CHAPTER 2-60: DIABETIC DRUGS

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–24 lists the various available antidiabetic agents. Metformin is also discussed in a separate chapter (see Metformin). Other drugs and poisons can also cause hypoglycemia (see Table I–25).

1. Parenteral agents

   1. Insulin. Blood glucose is lowered directly by the stimulation of cellular uptake and metabolism of glucose. Cellular glucose uptake is accompanied by an intracellular shift of potassium and magnesium. Insulin also promotes glycogen formation and lipogenesis. Insulin products are mostly given by the parenteral route. An orally inhaled delivery system for regular insulin was recently approved in the United States. All insulin produce effects similar to those of 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 (see 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 and led to removal of troglitazone from the US market.

   6. Dipeptidyl peptidase-4 (DDP-4) inhibitors. Incretin hormones are rapidly inactivated by the enzyme DDP-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, DDP-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–24 and II–66)

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, 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 orally 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 (90 times the maximum daily dose) of exenatide resulted in sustained nausea for 24 hours, during which the patient required insulin for the management of hyperglycemia. Overdose of 17.4 mg of liraglutide (10 times the maximum recommended dose) caused severe nausea and vomiting. Hypoglycemia was not reported.

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. Two 500-mg tablets of acetohexamide caused hypoglycemic coma in an adult. 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, fluoroquinolones (gatifloxacin and levofloxacin), sulfonamides, propranolol, salicylates, clofibrate, probenecid, pentamidine, valproic acid, dicumarol, cimetidine, monoamine oxidase (MAO) inhibitors, and alcohol. In addition, co-ingestion of alcohol may occasionally produce a disulfiram-like interaction (Disulfiram).

   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. Ingestion of 3,420 mg of nateglinide in a nondiabetic adult resulted in hypoglycemia lasting 6 hours.

6. DDP-4 Inhibitors. In a review of 650 cases of DDP-4 inhibitor ingestions, 3 patients, including 2 nondiabetics, developed hypoglycemia. A 27-year-old female who ingested 700 mg of sitagliptin complained of abdominal discomfort but did not become hypoglycemic. A 70-year-old female remained asymptomatic after ingestion of 1,800 mg of sitagliptin.

7. Metformin. See 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 may also be depressed. Note: In patients receiving beta-adrenergic–blocking agents, many of the manifestations of hypoglycemia (tachycardia, diaphoresis) may be blunted or absent.

2. SGLT2 inhibitors may cause hypotension due to intravascular volume depletion, and elevations in serum potassium, magnesium, and phosphate may occur.

3. Metformin can cause severe lactic acidosis (see Metformin), and occasionally hypoglycemia.

Overdose involving a sulfonylurea, meglitinide, or insulin should be suspected in any patient with hypoglycemia. Other causes of hypoglycemia that should be considered include alcohol ingestion (especially in children) and fulminant hepatic failure.

1. Specific levels

   1. Serum concentrations of many agents can be determined in commercial toxicology laboratories but have little utility in acute clinical management.

   2. Exogenously administered animal insulin can be distinguished from endogenous insulin (ie, in a patient with hypoglycemia caused by insulinoma) by determination of C-peptide (present with endogenous insulin secretion).

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 children 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, consider use of octreotide if 5% dextrose infusions do not maintain satisfactory glucose concentrations.

   3. Maintaining serum glucose concentrations above 90–100 mg/dL for the first 12 hours of therapy or longer is often necessary to prevent recurrent hypoglycemia. However, 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–38). 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. Forced diuresis and dialysis procedures are of no known value for other hypoglycemic agents. The high degree of protein binding of the sulfonylureas suggests that dialysis procedures would not generally be effective. However, charcoal hemoperfusion reduced the serum half-life of chlorpropamide in a patient with renal failure.

   2. Metformin (see Metformin) can be removed by hemodialysis.