How should I manage a 67‑year‑old underweight male with type 3c diabetes (very low C‑peptide, negative glutamic acid decarboxylase (GAD) antibodies), markedly elevated fasting and post‑prandial glucose, a 30‑year history of severe acute pancreatitis, current weight loss, vitamin D deficiency, borderline elevated amylase, low lipase, anemia, a dilated main pancreatic duct (MPD) with intraductal calculi and an atrophic pancreas on ultrasound, who experienced severe hypoglycaemia on glimepiride (a sulfonylurea) and metformin (biguanide), and is now on low‑dose NovoMix 30/70 (insulin aspart protamine/insulin aspart) with continuous glucose monitoring (CGM) showing an average glucose of about 169 mg/dL (glucose management indicator (GMI) 7.4) and no hypoglycaemia?

Management of Type 3c Diabetes (Pancreatogenic Diabetes) in an Underweight Older Adult with Chronic Pancreatitis

Immediate Priorities: Insulin Therapy and Nutritional Support

Your current approach of low‑dose NovoMix 30/70 (4 units before breakfast) with planned titration is appropriate, but you must immediately add pancreatic enzyme replacement therapy (PERT) and address the weight loss aggressively. Type 3c diabetes (T3cDM) arising from chronic pancreatitis with pancreatic atrophy, calculi, and duct dilation requires both insulin therapy and exocrine support to prevent further nutritional deterioration and metabolic bone disease 1, 2.

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Insulin Regimen: Titration and Monitoring

Current Regimen Assessment

• Your starting dose of 4 units NovoMix 30/70 before breakfast is conservative and appropriate given the patient's low BMI (18.22), history of severe hypoglycemia on sulfonylureas, and very low C‑peptide (fasting 0.25, stimulated 0.9 pmol/mL) indicating near‑absolute insulin deficiency 3, 4.
• The CGM data showing GMI 7.4, average glucose 169 mg/dL, no hypoglycemia after 5 days confirms the dose is safe but insufficient for optimal control 3.

Immediate Titration Protocol

• Increase NovoMix 30/70 by 2 units every 3 days if fasting glucose remains 140–179 mg/dL, or by 4 units every 3 days if fasting glucose is ≥180 mg/dL, targeting fasting glucose 80–130 mg/dL 3, 4.
• Given the post‑breakfast hyperglycemia on CGM, you will likely need to escalate to 8–12 units before breakfast within 2–3 weeks 3, 4.
• Monitor fasting glucose daily during titration and continue CGM to detect any hypoglycemia patterns 3.

Critical Threshold: When to Switch to Basal‑Bolus

• If the NovoMix dose exceeds 0.5 units/kg/day (≈30 units for a 60 kg patient) without achieving targets, transition to a basal‑bolus regimen (e.g., insulin glargine once daily + rapid‑acting insulin before meals) to avoid over‑basalization and allow independent adjustment of basal and prandial components 3, 4.
• Signs to watch for over‑basalization: bedtime‑to‑morning glucose differential ≥50 mg/dL, hypoglycemia despite overall hyperglycemia, or high glucose variability 3, 4.

Alternative: Basal‑Bolus from the Start

• Given the very low C‑peptide, post‑breakfast hyperglycemia, and need for flexible dosing, consider switching now to insulin glargine 10 units once daily at bedtime plus insulin aspart 4 units before breakfast (and later before lunch/dinner as needed) 3, 4.
• This approach allows you to titrate basal and prandial insulin independently, which is often superior in T3cDM with marked glycemic variability 1, 5.

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Pancreatic Enzyme Replacement Therapy (PERT): Non‑Negotiable

You must initiate PERT immediately, even in the absence of overt steatorrhea, because exocrine insufficiency is universal in T3cDM with pancreatic atrophy and contributes to malnutrition, weight loss, and metabolic bone disease 1, 2.

PERT Dosing

• Start with 25,000–40,000 units of lipase per meal and 10,000–25,000 units per snack, taken with the first bite of food 2.
• Titrate based on steatorrhea symptoms, weight gain, and fat‑soluble vitamin levels 2.
• Low lipase levels on labs support exocrine insufficiency, even if amylase is borderline elevated 1, 2.

Nutritional Support

• High‑calorie, high‑protein diet (≥1.5 g protein/kg/day) to reverse weight loss and prevent sarcopenia 2.
• Fat‑soluble vitamin supplementation (A, D, E, K) is essential; you have already started vitamin D, A, and E replacement, which is correct 1, 2.
• Monitor vitamin B12 levels if metformin is added later, as chronic pancreatitis and metformin both increase deficiency risk 3, 6.
• Calcium and vitamin D supplementation to prevent metabolic bone disease, which is common in T3cDM 1, 2.

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Metformin: First‑Line Therapy in T3cDM

Metformin should be the first‑line oral agent in T3cDM because it reduces hepatic insulin resistance (a hallmark of T3cDM due to pancreatic polypeptide deficiency) and has anti‑neoplastic properties, which is critical given the high pancreatic cancer risk in chronic pancreatitis 1, 7.

Metformin Initiation

• Start metformin 500 mg once daily with meals, titrating to 1000 mg twice daily (2000 mg/day) over 2–4 weeks to minimize gastrointestinal side effects 6, 8.
• Continue metformin even when insulin is intensified, as it reduces total insulin requirements by 20–30% and improves glycemic control 3, 6.
• Contraindications: hold if creatinine rises or if acute illness develops (your patient's creatinine is normal now) 3, 6.

Why Metformin Over Other Oral Agents

• Sulfonylureas and insulin secretagogues are contraindicated in T3cDM because they increase pancreatic cancer risk and caused severe hypoglycemia in your patient 1, 7.
• SGLT2 inhibitors are less effective at eGFR <45 mL/min and do not address hepatic insulin resistance in T3cDM 8.
• GLP‑1 receptor agonists may worsen nausea and are less effective in absolute insulin deficiency (C‑peptide 0.25 pmol/mL) 3, 8.

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Glycemic Targets: Individualized for Age and Comorbidities

For a 67‑year‑old underweight patient with chronic pancreatitis, anemia, and recent weight loss, target HbA1c 7.5–8.0% (current 9.2%) to balance glycemic control with hypoglycemia risk and quality of life 3, 8.

Specific Targets

• Fasting glucose: 100–140 mg/dL (less stringent than the standard 80–130 mg/dL to avoid hypoglycemia in this frail patient) 3, 8.
• Post‑prandial glucose: <180 mg/dL 3.
• Avoid glucose <70 mg/dL at all costs, given the history of severe hypoglycemia on sulfonylureas 3.

Rationale for Less Stringent Targets

• Older adults with limited life expectancy, weight loss, and anemia benefit from avoiding hypoglycemia more than achieving tight control 3.
• T3cDM is characterized by high glycemic variability due to loss of both insulin and glucagon, making tight control difficult and risky 1, 5, 7.

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Monitoring and Follow‑Up

Short‑Term (Next 2–4 Weeks)

• Daily fasting glucose to guide insulin titration 3.
• Continue CGM to detect hypoglycemia patterns and post‑prandial excursions 3.
• Weekly weight checks to assess response to PERT and nutritional support 2.
• Reassess insulin dose every 3 days during active titration 3, 4.

Medium‑Term (3–6 Months)

• HbA1c every 3 months until stable control is achieved 3, 6.
• Repeat vitamin D, A, E, B12 levels at 3 months to assess replacement adequacy 1, 2.
• Monitor hemoglobin to ensure anemia is improving with nutritional support 2.
• Repeat imaging (CT or MRI) if weight loss persists or CA 19‑9 rises, to rule out pancreatic cancer 1, 7.

Long‑Term (Every 6–12 Months)

• Annual screening for pancreatic cancer with CA 19‑9 and imaging, given the 75% prevalence of chronic pancreatitis in T3cDM and high cancer risk 1, 7.
• Bone density scan (DEXA) to screen for metabolic bone disease 1, 2.

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Gastroenterology Follow‑Up: Essential

Your plan for urgent gastro review is correct. The gastroenterologist should:

1. Confirm the diagnosis of chronic pancreatitis and rule out pancreatic cancer (atrophic pancreas, MPD 7.2 mm, intraductal calculi, and weight loss are concerning) 1, 7.
2. Optimize PERT dosing based on symptoms and nutritional status 2.
3. Manage pain if present (you mention "some mild upper abdominal pain") 2.
4. Screen for pancreatic cancer with repeat imaging and tumor markers 1, 7.

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Common Pitfalls to Avoid

1. Do not delay PERT initiation even if steatorrhea is absent; exocrine insufficiency is universal in T3cDM with pancreatic atrophy and contributes to malnutrition 1, 2.
2. Do not use sulfonylureas or insulin secretagogues in T3cDM due to hypoglycemia risk and increased pancreatic cancer risk 1, 7.
3. Do not discontinue metformin when insulin is added; the combination reduces insulin requirements and improves outcomes 3, 6, 1.
4. Do not target HbA1c <7% in this frail, underweight older adult; prioritize hypoglycemia avoidance and quality of life 3, 8.
5. Do not ignore weight loss; it signals inadequate PERT, malnutrition, or possible pancreatic cancer 1, 7, 2.

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Summary Algorithm

1. Continue NovoMix 30/70 4 units before breakfast and titrate by 2–4 units every 3 days based on fasting glucose, targeting 100–140 mg/dL 3, 4.
2. Switch to basal‑bolus (glargine + aspart) if NovoMix exceeds 0.5 units/kg/day or if glycemic variability persists 3, 4.
3. Start metformin 500 mg daily, titrating to 1000 mg twice daily over 2–4 weeks 6, 1.
4. Initiate PERT 25,000–40,000 units lipase per meal immediately 1, 2.
5. Continue vitamin D, A, E replacement and add calcium; monitor B12 1, 2.
6. Target HbA1c 7.5–8.0% and fasting glucose 100–140 mg/dL 3, 8.
7. Urgent gastro follow‑up to rule out pancreatic cancer and optimize PERT 1, 7, 2.
8. Monitor weight weekly, HbA1c every 3 months, and screen for pancreatic cancer annually 1, 7, 2.