Oral Hypoglycemic Agents and Insulin for Type 2 Diabetes
First-Line Therapy: Metformin
Metformin is the preferred initial pharmacologic agent for type 2 diabetes and should be started at diagnosis unless contraindicated or not tolerated. 1, 2
- Start metformin at a low dose with gradual titration to minimize gastrointestinal side effects (bloating, abdominal discomfort, diarrhea) 1
- Continue metformin indefinitely as long as tolerated and not contraindicated, even when adding other agents including insulin 1
- Metformin is effective, safe, inexpensive, and may reduce cardiovascular events and death 1
- Safe to use with eGFR ≥30 mL/min/1.73 m² per FDA labeling 1
- Monitor for vitamin B12 deficiency with long-term use, especially in patients with anemia or peripheral neuropathy 2
When to Start Insulin Immediately
Initiate insulin therapy from the outset when patients present with severe hyperglycemia, metabolic decompensation, or catabolic features. 1
Specific criteria for immediate insulin initiation:
- Blood glucose ≥300 mg/dL (16.7 mmol/L) 1
- HbA1c ≥10% (86 mmol/mol) 1
- Presence of hyperglycemic symptoms (polyuria, polydipsia, weight loss) 1
- Evidence of ongoing catabolism 1
- Ketonuria present 1
Once symptoms resolve, you can taper insulin and transition to oral agents in type 2 diabetes patients. 1
Second-Line Therapy After Metformin
Priority Agents Based on Comorbidities
For patients with established cardiovascular disease, kidney disease, or heart failure, add an SGLT-2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit, independent of HbA1c level. 1, 2
- SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiovascular events, chronic kidney disease progression, and heart failure hospitalizations 2
- GLP-1 receptor agonists reduce all-cause mortality, major adverse cardiovascular events, and stroke 2
- Prioritize SGLT-2 inhibitors for heart failure or chronic kidney disease 2
- Prioritize GLP-1 receptor agonists for stroke risk or when weight loss is needed 2
Other Second-Line Options
When cardiovascular/renal comorbidities are absent, choose from:
Sulfonylureas:
- High hypoglycemia risk 1
- Moderate weight gain 1
- Low cost 1
- Maximal glucose-lowering effect achieved at ~50% of maximum recommended dose 3
Thiazolidinediones (TZDs):
- Low hypoglycemia risk 1
- High weight gain 1
- Side effects: edema, heart failure, bone fractures 1
- High cost 1
DPP-4 Inhibitors:
GLP-1 Receptor Agonists:
- Low hypoglycemia risk 1
- Weight loss 1
- Gastrointestinal side effects 1
- High cost 1
- Preferred over insulin when greater glucose lowering is needed beyond oral agents 1
Combination Therapy Strategy
If metformin monotherapy fails to achieve HbA1c target after ~3 months, add a second agent. 1
- Early combination therapy can be considered at diagnosis if HbA1c ≥9% 1
- Each additional noninsulin agent typically lowers HbA1c by 0.9-1.1% 1
- When adding SGLT-2 inhibitors or GLP-1 agonists that provide adequate control, reduce or discontinue sulfonylureas or long-acting insulin to minimize hypoglycemia 2
- Do not delay treatment intensification if targets are not met 1
Insulin Therapy
Types of Insulin
Basal Insulins (Long-Acting):
- Insulin glargine 4
- Insulin detemir (may require higher doses than glargine) 1
- Insulin degludec 5
- NPH insulin (intermediate-acting, lower cost but higher nocturnal hypoglycemia risk) 1, 6
Prandial Insulins (Rapid-Acting Analogs):
- Insulin lispro 1, 7
- Insulin aspart 1
- Insulin glulisine 1
- These provide better postprandial control than regular human insulin and can be dosed just before meals 1
Initiating Basal Insulin
Start basal insulin at 10 units or 0.1-0.2 units/kg body weight. 1
- Continue metformin when starting insulin 1, 5
- Titrate based on fasting blood glucose monitoring 1
- If basal insulin alone (up to 1.5 units/kg/day) fails to achieve HbA1c target, advance to multiple daily injections with basal plus prandial insulin 1
Combination Injectable Therapy
When basal insulin is titrated to acceptable fasting glucose but HbA1c remains above target, consider adding a GLP-1 receptor agonist before advancing to multiple daily injections. 5
- Fixed combination products (insulin degludec plus liraglutide) are available 5
- Discontinue sulfonylureas and DPP-4 inhibitors when initiating combination injectable therapy 5
- SGLT-2 inhibitors may be continued as adjunctive therapy to reduce insulin requirements 5
Complex Insulin Regimens
Progress to multiple daily injections (basal plus prandial insulin) if combination therapy with basal insulin fails after 3-6 months. 1
- Design insulin programs to match dietary/exercise habits and glucose trends 1
- Provide comprehensive patient education on glucose monitoring, injection technique, insulin storage, hypoglycemia recognition/treatment, and sick day rules 1
Special Considerations for Hypoglycemia Risk
Metformin, thiazolidinediones, and acarbose carry low hypoglycemia risk and do not require dose reduction for hypoglycemia concerns. 8
- Glibenclamide (glyburide) carries the highest hypoglycemia risk among sulfonylureas 8
- Glimepiride may have lower hypoglycemia risk than glibenclamide 8
- Short-acting secretagogues (nateglinide, repaglinide) may reduce hypoglycemia risk compared to glibenclamide, particularly with flexible dosing 8
- For patients with frequent severe hypoglycemia on human insulins, switch to long-acting insulin analogs like insulin degludec 5
Glycemic Targets
Target HbA1c of 7-8% for most adults with type 2 diabetes. 2
- More stringent targets (<6.5%) may be appropriate for selected patients if achievable without significant hypoglycemia 1
- Consider deintensifying treatment if HbA1c <6.5% 2
- Individualize targets based on hypoglycemia risk, life expectancy, diabetes duration, vascular complications, and comorbidities 2
Monitoring
Reassess medication regimen every 3-6 months and adjust based on HbA1c results and patient-specific factors. 1