What are the recommended pharmacologic treatment options for type 1 and type 2 diabetes, including first‑line agents, second‑line choices, and insulin regimens?

Pharmacologic Treatment for Diabetes Mellitus

Type 1 Diabetes: Insulin is Mandatory

All patients with type 1 diabetes require immediate insulin therapy using either multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) via pump, with insulin analogs strongly preferred over human insulins to reduce hypoglycemia risk. 1, 2

Initial Insulin Regimen

• Start with 0.5 units/kg/day total daily insulin dose in metabolically stable patients, split approximately 50% as basal insulin and 50% as prandial insulin 1, 2
• Higher doses (up to 1.0 units/kg/day) are required during puberty, pregnancy, or acute illness 1, 2
• Patients presenting with diabetic ketoacidosis require higher weight-based dosing initially 1

Specific Insulin Selection

• Use rapid-acting insulin analogs (aspart, lispro, or glulisine) for prandial coverage rather than regular human insulin to minimize hypoglycemia 1, 2
• Use long-acting basal analogs (glargine, degludec) over NPH insulin due to reduced hypoglycemia risk and more stable pharmacokinetics 2
• Multiple daily injections with basal-bolus regimen is first-line treatment 2

Advanced Delivery Systems

• Automated insulin delivery systems should be considered for all adults with type 1 diabetes to improve glycemic control and reduce hypoglycemia 1, 2
• Insulin pump therapy (CSII) offers modest advantages, lowering A1C by approximately 0.30% and reducing severe hypoglycemia rates compared to MDI 3
• Consider CSII if not meeting glycemic targets, experiencing frequent/severe hypoglycemia, or pronounced dawn phenomenon 2

Adjunctive Therapy (Limited Role)

• Pramlintide is the only FDA-approved adjunctive agent for type 1 diabetes, showing variable A1C reductions (0-0.3%) and modest weight loss (1-2 kg) 3
• Metformin, GLP-1 receptor agonists, and SGLT2 inhibitors are not approved for type 1 diabetes despite some efficacy data 3
• SGLT2 inhibitors carry a two- to fourfold increased risk of ketoacidosis in type 1 diabetes and should be avoided 3

Critical Patient Education Requirements

• Educate on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity 1, 2
• Teach correction dose calculation based on concurrent glycemia and glycemic trends 1
• All patients must be prescribed glucagon with family/caregivers trained on administration 1, 2
• Glucagon preparations that do not require reconstitution are preferred for ease of emergency use 1

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Type 2 Diabetes: Metformin First, Then Individualize

Metformin is the preferred initial pharmacologic agent for type 2 diabetes and should be started at diagnosis along with lifestyle modifications unless contraindicated or not tolerated. 3, 2

First-Line Therapy

• Start metformin monotherapy combined with comprehensive lifestyle modification at the time type 2 diabetes is diagnosed 3
• Once initiated, metformin should be continued as long as tolerated and not contraindicated; other agents should be added to metformin, not substituted 3
• Early combination therapy can be considered in patients with newly diagnosed type 2 diabetes who have A1C ≥1.5% above their glycemic target 3

When to Start Insulin Immediately

Introduce insulin early if there is evidence of ongoing catabolism (weight loss), symptoms of hyperglycemia, or when A1C levels >10% (86 mmol/mol) or blood glucose levels ≥300 mg/dL (16.7 mmol/L). 3

Second-Line Agent Selection: Comorbidity-Driven Approach

Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD) or indicators of high cardiovascular risk, a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular benefit is recommended as part of the glucose-lowering regimen independent of A1C. 3

Specific Comorbidity Algorithms:

• ASCVD or high ASCVD risk: Add GLP-1 receptor agonist (preferred) or SGLT2 inhibitor with proven cardiovascular benefit 3
• Heart failure or high heart failure risk: Add SGLT2 inhibitor (preferred over GLP-1 receptor agonist) 3
• Chronic kidney disease: Add SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated renal benefit 3

Injectable Therapy Preference

In patients with type 2 diabetes who need greater glucose lowering than can be obtained with oral agents, GLP-1 receptor agonists are preferred to insulin when possible. 3

• If insulin is used, combination therapy with a GLP-1 receptor agonist is recommended for greater efficacy and durability 3

Treatment Intensification

• Do not delay intensification of treatment for patients not meeting glycemic goals 3
• Medication regimen should be reevaluated at regular intervals (every 3-6 months) and adjusted as needed 3
• Be aware of overbasalization with insulin therapy: signals include basal dose >0.5 IU/kg/day, high bedtime-morning glucose differential, hypoglycemia, and high glycemic variability 3

Important Metformin Considerations

• Long-term metformin use may be associated with vitamin B12 deficiency; periodic measurement of vitamin B12 levels should be considered, especially in patients with anemia or peripheral neuropathy 3

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Youth-Onset Type 2 Diabetes: Special Considerations

For youth with type 2 diabetes presenting with ketoacidosis, marked ketosis, random blood glucose ≥250 mg/dL, or A1C ≥8.5%, start with insulin therapy until glycemia is restored, then add metformin. 3

Pharmacologic Options in Youth

• When initial insulin is not required, metformin is recommended as first-line therapy 3
• GLP-1 receptor agonists are safe and effective for decreasing A1C and promoting weight loss in youth 3
• Empagliflozin (SGLT2 inhibitor) is now approved for youth with type 2 diabetes 3
• GLP-1 receptor agonists should not be used in individuals with family history of medullary thyroid cancer 3

Interprofessional Team Approach

• An interprofessional diabetes team including physician, diabetes care and education specialist, registered dietitian nutritionist, and behavioral health specialist is essential 3
• Family-centered approach to nutrition and lifestyle modification is critical, with culturally appropriate recommendations 3