Using underlying disease causes to guide medicine choices for multiple heart and metabolism conditions

The global prevalence of cardiometabolic multimorbidity (CMM)—with diabetes at its core—continues to rise and has become a major public-health challenge (1). Projections from the Global Burden of Cardiovascular Disease, 2020–2025, indicate that metabolic risk factors will remain the principal drivers of cardiovascular mortality (2). In a long-term cohort including 1.2 million participants, cardiometabolic multimorbidity was associated with a substantial reduction in life expectancy (3). This clustering of conditions not only markedly increases all-cause mortality, the risk of recurrent cardiovascular events, and hospitalizations, but also imposes a considerable economic burden on health systems. Although a number of clinical practice guidelines for individual cardiovascular or metabolic conditions have been developed both nationally and internationally, most are formulated from a single-disease perspective and lack comprehensive recommendations for multimorbidity management. In clinical practice, physicians often rely on multiple independent guidelines to develop treatment plans for patients with CMM, which may result in polypharmacy, increased risk of drug–drug interactions, decreased patient adherence, and cumulative adverse drug events. Furthermore, cardiovascular and metabolic diseases are pathophysiologically interconnected. Numerous studies have demonstrated that metabolic abnormalities—such as insulin resistance—can significantly influence the onset and progression of cardiovascular diseases (4, 5). However, current clinical strategies rarely adopt an integrated mechanistic approach to managing multimorbidity, making it difficult to simultaneously maximize therapeutic benefit and minimize pharmacologic risk.

Against this backdrop, the present review systematically summarizes recent advances (2020–2025) in the understanding of pathophysiological mechanisms underlying CMM. Special emphasis is placed on the clinical evidence and application of various therapeutic agents, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA), in the management of CMM. This review also seeks comprehensive clinical strategies for the optimization of multimorbidity care. To provide certain guiding significance for the precision medicine of comorbid populations.

Insulin resistance (IR) has long been recognized as a key pathophysiological mechanism underlying both cardiovascular and metabolic diseases (17). The triglyceride-glucose (TyG) index, a reliable surrogate marker for IR, has been shown to be associated with adverse cardiovascular outcomes in patients with diabetes and cardiovascular disease (CVD) (18, 19). Recent studies have not only reinforced this association but also elucidated its downstream effects in greater detail.

Dysregulated lipid-derived metabolic mediators—such as adipokines, excess lipids, and toxic lipid metabolites—released from adipose tissue contribute significantly to the development of IR (20). These adipose-derived factors can impair cardiomyocyte signaling, induce structural remodeling of the heart, and increase the incidence of CVD. They are also closely linked to the pathogenesis of obesity and type 2 diabetes mellitus (T2DM) (21).Excess circulating free fatty acids (FFAs) infiltrate the liver and skeletal muscle, enhancing gluconeogenesis and very low-density lipoprotein (VLDL) synthesis, thereby promoting hepatic and muscular insulin resistance (22). Hepatic IR leads to increased endogenous glucose production and elevated fasting plasmaglucose, which subsequently raises serum triglyceride (TG) levels and lowers high-density lipoprotein cholesterol (HDL-C), heightening thrombogenic risk (23).

In the insulin-resistant state, elevated insulin and aldosterone levels reduce nitric oxide (NO) bioavailability, leading to endothelial dysfunction and pathological arterial stiffening. This process also activates MAPK/ERK-mediated reactive oxygen species (ROS) generation, further increasing cardiovascular risk (17, 24). Additionally, recent evidence indicates that lipid accumulation in pancreaticβ-cells under IR conditions accelerates β-cell apoptosis and senescence, perpetuating a vicious cycle of metabolic deterioration (25, 26).IR is the pathological hub of CMM and links lipotoxicity, endothelial dysfunction and β-cell failure. Therefore, a drug combination that improves insulin resistance and reduces fat/weight serves as the starting point for downstream, multi-organ benefits.

SGLT2 inhibitors (SGLT2i), such as empagliflozin, dapagliflozin, and canagliflozin, have demonstrated benefits beyond glycemic control, showing pleiotropic effects across multiple organs and systems (51, 52). By inhibiting renal proximal tubule reabsorption of sodium and glucose, these agents induce osmotic diuresis and natriuresis, thereby reducing blood pressure and cardiac preload (53). They also enhance glycemic control and promote weight loss via increased urinary glucose excretion (54).

On the level of energy metabolism, SGLT2i promote substrate shift towards fatty acid and ketone utilization, improving myocardial and renal energy efficiency (55). Additionally, they exhibit anti-inflammatory and anti-fibrotic properties, partly through attenuation of NLRP3 inflammasome activation via Ca²⁺ modulation, thereby directly protecting cardiac and renal tissues (56, 57).

Multiple large-scale clinical trials have shown that SGLT2i significantly reduce the risk of cardiovascular death, heart failure hospitalization, and renal events in patients with T2DM complicated by atherosclerotic cardiovascular disease (ASCVD) or heart failure (58). Notably, these benefits extend to non-diabetic populations, such as patients with heart failure with reduced ejection fraction (HFrEF), in whom substantial clinical improvements have also been observed (59).

GLP-1 receptor agonists, including liraglutide, semaglutide, and dulaglutide, exert multifaceted effects by activating GLP-1 receptors in various tissues beyond the pancreas (9, 60). Their mechanisms of action and clinical benefits include the following:

In glucose and weight control, GLP-1 RA lower blood glucose levels and induce significant, sustained weight loss by centrally suppressing appetite and delaying gastric emptying (61 –63). In atherosclerosis prevention, these agents exert direct effects on vascular endothelial cells and immune cells, reducing inflammatory processes within atherosclerotic plaques, improving endothelial function, and lowering LDL-C and blood pressure levels (64, 65).

Cardiovascular outcome trials (CVOTs) have consistently demonstrated that GLP-1 RA reduce the risk of major adverse cardiovascular events (MACE), particularly nonfatal myocardial infarction and stroke (66, 67). However, their efficacy in reducing cardiovascular and renal outcomes among non-diabetic populations remains to be established. Currently, GLP-1 RA are especially recommended for patients with T2DM and established ASCVD or high ASCVD risk, as well as those requiring intensive weight management.

Finerenone, a next-generation nonsteroidal mineralocorticoid receptor antagonist (ns-MRA), inherits the anti-inflammatory and anti-fibrotic properties of traditional MRAs and offers additional therapeutic benefits. Preclinical and clinical data demonstrate its capacity to reduce fibrosis, lower pulmonary artery pressure, improve diabetic retinopathy, enhance endothelial function, and attenuate oxidative stress, thereby providing comprehensive cardiorenal protection (68, 69).

Finerenone exerts targeted anti-inflammatory and anti-fibrotic effects by selectively blocking mineralocorticoid receptor (MR) overactivation in cardiac, vascular, and renal tissues. This results in marked reductions in biomarkers such as NT-proBNP and UACR, which are closely associated with heart and kidney injury (70, 71). Although mild hyperkalemia may occur during early treatment, it does not negate the overall cardiorenal benefits of the drug. Furthermore, finerenone improves endothelial function, reduces vascular oxidative stress, and restores NO bioavailability, reinforcing its organ-protective profile (72).

Two large-scale trials involving 13,026 patients with chronic kidney disease (CKD) and T2DM confirmed that finerenone, compared to placebo, significantly reduces the risk of CKD progression and cardiovascular events while slowing the decline in estimated glomerular filtration rate (eGFR) (13, 15).

Statins remain the cornerstone of ASCVD prevention and treatment. Beyond their potent lipid-lowering effects, they also exhibit anti-inflammatory, antioxidant, plaque-stabilizing, and vasodilatory properties (73). However, recent studies have indicated that prolonged or high-dose statin use may be associated with an elevated risk of muscle-related adverse effects, hyperglycemia, hemorrhagic stroke, liver disease, and cognitive decline (74, 75). A meta-analysis by Soleimani et al. indicated that moderate-dose statins combined with ezetimibe provide greater LDL-C reduction and fewer adverse events than high-dose statins alone (76), highlighting the need for dose optimization in clinical practice to mitigate adverse effects. Additionally, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and sacubitril/valsartan not only reduce blood pressure but also confer renoprotective, anti-inflammatory, and endothelial function-improving benefits (77, 78), making them vital components of cardiovascular therapy.

All patients should initiate and maintain lifestyle interventions, including heart-healthy dietary patterns, regular physical activity, smoking cessation, and alcohol moderation, as the foundation of any pharmacological treatment.

For patients with ASCVD, the initiation of statin therapy at an appropriate dose should be promptly initiated based on baseline LDL-C levels. In instances where LDL-C targets are not met or cases of statin intolerance arise, combination therapy involving ezetimibe or a PCSK9 inhibitor should be contemplated.

For patients with heart failure with reduced ejection fraction (HFrEF), guideline-directed medical therapy (GDMT) should include the "four pillars" of pharmacologic management: β-blockers, ACEIs/ARBs/ARNIs, MRAs, and SGLT2i (Table 2).

Following the initiation of newer therapies with established multi-organ benefits, such as SGLT2i and GLP-1RA, regular reassessment of the pre-existing treatment regimen is essential. When glycemic and blood pressure control is achieved, clinicians should consider de-escalation strategies, including dose reduction or discontinuation of other antihyperglycemic agents (e.g., insulin) and antihypertensives, to mitigate the risks of hypoglycemia and hypotension.

Establishing a structured medication review schedule is a critical step in optimizing pharmacotherapy. It allows for timely evaluation of drug necessity, minimizes polypharmacy, reduces patient burden, and helps achieve individualized therapeutic goals more safely and efficiently (Table 3).

The management of cardiac metabolic comorbidities must move beyond a one-size-fits-all approach toward precision-based, phenotype-driven treatment strategies that are tailored to specific patient characteristics. Firstly, for elderly patients deemed to be frail, the management plans must be meticulously devised, in view of the complexities arising from polypharmacy and multiple coexisting conditions. This is particularly evident in patients aged ≥75 years with ≥4 chronic diseases, where treatment regimens require a delicate balance between efficacy and safety. It is recommended that streamlined management pathways be established for these patients, centered on the following: 1) Safe medication use: It is imperative to closely monitor and enhance surveillance for the emergence of acute kidney injury, hypovolemia, and hyperkalemia when administering SGLT2 inhibitors in conjunction with NSAIDs or ACEI/ARBs (91). 2) The step-down therapy approach is employed here. It is imperative to establish explicit criteria for the reduction or discontinuation of insulin or sulfonylureas, with the objective of averting hypoglycemic incidents and mitigating the risk of falls and other deleterious outcomes associated with polypharmacy (92).

The existence of gender-based differences in treatment response represents a critical aspect of precision medicine that cannot be overlooked. A mounting body of evidence suggests the presence of gender heterogeneity in the efficacy and tolerability of pharmaceuticals. For instance, subgroup analyses from trials such as DAPA-HF suggest that female patients may experience a greater decline in estimated glomerular filtration rate (eGFR) following SGLT2 inhibitor use compared to males (93). Meanwhile, studies have documented a higher prevalence of gastrointestinal intolerance to GLP-1 receptor agonists in female patients compared to male patients (94). Consequently, when recommending medications based on phenotype, it is imperative to consider gender factors comprehensively. For instance, a more gradual dose titration strategy should be adopted when initiating treatment for female patients, accompanied by enhanced monitoring of renal function and electrolyte levels to optimize treatment adherence and long-term prognosis.

In consideration of the national circumstances of differing countries, the "phenotype-first" treatment model that is proposed encounters considerable challenges in resource-constrained settings. In a multitude of low- and middle-income countries, the implementation of novel pharmaceuticals such as SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone may encounter significant challenges due to their substantial financial burden and restricted accessibility (95). This phenomenon, termed the "treatment gap," has been identified as a contributing factor to global health inequities. In light of this challenge, clinicians and healthcare system decision-makers must not relinquish mechanism-driven treatment principles but rather employ a creative approach in their application to available therapeutic options. The core strategy involves repurposing affordable, widely accessible medications and combining them with enhanced lifestyle interventions. The aim is to mimic or partially replicate the multi-pathway protective effects of novel drugs.

Structured lifestyle interventions constitute the basis of all treatment strategies, a fact that is especially evident in settings with limited resources. Enhanced lifestyle modifications, encompassing a heart-healthy diet, regular physical activity, and smoking cessation, constitute a potent "multi-targeted therapy" capable of simultaneously improving insulin resistance, lowering blood pressure, reducing weight, regulating lipids, and alleviating inflammation (96).When medications are available, priority should be given to novel agents with established organ-protective evidence, such as SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone, to ensure precise targeting of distinct phenotypes. In settings where resources are limited, it is imperative to adhere strictly to maximum tolerated doses of ACEI and ARB in order to reduce proteinuria and slow the progression of renal disease (97, 98). In order to manage cardiovascular risk, it is imperative to combine these with evidence-based statins in order to rigorously control lipids (99).

In instances where finerenone is not available, traditional MRAs remain a vital option based on the same core mechanism. Notwithstanding the necessity for close monitoring of serum potassium and renal function, the addition of spironolactone constitutes a physiologically sound, pragmatic strategy for T2D patients with albuminuria and high cardiovascular risk, following a thorough risk-benefit assessment. It is imperative that the global medical community collaborate to ensure the continuous reduction of barriers to accessing novel therapies. The objective of this initiative is to integrate mechanism-driven advanced treatment concepts with universally accessible healthcare equity, thereby ensuring that patients with CMM—regardless of their geographical location—receive optimal pathophysiology-based care.