What is the initial treatment for diabetes mellitus (DM), specifically type 2 diabetes mellitus (T2DM)?

Initial Treatment for Type 2 Diabetes Mellitus

The initial treatment for type 2 diabetes mellitus (T2DM) should begin with lifestyle modifications, and if these are not sufficient to achieve glycemic goals, metformin should be added at or soon after diagnosis as the preferred first-line pharmacologic agent. 1, 2

Lifestyle Modifications

• Newly diagnosed patients who are overweight or obese should begin lifestyle modifications, including physical activity, and be counseled to lose at least 5% of their body weight 1
• Physical activity should include aerobic, muscle-strengthening, and bone-strengthening activities, which can reduce HbA1c by 0.4% to 1.0% and improve cardiovascular risk factors 1, 3
• A family-centered approach to nutrition and lifestyle modification is essential, with nutrition recommendations being culturally appropriate and sensitive to family resources 1
• Despite the importance of lifestyle changes, many patients with T2DM do not perceive these changes, particularly in the area of physical activity, as an essential part of treatment 4

Pharmacological Treatment Algorithm

First-Line Therapy

• If lifestyle efforts are not sufficient to maintain or achieve glycemic goals, metformin therapy (if tolerated or not contraindicated) should be added at or soon after diagnosis 1
• Metformin is the preferred initial pharmacologic agent (A rating) because:
  • It is inexpensive
  • It has a long-established evidence base for efficacy and safety
  • It may reduce risk for cardiovascular events and death 1
  • It can be continued in patients with declining renal function down to a glomerular filtration rate (GFR) of 30 to 45 mL/min, although the dose should be reduced 1

Special Circumstances Requiring Insulin First

• Initial treatment should be with insulin instead of metformin in the following situations:
  • Patients presenting with ketosis or ketoacidosis 1
  • When the distinction between type 1 and type 2 diabetes is unclear 1
  • In patients with marked hyperglycemia (blood glucose ≥250 mg/dL, HbA1c ≥8.5%) who are symptomatic with polyuria, polydipsia, nocturia, and/or weight loss 1, 2
  • In patients with severe hyperglycemia (blood glucose ≥600 mg/dL) where hyperosmolar hyperglycemic syndrome should be considered 1

Combination Therapy

• When monotherapy with metformin at the maximum tolerated dose does not achieve or maintain the HbA1c target over 3 months, a second agent should be added 1
• Providers should consider a combination of metformin and one of these 6 treatment options:
  • Sulfonylureas
  • Thiazolidinediones
  • Dipeptidyl peptidase-4 inhibitors
  • Sodium–glucose cotransporter 2 (SGLT2) inhibitors
  • Glucagon-like peptide-1 (GLP-1) agonists
  • Basal insulin 1
• For patients with established cardiovascular disease, heart failure, or chronic kidney disease, add an SGLT-2 inhibitor 2
• For patients at increased risk for stroke or for whom weight loss is an important goal, add a GLP-1 receptor agonist 2
• Initial dual-regimen combination therapy should be used when the HbA1c level is 9% or greater to more quickly achieve glycemic control 1

Special Considerations for Youth with T2DM

• In youth with T2DM who are metabolically stable (A1C <8.5% and asymptomatic), metformin is the initial pharmacologic treatment of choice if renal function is normal 1
• Youth with marked hyperglycemia (blood glucose ≥250 mg/dL, A1C ≥8.5%) without acidosis who are symptomatic should be treated initially with long-acting insulin while metformin is initiated and titrated 1
• In youth with ketosis/ketoacidosis, treatment with insulin should be initiated to rapidly correct the hyperglycemia and metabolic derangement. Once acidosis is resolved, metformin should be initiated while insulin therapy is continued 1

Monitoring and Follow-up

• Measure HbA1c every 3 months until target is reached, then at least twice yearly 2
• Blood glucose monitoring plans should be individualized, taking into consideration the pharmacologic treatment of the person 1
• Self-monitoring of blood glucose might be unnecessary in patients receiving metformin combined with either an SGLT-2 inhibitor or a GLP-1 agonist 2

Common Pitfalls to Avoid

• Delaying treatment intensification when glycemic targets are not met (clinical inertia) 2
• Failing to consider cardiovascular and renal benefits of newer agents (SGLT-2 inhibitors and GLP-1 receptor agonists) when selecting add-on therapy 2, 3
• Not adjusting medications during periods of acute illness 2
• Overlooking the importance of a multidisciplinary diabetes team, including a physician, diabetes care and education specialist, registered dietitian nutritionist, and psychologist or social worker 1