Chapter 29 — Diabetes Pharmacology — Module 7 — Special Clinical Contexts in Diabetes Pharmacology
1. A 61-year-old man with type 2 diabetes mellitus (T2DM) is seen 10 weeks after a non-fatal myocardial infarction. He takes metformin, high-intensity statin, aspirin, and guideline-directed cardiac medications; HbA1c is 7.9% and estimated glomerular filtration rate (eGFR) is 72 mL per minute per 1.73 m squared. He has no heart failure symptoms. The priority is to reduce his risk of a further atherosclerotic event. Which add-on best serves this goal?
A) Glimepiride, to intensify glycemic control and thereby reduce atherosclerotic risk
B) Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for cardiovascular protection
C) A glucagon-like peptide-1 receptor (GLP-1R) agonist such as liraglutide or subcutaneous semaglutide, which reduced major adverse cardiovascular events including non-fatal myocardial infarction and stroke in cardiovascular outcome trials
D) Pioglitazone, for its peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mediated cardiovascular benefit
E) Acarbose, to blunt postprandial glucose and lower atherosclerotic risk
ANSWER: C
Rationale:
In a patient with established atherosclerotic cardiovascular disease whose dominant goal is reducing further atherosclerotic events, a GLP-1R agonist such as liraglutide or subcutaneous semaglutide is preferred because this class reduced major adverse cardiovascular events, including non-fatal myocardial infarction and stroke, in cardiovascular outcome trials such as LEADER.
Option A: Option A is incorrect because sulfonylurea-driven glycemic control does not reduce atherosclerotic events and adds hypoglycemia risk.
Option B: Option B is incorrect because DPP-4 inhibitors are cardiovascular-neutral, and saxagliptin additionally raises heart failure hospitalization.
Option D: Option D is incorrect because pioglitazone is not used for atherosclerotic event reduction and causes fluid retention.
Option E: Option E is incorrect because acarbose has no established atherosclerotic outcome benefit in this setting.
2. A 68-year-old woman with T2DM and prior coronary revascularization is admitted for her second heart failure hospitalization this year; left ventricular ejection fraction is 35%. Her atherosclerotic disease has been stable. She is on metformin and a GLP-1R agonist already. Which addition most directly targets her dominant problem of recurrent heart failure and cardiovascular death?
A) An SGLT-2 inhibitor such as empagliflozin or dapagliflozin, which reduces cardiovascular death and heart failure hospitalization
B) A second GLP-1R agonist to intensify atherosclerotic protection
C) Pioglitazone to improve insulin sensitivity
D) Saxagliptin for additional glycemic control
E) A long-acting sulfonylurea to tighten glycemic control
ANSWER: A
Rationale:
Her dominant clinical problem is recurrent heart failure with reduced ejection fraction, so an SGLT-2 inhibitor such as empagliflozin or dapagliflozin is the most direct choice because this class reduces cardiovascular death and heart failure hospitalization.
Option B: Option B is incorrect because a second GLP-1R agonist would not address heart failure and duplicating the class is inappropriate.
Option C: Option C is incorrect because pioglitazone causes fluid retention and is contraindicated in this degree of heart failure.
Option D: Option D is incorrect because saxagliptin increases heart failure hospitalization.
Option E: Option E is incorrect because a sulfonylurea does not improve heart failure outcomes and adds hypoglycemia risk.
3. A 59-year-old man with T2DM has diabetic kidney disease with an eGFR of 48 mL per minute per 1.73 m squared and a urinary albumin-to-creatinine ratio of 620 mg per gram despite a maximally tolerated angiotensin-converting enzyme (ACE) inhibitor. He has no heart failure. Which addition is best supported for slowing his kidney disease progression?
A) Increase the ACE inhibitor beyond the maximum tolerated dose to gain further albuminuria reduction
B) Add a sulfonylurea, since improved glycemic control alone will halt nephropathy
C) Add a DPP-4 inhibitor, which provides disease-modifying renal protection
D) Add an SGLT-2 inhibitor, which provided additive renal protection on a background of maximally tolerated RAAS blockade in patients with this degree of albuminuria and eGFR
E) Stop the ACE inhibitor and rely on glycemic control alone
ANSWER: D
Rationale:
Adding an SGLT-2 inhibitor is best supported because, in patients with diabetic kidney disease and significant albuminuria on a background of maximally tolerated renin-angiotensin-aldosterone system (RAAS) blockade, SGLT-2 inhibition produced additive renal protection through afferent arteriolar pressure reduction, as shown in the CREDENCE trial.
Option A: Option A is incorrect because escalating the ACE inhibitor beyond the maximum tolerated dose is not the recommended next step and risks hyperkalemia and hypotension.
Option B: Option B is incorrect because glycemic control with a sulfonylurea alone does not provide disease-modifying nephroprotection.
Option C: Option C is incorrect because DPP-4 inhibitors are not disease-modifying for kidney disease.
Option E: Option E is incorrect because stopping RAAS blockade would remove an established nephroprotective therapy.
4. A 74-year-old woman with T2DM presents for routine review. Her eGFR has declined to 32 mL per minute per 1.73 m squared. She currently takes metformin 1000 mg twice daily and glibenclamide (glyburide) 10 mg daily, and she reports two episodes of morning sweating and confusion relieved by juice. What is the most appropriate medication adjustment?
A) Continue both agents unchanged because her HbA1c is at goal
B) Reduce the metformin dose given the eGFR is between 30 and 45, and stop glibenclamide because its active renally cleared metabolites are accumulating and causing hypoglycemia at this level of renal function
C) Increase glibenclamide to better control fasting glucose and continue metformin unchanged
D) Stop metformin and double the glibenclamide dose
E) Add a second sulfonylurea to address the fasting hyperglycemia
ANSWER: B
Rationale:
At an eGFR of 32, metformin should be dose-reduced because the eGFR is between 30 and 45, and glibenclamide should be stopped because its active renally cleared metabolites accumulate in chronic kidney disease and are the likely cause of her hypoglycemic episodes.
Option A: Option A is incorrect because her symptomatic hypoglycemia and declining renal function mandate change despite an at-goal HbA1c.
Option C: Option C is incorrect because increasing glibenclamide would worsen the hypoglycemia.
Option D: Option D is incorrect because doubling glibenclamide intensifies the very agent causing harm.
Option E: Option E is incorrect because adding another sulfonylurea compounds the hypoglycemia risk.
5. A 63-year-old man with T2DM and diabetic kidney disease has persistent albuminuria (urinary albumin-to-creatinine ratio 480 mg per gram) despite a maximally tolerated angiotensin receptor blocker (ARB) and an SGLT-2 inhibitor; eGFR is 42 mL per minute per 1.73 m squared and serum potassium is 4.6 mmol/L. The nephrologist adds finerenone. Which monitoring priority and rationale are correct?
A) No additional monitoring is needed because finerenone has no effect on electrolytes
B) Monitor liver enzymes, because finerenone characteristically causes hepatotoxicity
C) Monitor serum potassium, because finerenone is a mineralocorticoid receptor antagonist that can raise potassium, although as a non-steroidal agent its hyperkalemia risk is lower than that of steroidal agents; it adds nephroprotection through a pathway distinct from RAAS blockade and SGLT-2 inhibition
D) Monitor for hypoglycemia, because finerenone lowers blood glucose substantially
E) Monitor coronary perfusion, because finerenone constricts the afferent arteriole like an SGLT-2 inhibitor
ANSWER: C
Rationale:
Finerenone is a non-steroidal mineralocorticoid receptor antagonist that can raise serum potassium, so potassium monitoring is the priority; its hyperkalemia risk is lower than that of steroidal mineralocorticoid receptor antagonists, and it adds nephroprotection through mineralocorticoid receptor blockade, a pathway distinct from the efferent action of RAAS blockade and the afferent action of SGLT-2 inhibition.
Option A: Option A is incorrect because finerenone can raise potassium and does require monitoring.
Option B: Option B is incorrect because hepatotoxicity is not the characteristic concern.
Option D: Option D is incorrect because finerenone does not act by lowering blood glucose.
Option E: Option E is incorrect because finerenone does not constrict the afferent arteriole; that is the SGLT-2 inhibitor mechanism.
6. A 70-year-old man with T2DM has heart failure with preserved ejection fraction (left ventricular ejection fraction 55%) and frequent heart failure clinic visits for congestion. His eGFR is 55 mL per minute per 1.73 m squared. He is on metformin. He asks whether any diabetes medication can also help his heart failure even though his ejection fraction is "normal." Which response reflects current evidence?
A) No diabetes agent helps heart failure when ejection fraction is preserved; only reduced ejection fraction responds
B) An SGLT-2 inhibitor (empagliflozin or dapagliflozin) reduces heart failure hospitalization across the ejection fraction spectrum, including heart failure with preserved ejection fraction, so it can benefit him despite a normal ejection fraction
C) Pioglitazone is the preferred agent for heart failure with preserved ejection fraction
D) A DPP-4 inhibitor is the disease-modifying choice for preserved ejection fraction
E) Only a GLP-1R agonist has proven benefit in heart failure with preserved ejection fraction
ANSWER: B
Rationale:
SGLT-2 inhibitors reduce heart failure hospitalization across the full ejection fraction spectrum, including heart failure with preserved ejection fraction as shown in trials such as EMPEROR-Preserved and DELIVER, so empagliflozin or dapagliflozin can benefit this patient despite a preserved ejection fraction.
Option A: Option A is incorrect because SGLT-2 inhibitors benefit preserved-ejection-fraction heart failure, not only reduced ejection fraction.
Option C: Option C is incorrect because pioglitazone causes fluid retention and worsens heart failure.
Option D: Option D is incorrect because DPP-4 inhibitors are not disease-modifying in heart failure.
Option E: Option E is incorrect because GLP-1R agonists have not demonstrated consistent heart-failure-specific benefit in preserved ejection fraction.
7. A 65-year-old woman with T2DM and heart failure with reduced ejection fraction is referred after a recent decompensation. Her regimen includes metformin and saxagliptin. The cardiologist asks whether the saxagliptin is appropriate given her heart failure. What is the best response and action?
A) Saxagliptin is protective in heart failure and should be continued
B) All DPP-4 inhibitors increase heart failure events, so the entire class is contraindicated
C) Saxagliptin is safe; the heart failure concern applies only to sitagliptin
D) Saxagliptin should be continued but the dose increased to gain cardiovascular benefit
E) Saxagliptin was associated with increased heart failure hospitalization in a cardiovascular outcome trial and should be avoided in established heart failure; switch to an agent that benefits or is neutral in heart failure, such as an SGLT-2 inhibitor
ANSWER: E
Rationale:
Saxagliptin was associated with increased heart failure hospitalization in the SAVOR-TIMI 53 trial and should be avoided in patients with established heart failure; switching to an SGLT-2 inhibitor is appropriate because that class benefits heart failure with reduced ejection fraction.
Option A: Option A is incorrect because saxagliptin is not protective and was linked to increased heart failure hospitalization.
Option B: Option B is incorrect because the heart failure signal is specific to saxagliptin, not a uniform class effect; sitagliptin and linagliptin were neutral.
Option C: Option C inverts the evidence, since the concern applies to saxagliptin, not sitagliptin.
Option D: Option D is incorrect because increasing saxagliptin would compound rather than mitigate the heart failure risk.
8. A 62-year-old man with T2DM on chronic empagliflozin is admitted with acute decompensated heart failure. He is dyspneic, fluid-restricted, and eating poorly; an intravenous insulin infusion is initiated for glycemic control. The covering team asks how to manage his empagliflozin and what glucose target to use. Which plan is correct?
A) Continue empagliflozin and target a glucose of 4.0 to 6.0 mmol/L (70 to 110 mg per deciliter)
B) Continue empagliflozin and withhold insulin to prevent sodium retention
C) Hold empagliflozin during the admission because the fasting, fluid-restricted state raises the risk of euglycemic diabetic ketoacidosis, and target an inpatient glucose of 7.8 to 10.0 mmol/L (140 to 180 mg per deciliter) while avoiding hypoglycemia
D) Hold empagliflozin but target a glucose of 4.0 to 6.0 mmol/L (70 to 110 mg per deciliter)
E) Discontinue insulin and resume empagliflozin immediately to accelerate diuresis
ANSWER: C
Rationale:
Empagliflozin should be held during acute decompensated heart failure because the fasting, fluid-restricted state increases the risk of euglycemic diabetic ketoacidosis, and the recommended inpatient glucose target is 7.8 to 10.0 mmol/L (140 to 180 mg per deciliter) while avoiding hypoglycemia.
Option A: Option A is incorrect because empagliflozin should be held and the target is not as tight as 70 to 110.
Option B: Option B is incorrect because insulin is the appropriate inpatient agent and should not be withheld.
Option D: Option D is incorrect because, although holding empagliflozin is right, a 70 to 110 target is too tight and risks hypoglycemia in a critically ill patient.
Option E: Option E is incorrect because resuming empagliflozin in the fasting decompensated state risks euglycemic diabetic ketoacidosis and excess volume depletion.
9. A 29-year-old woman at 29 weeks gestation has gestational diabetes mellitus. Despite two weeks of adequate medical nutrition therapy, her fasting glucose is persistently 5.8 mmol/L (105 mg per deciliter) and one-hour postprandial values exceed 8.3 mmol/L (150 mg per deciliter). She asks for the safest effective treatment. Which is the most appropriate pharmacological choice?
A) Initiate insulin, the standard of care in pregnancy, titrated to fasting below 5.3 mmol/L (95 mg per deciliter) and one-hour postprandial below 7.8 mmol/L (140 mg per deciliter)
B) Start empagliflozin, because SGLT-2 inhibitors are safe and effective in the third trimester
C) Start semaglutide, because GLP-1R agonists are preferred for postprandial control in pregnancy
D) Start pioglitazone, which is well tolerated across all trimesters
E) Continue medical nutrition therapy alone indefinitely and avoid all pharmacotherapy regardless of glucose values
ANSWER: A
Rationale:
Insulin is the standard of care for gestational diabetes when medical nutrition therapy fails, and it is titrated to pregnancy targets of fasting below 5.3 mmol/L (95 mg per deciliter) and one-hour postprandial below 7.8 mmol/L (140 mg per deciliter).
Option B: Option B is incorrect because SGLT-2 inhibitors are contraindicated in the second and third trimesters.
Option C: Option C is incorrect because GLP-1R agonists lack adequate pregnancy safety data and are not recommended.
Option D: Option D is incorrect because thiazolidinediones lack pregnancy safety data.
Option E: Option E is incorrect because pharmacotherapy is indicated once glucose targets are not met despite adequate medical nutrition therapy.
10. A 31-year-old woman with T2DM managed on metformin, semaglutide, and dapagliflozin tells her physician she plans to conceive within the next few months. Her HbA1c is 6.9%. What preconception medication plan is most appropriate?
A) Make no changes until pregnancy is confirmed, then reassess
B) Continue semaglutide and dapagliflozin through conception and the first trimester, stopping only at 20 weeks
C) Stop metformin now because it crosses the placenta, but continue semaglutide and dapagliflozin
D) Discontinue semaglutide in advance of conception per its label and plan to stop dapagliflozin when pregnancy is recognized, transitioning glycemic management to insulin as the standard of care for pregnancy
E) Switch to a long-acting sulfonylurea, the preferred preconception and pregnancy agent
ANSWER: D
Rationale:
Semaglutide carries a label recommendation to discontinue in advance of planned conception, and SGLT-2 inhibitors such as dapagliflozin should be stopped when pregnancy is recognized; glycemic management should transition to insulin, the standard of care in pregnancy.
Option A: Option A is incorrect because semaglutide should be stopped before conception rather than after pregnancy is confirmed.
Option B: Option B is incorrect because these agents should not be continued through the first trimester.
Option C: Option C is incorrect because metformin is not the agent that must be stopped preconception; semaglutide and dapagliflozin are the concerns.
Option E: Option E is incorrect because sulfonylureas are not the preferred pregnancy agent; insulin is.
11. An 83-year-old woman with T2DM, mild cognitive impairment, and frailty is brought in after a fall preceded by sweating and confusion. She lives alone and sometimes skips meals. Her medications include glibenclamide (glyburide) and metformin; HbA1c is 6.4%. Which management approach best fits her clinical situation?
A) Intensify therapy to drive the HbA1c below 6.0% for maximal microvascular protection
B) Continue glibenclamide unchanged because the HbA1c is excellent
C) Add basal insulin to further lower glucose
D) Add a second sulfonylurea to stabilize her fasting glucose
E) Stop glibenclamide, which is flagged as potentially inappropriate in older adults and is the likely cause of her hypoglycemia and fall, and relax the glycemic target to a less stringent range appropriate for her frailty and cognitive status
ANSWER: E
Rationale:
In a frail elderly woman with cognitive impairment, irregular meals, and a hypoglycemia-related fall, glibenclamide should be stopped because it is flagged as potentially inappropriate in older adults and is the likely cause of her hypoglycemia, and the glycemic target should be relaxed to a less stringent range appropriate for her frailty and cognitive status.
Option A: Option A is incorrect because driving the HbA1c below 6.0% maximizes hypoglycemia risk with negligible benefit over her remaining lifespan.
Option B: Option B is incorrect because the low HbA1c in this context reflects dangerous overtreatment, not success.
Option C: Option C is incorrect because adding basal insulin increases hypoglycemia risk in a patient who skips meals.
Option D: Option D is incorrect because a second sulfonylurea compounds the hypoglycemia that caused her fall.
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