SGLT2 Inhibitor Options
The three primary SGLT2 inhibitors available for clinical use are canagliflozin, dapagliflozin, and empagliflozin, all of which demonstrate proven cardiovascular and renal benefits. 1
Available SGLT2 Inhibitors
First-Generation Agents with Proven Outcomes
Empagliflozin (Jardiance): Administered as 10 mg or 25 mg once daily, this highly selective SGLT2 inhibitor was the first to demonstrate cardiovascular mortality reduction in the landmark EMPA-REG OUTCOME trial 2, 3
Dapagliflozin (Farxiga): Available as 5 mg or 10 mg once daily, dapagliflozin inhibits SGLT2 in the proximal renal tubules and has demonstrated benefits across heart failure and chronic kidney disease populations 4, 5
Canagliflozin: This agent has greater SGLT1 inhibition compared to empagliflozin and dapagliflozin, which affects intestinal glucose absorption in addition to renal effects 6, 3
Additional SGLT2 Inhibitors
- Ertugliflozin: Among the most selective inhibitors for SGLT2 compared to SGLT1, similar to empagliflozin and dapagliflozin 6
Dual SGLT1/SGLT2 Inhibitors
- Sotagliflozin: A dual SGLT1/SGLT2 inhibitor that differs mechanistically from the selective SGLT2 inhibitors 6
GLP-1 Receptor Agonists as Alternatives
When SGLT2 inhibitors are not tolerated or contraindicated, long-acting GLP-1 receptor agonists with proven cardiovascular benefits serve as interchangeable alternatives 1:
- Liraglutide: 0.6-1.8 mg subcutaneous once daily, approved for reducing cardiovascular death, MI, and stroke 1
- Dulaglutide: 0.75-1.5 mg subcutaneous once weekly 1
- Semaglutide: Subcutaneous once weekly formulation 1
- Exenatide XR: 2 mg subcutaneous once weekly 1
Key Selection Considerations
Renal Function Thresholds
For glucose-lowering efficacy: SGLT2 inhibitors progressively lose glycemic efficacy as eGFR declines below 45 mL/min/1.73 m², with substantially reduced effects below 30 mL/min/1.73 m² 6, 2
For cardiorenal protection: The cardiovascular and kidney benefits persist even when glycemic efficacy is lost, and these agents should be continued down to eGFR 20 mL/min/1.73 m² 1, 6
Specific Indications by Risk Stratification
Very high-risk CKD patients: Strong recommendation for SGLT2 inhibitors (canagliflozin, dapagliflozin, or empagliflozin) given high certainty evidence for mortality and kidney failure reduction 1
High-risk patients: Moderate certainty evidence supports use for reducing all-cause mortality, cardiovascular mortality, MI, and stroke 1
Moderate and low-risk patients: Weak recommendations favor SGLT2 inhibitors based on moderate certainty evidence for mortality and stroke reduction 1
Common Pitfalls to Avoid
Never discontinue SGLT2 inhibitors solely because glucose-lowering efficacy has declined - the cardiorenal benefits are out of proportion to glycemic effects and persist at low eGFR 6
Do not mistake the initial reversible eGFR dip as kidney injury - this represents hemodynamic changes from tubuloglomerular feedback and afferent vasoconstriction, not true kidney damage 3
Avoid routine use in hemodialysis patients - current evidence is insufficient to support SGLT2 inhibitor use in patients receiving kidney replacement therapy, despite benefits in earlier CKD stages 7
Safety Profile
All SGLT2 inhibitors share similar adverse effects 3, 5, 8:
- Increased risk of mycotic genital infections (most common)
- Minimal risk of urinary tract infections
- Volume depletion in susceptible patients
- Rare euglycemic diabetic ketoacidosis
- Canagliflozin specifically associated with increased amputation and fracture risk 5
Administration Details
Empagliflozin: May be administered with or without food; protein binding 86.2%; primarily metabolized via glucuronidation 2
Dapagliflozin: May be administered with or without food; protein binding 91%; primarily metabolized by UGT1A9 4
Both agents can be used without dose adjustment in hepatic impairment 2, 4