What is the treatment for type 2 diabetes?

Treatment of Type 2 Diabetes

Start metformin immediately at diagnosis alongside lifestyle modifications, then add an SGLT-2 inhibitor or GLP-1 receptor agonist when glycemic targets are not met—prioritize SGLT-2 inhibitors for patients with heart failure or chronic kidney disease, and GLP-1 receptor agonists for those needing weight loss or stroke prevention. 1, 2, 3

Initial Management: Metformin Plus Lifestyle

• Begin metformin 500 mg daily at the time of diagnosis, increasing by 500 mg every 1-2 weeks to reach 2000 mg daily in divided doses 2, 3
• Metformin reduces cardiovascular events and death, causes minimal hypoglycemia, and remains inexpensive compared to alternatives 1
• Implement lifestyle changes simultaneously—not as a prerequisite step before medication 1, 2
• Prescribe at least 150 minutes weekly of moderate-intensity activity or 75 minutes of vigorous activity, combining aerobic and resistance exercises 2
• Target 5-10% body weight reduction in overweight/obese patients through high-intensity interventions (≥16 sessions over 6 months) with 500-750 kcal/day deficit 2

Exception: When to Start Insulin First

• Use insulin immediately (not metformin) when fasting glucose ≥250 mg/dL, random glucose consistently >300 mg/dL, HbA1c >10%, or ketones are present 1
• Insulin is also required when the distinction between type 1 and type 2 diabetes is unclear 1
• After metabolic stabilization with insulin, you can add metformin and transition to oral agents if appropriate 1

Second-Line Treatment: SGLT-2 Inhibitors vs GLP-1 Receptor Agonists

When metformin plus lifestyle modifications fail to achieve HbA1c targets of 7-8%, the choice between SGLT-2 inhibitors and GLP-1 receptor agonists depends on comorbidities 1, 2, 3:

Choose SGLT-2 Inhibitors When:

• Heart failure is present (reduces hospitalization for heart failure by 18-25%) 3, 4
• Chronic kidney disease exists (reduces CKD progression by 24-39%) 3, 4
• Cardiovascular mortality reduction is the primary goal 3
• The patient has established atherosclerotic cardiovascular disease 1, 4

Choose GLP-1 Receptor Agonists When:

• Stroke risk is elevated (superior stroke reduction compared to SGLT-2 inhibitors) 3
• Weight loss is a major treatment goal (high-potency agents produce >5% weight loss in most patients, often exceeding 10%) 3, 4
• All-cause mortality reduction is prioritized 3
• The patient has atherosclerotic cardiovascular disease 1, 4

Both drug classes reduce major adverse cardiovascular events by 12-26% over 2-5 years in randomized trials. 4

Triple Combination Therapy

• When dual therapy (metformin plus SGLT-2 inhibitor OR GLP-1 receptor agonist) is insufficient, advance to triple combination: metformin + SGLT-2 inhibitor + GLP-1 receptor agonist 5
• Real-world evidence from Europe and the USA demonstrates this triple combination reduces 3-point MACE, total mortality, and heart failure better than other combinations 5
• Tirzepatide (dual GIP/GLP-1 receptor agonist) offers superior weight loss compared to traditional GLP-1 receptor agonists and should be prioritized when substantial weight reduction (>10% body weight) is needed 1, 3

Glycemic Targets and Monitoring

• Target HbA1c between 7% and 8% for most adults with type 2 diabetes 2, 3
• Deintensify treatment when HbA1c falls below 6.5% to prevent hypoglycemia and overtreatment 2, 3
• Assess glycemic status at least every 3 months 2
• Self-monitoring of blood glucose is unnecessary in patients on metformin alone or combined with SGLT-2 inhibitors or GLP-1 receptor agonists, as these combinations carry minimal hypoglycemia risk 2, 3

Critical Safety Measure: Preventing Hypoglycemia

When SGLT-2 inhibitors or GLP-1 receptor agonists achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins due to severe hypoglycemia risk. 2, 3

What NOT to Use

• Do not add DPP-4 inhibitors to metformin—they fail to reduce morbidity or all-cause mortality despite providing glycemic control 2, 3
• Sulfonylureas are no longer recommended due to higher mortality, hypoglycemia risk, and inferior cardiovascular outcomes compared to SGLT-2 inhibitors and GLP-1 receptor agonists 5
• Thiazolidinediones (pioglitazone) can reduce HbA1c by 0.8-1.7% when combined with metformin, sulfonylureas, or insulin, but cause weight gain and have inferior cardiovascular benefits compared to newer agents 6

Insulin Therapy

• Approximately one-third of patients with type 2 diabetes require insulin during their lifetime 4
• Initiate insulin when maximum doses of oral agents (including triple combination therapy) fail to achieve glycemic targets 1, 5
• In patients with predominant insulin deficiency at diagnosis, reverse the treatment order: insulin first, then add cardio-renal protective medications (SGLT-2 inhibitors, GLP-1 receptor agonists) 5
• Combination therapy with bedtime intermediate-acting insulin plus daytime oral agents can normalize glucose control without rigorous insulin regimens 7

Multidisciplinary Team Approach

• Assemble a team including physician, diabetes nurse educator, registered dietitian, and psychologist or social worker 1
• Clinical pharmacists should participate in medication management to reduce polypharmacy risks 3
• Address comorbidities including obesity, dyslipidemia, hypertension, and microvascular complications at initial treatment 1

Cost Considerations

• Prescribe generic medications when available rather than brand-name alternatives 2, 3
• No generic SGLT-2 inhibitors or GLP-1 receptor agonists currently exist, so discuss medication costs with patients when selecting specific agents within these classes 2, 3
• Metformin remains the most cost-effective first-line agent 1

Special Populations

Children and Adolescents with Type 2 Diabetes

• Only two drugs are FDA-approved for youth-onset type 2 diabetes: insulin and metformin 1
• Use insulin when random glucose ≥250 mg/dL or HbA1c ≥8.5%, or when ketoacidosis/ketosis is present 1
• Metformin alone provides durable glycemic control (HbA1c <8% for 6 months) in approximately half of adolescent patients 1
• Metabolic surgery may be considered for adolescents with BMI >35 kg/m² and uncontrolled glycemia despite lifestyle and pharmacologic intervention 1

Blood Pressure and Nephropathy Prevention

• Measure blood pressure at every visit 1
• If blood pressure exceeds the 95th percentile for age, sex, and height, intensify lifestyle modifications; if it remains elevated after 6 months, initiate antihypertensive therapy with ACE inhibitors or angiotensin receptor blockers 1