What are the treatment options for uncontrolled diabetes?

Treatment of Uncontrolled Diabetes

Start metformin immediately at diagnosis alongside lifestyle modifications for all patients with type 2 diabetes unless contraindicated, and add insulin promptly if A1C ≥10% (86 mmol/mol), blood glucose ≥300 mg/dL (16.7 mmol/L), or if catabolic symptoms (weight loss, ketosis) are present. 1

Initial Assessment and Immediate Treatment

Severe Hyperglycemia Requiring Insulin

• Initiate insulin immediately if any of the following are present 1:

  • A1C >10% (86 mmol/mol)
  • Blood glucose ≥300 mg/dL (16.7 mmol/L)
  • Evidence of catabolism (weight loss, ketonuria)
  • Symptomatic hyperglycemia (polyuria, polydipsia, weight loss)

• Start basal insulin at 10 units or 0.1-0.2 units/kg/day in combination with metformin 1

• Once glucose toxicity resolves, oral agents can often be intensified and insulin potentially withdrawn 1

Moderate Hyperglycemia (A1C <10%)

• Start metformin 500-850 mg daily, titrate up to 2000 mg/day as tolerated over 1-2 weeks 1
• Metformin is effective, safe, inexpensive, and may reduce cardiovascular events and death 1
• Continue metformin even when adding other agents unless contraindicated 1

Treatment Intensification Algorithm

When Metformin Monotherapy Fails (A1C remains above target after 3 months)

For patients with established cardiovascular disease, heart failure, or chronic kidney disease:

• Add a GLP-1 receptor agonist (preferred over insulin) with demonstrated cardiovascular benefit 1
• Alternative: Add SGLT2 inhibitor with cardiovascular/renal benefit 1
• These agents should be added independent of A1C level in patients with these comorbidities 1

For patients without cardiovascular/renal disease:

• Add one of the following based on patient factors 1:
  • GLP-1 receptor agonist (preferred if weight loss desired, lower hypoglycemia risk)
  • Basal insulin (most effective for severe hyperglycemia)
  • Sulfonylurea (effective but causes weight gain and hypoglycemia)
  • DPP-4 inhibitor (weight neutral, low hypoglycemia risk)
  • SGLT2 inhibitor (promotes weight loss, low hypoglycemia risk)
  • Thiazolidinedione (pioglitazone preferred over rosiglitazone) 1

Dual Therapy Failure

If A1C remains above target on metformin plus one agent:

• Add basal insulin if not already using it 1
• Start at 10 units or 0.1-0.2 units/kg daily, titrate based on fasting glucose 1
• Combine insulin with GLP-1 receptor agonist when possible to minimize weight gain and hypoglycemia 1
• Continue metformin; consider discontinuing sulfonylureas or DPP-4 inhibitors when starting complex insulin regimens 1

Basal Insulin Inadequate (Fasting glucose controlled but A1C still elevated)

Progress to combination injectable therapy 1:

1. Add GLP-1 receptor agonist to basal insulin (preferred—less hypoglycemia, promotes weight loss) 1
2. Add mealtime rapid-acting insulin before largest meal initially, then expand to other meals as needed 1
3. Switch to premixed insulin twice daily (70/30 NPH/regular or analogue mixes) 1

• Titrate both basal and prandial insulin based on glucose patterns 1
• If basal insulin dose exceeds 0.5 units/kg/day without achieving targets, consider "overbasalization"—add prandial coverage rather than increasing basal further 1

Critical Pitfalls to Avoid

Do not delay treatment intensification 1:

• Reassess every 3-6 months and adjust therapy if targets not met 1
• Progressive beta-cell failure means most patients will require multiple agents over time 1

Avoid inappropriate insulin escalation 1:

• Watch for overbasalization: basal dose >0.5 units/kg/day, high glucose variability, or hypoglycemia
• These signal need for prandial insulin, not more basal insulin 1

Monitor for metformin-associated vitamin B12 deficiency 1:

• Consider periodic B12 testing in patients on long-term metformin 1

Adjust metformin dose in renal impairment 1:

• Can continue with dose reduction down to GFR 30-45 mL/min 1

Special Populations

Youth with Type 2 Diabetes

• If A1C ≥8.5% (69 mmol/mol) or glucose ≥250 mg/dL at diagnosis: start basal insulin 0.5 units/kg/day plus metformin 1
• If A1C <8.5% without ketosis: start metformin alone, titrate to 2000 mg/day 1
• If targets not met: add liraglutide (age ≥10 years) or intensify insulin 1

Pregnancy

• Insulin is preferred treatment when pharmacotherapy needed 2
• Metformin and oral agents generally avoided 2