Type 2 Diabetes Mellitus Treatment Options
Start metformin alongside comprehensive lifestyle modifications as first-line therapy for all newly diagnosed T2DM patients, unless they present with ketosis, diabetic ketoacidosis, random blood glucose ≥250 mg/dL, or HbA1c >8.5%, in which case initiate insulin therapy immediately. 1
Initial Assessment and Treatment Algorithm
When to Start Insulin Immediately
Initiate insulin therapy without delay if any of the following are present: 1
- Ketosis or diabetic ketoacidosis
- Random blood glucose ≥250 mg/dL
- HbA1c ≥8.5% (or >9% in children/adolescents) 2, 3
- Unclear distinction between Type 1 and Type 2 diabetes
First-Line Therapy for All Other Patients
Metformin is the preferred initial pharmacologic agent and should be started at or soon after diagnosis. 2, 1
Metformin dosing protocol: 1, 3
- Start at 500 mg daily
- Increase by 500 mg every 1-2 weeks
- Target ideal dose of 2000 mg daily in divided doses
Metformin is inexpensive, has long-established efficacy and safety data, and may reduce cardiovascular events and death. 2 It can be continued in patients with declining renal function down to a GFR of 30-45 mL/min, though the dose should be reduced. 2
Lifestyle Modifications (Essential for All Patients)
Nutrition Interventions
Implement evidence-based nutrition guidelines focusing on weight management with a goal of at least 5% body weight loss. 2, 1
Recommended dietary patterns include: 1, 3
- Mediterranean diet
- DASH diet
- Vegetarian/vegan diets
Specific dietary recommendations: 3
- Focus on fiber-rich whole grains
- Avoid refined carbohydrates
- Reduce red meat consumption
- Increase vegetable intake
- Reduce alcohol and monosaccharide intake 2
Physical Activity Requirements
Adults should engage in at least 150 minutes per week of moderate-intensity or 75 minutes of vigorous-intensity physical activity. 1, 3, 4
Children and adolescents should engage in at least 60 minutes daily of moderate-to-vigorous exercise. 2, 3
Combine aerobic and resistance training for optimal glycemic control. 3 Physical activity can reduce HbA1c by 0.4% to 1.0% and improve cardiovascular risk factors. 4
Use the "talk test" to define activity level: 3
- During moderate activity: can talk but not sing
- During vigorous activity: cannot talk without pausing
Additional Lifestyle Measures
Limit non-academic screen time to less than 2 hours per day, and discourage video screens and TVs in children's bedrooms. 3
Treatment Intensification and Combination Therapy
When to Add Second Agent
When monotherapy with metformin at maximum tolerated dose does not achieve or maintain HbA1c target over 3 months, add a second agent. 2
Preferred Second-Line Agents for Patients with Cardiovascular Risk
For patients with cardiovascular disease, kidney disease, or high cardiovascular risk who do not achieve glycemic targets with metformin alone, add SGLT-2 inhibitor or GLP-1 receptor agonist. 1, 3, 4
These medications have demonstrated: 4
- 12-26% risk reduction for atherosclerotic cardiovascular disease
- 18-25% risk reduction for heart failure
- 24-39% risk reduction for kidney disease over 2-5 years
High-potency GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists result in weight loss exceeding 5% in most individuals, and may exceed 10%. 4
Other Combination Options
When cardiovascular/kidney disease is not present, consider adding one of these six options to metformin: 2
- Sulfonylureas
- Thiazolidinediones
- Dipeptidyl peptidase-4 (DPP-4) inhibitors
- SGLT-2 inhibitors
- GLP-1 receptor agonists
- Basal insulin
For HbA1c ≥9%, consider initial dual-regimen combination therapy to more quickly achieve glycemic control. 2
Insulin Therapy
Approximately one-third of patients with T2DM require insulin treatment during their lifetime. 4
When to consider insulin: 2
- Blood glucose levels 300-350 mg/dL or greater
- HbA1c levels 10-12%
- Symptomatic or catabolic features present
- Preferred initial regimen: basal insulin plus mealtime insulin
Many pediatric patients initially started on insulin can be gradually weaned and subsequently managed with metformin and lifestyle modification. 3
Monitoring Protocol
Monitor HbA1c every 3 months until target is reached. 1, 3
Recommend finger-stick blood glucose monitoring for: 1, 3
- Patients taking insulin or medications with hypoglycemia risk
- Patients initiating or changing treatment regimen
- Patients who have not met treatment goals
- Patients with intercurrent illnesses
Consider continuous glucose monitoring (CGM) in individuals requiring frequent blood glucose monitoring, though data in T2DM are limited. 2
Specific Medication Evidence
SGLT-2 Inhibitors (Empagliflozin)
Empagliflozin 10 mg or 25 mg in combination with metformin provided statistically significant reductions in HbA1c (0.6-0.8%), fasting plasma glucose (20-22 mg/dL), body weight (2.5-2.9%), and systolic blood pressure (4.1-4.8 mmHg) compared to placebo at 24 weeks. 5
Empagliflozin 10 mg in children aged 10-17 years reduced HbA1c by 0.84% from baseline compared to placebo, with no episodes of severe hypoglycemia. 2
Sulfonylureas (Glimepiride)
Glimepiride at doses of 1 mg, 4 mg, and 8 mg daily provided statistically significant improvements in HbA1c compared to placebo, with reductions of 1.2%, 1.8%, and 1.8% respectively. 6
GLP-1 Receptor Agonists
Randomized controlled trials in youth have shown GLP-1 receptor agonists are safe and effective for decreasing HbA1c, though they increase gastrointestinal side effects and should not be used in individuals with family history of medullary thyroid cancer. 2
Cardiovascular and Microvascular Protection
Control blood glucose, lower blood pressure, adjust lipids, and consider aspirin therapy to prevent diabetic cardiovascular and microvascular diseases in patients with cardiovascular risk factors. 2
Intensive glucose-lowering strategies (HbA1c <7%) have demonstrated absolute reductions in: 4
- Microvascular disease: 3.5%
- Myocardial infarction: 3.3-6.2%
- Mortality: 2.7-4.9%
Special Considerations for Pediatric Patients
A family-centered approach to nutrition and lifestyle modification is essential in children and adolescents with T2DM. 2, 3
An interprofessional diabetes team is recommended, including: 2, 3
- Physician
- Diabetes care and education specialist
- Registered dietitian nutritionist
- Psychologist or social worker
Initial treatment with insulin may increase long-term adherence by enhancing the patient's perception of disease seriousness. 3