{"id":138898,"date":"2025-09-04T20:55:25","date_gmt":"2025-09-05T00:55:25","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=138898"},"modified":"2026-01-28T15:07:49","modified_gmt":"2026-01-28T20:07:49","slug":"zilebesiran-may-benefit-selected-groups-of-uncontrolled-hypertension-with-high-cv-risk-kardia-3","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=138898","title":{"rendered":"Zilebesiran May Benefit Selected Groups of Uncontrolled Hypertension with High CV Risk: KARDIA-3"},"content":{"rendered":"<p><span style=\"font-weight: 400;\">Key Points:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Many patients do not achieve BP goals in hypertension (HTN) due to adherence issues, so zilebesiran, a twice-yearly dosed RNA-i antihypertensive, may demonstrate benefit in these patients<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">The KARDIA-3 trial was a phase 2, randomized, double-blind, placebo-controlled trial testing subcutaneous zilebesiran (300 or 600 mg) added to 2-4 background antihypertensives in adults with CVD or high CV risk<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">The study was negative for its primary endpoint: at 3 months, office SBP was lower vs placebo by -5.0 mmHg with 300 mg and -3.3 mmHg with 600 mg (not significant after multiplicity adjustment).<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">However, the trial was notable for signals of benefit, including larger ambulatory and nighttime BP reductions and a sizable effect in patients on diuretics with baseline SBP \u2265140 mmHg (-9.2 mmHg at 3 months)<\/span><\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p><span style=\"font-weight: 400;\">Despite broad availability of oral agents, many patients do not achieve sustained blood-pressure (BP) control, partly due to adherence barriers. Zilebesiran, an RNA-interference therapy that suppresses hepatic angiotensinogen (upstream in the RAAS), offers twice-yearly dosing and previously showed add-on efficacy in KARDIA-2. KARDIA-3 was designed to evaluate zilebesiran on top of multiple antihypertensives in a higher-risk population.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">KARDIA-3 was a double-blind, placebo-controlled, randomized trial conducted across five countries in adults with established cardiovascular disease (CVD) or high CV risk (e.g., 10-year ASCVD risk &gt;15% or eGFR 30\u201359 mL\/min\/1.73 m\u00b2) and uncontrolled hypertension (office SBP 140-170 mmHg; 24-hr SBP 130-170 mmHg) while taking 2-4 antihypertensives (including a CCB or a diuretic). The primary analysis set included patients with eGFR \u226545; those with eGFR 30 to &lt;45 will be reported separately. Participants were randomized 1:1:1 to single-dose zilebesiran 300 mg, 600 mg, or placebo; background therapy was held stable through 3 months unless clinically necessary. The primary endpoint was change from baseline in mean office SBP at 3 months.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Among 270 analyzed patients (median age 67, 45% women), baseline office BP averaged 144\/80 mmHg while on 2-4 agents. At 3 months, placebo-adjusted office SBP change was -5.0 mmHg (95% CI, -9.9 to -0.2) with 300 mg and -3.3 mmHg (95% CI, -8.2 to 1.6) with 600 mg; neither reached statistical significance after multiplicity correction. At 6 months, placebo-adjusted office SBP changes were -3.9 and -3.6 mmHg, respectively. Notably, 24-hour ambulatory SBP at 6 months favored zilebesiran by -5.5 (300 mg) and -7.4 mmHg (600 mg), with larger nighttime reductions (-6.6 and -8.2 mmHg). A post-hoc subgroup on diuretics with baseline SBP \u2265140 mmHg showed a larger office SBP reduction at 3 months (-9.2 mmHg). Adverse events (AEs), including hyperkalemia, kidney dysfunction, and hypotension, were mostly mild\/moderate and transient; serious AEs were similar to placebo (~4%).\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">KARDIA-3 did not meet its multiplicity-adjusted primary endpoint, limiting enthusiasm for broad add-on use. However, consistent ambulatory and nighttime BP reductions and the diuretic-treated subgroup signal suggest a biologically plausible effect (aligned with RAAS suppression and prior KARDIA-2 data) that may translate to outcome benefits in selected patients or combinations. Reflecting this \u201ctotality of evidence,\u201d the sponsors announced a global phase 3 cardiovascular outcomes trial (dose, population, and design informed by KARDIA-3). Trial presenter Neha Pagidipati, MD, emphasized that while the 3-month primary outcome was not statistically significant, \u201cthe trial met its objective of informing the design of future trials,\u201d and that the phase 2 program collectively supports proceeding to a phase 3 outcomes study in uncontrolled hypertension.<\/span><\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Key Points: Many patients do not achieve BP goals in hypertension (HTN) due to adherence issues, so zilebesiran, a twice-yearly dosed RNA-i antihypertensive, may demonstrate benefit in these patients The KARDIA-3 trial was a phase 2, randomized, double-blind, placebo-controlled trial testing subcutaneous zilebesiran (300 or 600 mg) added to 2-4 background antihypertensives in adults with [&hellip;]<\/p>\n","protected":false},"author":40613,"featured_media":138901,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[900,8],"tags":[45,901,47,185],"ppma_author":[1067],"class_list":{"0":"post-138898","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-esc-2025","8":"category-news","9":"tag-conference","10":"tag-esc2025","11":"tag-featured","12":"tag-news","13":"author-oludamilola-aladesanmi-md"},"authors":[{"term_id":1067,"user_id":40613,"is_guest":0,"slug":"oludamilola-aladesanmi-md","display_name":"Oludamilola Aladesanmi MD","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/5e6ceb579581d61ff9a0d36b0fce74899a775ad4d72a95a58d4a9e17cf8d9ac5?s=96&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138898","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/users\/40613"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=138898"}],"version-history":[{"count":1,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138898\/revisions"}],"predecessor-version":[{"id":138902,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/138898\/revisions\/138902"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/138901"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=138898"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=138898"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=138898"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=138898"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}