A 67-year-old woman comes to the office for follow-up of type 2 diabetes mellitus. She was diagnosed with diabetes 6 months ago. Lifestyle modification was initially advised, but the patient had no significant glycemic improvement. One month ago, the patient was started on metformin, to which she has been adherent; however, she has been experiencing abdominal discomfort and diarrhea attributed to the therapy. She has no other medical conditions. BMI is 28 kg/m². Physical examination is unremarkable. Laboratory tests show hemoglobin A1c is 8.2%. After further discussion, metformin is discontinued and glyburide is prescribed. Compared to metformin, this new therapy is most likely to increase the risk of which of the following?

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11ec160b_3bb3_e82f_9249_2d848751f613_MD0001_00 Metformin is the preferred initial medication for most patients with type 2 diabetes due to its overall efficacy and lack of hypoglycemia when used in monotherapy. However, metformin can cause bothersome gastrointestinal effects (eg, nausea, diarrhea), which may be severe enough to warrant a change in therapy. Sulfonylureas are second-line agents that are frequently used as add-on therapy or as a replacement for metformin. Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca²⁺ influx stimulates beta cell insulin release independent of blood glucose concentrations. Meglitinides (eg, repaglinide, nateglinide) are short-acting drugs that are functionally similar to sulfonylureas. Sulfonylureas continue to stimulate insulin secretion, even when blood glucose levels are normal and can therefore cause hypoglycemia. Hypoglycemia due to sulfonylureas can be induced by exercise, missed meals, acute illness, or initiation of additional antidiabetic medications. Longer-acting sulfonylureas (eg, glyburide) are more prone to causing hypoglycemia than shorter-acting drugs (eg, glipizide). (Choice A) Glucagonlike polypeptide-1 (GLP-1) regulates glucose by slowing gastric emptying and increasing insulin release. Pharmacologic GLP-1 agonists (eg, exenatide) lower blood glucose and promote weight loss. Acute pancreatitis is an uncommon but serious adverse effect. (Choice B) Renal dysfunction can occur with sodium-glucose cotransporter 2 (SGLT2) inhibitors due to excessive osmotic diuresis, but it is not a common adverse effect of sulfonylureas. However, preexisting renal impairment can increase the risk of hypoglycemia due to sulfonylureas and can increase the risk of lactic acidosis due to metformin. (Choice D) Metformin can decrease absorption of vitamin B₁₂, leading to B₁₂ deficiency in long-term use. Sulfonylureas do not have a significant effect on vitamin B₁₂ metabolism. (Choice E) SGLT2 inhibitors (eg, dapagliflozin) decrease renal reabsorption of glucose, leading to increased urinary glucose loss and lower blood glucose levels. The excess glucose in the urine can increase the risk of urinary tract infections and vulvovaginal candidiasis. They can also cause hypotension due to osmotic diuresis. Educational objective: Sulfonylureas inhibit the ATP-sensitive potassium channel on the pancreatic beta cell membrane, inducing depolarization and L-type calcium channel opening. The increased Ca²⁺ influx stimulates beta cell insulin release independent of blood glucose concentrations. Sulfonylureas stimulate insulin secretion, even when blood glucose levels are normal, which can lead to hypoglycemia.

A 67-Year-Old Woman Comes to the Office for Follow-Up of Type