Long-Term Effects of Oral Agents

Author: Judy Kohn, RN, BSN, CDE

Last Updated: Friday, September 21, 2007

Q: "I currently take Avandia® 4mg twice daily and Glucophage® 850mg twice daily. My typical fasting is 120. My question is: What are the long-term effects of the two drugs I am taking versus if I take the old and proven meds like Glucotrol® or Amaryl®."

A: You raise a very good question-now sit back and put your feet up as you read this very long explanation.

Glucotrol and Amaryl are both drugs from the category called Sulfonylureas.  Believe it or not, sulfonylureas were the only category of oral agents available to treat diabetes up until 1995!  Now there are six categories of oral agents from which to choose-each targeting a different defect - which makes it challenging to understand how all the drugs work as well as to know which would be best for you. There is no standard protocol to advise doctors which oral agents to use, and the decision is based on many factors:  which defect to target; ease of use of the drug (how often and when should it be taken-some drugs are taken with the first bite of food, others are taken with the meal, or at the end of the meal); cost of the drug; side effects, and contraindications. To explain this, let me first remind you how insulin is supposed to work in our bodies.

How the body uses glucose:

• The cells in your body need glucose to function.  Every time you eat, the level of glucose in your blood rises. Four to five hours after a meal, your blood glucose level returns to baseline. When you haven't eaten for awhile and during the night when you are sleeping, your liver releases stored glucose to supply you with energy.
• Insulin is released in response to glucose in the blood.

Insulin has 3 main roles:

1. Regulates the liver from releasing too much glucose (I like to say that insulin leans up against the door of the liver and only lets a little glucose out at a time). When there is enough glucose in the blood, insulin tells the liver to shut down its production of glucose.
2. Acts as a "doorman, or key" to open the doors of the cells (called receptors) and to allow glucose to enter the cells so the glucose can then be turned into energy.
3. Acts as a "traffic cop," directing some of the glucose to be stored back into the liver and the muscles, and if you eat more than you need, the excess energy is stored as fat.

There are 4 defects in type 2 diabetes that can be targeted by oral Agents:

1. Insulin resistance: In essence, the body is unable to use insulin effectively. There are various defects at the receptor level, it is as if there aren't enough doors on the cell wall, or the doors are stuck, or the lock has been changed, or once the glucose gets into the cell it doesn't know what to do.
2. Increased glucose production by the liver:  Usually, as soon as you begin eating, insulin and other hormones tell the liver to "shut its door" and to quit releasing glucose, since you can now get glucose from the food you're eating.  With diabetes, the liver doesn't shut off, so it continues to produce unnecessary glucose.
3. Decreased insulin production: Eventually, as diabetes progresses, the pancreas loses its ability to produce enough insulin-either it is delayed in releasing insulin, or it can't make enough-affectionately called a "pooped out pancreas."
4. Deficiency of GLP-1: Normally, within 10 minutes of eating, GLP-1 is released to enhance insulin secretion, slow stomach emptying, and suppress glucagon (to reduce glucose output from the liver).

Oral agents:  Targets and Side Effects

Keep in mind that the sulfonylureas you used to take mainly target the 3rd defect mentioned above:  they stimulate the pancreas to produce more insulin. This means that until 1995, we had no means to address the other two defects that are so prominent in type 2 diabetes.

Oral Med Category	Target Area in the Body	How it Works	Common Brand Names	Common Side Effects
Sulfonylureas	Pancreas	Causes the pancreas to release more insulin	Amaryl®, DiaBeta®, Diabinese®, Glucotrol®, Glyburide®, Glynase®, Micronase®, Tolinase®, Orinase®	Hypoglycemia, weight gain Use with caution with liver or kidney disease
Meglitinides	Pancreas	Very similar to Sulfonylureas, but is "fast in, fast out"	Prandin®, Starlix®	Hypoglycemia, although less often than with Sulfonylureas, and weight gain
Biguanides	Liver	Keeps the liver from releasing too much glucose	Glucophage®, also called Metformin	Nausea, diarrhea; avoid with kidney disease or excess alcohol intake
Alpha-Glucosidase Inhibitors	Small Intestine	Slows digestion of some carbohydrates, which lowers the post-meal glucose	Precose®, Glyset®	Flatulence (gas), diarrhea; avoid with bowel disease; special instructions to treat hypoglycemia
Thiazolidinediones (called TZDs)	Muscle cells/receptors	Targets insulin resistance: makes muscle cells more sensitive to insulin	Actos®, Avandia®	Weight gain, edema; monitor liver function; caution with heart problems (please read related question on Concerns about TZDs)
DPP-4 Inhibitors	Pancreas, liver	Inhibits an enzyme called DPP-4 to make more GLP-1 available	Januvia™	Upper respiratory infections, stuffy or runny nose and sore throat, headache, and increased risk of urinary tract infections

Conclusions:

• Important Note: I only listed the main points about each drug. I hope this background information will help you when you have a more detailed discussion with your healthcare team.
• Please refer to the oral agent category under the Ask the Expert archived questions, where you can read more details about each oral agent.
• Generally, oral agents are considered very safe and effective, when used wisely, and when your doctor monitors you regularly.
• It is very common to be on more than one category of drugs, as you currently are, since each category targets a different defect; taking a combination of these drugs often controls your diabetes more effectively than if taking only one type. There are also combination drugs, which you can read more about in the related question titled "Combination Pills."
• As always, you need to discuss all of this with your healthcare team.

Related Questions

Combination Pills
Q: "Are the combination pills, such as Avandamet®, Glucovance® and Metaglip® better than taking the individual pills?"

Insulin Resistance
Q: "Could you explain insulin resistance so that I can understand it? This term seems confusing to me."

Related Links

American Diabetes Association (ADA)
http://www.diabetes.org

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
http://www.niddk.nih.gov

FDA
http://www.fda.gov/diabetes

DOC09486-Rev-B 09/07