Available Combination Diabetes Medications
For type 2 diabetes requiring combination therapy, metformin should be paired with one of six evidence-based options: sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, or basal insulin. 1
Oral Combination Therapies
Metformin-Based Dual Combinations
When metformin monotherapy fails to achieve HbA1c targets after 3 months, add one of the following agents 1:
Metformin + Sulfonylurea: Reduces HbA1c by approximately 1.0 percentage point beyond metformin alone; most cost-effective option but carries hypoglycemia risk (15-43% incidence when combined with metformin) 1, 2
Metformin + DPP-4 Inhibitor (sitagliptin, saxagliptin, alogliptin): Reduces HbA1c by 0.69 percentage points less than metformin + sulfonylurea; weight-neutral with lower hypoglycemia risk 1
- Caution: Saxagliptin and alogliptin may increase heart failure risk, especially in patients with preexisting heart failure or renal impairment 1
Metformin + Thiazolidinedione (pioglitazone, rosiglitazone): Reduces HbA1c by 0.66 percentage points; causes weight gain (2.2 kg more than metformin alone) and increases bone fracture risk in postmenopausal women 1
Metformin + SGLT2 Inhibitor (canagliflozin, empagliflozin, dapagliflozin): Provides cardiovascular and renal benefits in high-risk patients; empagliflozin and liraglutide specifically reduce cardiovascular death in patients with established atherosclerotic disease 1
Metformin + GLP-1 Receptor Agonist (liraglutide, exenatide, dulaglutide): Liraglutide reduces cardiovascular events in patients with established cardiovascular disease; promotes weight loss (2.5 kg more than sulfonylureas) 1
Fixed-Dose Combination Products
Single-pill combinations improve adherence but limit dose flexibility 3:
- Metformin/sulfonylurea combinations
- Metformin/DPP-4 inhibitor combinations
- Metformin/SGLT2 inhibitor combinations
- Metformin/thiazolidinedione combinations
Injectable Combination Therapies
Metformin + Basal Insulin
When oral agents fail, add basal insulin (NPH, glargine, detemir, or degludec) to metformin 1
Fixed-Dual Injectable Combinations
Two once-daily products combine basal insulin with GLP-1 receptor agonist 1:
- Insulin glargine + lixisenatide
- Insulin degludec + liraglutide
These combinations provide potent glucose-lowering with less weight gain and hypoglycemia compared to intensified insulin regimens 1
Basal-Bolus Regimens
If basal insulin alone is insufficient (dose >0.5 units/kg/day or fasting glucose controlled but HbA1c remains elevated), advance to 1:
- Basal insulin + single prandial insulin dose (with largest meal)
- Basal insulin + multiple prandial doses
- Twice-daily premixed insulin (NPH/regular 70/30 or analog premixes)
Triple Combination Therapy
When dual therapy fails, common three-drug regimens include 1:
- Metformin + sulfonylurea + basal insulin: Most studied combination
- Metformin + sulfonylurea + DPP-4 inhibitor: Hypoglycemia rate 40.7-43.2% 2
- Metformin + pioglitazone + SGLT2 inhibitor: Hypoglycemia rate 2.7-5.3% 2
Critical Rule: When adding insulin to combination therapy, discontinue DPP-4 inhibitors and sulfonylureas to reduce hypoglycemia risk; maintain metformin, thiazolidinediones, or SGLT2 inhibitors as adjunctive agents 1
Initial Dual Therapy (Bypassing Monotherapy)
Start with two agents simultaneously when 1:
- HbA1c ≥9%: Begin metformin + second agent immediately
- HbA1c ≥10-12% with symptoms: Begin metformin + basal insulin
- Glucose ≥300-350 mg/dL with catabolic features: Begin basal + prandial insulin (may taper to oral agents once symptoms resolve) 1
Medication Selection Priority for High-Risk Patients
In patients with established cardiovascular disease, heart failure, or chronic kidney disease, prioritize SGLT2 inhibitors or GLP-1 receptor agonists over all other second-line agents, including sulfonylureas 4, 5
This recommendation supersedes cost considerations due to superior mortality and morbidity outcomes in these populations 1, 4