Combination Therapy for Type 2 Diabetes

Guideline Support

The American Diabetes Association recommends combining DPP-4 inhibitors (sitagliptin) and SGLT-2 inhibitors (empagliflozin) as appropriate combination therapy options when intensifying treatment beyond metformin 1, 2, 3
The European Society of Cardiology confirms that DPP-4 inhibitors like sitagliptin have a neutral effect on heart failure risk and may be considered in combination with other agents, including SGLT-2 inhibitors 4

Empagliflozin carries a Class I recommendation to reduce cardiovascular death (38% reduction) and heart failure hospitalization in patients with type 2 diabetes and established cardiovascular disease 2, 4
Sitagliptin has demonstrated cardiovascular safety with neutral effects on major cardiovascular events and heart failure risk 1, 4

Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative euglycemic ketoacidosis, and stop SGLT-2 inhibitors immediately if symptoms of ketoacidosis develop 1, 3
Avoid saxagliptin in combination with empagliflozin if the patient has heart failure, and use sitagliptin instead 4

In patients with established cardiovascular disease or chronic kidney disease, prioritize empagliflozin as the foundational agent given its mortality and cardiovascular event reduction benefits, then add sitagliptin if additional glycemic control is needed 4

The European Society of Cardiology recommends SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes and cardiovascular disease or high cardiovascular risk to reduce cardiovascular events 5, 6
The European Society of Cardiology suggests that DPP4 inhibitors, such as sitagliptin, have a neutral effect on the risk of heart failure and may be considered in patients with diabetes 5, 6, 7
SGLT2 inhibitors are recommended to reduce the progression of diabetic kidney disease 7
Unlike saxagliptin, sitagliptin is not contraindicated in patients with heart failure 5, 6, 7

Dapagliflozin works by inhibiting SGLT2 in the kidneys, increasing urinary glucose excretion and reducing hyperglycemia 8, 9

Dapagliflozin should be used with caution in patients with renal insufficiency (GFR < 45 mL/min/1.73 m²) 9, 10

When considering adding sitagliptin to dapagliflozin, assess renal function, as both medications have different considerations in renal impairment 9
The combination of sitagliptin and dapagliflozin may be particularly beneficial for patients not achieving glycemic targets on monotherapy 11

The American College of Cardiology recommends dapagliflozin for cardiovascular event reduction in patients with type 2 diabetes and cardiovascular disease, with benefits including a 18-26% reduction in cardiovascular death and heart failure hospitalization 12, 13
Dapagliflozin provides primary cardiovascular and mortality benefits in combination with DPP-4 inhibitors, with a 30% reduction in heart failure hospitalization in HFrEF and 18% in HFpEF 12
Sitagliptin has proven cardiovascular safety with neutral effects on major cardiovascular events and heart failure risk in the TECOS trial, and is preferred over linagliptin due to its more robust cardiovascular safety data 14

Dapagliflozin reduces progression of diabetic kidney disease with a 39% reduction in composite renal outcomes, and a 44% reduction in sustained eGFR decline ≥50%, end-stage kidney disease, or renal death 15
The European Society of Cardiology recommends continuing dapagliflozin for cardiorenal benefits even when eGFR falls below glycemic efficacy threshold 15
Linagliptin is preferred over sitagliptin if eGFR <45 mL/min/1.73 m² to avoid dose adjustments, with no dose adjustment required for linagliptin in renal impairment 16

The American College of Cardiology advises against using saxagliptin in patients with heart failure risk due to increased heart failure hospitalization, and recommends sitagliptin or linagliptin instead 14, 16
Dapagliflozin is contraindicated in patients with a history of serious hypersensitivity reaction, severe renal impairment (eGFR <25 mL/min/1.73 m²), end-stage renal disease, or dialysis for heart failure/CKD indications, and in patients with type 1 diabetes mellitus 17

The American Diabetes Association recommends prioritizing dapagliflozin as the foundational agent in patients with established cardiovascular disease, then adding sitagliptin if additional glycemic control is needed 17
Elderly patients require careful assessment of renal function and volume status before initiation of dapagliflozin due to higher incidence of adverse reactions related to hypotension and volume depletion 14