Until 1994 only one class of oral medications was used to treat type 2 diabetes in the United States. These drugs, known as sulfonylureas, work by enhancing pancreatic production of insulin to reduce glucose (blood sugar) levels. Today, there are a variety of antidiabetic agents available. Oral diabetes drugs sold in the United States belong to six classes, each with their own advantages and disadvantages:

• Sulfonylureas. Stimulate the beta cells in the pancreas (a gland in the abdomen) to make more insulin. They may cause hypoglycemia (low glucose), weight gain and sensitivity to the sun. Some controversial research has linked these medications to increased risk of cardiovascular problems and death, though some other studies have found they may have cardiovascular benefits. Sulfonylureas include:
  
• • chlorpropamide (Diabinese)
    
  • glimepiride (Amaryl)
    
  • glipizide (Glucotrol)
    
  • glyburide (Diabeta, Glibenclamide, Glycron, Glynase, Micronase)
    
  • tolazamide (Tolinase)
    
  • tolbutamide (Orinase)
    
  • acetohexamide (Dymelor), which is no longer available in the United States
    

• Meglitinides. Like sulfonylureas, these stimulate the beta cells in the pancreas to make more insulin. They may cause hypoglycemia and weight gain. Meglitinides include:
  
• • nateglinide (Starlix)
    
  • repaglinide (Prandin)
    
    
  Nateglinide has also been classified as the first in a type of antidiabetic agent called D-phenylalanine derivatives, which make the pancreas more sensitive to insulin.
  

• Biguanides. Diminish insulin resistance, decrease the amount of glucose produced by the liver and help muscles better absorb glucose in the blood. Unlike some other antidiabetic agents, they do not promote insulin secretion, making them less likely to trigger hypoglycemia. These medications are not recommended for patients with kidney damage or heart failure.
  
  The only biguanide approved by the U.S. Food and Drug Administration (FDA) is metformin, sold under the brand names Glucophage, Diabex, Diaformin, Fortamet, Glumetza and Riomet (a liquid). A biguanide called buformin might still be available in some other countries.
  

• Thiazolidinediones (TZDs). Help make muscle and fat more sensitive to insulin and reduce glucose production in the liver. These pills can significantly reduce the amount of insulin that patients need to take via injections. They may have rare but serious effects on the liver. TZDs include:
  
• • pioglitazone (Avandia)
    
  • rosiglitazone (Actos)
    
    
  In 2007 the FDA strengthened warning labels on TZDs because of new concerns about their cardiac risks. Also in 2007, the makers of both TZDs announced studies indicating the drugs might increase women's risk of bone fractures.
  

• Alpha-glucosidase inhibitors (AGIs). Prevent or slow the absorption of some carbohydrates in the intestine, which moderates blood glucose levels after meals. Diarrhea, flatulence and abdominal cramping have limited the use of these types of medications. AGIs include:
  
• • acarbose (Glucobay, Prandase, Precose)
    
  • miglitol (Glyset)
    
  • voglibose (Volix, Basen)
    

• DPP-4 inhibitors. These agents use a new approach that affects the pancreatic alpha cells and beta cells, resulting in reduced release of glucose from the liver and increased production of insulin. The FDA approved the first DPP-4 (dipeptidyl peptidase-4) inhibitor, sitagliptin (Januvia), in October 2006. The FDA has sought more safety data on a similar drug, vildagliptin (Galvus), which has received approval from European regulators. Other DPP-4 inhibitors under development include saxagliptin and SYR-322. DPP-4 inhibitors may be prescribed alone or in combination with metformin, sulfonylureas or TZDs. They are generally taken once a day.
  
  The most common side effects of sitagliptin have been upper respiratory infection, sore throat and diarrhea. The most common side effects of vildagliptin have been cold-like symptoms, headache and dizziness. Like other diabetes pills, DPP-4 inhibitors are not used to treat type 1 diabetes or diabetic ketoacidosis.
  
  

In addition to these oral medications, the FDA in 2005 approved two injected medications for diabetes:

• Incretin mimetics. Exenatide (Byetta) is the first in a new class of medications for type 2 diabetes called incretin mimetics. This class of drug is also known as an incretin or GLP agonist. Exenatide stimulates the body to release more insulin and reduce the levels of another hormone called glucagon. Glucagon is a "counter-regulatory" hormone that opposes the effects of insulin. Unlike most diabetes drugs, exenatide has helped many patients lose weight. Other incretins are being developed.
  
  Exenatide is a synthetic version of exendin-4, a hormone (natural chemical messenger) found in the saliva of the Gila monster. This venomous desert lizard eats only a few times a year. When not eating, it is able to turn off its pancreas, which stops the flow of insulin. When it is time to eat again, the Gila monster secretes exendin-4, which turns on the pancreas.
  
  Exenatide can be taken in addition to metformin, a sulfonylurea or a TZD. Patients inject it twice a day, before the morning and evening meals, using a 60-dose prefilled pen similar to an insulin pen.
  
  

  

  Before taking exenatide, according to the FDA, patients should inform their physician if they have gastroparesis, have severe kidney disease (e.g., diabetic nephropathy), are on dialysis, are pregnant or planning to become pregnant, or are breastfeeding. Possible side effects include decreased appetite, nausea, vomiting, diarrhea, dizziness, headache, jitteriness, acid stomach and, if taken with a sulfonylurea, hypoglycemia.
  
  
• Synthetic amylin. Pramlintide (Symlin) may be prescribed to people with type 1 diabetes or type 2 diabetes who already use insulin but need better control of their glucose. Pramlintide is the first drug other than insulin approved to treat type 1 diabetes. It is a synthetic version of amylin, a hormone made in the beta cells of the pancreas. It is taken at mealtimes and must be injected separately from insulin a different syringe.
  
  According to the FDA, patients should not use pramlintide if they have gastroparesis or hypoglycemia unawareness. Women are advised to notify their physician if they are breastfeeding, pregnant or planning to become pregnant. Possible side effects include hypoglycemia, nausea, decreased appetite, weight loss, vomiting, stomach pain, fatigue, dizziness or indigestion. The maker of pramlintide advises patients to perform glucose monitoring before and after every meal and at bedtime.
  

Because the various antidiabetic medications work in different ways, combinations of more than one drug can sometimes produce more effective treatment results. However, this benefit may also come with the added risk of increased side effects. Switching from one type of medication to another may not be as effective as adding another medication.

Combinations of antidiabetic agents that are prescribed include:

• AGIs with biguanides or sulfonylureas
  
• Biguanides with AGIs, DPP-4 inhibitors, incretins, meglitinides, sulfonylureas or TZDs
  
• DPP-4 inhibitors with biguanides, sulfonylureas or TZDs
  
• Incretins with biguanides, sulfonylureas or TZDs
• Meglitinides and biguanides
  
• Sulfonylureas with AGIs, biguanides, DPP-4 inhibitors or incretins
  
• TZDs with biguanides, DPP-4 inhibitors, incretins or sulfonylureas
  

Some of these combinations are available in single pills marketed under various brand names.

In addition, insulin may be prescribed in tandem with other diabetes medications, including:

• Biguanides
  
• Sulfonylureas
  
• Synthetic amylin
• A TZD (although warnings for insulin/TZD combinations have become more restrictive)
  

A physician takes several factors into account before selecting a specific diabetic treatment option. Considerations about patients include:

• Are they overweight?
  
• Do they have abnormal cholesterol levels?
  
• How is their kidney and liver function?
  
• When did their diabetes develop?
  
• How good are they about taking medications regularly?
  
• Do they monitor glucose as instructed?
  
• Do they have problems taking pills or making injections?
  
• Do they already have a sensitive stomach?
  
• What does their healthcare plan provide?
  
• Are they prone to hypoglycemia (excessive drop in blood glucose levels, sometimes triggered by diabetes medication) or hypoglycemia unawareness?