A 72-year-old woman is brought to the emergency department by her husband with confusion and slurred speech. She was diagnosed with type 2 diabetes mellitus a year ago, and her medication regimen has been changed multiple times due to medication intolerance. Three weeks ago, the patient was started on a single-drug diabetes regimen. Her husband reports that since that time, her home glucose readings have been "all over the place," and she has "stopped eating junk food to try to smooth them out." Medical history is notable for hypertension and hyperlipidemia, for which she takes lisinopril, chlorthalidone, and atorvastatin. The patient also has osteoarthritis of the knees and has been intermittently taking an over-the-counter medication for pain. She does not use tobacco or alcohol. Blood pressure is 142/70 mm Hg and pulse is 101/min and regular. Mucous membranes are moist. Bedside capillary blood glucose is 35 mg/dL. An intravenous glucose solution is administered, with rapid improvement in her mental state. A basic metabolic panel shows serum potassium of 3.8 mEq/L and serum creatinine of 1.7 mg/dL, with an estimated glomerular filtration rate of 50 mL/minute/1.73 m²; serum creatinine 2 weeks earlier was 1.3 mg/dL. Which of the following medications is most likely to have caused this patient's condition?

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Explanation: 11ec2b69_beb5_f995_8f63_7b942ad8fdf3_MD0005_00 This patient has symptomatic hypoglycemia associated with an acute decline in renal function, possibly due to concurrent use of nonsteroidal anti-inflammatory drugs for osteoarthritis and the ACE inhibitor lisinopril for hypertension. Hypoglycemia is a risk with insulin and several oral medications for diabetes, especially sulfonylureas (eg, glyburide, glipizide, glimepiride) and meglitinides (eg, nateglinide, repaglinide). These drugs increase insulin secretion by pancreatic beta cells even when blood glucose levels are normal. Nateglinide is a short-acting insulin secretagogue that is dosed 3 times a day with meals, which might explain this patient's fluctuating glucose measurements. Metabolism in the liver produces biologically active metabolites that are excreted by the kidneys. The risk of hypoglycemia with nateglinide increases in renal failure due to accumulation of these metabolites. The risk of hypoglycemia also increases in patients who consume alcohol excessively. (Choice A) Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (eg, canagliflozin) lower blood glucose by increasing renal glucose excretion. The main side effects are urinary tract infections, genital mycotic infections, and hypotension. Hypoglycemia does not occur with SGLT-2 inhibitor monotherapy. (Choice B) Glucagon-like peptide-1 (GLP-1) is produced in the gastrointestinal tract in response to food, and it increases glucose-dependent insulin secretion and suppresses glucagon release. GLP-1 mimetics (eg, exenatide, liraglutide) are injectable agents that mimic the actions of endogenous GLP-1. Dipeptidyl peptidase-4 inhibitors (eg, linagliptin) decrease the breakdown of GLP-1. The risk of hypoglycemia with these medications is low as increased insulin secretion occurs only when glucose levels are above normal. (Choice C) Metformin decreases hepatic glucose production and increases insulin sensitivity but does not stimulate insulin secretion and does not cause hypoglycemia when used in monotherapy. There is a risk of lactic acidosis with metformin when used in renal failure. It is contraindicated in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² and should be used with caution in those with eGFR 30-45 mL/min/1.73 m². However, it is safe to use in mild renal impairment, as in this patient. (Choice E) Thiazolidinediones (eg, pioglitazone) reduce blood glucose primarily by improving insulin sensitivity. Hypoglycemia is rare with these drugs when used in monotherapy. Common side effects include weight gain, heart failure, fluid retention, and bone fractures. Educational objective: Sulfonylureas and meglitinides increase insulin secretion, even when blood glucose levels are normal, and can cause hypoglycemia. Metformin, glucagon-like peptide-1 mimetics, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors do not cause significant hypoglycemia when used as monotherapy. References: A review of the efficacy and safety of oral antidiabetic drugs. (http://www.ncbi.nlm.nih.gov/pubmed/23241069)

A 72-Year-Old Woman Is Brought to the Emergency Department by Her