What is the next choice in medication for a patient with type 2 diabetes (T2D) and a history of coronary artery disease (CAD), hypertension (HTN), and hyperlipidemia, who is not tolerating metformin due to gastrointestinal side effects, specifically diarrhea?

Recommended Next Medication for Type 2 Diabetes with Coronary Artery Disease and Metformin Intolerance

Given your patient's established coronary artery disease and metformin intolerance, you should initiate an SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) as the next medication, with empagliflozin being the preferred choice due to its proven mortality benefit in patients with cardiovascular disease. 1

Primary Recommendation: SGLT2 Inhibitors

For patients with type 2 diabetes and established cardiovascular disease (including coronary artery disease), SGLT2 inhibitors are specifically recommended to reduce cardiovascular events and mortality. 1

Specific SGLT2 Inhibitor Selection:

• Empagliflozin is the strongest choice because it is the only SGLT2 inhibitor proven to reduce the risk of death in patients with type 2 diabetes and cardiovascular disease 1, 2
• Empagliflozin reduced cardiovascular death by 38% and all-cause mortality by 32% in the EMPA-REG OUTCOME trial 2
• Canagliflozin or dapagliflozin are acceptable alternatives, as both reduce cardiovascular events, though they lack the specific mortality benefit demonstrated with empagliflozin 1

Key Advantages in This Patient:

• Low hypoglycemia risk, which is particularly important in elderly patients 1, 3, 4
• Weight loss benefit (typically 2-3 kg), addressing a common comorbidity 3, 4
• Blood pressure reduction (systolic BP reduction of 3-5 mmHg), beneficial given her hypertension 3, 4
• Hospitalization for heart failure reduction, relevant given her cardiovascular disease 1

Dosing and Renal Considerations

Before initiating an SGLT2 inhibitor, check the patient's eGFR:

• eGFR ≥30 mL/min/1.73 m²: Standard dosing can be used 1
• eGFR 20-29 mL/min/1.73 m²: Can still initiate, though glycemic efficacy is reduced; cardiovascular and renal benefits persist 1
• eGFR <20 mL/min/1.73 m²: Do not initiate 1

Empagliflozin dosing:

• Start with 10 mg once daily
• Can increase to 25 mg once daily if additional glycemic control is needed and eGFR remains adequate 2, 5

Alternative Option: GLP-1 Receptor Agonists

If SGLT2 inhibitors are contraindicated or not tolerated, a GLP-1 receptor agonist with proven cardiovascular benefit should be the next choice. 1

Specific GLP-1 RA Selection:

• Liraglutide is preferred as it is the only GLP-1 RA proven to reduce both cardiovascular events AND mortality risk in patients with cardiovascular disease 1
• Semaglutide or dulaglutide are acceptable alternatives, as both reduce cardiovascular events (though mortality benefit is less established) 1

Important Considerations for GLP-1 RAs:

• Start with low doses and titrate slowly to minimize gastrointestinal side effects (nausea, vomiting, diarrhea), which is particularly important since your patient already has GI intolerance to metformin 1
• These agents cause weight loss, which may be beneficial or problematic depending on the patient's nutritional status 1
• Very low hypoglycemia risk when used without insulin or sulfonylureas 1

What NOT to Use

Avoid the following medication classes in this patient:

• Sulfonylureas (glipizide, glyburide, glimepiride): High hypoglycemia risk, weight gain, and increased fracture risk in elderly patients 1
• Thiazolidinediones (pioglitazone): Contraindicated or should be used with extreme caution due to fluid retention, heart failure risk, weight gain, and fracture risk, especially problematic in elderly patients with cardiovascular disease 1
• Saxagliptin: Not recommended in patients with high risk of heart failure 1

Practical Implementation

If you choose an SGLT2 inhibitor (recommended):

1. Verify eGFR is ≥20 mL/min/1.73 m² 1
2. Counsel patient about genital mycotic infections (most common side effect, occurring in 4-10% of patients) 6, 4, 5
3. Educate about signs of volume depletion, particularly if patient is on diuretics 6, 3
4. Monitor for rare but serious diabetic ketoacidosis, even with normal glucose levels 1
5. Expect modest A1C reduction of 0.5-0.8% as monotherapy 3, 4

If you choose a GLP-1 RA (alternative):

1. Start with lowest available dose 1
2. Titrate up slowly over 4-8 weeks to minimize GI side effects 1
3. Expect A1C reduction of 0.9-1.5% depending on agent and dose 1
4. Monitor for nausea, which typically improves over 2-4 weeks 1

Common Pitfalls to Avoid

• Do not delay SGLT2 inhibitor initiation waiting for metformin tolerance to improve; the cardiovascular benefits are time-sensitive in patients with established CAD 1
• Do not use DPP-4 inhibitors as second-line in patients with established cardiovascular disease, as they lack cardiovascular benefit and are less potent than SGLT2 inhibitors or GLP-1 RAs 1
• Do not attempt extended-release metformin if the patient has significant diarrhea, as GI side effects often persist across formulations 1
• Monitor renal function within 2-4 weeks after starting an SGLT2 inhibitor, as a small acute increase in creatinine (up to 0.2 mg/dL) is expected and reversible 1