Microvascular and macrovascular complications of type 2 diabetes mellitus in the context of current diabetological knowledge

Type 2 diabetes mellitus (T2DM) is one of the most significant chronic metabolic diseases of the modern era and represents a major medical, social, and economic problem of global scale. In recent decades, there has been a significant increase in the prevalence of the disease across all age groups, a trend closely linked to population aging, urbanization, sedentary lifestyle, poor dietary habits, and the growing prevalence of obesity (GBD 2021 Diabetes Collaborators, 2023; NCD Risk Factor Collaboration, 2024). T2DM is characterized by progressive insulin resistance, impaired insulin secretion, and chronic hyperglycemia, which lead to gradual damage to multiple organ systems and significantly affect patient prognosis (Lu et al., 2024).

Despite significant advances in diagnosis, monitoring, and pharmacological treatment, chronic complications of diabetes remain the leading cause of morbidity, mortality, and reduced quality of life in patients with T2DM. The clinical significance of the disease therefore lies not exclusively in glucose metabolism impairment but primarily in the development of long-term vascular complications, which substantially increase the risk of disability, hospitalization, and premature mortality (Wang et al., 2023). Chronic hyperglycemia, through multiple pathophysiological mechanisms, leads to progressive damage to the vascular endothelium, activation of oxidative stress, formation of advanced glycation end products, and chronic subclinical inflammation, all of which contribute to the development of both microangiopathic and macroangiopathic complications (Bhatti et al., 2022).

Microvascular complications primarily include diabetic retinopathy, nephropathy, and neuropathy, the development of which is closely associated with long-term metabolic decompensation and disease duration. Diabetic retinopathy is one of the leading causes of blindness in the working-age population, diabetic nephropathy represents the dominant cause of chronic kidney disease, and diabetic neuropathy significantly contributes to the development of diabetic foot syndrome and lower limb amputations (Cole and Florez, 2020; Lu et al., 2024). Simultaneously, patients with T2DM are exposed to a high risk of macrovascular complications, including ischemic heart disease, cerebrovascular diseases, and peripheral arterial disease, which represent the most frequent cause of mortality in the diabetic population (GBD 2021 Diabetes Collaborators, 2023).

From both epidemiological and clinical perspectives, chronic complications of diabetes represent a significant economic burden on healthcare systems. Their management requires a comprehensive multidisciplinary approach encompassing early diagnosis, regular screening for complications, optimization of metabolic control, and intensive management of associated cardiometabolic risk factors. Current diabetological knowledge emphasizes the importance of individualized treatment and the use of modern therapeutic strategies aimed at reducing cardiovascular and renal risk in patients with T2DM (ADA, 2025).

Materials and Methods

The presented article is a narrative review focused on microvascular and macrovascular complications of T2DM. Literature sources were searched in PubMed, ScienceDirect, Scopus, and Google Scholar databases, with the analysis primarily including systematic reviews, meta-analyses, observational studies, and expert recommendations published predominantly between 2020 and 2026. Source selection was based on thematic relevance, currency, and scientific value of publications, focusing on the pathophysiology, epidemiology, prevention, and management of secondary complications of T2DM. Data from the National Centre of Health Information of the Slovak Republic for the period 2015–2024 were also used to supplement the epidemiological context. The obtained findings were processed using a descriptive method and thematically divided into microvascular and macrovascular complications.

Pathophysiology of Secondary Complication Development

Secondary complications of T2DM represent the result of long-term complex metabolic and vascular damage arising from chronic hyperglycemia, insulin resistance, dyslipidemia, and chronic low-grade inflammation. Their development is conditioned by the mutual interaction of multiple pathophysiological mechanisms that lead to progressive endothelial damage, microcirculatory impairment, accelerated atherosclerosis, and subsequent organ damage. Microvascular complications, primarily diabetic retinopathy, nephropathy, and neuropathy, arise mainly on the basis of damage to small vessels and capillaries, whereas macrovascular complications are associated with the progression of atherosclerotic changes in large arteries and an increased risk of cardiovascular and cerebrovascular diseases (Roy, 2025; Singh et al., 2026).

The key initiating factor in the development of secondary complications is chronic hyperglycemia, which leads to excessive glucose entry into insulin-independent cells, particularly endothelial cells, neurons, retinal cells, and renal structures. Simultaneously, insulin resistance promotes glucose and lipid metabolism impairment, resulting in increased free fatty acid concentrations, lipotoxic tissue damage, and further deterioration of metabolic homeostasis. The combination of hyperglycemia and insulin resistance causes metabolic overload of cells, particularly mitochondria, leading to overproduction of reactive oxygen species (ROS) and the development of oxidative stress (Caturano et al., 2023; González et al., 2023).

Oxidative stress represents one of the principal mechanisms of diabetic vascular damage. Excessive ROS production occurs primarily in the mitochondrial respiratory chain, during NADPH oxidase activation, and throughout the chronic inflammatory response. Increased ROS generation causes damage to lipids, proteins, nucleic acids, and cell membranes, while simultaneously disrupting intracellular signaling and cellular energy metabolism. As a result of chronic oxidative damage, progressive mitochondrial dysfunction occurs, which further amplifies ROS production and creates a vicious circle leading to worsening cellular and vascular damage. Mitochondrial dysfunction is particularly significant in metabolically active tissues such as the myocardium, kidneys, neural tissue, and retina, where it contributes to the progression of diabetic nephropathy, retinopathy, neuropathy, and cardiovascular complications (Chen et al., 2025; Iheagwam et al., 2025).

Excessive ROS formation simultaneously activates multiple pathological metabolic pathways that contribute to further progression of diabetic damage. Activation of the polyol pathway leads to intracellular accumulation of sorbitol and increased NADPH consumption, resulting in weakened cellular antioxidant protection. Simultaneously, formation of advanced glycation end products (AGEs) increases, arising from non-enzymatic glycation of proteins, lipids, and nucleic acids. Binding of AGEs to the RAGE receptor activates pro-inflammatory and pro-oxidative signaling pathways including NF-κB, leading to increased expression of cytokines, adhesion molecules, and profibrotic factors. Hyperglycemia further supports activation of protein kinase C (PKC), which increases vascular permeability, promotes vasoconstriction, a prothrombotic state, and extracellular matrix remodeling. The hexosamine pathway also plays a significant role, influencing gene expression and contributing to the development of inflammation, fibrosis, and endothelial damage. These metabolic mechanisms play important roles in the development of diabetic kidney disease, retinopathy, and atherosclerotic vascular damage (Kleibert et al., 2023; Zhao et al., 2026).

Long-term activation of the aforementioned mechanisms leads to the development of endothelial dysfunction, which represents the central pathophysiological link between metabolic damage and clinical manifestation of vascular complications. Physiologically, the endothelium ensures regulation of vascular tone, hemostasis, vascular wall permeability, and anti-inflammatory response. In T2DM, however, there is reduced bioavailability of nitric oxide, increased production of vasoconstrictive factors, and activation of adhesion molecules that promote migration of inflammatory cells into the vascular wall. Oxidative stress simultaneously promotes formation of peroxynitrite, which further damages endothelial cells and impairs the vasodilatory capacity of blood vessels. The result is increased vascular permeability, microcirculatory impairment, increased thrombogenicity, and progression of atherosclerotic changes (Li et al., 2024; Yang et al., 2024).

Endothelial damage is closely related to chronic low-grade inflammation, which represents another significant factor in the progression of secondary complications of T2DM. Chronic hyperglycemia, oxidative stress, and AGE accumulation lead to activation of macrophages, monocytes, and pro-inflammatory cytokines, particularly TNF-α, IL-1β, and IL-6. Activation of inflammatory signaling pathways promotes further deterioration of insulin resistance, progression of endothelial damage, and increased ROS production, thereby creating a mutually amplifying pathophysiological cycle. Chronic inflammation simultaneously promotes proliferation of vascular smooth muscle cells, fibrosis, and destabilization of atherosclerotic plaques, significantly contributing to the development of macrovascular complications (Yousef et al., 2023; Weinberg Sibony et al., 2024).

In the microvascular bed, these mechanisms lead to damage to capillaries, basement membranes, and the microcirculation of individual organs. In diabetic retinopathy, there is damage to pericytes, increased capillary permeability, ischemic changes, and subsequent pathological neovascularization mediated primarily by vascular endothelial growth factor (VEGF). In the kidneys, the combination of glomerular hyperfiltration, oxidative stress, inflammation, and fibrosis causes progressive damage to glomeruli, albuminuria, and declining renal function. In diabetic neuropathy, metabolic damage to nerve cells, microvascular ischemia, and neuroinflammation contribute to impaired nerve impulse conduction and degeneration of peripheral nerves (Kleibert et al., 2023; Mimura and Noma, 2025; Roy, 2025).

Macrovascular complications arise primarily as a result of accelerated atherosclerosis. Chronic hyperglycemia, insulin resistance, dyslipidemia, endothelial dysfunction, and chronic inflammation promote oxidation of LDL particles, adhesion of monocytes to the vascular endothelium, and formation of foam cells within atherosclerotic plaques. Simultaneously, smooth muscle cell proliferation, vascular wall remodeling, and destabilization of atherosclerotic lesions occur. The result is increased risk of ischemic heart disease, stroke, and peripheral arterial disease. The risk of macrovascular complications is further increased by the concurrent presence of hypertension, obesity, smoking, and lipid metabolism disorders (Caturano et al., 2025; Hussain, 2025; Siddiquea et al., 2026).

The pathophysiology of secondary complications of T2DM thus represents a continuous and interconnected process in which chronic hyperglycemia and insulin resistance initiate metabolic overload of cells, subsequent ROS overproduction, mitochondrial dysfunction, activation of pathological metabolic pathways, endothelial damage, and chronic inflammation. These mechanisms mutually amplify each other and lead to progressive damage to both the microvascular and macrovascular systems, which constitutes the principal basis for morbidity and mortality in patients with T2DM (Fig. 1).

Figure 1 Complications of diabetes mellitus Illustration of the most common microvascular and macrovascular complications of diabetes mellitus, including damage to the retina, kidneys, nerve endings, cerebrovascular diseases, myocardial infarction, and diabetic foot syndrome.

Source: original processing.

Microvascular Complications

Diabetic Retinopathy

Diabetic retinopathy represents one of the most characteristic forms of diabetic microangiopathy and is also among the most frequent causes of visual impairment in adult patients with diabetes. Its development and progression are closely conditioned by long-term hyperglycemia, which leads to damage to the retinal microcirculation through complex metabolic, hemodynamic, and inflammatory mechanisms. The development of the disease involves activation of the polyol pathway, increased formation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, protein kinase C activation, and chronic subclinical inflammation, all of which lead to progressive damage to retinal capillary endothelium and disruption of the blood-retinal barrier (Biswas et al., 2024; Morya et al., 2024; Seo et al., 2025).

Its development is conditioned by damage to retinal capillaries, loss of pericytes, thickening of the basement membrane, and increased permeability of the blood-retinal barrier. In the initial stages, microaneurysms, small hemorrhages, and exudates form; later, capillary occlusion and retinal ischemia develop. Progressive impairment of retinal perfusion leads to the creation of a hypoxic environment, which stimulates expression of hypoxia-inducible factors and vascular endothelial growth factor (VEGF). Increased VEGF production promotes pathological angiogenesis, increased vascular permeability, and the formation of neovascularization characteristic of the proliferative stage of the disease (Kusuhara et al., 2024; Callan et al., 2025).

Clinically, diabetic retinopathy is classified into nonproliferative and proliferative forms. Nonproliferative diabetic retinopathy represents an earlier stage of the disease and is characterized by the presence of microaneurysms, intraretinal hemorrhages, hard exudates, cotton wool spots, and microvascular perfusion abnormalities. Depending on the extent of pathological changes, it is divided into mild, moderate, and severe forms. Continued retinal ischemia subsequently leads to the development of proliferative diabetic retinopathy, in which pathological neovascularization of the optic disc or retinal surface occurs. The newly formed vessels are fragile, have increased permeability, and predispose to vitreous hemorrhage, fibrosis, and tractional retinal detachment, which significantly increases the risk of irreversible vision loss (Ahmed et al., 2024; Ciorba et al., 2025).

An important clinical entity is also diabetic macular edema, which is associated with increased vascular permeability and represents a frequent cause of reduced central visual acuity. Its pathogenesis is primarily related to disruption of the blood-retinal barrier, extravasation of fluid into the macula, and local inflammatory activation. Macular edema development is contributed to by increased expression of VEGF, pro-inflammatory cytokines, and adhesion molecules, which promote vascular dysfunction and progression of retinal damage (Qian et al., 2025; Seo et al., 2025).

Current evidence further suggests that diabetic retinopathy is not merely purely vascular damage, but that neurodegenerative processes affecting retinal neurons and glial cells also play a role, potentially preceding overt microangiopathic lesions (Kulkarni et al., 2024). Retinal neurodegeneration is associated with microglial activation, ganglion cell apoptosis, mitochondrial dysfunction, and disruption of the neurovascular unit. An important role is also played by chronic neuroinflammation mediated by cytokines, chemokines, and glial activation, which contribute to progressive retinal tissue damage. This modern concept supports understanding diabetic retinopathy as a complex neurovascular disease in which vascular and neurodegenerative mechanisms are closely interconnected and mutually potentiate each other (Guo et al., 2026).

Diabetic Nephropathy

Diabetic kidney disease represents one of the most severe microangiopathic complications of T2DM and is also among the leading causes of chronic kidney disease and end-stage renal failure worldwide. Its development and progression are conditioned by the complex interaction of metabolic, hemodynamic, inflammatory, and fibrotic mechanisms that lead to progressive damage to glomeruli, tubulointerstitium, and the renal microcirculation. Chronic hyperglycemia plays a key role in initiating pathological processes, as long-term elevated glycemia promotes AGE formation, oxidative stress activation, mitochondrial dysfunction, and inflammatory processes leading to progressive damage to renal parenchyma (Jha et al., 2024; Joumaa and Asmar, 2025).

Diabetic kidney disease is another major microangiopathic complication of T2DM and represents one of the leading causes of chronic kidney disease and end-stage renal failure. Its pathogenesis is complex and encompasses both hemodynamic and metabolic mechanisms. In the early stages, glomerular hyperfiltration and intraglomerular hypertension develop, which lead to damage to glomerular capillaries. Simultaneously, hyperglycemia and AGE action promote mesangial expansion, extracellular matrix accumulation, glomerular basement membrane thickening, and gradual development of glomerulosclerosis. An important role is also played by inflammatory activation, podocyte dysfunction, and tubulointerstitial damage. Clinically, diabetic kidney disease initially manifests as albuminuria, followed by declining glomerular filtration and progression to stages of chronic kidney disease. In T2DM, however, it should be emphasized that renal involvement may have a heterogeneous course and may not always be accompanied by the typical sequence from microalbuminuria to macroalbuminuria, as some patients develop declining renal function even with less pronounced albuminuria (Faselis et al., 2020).

An important pathophysiological mechanism of diabetic kidney disease is activation of the renin-angiotensin-aldosterone system (RAAS), which leads to vasoconstriction of the efferent arteriole, increased intraglomerular pressure, and progression of proteinuria. Simultaneously, pro-inflammatory and profibrotic cytokines are activated, particularly transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interleukin-6, which promote extracellular matrix accumulation and development of renal fibrosis. An important role is also played by podocyte dysfunction, which leads to disruption of the glomerular filtration barrier and increased permeability to albumin (Jha et al., 2024; Verma et al., 2026).

Chronic hyperglycemia simultaneously activates multiple metabolic pathways, including the polyol pathway, protein kinase C, and hexosamine pathway, which contribute to increased reactive oxygen species production and endothelial dysfunction. Oxidative stress subsequently damages glomerular endothelial cells, mesangial cells, and tubular epithelium, thereby promoting progression of glomerulosclerosis and tubulointerstitial fibrosis. In advanced stages, irreversible nephron loss, progressive decline in eGFR, and development of chronic kidney disease occur (Li et al., 2024; Joumaa and Asmar, 2025).

Current evidence indicates that diabetic kidney disease does not represent solely a glomerular disease but rather complex damage encompassing glomeruli, tubules, interstitium, and the renal microvasculature. Tubulointerstitial damage is an important determinant of disease progression and closely correlates with declining renal function. In recent years, attention has therefore focused on identifying new biomarkers of renal damage, such as NGAL, KIM-1, cystatin C, and inflammatory biomarkers, which could enable earlier diagnosis and more precise risk stratification of diabetic kidney disease progression (Shetty et al., 2025; Wani et al., 2025).

Diabetic kidney disease is also significantly associated with increased cardiovascular risk. Patients with albuminuria and reduced glomerular filtration exhibit a higher incidence of ischemic heart disease, heart failure, and cardiovascular mortality. For this reason, early diagnosis and comprehensive management of diabetic kidney disease constitute an essential part of care for patients with T2DM. Current therapeutic strategies include optimization of glycemic control, management of arterial hypertension, RAAS blockade, and use of modern antidiabetic agents with known renoprotective effects, particularly SGLT2 inhibitors and GLP-1 receptor agonists, which can slow the progression of renal damage and reduce the risk of cardiovascular complications (Joumaa and Asmar, 2025; Verma et al., 2026).

Diabetic Neuropathy

Diabetic neuropathy is among the most common chronic complications of T2DM and represents a heterogeneous group of peripheral and autonomic nervous system disorders arising from long-term metabolic dysregulation. Its pathogenesis is complex and involves the concurrent action of hyperglycemia, insulin resistance, oxidative stress, microvascular damage, and chronic subclinical inflammation. An important role is also played by mitochondrial dysfunction and impairment of energy metabolism in nerve cells, which lead to progressive damage to peripheral nerves (Zhu et al., 2024; Fridman et al., 2026).

Chronic hyperglycemia activates multiple pathological metabolic pathways, primarily the polyol pathway, in which glucose is converted to sorbitol via aldose reductase. Intracellular sorbitol accumulation leads to osmotic stress, reduced myoinositol concentration, and disruption of Na+/K+-ATPase activity, which adversely affects nerve impulse conduction and axonal transport. Simultaneously, there is increased ROS production, mitochondrial damage, lipid peroxidation, and activation of pro-inflammatory signaling mechanisms. Oxidative stress promotes neuronal apoptosis and progression of neurodegenerative changes in the peripheral nervous system (Hosseini et al., 2013; Zhu et al., 2024).

An important pathophysiological mechanism is also AGE formation, which arises from non-enzymatic glycation of proteins and lipids. Their interaction with RAGE receptors leads to endothelial dysfunction, activation of inflammatory cytokines, and worsening of nerve tissue microcirculation. Damage to vasa nervorum causes reduced perfusion of peripheral nerves and development of chronic endoneurial hypoxia. As a consequence of ischemic and metabolic damage, demyelination, axonal degeneration, and progressive loss of nerve fibers occur (Gonçalves et al., 2017; Srivastava et al., 2025).

Pathological processes also affect Schwann cells, which provide myelination of peripheral nerve fibers and metabolic support for axons. Hyperglycemia and oxidative stress impair their regenerative capacity, promote demyelination, and reduce nerve impulse conduction velocity. Current evidence also points to the significance of neuroinflammation, macrophage activation, and chronic inflammatory response, which contribute to the progression of neuropathic damage (Abd Razak et al., 2024; Yang et al., 2025).

The most common clinical form is distal symmetric sensorimotor polyneuropathy, predominantly affecting the lower limbs. Typical manifestations include paresthesias, dysesthesias, neuropathic pain, impaired vibration and tactile sensitivity, weakened reflexes, and loss of protective sensation. Symptoms have a characteristic symmetric distal distribution primarily affecting the lower and upper extremities. Damage to thin nerve fibers is predominantly associated with painful neuropathy, whereas damage to thick fibers leads to impaired proprioception, gait instability, and increased fall risk (Jensen et al., 2023; Strand et al., 2024).

Also included among diabetic neuropathic forms are autonomic forms affecting multiple organ systems. Cardiovascular autonomic neuropathy may manifest as heart rate variability impairment, orthostatic hypotension, or resting tachycardia. Gastrointestinal involvement includes gastrointestinal motility disorders, including gastroparesis, while urogenital forms are associated with bladder dysfunction and sexual disorders. Sudomotor dysfunction leads to sweating disorders, skin xerosis, and increased skin vulnerability to damage (Fridman et al., 2026).

Diabetic neuropathy significantly contributes to the development of diabetic foot syndrome. Loss of protective sensation combined with foot deformities and microcirculatory impairment increases the risk of ulceration, secondary infections, and lower limb amputations. Neuropathy also represents a significant determinant of reduced quality of life in patients, chronic pain, functional limitations, and increased morbidity associated with T2DM (Faselis et al., 2020; Kulkarni et al., 2024).

Diabetic Foot Syndrome

Diabetic foot syndrome represents one of the most severe chronic complications of T2DM and is a significant cause of morbidity, hospitalization, and non-traumatic lower limb amputations. It is a multifactorial disease arising on the basis of a combination of diabetic peripheral neuropathy, lower limb ischemic disease, microcirculatory disorders, and increased susceptibility to infection. Diabetic foot syndrome is characterized by the development of ulceration, destruction of deep tissues, and impaired wound healing, with its progression potentially leading to gangrene and limb amputation (Kim, 2023; Srinivas-Shankar et al., 2026).

The pathophysiology of diabetic foot syndrome is complex and involves multiple interconnected mechanisms. Chronic hyperglycemia leads to activation of the polyol pathway, increased formation of advanced glycation end products (AGEs), oxidative stress, and endothelial dysfunction. These processes cause damage to peripheral nerve fibers, microcirculatory impairment, and progressive worsening of perfusion to lower limb tissues. Simultaneously, there is reduced tissue regeneration, impaired angiogenesis, and prolonged inflammation, which significantly worsens wound healing capacity (Kim, 2023; Dawi et al., 2025).

The key factor in diabetic foot development is diabetic peripheral neuropathy. Damage to sensory nerve fibers leads to loss of protective sensation, as a result of which the patient is unable to timely recognize pain or minor traumatic foot injuries. Repeated microtrauma subsequently leads to the formation of hyperkeratoses, calluses, and ulcerations. Motor neuropathy causes muscle imbalance and foot deformities, which alter plantar pressure distribution and promote the development of pressure lesions. Simultaneously, autonomic neuropathy leads to reduced sweating, skin drying, and formation of fissures that serve as entry points for infection (Kim, 2023; Rümenapf et al., 2024).

An important role in pathogenesis is also played by peripheral arterial disease of the lower extremities. DM promotes the development of atherosclerotic changes through chronic inflammation, endothelial dysfunction, dyslipidemia, and increased thrombogenicity. The result is reduced blood flow and tissue hypoxia, which lead to ischemic tissue damage and impaired wound repair. The combination of neuropathy and ischemic damage significantly increases the risk of ulceration progression, necrosis, and lower limb amputations (Rümenapf et al., 2024).

Infections of the diabetic foot represent another significant complication of diabetic foot syndrome. Hyperglycemia adversely affects the function of neutrophils, macrophages, and other immune system components, leading to weakened immune response and increased susceptibility to infection. Diabetic foot ulcerations are frequently colonized by polymicrobial flora, including gram-positive cocci, gram-negative bacteria, and anaerobes. Progression of infection can lead to cellulitis, abscesses, osteomyelitis, or systemic infectious complications (Maity et al., 2024; Dawi et al., 2025).

The clinical presentation of diabetic foot syndrome encompasses a wide spectrum of manifestations ranging from dry skin and hyperkeratoses to deep ulcerations, necrosis, and gangrene. Typical manifestations include sensory impairment, paresthesias, foot deformities, ingrown toenails, calluses, and chronic non-healing defects. In advanced stages, signs of infection, inflammation, and ischemic damage appear. Characteristic changes of diabetic foot syndrome are illustrated in Figure 2.

Figure 2 Pathophysiological and clinical manifestations of diabetic foot syndrome Illustration of reduced blood flow, peripheral nerve damage, ulcerations, hyperkeratoses, ingrown toenails, and dry skin in diabetic foot syndrome.

Source: original processing.

Diabetic foot syndrome represents a significant medical and public health problem given the high risk of chronic ulcerations, recurrent hospitalizations, and lower limb amputations. Its development and progression result from the complex interaction of neuropathic, ischemic, metabolic, and infectious mechanisms that mutually potentiate each other. Early identification of risk factors and understanding of pathophysiological processes play a crucial role in reducing severe complications and improving the prognosis of patients with T2DM.

Macrovascular Complications

Cardiovascular Diseases

Ischemic heart disease represents one of the most severe macrovascular complications of T2DM. Its essence is atherosclerotic involvement of coronary arteries, which leads to reduced myocardial blood flow and may clinically manifest as stable or unstable angina pectoris, silent myocardial ischemia, acute coronary syndrome, or myocardial infarction. In patients with T2DM, coronary atherosclerosis is often more extensive, more diffuse, and more calcified than in non-diabetic patients, which worsens prognosis and complicates interventional treatment. Parvez et al. (2025) demonstrated in their comparative study of patients with STEMI (ST Elevation Myocardial Infarction) that diabetic patients had more severe coronary involvement, more frequent multiple stenoses, and a more complex angiographic finding compared to non-diabetic patients.

Pathophysiologically, the increased risk of ischemic heart disease in T2DM is explained by the combination of chronic hyperglycemia, insulin resistance, atherogenic dyslipidemia, endothelial dysfunction, oxidative stress, and low-grade inflammation. These mechanisms accelerate atherosclerotic plaque formation, promote their destabilization, and increase the likelihood of thrombotic occlusion of the coronary artery. Kabibulatova et al. (2026) simultaneously point to the genetic predisposition of coronary disease risk in patients with T2DM, identifying associations particularly with genes involved in lipid metabolism, incretin signaling, and oxidative stress.

A particular problem in diabetic patients is also coronary microvascular dysfunction, which may cause ischemic symptoms even without significant obstructive stenosis of large coronary arteries. Yu et al. (2023) found that in diabetic patients without obstructive coronary disease, the incidence of microvascular myocardial ischemia was significantly higher than in the control group, and its presence was independently associated with anginal symptoms. This suggests that in T2DM patients, ischemic symptoms cannot be explained solely by stenosis of large coronary arteries, but also by impaired coronary microcirculation.

The clinical course of ischemic heart disease in diabetic patients is often atypical. Due to diabetic autonomic neuropathy, chest pain may be less pronounced or completely absent, leading to delayed recognition of myocardial infarction. Raveena, Naqvi et al. (2023) demonstrated that diabetic patients sought medical help for myocardial infarction later than non-diabetic patients, which may adversely affect treatment outcomes and increase the risk of complications.

An important aspect is also the presence of asymptomatic coronary atherosclerosis. Santilli et al. (2025) emphasize that in T2DM patients, coronary disease may remain subclinical for a long time, with its first manifestation potentially being an acute coronary syndrome. For this reason, in assessing cardiovascular risk in diabetic patients, it is important to consider not only traditional risk factors but also diabetes duration, metabolic control, presence of additional complications, and the patient's overall atherosclerotic risk profile.

Overall, ischemic heart disease in T2DM can be considered the result of the interconnection of metabolic, vascular, inflammatory, and genetic mechanisms. Compared to the non-diabetic population, T2DM patients have a higher risk of angina pectoris, silent ischemia, myocardial infarction, and more severe coronary involvement. These findings emphasize the need for early identification of cardiovascular risk and thorough monitoring of both clinical and subclinical manifestations of ischemic heart disease in T2DM patients.

Cerebrovascular Diseases

Stroke represents one of the most severe macrovascular complications of T2DM and is also among the leading causes of mortality, disability, and long-term neurological morbidity in patients with this disease. The presence of T2DM significantly increases the risk of both ischemic and hemorrhagic stroke, with diabetic patients more frequently experiencing severe neurological deficit, higher recurrence rates, and worse prognosis following acute cerebrovascular events (Wang et al., 2023; Mavridis et al., 2025).

The pathophysiological basis of increased stroke risk in T2DM is multifactorial and encompasses chronic hyperglycemia, insulin resistance, endothelial dysfunction, accelerated atherosclerosis, a pro-inflammatory state, and increased thrombogenic activity. Long-term hyperglycemia leads to vascular endothelial damage, increased formation of reactive oxygen species, and accumulation of advanced glycation end products (AGEs), which promote vascular inflammation and vascular wall remodeling. Simultaneously, there is worsening of cerebral perfusion, impaired cerebral blood flow autoregulation, and increased arterial stiffness, which significantly contribute to the development of ischemic cerebrovascular events (Gao et al., 2025).

The most common form of cerebrovascular involvement in T2DM patients is ischemic stroke, which arises on the basis of atherothrombotic occlusion of cerebral arteries or embolization. T2DM patients have an increased incidence of atherosclerotic changes in both extracranial and intracranial arteries, with diabetic dyslipidemia, arterial hypertension, and obesity synergistically accelerating atherosclerosis progression. An important role is also played by increased platelet aggregation and a hypercoagulable state, which promote thrombosis and ischemic damage to brain tissue (Wang et al., 2023).

In addition to ischemic stroke, the risk of hemorrhagic stroke is also increased in T2DM patients, though to a lesser degree. Hemorrhagic events are primarily related to chronic damage to small cerebral vessels, microangiopathy, arterial hypertension, and degenerative changes in the vascular wall. Long-term diabetes leads to weakened vascular integrity, increased capillary permeability, and impaired autoregulatory mechanisms, which may promote the development of intracerebral hemorrhage (Mavridis et al., 2025).

An important risk factor for cerebrovascular complications is also diabetes duration and glycemic control level. The study by Gao et al. (2025) demonstrated that higher HbA1c values and longer T2DM duration are associated with a progressive increase in the risk of both ischemic and hemorrhagic stroke. Inadequate glycemic control simultaneously worsens neurological outcome following stroke and increases mortality risk.

Cerebrovascular complications in T2DM represent a significant clinical and public health problem requiring a comprehensive preventive and therapeutic approach. Prevention includes strict glycemic control, blood pressure management, lipid profile optimization, body weight reduction, smoking cessation, and regular physical activity. Early identification of risk factors and intensive management of metabolic disorders can significantly reduce stroke incidence and improve the prognosis of T2DM patients.

Peripheral Arterial Disease

Peripheral arterial disease (PAD) represents a significant macrovascular complication of T2DM, characterized by progressive atherosclerotic involvement of lower extremity arteries. In T2DM patients, accelerated atherogenesis occurs as a result of chronic hyperglycemia, insulin resistance, endothelial dysfunction, oxidative stress, and systemic inflammation. These mechanisms lead to vascular wall damage, smooth muscle cell proliferation, and accelerated atherosclerotic plaque formation, causing narrowing or occlusion of peripheral arteries (Stoberock et al., 2021; Amin et al., 2026).

T2DM patients have a significantly higher risk of developing PAD compared to the non-diabetic population, and the disease typically follows a more aggressive course in these patients. Diabetes simultaneously promotes diffuse and multisegmental arterial involvement, particularly in the region of infrapopliteal vessels of the lower extremities. An important role is also played by diabetic microangiopathy, microcirculatory disorders, and neuropathy, which worsen tissue perfusion and the capacity for regeneration of ischemically damaged areas (Zemaitis et al., 2023; Minc and McGinigle, 2026).

The clinical presentation of peripheral arterial disease is variable and depends on the extent of ischemic damage. The typical manifestation is intermittent claudication, characterized by pain or muscle cramping of the lower limbs during physical exertion, which subsides at rest. With disease progression, ischemic pain at rest, a sensation of limb cooling, weakened or absent peripheral pulses, and trophic changes of skin and nails may develop. In diabetic patients, atypical or less pronounced symptoms are frequent due to the presence of peripheral neuropathy, which may lead to delayed diagnosis (Zemaitis et al., 2023).

A significant consequence of PAD in T2DM is impaired wound healing and development of ischemic ulcerations. The combination of macrovascular ischemia, microvascular damage, neuropathy, and impaired immune response creates conditions for the development of diabetic foot syndrome. Chronic tissue hypoperfusion leads to reduced oxygen and nutrient supply, which adversely affects tissue repair and promotes progression of necrosis and infectious complications. In advanced stages, PAD may progress to chronic limb-threatening ischemia, which is associated with a high risk of lower limb amputation and significant increase in patient mortality (Haliti et al., 2025; Flumignan et al., 2026).

Peripheral arterial disease simultaneously represents a marker of generalized atherosclerosis and is significantly associated with an increased risk of cardiovascular and cerebrovascular events. Early diagnosis, glycemic control, management of atherosclerotic risk factors, and regular screening for ischemic changes in the lower extremities are therefore of fundamental importance in preventing severe complications and amputations in T2DM patients (Amin et al., 2026; Minc and McGinigle, 2026).

Discussion

Statistical Trends and Incidence of Secondary Complications of T2DM

The most recent epidemiological data from recent years indicate that secondary complications of T2DM remain a significant cause of morbidity, mortality, and reduced quality of life in patients at both the global and European level. Despite advances in diagnosis and treatment, many countries are experiencing a further increase in complication incidence, which is closely linked to population aging, growing obesity prevalence, sedentary lifestyle, and increasing T2DM incidence in younger age groups.

Current international epidemiological studies show that microvascular complications occur more frequently than macrovascular complications. Systematic reviews and meta-analyses published between 2022 and 2025 report that microvascular complications affect approximately 30–55% of T2DM patients, whereas macrovascular complications occur in approximately 20–32% of patients. The most common microvascular complications include diabetic retinopathy, neuropathy, and nephropathy, while macrovascular complications primarily encompass ischemic heart disease, myocardial infarction, stroke, and peripheral arterial disease.

The extensive systematic review and meta-analysis by Aikaeli et al. (2022), analyzing patients with newly diagnosed T2DM in low- and middle-income countries, reported a prevalence of diabetic retinopathy of approximately 12–15%, diabetic neuropathy of 18–24%, and diabetic nephropathy of approximately 10–20%. Cardiovascular complications were present in approximately 10–15% of patients at the time of T2DM diagnosis, indicating that vascular damage often develops even before the disease itself is diagnosed.

More recent epidemiological works from 2024–2025 point to an even higher complication incidence in patients with longer disease duration. According to the recent study by Satapathy et al. (2025), at least one diabetic complication was present in as many as 74.7% of T2DM patients. Microvascular complications were recorded in 53% of patients, with diabetic retinopathy occurring in 32.5%, diabetic neuropathy in 26.5%, and diabetic nephropathy in 21.7% of patients. Macrovascular complications were present in approximately 32.5% of patients.

An important trend in recent years is the growing incidence of complications in patients with so-called young-onset T2DM, i.e., diabetes diagnosed before the age of 40. The scoping review published by Harihar et al. (2024) notes that these patients have a more aggressive disease course, faster development of vascular complications, and higher risk of premature mortality. After 20–25 years of T2DM duration, the prevalence of diabetic retinopathy reached approximately 58%, with diabetic nephropathy present in 30–45% of patients.

Current global data simultaneously confirm the significant impact of T2DM on the development of cardiovascular diseases. T2DM patients have approximately 72% higher risk of myocardial infarction, 52% higher risk of stroke, and up to 84% higher risk of heart failure compared to the non-diabetic population.

A similarly unfavorable situation is observed in Slovakia. Data from the National Centre of Health Information (NCZI) for the period 2015–2024 document a consistently high incidence of secondary complications and comorbidities in diabetic patients. The most frequently recorded were lipid metabolism disorders and arterial hypertension, which represent significant risk factors for the development of atherosclerosis and cardiovascular complications. In 2024, the incidence of lipid metabolism disorders reached 39.8 cases per 1,000 diabetic patients, and arterial hypertension 37.8 cases per 1,000 diabetic patients.

Among microvascular complications, diabetic neuropathy was most frequently documented in Slovakia, with its incidence rising from 19.6 cases per 1,000 diabetic patients in 2015 to 20.4 cases per 1,000 diabetic patients in 2024. Significant incidence was also recorded for ocular complications and diabetic nephropathy. Although ocular complications showed a slightly declining trend, 12.9 cases per 1,000 diabetic patients were still documented in 2024. Renal complications reached 11.8 cases per 1,000 diabetic patients, with the number of dialyzed patients remaining relatively stable.

Macrovascular complications, primarily myocardial infarction and stroke, showed a slightly fluctuating but consistently high incidence during the observed period. In 2024, the incidence of myocardial infarction was 6.5 cases per 1,000 diabetic patients and stroke 6.7 cases per 1,000 diabetic patients. A severe complication also remains diabetic foot syndrome and lower limb amputations, which significantly affect mobility, quality of life, and disability in patients.

Overall, epidemiological data from both Europe and Slovakia confirm that secondary complications of T2DM represent a serious health and socioeconomic problem. Microvascular complications and cardiometabolic comorbidities predominate, with their incidence increasing with disease duration and inadequate metabolic control. The results simultaneously emphasize the need for early screening, intensive glycemic control, cardiovascular risk factor management, and comprehensive multidisciplinary care for T2DM patients.

Prevention and Management

Secondary complications of T2DM, encompassing macrovascular complications (cardiovascular and cerebrovascular diseases), microvascular damage (diabetic nephropathy, retinopathy, and neuropathy), as well as neurocognitive disorders including dementia, represent the dominant determinant of morbidity, mortality, and reduced quality of life in T2DM patients. Their development is conditioned by the complex interaction of chronic hyperglycemia, insulin resistance, systemic subclinical inflammation, oxidative stress, endothelial dysfunction, and ectopic lipid accumulation. Current diabetological knowledge therefore emphasizes the need for a comprehensive therapeutic approach that transcends the traditionally glucose-centric treatment model and focuses on addressing all components of metabolic dysfunction syndrome, including obesity, arterial hypertension, dyslipidemia, and metabolically associated steatotic liver disease (Lu et al., 2024; Meir et al., 2024).

The fundamental pillar of prevention and management of secondary complications of T2DM remains intensive and long-term lifestyle modification. Early implementation of lifestyle measures including a calorically reduced and nutritionally balanced diet, particularly Mediterranean or low-carbohydrate dietary patterns, combined with regular aerobic and resistance physical activity, leads to reduced insulin resistance, weight loss, and improved metabolic control. Regular physical activity of at least 150 minutes of moderate-intensity exercise per week positively affects glycemia, lipid profile, blood pressure, and endothelial function, thereby significantly reducing the risk of progression of both microvascular and macrovascular complications (Crawford et al., 2024; Lu et al., 2024).

Modern T2DM pharmacotherapy is currently based not only on achieving target glycated hemoglobin values but primarily on reducing cardiovascular and renal risk. Treatment individualization reflects patient age, presence of comorbidities, disease duration, and hypoglycemia risk. Of particular importance have become sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists), which have demonstrated significant cardioprotective and renoprotective effects independent of glycemic reduction itself. Agents such as empagliflozin, dapagliflozin, liraglutide, semaglutide, or dulaglutide lead to reduction in the incidence of major adverse cardiovascular events (MACE), slow progression of chronic kidney disease, and simultaneously promote weight reduction and improvement of patients' metabolic profile (Guan et al., 2024; Lu et al., 2024).

An important position in T2DM management is also held by comprehensive management of the cardiorenal and metabolic continuum. Intensive treatment of arterial hypertension, dyslipidemia, and obesity constitutes an integral part of organ damage prevention. Pharmacological intervention including statins, fibrates, and antihypertensives contributes to reduction of atherosclerotic risk and stabilization of vascular endothelial function. Current therapeutic strategies are focused on addressing common pathophysiological mechanisms of chronic T2DM complications, including oxidative stress, chronic inflammation, endoplasmic reticulum stress, and lipotoxic tissue damage (Lu et al., 2024; Meir et al., 2024).

In recent years, growing attention has been devoted to neurocognitive complications of T2DM, as chronic hyperglycemia and insulin resistance significantly increase the risk of cognitive decline and development of neurodegenerative diseases including Alzheimer's disease. In this context, it is recommended to prefer antidiabetic treatment with potential neuroprotective effects, particularly pioglitazone and GLP-1 receptor agonists, while use of sulfonylurea derivatives may be associated with an increased risk of neurocognitive deterioration. In elderly patients and patients with a history of severe hypoglycemic episodes, regular cognitive function screening is recommended for early identification of neurodegenerative changes (Crawford et al., 2024).

Prevention and management of secondary complications of T2DM therefore require a multidisciplinary and individualized approach based on early diagnosis, intensive lifestyle modification, and personalized pharmacotherapy with emphasis on cardioprotection and renoprotection. The current therapeutic concept moves away from isolated glycemic control toward comprehensive management of metabolic and vascular risk with the goal of reducing organ damage, improving prognosis, and enhancing quality of life in T2DM patients.

Conclusion

T2DM represents a complex chronic metabolic disease with a progressive nature, whose clinical significance is determined primarily by the development of microvascular and macrovascular complications. Chronic hyperglycemia, insulin resistance, oxidative stress, endothelial dysfunction, and chronic subclinical inflammation create interconnected pathophysiological mechanisms leading to progressive damage to the vascular system and subsequent organ dysfunction. Secondary complications of T2DM therefore represent the dominant cause of morbidity, disability, reduced quality of life, and premature mortality in the diabetic population.

Microangiopathic complications, primarily diabetic retinopathy, diabetic kidney disease, neuropathy, and diabetic foot syndrome, significantly affect patients' functional status and are among the leading causes of blindness, chronic kidney disease, lower limb amputations, and long-term disability. Simultaneously, macroangiopathic complications, encompassing ischemic heart disease, cerebrovascular diseases, and peripheral arterial disease, remain the principal cause of cardiovascular mortality in T2DM patients. Epidemiological data simultaneously point to the growing incidence of complications also in patients with shorter disease duration and in young-onset T2DM, representing a significant medical and public health problem.

Current diabetological knowledge confirms that prevention and management of secondary complications cannot be based exclusively on glycemic control but require a comprehensive and individualized approach focused on addressing the entire cardiorenal-metabolic continuum. Of key importance are early diagnosis, regular screening for complications, intensive lifestyle modification, strict control of arterial hypertension, dyslipidemia, and obesity, as well as the use of modern pharmacological strategies with proven cardioprotective and renoprotective effects. Of significant therapeutic benefit in this regard are particularly SGLT2 inhibitors and GLP-1 receptor agonists, which in addition to improving metabolic control also positively affect patient prognosis and reduce the risk of organ damage.

The issue of secondary complications of T2DM therefore remains one of the principal challenges of modern diabetology. Growing disease prevalence, population aging, and high socioeconomic burden emphasize the need for multidisciplinary collaboration, implementation of preventive measures, and further research into the molecular mechanisms of diabetic damage. A better understanding of pathophysiological processes may in the future contribute to the development of targeted personalized treatment and more effective prevention of chronic complications, representing a fundamental prerequisite for improving the long-term prognosis and quality of life of T2DM patients.

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Authors: Mgr. Anastasiia Ostafiichuk, Institute of Public Health and Hygiene, Faculty of Medicine, P.J. Šafárik University, Košice prof. Mgr. MUDr. Erik Dorko, Phd., MPH, MBA, Institute of Public Health and Hygiene, Faculty of Medicine, P.J. Šafárik University, Košice doc. MUDr. Ingrid Dravecká PhD., First Department of Internal Medicine, P.J. Šafárik University Faculty of Medicine and University Hospital, Košice prof. MUDr. Kvetoslava Rimárová CSc., Institute of Public Health and Hygiene, Faculty of Medicine, P.J. Šafárik University, Košice Mgr. Ján Roman, Institute of Public Health and Hygiene, Faculty of Medicine, P.J. Šafárik University, Košice

This work was supported by grants KEGA 001UPJŠ-4/2024 and 003UPJŠ-4/2024 from the Ministry of Education, Research, Development and Youth of the Slovak Republic.