What are examples of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, how do they work, and what are their common adverse effects?

SGLT2 Inhibitors: Examples, Mechanism, and Adverse Effects

Examples of SGLT2 Inhibitors

The four FDA-approved SGLT2 inhibitors available in the United States are empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin 1, 2, 3. Empagliflozin is the only SGLT2 inhibitor specifically FDA-approved to reduce cardiovascular death in adults with type 2 diabetes and established cardiovascular disease 1.

Mechanism of Action

SGLT2 inhibitors work by blocking the sodium-glucose cotransporter 2 protein in the proximal renal tubules, which is responsible for approximately 90% of urinary glucose reabsorption 1. This mechanism operates through several key pathways:

Primary Glucose-Lowering Effect

• By inhibiting SGLT2, these medications reduce renal glucose reabsorption and lower the renal threshold for glucose (RTG) from approximately 240 mg/dL to 70-90 mg/dL 4
• This results in increased urinary glucose excretion of approximately 70-100 grams per day 1, 4
• The glucose-lowering effect is insulin-independent, making these agents effective regardless of diabetes duration or beta-cell function 1, 2
• Hypoglycemia risk is low when used as monotherapy, though it increases when combined with insulin or sulfonylureas 1

Additional Hemodynamic Effects

• SGLT2 inhibitors increase sodium delivery to the distal tubule, which increases tubuloglomerular feedback and reduces intraglomerular pressure 4, 5
• They produce diuretic and natriuretic effects, leading to modest reductions in systolic blood pressure of 3-5 mmHg 1, 2
• Weight loss of 1.5-3.5 kg occurs through caloric loss via glucosuria 1, 2

Cardiovascular and Renal Benefits

The cardiovascular and renal benefits appear disproportionate to glucose-lowering effects and persist even when glycemic efficacy is lost at lower eGFR levels 6. These benefits include:

• 14-38% reduction in cardiovascular death 1
• 35% reduction in heart failure hospitalization 1
• Slowed progression of chronic kidney disease 1

Common Adverse Effects

Genitourinary Infections (Most Common)

Genital mycotic infections are the most frequently reported adverse effect, occurring more commonly in women 1, 3, 7. Urinary tract infections also occur with increased frequency compared to placebo 3, 7.

Risk mitigation strategy: Counsel patients on proper hygiene practices to reduce infection risk 1.

Volume Depletion and Hypotension

• Osmotic diuresis can lead to volume depletion, particularly in patients already taking diuretics 1
• This risk is higher in elderly patients and those with impaired renal function 1

Important caveat: It is generally not necessary to discontinue or reduce diuretic therapy when initiating SGLT2 inhibitors 1.

Diabetic Ketoacidosis (Rare but Serious)

• Euglycemic diabetic ketoacidosis can occur, presenting with normal or mildly elevated glucose (<200 mg/dL) 1
• Risk factors include insulin therapy, reduced food intake, intercurrent illness, and alcohol consumption 1

Critical management point: Discontinue SGLT2 inhibitors 3-4 days before any elective surgical procedure 1.

Acute Kidney Injury

• An initial reversible decline in eGFR of 3-5 mL/min/1.73 m² occurs within the first 4 weeks of therapy 1
• This "eGFR dip" is hemodynamic, not nephrotoxic, and kidney function typically stabilizes or returns to baseline 1

Common pitfall to avoid: Do not discontinue therapy solely because of this initial eGFR decline, as it does not indicate kidney injury 1.

Agent-Specific Concerns

• Canagliflozin has been associated with increased risk of lower extremity amputation (6.3 vs 3.4 per 1000 person-years) and bone fractures (15.4 vs 11.9 per 1000 person-years) in the CANVAS trial 1
• The FDA has issued warnings about these risks specifically for canagliflozin 2

Less Common Adverse Effects

• Hyperkalemia reduction (beneficial effect) 1
• Increased urination due to osmotic diuresis 5
• Rare cases of Fournier's gangrene have been reported 2

Key Clinical Considerations

For renal function monitoring: The initial eGFR decline does not necessitate increased monitoring frequency or therapy discontinuation 1. SGLT2 inhibitors can be continued down to eGFR 20 mL/min/1.73 m² for cardiovascular and renal protection, even when glucose-lowering efficacy is minimal 1, 6.

For patients with eGFR <45 mL/min/1.73 m²: Glucose-lowering efficacy progressively declines, but cardiovascular and renal benefits persist 6. Continue therapy for cardiorenal protection rather than glycemic control in this population 6.