Why can't you take a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor and a Dipeptidyl Peptidase-4 (DPP-4) inhibitor at the same time?

Why SGLT2 Inhibitors and DPP-4 Inhibitors Should Not Be Used Together

GLP-1 receptor agonists should not be used in combination with DPP-4 inhibitors, as explicitly stated in clinical practice guidelines. 1

Mechanism and Rationale

The contraindication between SGLT2 inhibitors and DPP-4 inhibitors is often misunderstood. In fact, these two medication classes can be used together, but there are specific combinations that should be avoided:

What IS Contraindicated:

• GLP-1 receptor agonists should NOT be combined with DPP-4 inhibitors 1
• This is clearly stated in Practice Point 4.3.3 of the KDIGO 2020 clinical practice guidelines

Why GLP-1 RAs and DPP-4 Inhibitors Cannot Be Combined:

• Both medication classes work on the incretin pathway:
  • DPP-4 inhibitors prevent breakdown of endogenous GLP-1
  • GLP-1 receptor agonists directly stimulate GLP-1 receptors
• Using both simultaneously provides minimal additional benefit while increasing cost and potential side effects
• They have overlapping mechanisms that make combination therapy inefficient

SGLT2 Inhibitors and DPP-4 Inhibitors CAN Be Used Together

Contrary to common misconception, SGLT2 inhibitors and DPP-4 inhibitors can be used in combination:

• These medications have complementary mechanisms of action 1:

  • SGLT2 inhibitors work in the kidneys to increase glucose excretion
  • DPP-4 inhibitors work through the incretin pathway to increase insulin secretion and decrease glucagon

• The American College of Cardiology explicitly states: "it appears reasonable to use both an SGLT2 inhibitor and a GLP-1RA with demonstrated CV benefit concomitantly if clinically indicated" 1

• Several fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors are available, including:

  • Saxagliptin-dapagliflozin
  • Linagliptin-empagliflozin 2

Common Confusion Points

The confusion may arise from:

1. The contraindication between GLP-1 RAs and DPP-4 inhibitors (which is real)
2. Concerns about hypoglycemia when combining multiple diabetes medications
3. Cost considerations with using two newer medication classes

Appropriate Combination Therapy

When considering combination therapy:

• For patients not at glycemic target on metformin, adding either an SGLT2 inhibitor or a DPP-4 inhibitor is appropriate 1
• For patients with cardiovascular disease or kidney disease, SGLT2 inhibitors are preferred 1
• When using SGLT2 inhibitors with insulin or sulfonylureas, dose reductions of the latter may be needed to prevent hypoglycemia 1

Monitoring When Using Combination Therapy

When using SGLT2 inhibitors (alone or in combination):

• Monitor for genital mycotic infections
• Watch for signs of euglycemic diabetic ketoacidosis
• Assess volume status, especially if combined with diuretics
• Monitor renal function, though SGLT2 inhibitors can be continued even if eGFR falls below 30 ml/min/1.73m² as long as well tolerated 1

Bottom Line

The combination of SGLT2 inhibitors and DPP-4 inhibitors is not contraindicated and can be an effective treatment strategy for type 2 diabetes. However, GLP-1 receptor agonists should not be used with DPP-4 inhibitors due to their overlapping mechanisms of action.