What oral hypoglycemics (oral medications that lower blood sugar) can aid in weight loss?

Oral Hypoglycemic Medications That Help With Weight Loss

GLP-1 receptor agonists, SGLT2 inhibitors, and metformin are the oral hypoglycemic medications that can aid in weight loss, with newer oral GLP-1 receptor agonists showing the strongest weight loss effects.

Medications Associated with Weight Loss

GLP-1 Receptor Agonists

• GLP-1 receptor agonists are highly effective for glucose control and promote significant weight loss by suppressing appetite, delaying gastric emptying, and enhancing satiety 1, 2
• Injectable GLP-1 receptor agonists have been well-established, but oral formulations are now available 2
• Oral semaglutide was FDA-approved for type 2 diabetes in 2019 and shows promising weight loss effects 2
• Recent evidence shows that semaglutide can produce strong weight loss (greater than 5% of initial body weight) 3
• Other oral GLP-1 receptor agonists in development include danuglipron and orforglipron 2

SGLT2 Inhibitors

• SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) promote weight loss of approximately 1.5-3.5 kg 1
• They work by increasing urinary glucose excretion, which results in caloric loss 1
• Different SGLT2 inhibitors vary in their weight loss effects:
  • Empagliflozin produces mild weight loss (less than 3.2% of initial weight) 3
  • Canagliflozin, ertugliflozin, and dapagliflozin induce moderate weight loss (between 3.2% and 5%) 3
• SGLT2 inhibitors also provide cardiovascular and renal benefits beyond glycemic control 1, 4

Metformin

• Metformin is the preferred first-line agent for type 2 diabetes and is associated with modest weight loss or weight neutrality 1
• Studies show an average weight loss of 5.6±6.5% in overweight and obese patients treated with metformin 5
• Weight loss effects appear to be greater in insulin-resistant patients 5
• Metformin works primarily by reducing hepatic glucose production and improving insulin sensitivity 1

Medications Associated with Weight Gain

Sulfonylureas

• Sulfonylureas stimulate insulin secretion from pancreatic β-cells and are associated with weight gain 1
• The weight gain is relatively modest compared to insulin but still significant 1
• Newer-generation sulfonylureas (glipizide, glimepiride, gliclazide) may have a lower risk of hypoglycemia but still contribute to weight gain 1

Thiazolidinediones (TZDs)

• TZDs (pioglitazone, rosiglitazone) increase insulin sensitivity but are associated with significant weight gain 1
• They also cause fluid retention and edema, which contributes to the weight gain 1
• Lower-dose therapy (e.g., pioglitazone 15-30 mg) may mitigate weight gain but still has this effect 1

Insulin

• Insulin therapy is associated with the most significant weight gain among diabetes medications 1
• The weight gain is dose-dependent and can be substantial 1

Clinical Decision Algorithm for Weight-Conscious Medication Selection

1. First-line therapy: Metformin (unless contraindicated) due to its modest weight loss effects and established safety profile 1, 6

2. Second-line options (if additional glycemic control is needed):

   • For patients where weight loss is a primary concern: Add an SGLT2 inhibitor or GLP-1 receptor agonist 1
   • For patients with established cardiovascular disease: Consider SGLT2 inhibitors which offer both weight loss and cardiovascular benefits 4

3. Third-line options:

   • Consider combination therapy with metformin + SGLT2 inhibitor + GLP-1 receptor agonist for maximal weight loss effect 1
   • Avoid adding medications associated with weight gain (sulfonylureas, TZDs, insulin) unless absolutely necessary for glycemic control 6

Important Considerations and Caveats

• Patient selection: Weight loss effects vary between individuals; insulin-resistant patients may experience greater weight loss with metformin 5
• Medication costs: Newer agents (GLP-1 receptor agonists, SGLT2 inhibitors) are generally more expensive than older medications like metformin and sulfonylureas 1
• Side effects:
  • SGLT2 inhibitors: Monitor for genitourinary infections, ketoacidosis risk, and potential for dehydration 1
  • GLP-1 receptor agonists: Gastrointestinal side effects (nausea, vomiting) are common, especially during initiation 1
  • Metformin: Gastrointestinal side effects and rare risk of lactic acidosis in patients with renal insufficiency 1
• Elderly patients: Consider less stringent glycemic targets and carefully evaluate medication choices due to increased risk of adverse effects 1

Comparative Weight Effects of Oral Hypoglycemic Medications

• Strong weight loss (>5% of initial weight): Oral semaglutide 3
• Moderate weight loss (3.2-5%): Canagliflozin, ertugliflozin, dapagliflozin 3
• Mild weight loss (<3.2%): Metformin, empagliflozin, acarbose 3
• Weight neutral: DPP-4 inhibitors 1
• Weight gain: Sulfonylureas, thiazolidinediones, insulin 1