A 76-year-old woman is brought to the hospital after her daughter found her unresponsive in the morning. The patient and her daughter walked extensively during a family outing the previous day; the patient then skipped dinner and went to bed as soon as they returned home. Medical history includes type 2 diabetes mellitus managed with an oral medication. Blood pressure is 140/80 mm Hg and pulse is 102/min. The patient is diaphoretic and responds only to pain. Blood glucose is 34 mg/dL. Her condition rapidly improves after administration of an intravenous bolus of dextrose, but she becomes confused again several hours later. Repeat blood glucose is 39 mg/dL. Which of the following medications is the most likely cause of this patient's current condition?
Noninsulin antidiabetic agents for type 2 diabetes mellitus | ||
Agent | Mechanism of action | Adverse effects |
Insulin secretagogues
| ↑ Insulin secretion by inhibiting β-cell KATP channels |
|
Biguanides
| Stimulate AMPK & inhibit mitochondrial gluconeogenesis, ↓ hepatic glucose production & ↑ peripheral glucose uptake |
|
Thiazolidinediones
| Activate transcription regulator PPAR-γ, ↓ insulin resistance |
|
GLP-1 agonists
| ↑ Glucose-dependent insulin secretion, ↓ glucagon secretion, delayed gastric emptying |
|
DPP4 inhibitors
| ↑ Endogenous GLP-1 & GIP levels |
|
SGLT-2 inhibitors
| ↑ Renal glucose excretion |
|
| AMPK = AMP-activated protein kinase; DPP4 = dipeptidyl peptidase-4; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1; KATP = ATP-sensitive potassium; PPAR-γ = peroxisome proliferator–activated receptor γ; SGLT-2 = sodium-glucose cotransporter-2. | ||
This patient's persistent hypoglycemia indicates excessive insulin secretion caused by her diabetes medication, which is most likely a sulfonylurea (eg, glyburide, glimepiride). Sulfonylureas bind to a receptor on pancreatic beta cells and inhibit the ATP-sensitive potassium channel, altering the cell's resting potential and resulting in calcium influx stimulating exocytosis of insulin secretory granules. The increased insulin secretion occurs independent of blood glucose concentrations (ie, even when blood glucose concentrations are low).
Hypoglycemia with sulfonylureas can be induced by exercise, missed meals, or initiation of additional antidiabetic medications. The risk is greater in the elderly population and in patients with chronic kidney disease or hepatic impairment (due to slower drug metabolism and clearance). The hypoglycemia may reoccur following successful initial treatment until the drug has been fully cleared.
(Choice A) Acarbose is an alpha-glucosidase inhibitor that decreases intestinal carbohydrate digestion and glucose absorption, thereby blunting postprandial hyperglycemia. It is not associated with hypoglycemia because the medication does not induce insulin secretion.
(Choice C) Metformin is a biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption and increases peripheral glucose uptake and use. Because metformin does not increase endogenous insulin production, it is not associated with hypoglycemia.
(Choice D) Thiazolidinediones (eg, pioglitazone) increase insulin sensitivity by increasing glucose use and decreasing glucose production in adipose tissue, muscle, and liver. Thiazolidinediones do not increase endogenous insulin production and therefore carry a low risk of hypoglycemia.
(Choice E) Unlike sulfonylureas, dipeptidyl peptidase-4 inhibitors (eg, sitagliptin) and glucagon-like peptide-1 agonists (eg, exenatide) increase glucose-dependent insulin release from the pancreatic beta cells. The effects on insulin release diminish as glucose levels approach normal (eg, fasting state), and therefore, hypoglycemia risk is very low.
Educational objective:
Sulfonylureas (eg, glyburide, glimepiride) increase insulin secretion by pancreatic beta cells independent of blood glucose concentration. These medications have a high incidence of hypoglycemia, especially in the elderly population.