What is the first-line treatment for reducing the risk of atherosclerotic cardiovascular disease in patients with Diabetes Mellitus?

First-Line Treatment for Reducing ASCVD Risk in Diabetes Mellitus

For patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD), multiple ASCVD risk factors, or chronic kidney disease, initiate an SGLT2 inhibitor with demonstrated cardiovascular benefit alongside high-intensity statin therapy to reduce major adverse cardiovascular events, independent of glycemic control needs. 1

Primary Pharmacologic Strategy

SGLT2 Inhibitors or GLP-1 Receptor Agonists (First Priority)

• In patients with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, an SGLT2 inhibitor with demonstrated cardiovascular benefit is recommended as first-line therapy to reduce the risk of major adverse cardiovascular events and heart failure hospitalization. 1
• For patients with type 2 diabetes and established ASCVD or multiple risk factors, a GLP-1 receptor agonist with demonstrated cardiovascular benefit is recommended to reduce the risk of major adverse cardiovascular events. 1
• Combined therapy with both an SGLT2 inhibitor and a GLP-1 receptor agonist may be considered for additive reduction of cardiovascular and kidney events. 1

Specific agents with proven MACE reduction include:

• SGLT2 inhibitors: empagliflozin, canagliflozin, and dapagliflozin 2
• GLP-1 receptor agonists: dulaglutide, liraglutide, and injectable semaglutide 2

High-Intensity Statin Therapy (Concurrent First-Line)

• All patients with diabetes ages 40-75 years without established ASCVD should receive moderate or high-intensity statin therapy. 1
• For patients with diabetes and established ASCVD (secondary prevention), use high-intensity statin therapy to reduce LDL cholesterol by ≥50% from baseline to a goal of <55 mg/dL (<1.4 mmol/L). 1
• High-intensity statin therapy reduces MACE by approximately 15% compared to moderate-intensity statins. 2

Algorithmic Approach Based on Patient Characteristics

Patients WITH Established ASCVD:

1. Start high-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) targeting LDL-C <55 mg/dL 1
2. Add SGLT2 inhibitor with proven cardiovascular benefit 1
3. Add GLP-1 receptor agonist with proven cardiovascular benefit 1
4. If LDL-C goals not met on maximum tolerated statin, add ezetimibe or PCSK9 inhibitor 1

Patients WITHOUT Established ASCVD but WITH Multiple Risk Factors:

1. Start moderate to high-intensity statin based on age and risk factors 1
2. Add SGLT2 inhibitor if chronic kidney disease with albuminuria or high cardiovascular risk 1
3. Consider GLP-1 receptor agonist if additional ASCVD risk factors present 1

Patients WITH Chronic Kidney Disease:

1. SGLT2 inhibitor should be initiated when eGFR ≥20 mL/min/1.73 m² and continued until dialysis or transplantation 1
2. For patients with CKD and albuminuria on maximum tolerated ACE inhibitor or ARB, add nonsteroidal mineralocorticoid receptor antagonist 1
3. Continue SGLT2 inhibitor even if eGFR falls below 20 mL/min/1.73 m² until kidney replacement therapy is initiated 1

Role of Metformin

• Metformin is recommended as first-line pharmacologic therapy for newly diagnosed type 2 diabetes combined with lifestyle modification, specifically for glycemic control. 3
• However, metformin does NOT reduce ASCVD risk—SGLT2 inhibitors and GLP-1 receptor agonists are the first-line agents for cardiovascular risk reduction. 1, 2
• Metformin should be considered in overweight patients without established cardiovascular disease and at moderate cardiovascular risk. 3

Additional Cardiovascular Risk Reduction Strategies

Blood Pressure Control:

• Target blood pressure <130/80 mmHg in all patients with diabetes. 2
• Initiate ACE inhibitors or ARBs as first-line therapy in patients with hypertension and established ASCVD, which reduced MI, stroke, or vascular death by 25%. 2
• In individuals with diabetes aged ≥55 years with additional cardiovascular risk factors, ACE inhibitor or ARB therapy is recommended to reduce cardiovascular events and mortality. 1

Antiplatelet Therapy:

• Aspirin 75-100 mg daily for all patients with established atherosclerotic disease to reduce MACE. 2
• Aspirin is NOT recommended for primary prevention in diabetes without established ASCVD due to unfavorable risk/benefit ratio. 1
• Clopidogrel 75 mg daily is an alternative for aspirin-intolerant patients. 2

Critical Pitfalls to Avoid

• Do not rely solely on glycemic control to reduce ASCVD risk—intensive glucose control has not demonstrated consistent cardiovascular outcome benefits in major trials. 1
• Do not delay initiation of SGLT2 inhibitors or GLP-1 receptor agonists until glycemic targets are unmet—these agents provide cardiovascular benefit independent of glucose-lowering effects. 1, 4
• Do not use aspirin for primary prevention in diabetes without established ASCVD—bleeding risk outweighs benefit. 1
• Do not discontinue SGLT2 inhibitors when eGFR falls below initial prescribing thresholds—continue as tolerated until dialysis initiation. 1
• Avoid de-escalating high-intensity statin therapy in patients tolerating treatment, even if very low LDL-C levels are achieved. 2

Monitoring Requirements

• Reassess lipid levels 4-12 weeks after initiating or adjusting lipid therapy, targeting LDL-C <70 mg/dL (ideally <55 mg/dL in very high-risk patients). 2
• Monitor eGFR at least annually in patients with normal renal function and every 3-6 months when eGFR <60 mL/min/1.73 m². 3
• Assess cardiovascular risk factors every 3-6 months. 1