In a patient with type 2 diabetes who is not achieving glycemic targets on oral hypoglycemic agents alone, when should insulin be added and how should it be combined with oral agents such as metformin, sulfonylureas, thiazolidinediones, DPP‑4 (dipeptidyl peptidase‑4) inhibitors, SGLT2 (sodium‑glucose cotransporter‑2) inhibitors, and GLP‑1 (glucagon‑like peptide‑1) receptor agonists?

Combining Insulin with Oral Hypoglycemic Agents in Type 2 Diabetes

When oral agents fail to achieve glycemic targets after 3 months, add basal insulin while continuing metformin, and consider adding GLP-1 receptor agonists or SGLT2 inhibitors before intensifying to complex insulin regimens. 1

When to Add Insulin to Oral Agents

Insulin should be added when HbA1c remains ≥7.5% (≥58 mmol/mol) after 3 months of optimized oral therapy, or immediately when HbA1c is ≥10% (≥86 mmol/mol) or blood glucose ≥300 mg/dL. 1, 2

• For newly diagnosed patients with markedly symptomatic hyperglycemia or very elevated glucose levels, consider insulin therapy with or without additional agents from the outset 1
• The progressive nature of type 2 diabetes means insulin therapy eventually becomes necessary for many patients within 5-10 years of diagnosis 1

Which Oral Agents to Continue with Insulin

Always Continue:

• Metformin should be continued when adding insulin unless contraindicated or not tolerated 1
• Metformin combined with insulin reduces weight gain, lowers insulin dose requirements, and decreases hypoglycemia compared to insulin alone 2, 3

Consider Adding or Continuing:

SGLT2 Inhibitors (Preferred for patients with cardiovascular disease, heart failure, or CKD):

• SGLT2 inhibitors added to insulin lower HbA1c by 0.5-1.0% without increasing insulin doses, weight gain, or hypoglycemia 1, 4
• Particularly beneficial in patients requiring large insulin doses, as they improve control and reduce insulin requirements 1
• Can be initiated if eGFR is above 20 mL/min/1.73 m² 1
• Important caveat: Insulin dose may need reduction when adding SGLT2 inhibitors to prevent hypoglycemia 1

GLP-1 Receptor Agonists (Preferred alternative to intensifying insulin):

• GLP-1 receptor agonists are the preferred injectable therapy before adding insulin in patients not already receiving them 1
• When basal insulin plus GLP-1 receptor agonist is used, consider fixed-ratio combination products (IDegLira or iGlarLixi) 1
• This combination provides similar or better HbA1c reduction than insulin alone, with lower hypoglycemia risk, weight loss instead of weight gain, and less frequent dosing 1
• May be continued when adding basal insulin but typically discontinued if transitioning to basal-bolus or premixed insulin regimens 1

Agents to Modify:

Sulfonylureas:

• May be continued with basal insulin but should be discontinued if transitioning to basal-bolus or premixed insulin regimens due to increased hypoglycemia risk 1
• The combination of insulin plus sulfonylurea is more effective than insulin alone in patients with residual insulin secretory capacity 5

DPP-4 Inhibitors:

• May be continued with basal insulin but typically discontinued with more complex insulin regimens 1
• Never combine DPP-4 inhibitors with GLP-1 receptor agonists—there is no added glucose-lowering benefit 1, 4

Thiazolidinediones:

• May improve control and reduce insulin requirements in patients needing large insulin doses 1
• Major caveat: Avoid in patients with heart failure risk due to edema and increased fracture risk 1

Practical Algorithm for Insulin Initiation

Step 1: Start with Basal Insulin

• Begin with once-daily basal insulin (NPH or long-acting analog) while continuing metformin 1
• Long-acting analogs (glargine, degludec, detemir) have reduced hypoglycemia risk, particularly overnight, compared to NPH insulin 1, 3
• Titrate based on fasting plasma glucose targets 1

Step 2: If Basal Insulin Fails (after 3-6 months)

If fasting glucose is controlled but HbA1c remains above target, or if insulin dose exceeds 0.5 U/kg/day: 1

Option A (Preferred): Add GLP-1 receptor agonist to basal insulin

• Provides weight loss, lower hypoglycemia risk, and once-weekly dosing options 1
• Continue metformin; consider discontinuing sulfonylureas and DPP-4 inhibitors 1

Option B: Add SGLT2 inhibitor to basal insulin

• Particularly beneficial for patients with cardiovascular disease, heart failure, or CKD 1, 4
• Reduces insulin requirements without increasing hypoglycemia 1

Option C: Add single injection of rapid-acting insulin before largest meal

• More flexible meal planning than premixed insulin 1
• Continue metformin; may continue or discontinue other oral agents 1

Option D: Switch to twice-daily premixed insulin

• Targets both fasting and postprandial glucose 1
• Requires relatively fixed meal schedule 1

Step 3: Further Intensification if Needed

• Progress to basal-bolus regimen (multiple daily injections) with one or two noninsulin agents 1
• At this stage, typically discontinue sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists 1
• Continue metformin and consider SGLT2 inhibitors or thiazolidinediones to reduce insulin requirements 1

Critical Pitfalls to Avoid

Therapeutic Inertia:

• Do not delay treatment intensification beyond 3 months if glycemic targets are not met 1, 4
• Oral medications should not be abruptly discontinued when starting insulin due to rebound hyperglycemia risk 2

Medication Combinations to Avoid:

• Never combine GLP-1 receptor agonists with DPP-4 inhibitors 1, 4
• Do not discontinue metformin unless contraindicated 1, 4

Patient-Specific Considerations:

• For patients with established cardiovascular disease: prioritize SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit 1, 4
• For patients with obesity: avoid insulin intensification if possible; prefer GLP-1 receptor agonists or SGLT2 inhibitors 1, 4
• For patients with CKD: GLP-1 receptor agonists are effective regardless of kidney function; SGLT2 inhibitors can be used if eGFR >20 mL/min/1.73 m² 1, 4