1. A 79-year-old woman with an estimated glomerular filtration rate (eGFR) of 26 mL/min/1.73m2 takes glyburide. She is brought to the emergency department with a blood glucose of 38 mg/dL. After a single ampule of intravenous (IV) dextrose her glucose normalizes and she feels well. What is the most appropriate disposition?
A) Discharge home now, since her glucose has normalized after the dextrose bolus
B) Discharge with a prescription for a higher glyburide dose to prevent future lows
C) Admit for continuous IV dextrose infusion and observation until the drug and its active metabolites have cleared
D) Give oral glucose tablets and observe for one hour, then discharge
E) Administer glucagon and discharge once she tolerates oral intake
ANSWER: C
Rationale:
Glyburide's weakly active metabolites accumulate in renal impairment and continue to stimulate glucose-independent insulin secretion, so hypoglycemia is prolonged and recurrent; a single dextrose bolus only transiently corrects it. The correct disposition is admission for continuous IV dextrose infusion and observation until drug and metabolite clearance is complete.
Option A: Option A is incorrect because transient normalization after a bolus does not reflect resolution; recurrence is expected as insulin secretion continues.
Option B: Option B is incorrect because increasing the glyburide dose would worsen the hypoglycemia.
Option D: Option D is incorrect because oral glucose for one hour underestimates the prolonged duration of glyburide-induced hypoglycemia in CKD.
Option E: Option E is incorrect because glucagon provides only brief hepatic glucose release and does not address ongoing insulin secretion, making discharge unsafe.
2. A 54-year-old man is newly diagnosed with type 2 diabetes mellitus (T2DM). His eGFR is 50 mL/min/1.73m2, liver function is normal, and he has no established cardiovascular disease or heart failure. He is concerned about medication cost. Which agent is the most appropriate initial pharmacotherapy?
A) Metformin, the universal first-line agent, which is appropriate at this eGFR, is low-cost, and carries no intrinsic hypoglycemia risk
B) Glyburide, because secretagogues are first-line for all newly diagnosed patients
C) A GLP-1 (glucagon-like peptide-1) receptor agonist, because it is preferred regardless of cardiovascular status
D) Insulin, because oral agents are inappropriate as initial therapy in T2DM
E) Nateglinide, because prandial secretagogues are the standard first-line therapy
ANSWER: A
Rationale:
Metformin is the universal first-line agent for T2DM; at an eGFR of 50 mL/min/1.73m2 it can be used (full dosing is permitted above 45), it is inexpensive, and it does not cause hypoglycemia as monotherapy, fitting this cost-conscious patient without cardiorenal indications steering toward another class.
Option B: Option B is incorrect because sulfonylureas are not first-line; they are secondary agents.
Option C: Option C is incorrect because GLP-1 receptor agonists are preferred on the cardiovascular axis, which does not apply here, and cost is a concern.
Option D: Option D is incorrect because oral therapy, specifically metformin, is appropriate initial therapy in T2DM; insulin is not required at diagnosis here.
Option E: Option E is incorrect because meglitinides are not standard first-line therapy.
3. A 61-year-old woman on metformin is scheduled for elective major abdominal surgery. Her preoperative renal function is normal. What is the most appropriate perioperative management of her metformin?
A) Continue metformin through the day of surgery and the immediate postoperative period without interruption
B) Permanently discontinue metformin because surgery is a lifelong contraindication
C) Double the dose preoperatively to maintain tight glycemic control during the surgical stress response
D) Hold metformin around the time of surgery and resume it only after renal function is confirmed stable, because perioperative hemodynamic instability and nephrotoxic exposures can cause acute renal impairment with metformin accumulation
E) Switch to glyburide for the perioperative period because sulfonylureas are safest during surgery
ANSWER: D
Rationale:
Metformin should be held perioperatively for major surgery and resumed only after renal function is confirmed stable, because perioperative hemodynamic instability, blood loss, and nephrotoxic anesthetic or antibiotic exposures can precipitate acute renal impairment, leading to metformin and lactate accumulation.
Option A: Option A is incorrect because uninterrupted metformin through major surgery risks accumulation if renal function declines acutely.
Option B: Option B is incorrect because the hold is temporary, not a permanent contraindication.
Option C: Option C is incorrect because increasing the dose before potential renal compromise worsens the accumulation risk and raises hypoglycemia and lactic acidosis concerns.
Option E: Option E is incorrect because glyburide is hazardous with any acute renal decline due to metabolite accumulation and is not a safer perioperative substitute.
4. A 68-year-old man with established atherosclerotic cardiovascular disease (ASCVD) is on maximally tolerated metformin with an HbA1c (glycated hemoglobin) of 8.3 percent. Cost is not a barrier. Which second agent best aligns with his cardiovascular risk profile?
A) A sulfonylurea, because it provides the greatest HbA1c reduction at the lowest cost
B) An SGLT-2 (sodium-glucose cotransporter-2) inhibitor or GLP-1 (glucagon-like peptide-1) receptor agonist with proven cardiovascular benefit, which is preferred on the ASCVD axis
C) A meglitinide, because its short action reduces cardiovascular events
D) Chlorpropamide, because first-generation sulfonylureas have demonstrated cardiovascular protection
E) No second agent; continue metformin alone indefinitely despite the above-target HbA1c
ANSWER: B
Rationale:
For a patient with established ASCVD whose HbA1c remains above target on metformin, an SGLT-2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit is preferred, because these agents are favored on the cardiovascular axis of the ADA/EASD framework.
Option A: Option A is incorrect because, although a sulfonylurea is effective and inexpensive, it is not preferred on the ASCVD axis and lacks cardiovascular benefit.
Option C: Option C is incorrect because meglitinides have not been shown to reduce cardiovascular events.
Option D: Option D is incorrect because first-generation sulfonylureas have not demonstrated cardiovascular protection; the UGDP signal raised the opposite concern.
Option E: Option E is incorrect because an HbA1c of 8.3 percent above target warrants intensification rather than indefinite monotherapy.
5. A 57-year-old man with T2DM is well controlled on repaglinide. He is found to have severe hypertriglyceridemia, and a fibrate is being considered. What is the most appropriate course of action?
A) Add gemfibrozil at a reduced dose and monitor glucose closely, since the interaction is minor
B) Add gemfibrozil and reduce the repaglinide dose by half to offset the interaction
C) Continue both drugs unchanged, since fibrates and meglitinides do not interact
D) Stop repaglinide and replace it with glyburide so that gemfibrozil can be added safely
E) Avoid gemfibrozil with repaglinide and select an alternative lipid agent such as fenofibrate, because gemfibrozil inhibits CYP2C8 and raises repaglinide exposure approximately eight-fold, a contraindicated combination
ANSWER: E
Rationale:
Gemfibrozil potently inhibits CYP2C8 (cytochrome P450 2C8), raising repaglinide exposure approximately eight-fold and creating a severe hypoglycemia risk; the combination is contraindicated, so the correct action is to avoid gemfibrozil and choose an alternative such as fenofibrate.
Option A: Option A is incorrect because the interaction is not minor; the roughly eight-fold exposure increase makes co-administration unsafe even at reduced dose.
Option B: Option B is incorrect because dose-halving cannot reliably offset such a large, variable exposure increase from a contraindicated combination.
Option C: Option C is incorrect because gemfibrozil and repaglinide clearly interact through CYP2C8 inhibition.
Option D: Option D is incorrect because switching to glyburide introduces its own hypoglycemia hazards and is unnecessary when the fibrate itself can be changed.
6. A 31-year-old woman with gestational diabetes mellitus (GDM) has not achieved glycemic targets with diet and exercise. She strongly prefers not to use insulin. How should the clinician counsel her regarding pharmacotherapy?
A) Insulin is the ADA-preferred agent in pregnancy, but metformin is an acceptable alternative for GDM when patient-specific factors, such as a strong preference against insulin, support its use
B) Metformin is absolutely contraindicated in pregnancy because it causes major birth defects, so insulin is the only option
C) A sulfonylurea is the preferred first-line agent for GDM and should be started instead
D) No pharmacotherapy is appropriate in pregnancy; only continued lifestyle measures are permitted
E) Metformin does not cross the placenta, so it is uniformly preferred over insulin in all pregnancies
ANSWER: A
Rationale:
ADA guidelines recommend insulin as the preferred pharmacologic agent in pregnancy, but metformin is an acceptable alternative in GDM when patient-specific factors—such as a strong preference against insulin—support its use; multiple randomized trials have not shown an increase in major birth defects with first-trimester exposure.
Option B: Option B is incorrect because metformin is not contraindicated for causing major birth defects; the trial data do not support that claim.
Option C: Option C is incorrect because sulfonylureas are not the preferred first-line agent for GDM.
Option D: Option D is incorrect because pharmacotherapy is appropriate when lifestyle measures fail to meet targets.
Option E: Option E is incorrect because metformin does cross the placenta and reaches fetal concentrations comparable to maternal levels, and insulin remains the ADA-preferred agent.
7. A 70-year-old man on metformin presents critically ill with hypotension, acute kidney injury, and a high-anion-gap metabolic acidosis with a markedly elevated serum lactate. Which assessment and initial management is most appropriate?
A) This is diabetic ketoacidosis from metformin, treated with an insulin infusion and potassium repletion as the priority
B) This is hyperosmolar hyperglycemic state, managed with aggressive free-water replacement alone
C) This is metformin-associated lactic acidosis (MALA); stop metformin, provide aggressive supportive care, and consider hemodialysis to remove the drug and correct the acidosis
D) This is a benign lactate elevation requiring no change to metformin therapy
E) This is sulfonylurea-induced hypoglycemia, treated with continuous dextrose
ANSWER: C
Rationale:
The combination of critical illness, acute kidney injury, and a high-anion-gap acidosis with markedly elevated lactate in a metformin-treated patient is consistent with metformin-associated lactic acidosis (MALA); management is to stop metformin, provide aggressive supportive care, and consider hemodialysis, which both removes the drug and helps correct the acidosis.
Option A: Option A is incorrect because the picture is a lactic acidosis from impaired lactate clearance and accumulation, not ketoacidosis, and metformin does not cause DKA.
Option B: Option B is incorrect because this is not hyperosmolar hyperglycemic state, and free-water replacement alone does not address lactic acidosis.
Option D: Option D is incorrect because a markedly elevated lactate with acidosis in this context is not benign and mandates stopping the drug.
Option E: Option E is incorrect because metformin does not cause hypoglycemia, and the presentation is acidosis rather than hypoglycemia.
8. A 49-year-old woman benefits from metformin but reports persistent nausea and diarrhea on immediate-release (IR) metformin despite taking it with food and titrating the dose gradually. What is the most appropriate next step before abandoning metformin?
A) Stop metformin immediately and switch to a sulfonylurea, since gastrointestinal intolerance cannot be managed
B) Add an antiemetic indefinitely and keep the IR formulation at the same dose
C) Increase the IR dose, since higher doses reduce gastrointestinal effects
D) Transition to extended-release (XR) metformin, which slows luminal drug release and lowers peak proximal intestinal concentrations, reducing gastrointestinal adverse effects
E) Switch to nateglinide, since meglitinides never cause gastrointestinal effects
ANSWER: D
Rationale:
When gastrointestinal intolerance persists on immediate-release metformin despite dosing with food and gradual titration, transitioning to the extended-release (XR) formulation is the appropriate next step; XR slows luminal release and reduces peak proximal intestinal drug concentrations, lowering gastrointestinal adverse effects by roughly 30 to 40 percent. Only after XR and optimized titration fail is abandoning metformin justified.
Option A: Option A is incorrect because gastrointestinal intolerance can often be managed with the XR formulation rather than abandoning metformin outright.
Option B: Option B is incorrect because indefinite antiemetic use without changing the formulation does not address the concentration-dependent cause.
Option C: Option C is incorrect because higher IR doses increase, not decrease, gastrointestinal effects.
Option E: Option E is incorrect because switching prematurely to nateglinide is unnecessary, and the claim that meglitinides never cause gastrointestinal effects is not a valid basis for the decision.
9. A 28-year-old woman with polycystic ovary syndrome (PCOS), impaired glucose tolerance, and anovulation wishes to conceive. How should metformin be positioned in her care?
A) Metformin is the first-line agent for ovulation induction and should replace all other fertility treatments
B) Letrozole is first-line for ovulation induction in most patients, while metformin serves as an adjunct, particularly valuable here given her impaired glucose tolerance, by reducing hyperinsulinemia and improving menstrual regularity
C) Metformin is contraindicated in PCOS because it worsens hyperandrogenism
D) Metformin should be avoided in any woman who wishes to conceive because it prevents ovulation
E) Metformin cures PCOS, so no other monitoring or therapy is needed
ANSWER: B
Rationale:
In PCOS, letrozole has supplanted metformin as first-line therapy for ovulation induction in most patients, but metformin remains a useful adjunct—especially in a patient with impaired glucose tolerance—because it reduces hyperinsulinemia, lowers androgen production, and partially restores menstrual regularity and ovulation.
Option A: Option A is incorrect because metformin is not first-line for ovulation induction; letrozole is.
Option C: Option C is incorrect because metformin reduces, rather than worsens, hyperandrogenism in PCOS and is not contraindicated.
Option D: Option D is incorrect because metformin does not prevent ovulation; it can help restore it.
Option E: Option E is incorrect because metformin does not cure PCOS, which requires ongoing management.
10. An overweight, newly diagnosed patient with T2DM asks which oral agent has the strongest randomized evidence for reducing mortality, not just lowering blood glucose. Which agent, and on the basis of which landmark trial, best answers this?
A) Glyburide, based on the UGDP (University Group Diabetes Program) trial showing a mortality benefit
B) Repaglinide, based on a dedicated cardiovascular outcomes trial demonstrating reduced mortality
C) Chlorpropamide, based on first-generation sulfonylurea outcome data
D) Nateglinide, based on the NAVIGATOR trial showing reduced all-cause mortality
E) Metformin, based on the UKPDS (United Kingdom Prospective Diabetes Study) overweight subgroup, which showed reduced all-cause mortality and myocardial infarction with a sustained legacy effect on follow-up
ANSWER: E
Rationale:
The UKPDS overweight subgroup randomized to metformin showed a significant reduction in all-cause mortality and myocardial infarction compared with conventional therapy, and the post-trial follow-up demonstrated a sustained legacy effect; metformin is the oral agent with the strongest randomized mortality evidence.
Option A: Option A is incorrect because the UGDP trial raised a cardiovascular safety concern with tolbutamide rather than demonstrating a sulfonylurea mortality benefit.
Option B: Option B is incorrect because repaglinide has no dedicated cardiovascular outcomes trial demonstrating reduced mortality.
Option C: Option C is incorrect because chlorpropamide lacks outcome data showing a mortality benefit.
Option D: Option D is incorrect because the NAVIGATOR trial of nateglinide did not show a reduction in all-cause mortality.
11. A 75-year-old man with mildly reduced renal function and erratic food intake requires a sulfonylurea for cost reasons. Between glipizide and glyburide, which is the safer choice and why?
A) Glipizide, because it is metabolized by CYP2C9 (cytochrome P450 2C9) to inactive metabolites that do not accumulate in renal impairment, lowering the risk of prolonged hypoglycemia
B) Glyburide, because its active metabolites provide smoother, safer glucose control in older adults
C) Glyburide, because it has the shortest duration of action of any sulfonylurea
D) Either agent equally, because all sulfonylureas carry identical hypoglycemia risk regardless of renal function
E) Glipizide, because it is excreted unchanged by the kidney and therefore cannot accumulate
ANSWER: A
Rationale:
Glipizide is metabolized by CYP2C9 to inactive metabolites that do not accumulate as renal function declines, so it carries a lower risk of prolonged hypoglycemia than glyburide and is the safer choice in an older patient with reduced renal function and erratic intake.
Option B: Option B is incorrect because glyburide's weakly active metabolites accumulate in renal impairment and increase, rather than reduce, hypoglycemia risk.
Option C: Option C is incorrect because glyburide does not have the shortest duration of action; its effective duration is prolonged, especially in renal impairment.
Option D: Option D is incorrect because sulfonylureas do not carry identical risk; glyburide is distinctly more hazardous in renal impairment.
Option E: Option E is incorrect because glipizide is hepatically inactivated rather than excreted unchanged by the kidney; its safety derives from inactive metabolites, not renal excretion of unchanged drug.
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