Are DPP-4 (Dipeptidyl Peptidase-4) inhibitors associated with weight loss?

DPP-4 Inhibitors and Weight Effects

DPP-4 inhibitors are generally weight neutral and do not promote weight loss in most patients with type 2 diabetes. 1

Weight Effects of DPP-4 Inhibitors

Primary Weight Impact

• DPP-4 inhibitors are predominantly weight neutral in their effects 2, 1
• They do not typically cause the weight gain associated with other diabetes medications such as sulfonylureas, thiazolidinediones, or insulin
• Their weight neutrality contrasts with:
  • GLP-1 receptor agonists, which promote weight loss
  • SGLT-2 inhibitors, which are associated with modest weight loss

Evidence for Weight Neutrality

• The American College of Physicians and other major guidelines characterize DPP-4 inhibitors as weight neutral 1
• Clinical trials have consistently shown minimal to no effect on body weight when DPP-4 inhibitors are used as monotherapy 3
• The weight neutrality is considered an advantage over older agents that cause weight gain, but a disadvantage compared to newer agents that promote weight loss 1

Exceptions and Special Circumstances

• Some studies have reported modest weight loss with vildagliptin in patients with relatively low baseline glycemia 4
• One small study (n=18) reported significant weight reduction (-12.5%) when sitagliptin was combined with metformin in obese patients with type 2 diabetes 5, but this finding is inconsistent with larger clinical trials and guideline statements

Mechanism of Weight Neutrality

• DPP-4 inhibitors work by preventing the inactivation of endogenous GLP-1, resulting in only modest increases in GLP-1 levels 3
• Unlike GLP-1 receptor agonists that can be dosed to pharmacologic levels and directly activate GLP-1 receptors, DPP-4 inhibitors produce more subtle effects 3
• The weight neutrality may be partially explained by:
  • Low risk of hypoglycemia (avoiding defensive eating) 4
  • Potential effects on chylomicron lipid and apolipoprotein levels 4
  • Possible influences on fatty acid mobilization and oxidation 4

Clinical Implications

• When weight loss is a priority in diabetes management:

  • SGLT-2 inhibitors or GLP-1 receptor agonists are preferred over DPP-4 inhibitors 2, 1
  • For patients with BMI >35 kg/m², GLP-1 receptor agonists are recommended as second-line therapy due to their greater weight loss potential 2
  • For patients with BMI 30-35 kg/m², SGLT-2 inhibitors may be preferred over DPP-4 inhibitors due to weight loss effects 2

• For patients where weight neutrality is acceptable:

  • DPP-4 inhibitors may be appropriate for patients with BMI <30 kg/m² 2
  • They offer a safe alternative with minimal hypoglycemia risk and no weight gain 1

Comparative Weight Effects Among Diabetes Medications

• Weight-promoting agents: Sulfonylureas, thiazolidinediones, insulin
• Weight-neutral agents: DPP-4 inhibitors
• Weight-reducing agents: SGLT-2 inhibitors (modest loss), GLP-1 receptor agonists (greater loss) 2, 1

The Israel National Diabetes Council specifically notes that "DPP-4 inhibitors might not be preferred in [patients with BMI 30-35 kg/m²] owing to the agents' weight neutrality" 2, highlighting that when weight loss is desirable, other agents may be more appropriate.