DPP-4 Inhibitor and SGLT-2 Inhibitor: Switch vs Add-On Strategy
Primary Recommendation
Add an SGLT-2 inhibitor to metformin and discontinue the DPP-4 inhibitor, as SGLT-2 inhibitors provide superior mortality and cardiovascular benefits that DPP-4 inhibitors do not deliver. 1, 2
Why SGLT-2 Inhibitors Are Superior to DPP-4 Inhibitors
Mortality and Morbidity Benefits
SGLT-2 inhibitors reduce all-cause mortality in patients with type 2 diabetes, while DPP-4 inhibitors do not. 1, 2
SGLT-2 inhibitors reduce major adverse cardiovascular events (MACE), whereas DPP-4 inhibitors show no cardiovascular benefit. 1, 2
SGLT-2 inhibitors prevent chronic kidney disease progression and reduce heart failure hospitalizations—benefits completely absent with DPP-4 inhibitors. 3, 1, 2
The American College of Physicians issues a strong recommendation against adding DPP-4 inhibitors to metformin for reducing morbidity and mortality, based on high-certainty evidence showing they provide only glycemic control without improving outcomes that matter. 1, 2
Glycemic Efficacy Comparison
Both drug classes reduce HbA1c by approximately 0.5-0.8%, making them equivalent for glucose lowering alone. 3, 4, 5
DPP-4 inhibitors actually increase HbA1c by 0.12% compared to sulfonylureas and 0.19% compared to thiazolidinediones in head-to-head comparisons. 3
Safety Profile
Both SGLT-2 inhibitors and DPP-4 inhibitors have significantly lower hypoglycemia risk compared to sulfonylureas (odds ratio 0.09 and 0.14, respectively). 3
SGLT-2 inhibitors promote weight loss of 2-3 kg, while DPP-4 inhibitors are weight neutral. 3, 1
Neither drug class causes hypoglycemia when used with metformin alone. 1, 6
Clinical Decision Algorithm
Step 1: Assess Current Regimen
If the patient is currently on metformin + DPP-4 inhibitor with inadequate glycemic control:
Discontinue the DPP-4 inhibitor and add an SGLT-2 inhibitor. 1, 2
The rationale: DPP-4 inhibitors offer no mortality or cardiovascular benefit, making them inferior second-line agents. 1, 2
Step 2: Prioritize SGLT-2 Inhibitor Selection Based on Comorbidities
For patients with heart failure or at risk for heart failure:
- Prioritize SGLT-2 inhibitors, as they reduce heart failure hospitalizations more effectively than any other oral agent. 3, 2
For patients with chronic kidney disease (eGFR ≥30 ml/min/1.73 m²):
- KDIGO guidelines strongly recommend SGLT-2 inhibitors to slow CKD progression. 3, 2
- SGLT-2 inhibitors can be initiated down to eGFR ≥20 ml/min/1.73 m² and continued even if eGFR falls below 30 ml/min/1.73 m² unless not tolerated. 3, 7
For patients with established cardiovascular disease:
Step 3: Consider Add-On Combination (DPP-4i + SGLT-2i) Only in Specific Circumstances
When might you add an SGLT-2 inhibitor to an existing DPP-4 inhibitor rather than switching?
If the patient has achieved partial glycemic improvement on metformin + DPP-4 inhibitor but remains above target (HbA1c 7-8%). 3
If the patient has contraindications to discontinuing the DPP-4 inhibitor (though this is rare). 4, 5
Evidence supporting combination therapy:
- Combining SGLT-2 inhibitors and DPP-4 inhibitors produces additive glucose-lowering effects without pharmacokinetic interactions. 4, 6, 5
- The combination is safe and does not increase hypoglycemia risk. 6, 5, 8
- Two fixed-dose combinations are FDA-approved: empagliflozin-linagliptin and dapagliflozin-saxagliptin. 9, 5, 8
However, the additional glucose-lowering effect is more pronounced when an SGLT-2 inhibitor is added to a DPP-4 inhibitor than vice versa. 4, 5
Practical Implementation
When Switching from DPP-4i to SGLT-2i
Stop the DPP-4 inhibitor immediately when starting the SGLT-2 inhibitor. 3
Continue metformin at the current dose unless eGFR falls below 45 ml/min/1.73 m², at which point reduce to half the maximum dose. 3, 2
If the patient is also on a sulfonylurea or insulin, reduce or discontinue the sulfonylurea and consider reducing total daily insulin dose by ~20% to prevent hypoglycemia. 3, 1
Monitoring After Initiating SGLT-2 Inhibitor
Monitor renal function (eGFR) at least annually, increasing frequency to every 3-6 months if eGFR <60 ml/min/1.73 m². 3, 7
A reversible decrease in eGFR with SGLT-2 inhibitor initiation may occur and is generally not an indication to discontinue therapy. 3
Educate patients regarding genital mycotic infections, symptoms of dehydration (lightheadedness, orthostasis, weakness), and diabetic ketoacidosis symptoms (nausea, vomiting, abdominal pain). 3
Self-monitoring of blood glucose may be unnecessary when using metformin plus SGLT-2 inhibitor due to low hypoglycemia risk. 1, 2
Target HbA1c and Follow-Up
Target HbA1c between 7% and 8% for most adults with type 2 diabetes. 1, 2, 7
Reassess glycemic control after 3 months on the new regimen. 3, 7
If HbA1c remains above target after 3 months, consider increasing the SGLT-2 inhibitor dose (e.g., empagliflozin 10 mg to 25 mg) or adding a third agent such as a GLP-1 receptor agonist or basal insulin. 3, 7
Critical Pitfalls to Avoid
Never combine a DPP-4 inhibitor with a GLP-1 receptor agonist, as they share overlapping mechanisms of action. 1
Do not delay switching from a DPP-4 inhibitor to an SGLT-2 inhibitor in patients with heart failure, CKD, or established cardiovascular disease, as you are withholding proven mortality and morbidity benefits. 3, 1, 2
Withhold SGLT-2 inhibitors during prolonged fasting, surgery, or critical medical illness when patients may be at greater risk for ketosis. 3
Consider decreasing thiazide or loop diuretic dosages before starting an SGLT-2 inhibitor if the patient is at risk for hypovolemia. 3
Do not stop metformin when adding an SGLT-2 inhibitor unless eGFR falls below 30 ml/min/1.73 m² or other contraindications emerge. 3, 2