What are the initial management and treatment options for diabetes mellitus?

Initial Management and Treatment of Diabetes Mellitus

Type 2 Diabetes

Start metformin immediately at diagnosis alongside lifestyle modifications for all patients with Type 2 diabetes who have normal renal function, unless they present with severe hyperglycemia or ketoacidosis. 1, 2

Presentation-Based Treatment Algorithm

For patients with ketoacidosis or ketosis:

• Initiate insulin therapy (subcutaneous or intravenous) immediately to correct hyperglycemia and metabolic derangement 1
• Once acidosis resolves, start metformin while continuing subcutaneous insulin 1
• This applies regardless of ultimate diabetes type, as ketoacidosis requires urgent correction 1

For patients with marked hyperglycemia (blood glucose ≥250 mg/dL or HbA1c ≥8.5%) without acidosis:

• Start long-acting insulin at 0.5 units/kg/day while simultaneously initiating metformin 1
• Titrate insulin every 2-3 days based on blood glucose monitoring 1
• This approach allows β-cells to "rest and recover" and may improve long-term adherence 1
• Many patients can be weaned off insulin gradually (10-30% dose reduction every few days over 2-6 weeks) once glycemic targets are achieved 1, 2

For metabolically stable patients (HbA1c <8.5% and asymptomatic):

• Metformin is the sole initial pharmacologic agent 1, 2
• Start at 500 mg daily, increase by 500 mg every 1-2 weeks up to maximum 2000 mg daily in divided doses 1, 3
• Gastrointestinal side effects (abdominal pain, bloating, loose stools) are often transient 1, 3

Lifestyle Modifications (Mandatory for All Patients)

Weight loss and physical activity targets:

• Lose at least 5% of baseline body weight 1, 2, 4
• Perform at least 150 minutes of moderate-intensity aerobic activity per week 1, 2
• Include resistance training at least twice weekly 1, 2
• Reduce sedentary time 1, 2

Nutrition therapy:

• Individualized medical nutrition therapy program, preferably with a registered dietitian 1, 2
• Low-fat, reduced-calorie diet 5
• No single diet has proven superior for health outcomes, but dietary intervention is essential 4

Combination Therapy

When to add a second agent:

• If metformin monotherapy at maximum tolerated dose fails to achieve or maintain HbA1c target after 3 months 1, 2
• For patients with HbA1c ≥9% at diagnosis, consider initial dual-combination therapy to achieve glycemic control more rapidly 1, 2

Second-line agent options (add to metformin):

• GLP-1 receptor agonists (preferred if cardiovascular disease, kidney disease, or high cardiovascular risk present) 4
• SGLT2 inhibitors (preferred if cardiovascular disease, kidney disease, or high cardiovascular risk present) 4
• Sulfonylureas 1
• Thiazolidinediones 1
• DPP-4 inhibitors 1
• Basal insulin 1

Critical evidence: SGLT2 inhibitors and GLP-1 receptor agonists reduce atherosclerotic cardiovascular disease by 12-26%, heart failure by 18-25%, and kidney disease by 24-39% over 2-5 years compared to placebo 4. These agents should be prioritized in patients with or at high risk for these complications.

Glycemic Targets

• Target HbA1c <7% for most adults with Type 2 diabetes 1, 4
• Intensive glucose-lowering strategies reduce microvascular disease by 3.5%, myocardial infarction by 3.3-6.2%, and mortality by 2.7-4.9% over long-term follow-up 4
• Individualize targets based on hypoglycemia risk, comorbidities, and life expectancy 1

Monitoring

• Measure HbA1c every 3 months to evaluate treatment efficacy 2, 6
• Monitor serum creatinine/eGFR and potassium at least annually, especially if on ACE inhibitors, ARBs, or diuretics 2
• Metformin can be continued with dose reduction when GFR is 30-45 mL/min 1

---

Type 1 Diabetes

Treat all patients with Type 1 diabetes with multiple daily insulin injections (≥3 injections daily) or continuous subcutaneous insulin infusion from diagnosis. 1, 2

Insulin Regimen

• Intensive insulin therapy (≥3 injections daily or insulin pump) clearly reduces microvascular complications and cardiovascular disease compared to 1-2 injections daily 1, 2
• Use insulin analogues to reduce hypoglycemia risk 1
• Educate patients on matching prandial insulin doses to carbohydrate intake, preprandial glucose levels, and anticipated activity 1, 2

Advanced Technologies

• Continuous glucose monitoring systems significantly reduce severe hypoglycemia risk 1
• Insulin pump therapy with low glucose "suspend" feature reduces nocturnal hypoglycemia without increasing HbA1c 1

---

Children and Adolescents with Type 2 Diabetes

The approach differs from adults due to higher rates of ketoacidosis presentation and diagnostic uncertainty:

• Initiate pharmacologic therapy at diagnosis alongside behavioral counseling 1
• For HbA1c <8.5% without ketosis: start metformin up to 2000 mg daily 1
• For HbA1c ≥8.5% or blood glucose ≥250 mg/dL: start long-acting insulin (0.5 units/kg/day) plus metformin 1
• Check pancreatic autoantibodies to distinguish Type 1 from Type 2 diabetes 1
• If metformin fails to achieve targets, add GLP-1 receptor agonist (approved for age ≥10 years, excluding those with personal/family history of medullary thyroid carcinoma or MEN2) 1
• Target HbA1c <7% (lower than Type 1 diabetes targets due to lower hypoglycemia risk and higher complication risk) 1

Common Pitfalls

• Do not delay insulin in patients with severe hyperglycemia or ketoacidosis while waiting for diabetes type clarification 1
• Do not use metformin alone in patients with marked hyperglycemia (≥250 mg/dL or HbA1c ≥8.5%) 1
• Do not ignore cardiovascular and kidney risk factors when selecting second-line agents—SGLT2 inhibitors and GLP-1 receptor agonists provide proven cardiovascular and renal protection 4
• Do not continue metformin if GFR falls below 30 mL/min 1