Glucose-lowering Therapy in Patients with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease (ASCVD)

The image you provided relates to the management of cardiovascular disease in patients with type 2 diabetes mellitus (T2DM) with various cardiovascular complications such as atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD). Here's a summary of the key points in this management approach:

1. Assessment of Cardiovascular Risk:
   • Patients with T2DM are at high risk for cardiovascular disease (CVD), and the presence of atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) should guide the therapeutic choices.
2. Use of GLP-1 Receptor Agonists (GLP-1 RA):
   • GLP-1 RAs with proven cardiovascular benefits (e.g., liraglutide, semaglutide s.c., dulaglutide, and efpeglenatide) are recommended for patients with T2DM and ASCVD.
   • These agents lower glucose levels and have demonstrated cardiovascular benefits.
3. SGLT2 Inhibitors (SGLT2i):
   • SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, sotagliflozin) are recommended for patients with T2DM and ASCVD, heart failure, or chronic kidney disease.
   • These drugs not only lower blood sugar but also have benefits in reducing heart failure exacerbations and slowing the progression of CKD.
4. Heart Failure Management:
   • In patients with heart failure and reduced ejection fraction (HFrEF), SGLT2 inhibitors such as empagliflozin, dapagliflozin, and sotagliflozin are used.
   • For patients with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF), empagliflozin and dapagliflozin are also beneficial.
   • These agents have proven benefits in improving heart failure outcomes beyond glucose control.
5. Chronic Kidney Disease (CKD) Management:
   • SGLT2 inhibitors are particularly beneficial in patients with T2DM and CKD. These agents slow down the progression of renal disease.
   • Empagliflozin, dapagliflozin, and canagliflozin have shown benefits in patients with CKD, with some agents demonstrating cardiovascular and renal protection.
6. Combination Therapy:
   • For comprehensive cardiovascular protection, a combination of GLP-1 RA and SGLT2 inhibitors may be used depending on individual patient profiles, including the presence of heart failure or CKD.
7. Subcutaneous Administration (s.c.):
   • Some agents like semaglutide and liraglutide are administered subcutaneously, making it important to guide patients on correct administration techniques.
8. Overall Approach:
   • The management of T2DM in patients with CVD should focus not only on glucose control but also on the cardiovascular and renal benefits provided by certain classes of medications.
   • Treatment choices should be based on the patient's cardiovascular profile (ASCVD, heart failure, CKD), with an emphasis on agents that have proven benefits in these areas.

By integrating these therapies, the clinical management aims to reduce the risk of cardiovascular events, improve heart failure outcomes, and slow the progression of CKD, while managing blood sugar effectively.

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presents a guide for choosing glucose-lowering therapies in patients with type 2 diabetes mellitus (T2DM) based on cardiovascular risk, which is assessed by the presence of atherosclerotic cardiovascular disease (ASCVD), severe target-organ damage (TOD), and the 10-year cardiovascular disease (CVD) risk estimation using the SCORE2-Diabetes risk calculator.

1. Risk Categories:

The figure categorizes patients into different risk levels based on the presence of ASCVD, severe TOD, and their 10-year CVD risk. The categories are:

• Very High Risk: Presence of ASCVD (Class I recommendation).
• High Risk: No ASCVD or severe TOD, but 10-year CVD risk (SCORE2-Diabetes) is ≥10%.
• Moderate Risk: No ASCVD or severe TOD, and 10-year CVD risk (SCORE2-Diabetes) is <10%.
• Low Risk: No ASCVD or severe TOD.

2. Treatment Recommendations:

The image suggests glucose-lowering therapies based on the risk assessment:

• For Very High-Risk Patients (ASCVD):The Class I recommendations include:
  • GLP-1 RA (with proven cardiovascular benefits), such as liraglutide, semaglutide, dulaglutide, and efpeglenatide.
  • SGLT2 inhibitors (with proven cardiovascular benefits), such as empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin.
• For High-Risk Patients (No ASCVD but high CVD risk ≥10%): The Class IIb recommendation includes:
  • Metformin, along with SGLT2 inhibitors or GLP-1 RA. These are recommended to reduce cardiovascular risk and manage glucose levels.
• For Moderate Risk Patients (No ASCVD, lower CVD risk <10%): The Class IIa recommendation includes:
  • Metformin, which is usually the first-line therapy for glucose control in T2DM.

3. Definition of Severe Target-Organ Damage (TOD):

Severe TOD is defined as:

• Atherosclerotic Cardiovascular Disease (ASCVD):
  • This includes conditions like myocardial infarction (heart attack), stroke, or peripheral arterial disease.
• Severe Target Organ Damage (TOD):
  • This refers to significant damage caused by hypertension or diabetes to vital organs such as the heart, kidneys, eyes, or brain. Examples of severe TOD include:
    • Left Ventricular Hypertrophy (LVH) (thickening of the heart muscle)
    • Chronic Kidney Disease (CKD) with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m²
      • An estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m², regardless of albuminuria.
      • eGFR between 45–59 mL/min/1.73 m² with microalbuminuria (UACR 30–300 mg/g, stage A2).
      • Proteinuria (UACR >300 mg/g, stage A3).
    • Diabetic retinopathy (damage to the eyes due to diabetes)
    • Presence of microvascular disease in at least three sites (e.g., microalbuminuria with retinopathy and neuropathy).

4. Use of SCORE2-Diabetes:

• SCORE2-Diabetes is used to estimate the 10-year cardiovascular risk in patients with diabetes, helping to further categorize patients into high or moderate risk when ASCVD or TOD is absent.
  • Very High Risk (≥20%):
    • Patients in this category require intensive management. This often includes:
      • Statins to lower cholesterol.
      • Antihypertensives to control blood pressure.
      • Aspirin or other antiplatelet agents may be used for secondary prevention.
      • Optimizing glycemic control in diabetes.
    • Lifestyle changes such as smoking cessation, diet, and exercise are also critical.
  • High Risk (10% to <20%):
    • Similar management strategies apply here, focusing on blood pressure, lipid management, and glycemic control.
    • Patients may also need statins and antihypertensives, and should be encouraged to engage in lifestyle interventions.
  • Moderate Risk (5% to <10%):
    • Emphasis is placed on lifestyle changes (smoking cessation, healthy diet, regular physical activity).
    • Medical management may be considered depending on other risk factors, such as borderline blood pressure or cholesterol.
  • Low Risk (<5%):
    • These patients typically require preventive counseling rather than aggressive medical treatment.
    • Lifestyle modifications are encouraged to maintain a low risk.

Risk Factors for the SCORE2-Diabetes calculation:

1. Sex (Male or Female)
2. Age (in years)
3. Smoking status (Current smoker or not)
4. Systolic Blood Pressure (SBP) (in mm Hg)
   • Normal range: 100 - 120 mm Hg
5. Total Cholesterol (in mg/dL)
   • Normal range: 150 - 200 mg/dL
6. HDL Cholesterol (in mg/dL)
   • Normal range: 0 - 60 mg/dL
7. Risk Region (based on population risk data)
   • Categories: Low, Moderate, High, Very High

Summary of Therapy Classes:

• GLP-1 RA: Glucagon-like peptide-1 receptor agonists with cardiovascular benefits.
• SGLT2 inhibitors: Sodium-glucose co-transporter-2 inhibitors, which have shown benefits in reducing cardiovascular outcomes and protecting kidney function.
• Metformin: First-line therapy for most patients with T2DM, especially in those with lower cardiovascular risk.

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Introduction:

Patients with type 2 diabetes mellitus (T2DM) are at a significantly higher risk for developing atherosclerotic cardiovascular disease (ASCVD), which is one of the leading causes of morbidity and mortality in this population. The interplay between hyperglycemia, insulin resistance, and vascular inflammation accelerates the development of ASCVD, making it crucial to adopt a treatment approach that addresses both glucose control and cardiovascular risk reduction.

For Clinicians, understanding the pharmacological management of T2DM in patients with ASCVD is essential, as the approach goes beyond simply controlling blood sugar levels. Certain glucose-lowering agents have proven cardiovascular (CV) benefits and should be prioritized in this patient group. This article provides a comprehensive review of these agents, with practical insights for clinical decision-making.

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1. Cardiovascular Risk in T2DM:

T2DM is a major risk factor for ASCVD, increasing the risk of myocardial infarction, stroke, and cardiovascular death. The presence of chronic hyperglycemia, insulin resistance, and endothelial dysfunction accelerates atherosclerosis in these patients. In patients with both T2DM and ASCVD, therapeutic strategies should prioritize reducing cardiovascular events, as managing glucose alone does not sufficiently address the increased CV risk.

Key points to consider:

• Hyperglycemia's Role in ASCVD: Persistent hyperglycemia contributes to endothelial dysfunction, vascular inflammation, and lipid abnormalities, all of which accelerate atherosclerosis.
• Increased Mortality: Patients with T2DM and ASCVD face higher rates of cardiovascular events and mortality compared to non-diabetic individuals.

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2. Glucose-Lowering Agents with Proven Cardiovascular Benefits:

In recent years, clinical trials have demonstrated the cardiovascular benefits of certain glucose-lowering drugs, leading to a shift in treatment guidelines. Two key classes of medications—GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors—have emerged as first-line agents for patients with T2DM and ASCVD due to their ability to reduce major adverse cardiovascular events (MACE).

a) GLP-1 Receptor Agonists (GLP-1 RA):

GLP-1 RAs work by enhancing glucose-dependent insulin secretion and suppressing glucagon release, but their benefits extend beyond glucose control. Clinical trials such as the LEADER, SUSTAIN-6, and REWIND studies have shown that certain GLP-1 RAs significantly reduce MACE in patients with T2DM and ASCVD.

Examples of GLP-1 RAs with proven cardiovascular benefits:

• Liraglutide (LEADER trial)
• Semaglutide (SUSTAIN-6 trial)
• Dulaglutide (REWIND trial)
• Efpeglenatide

Mechanisms of cardiovascular benefit:

• Anti-inflammatory effects: GLP-1 RAs reduce vascular inflammation, contributing to improved endothelial function.
• Weight reduction: These agents promote weight loss, which lowers blood pressure and improves lipid profiles.
• Improved endothelial function: They enhance nitric oxide production, improving vascular reactivity and reducing atherosclerosis progression.

Clinical application:

• Use in patients with ASCVD: GLP-1 RAs should be considered in all patients with T2DM and established ASCVD to reduce the risk of cardiovascular events, independent of glucose control (Class I recommendation).
• Independent of HbA1c: Their use is recommended even if glucose control is not the primary concern.

b) SGLT2 Inhibitors:

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce blood glucose levels by promoting glucose excretion through the kidneys. However, their cardiovascular benefits, particularly in reducing heart failure hospitalizations and renal outcomes, have made them a crucial part of the management strategy for T2DM with ASCVD.

Examples of SGLT2 inhibitors with proven cardiovascular benefits:

• Empagliflozin (EMPA-REG OUTCOME trial)
• Canagliflozin (CANVAS trial)
• Dapagliflozin (DECLARE-TIMI 58 trial)
• Sotagliflozin

Mechanisms of cardiovascular benefit:

• Heart failure prevention: SGLT2 inhibitors reduce heart failure hospitalizations by promoting diuresis, reducing intravascular volume, and improving cardiac function.
• Renal protection: These agents slow the progression of diabetic kidney disease, another key factor in ASCVD.
• Blood pressure reduction: SGLT2 inhibitors reduce systolic blood pressure, contributing to their cardiovascular protective effects.

Clinical application:

• Use in patients with heart failure or renal disease: In patients with T2DM and heart failure or chronic kidney disease (CKD), SGLT2 inhibitors should be considered to reduce the risk of hospitalization and slow CKD progression (Class I recommendation).

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3. Additional Glucose-Lowering Agents for Glucose Control:

If further glucose control is required after initiating GLP-1 RAs or SGLT2 inhibitors, the following agents can be considered:

a) Metformin:

Metformin remains the first-line agent for glucose control in T2DM, with some evidence supporting its cardiovascular safety. In patients with T2DM and ASCVD, metformin can be added to the regimen if additional glucose control is needed, though it may not provide additional cardiovascular benefits.

Clinical application:

• Class IIa recommendation: Use metformin if additional glucose control is necessary, particularly if HbA1c remains above target despite GLP-1 RA or SGLT2 inhibitor therapy.

b) Pioglitazone:

Pioglitazone, a thiazolidinedione (TZD), can be used as an adjunct for glucose control but must be used cautiously in patients with ASCVD due to its potential to cause fluid retention and exacerbate heart failure.

Clinical application:

• Class IIb recommendation: Pioglitazone may be considered for glucose control in T2DM patients, but it should be avoided in those with heart failure. Careful monitoring is required in patients with CKD.

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4. Agents with Cardiovascular Safety but Limited Benefits:

Some glucose-lowering agents have been evaluated for cardiovascular safety, but they do not provide the same cardiovascular benefits as GLP-1 RAs or SGLT2 inhibitors.

a) DPP-4 Inhibitors:

Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, alogliptin, and linagliptin, have a neutral effect on cardiovascular outcomes. While they are safe to use in patients with ASCVD, they do not reduce the risk of MACE and should not be combined with GLP-1 RAs.

Clinical application:

• Safe for use: DPP-4 inhibitors are a viable option when glucose control is needed, but GLP-1 RAs should not be used concurrently.

b) Sulfonylureas and Insulins:

Sulfonylureas (e.g., glimepiride) and long-acting insulins (e.g., insulin glargine, insulin degludec) have been shown to have cardiovascular safety, but they do not provide additional CV benefits.

Clinical application:

• Second-line therapies: These agents can be used if other options are insufficient for glucose control, but their role in cardiovascular protection is limited.

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5. Agents Without Cardiovascular Safety Evaluation:

Some agents, such as short-acting insulins and older sulfonylureas, have not undergone comprehensive cardiovascular safety evaluations. These agents should be used cautiously and only when necessary for glucose control.

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Conclusion:

For patients with T2DM and ASCVD, the therapeutic focus should be on reducing cardiovascular risk as the primary goal, independent of glucose control. GLP-1 RAs and SGLT2 inhibitors have emerged as first-line therapies due to their proven cardiovascular benefits. When additional glucose control is needed, metformin or other agents can be added cautiously. Clinicians must be well-versed in these therapies, their mechanisms, and their clinical application to provide comprehensive, evidence-based care for this high-risk patient population.

Key Takeaways:

• Prioritize GLP-1 RAs and SGLT2 inhibitors in patients with T2DM and ASCVD.
• Consider additional agents like metformin or pioglitazone for glucose control, but with caution.
• Recognize the cardiovascular safety of DPP-4 inhibitors and insulins, but understand their limitations in reducing cardiovascular events.
• Focus on cardiovascular outcomes over strict glucose control in this patient group.

By following this guideline, Clinician can optimize the care of patients with T2DM and ASCVD, improving both cardiovascular outcomes and overall patient health.