Sulfonylureas

Sulfonylureas are insulin secretagogues which bind to pancreatic beta cell K⁺-ATP complex, thereby resulting in membrane depolarization, calcium influx, and secretion of insulin.

Sulfonylureas are inexpensive medications used to treat hyperglycemia in T2DM patients. They are utilized in combination with metformin for added control but can be used as monotherapy in patients who cannot tolerate metformin. They are expected to decrease HA1c by 1–2 %.

There is a moderate amount of drug interactions with sulfonylureas, and patients with difficult-to-treat glucose levels should have a review of medications to see whether certain agents may be enhancing or depressing the usual effects. The more common drugs that can cause an increase in the occurrence of hypoglycemia when used in combination with sulfonylureas are salicylates, sulfonamides, fibric acid derivatives (such as gemfibrozil), and warfarin.

Sulfonylureas are generally well tolerated. Hypoglycemia is the most common side effect, generally seen more frequently in longer-acting agents like glyburide. Sulfonylureas should be used with caution in elderly and renal patients. Weight gain and gastrointestinal disturbances may also occur. In addition, patients on sulfonylureas have been shown to have an increased odds ratio (OR = 2.77) for early mortality after acute MI and angioplasty [7]. It is known that ATP-dependent potassium channels exist on coronary vessels; thus, sulfonylureas prevent vasodilation, causing further myocardial damage. Another possible mechanism is interference in ischemic preconditioning. Therefore, sulfonylureas should be avoided in acute cardiac conditions or patients admitted for cardiac procedures. However, newer generation sulfonylureas are selective for pancreatic sulfonylurea receptors and have been shown to have similar cardiac outcomes compared to other secretagogues [8].

Meglitinides

Meglitinides block ATP-dependent K⁺ channels, thereby depolarizing the pancreatic beta cell membrane and facilitating calcium entry through calcium channels. This increase in intracellular calcium stimulates insulin release from the pancreatic beta cells. Though similar to sulfonylureas in action, they work via different receptors. Meglitinide-induced insulin release is glucose dependent.

Meglitinides increase insulin secretion with the expectation of lowering HA1c by 1–2 %. Monotherapy can be initiated, but in combination with metformin, it has superior glucose control. In comparison to sulfonylureas, the incidence of hypoglycemic episodes is lower.

Gemfibrozil combined with repaglinide has been show to enhance the hypoglycemic action.

The most common adverse event is hypoglycemia (20 % with repaglinide, uncommon with nateglinide). Meglitinides should be used with caution in patients with renal and/or severe liver disease. Nateglinide is hepatically metabolized with active metabolites that are renally excreted; therefore, it is better avoided in the renal patient. Repaglinide is metabolized via the liver and less than 10 % is renally excreted; thus, it does not need dose adjustment in renal patients. Other side effects include headache, arthralgia, upper respiratory tract infection, chest pain (3 % with repaglinide), and cardiac ischemia (2 % with repaglinide).

Biguanide

Biguanides decrease hepatic glucose output in the presence of insulin. They also increase insulin-mediated glucose utilization by peripheral tissues.

Metformin is an inexpensive medication that decreases hepatic glucose production while not causing hypoglycemia or weight gain. The expectation is for a reduction in HA1c by 1–2 %. It is usually the first treatment to be started in patients who cannot control glucose levels with lifestyle changes. Often as the glucose levels become less manageable, other oral hypoglycemics are added or even insulin is combined. Metformin is also used off-label for the treatment of oligomenorrhea, hirsutism, infertility, obesity, and prevention of T2DM in polycystic ovarian syndrome patients.

Patients receiving radiographic contrast are placed at risk for lactic acidosis as are acute or chronic alcohol consumers. Azole antifungal agents, levofloxacin, and monoamine oxidase inhibitors may increase the risk for hypoglycemia. Furosemide and nifedipine may enhance metformin absorption. Cationic drugs (amiloride, cimetidine, cotrimoxazole, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, and vancomycin) increase the risk for lactic acidosis by interfering with the renal tubular transport of metformin but can be used with close monitoring.

Possible side effects include diarrhea and nausea, which are common (30 %). Vitamin B12 can be lowered and should be checked every 2–3 years. Lactic acidosis is a very rare complication. There is a lack of evidence for increased risk with the use of biguanides during the perioperative period [9]. Therefore, biguanide use should not be a cause for delay or cancelation of surgery. Despite this, use should probably be stopped in the surgical patient 24 h prior and avoided in patients with renal dysfunction and in those likely to receive IV contrast. Creatinine levels should be reassessed 2–3 days after contrast to rule out nephropathy prior to reinitiating. Metformin should also be held in patients with decreased tissue perfusion or hemodynamic instability due to infection, concurrent liver disease, alcohol abuse, or heart failure.

Thiazolidinediones

Thiazolidinediones are peroxisome proliferator-activated receptor-gamma (PPARγ) agonists which lower blood glucose by improving target cell response to insulin without increasing pancreatic insulin secretion.

Thiazolidinediones decrease insulin resistance and increase glucose utilization. They are expected to decrease HA1c by 0.5–1.4 %. Due to the associated increase in side effects and expense, they are used as second-line therapy in patients with high risk for hypoglycemia or intolerance of or contraindications to metformin or sulfonylureas.

Controversial data shows possible interactions with statin therapy via the cytochrome P450 system.

Possible side effects include peripheral edema, congestive heart failure (CHF), weight gain, fractures, and macular edema. Rosiglitazone has been associated with increased risk for cardiovascular disease. Thiazolidinediones should be avoided in patients with CHF and liver disease (due to hepatotoxicity).

Alpha-glucosidase inhibitor

The alpha-glucosidase inhibitors are competitive, reversible inhibitors of alpha-amylase, which is produced in the pancreas, and of alpha-glucosidase, which is located on the brush border of the small intestine. This inhibition results in reduced postprandial increases in blood glucose levels by delaying the digestion of dietary carbohydrates.

It is helpful in reducing postprandial glycemia with the expectation of reducing HA1c by 0.5–0.8 %.

May reduce serum digoxin concentrations. Digestive enzymes and intestinal adsorbents, such as charcoal, should not be taken at the same time as the alpha-glucosidase inhibitors, as they will decrease the efficacy of the alpha-glucosidase inhibitors. Miglitol decreases the bioavailability of propranolol and ranitidine.

Gastrointestinal effects are very common including abdominal pain, diarrhea, and flatulence. Patients may also experience changes in liver function tests. It should be avoided in patients with inflammatory bowel disease, intestinal obstruction or predisposition to obstruction, colon ulceration, or other disorders of digestion or absorption. Used alone, alpha-glucosidase inhibitors do not cause hypoglycemia. However, hypoglycemia can occur when combined with other diabetic medications. Hypoglycemia should be treated with oral dextrose and not sucrose, which will be unable to be absorbed.

Dipeptidyl peptidase-4 (DPP-4) inhibitor

This medication prolongs action of endogenous glucagon-like peptide-1 (GLP-1) by deactivating DPP-4, an enzyme that deactivates various bioactive peptides.

There is an expected reduction of HA1c by 0.5–1 % without causing hypoglycemia. Yet due to its expense and limited experience in practice, it has not played a large role in diabetic management.

Minimal drug reactions but may need to decrease sulfonylurea dose due to risk of hypoglycemia.

One should consider reducing dose in renal patients. May increase risk for infection.

Bile Acid Sequestrants

This medication works as a bile acid sequestrant that lowers LDL.

In patients with hyperlipidemia, it is expected to decrease HA1c by 0.5 %.

This medication can interfere with absorption of other drugs such as glyburide, levothyroxine, and oral contraceptives containing ethinyl estradiol or norethindrone, by binding to them in the stomach and preventing their absorption into the body. It can also reduce phenytoin and warfarin activity. Drugs interacting with colesevelam should be given 4 h prior to its administration.

Known side effects include constipation, dyspepsia, abdominal pain, nausea, and difficult triglyceride control. It should be avoided in patients with intestinal obstruction.

Glucagon-like peptide (GLP)-1 agonists

This medication increases insulin while decreasing glucagon and slowing gastric emptying.

GLP-1 agonists result in satiety and weight loss with a projected decrease of HA1c by 0.5–1 %.

There is a risk of hypoglycemia with insulin secretagogues and other GI motility-slowing agents.

Nausea is a known side effect. These drugs should be used with caution in patients with renal disease and pancreatitis.

Amylin agonists

The mode of action includes slowing gastric emptying and decreasing glucagon secretion.

This medication reduces postprandial glycemia and causes weight loss and with an expected HA1c decrease by 0.25–0.5 %.

There is a risk of hypoglycemia with coadministration of insulin. It should also be used with caution in drugs that slow gastrointestinal motility.

Nausea is the most common side effect.

Insulin, short and long acting (See Table 20.2).