Recent advances have resulted in a dramatic increase in the number and types of drugs used to manage diabetes. These agents can be divided broadly into parenteral and oral drugs. Table II-23 lists the various available antidiabetic agents. Metformin is also discussed in a separate chapter. Other drugs and poisons can also cause hypoglycemia (see Table 1-25).

1. Parenteral agents
   1. Insulin lowers blood glucose by directly stimulating its cellular uptake and metabolism. Intracellular shifts of potassium and magnesium accompany cellular glucose uptake. Insulin also promotes glycogen formation and lipogenesis. It is primarily administered by the parenteral route; however, an inhaled delivery system for regular insulin is approved in the United States. All insulins produce effects similar to endogenous insulin; they differ in antigenicity and in onset and duration of effect.
   2. Amylin analogs. Pramlintide is a synthetic analog of amylin, a peptide hormone synthesized by and excreted from pancreatic beta cells along with insulin during the postprandial period. Amylin slows gastric emptying and suppresses glucagon secretion.
   3. Glucagon-like peptide 1 (GLP-1) receptor agonists. GLP-1 is released from the intestines in response to oral glucose intake. Stimulation of the GLP-1 receptors in pancreatic beta cells leads to increased insulin release in the presence of elevated glucose concentrations, while glucagon secretion is blocked.
      1. Exenatide is a GLP-1 mimetic that improves glycemic control through a combination of mechanisms.
      2. Liraglutide, an analog of human GLP-1, is a GLP-1 receptor agonist.
      3. Albiglutide is comprised of two copies of modified human GLP-1 fused to human albumin, allowing for once-weekly injections.
2. Oral agents
   1. Sulfonylureas lower blood glucose primarily by stimulating endogenous pancreatic insulin secretion and secondarily by enhancing peripheral insulin receptor sensitivity and reducing glycogenolysis.
   2. Meglitinides also increase pancreatic insulin release and can cause hypoglycemia in overdose.
   3. Biguanides.Metformin decreases hepatic glucose production (gluconeogenesis) and intestinal absorption of glucose while increasing peripheral glucose uptake and utilization. It does not stimulate insulin release.
   4. Alpha-glucosidase inhibitors delay the digestion of ingested carbohydrates, reducing postprandial blood glucose concentrations.
   5. Glitazones decrease hepatic glucose output and improve target cell response to insulin. Hepatotoxicity has been reported with chronic therapy for all the drugs in this class.
   6. Dipeptidyl peptidase-4 (DPP-4) inhibitors. Incretin hormones (eg, GLP-1) are rapidly inactivated by the enzyme DPP-4. Inhibition of these enzymes produces increased and prolonged active incretin levels, leading to increased insulin release and decreased glucagon levels in the circulation in a glucose-dependent manner.
   7. Sodium-glucose co-transporter 2 inhibitors (SGLT2). Expressed in the proximal renal tubules, SGLT2 is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Inhibition of SGLT2 reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, increasing urinary glucose excretion.
   8. Note: Although alpha-glucosidase inhibitors, glitazones, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors are not likely to cause hypoglycemia after an acute overdose, they may contribute to the hypoglycemic effects of sulfonylureas, meglitinides, or insulin. Metformin inhibits gluconeogenesis, and there are a few reports of hypoglycemia after overdose with this agent even when taken alone.
3. Pharmacokinetics (see Tables II-23 and II-63)

1. Insulin
   1. Severe hypoglycemic coma and permanent neurologic sequelae have occurred after injections of 800-3,200 units of insulin. Deliberate subcutaneous injection of 800 units of insulin lispro and 3,800 units of insulin glargine by a diabetic adult resulted in prolonged hypoglycemia. Plasma insulin levels returned to normal at 108 hours. A 26-year-old type 1 diabetic male who injected 4,800 units of insulin glargine and was treated with approximately 800 g per day of glucose supplementation developed acute hepatic injury. On day 4, a depot of insulin was excised from the patient's abdominal wall, with subsequent reduction in glucose requirements and improvement in liver function.
   2. Orally administered insulin is poorly absorbed and is generally not toxic. However, an intentional ingestion of 3,000 units of insulin aspart, lispro, and glargine produced symptomatic hypoglycemia within 1 hour in a nondiabetic 51-year-old male.
   3. Drug interactions: Albuterol increased the absorption of inhaled insulin by 25% in patients with asthma.
2. Pramlintide. Hypoglycemia is not expected from the drug alone but is possible when coadministered with other hypoglycemic agents. A 10-mg dose in healthy volunteers caused nausea, vomiting, vasodilation, and dizziness.
3. Deliberate injection of 1,800 mcg of exenatide resulted in sustained nausea for 24 hours without hypoglycemia, but hypoglycemia did occur in a diabetic patient who injected 600 mcg. Injection of 6 mg dulaglutide did not cause hypoglycemia in a diabetic. Overdose of 17.4 mg and 72 mg of liraglutide caused severe nausea and vomiting without hypoglycemia. However, hypoglycemia occurred after injection of 36 mg of liraglutide in a nondiabetic adult and 18 mg in a diabetic patient.
4. Sulfonylureas.Toxicity depends on the agent and the total amount ingested. Toxicity may also occur owing to drug interactions, resulting in impaired elimination of the oral agent.
   1. Ingestion of a single tablet of chlorpropamide (250 mg), glipizide (5 mg), or glyburide (2.5 mg) in each case produced hypoglycemia in children 1-4 years old. In a 79-year-old nondiabetic person, 5 mg of glyburide caused hypoglycemic coma.
   2. Interactions with the following drugs may increase the risk for hypoglycemia: other hypoglycemic agents, some fluoroquinolones, sulfonamides, propranolol, salicylates, clofibrate, probenecid, pentamidine, valproic acid, cimetidine, monoamine oxidase (MAO) inhibitors, and ethanol. In addition, co-ingestion of ethanol may occasionally produce a disulfiram-like interaction.
   3. Hepatic or renal insufficiency may impair drug elimination and result in hypoglycemia.
5. Meglitinides. A 4-mg dose of repaglinide produced hypoglycemia in a nondiabetic 18-year-old. A diabetic 15-year-old who ingested 10.5 mg of repaglinide developed delayed and prolonged hypoglycemia lasting 26 hours. Ingestion of 3,420 mg of nateglinide in a nondiabetic adult resulted in hypoglycemia lasting 6 hours.
6. DPP-4 Inhibitors. In a review of 650 cases of DPP-4 inhibitor ingestions, 3 patients, including 2 nondiabetics, developed hypoglycemia. A 27-year-old female who ingested 700 mg of sitagliptin had abdominal discomfort but did not become hypoglycemic. A 70-year-old female remained asymptomatic after ingestion of 1,800 mg of sitagliptin.
7. SGLT2 Inhibitors. A review of 88 SGLT2 inhibitor exposures found that 91% of patients remained asymptomatic, and hypoglycemia was not observed. Ingestion of 600 mg of canagliflozin by a 43-year-old woman resulted in vomiting, tachycardia and mild hypertension.Metformin..

1. Hypoglycemia may be delayed in onset, depending on the agent used and the route of administration (ie, subcutaneous vs. intravenous). Manifestations of hypoglycemia include agitation, confusion, coma, seizures, tachycardia, and diaphoresis. Serum potassium and magnesium levels can also be low. Note: In patients receiving beta-adrenergic-blocking agents, many of the manifestations of hypoglycemia (tachycardia, diaphoresis) can be blunted or absent.
2. SGLT2 inhibitors may cause hypotension due to intravascular volume depletion, and elevations in serum potassium, magnesium, and phosphate can occur. SGLT2 inhibitors can also cause euglycemic DKA.
3. Metformin can cause severe lactic acidosis, and occasionally hypoglycemia.

Consider an overdose involving a sulfonylurea, meglitinide, or insulin in any patient with hypoglycemia. Other causes of hypoglycemia to consider include ethyl alcohol ingestion (especially in children) and fulminant hepatic failure (see also Table 1-25).

1. Specific levels
   1. Serum concentrations of many agents can be determined in commercial toxicology laboratories but typically do not change acute clinical management.
   2. C-peptide (co-secreted with endogenous insulin secretion) can help distinguish exogenously administered animal insulin from endogenous insulin (ie, in a patient with hypoglycemia caused by insulinoma).
2. Other useful laboratory studies include glucose, electrolytes, magnesium, and ethanol. If metformin is suspected, obtain a venous blood lactate level (gray-top tube).

Observe asymptomatic patients for a minimum of 8 hours after ingestion of a sulfonylurea. Because of the potential for a delay in onset of hypoglycemia if the patient has received food or IV glucose, it is prudent to observe patients overnight or otherwise ensure that finger stick blood glucose checks can be obtained frequently at home for up to 24 hours.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma and seizures if they occur.
   3. Obtain finger stick blood glucose levels every 1-2 hours until stabilized.
   4. Monitor serum potassium, magnesium, and phosphate in patients with SGLT-2 inhibitor overdose.
2. Specific drugs and antidotes
   1. If the patient is hypoglycemic, administer concentrated glucose orally or IV. In adults, give 50% dextrose (D₅₀W), 1-2 mL/kg; in children, use 25% dextrose (D₂₅W), 2-4 mL/kg. Give repeated glucose boluses and administer 5-10% dextrose (D₅-D₁₀) as needed to maintain normal serum glucose concentrations (60-110 mg/dL).
   2. For patients with a sulfonylurea or meglitinide overdose and refractory hypoglycemia, consider use of octreotide.
   3. Once hypoglycemia resolves (usually 12-24 hours after the ingestion) and the patient no longer requires dextrose infusions, serum glucose concentrations should be allowed to normalize. Follow serum glucose levels closely for several hours after the last dose of dextrose.
3. Decontamination
   1. Oral agents. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
   2. Insulin. Orally ingested insulin is very poorly absorbed (<1% bioavailability), thus gut decontamination is not usually necessary.
4. Enhanced elimination
   1. Sulfonylureas. Alkalinization of the urine increases the renal elimination of chlorpropamide. Hemodialysis is not effective for any of the hypoglycemic agents,
   2. Metformin can be removed by hemodialysis.