Can Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as canagliflozin (Canagliflozin), be used for weight loss in patients with type 2 diabetes?

Weight Loss with SGLT2 Inhibitors in Type 2 Diabetes

SGLT2 inhibitors are effective for weight loss in patients with type 2 diabetes, typically resulting in 1-3 kg of weight reduction, and should be considered as second-line therapy particularly for patients with BMI >30 kg/m².

Mechanism of Action and Weight Loss Effects

SGLT2 inhibitors work through an insulin-independent mechanism by inhibiting glucose reabsorption in the proximal tubule of the kidney, leading to increased urinary glucose excretion. This mechanism results in several beneficial effects:

• Caloric loss through glucosuria (approximately 200-300 calories/day)
• Modest weight reduction of 1-3 kg 1
• Diuretic and natriuretic effects
• Lowering of systolic blood pressure 2

Clinical Recommendations Based on BMI

For Patients with BMI <30 kg/m²:

• SGLT2 inhibitors and DPP-4 inhibitors are equally preferable as second-line options after metformin 2
• Both classes are easy to administer and well-tolerated with good adherence

For Patients with BMI >30 kg/m²:

• For BMI 30-35 kg/m²: SGLT2 inhibitors are an excellent option
• For BMI >35 kg/m²: GLP-1 receptor agonists are first choice, with SGLT2 inhibitors as an acceptable alternative 2
  • GLP-1 RAs have greater potential for weight loss
  • GLP-1 RAs affect hunger-satiety mechanisms, while SGLT2 inhibitors do not 2

FDA-Approved Indications and Limitations

• SGLT2 inhibitors like canagliflozin and empagliflozin are FDA-approved for glycemic control in type 2 diabetes 3, 4
• They are specifically NOT approved for type 1 diabetes due to increased risk of diabetic ketoacidosis 5, 3, 4
• Canagliflozin is indicated "as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus" 3

Safety Considerations

Common Side Effects:

• Genital mycotic infections (approximately 10% in women vs. 3% with placebo) 6
• Urinary tract infections (9% in women vs. 7% with placebo) 6
• Increased urination due to osmotic diuresis

Important Precautions:

• Reduce dose of canagliflozin when eGFR <45 ml/min/1.73m² 2
• Discontinue when eGFR <30 ml/min/1.73m² 2
• Use with caution when combined with diuretics, ACE inhibitors, or angiotensin receptor blockers 2
• Risk of dehydration and orthostatic hypotension 2
• Canagliflozin specifically has been associated with increased risk of lower-limb amputation and fractures 2

Algorithm for SGLT2 Inhibitor Use for Weight Loss in T2DM

1. First-line therapy: Start with metformin and lifestyle modifications

2. Second-line therapy: Add SGLT2 inhibitor based on BMI:

   • For BMI <30 kg/m²: Either SGLT2 inhibitor or DPP-4 inhibitor
   • For BMI 30-35 kg/m²: Prefer SGLT2 inhibitor
   • For BMI >35 kg/m²: Consider GLP-1 RA first, SGLT2 inhibitor as alternative

3. Monitoring:

   • Track weight loss (expect 1-3 kg)
   • Monitor renal function (eGFR)
   • Watch for genital mycotic infections and UTIs
   • Assess for signs of dehydration or hypotension

4. Dose adjustment:

   • Reduce dose when eGFR <45 ml/min/1.73m²
   • Discontinue when eGFR <30 ml/min/1.73m²

Clinical Pearls

• Weight loss with SGLT2 inhibitors is modest but consistent across studies 1
• The effect appears to be most pronounced in the first 6 months of therapy
• Patients should be counseled about the potential for genital mycotic infections, particularly women with prior history 6
• SGLT2 inhibitors may be particularly beneficial in patients with T2DM complicated by hypertension due to their blood pressure-lowering effects 7
• When combined with dietary counseling, SGLT2 inhibitors may lead to greater loss of fat-free mass, which should be considered when prescribing 8

Remember that while SGLT2 inhibitors are effective for modest weight loss in type 2 diabetes, they are not approved for weight management in non-diabetic patients or in type 1 diabetes.