Anti-Obesity Drugs: Cardiovascular Benefit Beyond Weight Loss

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Undoubtedly, the most talked-about trend in cardiovascular medicine today is the latest generation of anti-obesity medications. The two most popular of these increasingly popular drugs – semaglutide and tirzepatide – demonstrate remarkable cardiovascular benefits that extend beyond weight management.

Clinical trial evidence is rolling in at a fast clip showing that these medications, both of which are for now delivered subcutaneously, can reduce the risk of major adverse cardiovascular events by up to 20% in patients with obesity and preexisting cardiovascular conditions. The mechanisms appear to extend beyond weight loss, with evidence suggesting direct protective effects on cardiac tissue and metabolic processes.

New research presented at AHA 2024 last fall illustrated just some of the accruing cardiovascular benefits seen with the two drugs.

Tirzepatide scored a huge win with the SUMMIT trial, which was simultaneously published in NEJM.¹ In SUMMIT, 364 patients received tirzepatide and 367 received a placebo, with a median follow-up of 104 weeks. Cardiovascular death or worsening heart failure (HF) occurred in 9.9% of tirzepatide patients vs. 15.3% of placebo patients (hazard ratio [HR], 0.62; p=0.026). Worsening HF was reported in 8.0% of tirzepatide patients and in 14.2% of controls (HR, 0.54; 95% CI, 0.34-0.85), and cardiovascular death in 2.2% and 1.4%, respectively (HR, 1.58; 95% CI, 0.52-4.83).

At 52 weeks, the mean change in the Kansas City Cardiomyopathy-Clinical Summary Score was 19.5 with tirzepatide and 12.7 with placebo (difference, 6.9; p<0.001). Drug discontinuation due to adverse events (mainly gastrointestinal) occurred in 6.3% of tirzepatide patients and 1.4% of placebo patients.

A cardiac magnetic resonance imaging substudy of the SUMMIT trial, published in JACC, demonstrated that tirzepatide therapy in obesity-related heart failure with preserved ejection fraction (HFpEF) led to reduced left ventricular (LV) mass and pericardiac adipose tissue as compared with placebo.² This change in LV mass parallelled weight loss and may contribute to the reduction in HF events seen in the main trial.

In a secondary analysis of the SELECT trial, patients who already had cardiac bypass surgery and living with obesity or overweight but not diabetes were randomized to receive once-weekly semaglutide or placebo to determine if it improved cardiac outcomes.

In the analysis, 2,057 participants had a history of CABG and 15,547 did not. Those with CABG were older (65 years old vs. 61 years old), 84% were male vs. 70%, 2.1% were Black vs. 4%, and they had a lower BMI (31.9 kg/m2 vs. 32.1 kg/m2). Semaglutide led to a consistent reduction in major adverse cardiovascular events in both groups, but the absolute risk reduction with semaglutide was greater in those with a history of CABG (2.3% vs. 1%). Semaglutide was also shown to reduce the incidence of diabetes in the CABG group.

"These studies reinforce the potential of GLP-1-based therapies not only to aid in weight loss but also to transform cardiac health, offering hope for patients living with obesity and cardiovascular disease," said Harlan M. Krumholz, MD, SM, editor-in-chief of JACC. "As the science evolves, we are achieving a deeper understanding of how weight loss, and treatment with these medications, can improve outcomes across diverse patient populations with obesity."

The AI Revolution: Precision Diagnostics and Predictive Care

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From drug discovery to coronary plaque analysis, artificial intelligence (AI) is rapidly emerging as a game-changer in cardiovascular medicine, offering unprecedented capabilities in diagnostics, risk assessment and personalized treatment planning. Machine-learning algorithms are now demonstrating remarkable accuracy in interpreting complex medical imaging, detecting subtle cardiac abnormalities at speed.

Particularly promising are neural networks that can analyze electrocardiograms (ECGs) and echocardiograms with high-level expertise. Rhythm classification was the initial application of AI-ECG technology, but since then AI-ECG models have been developed to screen for structural heart diseases, including hypertrophic cardiomyopathy, cardiac amyloidosis, aortic stenosis, pulmonary hypertension and LV systolic dysfunction.³ Additionally, these AI models appear to be able predict future events such as the development of systolic HF and atrial fibrillation.

AI-ECG also shows promise in addressing acute cardiac events and noncardiac conditions, including acute pulmonary embolism, electrolyte imbalances, drug therapy monitoring, sleep apnea, and predicting all-cause mortality.

In a late-breaking session at AHA 2024 highlighting new research focusing on "smart cardiology" innovations, AI- and machine learning-based systems demonstrated efficacy in improving HF care in the Veterans Health Administration System, streamlining and improving analysis of echocardiographic examinations, and enabling better hemodynamic-guided remote monitoring of HF patients.

Research institutions are racing to develop AI-powered tools that can predict cardiovascular events with unprecedented precision. These systems analyze vast datasets, incorporating everything from genetic markers to lifestyle factors, creating comprehensive risk profiles that go far beyond traditional screening methods.

For example, the GRACE 3.0 score is an AI-enhanced risk assessment tool designed to improve the prediction of in-hospital mortality and guide treatment for patients presenting with non-ST-elevation acute coronary syndromes (NSTE-ACS).⁴ It builds on the GRACE 2.0 score by incorporating machine learning to account for complex, nonlinear relationships and demographic differences, such as sex-based variations.

In testing, the GRACE 3.0 led to a significant reclassification of female patients to the high-risk group with important clinical implications. It's among the first cardiovascular AI tools endorsed by international guidelines.⁴

Inflammation: The Hidden Cardiovascular Threat

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It's been a while since inflammation was viewed as a passive biological response rather than a critical and active participant in cardiac disease progression. At this point, the involvement of inflammation in atherosclerosis is well accepted. This paradigm shift and a greater understanding of the complex relationship between inflammation and cardiovascular disease is driving a number of emerging therapeutic strategies targeting inflammatory mediators aim to reduce cardiovascular risk beyond that achieved by lipid-lowering therapies.

Moving beyond the IL-1β inhibitor canakinumab and the CANTOS trial, which demonstrated that targeted anti-inflammatory treatments could significantly reduce cardiovascular events in patients with existing heart disease, emerging research is exploring more complex inflammatory pathways, investigating how specific inflammatory molecules contribute to cardiovascular disease.⁵ This deep molecular understanding is paving the way for more precise therapeutic strategies.

In a silo-breaking multidisciplinary effort published in the European Journal of Clinical Investigation in July, investigators led by Peter Libby, MD, FACC (Brigham and Women's Hospital, Boston) and Robert S. Rosenson, MD, FACC (Mount Sinai Hospital, New York) make the case that common inflammatory pathways participate in the pathogenesis of multiple acute and chronic diseases and urge researchers towards greater collaboration and cross fertilization to speed the development and application of therapies with interdisciplinary benefit.⁶

"We outline opportunities to synergize, reduce duplication and consolidate efforts of the clinical, research and pharmaceutical communities," write Libby, et al. "Enhanced recognition of these commonalties should promote cross-fertilization and hasten progress in this rapidly moving domain."

CRISPR: Genetic Editing's Promise in CV Medicine

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The potential of CRISPR gene-editing in cardiovascular medicine is nothing short of revolutionary. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats and is a technology used to selectively modify the DNA of living organisms. Hereditary conditions like familial hypercholesterolemia are prime targets for CRISPR interventions.

Beyond treatment, CRISPR is opening new frontiers in understanding cardiovascular disease mechanisms. By precisely manipulating genes associated with heart function, researchers can create more accurate disease models, accelerating understanding of complex cardiac conditions.

In a phase 1, single-group, open-label study presented at AHA 2024, nexiguran ziclumeran (nex-z), a CRISPR-Cas9-based (associated Cas9 endonuclease) investigational therapy for transthyretin amyloidosis cardiomyopathy (ATTR-CM), revealed promising results in reducing serum transthyretin levels.⁷

Led by Marianna Fontana, MD (University College London, UK), the study involved 36 patients who received a single two-hour intravenous infusion. Participants were predominantly older men (median age, 78), with half in NYHA class III and 31% having variant ATTR-CM. The trial's dual primary objectives were assessing safety and pharmacodynamics including the serum TTR level.

A mean serum TTR level reduction of 89% was seen at 28 days, persisting at 90% at 12 months. Thirty-four patients experienced adverse events, with 14 being serious. Minimal changes in NT-proBNP and cardiac troponin T levels and only a modest 5-meter improvement in 6-minute walk distance were noted. Fully 92% of the patients showed no disease progression or improvement in NYHA class. Further investigation is ongoing in the phase 3 MAGNITUDE trial involving patients with ATTR-CM.

Commenting on the trial, Sarah Cuddy, MD, FACC (Brigham and Women's Hospital, Boston), called the study's findings "really promising" and said the trial "has opened up the door for gene editing, a permanent approach to therapy."

Amyloidosis: A New Frontier in Cardiac Care

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The CRISPR trial is just one of the recent advances in the treatment of cardiac amyloidosis. Once considered rare, the condition is experiencing a renaissance in diagnostic and treatment approaches, with advanced imaging techniques and genetic screening enabling earlier detection. Emerging therapies offer new hope for patients.

ATTR-CM results from the misfolding of transthyretin (TTR), a protein primarily produced in the liver. The disease progresses due to the accumulation of amyloid fibrils in the heart, leading to restrictive cardiomyopathy. Treatment strategies for ATTR-CM aim to either stabilize TTR tetramers, reduce their synthesis, disrupt amyloid fibrils or enhance fibril clearance.

ATTR-CM, in particular, has seen significant breakthroughs. Tafamidis remains the gold standard for ATTR amyloidosis, stabilizing transthyretin protein, while acoramidis, a next-generation stabilizer that received U.S. Food and Drug Administration (FDA) approval in late November 2024, has shown significant improvements in mortality, morbidity and biomarkers compared to placebo.

Two small interfering RNA (siRNA) therapies, patisiran and inotersen, show promise in reducing TTR protein production. In HELIOS-B, vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events compared with placebo (HR, 0.72; p=0.01) and preserved functional capacity and quality of life.⁸ Patisiran and vutrisiran are currently FDA approved for patients with ATTR-polyneuropathy.

Another RNA-based therapy that targets the production of abnormal TTR protein is eplenotersen, which is currently being tested for ATTR-CM in the CardioTTRansform trial and was recently approved for ATTRv amyloid polyneuropathy as well.

Innovations, including chemotherapy, monoclonal antibodies and autologous stem cell transplantation, are also improving survival rates and cardiac outcomes for patients with amyloid light chain cardiomyopathy.

The rapid evolution of amyloidosis treatment is ushering in an era of precision medicine. Experimental therapies like CRISPR-Cas⁹ gene editing and monoclonal antibodies promise targeted interventions with transformative potential. However, challenges remain, including high drug costs and disparities in diagnosis and treatment access. Ensuring equitable availability of these therapies is essential as the field progresses.