Pathophysiology
I-11. Macrovascular complications of diabetes mellitus
糖尿病の大血管合併症
Significance
- Macrovascular complications are the major cause of death in diabetes.
- CVD prevalence is 3× higher than in non-diabetics, and ~80% of diabetic patients die from macrovascular complications, with worse outcomes.
- Types: heart disease (IHD, MI), cerebrovascular disease (stroke, TIA), peripheral/lower-extremity arterial disease.
Atherosclerosis — Plaque Formation
- Initial lesion → intimal thickening (isolated foam cells, SMC migration).
- Fatty streak → intracellular lipid (confluent foam cells).
- Intermediate lesion (pre-atheroma) → intra- + extracellular lipid.
- Atheroma → extracellular lipid core.
- Fibroatheroma → multiple lipid cores + fibrotic layers (calcification).
- Complicated lesion → surface defect, hemorrhage, thrombosis.
Risk factors for AS
- Hypercholesterolemia: ↑macrophage lipid uptake (cholesterol-rich small lipoproteins), low HDL disrupts reverse cholesterol transport, and wall thickening blocks efflux.
- Hypertension: ↑shear stress → intimal thickening, ↑cholesterol export blocks reverse transport, ↑surface-injury risk.
- Smoking: oxidizes lipids/lipoproteins (ox-LDL), oxidative stress consumes NO + inflames vessel wall, and ↑thrombosis (↑clotting factors, platelet aggregation).
- These potentiate each other.
Residual Risk
Diabetics have higher CV mortality even with equal treatment — explained by accelerated atherosclerosis due to:
- Atherogenic dyslipidemia
- Platelet hyperreactivity
- Hyperglycemia-induced endothelial injury
- Autonomic neuropathy
These add to classic risk factors, speeding CVD progression and worsening prognosis.
Atherogenic Dyslipidemia
- Driven by insulin resistance/deficiency and worsened by CKD. Raises chronic + acute coronary syndrome risk.
- Main abnormalities: ↑triglycerides, ↓HDL (blocked reverse transport), ↑small-dense LDL (sdLDL → ↑cholesterol export to tissue).
- ⇒ Vulnerable plaques (thin cap, large lipid-rich necrotic core, intra-plaque hemorrhage, inflammation) rupture easily → thrombosis → acute coronary syndromes.
Platelet Hyperreactivity
Worsens prognosis of ACS and stroke. Present already in prediabetes. Due to changes in:
- Coagulation cascade: ↑PAI (↓plasmin → slowed fibrinolysis, prolonged platelet activation) and ↑fibrinogen (↑aggregation/plug formation).
- Endothelial function: ↓anticoagulant/anti-platelet factors — ↓heparan sulfate, ↓thrombomodulin, ↑tissue factor, ↓NO, ↓prostacyclin.
- Intrinsic platelet function: ↑thromboxane, ↓response to prostacyclin/NO, hyperreactive to ADP.
Management & Treatment
- CV risk is a major problem — glycemic control alone is insufficient, so risk factors need more aggressive control (lower lipid targets, consider antiplatelet therapy).
- Lipid-lowering: statins (HMG-CoA reductase), ezetimibe (cholesterol absorption), PCSK9 inhibitors.
- Antiplatelet: aspirin (COX/thromboxane), P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor), GP IIb/IIIa inhibitors (abciximab, tirofiban).
一問一答
▶How much higher is cardiovascular disease prevalence in diabetics versus non-diabetics?
About 3 times higher.
▶Why are macrovascular complications so significant in diabetes?
They are the major cause of death — about 80% of diabetic patients die from macrovascular complications, and outcomes are worse than in non-diabetics.
▶What are the three types of diabetic macrovascular complications?
Heart disease (IHD, MI), cerebrovascular disease (stroke, TIA), and peripheral/lower-extremity arterial disease.
▶What is the sequence of atherosclerotic plaque formation?
Initial lesion → fatty streak → intermediate lesion (pre-atheroma) → atheroma → fibroatheroma → complicated lesion.
▶What characterizes a complicated atherosclerotic lesion?
A surface defect, hemorrhage, and thrombosis.
▶How does hypercholesterolemia promote atherosclerosis?
It increases macrophage lipid uptake (cholesterol-rich small lipoproteins); low HDL disrupts reverse cholesterol transport; and wall thickening blocks cholesterol efflux.
▶How does smoking promote atherosclerosis?
It oxidizes lipids/lipoproteins (ox-LDL), causes oxidative stress that consumes NO and inflames the vessel wall, and increases thrombosis (more clotting factors and platelet aggregation).
▶What is "residual risk" in diabetic macrovascular disease?
Diabetics have higher cardiovascular mortality even with equal treatment, explained by accelerated atherosclerosis.
▶What are the three lipid abnormalities of diabetic atherogenic dyslipidemia?
Increased triglycerides, decreased HDL, and increased small-dense LDL (sdLDL).
▶What four factors accelerate atherosclerosis in diabetes?
Atherogenic dyslipidemia, platelet hyperreactivity, hyperglycemia-induced endothelial injury, and autonomic neuropathy.
▶What features make an atherosclerotic plaque "vulnerable"?
A thin fibrous cap, a large lipid-rich necrotic core, intra-plaque hemorrhage, and inflammation — these rupture easily → thrombosis → acute coronary syndromes.
▶What endothelial changes promote platelet hyperreactivity in diabetes?
Reduced anticoagulant/anti-platelet factors: ↓heparan sulfate, ↓thrombomodulin, ↑tissue factor, ↓NO, and ↓prostacyclin.
▶What intrinsic platelet changes occur in diabetes?
Increased thromboxane production, decreased response to prostacyclin/NO, and hyperreactivity to ADP.
▶What coagulation-cascade changes contribute to platelet hyperreactivity in diabetes?
Increased PAI (reduced plasmin → slowed fibrinolysis, prolonged platelet activation) and increased fibrinogen (greater aggregation/plug formation).
▶At what stage does platelet hyperreactivity already appear in diabetes?
It is present already in prediabetes.
▶What are the main lipid-lowering drug classes and their targets?
Statins (HMG-CoA reductase), ezetimibe (cholesterol absorption), and PCSK9 inhibitors.
▶What are the main antiplatelet drug classes and examples?
Aspirin (COX/thromboxane), P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor), and GP IIb/IIIa inhibitors (abciximab, tirofiban).
▶Why is glycemic control alone insufficient for managing diabetic macrovascular risk?
Cardiovascular risk requires more aggressive control of risk factors — e.g., lower lipid targets and consideration of antiplatelet therapy — beyond glucose lowering.
▶Why is small-dense LDL (sdLDL) particularly atherogenic?
sdLDL exports more cholesterol into the tissue/vessel wall, accelerating atherosclerosis.
▶What drives atherogenic dyslipidemia in diabetes, and what worsens it?
It is driven by insulin resistance/deficiency and is worsened by chronic kidney disease, raising both chronic and acute coronary syndrome risk.