Cardiovascular disease in diabetes

Cardiovascular disease in diabetes comprises the cardiac, cerebrovascular, and peripheral arterial manifestations that occur with increased frequency in people with diabetes mellitus, particularly through the interaction of chronic hyperglycemia, insulin resistance, endothelial dysfunction, inflammation, thrombogenicity, kidney disease, visceral obesity, and lipid abnormalities. It is therefore not limited to coronary artery disease, but includes atherosclerotic cardiovascular disease (ASCVD), heart failure, arrhythmias—especially atrial fibrillation—ischemic cerebrovascular disease, and peripheral artery disease of the lower limbs. In addition to these forms, diabetes may also promote more direct myocardial injury, often referred to as diabetic cardiomyopathy, in which remodeling, fibrosis, and ventricular stiffness develop even in the absence of hemodynamically dominant epicardial coronary stenoses.

From an epidemiologic standpoint, the cardiovascular burden of diabetes is enormous. The risks of myocardial infarction, stroke, heart failure, atrial fibrillation, and peripheral artery disease are significantly higher than in people without diabetes, and the impact is not limited to major events but extends to subclinical progression of atherosclerosis, microvascular dysfunction, reduced coronary reserve, chronic kidney disease, and systemic frailty. In type 2 diabetes, cardiovascular disease is the leading cause of hospitalization and death; in type 1 diabetes, cardiovascular risk increases particularly with disease duration, poor metabolic control, and the presence of albuminuria, hypertension, or kidney disease. The coexistence of diabetes and cardiovascular disease therefore defines a very-high-risk population in which prognosis after a first event is also worse than in people without diabetes.

Clinically, the relationship between diabetes and the cardiovascular system is particularly insidious because injury may progress silently or with atypical symptoms for years. Myocardial ischemia may present with dyspnea or fatigue rather than typical chest pain; coronary disease is often more diffuse, multivessel, and calcific; heart failure may arise early as diastolic and congestive dysfunction before overt systolic impairment; atrial fibrillation may be intermittent and unrecognized; and peripheral artery disease may be masked by sedentary behavior, neuropathy, or other functional limitations. Cardiovascular disease in diabetes should therefore be understood as a complex systemic condition requiring aggressive primary prevention, early recognition of clinical signs, and targeted use of therapies with demonstrated cardiovascular benefit.

The underlying etiology is diabetes itself, but cardiovascular injury does not arise from a single mechanism. In type 2 diabetes, the pathophysiologic basis is dominated by insulin resistance, visceral adiposity, early hyperinsulinemia, atherogenic dyslipidemia, hypertension, and chronic low-grade inflammation. In type 1 diabetes, the causal role of chronic hyperglycemia is even more evident, but cardiovascular risk rises especially when kidney disease, hypertension, lipid abnormalities, and long disease duration coexist. In both cases, cardiovascular injury is the end product of interactions among metabolic, hemodynamic, inflammatory, coagulation, and neurohormonal factors.

One of the most important steps is endothelial dysfunction. Chronic exposure to elevated glucose reduces nitric oxide bioavailability, increases oxidative stress, alters the vascular glycocalyx, and promotes vasoconstriction, leukocyte adhesion, and endothelial permeability. In parallel, damaging metabolic pathways are activated, including excess advanced glycation end products (AGEs), activation of protein kinase C (PKC), flux through the polyol pathway, and mitochondrial overproduction of reactive oxygen species. These processes transform the vascular wall into a proinflammatory and proatherogenic environment in which the response to injury becomes self-perpetuating.

Atherosclerotic pathogenesis in diabetes is further accelerated by the characteristic diabetic dyslipidemia, consisting mainly of hypertriglyceridemia, increased triglyceride-rich lipoproteins, a predominance of small dense and more atherogenic low-density lipoproteins, and impaired high-density lipoprotein function. This profile promotes subendothelial retention of atherogenic particles, lipid oxidation, monocyte recruitment, foam-cell formation, and plaque growth. In diabetes, plaque is not only more common but tends to be more extensive and diffuse, often accompanied by substantial vascular calcification and multivessel disease. This explains why coronary artery disease in diabetes more often has complex anatomy and a worse prognosis after acute coronary syndrome or revascularization.

Alongside epicardial atherosclerosis, microvascular dysfunction makes an important contribution. Diabetes impairs vasodilation in the coronary microcirculation, disrupts coupling between metabolic demand and blood flow, and reduces coronary flow reserve. Myocardial ischemia may therefore occur even without severe coronary stenoses on angiography. This mechanism helps explain apparently paradoxical clinical presentations, such as patients with diabetes who have atypical pain, exertional dyspnea, or ischemic abnormalities on functional testing without critical coronary obstruction, or individuals with myocardial infarction whose coronary anatomy does not appear fully proportional to the severity of the clinical presentation.

Diabetes also creates a prothrombotic environment. Platelets are more reactive, coagulation activation is increased, fibrinolysis is less effective, and clots tend to have a denser structure that is more resistant to lysis. This thrombogenic state makes plaque rupture or erosion more dangerous and contributes to the greater severity of acute coronary syndromes and cerebrovascular events. The combination of more diffuse atherosclerosis and more effective thrombosis is one of the main reasons why, for the same event, a person with diabetes often has a worse prognosis than a person without diabetes.

In the myocardium, diabetes promotes abnormalities extending beyond ischemic disease. Excess free fatty acids, reduced metabolic flexibility, intracellular accumulation of toxic lipids, mitochondrial dysfunction, altered calcium homeostasis, and activation of profibrotic pathways cause hypertrophy, increased ventricular stiffness, interstitial fibrosis, and impaired relaxation. This process, known as diabetic cardiomyopathy, initially tends to manifest as diastolic dysfunction and a heart failure with preserved ejection fraction (HFpEF) phenotype. At more advanced stages, especially when ischemia, hypertension, and kidney disease coexist, systolic dysfunction may also develop with a heart failure with reduced ejection fraction (HFrEF) phenotype.

Another pathogenic mechanism is cardiovascular autonomic neuropathy. Loss of autonomic control alters resting heart rate, sinus variability, exercise tolerance, the orthostatic blood pressure response, and perception of ischemic pain. Ischemia in people with diabetes may therefore be silent or minimally symptomatic, resting tachycardia may persist, arrhythmias may develop on a less apparent substrate, and the risk of sudden death may rise. Neuropathy does not itself create plaque or heart failure, but it profoundly alters how cardiovascular injury manifests and is recognized.

Diabetes provides fertile ground for atrial fibrillation for many reasons: atrial enlargement related to hypertension and diastolic dysfunction, fibrotic infiltration, inflammation, obesity, obstructive sleep apnea, and chronic kidney disease. Likewise, peripheral artery disease and cerebrovascular disease arise from the same systemic atherosclerotic substrate, but in diabetes they are amplified by microvascular vulnerability, neuropathy, and impaired tissue repair.

The result is an integrated pathophysiology in which diabetes produces accelerated atherosclerosis, microvascular dysfunction, direct myocardial injury, increased thrombogenicity, and autonomic instability. The final consequence is a broader and more severe spectrum of cardiovascular manifestations than in the general population, with continuous progression from subclinical disease to coronary artery disease, from early heart failure to overt congestion, from silent arrhythmia to cardioembolic stroke, and from peripheral artery disease to critical limb ischemia. Cardiovascular disease in diabetes therefore cannot be reduced to a simple comorbidity: it is a structural part of the natural history of diabetes itself.

Coronary artery disease and myocardial ischemia

Heart failure and diabetic cardiomyopathy

Arrhythmias, cerebrovascular disease, and peripheral artery disease

There are no single diagnostic criteria for “cardiovascular disease” in diabetes as one entity because the term encompasses different phenotypes. The diagnostic workup must therefore be constructed narratively and rationally, beginning with clinical suspicion and risk stratification and then determining whether the patient predominantly has coronary artery disease, heart failure, an arrhythmia, cerebrovascular disease, or peripheral artery disease. Initial assessment always includes a careful cardiovascular history, blood pressure measurement, assessment of smoking, family history, duration of diabetes, microvascular complications, current treatment, hypoglycemia, body weight, lipid profile, kidney function, and albuminuria; a baseline electrocardiogram should be added when indicated by the clinical presentation or risk profile.

According to European Society of Cardiology (ESC) and American Diabetes Association (ADA) guidelines, cardiovascular assessment of a patient with diabetes requires:

• systematic evaluation for clinical ASCVD, heart failure, chronic kidney disease, atrial fibrillation, and peripheral artery disease;
• assessment of traditional risk factors and markers of target-organ damage, particularly albuminuria, estimated glomerular filtration rate, and the presence of microvascular complications;
• estimation of cardiovascular risk in individuals with type 2 diabetes without overt ASCVD or severe target-organ damage, using dedicated tools such as SCORE2-Diabetes when appropriate;
• opportunistic screening for atrial fibrillation by pulse palpation or electrocardiogram in at-risk individuals;
• targeted use of cardiac imaging, ischemia testing, and peripheral vascular assessment when symptoms, physical examination, or the risk profile warrant it;
• determination of the likely benefit from therapies with specific cardiorenal indications, independently of the glycated hemoglobin value alone.

When coronary artery disease is suspected, a resting electrocardiogram is the first test but is rarely sufficient by itself. If the patient reports suggestive symptoms, reduced functional capacity, unexplained exertional dyspnea, electrocardiographic abnormalities, or signs of ventricular dysfunction, functional stress testing or coronary computed tomography angiography is performed according to pretest probability, local availability, and patient characteristics. In diabetes, the objective is not merely to confirm ischemia but to define the extent, severity, and prognostic impact of disease because coronary artery disease is often multivessel and more diffuse. Indiscriminate screening for coronary disease in completely asymptomatic people without clinical warning signs is not the cornerstone of the modern approach; greater value lies in selective assessment guided by symptoms, function, electrocardiography, echocardiography, kidney disease, peripheral artery disease, or other clues to advanced systemic disease.

When heart failure is suspected, diagnosis is established through history, physical examination, electrocardiography, measurement of natriuretic peptides—especially B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP)—and echocardiography. Echocardiography is essential for defining ejection fraction, ventricular geometry, wall thickness, diastolic function, estimated filling pressures, atrial function, valvular disease, and signs of congestion or pulmonary hypertension. In diabetes, echocardiography has particular value because it can detect concentric remodeling, hypertrophy, and diastolic abnormalities even before overt heart failure. If diabetic cardiomyopathy remains suspected or the presentation is complex, cardiac magnetic resonance imaging can provide information on fibrosis, infiltration, and the pattern of myocardial injury.

Atrial fibrillation requires electrocardiographic documentation because the subjective sensation of palpitations alone is insufficient. Patients with intermittent symptoms undergo Holter monitoring, prolonged monitors, or longer-term recording devices when necessary. Once confirmed, assessment must extend to thyroid function, atrial size, ventricular function, valvular disease, thromboembolic risk, and bleeding profile. Atrial fibrillation is particularly important in people with diabetes because it is associated with higher risks of stroke and heart failure.

Diagnosis of peripheral artery disease begins with pulse palpation, auscultation for bruits, and assessment of exertional and resting symptoms. The first instrumental test is the ankle-brachial index, which may be falsely normal or elevated in diabetes because of medial calcification; when clinical suspicion remains high, the toe-brachial index, arterial duplex ultrasonography, and, in candidates for intervention, computed tomography angiography or magnetic resonance angiography are also used. In asymptomatic but very-high-risk patients, especially older adults or those with additional aggravating factors, selective and contextualized screening for peripheral artery disease may be considered.

Cerebrovascular disease follows the standard neurologic and vascular diagnostic pathway, with urgent neuroimaging during an acute event and subsequent etiologic evaluation through imaging of the supra-aortic trunks, cardiac rhythm monitoring, echocardiography in selected cases, and identification of the main embolic or atherothrombotic mechanisms.

In summary, cardiovascular diagnosis in diabetes is not limited to “looking for an obstructed coronary artery,” but must establish which predominant phenotype is present, how much risk remains subclinical, which target organs are already involved, and which cardiorenal therapies should be initiated promptly. Diagnostic accuracy arises precisely from this integrated perspective.

Treatment of cardiovascular disease in diabetes is now necessarily multifactorial. Lowering blood glucose is not enough: blood pressure, lipid profile, body weight, sedentary behavior, smoking, albuminuria, thrombotic risk, and choice of glucose-lowering medication must all be addressed simultaneously. This paradigm shift is one of the most important developments in modern diabetology because some glucose-lowering drugs have demonstrated cardiovascular and cardiorenal benefits independent of glucose reduction alone.

The foundation of treatment remains comprehensive cardiovascular prevention. Smoking cessation, reduction of excess weight, a high-quality Mediterranean-style diet, progressive increases in physical activity, and correction of sedentary behavior have broad effects on blood pressure, inflammation, insulin sensitivity, lipids, hepatic steatosis, and endothelial function. Arterial hypertension should be treated to individualized but generally intensive targets when well tolerated, with preference in many patients for agents blocking the renin-angiotensin system when albuminuria, kidney disease, or heart disease is present. Statin therapy is a cornerstone of lipid lowering: in patients with ASCVD or very high risk, treatment intensity should be maximal or near maximal, with addition of ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors when low-density lipoprotein cholesterol remains above recommended targets.

In antithrombotic prevention, low-dose aspirin has an established role in secondary prevention, meaning in patients with documented atherosclerotic disease, whereas in primary prevention the balance between ischemic benefit and bleeding risk requires more careful selection. After acute coronary syndrome or percutaneous coronary intervention, patients with diabetes follow cardiology principles for dual antiplatelet therapy, with particular attention to their high ischemic risk but also their bleeding vulnerability, often accentuated by advanced age and chronic kidney disease.

Glucose-lowering management should be guided by the cardiovascular phenotype. In type 2 diabetes with established ASCVD, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) with proven benefit have become central components of therapy, regardless of whether the patient is already at the glycemic target. GLP-1 RAs have demonstrated reductions in atherothrombotic events, especially myocardial infarction and stroke in appropriate settings, while SGLT2is have shown particularly robust protection against heart failure and across the cardiorenal axis. Drug selection can therefore no longer be based solely on glycated hemoglobin, weight, or hypoglycemia risk, but must begin with the clinical question: does the patient have atherosclerosis, heart failure, kidney disease, or a combination of these conditions?

In heart failure, SGLT2is have assumed a broad role because they reduce heart failure hospitalizations across a wide spectrum of ejection fractions, including preserved and mildly reduced phenotypes. In patients with HFrEF, they are integrated into standard heart failure therapy together with renin-angiotensin system blockers or angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists when indicated. In patients with diabetes and albuminuric chronic kidney disease, finerenone, a nonsteroidal mineralocorticoid receptor antagonist, adds another level of cardiovascular and renal protection. Pioglitazone, by contrast, is contraindicated in patients with current or prior heart failure because of the risk of fluid retention and worsening congestion.

In patients with chronic coronary artery disease or acute coronary syndrome, treatment follows standard cardiology principles, but diabetes influences both pharmacologic choice and the revascularization strategy. In complex multivessel disease, coronary artery bypass grafting often retains a prognostic advantage over percutaneous revascularization in selected patients, especially when anatomy is diffuse and the atherosclerotic burden is high. The decision must nevertheless be individualized by a heart team, taking into account coronary anatomy, frailty, ventricular function, renal comorbidities, and expected treatment adherence.

In atrial fibrillation, treatment includes rate or rhythm control according to the clinical presentation, correction of precipitating factors, and anticoagulation in patients with an indication because diabetes contributes to thromboembolic risk. Prevention of cerebrovascular events requires aggressive treatment of blood pressure, lipids, smoking, atrial fibrillation, and carotid or intracranial atherosclerosis. In peripheral artery disease, smoking cessation, structured walking, high-intensity statin therapy, antithrombotic treatment when indicated, and revascularization for disabling symptoms or critical ischemia are fundamental.

Prognosis depends on the combination of cardiovascular phenotypes, the presence of kidney disease, how rapidly appropriate cardiorenal therapies are instituted, and the quality of multifactorial control over time. A patient with diabetes, albuminuria, heart failure, and multivessel coronary disease has a markedly worse prognostic trajectory than a person with recently diagnosed diabetes and no target-organ damage. Prognosis is not immutable, however: early intensive correction of risk factors together with use of drugs with proven cardiovascular benefit has substantially altered the natural history of this condition. The decisive point is to intervene before damage becomes irreversible and, once cardiovascular disease has developed, to treat it through an integrated rather than fragmented cardiometabolic approach.

The most immediate complication of cardiovascular disease in diabetes is the greater likelihood of major atherothrombotic events. Diabetic coronary artery disease is more often multivessel, calcific, and diffuse; consequently, myocardial infarction, reinfarction, residual ischemia, and cardiovascular death tend to be more frequent and severe. Even after revascularization, people with diabetes retain a high residual risk related to disease progression, thrombosis, restenosis, persistent inflammation, and involvement of other target organs.

Heart failure is a central and independent complication. It may be the final consequence of repeated myocardial infarctions, but it may also develop progressively on a metabolic, fibrotic, and microvascular basis. Once established, it tends to interact adversely with kidney function, anemia, autonomic neuropathy, and frailty. Rehospitalizations for congestion are common and have a major prognostic impact.

Arrhythmias, especially atrial fibrillation and ventricular tachyarrhythmias in patients with ischemic scars or structurally abnormal myocardium, are another important complication. Atrial fibrillation increases the risk of ischemic stroke and worsens heart failure; ventricular arrhythmias and sudden death are promoted by ischemia, myocardial fibrosis, autonomic neuropathy, and electrolyte disturbances, which are more common in patients with kidney disease or receiving diuretic therapy.

Ischemic stroke and recurrent cerebrovascular events are particularly serious complications because they combine neurologic disability, loss of independence, and worsening metabolic control. Functional recovery may be more difficult in people with diabetes because microangiopathy, neuropathy, sarcopenia, and chronic kidney disease often coexist.

Peripheral artery disease may progress to chronic limb-threatening ischemia, ischemic ulcers, infection, and amputation. Even when the local presentation appears peripheral, its prognostic significance is systemic: peripheral arterial disease identifies a patient with diffuse atherosclerosis and a very high risk of myocardial infarction, stroke, and death.

A major cross-cutting complication is cardiorenal syndrome. Diabetes simultaneously promotes renal and cardiovascular injury; when the two conditions coexist, they perpetuate one another through sodium and water retention, neurohormonal activation, inflammation, anemia, oxidative stress, and progressively fewer therapeutic options. Chronic kidney disease worsens outcomes of coronary artery disease, heart failure, peripheral artery disease, and atrial fibrillation, while also increasing bleeding risk and procedural complications.

Finally, cardiovascular disease in diabetes causes broad functional and prognostic consequences: reduced ability to work, poorer quality of life, depression, vascular cognitive decline, limited physical activity, repeated hospitalizations, and a marked increase in all-cause mortality. In many patients, cardiovascular injury is therefore not a single complication but the main determinant of the overall clinical trajectory of diabetes.