SGLT2 Inhibitors: Mechanism of Action, Side Effects, and Drug Interactions
SGLT2 inhibitors work by blocking glucose reabsorption in the kidneys, leading to increased urinary glucose excretion, with common side effects including genitourinary infections, volume depletion, and potential for euglycemic diabetic ketoacidosis, while requiring caution when combined with insulin, diuretics, and medications affecting renal function. 1, 2
Mechanism of Action
SGLT2 inhibitors target a specific mechanism in the kidneys:
Primary mechanism: They inhibit sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubules, which is responsible for approximately 90% of glucose reabsorption from the tubular lumen 2
Physiological effect: By inhibiting SGLT2, these medications:
Insulin-independent action: Unlike many other diabetes medications, SGLT2 inhibitors work independently of insulin secretion or action, making them effective at any stage of type 2 diabetes 1
Secondary effects: SGLT2 inhibitors increase sodium delivery to the distal tubule, which:
Clinical Effects
SGLT2 inhibitors provide multiple benefits beyond glucose control:
- Glycemic control: Reduce HbA1c by 0.5-1.0% 1, 3
- Cardiovascular benefits: Reduce major adverse cardiovascular events and hospitalization for heart failure by 27-35% 1
- Renal protection: Slow progression of kidney disease and reduce risk of end-stage kidney disease 1
- Weight reduction: Promote weight loss through caloric loss via glucosuria 3
- Blood pressure reduction: Lower systolic blood pressure through osmotic diuresis and natriuresis 3
Common Side Effects
SGLT2 inhibitors have several notable side effects:
Genitourinary infections: Increased risk of genital mycotic infections due to glucosuria 1
Volume depletion/hypotension: Due to osmotic diuresis and natriuresis effects 1
Euglycemic diabetic ketoacidosis: A rare but serious adverse effect that can occur even with normal blood glucose levels (<250 mg/dL) 1, 3
Urinary tract infections: More common with SGLT2 inhibitor use 1
Specific to canagliflozin:
- Increased risk of lower limb amputations
- Higher risk of bone fractures compared to other SGLT2 inhibitors 1
Drug Interactions
Key drug interactions to be aware of:
Insulin and insulin secretagogues: Consider reducing doses when adding SGLT2 inhibitors to prevent hypoglycemia
- Reduce sulfonylurea dose by 50% or consider discontinuation if on minimal dose
- Reduce total daily insulin dose by approximately 20% 1
Diuretics: Consider reducing diuretic doses when initiating SGLT2 inhibitors in patients at risk for volume depletion 1
Combination with GLP-1 receptor agonists: Provides complementary mechanisms with additive effects on weight loss and glycemic control 1
Contraindications and Precautions
SGLT2 inhibitors should be used with caution or avoided in:
- Severe renal impairment: Efficacy is reduced in patients with eGFR <45 mL/min/1.73m² 1
- History of serious hypersensitivity reactions to the medication 1
- End-stage renal disease or dialysis: Not recommended in these populations 1
- Patients at risk for diabetic ketoacidosis: Monitor closely for symptoms including nausea, vomiting, abdominal pain, fatigue, and trouble breathing 1
Comparison of Available SGLT2 Inhibitors
Different SGLT2 inhibitors have varying characteristics:
| SGLT2 Inhibitor | Selectivity | Key Indications |
|---|---|---|
| Dapagliflozin | High | T2DM, CKD, CV risk reduction |
| Empagliflozin | High | T2DM, CKD, CV risk reduction |
| Ertugliflozin | High | T2DM, CKD, CV risk reduction |
| Canagliflozin | Low | T2DM, CKD, CV risk reduction |
| Sotagliflozin | Dual (SGLT1/2) | T2DM, CKD, CV risk reduction |
SGLT2 inhibitors represent a significant advancement in diabetes management with benefits extending beyond glycemic control to cardiovascular and renal protection. Their unique mechanism of action and favorable risk profile make them valuable additions to diabetes treatment regimens, particularly for patients with established cardiovascular disease or chronic kidney disease.