049. Similar results were obtained when lercanidipine was combined with an angiotensin converting enzyme inhibitor (ACEi) or an angiotensin-II receptor blocker (ARBs) 12. In a prospective observational study that enrolled 162 patients with uncomplicated primary hypertension, combination of lercanidipine with an ACEi or ARB decreased significantly apart from BP levels, also fasting plasma glucose and serum levels of triglycerides 12. In addition, in a randomized, double-blind study that enrolled 120 hypertensive patients, L/E SPC decreased significantly lipoprotein(a) ((P < 0.001 vs. baseline) 50. Finally, in a randomized double-blind crossover study the authors compared L/E combination with enalapril–felodipine combination in order to assess the BP lowering effects of these drugs as well as the effects of the drugs in the neurometabolic alterations and homeostasis model assessment (HOMA) index in obese hypertensive patients 36. For the same ambulatory blood pressure monitoring (ABPM) BP levels reduction L/E combination decreased HOMA index while in the felodipine/enalapril group remained unchanged. Moreover, felodipine/enalapril group showed a more pronounced sympathetic activation in comparison to the LE group 36.

The majority of the dihydropyridine CCBs, activates sympathetic nervous system increasing heart rate and cardiac output, enhancing the risk for a subsequent arrhythmic event 51. On the other hand, lercanidipine seems to decrease sympathetic overdrive associated with hypertension. Chronic administration of lercanidipine doesn’t increase norepinephrine plasma concentration while decreasing muscle sympathetic nerve traffic 52. The most common adverse events (AE) induced by DHP-CCBs are related to systemic vasodilation and include ankle edema, dizziness, headache, flushing, palpitations, and vertigo. Lercanidipine may present AE, however, to a lesser extent. In the ELLE study 31, the incidence of AE was 19.4% in the lercanidipine group, 28.4% in the nifedipine group, and 27.1% in the lacidipine group. More precisely, edema was 2.8% in the LE group, 7.5% in the lacidipine group, and 10.1% in the nifedipine group (Figure 3). Similar AE was observed in another randomized controlled trial,29 where edema-related symptoms were significantly higher with amlodipine 50% than with LE 35% and lacidipine 34% (p<0.01). In a meta-analysis that included 8 RCTs (from 39 identified), the authors concluded that first generation CCBs presented higher risk than LE and second-generation, dihydropyridine CCBs of peripheral edema and a treatment withdrawal because of peripheral edema 53.