# Broad cardiovascular prevention, lipid therapies and screening

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Tags: [Screening and earlier detection](../BROWSE.md#screening) · [Drugs and biologics](../BROWSE.md#drugs) · [Devices and procedures](../BROWSE.md#devices-procedures)

## Current state

AMBIENCE and plaque-guided prevention studies ask clinical-event and clinical-utility questions. ARO-DIMERPA’s primary-completion estimate moves to July 2027; its early safety and lipid measurements remain separate from cardiovascular benefit.

Status: active. Initial evidence brief completed 2026-09-12; ongoing monitoring follows this baseline.

## Questions to follow

- Added 2026-09-12: CAC, CCTA and AI plaque screening; prioritize clinical utility and distinguish asymptomatic prevention from symptomatic diagnosis.
- Follow VERVE programs and other therapies addressing elevated lipids and broadly relevant atherosclerotic cardiovascular risk.
- Include human-stage approaches targeting LDL cholesterol, ApoB-containing particles, lipoprotein(a), and triglyceride-rich lipoproteins; investigate relevant gene editing, RNA-based, antibody, and small-molecule programs.
- Track cardiovascular events, mortality, and safety separately from lipid lowering. Durability and irreversible or long-lasting risks matter for gene-based treatments.
- Early studies in familial hypercholesterolemia or other high-risk populations are relevant when they could inform a broadly useful lipid platform; label limits to generalizability.
- Identify exact program names, aliases after acquisitions or renaming, trial IDs, enrollment, readouts, holds, and U.S. status.

## Programs and next milestones

### Focused update — 2026-10-16

No additional finding was selected from these checked sources. Coverage remains incomplete; this is not a full-topic “no news” conclusion.

**Remaining gaps:** Read current canonical scope, shared summaries, state and assigned topic notes. Bounded registry discovery covered September 5–October 16, 2026; prior October 13 findings were deduplicated. Full-topic successful-check dates remain unchanged.; Retrieved all 572 records across 6 pages of the bounded ClinicalTrials.gov query, plus 19 named records. Selected relevant new/changed protocols were appraised; downloading all records does not establish exhaustive safety/results review.; Europe PMC original-literature discovery failed with HTTP 503 for this topic. Targeted primary-source web searches supplied a partial fallback. Worldwide literature, regulators, international registries and complete original conference/podcast recordings remain incomplete.; Named VERVE/PCSK9/Lp(a), plaque and outcomes studies were refreshed without a selected new result. Newly registered folate-PET vascular-inflammation imaging is not an asymptomatic screening-outcome trial and was not promoted. LDL surrogate, prevention population and clinical outcomes remain separate. Worldwide safety/approval and source-video coverage are incomplete.

**Informal-source coverage:** Targeted PCSK9, LDL and Lp(a) informal searches surfaced older discussions and recycled projections, with no new attributable development rumor selected. Full original lipid podcasts/Q&A remain unreviewed; this is a coverage gap, not a no-rumors conclusion.

[Full coverage record](../updates/2026-10-16_scheduled_research_update.md).


### Focused update — 2026-10-13

<span class="note-anchor" id="note-2026-10-13-arodimerpa-timing"></span>

#### ARO-DIMERPA’s primary-completion estimate moves to July 2027

**Timing revision — NCT07223658, October 13 update.** Arrowhead's masked randomized Phase 1/2 **ARO-DIMERPA** study in adults with mixed hyperlipidemia remains recruiting **78 planned participants**. Its primary endpoint is treatment-emergent adverse events through **36 weeks**; biomarker lowering is distinct from reduced heart attacks or mortality.

The live record now estimates **July 2027 for both primary and final completion**, superseding the **September 30, 2026 primary-completion estimate** in the August 18 record reviewed previously. This resolves an elapsed estimated window by moving it; it does not establish completed enrollment, results, a clinical hold or failure. Actual study start remains **December 22, 2025**. No posted results, public-result date or U.S. approval for ARO-DIMERPA is established.

**Sources:** [Source 1](https://clinicaltrials.gov/study/NCT07223658).

**Remaining gaps:** Read current canonical scope, shared summaries/state and assigned topic notes. September 5–October 13 overlap preserves the September 12 full-review dates; October 6/9 entries were deduplicated. All pages of each bounded ClinicalTrials.gov query were downloaded, and named records plus selected relevant new/changed protocols were appraised. This is focused partial review, not a worldwide full literature/regulator/safety census; successful full-topic dates must remain unchanged.; Bounded query retrieved 514 records across 6 pages; incidental studies excluded. Named topic records refreshed: 19. Full older evidence, international registries, comprehensive harms and all original conference/podcast recordings remain gaps.; ARO-DIMERPA revised completion was compared with saved October 9 raw August 18 record. Existing HEART-3, AMBIENCE, REFINE-CAC and lipid/outcome disclosures deduplicated. Root owns new zoster-vaccine MACE registration; cross-link infections once. No comprehensive international gene-editing, regulatory-label or long-term safety review completed.

**Informal-source coverage:** Targeted PCSK9/LDL Reddit and official-source searches; no distinct original development rumor selected. Original Curbsiders lipid-guidance notes retained without re-alert. Some exact-date searches returned irrelevant/old results; full podcast transcript/Q&A review remains incomplete.

[Full coverage record](../updates/2026-10-13_scheduled_research_update.md).


### Focused update — 2026-10-09

**Related evidence:** [FDA accepts finerenone application for chronic kidney disease without diabetes](17_kidney.md#note-2026-10-08-finerenone-nondiabetic-filing).

No additional finding was selected from the reviewed sources. Coverage remains incomplete; this is not a full-topic “no news” conclusion.

**Remaining gaps:** Window: September 5–October 9, 2026, retaining the seven-day overlap from the last full successful check on September 12. October 6 findings were deduplicated.; 93 named NCT records across the ten topics and ten discovery queries downloaded successfully through the ClinicalTrials.gov public API. Download is not a claim that all fields/safety/results were exhaustively appraised.; Focused review only. Do not advance full successful-check timestamps or label incomplete remaining searches as no news.; Broad discovery returned 494 records; first 100 downloaded; selected relevant records screened. Remaining pages and a worldwide lipid/gene-editing/safety census not completed. Saved AMBIENCE, REFINE-CAC and DR10624 October 6 entries retained rather than repeated.; Curbsiders October 5 original show page recovered after the prior fetch gap. It discusses established 2026 lipid guidance and awaiting inclisiran outcomes, not a new trial readout. Full YouTube transcript/audio not appraised.

**Informal-source coverage:** Original Curbsiders episode #541, October 5, Daniel Edmundowicz: show notes reviewed; LDL-target jokes and vaccine analogy not converted into medical recommendations. No full transcript/timestamp appraisal; no new attributable development rumor from this page.

[Full coverage record](../updates/2026-10-09_scheduled_research_update.md).


### Focused update — 2026-10-06

<span class="note-anchor" id="note-2026-10-06-ambience"></span>

#### Zenagamtide registers an 8,500-person cardiovascular-outcomes trial

**Source/event date: October 6, 2026. Evidence: new trial registration.** AMBIENCE / NN9490-8037 plans 8,500 adults with established ASCVD and overweight/obesity; stable type 2 diabetes is allowed. This phase 3 randomized, quadruple-masked trial compares subcutaneous zenagamtide with placebo. Its primary endpoint is time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart-failure hospitalization/urgent visit, over approximately 203 weeks or longer. Three-point MACE and an eGFR outcome in participants with baseline eGFR<60 are secondary.

The record is NOT_YET_RECRUITING, with October 26, 2026 estimated start and September 16, 2030 estimated primary/final completion. No results or human safety estimates are posted. This is a concrete clinical-outcomes program, distinct from prior weight/A1c results; it creates no demonstrated cardiovascular or renal benefit. The registry calls zenagamtide investigational and unavailable for prescription. Next: confirmed recruitment/first dosing; completion dates are estimates, not promised readouts.

[Source 1](https://clinicaltrials.gov/api/v2/studies/NCT07861100) · [Source 2](https://clinicaltrials.gov/study/NCT07861100)

<span class="note-anchor" id="note-2026-10-02-refinecac"></span>

#### REFINE-CAC will test how AI plaque disclosure changes preventive care

**Source/event date: October 2, 2026. Evidence: new trial registration.** REFINE-CAC plans 500 asymptomatic adults without prior ASCVD, with coronary calcium 1–299 or incidental CAC and visible plaque on CCTA. The randomized portion compares disclosed Heartflow analyses with usual care in which CCTA/Heartflow findings remain blinded; the registry also includes an unblinded registry arm. The primary endpoint is the proportion initiating, intensifying, stopping or reducing lipid-lowering treatment by 90 days. Longer follow-up includes LDL-C, plaque volumes and clinical events.

NOT_YET_RECRUITING; November 2026 estimated start and June 2029 completion. No safety or efficacy results. This tests whether imaging information changes care; its primary endpoint does not establish fewer infarctions or survival benefit. CCTA radiation/contrast and downstream treatment/procedure burdens require follow-up. Registration creates no new FDA clearance or approval.

[Source 1](https://clinicaltrials.gov/api/v2/studies/NCT07853716) · [Source 2](https://clinicaltrials.gov/study/NCT07853716)

**Coverage:** 2026-10-06: lipid lipoprotein cholesterol trial October2026 results; 2026-10-06: NST1024 title PubMed/publisher; 2026-10-06: ClinicalTrials.gov September5–October6 interventional PCSK9/lipoprotein(a)/coronary plaque first50; 2026-10-06: October2026 lipoprotein podcasts; Curbsiders541

**Remaining gaps:** September5–October6 recent registry discovery; first50 records plus direct HEART3/DR10624 statuses and sponsor discovery. Broad search is nonspecific and paginated; no complete Lp(a)/ApoB/prevention-screening census.; COR2003/COR1004 NCT07858019 is a newly registered phase1 lead; target/mechanism not independently verified, so no precise target claim. NST1024 September29 journal publication found, but full primary effect/safety details unavailable; remains coverage gap. COMPETE SWITCH CV original HR orientation/counts remain unresolved.

**Informal-source coverage:** Curbsiders Oct5 lipid-guideline episode discovered; page fetch failed and audio not appraised. Recent commentary mainly repeats HORIZON failure. No original new outcome leak verified.

[Full coverage record](../updates/2026-10-06_scheduled_research_update.md).


### Focused update — 2026-10-02

#### HEART-3 registers placebo-controlled phase 2 VERVE-102 study

**Source/event date:** 2026-09-24. **Evidence:** Newly recovered trial registration.

NCT07839936, first posted September 24, provides the concrete phase 2 plan behind the earlier end-2026 forecast. HEART-3 plans 175 adults with or at high risk for ASCVD who need additional LDL lowering, randomized and double-blind against placebo. The primary endpoint is LDL-C change at day 90; ApoB and other lipids are secondary. The record is NOT_YET_RECRUITING, with October 2026 estimated start, August 2028 primary completion and March 2030 final completion. These are estimates, not first dosing or readout promises. No efficacy or safety results are posted. VERVE-102/LY4636581 remains investigational; irreversible editing and long-term safety remain distinct from near-term LDL reduction.

**Next milestone:** October 2026 estimated start; August 2028 estimated primary completion.

[Source 1](https://clinicaltrials.gov/study/NCT07839936).

#### DR10624 adds a triglyceride trial in diabetic kidney disease

**Source/event date:** 2026-09-30. **Evidence:** New phase 2 trial registration.

NCT07848880, first posted September 30, plans a 315-person randomized, masked, placebo-controlled study of weekly DR10624 in hypertriglyceridemia with diabetic kidney disease. The primary endpoint is fasting triglyceride percentage change at week 26. Secondary measures include other lipids, urine albumin, eGFR and MRI liver fat through the treatment period. The record is NOT_YET_RECRUITING; October 2026 start, April 2028 primary completion and March 2029 final completion are estimates. No results are posted. The trial can explore lipid and kidney biomarkers; it does not yet establish fewer cardiovascular events or kidney failure. No U.S. approval is established.

**Next milestone:** October 2026 estimated start; April 2028 estimated primary completion.

[Source 1](https://clinicaltrials.gov/study/NCT07848880).

**Related findings:**

- [SPINOZA now listed as recruiting](08_alzheimers.md#spinoza-now-listed-as-recruiting).
- [Explore-CKD publication reports short-term blood-pressure and albuminuria effects](17_kidney.md#explore-ckd-publication-reports-short-term-blood-pressure-and-albuminuria-effects).

**Coverage:** VERVE102 October 2026 phase2 HEART3 NCT07839936; new lipid lowering trial September30 October1 DR10624; Reddit cholesterol CRISPR trial September2026.

**Remaining gaps:** No complete Lp(a), gene-editing, ApoB or screening registry refresh. COMPETE SWITCH CV original HR orientation and event counts remain unresolved; not inserted into randomized plots.

**Informal-source coverage:** CRISPR Reddit headlines repeat earlier CTX310 findings, not independent new results. No original new VERVE data leak or recording appraised.

**Next update:** HEART-3 and DR10624 October 2026 estimated starts; neither verified recruiting. STX-1150 initial data H1 2027 remains a sponsor forecast.

[Full coverage record](../updates/2026-10-02_scheduled_research_update.md).

### Focused update — 2026-09-29

#### Claims-data analysis compares semaglutide escalation with tirzepatide switching

**Source date:** 2026-09-29. **Evidence:** Sponsor-reported retrospective observational conference analysis.

COMPETE SWITCH CV reports an association favoring semaglutide dose escalation among prior semaglutide 1-mg users; it cannot establish drug superiority. The release cites a 636,525-person source cohort but specifies 185,705 semaglutide escalators and 23,104 tirzepatide switchers (208,809 total) in its exposure groups. Its composite includes all-cause death, myocardial infarction and stroke, rather than cardiovascular-death MACE-3.

**Limitations:** Treatment selection and residual confounding prevent causal superiority claims. Only about 31% of switchers reached tirzepatide ≥10 mg. The release gives HR 1.06 (95% CI 1.04–1.08) and p=.005, alongside a “6% lower” semaglutide headline, without clear reference orientation or a reconciled statistical table. No numerical comparative estimate is added to the preview or plot. Absolute event rates and prevention-setting split remain unavailable.

**Safety:** Safety outcomes were not assessed.

**U.S. status:** No new approval or indication.

**Next milestone:** Original conference table/full methods and event counts; no date announced.

[Novo-authored UK release with exposure-group counts](https://www.prnewswire.co.uk/news-releases/novos-ozempic-semaglutide-2-mg-associated-with-lower-risk-of-major-adverse-cardiovascular-events-death-heart-attack-and-stroke-in-adults-with-type-2-diabetes-compared-to-switching-to-mounjaro-tirzepatide-in-real-world--302892062.html); [Novo sponsor release](https://www.prnewswire.com/news-releases/novos-ozempic-semaglutide-2-mg-associated-with-lower-risk-of-major-adverse-cardiovascular-events-death-heart-attack-and-stroke-in-adults-with-type-2-diabetes-compared-to-switching-to-mounjaro-tirzepatide-in-real-world--302892049.html); [Readable syndication of Novo-authored release](https://www.streetinsider.com/PRNewswire/Novos%2BOzempic%C2%AE%2B%28semaglutide%29%2B2%2Bmg%2Bassociated%2Bwith%2Blower%2Brisk%2Bof%2Bmajor%2Badverse%2Bcardiovascular%2Bevents%2B%28death%2C%2Bheart%2Battack%2C%2Band%2Bstroke%29%2Bin%2Badults%2Bwith%2Btype%2B2%2Bdiabetes%2Bcompared%2Bto%2Bswitching%2Bto%2BMounjaro/27116510.html).

**Coverage:** Rechecked lipid/prevention news, pelacarsen repeat-news deduplication and new COMPETE SWITCH CV observational report.

**Remaining gaps:** Not all VERVE/olpasiran/lepodisiran or screening registries refreshed. Original COMPETE table, HR orientation, event counts and prevention-setting split not retrieved.

**Informal-source coverage:** September28 CRISPR Reddit headline recycles earlier experimental lipid-lowering context; no independently verified new readout from that post. https://www.reddit.com/r/Cholesterol/comments/1wspp8m/crispr_phase_1_trial_big_reductions/ . Existing obicetrapib Alzheimer-prevention hypothesis not reevaluated beyond cross-topic coverage; no new benefit inferred.

**Next update:** Original COMPETE methods/event counts undated; saved VERVE end-2026 phase 2 and STX-1150 H1 2027 forecasts remain unverified.

[Full coverage record](../updates/2026-09-29_scheduled_research_update.md).

### Focused update — 2026-09-27

#### New-to-watch PCSK9 epigenetic-silencing program is recruiting

**Source date:** 2026-09-21. **Event date:** 2026-06-30. **Evidence:** Trial registry and sponsor/investigator baseline. **Baseline addition; not newly initiated research.**

STX-1150 adds a human-stage approach intended to silence PCSK9 expression without changing its DNA sequence. NCT07428473: recruiting Phase 1 open-label dose-escalation/expansion study, 64 planned adults with elevated LDL-C; actual start June 30, 2026. Monash leads, with Scribe collaboration; Australia/New Zealand program.

**Limitations:** Older program recovered, not September trial initiation. Long duration and DNA-sparing mechanism are design goals, not proven lifetime safety or cardiovascular benefit. No human efficacy results posted.

**Safety:** Primary endpoints are adverse/serious/special-interest events through 52 weeks.

**U.S. status:** Investigational; no U.S. approval.

**Next milestone:** Initial safety/LDL data H1 2027 sponsor forecast; registry primary/final completion December 30, 2028.

[STX-1150 original registry](https://clinicaltrials.gov/study/NCT07428473); [Scribe September 2 corporate update](https://www.globenewswire.com/news-release/2026/09/02/3355504/0/en/scribe-therapeutics-reports-second-quarter-2026-financial-results-and-recent-corporate-highlights.html); [Monash first-human trial announcement](https://monashhealth.org/news/victorian-heart-hospital-world-first-clinical-trial-for-cholesterol-treatment/).

#### Evolocumab trial will test AI-measured subclinical coronary plaque

**Source date:** 2026-09-21. **Event date:** 2026-09-04. **Evidence:** New-to-watch trial registration. **Baseline addition; not newly initiated research.**

A planned randomized trial compares evolocumab plus routine lipid management with routine lipid management alone in subclinical atheroma. Amgen Phase 4 NCT07803679, 308 planned participants, open-label with blinded primary endpoint. Primary outcome: change in noncalcified plaque volume on AI-enabled quantitative CCTA over 72 weeks.

**Limitations:** First posted September 4; updated September 21. Not yet recruiting. Plaque-volume modification is not proof of fewer heart attacks, improved survival or benefit from population screening.

**Safety:** No results; treatment and scan-related safety remain prospective.

**U.S. status:** Evolocumab is already approved; registration creates no new indication.

**Next milestone:** Estimated start January 31, 2027; primary/final completion April 30, 2029. These are registry estimates, not results dates.

[Original subclinical-atheroma trial registry](https://clinicaltrials.gov/study/NCT07803679).

**Related findings:**

- [Short pharmacogenomic hypertension trial reports better blood-pressure control, with major design limits](28_genetic_screening.md#programs-and-next-milestones).
- [Enicepatide reports Phase 2 diabetes and weight-loss results](03_glp1.md#programs-and-next-milestones).

**Coverage:** Lipid development and coronary plaque/CCTA discovery; verified STX-1150 and subclinical-evolocumab registries; pelacarsen September 25 JAMA news is a repeat of September 4 failure.

**Remaining gaps:** No new verified VERVE Phase 2 start, full HORIZON statistics or final obicetrapib EC documents. Prevention/AI-CAC evidence census incomplete.

**Informal-source coverage:** Reddit Lp(a) and plaque threads contain interpretations of already reported HORIZON/SCAPIS, not new outcome data. No new STX-1150 leak surfaced. Example: https://www.reddit.com/r/Cholesterol/comments/1w7h6r5/disapointing_outcome_for_pelacarsenlpa_horizon/ . Full podcast recordings not reviewed.

**Next update:** STX-1150 first human data forecast H1 2027; evolocumab subclinical-plaque trial start estimated January 31, 2027. VERVE Phase 2 target remains end-2026, unverified.

[Full coverage record](../updates/2026-09-27_scheduled_research_update.md).

### Focused update — 2026-09-22

#### First obicetrapib approvals announced in Europe

**Source date:** 2026-09-21. **Event date:** 2026-09-21. **Evidence:** Regulatory action announced by sponsor.

Menarini and NewAmsterdam announced European Commission authorization of Ubeslo (obicetrapib 10 mg) and Evlarco (obicetrapib 10 mg/ezetimibe 10 mg) for primary hypercholesterolaemia or mixed dyslipidaemia. The announcement identifies this as the first global approval. EMA's retrieved Ubeslo/Evlarco pages still show July 23 positive CHMP opinions; the formal Commission decision and final updated SmPC were not recovered.

**Limitations:** Lipid-lowering authorization is not proof of lower cardiovascular mortality or the pending PREVAIL outcome. Authorization, national launch and reimbursement are separate.

**Safety:** EMA positive-opinion summaries list hypertension, dizziness, headache, diarrhoea and abdominal pain among common adverse effects. Full final SmPC verification remains pending.

**U.S. status:** No U.S. approval verified; the reported action is European.

**Next milestone:** PREVAIL cardiovascular results remain pending. Registry NCT05202509 estimates completion November 2026 but was last updated June 2024; not a promised readout date.

[Menarini September 21 authorization announcement](https://www.menarini.com/en-us/news/news-detail/menarini-group-and-newamsterdam-pharma-receive-european-commission-approval-for-ubeslo-obicetrapib-monotherapy-and-evlarco-obicetrapib-plus-ezetimibe-fixed-dose-combination.html); [EMA Ubeslo opinion](https://www.ema.europa.eu/en/medicines/human/EPAR/ubeslo); [EMA Evlarco opinion](https://www.ema.europa.eu/en/medicines/human/EPAR/evlarco); [NCT05202509 registry](https://clinicaltrials.gov/study/NCT05202509).

#### Novo plans first human study of a PCSK9/GLP-1 combination

**Source date:** 2026-09-21. **Event date:** 2026-09-21. **Evidence:** Sponsor forecast of planned human trial.

A Phase 1 bioavailability study of co-formulated oral PCSK9 inhibitor and GLP-1 therapy is planned for 2027. Novo's cardiovascular presentation also discusses injectable formulations. The displayed LDL data are from the PCSK9 component's earlier Phase 2 trial, not the combination.

**Limitations:** No combination efficacy, safety, trial identifier or actual dosing verified. Suggested early-2030s launch is an aspiration, not a regulatory schedule.

**Safety:** No human combination safety result.

**U.S. status:** Combination investigational; no approval.

**Next milestone:** First human dose/Phase 1 bioavailability study during 2027, sponsor forecast.

[Novo Cardiovascular and liver CMD, slide 14](https://www.novonordisk.com/content/dam/nncorp/global/en/investors/pdfs/capital-markets-day/2026/CVD-liver-presentation.pdf).

**Related findings:**

- [EASi-KIDNEY stopped after lack of expected clinical benefit](17_kidney.md#programs-and-next-milestones).
- [SPINOZA is formally registered to test obicetrapib in preclinical Alzheimer disease](08_alzheimers.md#programs-and-next-milestones).

**Coverage:** EU obicetrapib announcement/EMA opinions; Novo oral PCSK9/GLP-1 plan; VERVE-102, Lp(a) outcome registries, new lipid entrants and ARO-DIMER target correction. Cross-topic ZEUS/EASi gaps.

**Remaining gaps:** Formal European Commission decision and updated final obicetrapib SmPC not retrieved; authorization is sponsor-announced. PREVAIL old completion estimate is not a confirmed readout schedule; no new results. VERVE Phase 2 initiation and full ASCVD screening/CAC/CCTA/AI-plaque census incomplete. MWX203 precise target mechanism not verified, so not assigned from biomarker lists.

**Informal-source coverage:** Obicetrapib approval lead corroborated by original sponsor. Existing Attia/Davidson Alzheimer's-prevention hypothesis has no newly verified clinical outcome; root/Alzheimer's topic owns unchanged rumor. Investor posts and republished ZEUS news not counted as new findings.

[Full coverage record](../updates/2026-09-22_scheduled_research_update.md).

**Next update:** European obicetrapib authorization is sponsor-announced; U.S. decisions and PREVAIL event results remain separate. VERVE phase 2 remains targeted **by end-2026**.

### Focused update — 2026-09-18

#### Dual-target RNAi lowers LDL, ApoB and triglyceride biomarkers

**Source date:** 2026-09-15. **Evidence:** Sponsor interim topline.

Arrowhead reports early ARO-DIMER-PA human data targeting PCSK9 and APOC3 with one RNAi molecule. The placebo-controlled phase 1/2a dose-escalation study, NCT07223658, plans to enroll up to 78 adults with mixed hyperlipidemia. Reported mean maximal reductions after a single dose were 54% for LDL-C, 50% for ApoB, 73% for triglycerides and 61% for non-HDL cholesterol. Target-protein reductions were 72% for PCSK9 and 88% for APOC3.

**Limitations:** Analyzed cohort sizes, uncertainty intervals, placebo-adjusted estimates and common measurement timepoints were not provided. Maximal biomarker reductions do not establish cardiovascular benefit and cannot support a comparable endpoint plot without further details.

**Safety:** Injection-site events and headache were the most common adverse events. No drug-related serious adverse events were reported. Safety with multiple doses remains under study.

**U.S. status:** Investigational; no U.S. approval.

**Next milestone:** Additional congress details are undated. The registry lists the trial as recruiting, with estimated primary completion on September 30, 2026 and overall completion in July 2027. These are not promised results dates.

[Arrowhead September 15 release](https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-announces-interim-topline-clinical); [ARO-DIMERPA registry](https://clinicaltrials.gov/study/NCT07223658).

#### Older missing ZEUS negative outcome and infection signal

**Source date:** 2026-07-31. **Evidence:** Historical evidence recovered.

Ziltivekimab lowered inflammation but did not lower MACE in ZEUS. ZEUS enrolled more than 6,300 participants with established atherosclerotic cardiovascular disease, CKD and hsCRP of at least 2 mg/L. The hazard ratio for three-component MACE was 0.99 (95% CI 0.88–1.11).

**Limitations:** The July 31 announcement was omitted from the baseline; it is not a new September trial result. Numerical infection counts remain unavailable. The failure should not be generalized to every anti-inflammatory target.

**Safety:** Overall adverse-event and serious-adverse-event rates were similar between groups, but serious infections were more frequent with ziltivekimab. No difference in all-cause mortality was observed.

**U.S. status:** Investigational.

**Next milestone:** Full results are expected at an unspecified 2026 scientific meeting. The July forecast that HERMES would continue must be updated against its termination record.

[Novo original July31 announcement](https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=916587).

#### HERMES trial is terminated

**Source date:** 2026-09-10. **Evidence:** Trial-registry development update.

Fresh registry confirms ziltivekimab HERMES termination, superseding the earlier continuation forecast. NCT05636176 lists 4,899 actual participants, actual completion September 3 and last update September 10. No results posted. This is a heart-failure program followed as context to the broader ziltivekimab prevention program.

**Limitations:** The reason field says only that the trial is no longer looking for participants. The registry alone does not establish futility or a safety cause. ATHENA, NCT06200207, remains active and not recruiting in an older September 1 record, so later reports that it stopped remain unreconciled.

**Safety:** No new safety or outcome estimates posted.

**U.S. status:** Investigational.

**Next milestone:** Detailed program explanation and full ZEUS results undated.

[NCT05636176 current primary registry](https://clinicaltrials.gov/study/NCT05636176); [NCT06200207 current primary registry](https://clinicaltrials.gov/study/NCT06200207).

**Coverage:** ARO-DIMER-PA sponsor interim data and registry; previously omitted ZEUS negative and safety evidence; verified HERMES termination; broader discovery searches for lipid therapies, CAC, CCTA and AI plaque assessment. This is a focused review, not a complete re-review of every program.

**Remaining gaps:** Full pelacarsen HR, safety and congress date remain unavailable. ATHENA September 1 registry is older than reports of stopping; no original later sponsor correspondence retrieved. Other VERVE/olpasiran/lepodisiran records and new AI-CAC/CCTA studies not comprehensively refreshed.

**Informal-source coverage:** Read September 5 r/medicine pelacarsen discussion; a November presentation expectation remains unverified by sponsor date. Podcast search mainly found older material. No complete original-recording sweep.

[Full coverage record](../updates/2026-09-18_scheduled_research_update.md).

### Focused update — 2026-09-14

**Coverage:** No material additional update in checked sources; September 4 pelacarsen failure already recorded. Full pelacarsen HR/CI and congress date remain unavailable. Informal speculation about results in November lacks a verified sponsor date and is not promoted. No exhaustive prevention/registry census; out-of-scope atrial-fibrillation trial excluded. This was a focused refresh, not a complete re-review of every program.

Checked sources: [Source 1](https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd); [Source 2](https://www.novartis.com/news); [Source 3](https://www.bayer.com/media/en-us); [Source 4](https://www.reddit.com/r/Cholesterol/comments/1w8aeme/pelacarsen_missed_its_primary_endpoint_in/).

**Next update:** Full pelacarsen data at an undated upcoming congress; VERVE phase 2 start targeted **by end-2026**. Other outcomes studies extend into **2028–2029**; TRANSFORM screening-study completion estimated **March 2029**.

### Tracked programs and current evidence

#### Initial brief — evidence available through 2026-09-12

**Current assessment:** important advances span oral LDL lowering, longer-lasting RNA medicines, and gene editing. Their evidence differs: an LDL/Lp(a)/triglyceride reduction, a pancreatitis reduction, and a reduction in heart attacks or strokes are separate findings. The most consequential recent news is that pelacarsen's first large Lp(a) outcomes trial missed its primary endpoint.

**VERVE-102 / Lilly — early human gene-editing evidence.** The May 25, 2026 **Heart-2 phase 1b** report included 35 adults with heterozygous familial hypercholesterolemia or premature coronary disease. Mean LDL-C reduction reached **62% at the highest tested dose**, with follow-up up to 18 months in a subset. No treatment-related serious adverse events or dose-limiting toxicity were reported in this small interim cohort. The results were simultaneously published in NEJM. **NCT06164730**; investigational in the U.S., with Fast Track designation, which is not approval. Lilly planned phase 2 enrollment by the end of 2026; that is a sponsor target, not a confirmed start. This supports durable LDL lowering, not yet cardiovascular-event prevention or lifetime safety. [Lilly's dated report](https://lilly.gcs-web.com/news-releases/news-release-details/single-dose-lillys-pcsk9-base-editor-verve-102-reduced-pcsk9-88), [Heart-2 registry](https://clinicaltrials.gov/study/NCT06164730).

VERVE-201, targeting **ANGPTL3**, was also in the ongoing phase 1b Pulse-1 program in that report. Keep VERVE-101 separate: its Heart-1 enrollment was previously paused after liver-enzyme and platelet abnormalities, with development prioritized toward VERVE-102. Do not transfer either the predecessor's safety problems or the newer formulation's early tolerability findings across products without evidence. [Verve's historical safety disclosure](https://ir.vervetx.com/static-files/0ea2cb73-ebd9-4cc1-a8a9-71c9d60648d4).

**Enlicitide / Lipfendra, formerly MK-0616 — newly U.S.-approved oral PCSK9 inhibition.** FDA records date approval to **July 15, 2026**; FDA announced it July 17. Its indication is LDL-C lowering in adults with hypercholesterolemia, including HeFH. Placebo-adjusted LDL reductions at week 24 were approximately 56% and 59% in the pivotal populations. The separate phase 3 **CORALreef Outcomes trial, NCT06008756**, remains active, not recruiting. Watch cardiovascular outcomes and real-world tolerability/access; approval for lipid lowering does not mean its own outcomes trial has already proven event reduction. [FDA approval list](https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2026), [FDA announcement](https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-pcsk9-inhibitor-lower-ldl-cholesterol-adults-high-cholesterol), [pivotal efficacy report](https://www.merck.com/news/mercks-lipfendra-enlicitide-is-the-first-and-only-once-daily-oral-pcsk9-inhibitor-approved-by-the-u-s-fda-to-reduce-ldl-c-in-adults-with-hypercholesterolemia/), [outcomes trial](https://www.merckclinicaltrials.com/trial/nct06008756/).

**Pelacarsen / Novartis–Ionis — negative phase 3 topline, September 4, 2026.** **Lp(a)HORIZON, NCT04023552**, randomized 8,323 people with established cardiovascular disease and high Lp(a). The sponsor reported that the cardiovascular-event primary endpoint was not met despite Lp(a) lowering. Full data are promised at an upcoming congress; effect estimates and detailed subgroup/safety results were not in the topline announcement. No targeted Lp(a) treatment was approved at this cutoff. Watch the complete results before concluding why the trial failed or extrapolating to every Lp(a) drug. [Novartis topline](https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd).

**Olpasiran and lepodisiran — Lp(a) outcomes still pending.** Amgen's August 4 update confirms olpasiran's phase 3 **OCEAN(a)-Outcomes, NCT05581303**, is ongoing, with a separate primary-prevention study enrolling. Lilly's **ACCLAIM-Lp(a), NCT06292013**, testing lepodisiran, is active, not recruiting. These RNA therapies have strong biomarker effects; neither has established cardiovascular benefit. The next decisive milestone is adjudicated cardiovascular outcomes, especially after HORIZON. [Amgen status](https://amgen.gcs-web.com/news-releases/news-release-details/amgen-reports-second-quarter-2026-financial-results), [OCEAN registry](https://clinicaltrials.gov/study/NCT05581303), [ACCLAIM registry](https://clinicaltrials.gov/study/NCT06292013).

**Olezarsen / Tryngolza — broader U.S. indication now includes clinical benefit.** FDA approved use with diet for severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL) on **June 24, 2026**, to reduce triglycerides **and acute-pancreatitis risk**. The supporting randomized trials, **NCT05079919 and NCT05552326**, included 1,061 adults. This is broader than the original rare-disease setting, but pancreatitis prevention does not establish heart-attack or stroke prevention. Watch durability, safety, and trials addressing broader atherosclerotic risk. [FDA approval and evidence](https://content.govdelivery.com/accounts/USFDA/bulletins/41d837e).

#### When to expect the next useful update

| Program | Timing and confidence | What to watch |
| --- | --- | --- |
| VERVE-102 | **Sponsor target: phase 2 enrollment by end-2026**, from Lilly's May 25 release; not confirmed started here. | Actual trial launch, dose selection and longer-term safety. |
| Pelacarsen | **Announced: an upcoming medical congress; no congress/date specified** in the September 4 topline release. | Full effect estimates, endpoint components, subgroup analyses, safety and development plans. |
| Olpasiran OCEAN(a)-Outcomes | **Registry estimate: March 31, 2028 primary completion**, in the record updated February 27, 2026. This supersedes the December 2026 estimate in older versions; it is not a promised publication date. [Current results/status record](https://clinicaltrials.gov/study/NCT05581303?cond=NCT05581303&rank=1&tab=results). | Event-driven readout announcement; early announcements can differ from registry completion. |
| Lepodisiran ACCLAIM-Lp(a) | **Sponsor/registry projection: March 2029 primary completion**, from Lilly's February 2026 trial summary; publication timing unannounced. [Lilly trial timeline](https://investor.lilly.com/static-files/45a92498-43d0-4e2d-a4e6-a9131841cfd6). | CV outcomes in established disease and high-risk first-event prevention. |
| Enlicitide CORALreef Outcomes | **Registry estimate: November 29, 2029 primary completion**; longer overall follow-up through 2031. [April 23, 2026 trial record](https://clinicaltrials.gov/study/NCT06008756?rank=7&term=R+2323&viewType=Table). | Cardiovascular outcomes, distinct from its existing LDL-lowering approval. |
| Olezarsen | **Approval already occurred; no specific next major readout date verified.** | Long-term safety/efficacy, broader indications and cardiovascular outcomes rather than pancreatitis alone. |

These are announced targets or registry estimates, not analyst forecasts or guaranteed availability dates.

### Baseline evidence

#### 2026-09-12 — Scope expansion: coronary plaque and risk screening

**Added scope:** coronary artery calcium (CAC), coronary CT angiography (CCTA), and AI plaque quantification when they guide prevention. Track randomized clinical utility, risk reclassification, treatment changes, radiation/contrast burden, downstream procedures and harms. Keep asymptomatic screening separate from diagnosis in patients with chest pain; this entry does not recommend personal screening.

**The key distinction is prediction versus improved outcomes.** CAC measures calcified plaque, whereas CCTA can assess coronary anatomy and noncalcified plaque; AI can quantify features within an acquired scan. Better risk prediction or a changed prescription is not automatically proof that offering that pathway prevents heart attacks. Device clearance, reimbursement and analytic agreement are separate milestones from clinical benefit.

**SCOT-HEART supplies useful but population-specific outcome evidence.** In 4,146 patients assessed for stable chest pain, adding CCTA to standard care reduced coronary heart disease death/nonfatal myocardial infarction over ten years: 6.6% versus 8.2%. These published randomized data support the tested diagnostic-management strategy; they do not establish the benefit of screening asymptomatic adults or of adding a particular AI plaque product. [2025 ten-year paper](https://pubmed.ncbi.nlm.nih.gov/39863372/).

**Population screening has mixed evidence and potential treatment harms.** DANCAVAS randomized 46,611 older men to invitation for a combined cardiovascular screen or usual care. After median 5.6 years, all-cause mortality was not significantly reduced (hazard ratio 0.95, 95% CI 0.90–1.00; P=0.06). Because the screen combined CAC with other testing and treatment, its result cannot isolate CAC. The DANCAVAS II report in men aged 60–64 similarly found no significant overall mortality benefit, while severe bleeding requiring hospital admission was higher: 5.97% versus 5.08%. This likely reflects downstream treatment as well as the screening pathway, rather than radiation alone. [DANCAVAS paper](https://www.nejm.org/doi/abs/10.1056/NEJMoa2208681); [DANCAVAS II paper, 2026 issue](https://academic.oup.com/eurheartj/article/47/15/1814/8243695).

**TRANSFORM (NCT06112418), sponsored by Cleerly, is a direct watch priority.** The registry lists a recruiting, randomized, prospective open-label/blinded-endpoint, event-driven trial in higher-risk people without known symptomatic cardiovascular disease. It compares plaque-stage-guided care against conventional risk-factor-guided care, testing a clinical-events question rather than prediction alone. The June 2, 2026 registry update gives estimated completion March 5, 2029; this is a study forecast, not a promised paper or readout. Earlier recruitment and protocol updates may occur, but no firm interim-results date was verified. [Current registry](https://clinicaltrials.gov/study/NCT06112418?rank=2&term=AREA%5BSponsorSearch%5D%28COVERAGE%5BFullMatch%5DEXPANSION%5BNone%5D%28%22Cleerly%2C+Inc.%22%29%29).

## Dated history

### 2026-10-02 — Scheduled focused review

2 newly recorded findings or milestones; primary evidence, uncertainty and incomplete coverage are detailed above and in the [run record](../updates/2026-10-02_scheduled_research_update.md). Full-topic successful-check dates remain unchanged.

- **2026-09-29:** 1 sourced entries, 0 cross-topic links and 0 informal-source checks. [Coverage and gaps](../updates/2026-09-29_scheduled_research_update.md).

- **2026-09-27:** 2 sourced entries and 2 cross-topic links from a focused scheduled check. [Coverage and remaining gaps](../updates/2026-09-27_scheduled_research_update.md).

- **2026-09-22:** Focused scheduled research retry; 2 sourced entries and 2 cross-topic links. [Coverage and gaps](../updates/2026-09-22_scheduled_research_update.md).

### Dated findings

- **2026-09-12:** Established the initial brief. Priority follow-ups: full HORIZON data; VERVE-102 phase 2 start and longer safety follow-up; Lp(a) and oral-PCSK9 cardiovascular outcomes; broader triglyceride-therapy clinical endpoints. Future dates remain estimates unless a dated primary source confirms the event.

- **2026-09-13:** Prepared separate [cardiovascular-outcome](https://medicineahead.com/#/visuals/lipid-outcomes) and [lipid-marker](https://medicineahead.com/#/visuals/lipid-lowering) visualizations. Historical clinical trials and newer biomarker studies retain their source dates, populations, safety and analysis methods. See the [visualization coverage record](../updates/2026-09-13_lipid_visualizations.md). This entry documents the new interface, not a claim of a new trial readout.

### 2026-09-14 — Ad-hoc focused review

No material additional update in checked sources; September 4 pelacarsen failure already recorded. Original event dates and sources are recorded above; unchanged historical trial results remain dated. Full pelacarsen HR/CI and congress date remain unavailable. Informal speculation about results in November lacks a verified sponsor date and is not promoted. No exhaustive prevention/registry census; out-of-scope atrial-fibrillation trial excluded.

### 2026-09-18 — Scheduled focused review

ARO-DIMER-PA sponsor interim data and registry; previously omitted ZEUS negative and safety evidence; verified HERMES termination; broader discovery searches for lipid therapies, CAC, CCTA and AI plaque assessment. Original event dates, safety and limitations are retained in the September 18 update above. The complete-topic successful-check date was not advanced because the listed gaps remain. [Run record](../updates/2026-09-18_scheduled_research_update.md).