What is the recommended treatment plan for a patient with type 2 diabetes mellitus who has a C‑peptide level of 1.34 ng/mL, hemoglobin A1c of 10 % and fasting plasma glucose of 220 mg/dL?

Treatment Plan for Type 2 Diabetes with C-Peptide 1.34 ng/mL, A1c 10%, and Fasting Glucose 220 mg/dL

Start immediate dual therapy with metformin 500 mg twice daily (titrated to 2000 mg/day) plus basal insulin 10 units at bedtime, then add a GLP-1 receptor agonist within 3 months if A1c remains >7%. 1, 2

Diagnostic Interpretation of C-Peptide

• The C-peptide level of 1.34 ng/mL (approximately 445 pmol/L) confirms type 2 diabetes with preserved beta-cell function, ruling out type 1 diabetes which typically shows C-peptide <0.2 nmol/L (0.6 ng/mL). 2, 3, 4
• This C-peptide concentration indicates substantial endogenous insulin production but relative insulin deficiency for the degree of hyperglycemia and insulin resistance present. 2
• The combination of high C-peptide with severe hyperglycemia (A1c 10%, fasting glucose 220 mg/dL) reflects marked cellular insulin resistance limiting glucose uptake despite adequate insulin secretion. 2

Immediate Treatment Initiation

Dual Therapy is Mandatory at This A1c Level

Metformin plus basal insulin should be started simultaneously because A1c ≥10% requires aggressive treatment to prevent metabolic decompensation and preserve remaining beta-cell function. 1, 5

• The 2025 ADA Standards recommend initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who have A1c ≥10% or blood glucose ≥300 mg/dL. 1
• Delaying insulin initiation while waiting for oral agents to work is inappropriate—at A1c 10%, only combination therapy or injectable agents can reduce A1c to target, as most oral agents reduce A1c by <1%. 5
• Short-term intensive insulin therapy at this A1c level helps reverse glucotoxicity and lipotoxicity while preserving beta-cell function. 5

Metformin Dosing

• Start metformin 500 mg once or twice daily with meals, then titrate by 500 mg weekly to a target dose of 2000 mg daily (1000 mg twice daily). 1, 5
• Metformin must be continued as the foundation of therapy even when insulin is added, unless contraindicated (eGFR <30 mL/min/1.73 m²). 1, 5
• Metformin provides cardiovascular mortality benefit, reduces insulin requirements when used in combination, and carries minimal hypoglycemia risk. 1, 5
• Long-term metformin use may cause vitamin B12 deficiency; periodic measurement should be considered, especially if anemia or peripheral neuropathy develops. 1, 5

Basal Insulin Initiation

• Start basal insulin (NPH or long-acting analog) at 10 units once daily at bedtime, or calculate 0.1–0.2 units/kg body weight. 1, 5
• For patients with A1c ≥10%, consider starting doses of 0.3–0.5 units/kg/day as total daily insulin for more aggressive initial control. 5
• Titrate basal insulin by 2–4 units every 3 days until fasting glucose reaches 80–130 mg/dL without hypoglycemia. 1, 5
• If hypoglycemia occurs, determine the cause and reduce the corresponding dose by 10–20%. 1

Adding GLP-1 Receptor Agonist as Third Agent

If A1c remains >7% after 3 months of optimized metformin plus basal insulin, add a GLP-1 receptor agonist rather than intensifying insulin further. 1, 2, 5

• GLP-1 receptor agonists provide superior A1c reduction (0.6–0.8% additional lowering) compared to insulin intensification alone, with proven cardiovascular benefits in patients at high cardiovascular risk. 1, 5
• GLP-1 receptor agonists cause weight loss (2–5 kg) rather than weight gain and have minimal hypoglycemia risk when used without sulfonylureas. 1, 5
• The combination of metformin, basal insulin, and GLP-1 receptor agonist addresses multiple pathophysiologic defects while minimizing hypoglycemia risk. 5
• Consider semaglutide (greatest A1c reduction up to 1.5% at 2.0 mg dose), liraglutide (22% reduction in cardiovascular death in LEADER trial), or dulaglutide (cardiovascular benefit in REWIND trial). 5

Role of Insulin Sensitizers Given High C-Peptide

• The preserved C-peptide level makes this patient an ideal candidate for insulin-sensitizing agents (metformin is the primary insulin sensitizer). 2
• Thiazolidinediones could theoretically be considered for patients with robust C-peptide levels to enhance cellular insulin responsiveness, but GLP-1 receptor agonists are preferred due to superior cardiovascular and weight profiles. 2
• Intensive lifestyle modification including nutrition counseling aimed at weight reduction is essential, as excess adiposity drives insulin resistance in this population. 2
• Target at least 60 minutes daily of moderate-to-vigorous exercise to enhance insulin sensitivity. 2

Monitoring Strategy

• Reassess A1c every 3 months until target <7% is achieved, then every 6 months once stable. 2, 5
• Monitor fasting glucose trends, weight, blood pressure, and any hypoglycemia episodes at monthly visits initially. 5
• Check eGFR at diagnosis and annually thereafter to ensure continued safety of metformin therapy. 1
• If A1c remains >7% after 3–6 months despite optimized basal insulin and GLP-1 receptor agonist, add prandial insulin starting with 4 units of rapid-acting insulin before the largest meal or 10% of the basal dose. 1, 5

Critical Pitfalls to Avoid

• Do not delay insulin initiation waiting for metformin alone to work—at A1c 10%, monotherapy is insufficient and prolongs exposure to hyperglycemia. 5
• Do not discontinue metformin when insulin is added; it must remain the foundational therapy throughout intensification. 1, 5
• Do not add sulfonylureas to this regimen, as they increase hypoglycemia risk substantially (7-fold higher risk of major hypoglycemic events compared to metformin) without providing the cardiovascular benefits of GLP-1 receptor agonists. 5
• Do not use GLP-1 receptor agonists together with DPP-4 inhibitors, as there is no added glucose-lowering benefit beyond the GLP-1 receptor agonist alone. 1
• Therapeutic inertia must be avoided—treatment intensification should not be delayed beyond 3 months if A1c remains above target. 1, 5

Expected Outcomes

• Metformin plus basal insulin should reduce A1c by approximately 2–3%, potentially achieving 7–8% within 3 months. 5
• Adding a GLP-1 receptor agonist provides an additional 0.6–0.8% A1c reduction, moving toward the target of <7%. 1, 5
• Weight is expected to remain stable or decrease slightly with metformin and GLP-1 receptor agonist, offsetting modest weight gain from basal insulin. 1, 5
• Cardiovascular risk profile improves owing to metformin's demonstrated mortality benefit and GLP-1 receptor agonist's proven cardiovascular protection. 1, 5