Cardiovascular And Metabolic Health

A groundbreaking new treatment known as VERVE-102 is poised to revolutionize the way we prevent heart attacks. Unlike traditional cholesterol-lowering medications like statins, which must be taken daily for life, VERVE-102 offers a one-time gene-editing injection that could provide lifelong benefits. The therapy works by targeting and deactivating a specific gene in the liver, PCSK9, which plays a crucial role in regulating levels of low-density lipoprotein (LDL) cholesterol — commonly referred to as "bad" cholesterol. By switching off this gene, the liver becomes more efficient at clearing LDL from the bloodstream, resulting in a sustained 50% reduction in cholesterol levels. This treatment is currently in clinical trials and has already been administered to patients in the UK, including at University College London and Barts Health NHS Trust. According to Prof. Riyaz Patel, an academic cardiologist involved in the trials, the results so far have been “spectacular.” He emphasized that this is not a concept out of science fiction — it is real, in practice, and may fundamentally change the landscape of cardiovascular health management. For patients who struggle with daily medications or who experience side effects from statins, VERVE-102 represents a potential lifesaving alternative that simplifies long-term care. What makes VERVE-102 especially significant is its gene-editing approach, which involves altering a very small section of DNA to suppress PCSK9 production. This strategy not only ensures a permanent effect but also opens doors to similar interventions for other chronic conditions. If approved after further safety and efficacy trials, it could mark a paradigm shift in preventive medicine, reducing the global burden of heart disease, one of the leading causes of death worldwide.

At least 10% of the population has a significantly elevated Lp(a) above 50 mg/dL (~125 nmol/L), which carries an increased risk of atherosclerotic cardiovascular disease. While we've known that for decades, we've never had a drug to treat it. There are 5 programs in advanced trials (Table below, 3 in phase 3, pivotal, CV outcomes as endpoint). We may see the results for the first drug (pelacarsen) soon, by end August, and FDA approval is expected in 2027. This likely represents a major advance for preventing heart disease, adding to the first oral PCSK9 blocker approved this week.

Madrigal just bet $2B on a drug still in preclinical development: No FDA approval. No clinical data. But experts are calling it the next big move in metabolic disease. Here's why it might be the smartest pharma move of 2025: On July 30, 2025, Madrigal signed this massive deal with China's CSPC Pharma for an oral GLP-1 drug called SYH2086. The upfront payment of $120 million alone could fund a small biotech for years. Up to $2 billion more hangs on development milestones. But there's something deeper happening here that most analysts miss entirely. The animal data showed strong receptor activity, significant weight loss across multiple species, glucose-lowering effects, and no major safety issues. While animal data doesn't always translate to humans, the signals across multiple species are unusually strong. So why would Madrigal take this risk now? Timing is everything. Novo Nordisk just posted positive phase 3 MASH results. In my experience, innovating into the teeth of competition is where market leadership is made or lost. But they're not just buying a drug. They're buying strategic positioning. Madrigal owns Rezdiffra - the first ever FDA-approved MASH treatment. It pulled in $137M in Q1 2025, beating every projection. And buried in the patient data is a signal that could change everything. Combination therapy with Rezdiffra and GLP-1s is gaining scientific interest. Doctors are exploring it for patients with overlapping metabolic needs. It's clinician-guided today, but real-world use will shape the future of MASH treatment. The Maestro-NASH phase 3 trial proved just 5% weight loss amplified Rezdiffra's antifibrotic benefits. This isn't convenience. It's clinically validated synergy. GLP-1 + Rezdiffra = Complete MASH solution. The genius lies in how they structured this deal: Yes, $120M is big for a preclinical drug. But with ~$2B in milestones tied to later success, the structure balances risk and reward. It limits downside if it fails, preserves upside if it works. We're seeing rapid growth in China-focused R&D partnerships. Just weeks ago, CSPC signed a $110M upfront deal with AstraZeneca. Global players are moving earlier, seeking innovation upstream. Madrigal connected 3 dots: patient behavior, clinical data, and competitive pressure. Then structured a deal capturing massive upside with capped risk. Human trials start H1 2026. The race is on. For my fellow biotech executives: This is the new playbook. Listen to patients first. Move fast when competition enters. Structure deals that let you take transformative bets without existential risk. Bold vision paired with disciplined execution - that's how you build category-defining products. Biotech deal flow and market trends are complex, but approachable with the right guidance. At Kybora.com, we support leaders navigating these challenges with authentic, insightful content. Follow me for more on biotech M&A, market shifts, & strategy.

When older adults in their 80’s & 90’s or older come to clinic with structural heart issues, the mission is clear. Help find solutions to enhance quality of life and preserve independence. Shortness of breath, leg swelling, abdominal fullness and swelling, fatigue & disruption of quality of life removing ability to remain independent. These are symptoms that are commonly part of the presentation of patients with a leaky tricuspid valve and truly severe regurgitation. In some cases, diuretics are helpful, but in many cases are ineffective, a short-lived solution, and have destructive side effects. It used to be a heartbreaking situation where we just told them there was no option other than a high or prohibitive risk surgery. Many would decline, appropriately so and clinically circle the drain. It was very frustrating and heart-breaking to say there’s nothing else to offer. But it was the reality. We would often just follow patients along because we hoped that over time newer therapies would become available. It makes it all the more amazing that we are on the cusp of tricuspid interventions becoming routine and mainstream whether through availability of commercially available devices or through clinical device trials. It has absolutely changed the game for many patients who simply had no other options prior and can now thrive with a meaningful quality of life. Challenges remain including expense, ability to tackle all forms of anatomy, treat larger valve sizes, & overcome imaging challenges and infrastructure that are very real limitations preventing scaling of these therapies. The fact is though the first big steps have been taken and the progress is exciting. Device time for both cases shown in the video was approximately 30 minutes only. On the left is the commercially available tricuspid valve clip (Abbott | Cardiovascular) and on the right is tricuspid valve replacement as part of an early feasibility process (Medtronic Cardiac and Vascular ). The clinical impact of reducing TR to trace in both these cases was remarkable on follow up, so many patients stand to benefit! UAB Medicine Mouhamed Amr Sabouni Ali Ebrahimi Madhura Myla Baran Aksut Hassan Alkhawam James Davies Kyle W Eudailey, MD, Panos N. Vardas Sasha Still Amr Salama Abdullah Mahmood Weihan Chen Phillip Smith Darryl Prime Ashley Reed Raegan White Medtronic Jeffrey J. Popma Robby Hendrix Stedman Poe, CRNP Philips Imaging Paul M. Khait Alexander Haak Michael A. Donovan, MBA, Abbott Amy Woodard Michael Dove

Over 50% of American adults have elevated cholesterol levels, yet the market remains dominated by statins approved decades ago. A new wave of innovation with siRNA, oral, and gene editing options is poised to change that: In most cases, statins remain first-line. When targets aren’t achieved, guidelines increasingly add PCSK9 inhibitors such as Repatha, Praluent, or Leqvio. These agents have demonstrated substantial LDL-C reductions and cardiovascular outcomes benefits, with Leqvio offering the convenience of twice-yearly dosing. One of the biggest changes coming up will be the arrival of small-molecule options: Merck’s enlicitide decanoate (MK-0616) has reported positive Phase 3 results across multiple CORALreef trials, and an outcomes study is already fully enrolled. AstraZeneca’s AZD0780 achieved around 50% LDL-C lowering in the Phase IIb PURSUIT trial. If approved, these oral options could dramatically expand access and adherence compared to injections. siRNA therapies continue to advance. Novartis’ Leqvio (inclisiran) has reshaped practice by offering sustained LDL-C reductions with only twice-yearly office-based injections. Its U.S. label was broadened in July of this year to enable earlier and without use of statins in high-risk patients, signaling how durable dosing schedules are shifting the treatment landscape. Antibody inhibitors such as Repatha (evolocumab) and Praluent (alirocumab) remain essential, especially for very high-risk patients, consistently delivering around 60% LDL-C reductions and significant cardiovascular event reductions. On the frontier, gene editing approaches promise a one-and-done solution. Verve’s VERVE-102, which uses in vivo base editing to inactivate PCSK9, achieved mean LDL-C reductions of 53% (with some patients nearing 70%) in early Heart-2 data. While still in early-stage testing, these results hint at the possibility of durable cholesterol control with a single treatment. Beyond PCSK9, other mechanisms are also gaining momentum. Obicetrapib, an oral CETP inhibitor from NewAmsterdam, is showing 35–40% LDL-C reductions as monotherapy, based on results shared (December, 2024) from a Phase 3 BROADWAY trial.  Unlike PCSK9 inhibitors, which are highly specific to LDL-C, Obicetrapib offers broader lipid effects, including raising HDL-C and lowering ApoB and lipoprotein(a), which could translate into additional cardiovascular benefit. Meanwhile Zodasiran, Arrowhead’s siRNA targeting ANGPTL3, is moving into Phase 3 after demonstrating strong and durable effects on atherogenic lipids such as triglycerides and non-HDL cholesterol. Final take: While initial PCSK9 inhibitors like Praluent and Repatha didn’t initially live up to their commercial expectations, there’s good reason to believe that newer options, whether twice-yearly siRNAs or oral medicines, will improve access, sales, and ultimately help patients address a serious set of cardiovascular risks.

Complete transcatheter mitral and tricuspid valve repair with Edwards Evoque and Pascal platforms in a 78-year-old female with severe mitral and torrential tricuspid regurgitation Professor Sagar Doshi BSc MBChB FRCP MD FACC and Dr. Adnan Nadir MD FACC FESC at University Hospitals Birmingham NHS Foundation Trust Case history A 78-year-old female with severe mitral regurgitation and torrential tricuspid regurgitation (atrial functional aetiology) was referred to our institution. She was deemed high-risk for open-heart surgery and was referred for transcatheter treatment. Under general anaesthesia and TEE guidance the mitral valve was repaired using the Edwards Pascal mitral repair system with implantation of a P5 and P10 device. A few weeks later she underwent implantation of a 56 mm Edwards Evoque valve. An excellent repair was achieved in both valves with trivial residual regurgitation. There was no conduction disturbance and she was discharged uneventfully after each procedure. Take home messages · Fully percutaneous repair of the mitral and tricuspid valves is feasible in patients at high risk for open heart surgery using the Edwards Pascal mitral repair system and the Edwards Evoque valve University College Birmingham University of Birmingham Edwards Lifesciences

Metabolic liver disease is the silent partner in ASCVD… and we’re missing it every day. A recent JAMA review on Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) really drove this home for me: 👉 MASLD affects roughly 1 in 3 adults 👉 The leading cause of death in MASLD isn’t liver failure — it’s cardiovascular disease 👉 The same forces we talk about in prevention every day — ApoB, insulin resistance, visceral fat, inflammation — are also driving liver injury and fibrosis In other words: If you’re treating ASCVD risk, you’re treating metabolic liver disease whether you know it or not. 🧪 What should we actually be checking? 🧪 From basic “CMP + CBC” labs: 🟡 ALT — early metabolic liver stress 🔴 AST — fibrosis signal (especially when ≥ ALT) 🟣 Platelets — silent marker of portal pressure/fibrosis 🔀 AST/ALT ratio — pattern recognizer ❤️ From cardiometabolic workup: 🧬 ApoB 📈 Triglycerides 🍬 A1c / fasting glucose / fasting insulin 📏 Waist circumference 💓 Blood pressure 👤 Age — risk multiplier Bottom line: If it’s metabolic, it’s very likely hepatic. If it’s hepatic, it’s cardiovascular. 🧮 Don’t forget FIB-4 One of the simplest moves we can make in preventive cardiology and lipidology is to routinely calculate a FIB-4 score (Age, AST, ALT, platelets) in patients with metabolic risk. It’s fast, free, and gives a useful signal about whether you should think about further liver evaluation (like elastography/FibroScan) instead of assuming “normal LFTs” means “normal liver.” ❤️ The good news MASLD is: • 🔍 Detectable early with the labs we already draw • ✨ Modifiable and often reversible with: • 🧬 ApoB lowering • 🏋️ Weight loss and muscle gain • 🍏 Better glycemic control • 🥗 Improved nutrition and movement • 💡 Thoughtful use of modern metabolic therapies If we’re serious about prevention, metabolic liver disease has to be part of the conversation. 👇 Link to the JAMA review: https://lnkd.in/eicAFHFY Disclaimer: This post reflects my own clinical perspective and is for educational purposes only. It is not personal medical advice and does not represent the views of my employers or affiliates. #MOOV.Health #MASLD #ASCVDPrevention #Lipidology #MetabolicHealth #CardiometabolicMedicine #ApoB #PreventiveCardiology #PrimaryCare #Hepatology #LongevityMedicine

A detailed understanding of the delivery system itself is fundamental to achieving precise leaflet grasping and optimising procedural outcomes. Karim Al-Azizi, MD, FACC, FSCAI, FESC walks through the key components of the Abbott | Cardiovascular TriClip G4 system, highlighting several design features that have been developed specifically for the unique anatomical challenges of the tricuspid valve. - Controlled Gripper Actuation (enables independent leaflet capture, allowing operators to optimise leaflet insertion before final clip deployment. - The delivery catheter is designed to facilitate controlled advancement beneath the tricuspid leaflets, with flex and extend controls providing precise steering from the right atrium into the right ventricle. - One of the major differentiators from the MitraClip system is the dedicated septal–lateral steering mechanism, providing additional manoeuvrability to achieve optimal device positioning within the larger and more variable tricuspid anatomy. -The steerable guide catheter allows operators to finely adjust height and orientation above the valve, helping to optimise the trajectory before leaflet capture. Karim also discusses the available clip configurations, noting that the XTW device has become the workhorse for many transcatheter tricuspid edge-to-edge repair procedures due to its balance of clip width and arm length. As transcatheter therapies for tricuspid regurgitation continue to mature, understanding how individual design features translate into procedural control is becoming increasingly important. Device engineering, catheter manoeuvrability and independent leaflet optimisation all play a role in improving procedural precision and expanding the range of anatomies that can be treated.

The Future of Type 2 Diabetes Treatment: A Paradigm Shift Despite having 9+ drug classes available, over 40% of people with type 2 diabetes still don’t achieve glycemic targets. A review in Diabetologia shares what’s coming next—and it’s transformative. 🎯 The Current Paradigm We’ve moved beyond glucose-centric care. Future therapies must deliver: ✅ Excellent glycemic lowering ✅ Substantial weight loss ✅ Cardiometabolic protection ✅ Minimal hypoglycemia risk ✅ Quality of life improvements 🚀 Game-Changing Therapies in the Pipeline 1. Multi-Agonist Incretin Peptides >> hit multiple targets simultaneously: • Retatrutide (triple agonist): HbA1c ↓2.01%, weight ↓13.9%, liver fat ↓82.4% • CagriSema (amylin + GLP-1): Weight ↓20.4% in obesity, ↓10.4% with HbA1c ↓1.4% in T2D • Survodutide, Mazdutide, Pemvidutide: All showing 13-15% weight loss Benefits >> beta cell preservation, cardiovascular protection, and fatty liver improvement. 2. Small Molecule GLP-1 Agonists (“Gliprons”) Oral, potentially more affordable alternatives: • Orforglipron (Phase 3): HbA1c ↓1.07%, weight ↓5.9 kg • Multiple others in development (CT-996, Aleniglipron, CX11) 3. Novel Mechanisms • MariTide (monthly injection): Weight ↓13.7%, sustained 2-3 months post-treatment • Imeglimin (approved in Japan/India): Enhances mitochondrial function • Oral amycretin: 13.1% weight loss at 12 weeks 💡 What This Means for Practice POSSIBLE IN NEAR FUTURE (2-5 years): → Monthly-dosing options → Oral small molecule GLP-1RAs → Fixed-dose multi-agonist combinations → Muscle-preserving weight loss agents ⚠️ Reality Check Challenges remain: • GI tolerability with incretin therapies • Cost and access barriers • Muscle mass preservation during rapid weight loss • Long-term safety data still emerging • Beta cell regeneration—not imminent • Cure—not on the horizon Critical insight: Drugs alone won’t solve medication-taking behavior, health literacy, or healthcare access issues. 🔬 Lessons from Failed Approaches Many promising preclinical therapies failed due to: • Off-target effects • Inability to target specific tissues • Rate-limiting bottlenecks in insulin signaling • Safety concerns This reminds us: impressive lab results ≠ clinical success. 📊 The Bottom Line The pipeline is exceptionally robust. Multi-agonist peptides are delivering: • 10-20% weight loss • >2% HbA1c reductions • Cardiorenal benefits • Metabolic improvements across the board We’ve definitively shifted from glucose-centric to comprehensive risk reduction strategies—addressing the true multimorbidity nature of type 2 diabetes. The next 5 years will bring more options than ever. The question isn’t whether exciting therapies are coming—it’s how we’ll ensure equitable access and optimal implementation. https://lnkd.in/ezfcMrmF #Diabetes #CardioMetabolic #Healthcare