The primary clinical objective for patients with T2DM is to prevent or delay the progression of complications and improve quality of life [103]. While glycemic control has long been considered the cornerstone for mitigating the risk of macrovascular complications in T2DM patients, recent studies have revealed that cardiovascular complications remain significantly prevalent even under stringent glycemic control [13]. In addition to traditional glycemic management, alternative strategies must be explored to prevent diabetes-related cardiovascular complications. A comprehensive approach encompassing biomarker monitoring and management, lifestyle interventions, and pharmacological prevention has proven effective (Table 1).

Current guidelines for T2DM management are gradually shifting toward personalized glycemic targets and precision medicine paradigms [104]. This shift focuses not only on achieving significant glycemic control but also on optimizing safety and nonglycemic benefits to enhance the added value of preventing macrovascular complications [104]. Within this framework, biomarkers have emerged as critical factors warranting clinical attention [104].

In the management of T2DM, traditional biomarkers such as HbA1c, blood pressure, lipid levels, heart rate, body weight, and serum uric acid, along with their variabilities, are of paramount importance [105]. In particular, HbA1c is the most commonly used parameter for assessing glycemic control [106]. However, modern approaches in glycemic management extend beyond achieving optimal HbA1c levels as early as possible. These strategies are aimed at reducing postprandial hyperglycemia and glycemic variability as well as maximizing the duration of time in the near-normal glycemic range [107]. Importantly, HbA1c variability is a predictor of cardiovascular complications in patients with T2DM, regardless of whether glucose levels have reached the target. Furthermore, variabilities in other risk factors, such as blood pressure, lipid profile, heart rate, body weight, and serum uric acid levels, also play a significant role in the development of diabetes-related complications [105]. The variability of each risk factor and their combined effects may amplify the risk of atherosclerotic cardiovascular disease (ASCVD) in T2DM patients.

Notably, a range of biomarkers, including relative leukocyte telomere length, serum endotrophin, and circulating palmitoyl sphingomyelin, have been identified as risk factors for cardiovascular complications in T2DM patients [108,109,110]. These biomarkers offer robust tools for more precisely assessing cardiovascular risk and providing personalized management recommendations. In addition, protein carbonyls, hydroxymethylfurfural and fibrinogen stand out for their validated use in assessing an individual's resistance to macrovascular complications, with their altered levels in T2DM patients mirroring the heightened chronic inflammation and oxidative stress that are central to the pathogenesis of such complications [28]. Recent studies have revealed significant correlations between novel inflammatory biomarkers, such as the neutrophil-to-high-density lipoprotein ratio, monocyte-to-high-density lipoprotein ratio, platelet-to-high-density lipoprotein ratio, systemic immune-inflammation index, systemic inflammatory response index, aggregate inflammatory index, and peripheral arterial disease, and T2DM [111]. Notably, the combined model of the neutrophil-to-high-density lipoprotein ratio and systemic inflammatory response index has demonstrated the highest predictive value for T2DM-PAD [111]. These markers identified in T2DM-PAD patients independently correlate with disease severity and can be readily assessed through standard laboratory indices, offering significant potential for clinical application.

In the context of diabetes-related vascular complications, emerging evidence suggests that in Australia's indigenous population, dysregulated HDL-miRNA profiles could undermine HDL functionality, potentially serving as biomarkers for the exacerbation of these complications [112]. Asprosin, a recently discovered adipokine, has been identified as an independent risk factor for PAD in T2DM patients. Elevated circulating levels of asprosin have been found to be significantly correlated with PAD and negatively correlated with the diagnostic marker the ankle-brachial index [51]. Cysteine-rich angiogenic inducer 61 (Cyr61) is significantly correlated with PAD in T2DM patients [113]. Cyr61, a 40-kD secretory protein, has been shown to play a crucial role in regulating cellular physiological processes [113]. This study indicated that Cyr61 levels are significantly increased in PAD patients with T2DM and are positively correlated with disease severity [113]. Additionally, urinary thromboxane A2 metabolites are considered noninvasive biomarkers for elevated cardiovascular risk and are valuable tools for secondary prevention of T2DM [55].

In summary, the integration of personalized medicine and precision mechanisms offers a promising avenue for effectively preventing cardiovascular and macrovascular complications in patients with diabetes. This requires a multidisciplinary approach, including basic research, clinical trials, and the development of personalized treatment plans [114]. Future research is expected to reveal genetic markers that can predict the likelihood of enhanced responses to antidiabetic medications and the onset of complications [104].

Lifestyle interventions constitute a critical component of the management of T2DM and its macrovascular complications. In addition to genetic factors, unhealthy dietary habits, physical inactivity, and weight gain disrupt circadian physiological processes, leading to metabolic dysregulation and elevating the risk of T2DM and its complications [115]. Comprehensive lifestyle management, encompassing medical nutrition therapy, weight reduction, and physical activity, serves as an effective strategy for mitigating the risk of macrovascular complications [5].

The primary goal of medical nutrition therapy used in the management of T2DM is to achieve optimal metabolic control—maintaining blood glucose and lipid levels within recommended ranges—to reduce the risk of macrovascular complications [116]. In medical nutrition therapy, a balanced diet and judicious micronutrient supplementation are considered effective strategies [117]. Various diets, including the Mediterranean and Paleolithic diets and low-carbohydrate, high-protein, vegetarian, and nut-rich diets, are recommended [5, 63, 116, 118]. Conversely, a poor diet involving the consumption of, for example, sugary beverages, foods high in sugar and fat, and minimal fresh fruits and vegetables increases the risk of weight gain and T2DM complications [119,120,121]. Disruptions in nutrient sensing and responses to internal levels of nutrients, such as glucose, lipids, and amino acids, are closely associated with metabolic diseases, such as obesity, T2DM, and other metabolic syndromes and their complications [122]. Recent meta-analyses of 884 randomized controlled trials provide moderate-to-high-quality evidence that micronutrients, such as n-3 fatty acids, folic acid, and coenzyme Q10, can reduce the risk of macrovascular diseases in T2DM patients [123]. However, supplementation with certain micronutrients, such as β-carotene, may increase all-cause mortality and CVD risk [123]. BCAAs play pivotal roles in protein synthesis, energy metabolism, and cellular regulation. However, chronic accumulation of BCAAs, induced by either dietary or genetic factors, is associated with metabolic dysregulation, insulin resistance, and increased cardiovascular risk, particularly in patients with obesity and diabetes [117, 124]. When micronutrient supplementation is recommended for T2DM patients for cardiovascular complication prevention, various factors, including the type, dosage, and timing of nutrient intake and overall health status, should be carefully considered.

Recent studies have revealed the impact of a high-fat diet on the adaptive process of β-cell function, the transition from compensation to decompensation, and how dietary interventions can reverse this process [125]. Dietary interventions in the prediabetic stage can fully restore β-cell function and significantly reverse the chromatin and transcriptomic reprogramming induced by a high-fat diet [125]. Healthy diets can also reverse hepatic insulin resistance and steatosis caused by ER-mitochondrial miscommunication, suggesting a potential therapeutic target for restoring metabolic balance [126]. Furthermore, research indicates that a caloric restriction of approximately 14% in healthy populations can significantly improve thymic output and induce transcriptomic reprogramming in adipose tissue within two years via pathways that regulate mitochondrial bioenergetics, anti-inflammatory responses, and longevity [127]. Specifically, caloric restriction can inhibit the expression of the platelet-activating factor acetylhydrolase gene, which is associated with slowing thymic atrophy, reducing inflammation, and improving metabolic health [127].

The clinical demarcations for overweight and obesity are a BMI exceeding 25 kg/m2 and 30 kg/m2, respectively, and excess adiposity is intricately linked with adverse cardiovascular outcomes [5]. The pathophysiological cascade initiated by excess adiposity extends beyond mere weight gain, engendering hypertension, dyslipidemia, endothelial dysfunction, and a heightened inflammatory milieu [5, 128]. Central to these processes is metabolic turmoil within adipose tissue, characterized by hypoxia, perturbed protein folding, and an increase in circulating free fatty acids, which collectively precipitate systemic inflammatory pathways [5, 40, 128]. This insidious inflammatory state not only fosters insulin resistance and pancreatic β-cell impairment but also accelerates the progression of T2DM and its macrovascular sequelae [5, 128]. Recently, both the American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update their consensus statement on adult T2DM management, emphasizing the importance of weight management within the overall approach to diabetes care [129]. Similarly, the American Heart Association underscores that moderate and sustained weight loss can offer substantial cardiovascular benefits [5]. This perspective is supported by recent Mendelian randomization studies, highlighting the significance of effective weight management in reducing macrovascular complication risks in T2DM patients [130]. Different types of adipose tissue contribute variably to vascular dysfunction and subsequent CVD. The accumulation of visceral adipose tissue is associated with immune cell infiltration and increased secretion of vasoconstrictive mediators, thereby elevating the risk of vascular complications [131, 132]. Weight reduction benefits T2DM patients in terms of glycemic control, concentric left ventricular remodeling, aortic stiffness, and reduced risk of heart failure [114, 133].

Increased physical activity and exercise have been shown to reduce weight and improve various parameters, including blood glucose, lipids, blood pressure, insulin sensitivity, and inflammatory biomarkers, in a dose-dependent manner [5, 118, 134]. Clinical studies indicates that various types of exercise interventions, including dynamic aerobic exercise, combined aerobic and resistance training, dynamic resistance exercise, and mind–body therapies, can offer significant health benefits to diabetic patients [135, 136]. The median duration of exercise interventions at 135 min per week demonstrates that increasing the level of physical activity can effectively reduce the risks of all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke. Particularly, a high level of physical activity, compared to a low level, can significantly reduce the incidence rate of total cardiovascular diseases by 16%, coronary heart disease by 16%, cerebrovascular events by 26%, and the occurrence of heart failure by 24% [135, 136].

While the positive impacts of exercise are widely acknowledged, the underlying molecular mechanisms are not fully understood. In both acute and/or chronic exercise states, signaling molecules are released through endocrine, paracrine, or autocrine pathways. Various organs, cells, and tissues, such as skeletal muscles (myokines), heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines), and neurons (neurokines), are involved in the release of these signaling molecules [134]. Recent mechanistic studies have identified specific signaling molecules, such as N-lactoylphenylalanine (Lac-Phe), that are induced by exercise and act as appetite and obesity suppressors [137]. Long-term administration of Lac-Phe has demonstrated potential for maintaining energy balance by regulating food intake and weight control [137]. Other studies have revealed that exercise improves the metabolic rate and resistance to obesity by activating mild mitochondrial stress responses in hypothalamic POMC neurons [138]. A recent study provided the first empirical evidence that early moderate or high-intensity exercise can effectively prevent and ameliorate diabetic heart disease, partially through the regulation of cardiovascular-specific microRNAs [139].

In addition to lifestyle interventions, drug intervention and surgical approaches have shown superiority in weight reduction and prevention of macrovascular complications in T2DM patients. In managing T2DM, semaglutide, a GLP-1 receptor agonist, has demonstrated significant efficacy in weight management alongside glycemic control [140, 141]. The STEP 2 and PIONEER PLUS trials elucidated the benefits of semaglutide at dosages up to 2.4 mg subcutaneously weekly and 25 mg to 50 mg orally daily, revealing marked reductions in body weight and HbA1c levels [140, 141]. These studies highlight the dual effects of semaglutide, which results in both hyperglycemia and obesity in T2DM patients and tolerable gastrointestinal side effects. This evidence positions semaglutide as a key therapeutic option, expanding the role of GLP-1 receptor agonists beyond glucose regulation to encompass weight management, thereby enriching the treatment arsenal for T2DM with a focus on comprehensive metabolic health improvement.

Beyond pharmacological treatments, bariatric surgery has emerged as a complementary intervention with profound metabolic effects. Bariatric surgery, as a complementary intervention to pharmacological treatments, plays a pivotal role in modifying the gut hormonal milieu, thereby enhancing the glucose regulatory and weight loss effects of semaglutide [142]. Furthermore, Roux-en-Y gastric bypass surgery exhibits particular potential in this domain, especially in influencing glucose excretion in the small intestine. A recent study revealed that Roux-en-Y gastric bypass surgery enhances glucose excretion in the small intestine by activating the AREG/EGFR/mTOR/AKT/GLUT1 signaling pathway, thereby improving glycemic levels [143]. Research shows that any type of weight loss surgery outperforms nonsurgical interventions in improving outcomes related to weight reduction and macrovascular complications in T2DM patients [144]. However, drastic weight fluctuations may also increase cardiovascular risk [145]. Studies indicate that in T2DM patients, weight changes exceeding 5% in one direction within two years are associated with increased risks of major cardiovascular events, emphasizing the importance of maintaining weight stability [145].

Glycemic management in T2DM patients has traditionally centered on glycated hemoglobin (HbA1c) levels as the principal parameter for assessing glycemic control and predicting the risk of macrovascular complications [114, 146,147,148]. If lifestyle modifications do not sufficiently lower HbA1c levels to below 7%, as recommended for patients with early-stage diabetes and without complications based on UKPDS observations and recent meta-analysis, the initiation of antidiabetic medication is justified [4, 88]. However, recent insights have led to a paradigm shift in our understanding of hyperglycemia. It is now recognized that effective glycemic management encompasses not only the achievement and maintenance of optimal HbA1c levels but also the reduction of postprandial hyperglycemia, the minimization of glycemic variability, and the maximization of time spent within the near-normoglycemic range, as these conditions are independently associated with macrovascular complications [106,