What is the recommended starting dose and potential benefits of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as empagliflozin (Jardiance) or canagliflozin (Invokana), in patients with type 2 diabetes?

SGLT2 Inhibitors: Dosing and Clinical Benefits in Type 2 Diabetes

Recommended Starting Doses

Start empagliflozin at 10 mg once daily or canagliflozin at 100 mg once daily, taken in the morning with or without food, and do not increase the dose for cardiovascular or renal protection—the lowest dose provides full cardioprotective benefit. 1, 2, 3

Specific Agent Dosing

• Empagliflozin: 10 mg orally once daily is the recommended starting and maintenance dose for cardiovascular risk reduction 1, 2

  • May increase to 25 mg daily only if additional glycemic control is needed, but this provides no additional cardiovascular benefit 1, 2

• Canagliflozin: 100 mg orally once daily is the starting dose 1, 3

  • May increase to 300 mg daily only in patients with eGFR ≥60 mL/min/1.73 m² who need additional glycemic control 1, 3
  • Maximum dose is 100 mg daily when eGFR is 45-59 mL/min/1.73 m² 1

• Dapagliflozin: 10 mg orally once daily (standard dose, no titration needed) 1

Renal Function Requirements and Monitoring

Assess eGFR before initiating any SGLT2 inhibitor and do not start if eGFR is below 45 mL/min/1.73 m² for empagliflozin, though canagliflozin and dapagliflozin can be initiated down to eGFR 30 mL/min/1.73 m² for cardiovascular and renal protection. 1, 2

eGFR-Based Initiation Thresholds

• Empagliflozin: Do not initiate if eGFR <45 mL/min/1.73 m² 1, 2
• Canagliflozin: Can initiate down to eGFR 30 mL/min/1.73 m² (use 100 mg daily maximum) 1, 3
• Dapagliflozin: Can initiate down to eGFR 25 mL/min/1.73 m² for kidney protection, down to eGFR 20 mL/min/1.73 m² per most recent guidance 1

Continuation at Lower eGFR

Once initiated, continue SGLT2 inhibitors even if eGFR falls below initiation thresholds, as cardiovascular and renal benefits persist—only discontinue if dialysis is initiated or the patient cannot tolerate the medication. 1

• Empagliflozin: FDA label states to discontinue if eGFR persistently falls below 45 mL/min/1.73 m², but newer evidence supports continuation 1, 2
• Canagliflozin and dapagliflozin: Continue until dialysis for cardiovascular and renal benefit 1

Cardiovascular and Renal Benefits

SGLT2 inhibitors reduce cardiovascular death, heart failure hospitalization, and progression of kidney disease independent of their glucose-lowering effects—these benefits are the primary reason to prescribe them in patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease. 1

Major Cardiovascular Outcomes

• Cardiovascular death: Empagliflozin reduced CV death by 38% (HR 0.62,95% CI 0.49-0.77) 1
• Heart failure hospitalization: Reduced by approximately 30-35% across SGLT2 inhibitors 1
• Major adverse cardiovascular events (MACE): Reduced by 14% with both empagliflozin and canagliflozin 1
• All-cause mortality: Empagliflozin reduced all-cause mortality by 32% (HR 0.68,95% CI 0.57-0.82) 1

Renal Protection

• Reduces risk of end-stage kidney disease, doubling of serum creatinine, and renal death 1
• Canagliflozin has FDA approval specifically for reducing risk of end-stage kidney disease in diabetic nephropathy with albuminuria 1, 3
• Initial eGFR decline of 3-5 mL/min/1.73 m² is expected and reversible—this does not require discontinuation 1

Glycemic Control

• Reduces HbA1c by 0.6-0.8% (6-8 mmol/mol) without increasing hypoglycemia risk when used as monotherapy 1, 4, 5
• Induces weight loss of 2-3 kg on average 4, 5
• Reduces systolic blood pressure by 3-5 mmHg through osmotic diuresis 4, 5

Patient Selection and Indications

Initiate an SGLT2 inhibitor with proven cardiovascular benefit in all patients with type 2 diabetes and established atherosclerotic cardiovascular disease, regardless of baseline HbA1c or current glucose control. 1

Priority Populations

• Type 2 diabetes with established atherosclerotic cardiovascular disease (prior MI, stroke, peripheral artery disease) 1
• Type 2 diabetes with heart failure (especially HFrEF) 1
• Type 2 diabetes with chronic kidney disease and eGFR ≥20 mL/min/1.73 m² 1
• Type 2 diabetes with diabetic nephropathy and albuminuria 1, 3

Agent Selection Based on Evidence

Empagliflozin is the preferred SGLT2 inhibitor based on the strongest mortality benefit demonstrated in EMPA-REG OUTCOME, showing a 32% reduction in all-cause mortality and 38% reduction in cardiovascular death. 1

• Canagliflozin is an alternative with proven MACE reduction and specific FDA approval for renal outcomes in diabetic nephropathy 1, 3
• Dapagliflozin has the broadest FDA approval including heart failure with reduced ejection fraction regardless of diabetes status 1

Critical Safety Considerations and Management

Volume Depletion Risk

Assess volume status before initiating SGLT2 inhibitors and consider reducing loop diuretic dose by 50% in patients on high-dose diuretics (furosemide ≥80 mg daily) to prevent symptomatic hypotension. 1, 6

• Higher risk in elderly patients, those with eGFR 30-60 mL/min/1.73 m², baseline systolic BP <110 mmHg, or concurrent diuretic use 1
• Monitor for orthostatic symptoms, dizziness, and syncope in first 2-4 weeks 6

Euglycemic Diabetic Ketoacidosis

Counsel all patients to temporarily discontinue SGLT2 inhibitors at least 3 days before planned surgery, during prolonged fasting, or during acute illness to prevent euglycemic ketoacidosis. 1, 3

• Presents with nausea, vomiting, abdominal pain, and malaise but blood glucose may be <250 mg/dL 1
• Check ketones (blood or urine) if metabolic acidosis is suspected regardless of glucose level 1
• Higher risk in insulin-dependent patients—maintain at least low-dose basal insulin when using SGLT2 inhibitors 1

Hypoglycemia Prevention

Reduce insulin dose by approximately 20% and reduce or discontinue sulfonylureas when initiating SGLT2 inhibitors in patients with well-controlled HbA1c (<7.5%) to prevent hypoglycemia. 1

• SGLT2 inhibitors alone do not cause hypoglycemia but increase risk when combined with insulin or sulfonylureas 1

Genital Mycotic Infections

Warn patients about increased risk of genital yeast infections (6% vs 1% with placebo), which are typically mild and easily treated with topical antifungals, but counsel on proper genital hygiene. 1

• Higher risk in women than men 1
• Rare cases of Fournier's gangrene (necrotizing fasciitis of perineum) have been reported—discontinue immediately if suspected 1, 3

Amputation Risk (Canagliflozin-Specific)

Avoid canagliflozin in patients with prior amputation, active diabetic foot ulcers, severe peripheral vascular disease, or severe peripheral neuropathy—use empagliflozin or dapagliflozin instead. 1

• Increased amputation risk observed only with canagliflozin in CANVAS trial, not with empagliflozin or dapagliflozin 1

Bone Fracture Risk (Canagliflozin-Specific)

Consider fracture risk factors before initiating canagliflozin, particularly in patients with osteoporosis—this concern is specific to canagliflozin and not observed with other SGLT2 inhibitors. 1, 3

Contraindications

• History of serious hypersensitivity reaction to the specific SGLT2 inhibitor 1, 2, 3
• Severe renal impairment, end-stage renal disease, or dialysis (per FDA labels, though newer guidelines support use down to dialysis initiation) 1, 2
• Type 1 diabetes mellitus (not FDA-approved, higher ketoacidosis risk) 1, 2, 3

Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors when eGFR falls below initiation threshold—cardiovascular and renal benefits persist at lower eGFR 1
• Do not uptitrate dose for cardiovascular benefit—10 mg empagliflozin or 100 mg canagliflozin provides full cardioprotection 1
• Do not withhold in patients with "controlled" diabetes (HbA1c <7%)—cardiovascular benefits are independent of glucose lowering 1
• Do not forget to counsel about sick day management—temporary discontinuation during acute illness prevents ketoacidosis 1, 3
• Do not combine with metformin in patients with eGFR <30 mL/min/1.73 m²—metformin is contraindicated at this level 1