9 Interactive Clinical Scenarios Grounded in the 2025 JAMA Clinical Review (JAMA. 2025;334(11):985-1002)
Case 01The Falsely Elevated A1C with Iron Deficiency
Paired with Card 01
Patient Presentation: A 42-year-old female presents for annual checkup with fatigue. Mother has T2D. Exam: BP 122/78, BMI 26.4. Labs: Fasting Plasma Glucose (FPG) 106 mg/dL, HbA1C 6.8%, CBC shows Microcytic Anemia (Hb 9.4 g/dL, MCV 71, Ferritin 8 ng/mL) from heavy menses. Resident Assessment: "Her A1C is 6.8% (≥6.5%), so I will diagnose T2D today and initiate Metformin 500 mg daily."
Discussion Questions for Residents
Does this patient meet criteria for Type 2 Diabetes today? Why or why not?
What is the physiologic mechanism linking her iron deficiency to this A1C value?
What is your next diagnostic and therapeutic step?
1. Diagnostic Rule: NO. Asymptomatic patients require two abnormal tests above the threshold. Her FPG (106 mg/dL) is only in the prediabetes range (100–125), not diabetes (≥126).
2. A1C Confounder: In iron deficiency anemia, reduced RBC turnover prolongs RBC survival. Older circulating RBCs undergo prolonged non-enzymatic glycation, creating a falsely elevated A1C that overstates actual glycemia!
3. Next Step: Re-test with plasma glucose criteria (repeat FPG or 2h OGTT). Treat iron deficiency and recheck A1C once hematocrit normalizes.
💡 Preceptor Pearl: Hemolysis, hemodialysis, and blood loss cause falsely low A1C. Iron deficiency causes falsely high A1C. When in doubt, rely on plasma glucose!
Case 02The "Non-Responding" Lean 34-Year-Old
Paired with Card 02
Patient Presentation: A 34-year-old lean male (BMI 21.8 kg/m²) diagnosed with T2D 3 months ago returns with worsening thirst, polyuria, and 7 kg (15.4 lbs) unintentional weight loss despite taking Metformin 1000 mg BID and Glimepiride 2 mg daily. Today's fingerstick glucose: 312 mg/dL, A1C: 10.2%. Urine dipstick shows moderate ketones. Resident Assessment: "His T2D is uncontrolled. I want to double his glimepiride to 4 mg and add empagliflozin 10 mg."
Discussion Questions for Residents
What critical diagnosis must be suspected, and why is adding an SGLT2i dangerous here?
What diagnostic lab tests must be ordered immediately?
What is the immediate treatment required today?
1. Critical Diagnosis: Latent Autoimmune Diabetes in Adults (LADA / Adult-onset T1D). Adding an SGLT2i in an insulin-deficient patient with ketonuria drastically triggers Euglycemic DKA (euDKA)!
2. Diagnostic Labs: Order Anti-GAD65 antibodies (first-line) and a simultaneous stimulated C-peptide (<200 pmol/L confirms insulin deficiency).
3. Immediate Treatment: Initiate Insulin therapy immediately (0.1–0.2 U/kg basal insulin). Assess for metabolic acidosis with a BMP.
💡 Preceptor Pearl: Up to 10% of adult T2D diagnoses are misclassified LADA. If a lean, young-to-middle-aged adult fails to respond to oral agents and loses weight, check antibodies before escalating oral drugs!
Case 03The 78-Year-Old with Recurrent Falls
Paired with Card 03
Patient Presentation: A 78-year-old male with mild dementia, Stage 3b CKD (eGFR 38 mL/min), and 20-year T2D history presents after two morning falls with confusion and sweating. Meds: Metformin 500 mg BID, Glyburide 5 mg BID, Glargine 22 units qHS. Today's A1C is 6.2%. Resident Assessment: "His A1C is great at 6.2%, so his diabetes is tightly controlled. His falls must be purely mechanical."
Discussion Questions for Residents
Critique the A1C of 6.2% in this patient using the ACCORD and ADVANCE trial lessons.
Which medication is the primary culprit precipitating his falls?
What should his individualized A1C goal be, and how should his regimen be de-intensified?
1. ACCORD Trial Lesson: Targeting A1C <6.0% in older/high-risk patients increased all-cause mortality by 22% (HR 1.22) and tripled hypoglycemia. In an elderly patient with CKD and dementia, an A1C of 6.2% indicates dangerous overtreatment.
2. Culprit Drug:Glyburide has active renal metabolites that accumulate in CKD (eGFR <60), causing prolonged, severe nocturnal hypoglycemia.
3. Action & Target: Relax A1C target to 7.5%–8.5%. Discontinue glyburide immediately. Reduce glargine by 30%–50% (down to 10–12 units).
💡 Preceptor Pearl: In older adults, hypoglycemia causes immediate fractures, strokes, and death. Never use glyburide in CKD or the elderly, and de-intensify when A1C < 6.5%.
Case 04The Motivated Patient Inquiring About Remission
Paired with Card 04
Patient Presentation: A 48-year-old male recently diagnosed with T2D (A1C 7.3%, BMI 31.3 kg/m²) asks: "Doctor, can I cure my diabetes without taking medications forever?" He has no cardiovascular or renal comorbidities. Resident Assessment: "Is remission real in primary care, or should I just put him on metformin and tell him diabetes is permanent?"
Discussion Questions for Residents
How does the JAMA 2025 review define diabetes remission?
What did the landmark DiRECT trial demonstrate in primary care?
What practical lifestyle prescription (diet, caloric deficit, exercise) will you write?
1. Remission Definition: A1C < 6.5% sustained for ≥ 3 months without any diabetes medications.
2. DiRECT Trial Evidence: In UK primary care practices, a low-calorie formula diet (825–853 kcal/d) achieved 46% diabetes remission at 1 year (86% if ≥15 kg lost).
💡 Preceptor Pearl: Frame it as "remission" rather than "cure." Ongoing surveillance is required because hyperglycemia recurs if weight is regained.
Case 05Optimizing Pharmacotherapy in Stage 3b CKD
Paired with Card 05
Patient Presentation: A 62-year-old male with T2D on Metformin 1000 mg BID presents with A1C 8.3%. Labs reveal eGFR has declined to 36 mL/min/1.73m² and spot UACR is 180 mg/g. Resident Assessment: "I'll keep metformin at 2000 mg/d and add glimepiride 4 mg + sitagliptin 100 mg."
Discussion Questions for Residents
What adjustment must be made to Metformin today based on his eGFR?
What is wrong with the resident's proposed add-ons (Glimepiride and Sitagliptin)?
Which evidence-based add-on should be prescribed based on Cards 5 & 6?
1. Metformin Cap: When eGFR is 30–45 mL/min, maximum metformin dose is 1000 mg/day. Reduce today.
2. Drug Errors: Glimepiride carries high hypoglycemia risk in CKD (glipizide is safer). Sitagliptin dose must be cut to 50 mg in Stage 3b (or switch to linagliptin 5 mg which needs no renal dose adjustment).
3. Evidence-Based Choice: Add an SGLT2 inhibitor (Empagliflozin or Dapagliflozin). Cardiorenal protection persists down to dialysis initiation! Consider adding GLP-1 RA (semaglutide, FLOW trial).
💡 Preceptor Pearl: Always check eGFR before renewing or escalating diabetes meds. Metformin max 1000 mg if eGFR 30–45; SGLT2i preserves nephrons even when glucose-lowering fades.
Case 06The Post-STEMI / Heart Failure Patient
Paired with Card 06
Patient Presentation: A 58-year-old female presents after hospital discharge for anterior STEMI with stent. Echo shows LVEF 35% (HFrEF). On Metformin 1000 mg BID, GDMT for HF, and statin. Today's A1C is 7.1%. Resident Assessment: "Her A1C is 7.1%, which is right at goal. Since her blood glucose is controlled on metformin alone, no diabetes changes are needed."
Discussion Questions for Residents
Why does the modern 2025 guideline paradigm contradict the resident's decision?
Which medication class should be started immediately and why?
Which two glucose-lowering classes are strictly contraindicated or harmful here?
1. Modern Paradigm: Cardiorenal drugs (SGLT2i or GLP-1 RA) are indicated based on comorbidities independent of baseline A1C and independent of background metformin!
2. Indicated Drug:SGLT2 inhibitor (Dapagliflozin 10 mg or Empagliflozin 10 mg) to reduce CV death and HF hospitalizations.
3. Harmful Classes:Pioglitazone (contraindicated in NYHA III/IV HF due to fluid retention) and Saxagliptin (increases HF hospitalizations).
💡 Preceptor Pearl: Treat organ risk, not just glycemia! An HF patient with T2D needs an SGLT2i even if their A1C is already 6.5%.
Case 07Severe Catabolic Hyperglycemia
Paired with Card 07
Patient Presentation: A 54-year-old male presents with 4 weeks of severe polyuria, polydipsia, and 6 kg unintentional weight loss. POC glucose is 364 mg/dL, A1C is 11.4%. BMP shows bicarb 22, anion gap 10 (no DKA). Resident Assessment: "He doesn't have DKA and hates needles. Can we just start maximum metformin and oral semaglutide?"
Discussion Questions for Residents
Why is oral therapy inappropriate as initial therapy in this patient?
What are the 2025 JAMA criteria for first-line insulin?
Write the exact basal insulin starting dose and titration instructions.
1. Glucotoxicity: Glucose >300 and A1C >10% cause severe β-cell glucotoxicity. Oral meds and incretins take weeks to titrate and cannot rapidly halt ongoing catabolism.
3. Basal Protocol: Start Glargine or Degludec at 10 units daily (or 0.1–0.2 U/kg). Titrate: +2 units every 3 days until fasting morning glucose is 80–130 mg/dL.
💡 Preceptor Pearl: "10 units, +2 units every 3 days until fasting is 80–130." Clear, actionable, and overcomes clinical inertia.
Case 08Pre-op Holds & Euglycemic DKA
Paired with Card 08
Patient Presentation: A 55-year-old female taking Empagliflozin 25 mg daily, Metformin 1000 mg BID, and weekly Subcutaneous Semaglutide 1.0 mg is scheduled for elective laparoscopic cholecystectomy in 4 days. The surgical clinic told her to take everything the morning of surgery except metformin. Resident Assessment: She calls your clinic asking if that advice is correct.
Discussion Questions for Residents
What major error was made regarding Empagliflozin?
What is Euglycemic DKA (euDKA) and why does it occur with SGLT2i?
What is the pre-op holding rule for weekly Semaglutide and why?
1. SGLT2i Hold Rule: SGLT2 inhibitors MUST be held 3 to 4 days prior to surgery. Failing to hold creates high risk of post-op euDKA.
2. euDKA Mechanism: Continued urinary glucose loss keeps blood glucose normal (<250 mg/dL), but operative stress/fasting causes glucagon surge and severe ketoacidosis!
3. GLP-1 RA Hold: Hold weekly GLP-1 RAs 1 week prior to elective procedures because delayed gastric emptying creates pulmonary aspiration risk under anesthesia.
💡 Preceptor Pearl: SGLT2i: hold 3-4 days pre-op; GLP-1: hold 1 week; Metformin: hold day of & 48h post-contrast; SU: hold day of.
Case 09The Comprehensive Annual Audit & Endo Referral
Paired with Card 09
Patient Presentation: A 65-year-old male with 14-year T2D takes Insulin Glargine 110 units BID (220 U/d) + Lispro 25 units TID (75 U/d), total 295 units/day. A1C is 9.8%, BMI 38.4, eGFR 52, UACR 240 mg/g. Hasn't seen an eye doctor in 4 years and feet haven't been examined. Resident Assessment: "Should I just increase his glargine to 130 units BID, or refer him to endocrinology?"
Discussion Questions for Residents
What annual surveillance exams and referrals must be ordered today?
What problem occurs when injecting >200 U/day of U-100 insulin, and what formulation solves it?
What criteria here trigger an Endocrinology and Metabolic Surgery referral?
2. High-Volume Problem: Large subcutaneous depots (>50-100 U/injection) lead to erratic absorption and lipohypertrophy. Switch to concentrated insulins: U-200, U-300 Glargine, or U-500 Regular.
💡 Preceptor Pearl: If insulin dose exceeds 200 U/day, don't just increase U-100. Switch to concentrated insulin, add an incretin to reduce insulin requirements, and refer to endocrinology!