In a patient with type 2 diabetes, HbA1c 12.8%, fasting c‑peptide 1.28 ng/mL, who is resistant to insulin but has been started on basal insulin glargine (Basaglar) plus sitagliptin (Zitavu) and metformin, does a decreasing c‑peptide level indicate reduced β‑cell function and therefore necessitate insulin therapy?

C-Peptide Interpretation and Management in Uncontrolled Type 2 Diabetes

Understanding Your Patient's C-Peptide Level

Yes, as C-peptide levels decrease, this indicates progressive loss of beta cell function, but your patient's C-peptide of 1.28 ng/mL actually demonstrates substantial residual insulin production and confirms type 2 diabetes with insulin resistance as the primary problem, not absolute insulin deficiency. 1, 2

What the C-Peptide Value Tells You

• A C-peptide concentration well above 0.6 ng/mL (>200 pmol/L) argues strongly against type 1 diabetes, which is characterized by low or undetectable C-peptide levels 1, 2
• Your patient's value of 1.28 ng/mL indicates preserved beta cell function and reflects the type 2 diabetes phenotype where insulin production is normal or even increased in absolute terms, but disproportionately low for the degree of insulin resistance 2, 3
• In type 2 diabetes, high C-peptide represents "relative insulin deficiency"—the pancreas secretes substantial insulin, but marked cellular insulin resistance prevents adequate glucose uptake, sustaining severe hyperglycemia 2

Clinical Significance for Your Patient

• The presence of measurable C-peptide does not correlate with response to insulin therapy in patients judged to be clinically insulin deficient 1
• A low C-peptide value should not be required for insulin coverage in patients with type 2 diabetes, including for insulin pump eligibility 1
• With an A1c of 12.8%, your patient has severe hyperglycemia that warrants insulin therapy regardless of C-peptide level, as this degree of glucotoxicity impairs beta cell function and perpetuates the metabolic derangement 4

Your Treatment Plan: Appropriate but Needs Optimization

Why Your Approach is Correct

Starting basal insulin (Basaglar) in combination with metformin and sitagliptin is appropriate for this patient with severe hyperglycemia and preserved beta cell function. 2, 5

• Metformin should be continued as first-line therapy because preserved beta cell function makes this patient an ideal candidate for insulin-sensitizing agents 2
• Sitagliptin (a DPP-4 inhibitor) complements metformin by providing glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion without causing hypoglycemia 5
• The combination of metformin and sitagliptin has been shown to reduce HbA1c by 2.1% from baseline levels of 8.8%, with greater reductions (2.6%) in patients with baseline HbA1c >9% 4

Expected Outcomes and Monitoring

• Drug-naïve patients with type 2 diabetes and baseline HbA1c >11% can achieve HbA1c reductions to approximately 6-7% with metformin-based dual oral therapy, though your patient will likely need the added basal insulin given the A1c of 12.8% 4
• Monitor HbA1c every 3 months and intensify treatment if goals are not met 2
• Target HbA1c <7.0% in most patients to reduce microvascular disease risk 2

Addressing Patient Resistance to Insulin

Key Points to Discuss with Your Patient

• Preserved C-peptide (1.28 ng/mL) means their pancreas is still working, but the severe hyperglycemia (A1c 12.8%) creates "glucotoxicity" that further impairs beta cell function 4
• Starting insulin now may actually preserve remaining beta cell function by reducing the metabolic stress on the pancreas 6
• Once glycemic control improves, it may be possible to reduce or discontinue insulin if aggressive lifestyle modification and oral agents can maintain control 1, 4

Alternative Considerations if Insulin Resistance Persists

• GLP-1 receptor agonists may offer superior HbA1c reduction compared to basal insulin alone in patients with baseline HbA1c >9%, with the added benefit of weight loss rather than weight gain 4
• Studies comparing exenatide weekly and liraglutide to insulin glargine showed 0.2-0.3% greater HbA1c reductions in patients with baseline HbA1c ≥8.9-9.0% 4
• In patients with HbA1c 10.6%, both liraglutide and insulin glargine achieved 3.1% HbA1c reduction, but the GLP-1 agonist avoided weight gain and hypoglycemia 4

Essential Lifestyle Interventions

Intensive lifestyle modification is mandatory and should be implemented immediately alongside pharmacotherapy. 2

• Nutrition counseling aimed at weight reduction is essential since 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
• A balanced diet (approximately 50% carbohydrate, 20% protein, 30% fat with increased fiber) combined with at least 30 minutes of moderate-intensity physical activity daily has been shown to improve insulin sensitivity 7

Monitoring Beta Cell Function Over Time

• Serial C-peptide measurements can track beta cell function, with declining values indicating progressive beta cell failure and increased insulin requirement 3, 6
• Postprandial C-peptide to glucose ratio likely better reflects maximum beta cell secretory capacity compared with fasting measurements 3
• If C-peptide levels decline significantly over time (approaching 0.6 ng/mL or lower), this would indicate progression toward absolute insulin deficiency and permanent insulin requirement 1, 2

Common Pitfalls to Avoid

• Do not measure C-peptide within 2 weeks of a hyperglycemic emergency, as results will be unreliable 2
• Do not delay insulin intensification if HbA1c remains >9% after 3 months of current therapy, as prolonged severe hyperglycemia causes irreversible beta cell damage 2
• Do not assume that high C-peptide means insulin is unnecessary—the severe hyperglycemia (A1c 12.8%) indicates that endogenous insulin production, while present, is inadequate for current metabolic demands 2, 4