Indications for SGLT2 Inhibitors and GLP-1 Receptor Agonists
Both SGLT2 inhibitors and GLP-1 receptor agonists should be initiated in patients with type 2 diabetes based on their specific cardiovascular and renal risk profiles, independent of baseline HbA1c or glycemic targets. 1
SGLT2 Inhibitor Indications
FDA-Approved Indications
- Empagliflozin: Improve glycemic control in adults with type 2 diabetes AND reduce cardiovascular death in patients with type 2 diabetes and established cardiovascular disease 2
- Canagliflozin: Improve glycemic control, reduce major adverse cardiovascular events (MACE) in patients with established cardiovascular disease, AND reduce end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and heart failure hospitalization in patients with diabetic nephropathy with albuminuria 3
Guideline-Based Clinical Indications
Heart Failure (Primary Indication)
- Initiate SGLT2 inhibitors in all patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction (HFrEF, EF <45%), to reduce hospitalization for heart failure, MACE, and cardiovascular death 1
- SGLT2 inhibitors reduce heart failure hospitalization by 27-39% across multiple trials 4
- This indication applies regardless of presence or absence of established atherosclerotic cardiovascular disease 1
Chronic Kidney Disease (Primary Indication)
- Initiate SGLT2 inhibitors in patients with type 2 diabetes and CKD defined as eGFR 30 to ≤60 mL/min/1.73 m² OR urinary albumin-to-creatinine ratio (UACR) >30 mg/g, particularly UACR >300 mg/g 1
- SGLT2 inhibitors can be started down to eGFR ≥20 mL/min/1.73 m² for CKD progression prevention and cardiovascular event reduction 1
- In the DAPA-CKD trial, dapagliflozin reduced the primary composite renal outcome by 39% (HR 0.61,95% CI 0.51-0.72) 1, 4
Established Atherosclerotic Cardiovascular Disease
- SGLT2 inhibitors reduce MACE by approximately 10% (HR 0.90,95% CI 0.83-0.98) in patients with established atherosclerotic cardiovascular disease 4
- However, GLP-1 receptor agonists have stronger evidence for MACE reduction in this population 1
Critical Dosing Considerations
- Empagliflozin: Can be initiated with eGFR >30 mL/min/1.73 m²; do not initiate if eGFR <45 mL/min/1.73 m² for glycemic control, but continue for cardiovascular/renal benefits 1
- Canagliflozin: Can be initiated down to eGFR 30 mL/min/1.73 m²; limit to 100 mg daily if eGFR 45-59 mL/min/1.73 m² 1
Important Safety Caveat
- Patients with foot ulcers or high amputation risk should only receive SGLT2 inhibitors after careful shared decision-making with comprehensive foot care education 1
- Canagliflozin showed increased amputation risk in the CANVAS trial; consider empagliflozin in patients with osteoporosis or prior amputation 5
GLP-1 Receptor Agonist Indications
FDA-Approved Indications
- Semaglutide (Ozempic): Improve glycemic control in adults with type 2 diabetes AND reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 6
Guideline-Based Clinical Indications
Established Atherosclerotic Cardiovascular Disease (Primary Indication)
- Initiate GLP-1 receptor agonists in all patients with type 2 diabetes and established atherosclerotic cardiovascular disease (prior myocardial infarction, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or revascularization of coronary, carotid, or peripheral arteries) where MACE is the gravest threat 1
- Semaglutide reduces MACE by 26% (HR 0.74,95% CI 0.58-0.95) in the SUSTAIN-6 trial 7
- GLP-1 receptor agonists have the strongest evidence for MACE reduction compared to SGLT2 inhibitors in this population 1
High-Risk Primary Prevention (Expanded Indication)
- Consider GLP-1 receptor agonists in patients aged ≥55 years WITHOUT established cardiovascular disease but with ANY of the following high-risk indicators: 1
- Coronary, carotid, or lower extremity artery stenosis >50%
- Left ventricular hypertrophy
- eGFR <60 mL/min/1.73 m²
- Albuminuria
- This recommendation is based primarily on the REWIND trial with dulaglutide, which showed MACE reduction (HR 0.88,95% CI 0.79,0.99) in a population where 68.5% had no prior established cardiovascular disease 1
Chronic Kidney Disease
- GLP-1 receptor agonists provide renal benefits but with less robust evidence than SGLT2 inhibitors 8
- Semaglutide reduced major kidney disease events by 24% in patients with type 2 diabetes and CKD (eGFR 25-75 mL/min/1.73 m²) 7
- Advantage over SGLT2 inhibitors: Can be used in more advanced kidney disease (eGFR as low as 25 mL/min/1.73 m²) without eGFR-related efficacy limitations 7
Important Safety Considerations
- Not studied in patients with history of pancreatitis; consider alternative therapy 6
- Reduce insulin or sulfonylurea dose by approximately 20% when initiating GLP-1 receptor agonist to prevent hypoglycemia 7
- Common adverse effects include nausea, vomiting, diarrhea, abdominal pain, and constipation (≥5% of patients), typically transient 7
Clinical Decision Algorithm
Step 1: Identify Primary Comorbidity
- Heart failure (especially HFrEF) → SGLT2 inhibitor is first choice 1
- Established atherosclerotic cardiovascular disease → GLP-1 receptor agonist is first choice for MACE reduction 1
- CKD with eGFR 30-60 or albuminuria → SGLT2 inhibitor is first choice 1
Step 2: Consider Combination Therapy
- Patients with both established cardiovascular disease AND heart failure or CKD may benefit from both classes, though additive cardiovascular benefits remain unknown 7
Step 3: Independent of Glycemic Control
- These decisions should be made independently of baseline HbA1c or individualized HbA1c target 1
- The cardiovascular and renal benefits are glucose-independent 9
Key Pitfall to Avoid
Do not wait for inadequate glycemic control to initiate these agents in high-risk patients. The cardiovascular and renal benefits occur independently of glucose-lowering effects and emerge within 2 years of treatment 7, 9. Early initiation provides the greatest benefit for preventing complications 9.