Cardiovascular–Endocrine–Metabolic Medicine: Proposing a New Clinical Sub-Specialty Amid the Cardiometabolic Pandemic

Diets rich in whole grains, fruits, vegetables, low in saturated and trans fats, and rich in monounsaturated and polyunsaturated fats found in olive oil, nuts, and fatty fish—such as the Mediterranean or DASH (Dietary Approaches to Stop Hypertension) diets—are effective in lowering BP, lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride levels by up to 10%, increasing high-density lipoprotein cholesterol (HDL-C) by up to 10%, improving glycemic control, and reducing cardiovascular risk [23,67,68,69]. A high intake of refined carbohydrates and added sugars, such as fructose and sucrose, worsens lipid profiles, increases triglycerides, reduces HDL-C, and impairs glycemic control. Reducing the consumption of these simple sugars and emphasizing complex carbohydrates and soluble fiber—found in whole grains, oats, barley, and legumes—can improve insulin sensitivity and lipid profiles and reduce cardiovascular risk [23,67,68,69].

Excessive dietary sodium intake is positively correlated with elevated BP and an increased risk of cardiovascular events. Reducing sodium intake to less than 2 g per day (approximately 5 g of salt) can result in significant reductions in systolic BP, with decreases of up to 5–6 mmHg in hypertensive patients. Notably, pooled data from salt-reducing trials have shown that reducing salt by 2.5 g/day is associated with a 20% decrease in the risk of cardiovascular events [70]. Concurrently, increasing dietary potassium intake—through the consumption of fruits, vegetables, and legumes—can further lower BP and mitigate the adverse effects of high sodium intake. An increase in potassium intake by 0.5–1.0 g/day may be considered to achieve a Na⁺/K⁺ ratio of 1.5–2.0, as proposed by the 2024 ESC guidelines with a class IIa recommendation. However, caution is warranted in patients with CKD and/or those taking potassium-sparing medications [23,67,68,69]. Energy drinks containing sugar and sodium and sugar-sweetened beverages should be avoided due to their potential to elevate BP and contribute to weight gain [23,67,68,69].

Physical activity and exercise are critical components of lifestyle medicine. Physical activity refers to any bodily movement produced by skeletal muscles resulting in energy expenditure, while exercise is a subset of physical activity that is planned, structured, and repetitive and aims to improve or maintain physical fitness [23,67,68,69].

Regular physical activity, including both aerobic exercise and resistance training, of sufficient intensity and duration offers significant benefits in managing hypertension and other cardiometabolic risk factors. Aerobic exercise, such as brisk walking or cycling for at least 150 min per week, can reduce systolic BP by approximately 7–8 mmHg and diastolic BP by 4–5 mmHg [71,72]. Dynamic resistance training and isometric exercises also contribute to BP reduction and improve vascular health [23,67,68,69].

Furthermore, engaging in regular physical activity favorably modifies lipid profiles by decreasing LDL-C levels by up to 5% and increasing HDL-C levels by more than 10%. Additionally, exercise interventions have been shown to reduce glycated hemoglobin (HbA1c) levels by approximately 0.6% in patients with T2DM [73]. Combining aerobic exercise with resistance training yields greater improvements in glycemic control compared to either modality alone, which can be attributed to enhanced insulin sensitivity and increased glucose uptake by skeletal muscles via GLUT4 [23,67,68,69].

Higher levels of total physical activity are associated with a lower risk of cardiovascular mortality and all-cause mortality. In a prospective cohort and meta-analysis, individuals with high total physical activity had a hazard ratio of 0.60 (95% CI, 0.49–0.73) for all-cause mortality compared to those with low physical activity levels [74].

Exercise prescriptions should be individualized, considering the patient's age, comorbidities, physical fitness level, and personal preferences. Consistency is key to maintaining BP reductions and other health benefits. The World Health Organization recommends that adults engage in at least 150 min per week of moderate-intensity aerobic physical activity or at least 75 min per week of vigorous-intensity aerobic activity or an equivalent combination. Muscle-strengthening activities involving major muscle groups should be performed on two or more days per week. Patients should be encouraged to increase their daily physical activity by incorporating more steps, using stairs instead of elevators, walking or cycling for transportation, and minimizing sedentary behavior [23,67,68,69].

Obesity, particularly central adiposity, is strongly associated with insulin resistance, T2DM, arterial hypertension, dyslipidemia, and increased cardiovascular risk. Weight reduction improves these risk factors and reduces mortality. A modest weight loss of 5% can lead to significant health benefits, including improvements in glycemic control and reductions in systolic and diastolic BP by approximately 4.4 mmHg and 3.6 mmHg, respectively [75]. Weight loss of 5–10% can decrease LDL-C and triglyceride levels by up to 10% and increase HDL-C levels by up to 10%. Maintaining a normal body mass index (BMI) between 20 and 25 kg/m² and a waist circumference of less than 94 cm in men and less than 80 cm in women is crucial to ensuring cardiovascular risk. Lower targets for these measures of adiposity, with their well-recognized caveats, may be optimal for some populations [23,67,68,69].

Lifestyle interventions for weight management primarily include adopting a hypocaloric diet and increasing physical activity. Combining dietary calorie restriction with regular exercise is more effective for weight loss than either intervention alone. Various dietary approaches—such as low-calorie diets, low-carbohydrate diets, and low-fat diets—have been effective when adherence is maintained. While intermittent fasting has gained popularity, recent studies suggest that certain patterns of intermittent fasting may not confer additional cardiovascular benefits and may even pose risks in some populations; however, evidence is mixed, and more research is needed [76].

Alcohol consumption has a dose-dependent relationship with BP and cardiovascular risk. Even moderate alcohol intake (up to one drink per day for women and up to two drinks per day for men) can increase BP, worsen glycemic control, and elevate triglyceride levels. Limiting alcohol intake is crucial in managing CRHM diseases. Moderate coffee consumption (3–4 cups per day) is generally considered safe and may confer cardiovascular benefits due to its antioxidant properties. However, excessive caffeine intake can cause transient increases in BP and arrhythmias in susceptible individuals [23,67,68,69].

Smoking is a major modifiable risk factor for CVD, contributing to endothelial dysfunction, inflammation, oxidative stress, and thrombogenesis. It acutely raises BP and heart rate, exacerbates insulin resistance, decreases HDL-C levels, and increases LDL-C oxidation. Smoking cessation is paramount in reducing cardiovascular risk. Comprehensive cessation programs combining behavioral counseling with pharmacotherapy (e.g., nicotine replacement therapy, varenicline, bupropion) are more effective than minimal interventions. GLP-1RAs are being evaluated as a potential new option to aid smoking cessation. Clinicians should actively engage patients in smoking cessation efforts and provide ongoing support [23,67,68,69].

Integrating lifestyle medicine into Cardiovascular–Endocrine–Metabolic Medicine necessitates an interdisciplinary, patient-centered approach. Clinicians should develop competencies in nutritional counseling, exercise prescription, and behavior change techniques to effectively design and implement comprehensive lifestyle intervention programs. This holistic approach can address the multifactorial and interconnected nature of CRHM diseases, targeting multiple risk factors simultaneously [23,67,68,69].

By establishing lifestyle medicine as a fundamental pillar, the proposed sub-specialty aims to bridge gaps in care delivery, slow disease progression, and enhance long-term clinical outcomes. Continuous patient education, motivational support, and regular monitoring are critical components of successful lifestyle interventions. Incorporating technological advancements such as telemedicine, wearable devices, and mobile health applications can further facilitate patient engagement and adherence to lifestyle modifications [23,67,68,69].

Lifestyle medicine interventions have proven to be crucial in promoting healthy aging and longevity. As described in our previous manuscript, individuals living in Blue Zones—regions known for their extreme longevity—naturally incorporate habits into their everyday lives that align with the recommendations of the American Society of Lifestyle Medicine, as illustrated in Figure 3 [58].

The contribution of cardiologists to diabetes care has been well documented, even before the widespread adoption of glucose-lowering medications with proven cardiovascular benefits in HF and ASCVD. In the United States in 2016, cardiologists were the most frequently involved specialists in diabetes care (n = 22,848), followed by endocrinologists (n = 7793) and nephrologists (n = 7504). Additionally, at a tertiary care center, the ratio of cardiologist-to-endocrinologist outpatient encounters among patients with diabetes was approximately 3:1. This ratio was even higher—around 5:1—for patients with comorbid CVD [77]. Currently, obesity and T2DM are primarily managed by endocrinologists and internists–diabetologists, even though their most serious complications—cardiovascular and renal—fall within the expertise of cardiologists and nephrologists. The lack of integrated care often complicates management, especially for patients with established ASCVD, HF, or CKD. While collaboration between cardiologists, endocrinologists, and nephrologists is clearly important for these patients, it often leads to fragmented care, medication errors, conflicting advice, the duplication of laboratory tests, patient confusion, and ultimately suboptimal clinical outcomes [49,50,51,52,53]. In contrast, arterial hypertension—a systemic disease like T2DM that promotes vascular complications—is primarily managed by cardiologists and primary care physicians. Given that both T2DM and arterial hypertension are key risk factors for the same complications—ASCVD, HF, CKD, and retinopathy—it raises the question of why their management is divided between endocrinology and cardiology rather than being unified under a single expert with comprehensive knowledge of both fields. The management of arterial hypertension is further complicated by the involvement of multiple specialties in specific contexts. Endocrinologists often play a role in cases of secondary hypertension, as several common causes are endocrine in origin, including hypothyroidism, hyperthyroidism, primary hyperaldosteronism, Cushing's syndrome, primary hyperparathyroidism, and pheochromocytoma [78]. Similarly, nephrologists play a crucial role in managing hypertension, particularly for patients with primary arterial hypertension complicated by CKD, as well as those with nephrogenic causes of secondary hypertension, including CKD of any origin, glomerular diseases, and scleroderma renal crisis [79].

Dyslipidemia—which is a condition with complex bidirectional associations with other CRHM diseases—is managed across multiple specialties, including cardiology, endocrinology, internal medicine, and primary care. This underscores the persistent fragmentation of care in Cardiometabolic Medicine, particularly in the era of specialized treatments for dyslipidemia. These treatments include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and an expanding body of research on small interfering RNA (siRNA) therapies targeting lipoprotein(a) [68,80,81].

The management of obesity is central to cardiometabolic care. Recent advances in obesity management have demonstrated significant potential for weight reduction through the agonism of incretin receptors, as highlighted by several landmark trials. The STEP 1 trial evaluated semaglutide 2.4 mg weekly for 68 weeks in 1961 adults without diabetes, achieving an average weight loss of −14.9% (−15.3 kg) compared to −2.4% (−2.6 kg) with a placebo (treatment difference: −12.4% [−12.7 kg], 95% CI: −13.4 to −11.5, p < 0.001) [19]. Similarly, the STEP 2 trial in 1210 adults with T2DM reported a weight loss of −9.6% (−9.6 kg) with semaglutide at 2.4 mg compared to −3.4% (−3.6 kg) with a placebo (difference: −6.2% [−6.0 kg], 95% CI: −7.3 to −5.2, p < 0.0001) over 68 weeks [20].

The SURMOUNT-1 trial assessed tirzepatide (a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist) in 2539 adults over 72 weeks, demonstrating dose-dependent weight losses of −15.0% (−15.7 kg), −19.5% (−20.9 kg), and −20.9% (−22.5 kg) with tirzepatide at 5 mg, 10 mg, and 15 mg, respectively, versus −3.1% (−3.2 kg) with a placebo (p < 0.001 for all comparisons) [31]. The SURMOUNT-2 trial extended these findings in patients with T2DM, where tirzepatide at 15 mg achieved −13.8% (−13.8 kg) weight loss compared to −3.3% (−3.6 kg) with a placebo (p < 0.001) [32]. In the extended analysis of SURMOUNT-1 participants with prediabetes, three years of tirzepatide intake at 15 mg reduced the risk of progression to T2DM by 93% (hazard ratio: 0.07, 95% CI: 0.0 to 0.1, p < 0.001), corresponding to an absolute risk reduction of 12.4% (13.7% incidence with placebo vs. 1.3% with tirzepatide). This significant reduction in diabetes risk was accompanied by substantial and sustained weight reductions, with participants achieving an average weight loss of −19.7% (−21.3 kg) from baseline at 176 weeks compared to −1.3% (−1.4 kg) with a placebo. After the 17-week off-treatment period, the tirzepatide group maintained a weight reduction of −17.3% (−18.7 kg) relative to baseline [33]. Notably, the phase 2 trial of retatrutide, a novel triple GIP/GLP-1/glucagon receptor agonist, showed substantial efficacy, with the 12 mg dose achieving −24.2% (−23.6 kg) at 48 weeks compared to −2.1% (−2.1 kg) with a placebo (p < 0.001, 95% CI: −26.1 to −22.3) [34].

The management of HF, CAD, and CKD increasingly incorporates anti-diabetic medications. For HF, SGLT2 inhibitors have become a standard guideline-directed medical therapy across the entire spectrum of the left ventricular ejection fraction, regardless of diabetes status, according to recent landscape-event-driven trials (EMPEROR-Preserved, EMPEROR-Reduced, DELIVER, DAPA-HF) [3,4,5,6,7,8,9,10].

The use of anti-diabetic medications for managing heart failure (HF), coronary artery disease (CAD), and chronic kidney disease (CKD) has grown significantly, reflecting the broader recognition of their cardiometabolic benefits. In particular, SGLT2 inhibitors (SGLT2i) have evolved into guideline-directed medical therapy for HF with both a reduced and preserved ejection fraction, regardless of diabetes status, as demonstrated by event-driven trials such as EMPEROR-Preserved, EMPEROR-Reduced, DELIVER, and DAPA-HF [3,4,5,6,7,8,9,10]. Meta-analyses and the 2023 guidelines of the European Society of Cardiology (ESC) further reinforce this trend by designating a Class I recommendation for SGLT2i and GLP-1 receptor agonists (GLP-1RAs) in patients with established atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes, irrespective of their degree of glycemic control [21,22,23].

Furthermore, according to meta-analyses, the 2023 guidelines of the European Society of Cardiology for the management of CVD have established a Class I recommendation for the use of SGLT2i and GLP-1RAs in patients with established ASCVD and T2DM, irrespective of glycemic control or the use of other anti-diabetic medications [21,22,23]. The SELECT trial further expanded the role of anti-diabetic medications in cardiometabolic care. This event-driven trial demonstrated that semaglutide reduces hard cardiovascular endpoints, including cardiovascular mortality, in overweight or obese patients with ASCVD [27]. As a result, the 2024 guidelines of the European Society of Cardiology for the management of Chronic Coronary Syndromes established a Class IIa recommendation for the use of GLP-1RAs in patients with overweight or obesity and ASCVD in the absence of diabetes [82].

A prespecified secondary analysis of the SELECT trial showed that semaglutide also significantly reduced cardiovascular mortality and HF hospitalizations in patients with HF [28]. Additionally, a pooled analysis of the STEP-HFpEF program, the FLOW trial, and the SELECT trial for patients with HFpEF revealed that semaglutide significantly reduces the composite of cardiovascular death or HF hospitalization [30].

For CKD, SGLT2 inhibitors have been incorporated into the guidelines based on the results of the EMPA-Kidney and DAPA-CKD trials, irrespective of diabetes status [11,12]. Furthermore, the FLOW trial demonstrated that semaglutide improves both renal and cardiovascular hard endpoints in patients with diabetic nephropathy, regardless of body mass index [29].

Furthermore, the recently published SUMMIT trial evaluated the effects of tirzepatide on patients with HFpEF and obesity. In this double-blind, placebo-controlled study, 731 participants with an ejection fraction of at least 50% and a body mass index (BMI) of 30 or higher were randomized to receive either tirzepatide (up to 15 mg weekly) or a placebo for a minimum of 52 weeks. Over a median follow-up of 104 weeks, the primary composite outcome of cardiovascular death or worsening heart failure occurred in 9.9% of the tirzepatide group compared to 15.3% in the placebo group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.41 to 0.95; p = 0.026). These findings suggest that tirzepatide may reduce the risk of cardiovascular events in patients with HFpEF and obesity [83].

Recent advancements in the treatment of MASLD highlight the potential role of GLP-1RAs and dual GLP-1/GIP receptor agonists like tirzepatide [35,36,37]. In a placebo-controlled phase II trial, semaglutide taken at 0.4 mg daily significantly improved the resolution of NASH without worsening fibrosis (59% vs. 17%; p < 0.001) in patients at the F2–F3 elastography stage, although it did not demonstrate a statistically significant improvement in the fibrosis stage [35]. Furthermore, semaglutide at 2.4 mg weekly in NASH-related compensated cirrhosis showed improvements in liver steatosis and cardiometabolic parameters but failed to achieve significant histologic improvements in fibrosis or NASH resolution [36]. Moreover, a phase II trial evaluating tirzepatide for MASH with moderate-to-severe fibrosis (F2–F3) at higher doses (10–15 mg weekly) achieved a resolution of MASH in 56–62% of participants compared with 10% in the placebo group (p < 0.001) and an improvement in fibrosis in 51% compared with 30% in the placebo group [37]. Definite conclusions regarding the efficacy of semaglutide in the management of MASLD with significant fibrosis will be provided by the ongoing phase III ESSENCE trial [84].

The efficacy of tirzepatide has also been tested in OSA, which is commonly associated with obesity and other CRHM diseases [38]. SURMOUNT-OSA trials have demonstrated the efficacy of tirzepatide in managing moderate-to-severe OSA among individuals with obesity. In two phase 3, randomized, double-blind, placebo-controlled trials, tirzepatide significantly reduced the apnea–hypopnea index (AHI), which is a key marker of OSA severity, compared with a placebo. In participants not receiving positive airway pressure (PAP) therapy (Trial 1), tirzepatide reduced AHI by 25.3 events per hour at 52 weeks compared to a 5.3 event reduction in the placebo group, yielding a treatment difference of −20.0 events per hour (95% CI, −25.8 to −14.2; p < 0.001). In participants already on PAP therapy (Trial 2), tirzepatide reduced AHI by 29.3 events per hour compared to a 5.5 event reduction with a placebo, with a treatment difference of −23.8 events per hour (95% CI, −29.6 to −17.9; p < 0.001). Secondary endpoints also favored tirzepatide, with reductions in body weight, hypoxic burden, hsCRP levels, and systolic blood pressure, along with improved patient-reported sleep quality and disturbance outcomes. These findings suggest that tirzepatide offers a novel, multifaceted approach to managing OSA in patients with obesity, targeting both respiratory events and underlying cardiometabolic risk factors [38].

The above studies highlight the expanding role of cardiologists, nephrologists, and gastroenterologist–hepatologists in prescribing anti-diabetic therapies. However, these specialists may sometimes hesitate to initiate certain treatments, particularly GLP-1RAs, potentially missing opportunities to improve clinical outcomes. Data from 2015 to 2020 showed that less than 5–10% of patients with T2DM and CVD received GLP-1RAs and/or SGLT2i despite the fact that strong evidence from trials was already available [85]. Moreover, the introduction of these therapies often requires careful reconciliation with existing glucose-lowering regimens. For instance, dipeptidyl peptidase-4 inhibitors (DPP4is) should not be combined with GLP-1RAs. In patients with HF, thiazolidinediones (TZDs) should be discontinued due to the risk of fluid retention. In patients with CKD, many glucose-lowering medications require dosage adjustments; for example, metformin is contraindicated in individuals with an eGFR <30 mL/min due to the risk of lactic acidosis [86]. Given these complexities, a specialist with comprehensive expertise in managing coronary artery disease (CAD), HF, and T2DM is critical to optimizing medical therapy and improving patient outcomes.

Although these novel medications for managing CRHM diseases present a promising path forward, several practical and systemic barriers must be addressed to ensure the broad adoption of these therapies. One major issue is cost and accessibility. Medications such as GLP-1RAs, SGLT2i, and newer dual-agonist agents can be expensive, which may limit their use in health systems with inadequate funding or among uninsured and underinsured patients. Even when these medications are recommended in guidelines, heterogeneity in reimbursement policies and coverage can further restrict their availability. Adverse effects and real-world safety also merit consideration. Clinical trials generally indicate positive safety profiles; however, there is limited evidence of long-term safety, which is being constantly evaluated. Initial concerns regarding non-ischemic anterior optic neuropathy were overestimated, and a very recent study has shown that semaglutide does not increase the risk compared to other anti-diabetic medications [87].

Many healthcare systems maintain long-standing departmental boundaries, which can impede cross-disciplinary collaboration. The lack of standardized training in integrated cardiometabolic care, combined with concerns about overlapping clinical domains, can create both logistical and professional conflicts. Without clear pathways for shared governance and consensus on role delineation, efforts to establish and operationalize a new sub-specialty may face significant institutional hurdles.

The above underscores the absence of a unified approach to managing CRHM diseases, leading to fragmented care and suboptimal outcomes. Consequently, the management of major cardiovascular risk factors—T2DM, arterial hypertension, dyslipidemia, and obesity—often remains disconnected. Addressing this challenge requires the establishment of a dedicated sub-specialty that integrates expertise across multiple disciplines. Such an integrated approach would ensure comprehensive and cohesive care, ultimately improving outcomes for the growing population of patients with CRHM diseases.

Neurohormonal activation is the major pathophysiological mechanism driving HF with reduced ejection fraction (HFrEF). This model involves the excessive activation of sympathetic and renin–angiotensin–aldosterone systems and has been the cornerstone for the development of most guideline-directed medical therapies (GDMTs) for HFrEF [88]. Furthermore, metabolic abnormalities have also been implicated in the pathophysiology of both HFpEF and HFrEF, with SGLT2i forming part of the GDMT and GLP-1RA showing promising results, as already analyzed [89].

The TOSCA registry revealed that over 90% of HF patients were deficient in at least one anabolic hormone (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor-I (IGF-I), or triiodothyronine), and more than two-thirds had deficiencies in two or more. The prevalence of IGF-I deficiency, based on age-adjusted cutoffs, was nearly 50%. More importantly, multiple hormonal and metabolic deficiency syndrome (MHDS) was associated with a significantly higher risk of hospitalization or death [42]. While these findings underscore the potential clinical impact of hormonal imbalances in HF, TOSCA is an observational study and, thus, cannot establish causality or exclude confounding factors. A schematic illustration of the main pathophysiological pathways (neurohormonal, metabolic, and MHDS) implicated in HF is presented in Figure 4. While the findings from the TOSCA registry highlight the prevalence and prognostic significance of hormonal deficiencies in HF, they are not sufficient to conclude that correcting these deficiencies will improve cardiovascular function, symptoms, or outcomes. To address this, studies have explored the potential benefits of hormone replacement therapies in this population.

Coupled with insights from MHDS in HF prognosis, TTh appears to be a promising management strategy for HF. In a systematic review of randomized controlled trials, TTh led to significant improvements in muscle strength and aerobic capacity, as well as increases in lean muscle mass and decreases in fat mass in certain trials. Additionally, improvements in insulin sensitivity and shortening of the QT interval have been reported. TTh did not consistently affect blood pressure, lipid profiles, or heart rate, nor did it lead to any serious adverse effects [43]. Another systematic review and meta-analysis of randomized controlled trials showed that, in patients with hypogonadism and HF, TTh significantly delayed the time to ischemia in patients with chronic angina, increased VO2, ameliorated heart rate, and improved insulin sensitivity. However, in this study, these benefits did not translate to improvements in the NYHA class or LVEF [90]. Furthermore, an additional meta-analysis of randomized controlled trials demonstrated that TTh significantly improved VO2 by 2.70 mL/kg/min (95% CI, 2.68–2.72 mL/kg/min) and exercise capacity, as assessed via the 6 min walk test (+54.0 m; 95% CI, 43.0–65.0 m) or the incremental shuttle walk test (+46.7 m; 95% CI, 12.6–80.9 m) [91]. It should be noted, however, that caution is advised when using TTh in patients with severe cardiac, hepatic, or renal dysfunction due to the risk of congestion and/or HF decompensation. Furthermore, as there is a lack of event-driven trials, no universal recommendation can be made for the use of TTh in patients with HF.

In addition to testosterone, growth hormones (GHs) play a role in regulating various physiological processes, including cardiovascular function. GH stimulates hepatic IGF-I secretion, which promotes protein synthesis, tissue repair, and cellular growth [44,45]. Notably, there are various reports in the literature on the local expression of GH receptors in cardiac and vascular cells, signifying potential IGF-I-independent effects of GH in the cardiovascular system. Furthermore, the local production of IGF-I by cardiac and vascular cells has been implicated in various physiological and pathophysiological processes. In the cardiovascular system, GH and IGF-I can increase myocardial mass and contractility, enhancing ventricular performance. They also reduce peripheral vascular resistance and improve endothelial function. Key non-cardiac effects include stimulating lipolysis, increasing skeletal muscle mass and strength, enhancing bone density, and exerting insulin-like glycemic effects through IGF-I [44,45]. According to our recently published meta-analysis of randomized-controlled trials, GH therapy significantly improved left ventricular ejection fraction (3.34%, 95% CI: 1.09% to 5.59%, p = 0.0037), peak oxygen consumption (2.84 mL/kg/min, 95% CI: 1.32 mL/kg/min to 4.36 mL/kg/min, p = 0.0002), and New York Heart Association class (−0.44, 95% CI: −0.08 to −0.81, p = 0.023). GH therapy also reduced the composite of death, worsening HF, or ventricular tachycardia by 41% (95% CI: 0.39–0.90, p = 0.013). Subgroup analyses indicated that patients with ischemic cardiomyopathy, baseline ejection fraction ≥30%, and longer treatment duration experienced greater benefits [45]. However, before a guideline-directed recommendation can be safely made, there is a need to conduct large-scale, event-driven, randomized-controlled trials to confirm these benefits.

In addition to TTh and GH therapy, there are additional insights for the use of T3 in the management of MHDS with low T3 syndrome. According to a meta-analysis in patients with HF and low T3 syndrome, thyroid hormone therapy significantly enhanced left ventricular ejection fraction (5.61%, 95% CI: 4.38% to 6.85%, p < 0.01) and cardiac output (0.65 L/min, 95% CI: 0.42 to 0.89 L/min, p < 0.01). Additionally, early-to-late diastolic transmitral flow velocity was higher in the thyroid hormone group compared to the control group (0.29, 95% CI 0.15 to 0.42, p < 0.01). Furthermore, brain natriuretic peptide levels were lower in patients receiving thyroid hormone therapy (−1.49, 95% CI: −2.15 to −0.84; p < 0.01) [46].

Moreover, as demonstrated in our recently published state-of-the-art review, there is emerging evidence for the use of ghrelin for HF management. Clinical trials investigating ghrelin's acute effects in HF patients have demonstrated significant improvements in cardiac output, ranging from 15 to 30%. Moreover, one study showed that a 3-week course of ghrelin therapy significantly increased maximal oxygen consumption, lean body mass, and grip strength in HF patients. Preclinical studies further support these clinical findings, highlighting additional benefits of ghrelin, including the modulation of the autonomic nervous system, the promotion of vasodilation, the enhancement of endothelial function, the prevention of myocardial remodeling, the reduction in arrhythmogenic risk, and increased muscle mass in HF models. As a result, ghrelin is a promising therapeutic option for HF, particularly as an inotropic agent with multifaceted benefits, including autonomic nervous system modulation, anabolic effects, and metabolic regulation. However, further trials are required to confirm its long-term efficacy and safety and assess whether its benefits can translate into reductions in hard clinical endpoints [47].

Adipokines play a pivotal role in the pathophysiology of HF, with distinct implications in HFpEF and HFrEF [92]. Chronic hyperleptinemia, a hallmark of obesity, has been strongly implicated in the development of HFpEF. Elevated leptin levels in HFpEF patients are largely attributable to higher body mass index, as obesity is both a driver of HFpEF pathogenesis and a key factor in increased leptin production. Leptin contributes to insulin resistance, chronic inflammation, diastolic dysfunction, myocardial remodeling, and arterial stiffness—processes central to HFpEF. Notably, leptin levels in HFpEF are not significantly correlated with N-terminal prohormones of the brain natriuretic peptide (NT-proBNP), suggesting that leptin's role may be more causative, reflecting systemic metabolic dysfunction rather than cardiac wall stress. This aligns with the concept of HFpEF as a metabolic-driven disease rather than a primarily hemodynamic syndrome. In HFrEF, the metabolic profile differs markedly. Despite the catabolic state often seen in HFrEF, leptin levels are significantly higher than in controls. This may be driven by neurohormonal activation, chronic inflammation, tissue hypoxia, and ectopic leptin production via hypoxia-inducible factor 1-alpha (HIF-1α) pathways. Interestingly, higher leptin levels in HFrEF are inversely correlated with NT-proBNP and associated with a lower risk of adverse outcomes, although this significance disappears after adjusting for NT-proBNP. This relationship may reflect the "obesity paradox", where higher leptin levels in non-cachectic patients are indicative of better nutritional status and prognosis. Adiponectin, in contrast, exhibits beneficial effects on cardiovascular health and insulin sensitivity. Adiponectin levels are elevated in HFrEF, correlating positively with NT-proBNP. This elevation is likely a consequence of the catabolic state, with reduced fat stores driving increased adiponectin production [92]. Higher adiponectin levels in HFrEF are associated with a numerically increased risk of adverse events, though this association is not statistically significant after adjustment for NT-proBNP, suggesting that adiponectin reflects disease severity rather than directly influencing outcomes. However, HFpEF patients often have adiponectin levels comparable to non-HF controls, likely due to the obesity-associated suppression of adiponectin. These findings underscore the complex and contrasting roles of adipokines in HF sub-types, particularly highlighting HFpEF as a metabolic-driven condition. Therefore, future research into adipokines is crucial to further advance hormonal insights into the pathophysiology and management of HF [92].

The aforementioned studies have demonstrated the implications of hormonal dysregulation in HF pathophysiology and prognosis, as well as the potential of hormonal therapy to improve cardiac function, symptoms, and possibly hard endpoints. Despite this preliminary evidence from mechanistic studies, small trials, and meta-analyses on the use of hormonal therapies for managing MHDS associated with HF, there remains a lack of large-scale, event-driven randomized controlled trials. This limitation prevents the establishment of robust guideline-directed recommendations. Such trials are essential and should be conducted in the future to address this gap in evidence. A cardiologist, while highly skilled in advanced heart failure management, may lack the specialized knowledge required for hormonal therapies. Conversely, an endocrinologist or metabolic medicine physician may have deep expertise in hormonal regulation, diabetes, or lipid disorders but a limited understanding of heart failure pathophysiology. This gap underscores the necessity of this new sub-specialty—Cardiovascular–Endocrine–Metabolic Medicine—that integrates expertise from these fields to effectively address this emerging therapeutic domain.

Male FHH is commonly observed in conditions such as obesity, insulin resistance, T2DM, dyslipidemia, and arterial hypertension, with a bidirectional association between these conditions and low testosterone levels. TTh has been shown to improve body composition by increasing muscle mass and decreasing fat mass, as well as enhancing metabolic parameters in several studies [48]. There has been a long-running debate about the potential risks and benefits of TTh [93]. Beyond improving symptoms of hypogonadism, TTh has shown potential benefits in patients with FHH, particularly in cardiometabolic conditions [40,94]. The T4DM trial demonstrated that TTh in prediabetic men with total testosterone levels <400 ng/dL reduced the progression to T2DM by 40% over two years while also improving lean mass and sexual symptoms [40]. Furthermore, studies, including meta-analyses, have shown that TTh in adult patients with hypogonadism can improve all-cause mortality [95,96]. A generally reassuring safety profile was demonstrated in the TRAVERSE study [41]. TRAVERSE enrolled men aged 45 to 80 with symptoms compatible with hypogonadism, serum testosterone levels of <300 ng/dL, and those who were at high risk for cardiovascular events. No adverse effects of TTh were observed in blood pressure or lipid profiles, and there was no excess of major adverse cardiac events observed between the TTh and placebo groups over a mean of 22 months (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; p < 0.001 for noninferiority). However, a higher incidence of pulmonary embolism (0.9% vs. 0.5%), nonfatal arrhythmias requiring intervention (5.2% vs. 3.3%), atrial fibrillation (3.5% vs. 2.4%), and acute kidney injury (2.3% vs. 1.5%) was observed with TTh versus the placebo [41].

Combined with the generally positive effects of TTh on sexual function, quality of life, bone mass, and hemoglobin levels, its administration in patients with CRHM diseases should be considered in clinical practice, provided that there are no contraindications [48].

POI, defined as the loss of normal, predictable ovarian activity before the age of 40 years, is a cause of infertility and endocrine dysfunction in women [97]. POI, which affects approximately 1% of women under the age of 40, has adverse implications for cardiovascular health within a wider range of physical and emotional issues [98,99]. This heterogeneous disorder is characterized biochemically by amenorrhea with hypoestrogenemia and elevated gonadotrophins [98]. Spontaneous and iatrogenic POI is associated with increased risks of hyperlipidemia, hypertension, and T2DM, compared with the average age for menopause [100]. The risk of CVD is increased in women with POI [101]. While menopausal hormone therapy (MHT) can mitigate some aspects of POI, many uncertainties remain regarding optimal management; individualized care that includes attention to cardiovascular risk profiles is recommended [102].

The practical implementation of training in this sub-specialty could begin with the establishment of integrated outpatient clinics that combine cardiology, endocrinology, and metabolic medicine in a single framework. For example, a specialized center might offer same-day consultations with a cardiologist, endocrinologist, and dietitian to jointly evaluate patients with obesity and/or T2DM. This model reduces the need for multiple referrals, avoids duplicative testing, and accelerates the initiation or adjustment of new cardiometabolic therapies. Another effective strategy involves creating a shared inpatient service for individuals admitted with acute decompensated HF and concomitant metabolic disorders, as well as those presenting with diabetic complications and established CVD. Here, a multidisciplinary team can address both the immediate clinical issues and long-term prevention strategies, providing an excellent environment for fellows to learn collaborative care. Rotating individuals through cardiology, endocrinology, nephrology, and hepatology departments can further expose them to the diverse facets of cardiovascular, renal, hepatic, and metabolic medicine, ultimately enriching both patient care and research. This approach trains future specialists to recognize the intricate interplay among these organ systems, equipping them to deliver truly integrated, comprehensive care.

Future research in this field should prioritize large, event-driven, randomized controlled trials that evaluate GLP-1Ras and dual agonists across the entire cardiometabolic spectrum, addressing gaps that persist in conditions like MASLD, non-diabetic CKD, PCOS, and HF or CAD without obesity. Additionally, large trials examining newer anti-obesity medications—particularly triple agonists and agents that modulate adipokine profiles—are also warranted, as mechanistic benefits have yet to fully translate into routine clinical practice. In addition, the absence of event-driven evidence for hormonal therapies (e.g., testosterone, GH, triiodothyronine, and ghrelin) in HF remains a critical area for investigation, given the preliminary promise that these treatments hold for improving outcomes. Beyond pharmacotherapies, research should also explore cost-effectiveness, patient-reported outcomes, and the real-world impact of integrated care models and multidisciplinary training curricula. Such evidence would not only optimize clinical decision-making but also strengthen the foundation for future guidelines in Cardiovascular–Endocrine–Metabolic Medicine.