What are the recommendations for using SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors or GLP-1 (Glucagon-Like Peptide-1) receptor agonists in a patient with type 2 diabetes, particularly those with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease?

SGLT2 Inhibitors and GLP-1 Receptor Agonists in Type 2 Diabetes: Comprehensive Clinical Guide

When to Use Each Drug Class

For patients with type 2 diabetes and established atherosclerotic cardiovascular disease (prior MI, stroke, or revascularization), GLP-1 receptor agonists provide the strongest evidence for reducing major adverse cardiovascular events (MACE), while SGLT2 inhibitors are the preferred choice for patients with heart failure with reduced ejection fraction or chronic kidney disease. 1

Primary Indication Algorithm

Choose GLP-1 Receptor Agonists when:

• Established atherosclerotic cardiovascular disease is the dominant problem (prior MI, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or coronary/carotid/peripheral revascularization) 1
• High cardiovascular risk without established disease: age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria 1
• Obesity (BMI >35 kg/m²) where weight loss is a priority 2
• Metabolic dysfunction-associated steatotic liver disease (MASLD) 2

Choose SGLT2 Inhibitors when:

• Heart failure with reduced ejection fraction (EF <45%) is present, regardless of baseline glucose control 1, 2
• Chronic kidney disease with eGFR 30-60 mL/min/1.73 m² or urinary albumin-to-creatinine ratio >30 mg/g (particularly >300 mg/g) 1, 2
• Heart failure predominates over atherosclerotic disease 3
• CKD progression prevention is the primary goal 1

Use Both Agents when:

• Both established atherosclerotic cardiovascular disease AND chronic kidney disease are present 1, 4
• High-risk patients with multiple comorbidities benefit from combination therapy 2, 5
• The cardiovascular and kidney benefits are additive and consistent regardless of concurrent use 5

---

GLP-1 Receptor Agonist Specifics

Agent Selection and Efficacy

Use semaglutide, liraglutide, or dulaglutide exclusively—these are the only GLP-1 receptor agonists with proven MACE reduction. 3

• Semaglutide provides the greatest weight loss (superior to liraglutide and dulaglutide) and has the strongest MACE data 3, 2
• All three agents reduce MACE by 12-26% 3
• HbA1c reduction: 0.8-1.5% 3
• Weight loss: 1.5-3.5 kg (2-4 kg in most studies, higher in non-diabetic patients) 3
• Low hypoglycemia risk when used alone due to glucose-dependent mechanism 3

Cardiovascular and Metabolic Benefits

• Reduce major adverse cardiovascular events (MACE) by 14% (HR 0.86,95% CI 0.80-0.93) 3
• Reduce cardiovascular death 3
• Improve lipid profiles: decrease triglycerides and increase HDL cholesterol 3
• The cardioprotective effects are mediated through multiple mechanisms including improved lipid profiles 3

Dosing and Titration

Start at the lowest dose and titrate slowly over several weeks to minimize gastrointestinal side effects. 3, 2

• Liraglutide and dulaglutide require similar gradual titration 3
• When baseline glucose is well-controlled, reduce sulfonylurea dose by 50% or basal insulin by 20% before starting 2
• Discontinue DPP-4 inhibitors before initiating GLP-1 receptor agonists 2

Side Effects and Management

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur in 15-20% of patients 3
• These symptoms are typically transient, dose-dependent, and occur mainly during initial treatment 3
• Slow titration improves tolerability 3

Special Populations and Precautions

Chronic Kidney Disease:

• GLP-1 receptor agonists retain glucose-lowering efficacy even with eGFR as low as 15 mL/min/1.73 m², including dialysis patients 3
• Hypoglycemia rates are reduced by half even with concurrent insulin therapy in moderate-to-severe CKD 3
• Preferred when SGLT2 inhibitors are contraindicated or not tolerated 2

Heart Failure:

• Exercise caution in heart failure with reduced ejection fraction (HFrEF), particularly with recent decompensation 3
• Small trials showed no benefit and numerically increased risk of death and heart failure hospitalization with liraglutide in patients with recent decompensation 3
• If heart failure predominates, SGLT2 inhibitors are preferred 3

Contraindications:

• History of medullary thyroid cancer 6, 2
• Use with caution in patients with history of pancreatitis of known cause 6, 2
• Use with caution in gastroparesis 2

---

SGLT2 Inhibitor Specifics

Indications and Efficacy

SGLT2 inhibitors reduce hospitalization for heart failure, cardiovascular death, and progression of chronic kidney disease independent of glucose-lowering effects. 1, 7, 8

• Reduce sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression 7
• Reduce cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure 7
• Reduce hospitalization for heart failure in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors 7
• Reduce cardiovascular and all-cause mortality 6, 9

Dosing and Initiation

For glycemic control: Start with 5 mg orally once daily, can increase to 10 mg once daily for additional glycemic control 7

For cardiovascular/renal protection: Use 10 mg orally once daily 7

Initiate when eGFR ≥20 mL/min/1.73 m² and continue as tolerated until dialysis or transplantation. 2

• Most effective for glucose lowering if eGFR >60 mL/min/1.73 m² at initiation 6
• For glycemic control, not recommended with eGFR <45 mL/min/1.73 m² (likely ineffective based on mechanism of action) 7
• However, cardiovascular and renal benefits persist at lower eGFR levels 2, 7

Pre-Initiation Assessment and Adjustments

Assess renal function and volume status before initiating; correct volume depletion first. 7, 2

• Reduce sulfonylurea dose by 50% or basal insulin by 20% if glucose is well-controlled at baseline 2
• Consider reducing diuretic doses if volume depletion is a concern 2
• Withhold for at least 3 days prior to major surgery or procedures with prolonged fasting 7

Safety Monitoring and Adverse Effects

Monitor for genital mycotic infections and provide education on genital hygiene. 2

• Assess for diabetic ketoacidosis regardless of presenting blood glucose levels if suspected 7
• Consider ketone monitoring in patients at risk for ketoacidosis 7
• Discontinue if ketoacidosis is suspected and monitor for resolution before restarting 7

Special Populations and Contraindications

Amputation Risk:

• Use with caution in patients with foot ulcers or at high risk for amputation, particularly with canagliflozin 2, 1
• Only treat after careful shared decision-making with comprehensive education on foot care and amputation prevention 1

Not Recommended:

• Type 1 diabetes mellitus (for glycemic control) 7
• Polycystic kidney disease 7
• Patients requiring or with recent history of immunosuppressive therapy for kidney disease (not expected to be effective) 7

Contraindications:

• History of serious hypersensitivity reaction to the specific SGLT2 inhibitor 7

---

Combination Therapy Considerations

When to Use Both Drug Classes

In patients with both established atherosclerotic cardiovascular disease AND chronic kidney disease, use both an SGLT2 inhibitor and a GLP-1 receptor agonist for maximal cardiorenal protection. 1, 4, 5

• The cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use 5
• Effects on MACE (HR 0.77-0.79), hospitalization for heart failure (HR 0.58-0.73), composite kidney outcomes (risk ratio 0.79), and eGFR slope (0.78 mL/min/1.73 m²/y) do not vary by SGLT2 inhibitor use 5
• Serious adverse effects and severe hypoglycemia are similar regardless of concurrent SGLT2 inhibitor use 5

Prioritization Strategy

Prioritize GLP-1 receptor agonists over insulin when additional glucose-lowering beyond oral agents is needed. 2

• Combination of GLP-1 agonist with insulin provides greater glycemic effectiveness with beneficial effects on weight and hypoglycemia risk 2
• Both GLP-1 receptor agonists and SGLT2 inhibitors reduce mortality compared to usual care and insulin 2

Decision-Making Independent of Glucose Control

The decision to treat with a GLP-1 receptor agonist or SGLT2 inhibitor to reduce MACE, hospitalization for heart failure, cardiovascular death, or CKD progression should be considered independently of baseline HbA1c or individualized HbA1c target. 1

---

Risk Stratification for Treatment Decisions

Very High Risk (Strong Recommendation for SGLT2 Inhibitors)

• Established cardiovascular disease AND chronic kidney disease 1, 4
• Heart failure with reduced ejection fraction 1
• CKD with eGFR 30-60 mL/min/1.73 m² or UACR >300 mg/g 1

High Risk (Weak Recommendation for Both Agents)

• Established atherosclerotic cardiovascular disease alone 1, 4
• Established chronic kidney disease alone 1, 4
• Age ≥55 years with arterial stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria 1, 3

Moderate Risk (Weak Recommendation for SGLT2 Inhibitors, Weak Against GLP-1 Receptor Agonists)

• More than three cardiovascular risk factors without established CVD or CKD 4
• Type 2 diabetes duration ≥10 years without target organ damage plus any additional risk factor 1

Lower Risk (Weak Recommendation Against)

• Three or fewer cardiovascular risk factors without established CVD or CKD 4
• Young patients (type 1 diabetes <35 years; type 2 diabetes <50 years) with diabetes duration <10 years without other risk factors 1

---

Practical Implementation Pearls

Common Pitfalls to Avoid

Do not wait for inadequate glycemic control to initiate these agents in high-risk patients—cardiovascular and renal benefits are independent of glucose-lowering effects. 1, 6

Do not avoid SGLT2 inhibitors in patients with lower eGFR for cardiovascular/renal protection—benefits persist even when glucose-lowering efficacy is reduced. 2, 7, 6

Do not use GLP-1 receptor agonists other than semaglutide, liraglutide, or dulaglutide for cardiovascular protection—only these three have proven MACE reduction. 3

Shared Decision-Making Points

• Engage in shared decision-making around initial combination therapy in new-onset type 2 diabetes 1
• For patients committed to further reducing cardiovascular and CKD risk, SGLT2 inhibitors may be preferred over GLP-1 receptor agonists based on broader evidence 4
• Discuss amputation risk with SGLT2 inhibitors in high-risk patients before initiating 1, 2