Atherosclerosis and the Bidirectional Relationship Between Cancer and Cardiovascular Disease: From Bench to Bedside, Part 2 Management

1. Introduction

The secular trend in hospital admissions indicates an increasing recognition of cancer among patients hospitalized for cardiovascular disease (CVD) [1]. Population-based studies further demonstrate that optimal control of atherosclerotic cardiovascular disease (ASCVD) risk factors—through appropriate behaviours and treatments as recommended by the American Heart Association (AHA) [2] — reduces the incidence of both cancer and CVD, as well as lowers all-cause, cardiovascular, and cancer-specific mortality [3,4]. These interventions include maintaining healthy sleep patterns, avoiding smoking, achieving normal plasma glucose and cholesterol levels, adopting a healthy diet, preventing obesity, engaging in regular physical activity, and managing blood pressure within the normal range. Importantly, these findings support the hypothesis of a shared pathophysiological "common soil" between cancer and CVD [5]. This notion is further emphasized by contemporary international clinical guidelines, which highlight cancer as a clinical condition warranting special attention in the management and prevention of ASCVD [6,7].

However, ASCVD risk is often underestimated and undertreated in oncological patients [8,9,10,11,12,13], and the interactions between environmental exposures (the exposome) and cardiometabolic risk factors remain dangerously neglected. This situation is no longer acceptable, especially given the progressive improvement in cancer patient survival, the aging of the general population, and the increasing incidence of early-onset cancer (before the age of 50). In the first part of this review, we discussed the evolving landscape of atherosclerosis and the central role of chronic low-grade inflammation in both CVD and cancer [14]. In this second part, we will explore the intricate interconnectedness of environmental exposures and cardiometabolic risk factors through a syndemic approach, which adds complexity to the management of contemporary oncological patients. From this perspective, we aim to define an updated strategy for managing ASCVD in patients with a history of or active cancer, with a particular focus on preventive cardio-oncology.

2. How to Manage Atherosclerosis -Driven Chronic Diseases in Cancer Patient

NON pharmacologic treatments

The importance of lifestyle in preventing NCDs is well-established. Risk factors such as tobacco use; unhealthy diets high in saturated and trans fats, salt, and sugar; physical inactivity, and excessive alcohol consumption are responsible for more than two-thirds of all new NCD cases and significantly increase the risk of complications [19].

Diet. The EUROASPIRE V study highlights the importance of dietary guidance in managing patients at high CV risk [142]. Both vegetarian and Mediterranean diets, low in saturated fats and red meat, have been shown to improve blood lipid profiles, blood pressure, fasting glucose, and glycosylated haemoglobin levels. These diets also positively influence inflammation, oxidative stress markers, insulin sensitivity, and endothelial and antithrombotic function [143,144,145,146,147]. Meta-analyses of observational studies and randomized trials confirm the protective effect of Mediterranean diet against all-cause mortality, CVD, CAD, MI, cancer, neurodegenerative diseases, and diabetes [148,149]. In the Women's Health Study, a 25-year cohort of 25,315 women, those with greater adherence to the Mediterranean diet had a 23% reduced risk of all-cause mortality. This effect was largely attributed to improvements in small molecule metabolites, inflammation, triglyceride-rich lipoproteins, insulin resistance, and BMI, with less impact from traditional cholesterol or glycaemic markers [150]. For patients with established CAD, the Mediterranean diet with extra virgin olive oil (EVOO) outperformed low-fat diets in preventing major CV events [151], slowing atherosclerosis progression [152], and preserving kidney function in obese patients with type 2 diabetes [153]. A strong inverse association between Mediterranean diet adherence and cancer risk has also been observed, particularly for breast cancer (BC). In the Women's Health Initiative study, postmenopausal women with BC following a diet rich in vegetables, whole grains, fruits, and reduced fat intake showed a 38% reduction in CV deaths over 10 years [154]. Similarly, the PREDIMED trial found that women at high CV risk who followed a Mediterranean diet enriched with EVOO had a reduced incidence of BC [155]. The MOLI-SANI study further underscored the importance of dietary quality, demonstrating that higher olive oil consumption was linked to lower rates of cancer, CV, and all-cause mortality, independent of overall diet quality [156]. In the Multi-Ethnic Study of Atherosclerosis (MESA), consumption of plant-based foods and beverages high in bioflavonoids was inversely associated with subclinical atherosclerosis in peripheral and carotid arteries [157].

In contrast, there is growing concern about the health impacts of ultra-processed foods (UPFs), which are typically high in energy, sugars, unhealthy fats, salt, and low in fibres, protein, vitamins, and minerals. Greater consumption of UPFs, as classified by the NOVA system [158], has been linked to increased cardiometabolic risk, depression, and mortality [159,160]. A systematic review of eight retrospective and three prospective cohort studies found that a 10% increase in UPF daily consumption was associated with a higher risk of overall cancer (HR = 1.13, 95% CI 1.07–1.18) [161]. Children are also affected by high UPF consumption. In the CORALS (Childhood Obesity Risk Assessment Longitudinal Study) cohort of 1,426 children (mean age 5.8 years), higher UPF intake was significantly associated with increased adiposity and worse cardiometabolic risk. Mothers of children with high UPF consumption tended to be younger, with higher BMIs, lower education levels, and lower employment rates [162]. Given these findings, reducing UPF consumption is crucial. The 2022 ESC Guidelines on Cardio-Oncology recommend dietary patterns rich in vegetables, fruits, and whole grains, which are associated with lower mortality and cancer recurrence compared to diets high in refined grains, processed and red meats, and high-fat dairy products [129]. According to the American Cancer Society Guidelines for Cancer Prevention the “healthy eating pattern includes a variety of vegetables (dark green, red, and orange), fiber-rich legumes (beans and peas), fruits, especially whole fruits with a variety of colors; and does not include red and processed meats, sugar-sweetened beverages and highly processed foods and refined grain products” [163].

Microbiota and microbiome. Diet plays a crucial role in regulating gut microbiota, a complex community of intestinal microorganisms, including bacteria, archaea, viruses, and fungi. The intestinal microbiota is often considered the largest endocrine organ in the human body, supporting immune responses against pathogens, aiding food digestion, and facilitating vitamin production [164]. A healthy gut microbiota stabilizes its host, contributing to CV health (CVH) and cardiovascular-kidney-metabolic health (CVKMH) [165], although the exact mechanisms and the influences of genetic and environmental factors on microbiota composition are not yet fully understood [166,167]. Dysregulated microbiota can exacerbate inflammatory pathways, including IL-6, CRP, lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), mitogen-activated protein kinase (MAPK), nuclear factor-kB (NF-kB), and oncometabolite production [168]. Current research actively investigates the potential link between alterations in faecal microbial community composition and conditions such as obesity, insulin resistance, atherosclerosis, CVD, and cancer [169,170,171,172]. Preliminary pooled analyses suggest that manipulating intestinal flora may improve cardio-metabolic risk [173]. In a recent small randomized clinical trial, obese patients with type 2 diabetes who combined an appropriate lifestyle with "lean-associated" faecal microbiota transplantation showed significant improvements in lipid profiles and liver stiffness—markers of predisposition to atherosclerosis, cirrhosis, and hepatocellular carcinoma [174]. Initial studies exploring the causal relationship between the gut microbiome and CVD focused on trimethylamine N-oxide (TMAO), an intestinal microbiota-dependent metabolite derived from the choline head group of phosphatidylcholines, mainly found in Western dietary nutrients (e.g., lecithin, choline, carnitine). Elevated plasma levels of TMAO, produced by gut microbiota, are significantly predictive of major adverse CV events [175], facilitating atherosclerosis through dysregulated lipid metabolism, adiposity, impaired glucose homeostasis, high blood pressure, platelet reactivity, thrombosis, and vascular inflammation [176]. The relationship between dietary patterns and gut microbiota is evidenced by the correlation between prolonged red meat consumption and increased TMAO levels; conversely, an isocaloric-isoprotein diet without red meat can reduce TMAO levels [175]. Emerging data also suggest a link between microbiota and cancer development, as well as responses to oncological treatments [177,178,179]. Many bacterial species within the microbiome may play oncogenic roles, making the influence of bacterial flora potentially relevant in the context of personalized oncology treatments [180]. Recent observations indicate that intestinal flora may impact the development of early-onset cancer [181,182,183] and the response to immunotherapy [184,185,186].

Alcohol. Traditional population studies have suggested a J- or U-shaped relationship between alcohol consumption and cardiovascular health (CVH), indicating that mild to moderate use may offer cardioprotective effects, while alcohol abuse is cardiotoxic [187]. However, recent findings have called into question the protective effects of moderate or mild alcohol consumption, citing potential confounding factors such as genetic polymorphisms, lifestyle behaviours among light drinkers, and inadequate analyses of social and economic influences [188,189,190,191,192]. In oncology, alcohol consumption has been causally linked to several types of cancer, with no safe level of intake. The risk of alcohol-associated cancer increases with consumption, and this risk is consistent across all ethanol-containing beverages. Regarding CV prevention, the 2021 ESC Guidelines on CVD prevention recommend limiting alcohol consumption to a maximum of 100 g per week (about 5–6 standard UK glasses of wine or pints of beer per week) [6] while the American Cancer Society's Guidelines for Diet and Physical Activity for Cancer Prevention advise against alcohol consumption, stating that individuals who choose to drink should limit their intake to no more than one drink per day for women and two drinks per day for men [163].

Physical activity (PA) In oncology, PA significantly impacts cellular processes and tumour growth [193] by modulating insulin and glucose metabolism, immune function, inflammation, sex hormones, oxidative stress, genomic instability, and myokines [163,194,195]. Furthermore, PA may reduce cancer risk related to obesity. The physical effects of PA, such as increased blood flow, shear stress on the vascular system, pH regulation, heat production, and sympathetic activation, along with endocrine effects like stress hormones, myokines, and circulating exosomes, may help regulate cancer progression and biology by affecting tumour growth, metastatic potential, tumour metabolism, and the immunogenic profile of tumours. Exercise also has beneficial effects on cancer symptoms and treatment-related adverse effects [196].

Smoking cessation is a critical priority for preventing both CVD and cancer. Smoking significantly increases mortality from all causes and is a leading contributor to ASCVD. Cigarette smoke contains over 7,000 chemical compounds, including at least 72 known carcinogens and numerous pro-carcinogens [197,198]. Tobacco use is causally linked to various CVD phenotypes, ranging from early-onset atherosclerosis in adolescents and young adults to increased risks of acute MI, stroke, peripheral artery disease, aortic aneurysm, and sudden death [199]. Both cigarette smoke and second-hand smoke activate, damage, and kill endothelial cells, leading to lipid and inflammatory cell infiltration. Additionally, activated leukocytes release inflammatory cytokines and enhance the expression of adhesion molecules, contributing to the formation of vulnerable plaques, a pro-thrombotic environment, and reduced fibrinolytic capacity [200]. Smoking also contributes to the development of diabetes and dyslipidaemia [201]. In 1964, the Surgeon General's report first established the causal link between smoking and lung cancer [202]. Fifty years later, the 2014 report highlighted the increased risk of smoking exposure for several other cancers. While lung, laryngeal, and pharyngeal cancers have the highest relative risks for current smokers, elevated risks have also been observed for cancers of the upper digestive tract, oral cavity, lower urinary tract, oesophagus, nasopharynx, cervix, pancreas, stomach, kidney, liver, and colorectal regions [199,203]. Meta-analyses have confirmed smoking as a major risk factor for urothelial bladder cancer [204,205] and for an unfavourable course of prostate cancer [206].

Social and psychological determinants of health. Inequalities in wealth, income, and education are key factors in the development and progression of multimorbidity. Low socioeconomic status is a recognized risk factor for many mental and behavioral problems, that eventually lead to lifelong physical diseases [207,208]. Food insecurity (FI), or “the lack of consistent access to enough food for an active and healthy life” [209] has indeed been associated to ASCVD risk through the nutrition/anthropometric, psychological/mental health, and access to care pathways [210].

In 2019, Tawakol et al. documented a link between socioeconomic disparities and CVD through a stress-related neurobiological pathway [211]. In 2022, the American Heart Association (AHA) included sleep as an essential component of CVH and addressed social determinants of health (SDOH) and psychological well-being, recognizing their importance for achieving equitable CVH outcomes [2]. Positive psychological traits, such as optimism, purpose in life, environmental mastery, perceived social role reward, and resilient coping, have been associated with better CVH, while psychosocial stress and depression are linked to worse outcomes [2,212]. Loneliness, a recognized SDOH, is also a risk factor for both CVD and cancer [213,214,215]. In a systematic review of 51 cohort studies involving 2,611,907 participants with an average follow-up period of 10.3 years, depression and anxiety were associated with a significantly higher risk of cancer incidence (adjusted RR: 1.13; 95% CI: 1.06-1.19), specific cancer mortality (1.21; 1.16-1.26) and all-cause mortality in cancer patients (1.24; 1.13-1.35) [216]. Psychological distress is common in cancer [217,218] and may intersect with the cognitive change associated with therapy, or “chemo-brain” [219], an entity that has been identified in people with a variety of cancers who have undergone chemotherapy and/or hormone treatment. These patients may have difficulties in executive functions, multitasking, short-term memory and attention and coping ability. Anxiety and depression are emerging as significant risk factors for subclinical atherosclerosis [220,221,222], in the context of cardio-oncology there is an urgent need to address these novel risk enhancers. An example is offered by the positive impact of spirituality in serious health conditions and its ability to counter loneliness, hopelessness, and depersonalization, often overlooked in patient-centred care [223]. Spirituality can enhance coping abilities [224] and potentially improve outcomes through effects on the autonomic nervous system, and hormonal, immunological, and neurological pathways [225]. Since 2008 The Institute of Medicine (IOM) stated: “Attending psychosocial needs should be an integral part of quality cancer care. All components of the health care system involved in cancer patient management should explicitly incorporate attention to psychosocial needs into their policies, practices, and standards addressing clinical care” [226,227]. Psychotherapeutic interventions useful for mental health in cancer patients are based on emotional support and include education, behavioural training, group interventions and individual psychotherapy.

Pollution is an increasingly significant health issue, acting as a "syndemic" risk factor when combined with traditional risk factors. Air and noise pollution, light disruption at night, climate change, and chemical exposure contribute to the development and progression of cardiometabolic multimorbidity [228]. Studies on populations living near airports, heavy road traffic, and industrial zones highlight the impact of environmental pollution on cardio-metabolic and oncological risks [229,230,231,232,233]. These stressors—through mechanisms such as altered stress responses, circadian rhythm disruption, immune activation, inflammation, oxidative stress, microvascular dysfunction, heart rate variability, and hypercoagulability—heighten CV risk and burden [52]. For example, air pollution amplifies the adverse effects of heat, particularly in vulnerable elderly populations, while exposure to heavy metals like lead and mercury has been linked to hyperlipidaemia [234]. Addressing pollution from an "exposomic" perspective, which considers the total environmental exposure across an individual's life, is a crucial issue. Simply controlling traditional risk factors will not be enough to reverse the rising trend of NCDs. Efforts must focus on improving environmental conditions alongside traditional risk factor management.

Pharmacologic therapies: cardiometabolic and anti-inflammatory agent

2.2.1.

Cardiometabolic Therapies and Their Impact on Atherosclerotic Plaque

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Lipid-lowering therapies (LLTs), including statins, ezetimibe, polyunsaturated fatty acids (PUFAs), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have been extensively studied for their beneficial effects on atherosclerotic plaque regression, both as monotherapies and in combination [235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256]. LLTs also influence platelets and interact with various atherosclerosis mediators, including the endothelium, monocytes, and smooth muscle cells [257]. Table 1 summarizes key studies on LLTs and their effects on atherosclerotic plaques.

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Metformin, first introduced in the late 1950s and still widely used today, targets three key molecular pathways: complex 1 of the mitochondrial electron transport chain (ETC), adenosine monophosphate (AMP)-activated protein kinase (AMPK), and mechanistic target of rapamycin complex 1 (mTORC1). Inhibition of hepatic gluconeogenesis is linked to its effect on mitochondrial complex 1, which reduces ATP levels and increases the AMP/ATP ratio, activating AMPK and further inhibiting gluconeogenesis [258,259]. Metformin also stimulates the release of glucagon-like peptide 1 (GLP-1) from the intestine [260]. Additionally, AMPK can be activated via the serine-threonine liver kinase B1 (LKB1) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), which increases the cytosolic redox state [261,262]. Activation of AMPK by metformin results in reduced blood sugar, improved inflammatory control, enhanced oxidative status, and activation of endothelial nitric oxide synthase, which may explain metformin's protective effect on endothelial function. Preclinical studies suggest that metformin stabilizes atherosclerotic plaques by inhibiting matrix metalloproteinase 9 (MMP-9), an enzyme responsible for degrading the extracellular matrix (ECM) of blood vessels [263,264]. A retrospective clinical study of 313 patients with type 2 diabetes and CAD found that metformin, particularly when not combined with insulin, reduced the prevalence of vulnerable plaque features based on optical coherence tomography (OCT) analysis of 409 non-culprit plaques [265].

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Preclinical studies in animal models have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors) have favourable effects on plaque size, composition, and inflammatory pathways [266,267]. However, there are limited data on these effects in humans [268,269,270], they are summarized in Table 2.

2.2.2.

Cardiometabolic Therapies and Their Potential Effect in Cardioncology

The shared mechanisms between CVD and cancer explain the unexpected anticancer effects of many cardiometabolic drugs. These effects are largely due to metabolic remodelling in cancer cells.

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Statins. Statins reduce low-density lipoprotein cholesterol (LDL-C) in a dose-dependent manner, lower triglycerides (TG) by 10-20% (with greater reductions from high-intensity statins), and have a minimal effect on lipoprotein(a) [Lp(a)] [271]. Their beneficial impact on CV morbidity and mortality is well-documented [272,273,274,275]. Statins can be safely and effectively used in elderly patients, including those over 75 years of age [276]. The ESC Guidelines on CVD prevention (Class I A) recommend high-intensity statins at the highest tolerated dose to achieve LDL-C targets based on specific risk groups [6]. Statins may have anticancer properties due to their cholesterol-lowering effects [277,278] and ability to enhance efficacy of ICIs [279,280]. Preclinical studies have shown statins' direct antiproliferative and immunomodulatory effects, promoting immunogenic cell death in KRAS (Kirsten rat sarcoma viral oncogene homolog) -mutated cancer cells. This occurs through increased expression of "eat me" signals and damage-associated molecular patterns, while reducing proteins that suppress T cell antitumor responses [281].

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Ezetimibe. In a meta-analysis of eight randomized, double-blind, placebo-controlled trials (12-week duration), Ezetimibe showed a significant reduction in LDL-C compared to placebo [282]. When combined with statins, it provided an additional 21-27% reduction in LDL-C [283]. The IMPROVE-IT trial, involving over 18,000 patients with acute coronary syndrome (ACS), demonstrated a modest but significant CV benefit from adding ezetimibe to simvastatin, with encouraging safety data [284]. These findings support the use of ezetimibe as second-line therapy alongside statins when LDL-C targets are unmet, or statins are not viable options.

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Bempedoic acid inhibits ATP citrate lyase, a cytosolic enzyme upstream of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, and reduces LDL-C levels. It has a low incidence of muscle-related side effects, making it suitable for patients who are statin-intolerant. The CLEAR OUTCOMES trial, a double-blind, placebo-controlled study that included high-risk CVD patients who could not tolerate statins, has documented a significantly lower risk of major adverse CV events (MACE), including CV death, nonfatal MI, stroke, or coronary revascularization in patients treated with bempedoic acid [285]. The 2024 ESC Guidelines on chronic coronary disease (CCD) recommend bempedoic acid in combination therapy for statin-intolerant patients or those not reaching LDL-C goals on maximum tolerated statin and ezetimibe therapy [286].

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PCSK9 inhibitors (PCSK9Is). PCSK9Is target the PCSK9 protein, which regulates LDL receptors (LDLRs). These inhibitors work through monoclonal antibodies (mAbs) that lower plasma PCSK9 levels by reducing its binding to LDLRs, and through a small interfering RNA (siRNA), Inclisiran, that inhibits PCSK9 synthesis. The result is a significant reduction in plasma LDL-C levels. Alirocumab and evolocumab effectively lower LDL-C in high or very high CV risk patients, including those with T2DM, and reduce CVD events [287,288]. Statins increase circulating PCSK9 levels, enhancing the benefits of the mAbs. These drugs are recommended for secondary prevention in patients who do not achieve LDL-C targets with statins and ezetimibe [6,286]. The long-term benefits of PCSK9 inhibitors (PCSK9Is) were evaluated in the FOURIER-Open Label Extension (FOURIER-OLE) study, which followed individuals originally randomized to evolocumab in the FOURIER trial [288]. The study confirmed both the efficacy and safety of extended PCSK9I use [289], which Shapiro described as "the gift that keeps giving" [290]. The efficacy in lowering LDL-C of Inclisiran was demonstrated in the ORION trials in patients with familial hypercholesterolemia, atherosclerosis, and high CV risk [291,292]. Beyond LDL-C lowering, PCSK9Is have pleiotropic effects, such as reducing platelet reactivity, decreasing smooth muscle cell proliferation, limiting macrophage accumulation, and promoting plaque regression and stabilization [293]. Emerging data suggest a link between PCSK9 and cancer: PCSK9 gain-of-function variants are associated with higher LDL-C and an increased risk of BC, while loss-of-function variants show the opposite effect [294]. PCSK9Is may also enhance the anticancer efficacy of immune checkpoint inhibitors (ICIs), as seen in colorectal cancer, where PCSK9 inhibition boosts the effectiveness of PD-1 blockade by reducing LDL-R and transforming growth factor-β (TGF-β) levels [295].

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Fibrates (bezafibrate and fenofibrate) are used to lower triglyceride levels, but their limited impact on CV outcomes has led to a Class IIb recommendation in the 2021 ESC Guidelines on CVD prevention. They are suggested for patients on statins who have reached LDL-C targets but still have triglyceride levels >2.3 mmol/L (200 mg/dL) [6]. A recent meta-analysis of 12 trials involving over 50,000 patients found that fibrate therapy was associated with a reduced risk of major adverse CV events (MACE); however, this benefit was attributed to LDL-C reduction rather than changes in triglyceride levels [296].

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Metformin. Untreated patients with type 2 diabetes (T2DM) have an increased risk of cancer, likely due to the growth-promoting effects of chronically elevated glucose and insulin levels. This heightened risk is most pronounced for cancers of the liver, pancreas, endometrium, colon, breast, and bladder [297]. The anticancer potential of metformin has been widely studied, but its preventive role remains debated. A review and meta-analysis of 27 trials involving over 10,000 patients found no significant reduction in cancer incidence with metformin use [298]. However, another meta-analysis of 166 studies indicated a decreased risk of T2DM-associated cancers (gastrointestinal, urologic, and hematologic), suggesting metformin may reduce cancer risk indirectly by improving diabetes control [299]. A recent review by Galal et al. [300] highlights metformin influence on cancer cell biology through its effects on energy metabolism, cellular growth, angiogenesis, and programmed cell death. Metformin exerts both direct (insulin-independent) and indirect (insulin-dependent) effects on cancer cells, which may interact with each other. However, in recent clinical trials, metformin failed to improve the clinical course of prostate cancer [301,302] and BC [303]. Metformin has also been proposed as an immuno-metabolic adjuvant for cancer therapy. Preclinical studies suggest it can alter the tumor immune microenvironment [304,305] and reduce programmed death ligand 1 (PD-L1) expression, enhancing its degradation [306,307]. However, the "boosting" effect of metformin on cancer immunotherapy has been questioned due to confounding factors [308]. A meta-analysis of 22 studies involving over 9,000 patients revealed a significant association between metformin use and poorer overall survival, suggesting an adverse prognosis when combined with immune checkpoint inhibitors (ICIs) [309]. Further research is needed to fully assess metformin’s clinical and immunomodulatory potential in cancer treatment.

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Glucagon-like peptide 1 Receptor Agonists Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-based therapies that enhance insulin secretion in response to meals [310]. In addition to their role in glucose regulation, they promote weight loss, reduce chylomicron secretion, and lower blood pressure [311,312]. GLP-1 RAs, such as Liraglutide, Semaglutide, Exenatide, Albiglutide, and Dulaglutide, are approved for treating type 2 diabetes mellitus (T2DM) and have shown CV benefits in several trials [313,314,315,316,317,318,319]. A meta-analysis of 40 randomized controlled trials demonstrated that GLP-1 RAs significantly reduce inflammatory markers such as CRP, tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA) [320]. Notably, the effects of Liraglutide and Semaglutide on CV outcomes are independent of baseline blood pressure [321], BMI [322], glycated hemoglobin A_1c (HbA_1c) levels [323], and triglycerides [324]. The 2023 ESC Guidelines for the management of CVD inpatients with diabetes recommend GLP-1 RAs with proven CV benefits (Liraglutide, Semaglutide, Dulaglutide, Efpeglenatide) for patients with T2DM and ASCVD to reduce CV events, irrespective of baseline HbA1c or other glucose-lowering treatments [325]. Liraglutide and Semaglutide have also been approved for obesity treatment. Liraglutide approval for weight loss followed the SCALE program [326], while Semaglutide approval was based on the STEP program, which included four key trials [327,328,329,330]. A recent trial demonstrated a significant reduction in death from CV causes, nonfatal MI, and nonfatal stroke with weekly Semaglutide (2.4 mg) in overweight or obese patients with preexisting CV disease but without diabetes, over a 39.8-month follow-up [331]. The 2024 ESC Guidelines for CCD recommend Semaglutide for patients without diabetes but with overweight or obesity (BMI >27 kg/m²) to reduce CV mortality, MI, or stroke (class IIa, B) [286]. GLP-1 receptor agonists (GLP-1 RAs) may have a potential role in reducing obesity-related cancer risk [332]. A recent study involving over 1.6 million patients with type 2 diabetes (T2DM) compared the incidence of 13 obesity-associated cancers among those treated with GLP-1 RAs, insulin, or metformin. GLP-1 RA treatment was associated with a significant reduction in the risk of 10 cancers, including esophageal, colorectal, endometrial, gallbladder, kidney, liver, ovarian, and pancreatic cancers, as well as meningioma and multiple myeloma, compared to insulin-treated patients. When compared to metformin, GLP-1 RAs showed a beneficial effect in reducing the risk of colorectal and gallbladder cancer [333]. In preclinical studies liraglutide has shown potential to enhance the anti-tumor efficacy of immune checkpoint inhibitors (ICIs) in lung and liver cancers [334]. However, conflicting data exist regarding the effects of GLP-1 RAs on cancer initiation and progression. The expression of the GLP-1 receptor (GLP-1R) varies across different tumor types, as well as between healthy and diseased tissues [335]. GLP-1R is highly expressed in endocrine tumors and has also been detected in embryonic cancers, nervous system tumors, and certain carcinomas. It is also expressed in various healthy tissues, including the pancreas, digestive tract, heart, skeletal muscle, liver, central nervous system, and immune cells, where it can be activated [336]. The effects of GLP-1 RAs appear to be tumor-specific. Notably, Semaglutide carries a boxed warning from the Food and Drug Administration (FDA) regarding the potential risk of thyroid C-cell cancer, specifically medullary thyroid carcinoma; [337]; this increased risk has not been observed with liraglutide A recent French multicenter registry reported an association between GLP-1 RA use for 1-3 years and an increased risk of thyroid cancers (adjusted hazard ratio [HR] 1.58, 95% CI 1.27-1.95) [338], a finding supported by a systematic review of 64 randomized controlled trials [339].

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SGLT2 Inhibitors Numerous trials have evaluated the effects of SGLT2 Inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin) on CV morbidity and mortality, as well as the effects of Canagliflozin and Sotagliflozin on reducing the risk of kidney failure and CV events [340,341,342,343,344,345,346,347,348,349]. According to the 2023 ESC Guidelines for managing CVD in patients with diabetes, empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin are recommended for patients with T2DM and ASCVD to reduce CV events, regardless of baseline or target HbA1c levels and independent of other glucose-lowering treatments [325]. In T2DM patients without ASCVD or severe target organ damage (TOD), but with a 10-year CV risk of ≥10% according to the SCORE2-Diabetes algorithm, SGLT2 inhibitors may also be considered to lower CV risk, a benefit that appears to be independent of their glucose-lowering effects [350,351]. Empagliflozin and dapagliflozin have shown impressive results in improving outcomes for patients with symptomatic heart failure (HF), regardless of ejection fraction [352]. SGLT2 inhibitors have demonstrated antiproliferative effects against certain tumor types. Cancer cells often exhibit high glucose uptake and glycolysis, and the antineoplastic activity of SGLT2 Inhibitors is partially attributed to their ability to block glucose uptake in metabolically reprogrammed cancer cells expressing SGLT2 receptors. However, preclinical studies suggest that the anticancer effects of SGLT2 Inhibitors are multifactorial, involving several metabolic pathways [353]. Beyond their potential direct anticancer effects, SGLT2 Inhibitors may offer protective benefits against cancer therapy-induced CV toxicity. Preclinical studies have shown significant cardioprotective effects against anthracycline exposure [354,355] and ponatinib-induced cardiac toxicity [356]. Clinical studies have also reported favorable outcomes in patients with cancer and T2DM treated with anthracyclines [357], as well as improved outcomes in patients with cancer therapy-related cardiac dysfunction or heart failure [358].

2.2.4.

Anti-Inflammatory Agents in CVD and Cancer

In atherosclerosis, the NLRP3 inflammasome (nucleotide oligomerization domain-like receptor protein 3) detects environmental danger signals—such as cholesterol, disturbed blood flow, and dead cells—and activates caspase-mediated processing of pro-IL-1β into its active form, IL-1β. This promotes an inflammatory response in endothelial cells, triggering the activation of adhesion molecules such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1); and chemokines like monocyte chemoattractant protein-1 (MCP-1), which recruit leukocytes to the site [359]. Cells in atherosclerotic plaques can also produce IL-1 in response to inflammatory stimuli [360]. The association of inflammatory biomarkers, such as hsCRP and interleukin-6 (IL-6), with CV risk—independent of cholesterol levels—has been well established [361,362,363]. Numerous studies have shown improved outcomes with reductions in both LDL-C and CRP [364,365,366,367,368]. A recent meta-analysis of 53 randomized controlled trials involving 171,668 subjects found that statins, bempedoic acid, ezetimibe, and omega-3 fatty acids significantly reduced CRP levels, independent of LDL-C reduction [369]. Notably, in high-risk, statin-intolerant patients, inflammation (assessed by hsCRP) was a stronger predictor of future CV events than hyperlipidaemia (assessed by LDL-C) [370]. The critical role of inflammation in atherosclerosis has sparked interest in clinical trials investigating anti-inflammatory therapies, such as the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) with the IL-1 inhibitor canakinumab [371], and colchicine studies [372,373,374] with potential interest in cardioncology.

(i)

Interleukin inhibitors - The CANTOS trial was the first to test the inflammatory hypothesis of atherosclerosis by selectively inhibiting interleukin-1β with canakinumab in 10,061 patients with a history of MI and hsCRP levels of 2 mg/L or higher. Treatment with canakinumab (150 mg every 3 months) significantly reduced the incidence of the primary endpoint (nonfatal MI, nonfatal stroke, or CV death) and the secondary endpoint (including urgent revascularization), independent of lipid lowering [371]. Interestingly, CANTOS also observed a reduced incidence of lung cancer in the canakinumab group [375]. However, later trials failed to demonstrate a survival benefit in patients with resected or advanced non–small-cell lung cancer (NSCLC) [376,377,378]. These contradictory findings highlight the complex, pleiotropic role of IL-1 signalling [379]. Elevated IL-1 levels are associated with poor prognosis in various cancers [380] and promotes carcinogenesis by driving chronic inflammation and establishing a protumor cytokine network [381]. Furthermore, IL-1 exert paradoxical effects on antitumor immunity. While it enhances the activation of natural killer- and T- cells, promoting antitumor activity [382], it also contributes to immunosuppression by facilitating the expansion and mobilization of immune cells such as myeloid-derived suppressor cells (MDSCs) [383]. As a result, therapeutic strategies targeting IL-1 require further clinical studies to determine the efficacy and optimal use of anti-IL-1 therapies in specific clinical contexts. The phase II RESCUE trial showed that Ziltivekimab, a monoclonal antibody targeting the IL-6 ligand, significantly reduced inflammation and thrombosis biomarkers linked to atherosclerosis [384]. The results of this small study with Ziltivekimab are particularly intriguing from a cardio-oncology perspective. IL-6 plays a key role in tumorigenesis, cancer progression, and treatment resistance [385]. In preclinical studies, IL-6 inhibition combined with immune checkpoint blockade (ICB) enhanced antitumor immunity and slowed tumor progression across various cancer models [386,387,388]. IL-6 is also implicated in the development of immune-related adverse events (irAEs) associated with ICB, as shown by the effectiveness of tocilizumab, an IL-6 receptor inhibitor in managing these events in clinical practice. Thus, combining IL-6 inhibitors with ICB holds promise for improving cancer immunotherapy while reducing the risk of adverse events [389,390], including atherosclerosis [391]. More definitive data are expected from the ongoing ZEUS trial, which is investigating the effects of Ziltivekimab on CV outcomes (CV death, nonfatal MI, and nonfatal stroke) in 6,000 patients with CVD, CKD and systemic inflammation [392].

(ii)

Colchicine is a potent anti-inflammatory agent that works by inhibiting microtubule polymerization, neutrophil extracellular trap (NET) release, platelet activation, and the NLRP3 inflammasome [393,394]. Its effects on the NLRP3 inflammasome limit the activation of inflammatory cytokines, such as interleukin-1 and interleukin-18, in response to danger signals. Preclinical studies have shown that low-dose colchicine exerts anti-atherosclerotic and plaque-stabilizing effects, strongly inhibiting foam cell formation and cholesterol crystal-induced inflammation [395]. In 2013, Nidorf et al. reported a significant reduction in the primary outcome (a composite of ACS, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke) after a 3-year follow-up in patients with stable coronary disease treated with colchicine in addition to aspirin (and/or clopidogrel) and statins, compared to those who did not receive colchicine [372]. These findings were confirmed in 2019 by a larger study on patients within 30 days of AMI [373]. Low-dose colchicine also showed benefits in chronic coronary disease, as demonstrated in the LoDoCo2 RCT, where colchicine-treated patients had a significantly lower incidence of CV events (CV death, non-procedural MI, ischemic stroke, or ischemia-driven coronary revascularization) after a 28.6-month follow-up compared to placebo [374]. Colchicine reduces hsCRP levels and may decrease coronary artery plaque volume [396]. A low-dose regimen (0.5 mg daily) has been approved by the FDA for secondary prevention in patients with CAD [397]. The drug's role in oncogenicity remains unclear. In the LoDoCo2 trial, non-cardiovascular deaths were more frequent in colchicine-treated patients than in the placebo group (hazard ratio, 1.51), although cancer diagnosis rates were similar [374]. However, a study of 85,374 Israeli patients with Familial Mediterranean Fever (FMF) showed a significantly lower incidence of cancer compared to the general population, potentially due to colchicine treatment [398]. Shared risk factors between gout and cancer (e.g. obesity and alcohol) have suggested a potential cancer susceptibility in gout patients, as demonstrated in a study of 8,408 male gout patients [399]. A further analysis of 24,050 gout patients found that those diagnosed with cancer were older and had a lower rate of colchicine prescriptions than those without cancer [400]. Interestingly, preclinical studies have shown a cardioprotective effect of low-dose colchicine in doxorubicin-induced cardiotoxicity, likely through the restoration of autophagy [401]. A recent study has documented, in mice and humans carrying CHIP (clonal hematopoiesis of indeterminated potential)-mutations, that colchicine can blunt the higher risk of ASCVD associated with somatic TET2 mutation-driven CHIP by suppressing IL-1β overproduction [402].