Can sitagliptin and empagliflozin (SGLT2 inhibitor) cause weight loss in a patient with type 2 diabetes mellitus (T2DM) and stable renal function?

Weight Loss Effects of Sitagliptin and Empagliflozin

Empagliflozin causes modest weight loss (typically 1.5-3.5 kg), while sitagliptin has a neutral effect on weight and does not cause weight loss. 1, 2

Empagliflozin (SGLT2 Inhibitor) and Weight Loss

Mechanism of Weight Loss

• Empagliflozin increases urinary glucose excretion by approximately 64-78 grams per day (equivalent to 200-400 kcal/day energy loss), which directly contributes to weight reduction 3, 4
• The drug promotes lipolysis and shifts metabolism toward fat utilization by increasing glucagon levels while reducing carbohydrate availability through glucosuria 2
• This metabolic shift creates a state where fat becomes the primary energy source, contributing to the observed weight loss 2

Expected Weight Loss Magnitude

• Clinical trials consistently demonstrate weight reductions of 1.5-3.5 kg with empagliflozin treatment 2
• Both early-stage and late-stage T2DM patients experience significant weight reduction, with late-stage patients showing greater weight loss 5
• The weight loss effect is maintained over time and does not diminish with continued treatment 6, 4

Important Caveat on Weight Loss

• The actual weight loss observed is less than predicted based solely on caloric loss from glucosuria 7
• Compensatory metabolic adaptations occur that partially offset the expected weight loss, including reductions in fibroblast growth factor 21 (FGF21) and changes in metabolic rate 7
• Despite these adaptations, clinically meaningful weight loss still occurs 2, 5

Renal Function Considerations

• Weight loss benefits are present when eGFR ≥45 mL/min/1.73 m², as glucose-lowering efficacy (and therefore glucosuria) is maintained at this level 8, 6
• As eGFR declines below 45 mL/min/1.73 m², the glucose-lowering and weight loss effects progressively diminish due to reduced filtered glucose load 8, 6
• For patients with stable renal function (eGFR ≥45), full weight loss benefits are expected 8

Sitagliptin (DPP-4 Inhibitor) and Weight

Weight Neutrality

• Sitagliptin and other DPP-4 inhibitors (linagliptin) have a neutral effect on weight and do not cause weight loss 1
• This weight-neutral profile distinguishes DPP-4 inhibitors from both SGLT2 inhibitors (which cause weight loss) and GLP-1 receptor agonists (which cause significant weight loss) 1

Clinical Positioning

• Guidelines acknowledge that sitagliptin has neutral effects on heart failure risk and can be used safely in patients where weight gain is a concern, but it should not be expected to contribute to weight reduction 1

Practical Clinical Summary

For a patient with T2DM and stable renal function:

• Empagliflozin will produce modest but consistent weight loss of 1.5-3.5 kg through increased urinary glucose excretion and metabolic shifts toward fat utilization 2, 5
• Sitagliptin will not cause weight loss or weight gain—it is weight-neutral 1
• If weight loss is a therapeutic goal, empagliflozin provides this benefit in addition to its cardiovascular and renal protective effects 1, 9