What is the efficacy of combining SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors and GLP1 (Glucagon-Like Peptide-1) drugs for treating type 2 diabetes?

SGLT2 Inhibitors and GLP-1 Receptor Agonists in Type 2 Diabetes

Both SGLT2 inhibitors and GLP-1 receptor agonists reduce all-cause mortality and major adverse cardiovascular events in patients with type 2 diabetes, and using them together is reasonable and likely provides additive benefits for cardiovascular and renal protection, even though combination therapy has not been formally studied in cardiovascular outcomes trials. 1

Individual Drug Class Benefits

SGLT2 Inhibitors

• Reduce all-cause mortality and cardiovascular death with high certainty evidence compared to usual care 1
• Most effective for heart failure prevention, particularly in patients with heart failure with reduced ejection fraction (EF <45%), reducing hospitalizations for heart failure more than GLP-1 agonists 1, 2
• Superior for kidney protection, preventing progression of chronic kidney disease in patients with eGFR 30-60 mL/min/1.73m² or albumin-to-creatinine ratio >30 mg/g (especially >300 mg/g) 1, 2
• Reduce severe hypoglycemia compared to insulin or sulfonylureas with high certainty evidence 1
• Primary adverse effect is genital mycotic infections (high certainty), with rare risk of euglycemic diabetic ketoacidosis 1, 2

GLP-1 Receptor Agonists

• Reduce all-cause mortality and MACE with high certainty evidence, particularly in patients with established atherosclerotic cardiovascular disease 1
• Most effective for stroke prevention, reducing non-fatal stroke more than SGLT2 inhibitors (which show no stroke benefit) 1, 2, 3
• Strongest evidence for MACE reduction in patients with prior myocardial infarction, ischemic stroke, or coronary/carotid/peripheral revascularization 1
• Can be considered in high-risk patients without established CVD (age ≥55 with >50% arterial stenosis, left ventricular hypertrophy, eGFR <60, or albuminuria) 1
• Main adverse effects are gastrointestinal (nausea, vomiting) with possible severe gastrointestinal events (low certainty) 2

Combination Therapy Rationale

Using both drug classes together is reasonable despite lack of cardiovascular outcomes trial data, based on the following evidence:

• Mechanistically complementary effects: SGLT2 inhibitors and GLP-1 agonists have opposite effects on glucagon but additive effects on blood pressure and weight reduction 1, 4
• DURATION-8 trial demonstrated additive benefits with greater reductions in blood pressure and body weight when exenatide and dapagliflozin were combined versus either alone 1
• Combination therapy accords with current diabetes management guidelines for patients requiring additional glycemic control or cardiovascular/renal protection 1
• No evidence of harmful interactions between the two drug classes 4, 5

When to Use Combination Therapy

Add both agents when:

• Patient has both heart failure (favoring SGLT2 inhibitor) AND high atherosclerotic cardiovascular disease risk (favoring GLP-1 agonist) 1, 3
• Patient has chronic kidney disease AND established atherosclerotic disease requiring maximal cardioprotection 5, 6
• Glycemic targets not met with single agent plus metformin 7
• Patient requires substantial weight loss and blood pressure reduction beyond what single agent provides 4, 5

Clinical Decision Algorithm

For patients with established atherosclerotic CVD (prior MI, stroke, revascularization):

• Prioritize GLP-1 agonist (liraglutide, semaglutide, dulaglutide, or albiglutide) as level of evidence for MACE benefit is greatest 1
• Add SGLT2 inhibitor if patient also has heart failure or CKD 1

For patients with heart failure (especially HFrEF with EF <45%):

• Prioritize SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) as level of evidence for heart failure hospitalization reduction is greatest 1
• Add GLP-1 agonist if patient also has atherosclerotic disease 3

For patients with CKD (eGFR 30-60 or UACR >30 mg/g):

• Prioritize SGLT2 inhibitor for CKD progression prevention with high certainty evidence 1, 2
• Add GLP-1 agonist for additional cardiovascular protection 6

For patients without established CVD, heart failure, or CKD but with high cardiovascular risk:

• Either drug class is appropriate, with choice based on patient-specific factors 1
• GLP-1 agonist preferred if stroke risk is primary concern 2, 3
• SGLT2 inhibitor preferred if heart failure prevention is priority 1, 3

Important Considerations

Baseline A1C Does Not Matter

• Cardiovascular and renal benefits occur independently of baseline A1C or A1C targets 1
• These agents should be considered for organ protection even in patients with well-controlled diabetes 1

Monitoring and Dose Adjustments

• Reduce insulin dose by <20% when initiating SGLT2 inhibitor to avoid euglycemic ketoacidosis 1
• Reduce sulfonylurea or insulin doses when adding either agent to prevent hypoglycemia 1
• Monitor for genital infections with SGLT2 inhibitors; treat with topical antifungals initially 1
• Counsel patients on diabetic ketoacidosis symptoms (nausea, vomiting, abdominal pain) with SGLT2 inhibitors 1

Special Populations

• Avoid SGLT2 inhibitors in patients with foot ulcers or high amputation risk without careful shared decision-making 1
• Both drug classes reduce severe hypoglycemia compared to insulin or sulfonylureas (low to high certainty) 1
• Weight loss occurs with both classes, with additive effect when combined (low certainty for magnitude) 2

Cost Considerations

• Out-of-pocket costs are very high when using both drug classes together 1
• However, both SGLT2 inhibitors and GLP-1 agonists are of intermediate value when added to metformin for cardiovascular/renal outcomes 7