"New triple-combination therapy Levosartan Plus for hypertension"

[DP Interview] Professor Seok-Min Kang of the Division of Cardiology at Severance Hospital

Triple-combination therapy containing 'valsartan + S-amlodipine + indapamide'…the first API‧combination in South Korea

“Indapamide lowers risk of electrolyte imbalance aberrations…synergy with other ingredients"

"Expected to be effective in hypertensive patients with various comorbidities, including diabetes‧CKD…improves patient adherence"

Ahngook Pharmaceutical recently launched ‘Levosartan Plus Tab’, a triple combination therapy for hypertension. The product contains valsartan (an ARB) + S-amlodipine (a CCB) + indapamide (a diuretic). It is the first time this active pharmaceutical ingredient (API) combination has been approved in South Korea.

Professor Seok-Min Kang of the Division of Cardiology at Severance Hospital, who led the clinical trial for regulatory approval, stated, “As the comorbidities of patients with hypertension become increasingly diverse, the importance of combining drugs with different mechanisms of action (MOAs) is growing. It will be highly useful, particularly for elderly patients or high-risk hypertensive patients with multiple underlying conditions.”

Korea's first triple combination hypertension therapy, additional blood pressure-lowering efficacy compared to dual therapy

Professor Seok-Min Kang of the Division of Cardiology at Severance Hospital

The approval basis of trial for Levosartan Plus Tab was conducted over 3 years, starting in April 2022, and enrolled 306 hypertensive patients across 30 hospitals in South Korea. The study evaluated the incremental blood pressure-lowering efficacy of the triple combination therapy compared with conventional ARB·CCB dual fixed-dose combinations.

The trial results demonstrated that Levosartan Plus Tab achieved an additional reduction of 6.3 mmHg in systolic blood pressure (SBP) and 3.69 mmHg in diastolic blood pressure (DBP) compared to the control group (dual combination). After 10 weeks, the blood pressure normalization rate in the investigational group was statistically significantly higher than that of the control group.

Professor Kang said, “Tertiary hospitals see many high-risk hypertensive patients with various comorbidities such as diabetes, chronic kidney disease (CKD), stroke, and myocardial infarction (MI), making blood pressure management challenging with single-mechanism therapies alone," and added, "This clinical trial confirmed that the combination of three components with distinct MOAs offers incremental efficacy in controlling blood pressure in actual Korean hypertensive patients.”

​“Indapamide lowers risk of electrolyte imbalance aberrations...Synergy with valsartan and S-amlodipine”

The most differentiating component in this combination is the diuretic, indapamide. Previously, the South Korean market for hypertension combination drugs predominantly utilized diuretics from the chlorthalidone or hydrochlorothiazide classes.

Professor Kang cited the HYVET (Hypertension in the Very Elderly Trial) study as evidence for indapamide. Published in 2008, the study demonstrated that indapamide-based treatment reduced the ▲risk of mortality  ▲fatal stroke  ▲heart failure incidence ▲cardiovascular events compared to placebo. “In elderly hypertensive patients, indapamide-based therapy showed positive outcomes not only in blood pressure control but also in terms of cardiovascular prognosis,” Professor Kang explained.

Professor Kang highlighted safety as a key advantage of indapamide. He explained that while conventional diuretics often pose a burden to elderly patients by lowering serum sodium and potassium levels, indapamide carries a relatively lower risk of such adverse effects.

​“While chlorthalidone offers potent antihypertensive efficacy, it can induce hyponatremia and hypokalemia in some elderly patients,” Professor Kang said. “In contrast, indapamide tends to be used stably in clinical practice.” Kang further emphasized, “The risk of metabolic side effects, such as elevated cholesterol, is also relatively low, making it highly applicable for hypertensive patients with concurrent hyperlipidemia.”

The other two components, valsartan and S-amlodipine, are also evaluated as having distinct therapeutic roles. Professor Kang anticipated synergistic effects arising from the unique strengths of each component.

“Amlodipine is a long-established CCB-class antihypertensive drug, but it can cause side effects like edema in elderly patients,” Professor Kang said. “In contrast, because S-amlodipine isolates only the active S-enantiomer responsible for lowering blood pressure, it carries a lower risk of adverse events such as edema or facial flushing compared to conventional amlodipine.”

Regarding valsartan, Kang noted, “It is a drug with significant clinical evidence. In addition to lowering blood pressure, valsartan acts as an RAS (renin-angiotensin system) blocker, providing renal and cerebral protection. It can be utilized with a relatively stable safety profile even in patients with early-stage diabetes or those with a high metabolic risk profile.”

​“Complementary actions of three components... Expected to benefit elderly and high-risk hypertensive patients”

Professor Kang projected that the new combination therapy containing valsartan + S-amlodipine + indapamide would benefit hypertensive patients who are elderly or present with underlying comorbidities. “It could be considered a preferred option for hypertensive patients with early-stage diabetes, obesity, or chronic kidney disease,” Professor Kang said. “It is also suitable for patients who previously suffered from ankle edema when using standard CCBs.”

Professor Kang noted that the competitive edge of this therapy among the numerous existing hypertension combinations lies in its drug synergy. “It is designed for stable blood pressure control with S-amlodipine, the enhanced antihypertensive efficacy of indapamide, and the long-term clinical evidence and organoprotective effects of valsartan to complement one another.,” Professor Kang assessed. “It is a combination designed not just for efficacy in lowering blood pressure, but also taking into account real-world clinical experience.”

Professor Kang also anticipated improvements in patient medication adherence. “Most hypertensive patients are elderly and take a load of medicines,” Professor Kang noted. “Taking a single pill is far more convenient than taking three separate medications," and concluded that "This will improve patient adherence, leading to a reduction in cardiovascular events.”