What are the SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors for a patient with diabetes?

SGLT2 Inhibitors: Definition and Clinical Overview

What Are SGLT2 Inhibitors?

SGLT2 inhibitors are oral medications that lower blood glucose by blocking sodium-glucose cotransporter-2 proteins in the kidney, thereby increasing urinary glucose excretion and providing substantial cardiovascular and renal protection independent of their glucose-lowering effects. 1

Available SGLT2 Inhibitors

The FDA-approved SGLT2 inhibitors include:

• Canagliflozin (Invokana) - approved for glycemic control, cardiovascular risk reduction, and diabetic kidney disease 2
• Dapagliflozin (Farxiga) - approved for type 2 diabetes, heart failure, and chronic kidney disease 3
• Empagliflozin (Jardiance) - approved for glycemic control and cardiovascular death reduction 4
• Ertugliflozin - approved for type 2 diabetes management 1
• Sotagliflozin - a dual SGLT1/SGLT2 inhibitor with cardiovascular benefits 1

Mechanism of Action

SGLT2 inhibitors work through an insulin-independent mechanism by blocking glucose reabsorption in the proximal renal tubules, specifically the S1 and S2 segments 5. Under normal conditions, SGLT2 proteins reabsorb approximately 90% of filtered glucose, but when blood glucose exceeds approximately 180 mg/dL, this system becomes saturated and glucose appears in the urine 1. By inhibiting SGLT2, these medications force glucose excretion regardless of insulin levels 1, 6.

The mechanism provides several advantages:

• No stimulation of insulin release, thereby improving β-cell function by reducing glucotoxicity 7
• Minimal hypoglycemia risk when used alone or with metformin 1
• Can be combined with all other antidiabetic medications including insulin due to the insulin-independent pathway 6

Cardiovascular and Renal Benefits

Cardiovascular Protection

The cardiovascular benefits of SGLT2 inhibitors extend far beyond glucose control and represent their most compelling indication:

• Empagliflozin reduced cardiovascular death by 38% and heart failure hospitalization by 35% in patients with type 2 diabetes and established cardiovascular disease 1
• Canagliflozin reduced major adverse cardiovascular events by 14% and heart failure hospitalization by 33% 1
• Dapagliflozin reduced cardiovascular death or heart failure hospitalization by 26-29% in patients with heart failure 1, 3

These benefits occur through both direct cardiac effects (reducing fibrosis and inflammation, improving cardiac remodeling) and indirect effects (volume reduction, blood pressure lowering, improved renal hemodynamics) 1.

Renal Protection

SGLT2 inhibitors provide robust kidney protection that persists even when glucose-lowering efficacy is lost:

• Dapagliflozin reduced the composite renal outcome (≥50% sustained eGFR decline, end-stage kidney disease, or renal death) by 44% in patients with chronic kidney disease 3
• Canagliflozin reduced end-stage kidney disease, doubling of serum creatinine, and cardiovascular death in diabetic nephropathy 2
• All SGLT2 inhibitors slow the rate of eGFR decline and reduce progression to dialysis 1, 3

The renal benefits are mediated by reducing the oxygen and ATP burden on proximal tubular cells, relieving renal cortical hypoxia, and improving tubular structure 1.

Glucose-Lowering Efficacy

SGLT2 inhibitors reduce HbA1c by approximately 0.5-1.0% depending on baseline glucose levels and renal function 1, 7. However, glucose-lowering efficacy is highly dependent on kidney function:

• eGFR ≥45 mL/min/1.73 m²: Full glucose-lowering efficacy expected 5
• eGFR 30-45 mL/min/1.73 m²: Substantially reduced glucose-lowering efficacy 5
• eGFR <30 mL/min/1.73 m²: Minimal to no glucose-lowering effect 5

Critical point: The cardiovascular and renal benefits are out of proportion to glucose-lowering effects and persist even when glycemic efficacy is lost, extending down to eGFR 20-25 mL/min/1.73 m² 5.

Additional Metabolic Benefits

Beyond glucose control, SGLT2 inhibitors provide:

• Weight loss of 2.9-4.7 kg through caloric loss via glucosuria 1, 8
• Blood pressure reduction of 3-5 mmHg systolic and ~2 mmHg diastolic through osmotic diuresis and sodium excretion 1, 8
• Serum uric acid reduction which may benefit patients with gout 9
• No increase in hypoglycemia risk when used as monotherapy or with metformin 1

Dosing Considerations by Indication

For Glycemic Control

• Initiate only if eGFR ≥45 mL/min/1.73 m² as glucose-lowering efficacy is inadequate below this threshold 1, 3
• Standard doses: Canagliflozin 100-300 mg daily, Dapagliflozin 5-10 mg daily, Empagliflozin 10-25 mg daily 2, 4

For Cardiovascular/Renal Protection

• Can initiate if eGFR ≥25 mL/min/1.73 m² (some guidelines allow ≥20 mL/min/1.73 m²) 3, 5
• Fixed doses for protection: Dapagliflozin 10 mg daily, Empagliflozin 10 mg daily, Canagliflozin 100 mg daily 1
• Continue therapy even if eGFR falls below initiation threshold until dialysis is required 3, 5

Safety Profile and Adverse Events

Common Adverse Events

• Genital mycotic infections occur in ~6% of patients (vs 1% placebo), manageable with hygiene and antifungal treatment 1, 3
• Urinary tract infections are slightly increased but generally mild 1
• Volume depletion particularly in elderly patients or those on diuretics, requiring volume assessment before initiation 1, 2

Serious but Rare Adverse Events

• Euglycemic diabetic ketoacidosis can occur even with normal blood glucose (150-250 mg/dL range), particularly during illness, surgery, or reduced food intake 1, 2
• Lower limb amputation risk specifically with canagliflozin in patients with prior amputation, severe peripheral arterial disease, or active diabetic foot ulcers 1, 2
• Fournier's gangrene (necrotizing fasciitis of the perineum) is extremely rare but requires immediate treatment 3

Critical Safety Precautions

Sick Day Management

Withhold SGLT2 inhibitors during any acute illness, particularly with fever, vomiting, diarrhea, or reduced oral intake 3. Patients must be educated to stop the medication immediately when sick and contact their provider 3. Maintain at least low-dose insulin in insulin-requiring patients even when SGLT2 inhibitors are held 3.

Surgical Considerations

Discontinue SGLT2 inhibitors at least 3 days before major surgery or procedures with prolonged fasting to prevent postoperative ketoacidosis 1, 3, 2.

Volume Management

Assess volume status before initiation and consider reducing concurrent diuretic doses to prevent excessive volume depletion, especially in elderly patients or those with eGFR 25-45 mL/min/1.73 m² 1, 3.

Guideline Recommendations

The 2024 American Diabetes Association and 2020 American College of Cardiology provide Class I, Level A recommendations for SGLT2 inhibitors in:

• Patients with type 2 diabetes and established cardiovascular disease 1
• Patients with type 2 diabetes and heart failure 1
• Patients with diabetic kidney disease (eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g) 1, 3

SGLT2 inhibitors should be initiated independent of baseline HbA1c or need for additional glucose lowering, prioritizing cardiovascular and renal protection over glycemic control 3.

Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors solely because eGFR falls below 45 mL/min/1.73 m² - cardiovascular and renal protective benefits persist even when glycemic efficacy is lost 3, 5
• Do not mistake the initial reversible eGFR dip (3-5 mL/min/1.73 m² in first 1-4 weeks) as kidney injury - this is hemodynamic and actually predicts better long-term renal outcomes 3
• Do not reduce sulfonylurea or insulin doses preemptively when adding SGLT2 inhibitors unless HbA1c is already well-controlled or patient has history of hypoglycemia 1
• Do not use SGLT2 inhibitors in type 1 diabetes for glycemic control due to high ketoacidosis risk 2, 4, 2