Exenatide and Pramlintide

New Meds on the Block

“A dream becomes a goal when action is taken toward its achievement.”

—Bo Bennett

In 2005, two new diabetes medicines—exenatide (brand name Byetta) and pramlintide (Symlin)—became available. Both medicines work differently from any previously approved diabetes drugs. Exenatide belongs to a class of drugs called incretin mimetics, so called because they imitate natural hormones called incretins. Pramlintide is a synthetic amylin analog, meaning it is chemically identical to a hormone produced by the pancreas called amylin. Both drugs lower blood glucose levels, but by somewhat different means.



The “incretin effect” was discovered many years ago, when it was noticed that the pancreas releases more insulin when a person eats carbohydrate-containing foods than it does when a comparable amount of glucose is infused intravenously, or directly into a vein. Based on this finding, it was hypothesized that factors in the gastrointestinal tract play a role in blood glucose control. Indeed, that seems to be the case.

Several hormones called incretins are released from cells in the gut in response to food. One of these is glucagon-like peptide-1, or GLP-1. Exenatide acts similarly to GLP-1 in the body. Both GLP-1 and exenatide lower blood glucose in the following ways:

  • They improve the normal release of insulin from the pancreas.
  • They suppress the secretion of glucagon, another hormone produced by the pancreas that normally stimulates the liver to release stored glucose into the bloodstream.
  • They slow the speed with which food leaves the stomach and promote a feeling of fullness.

Exenatide is approved for use in people with Type 2 diabetes who take a sulfonylurea drug, such as glyburide (DiaBeta, Micronase, Glynase), glipizide (Glucotrol, Glucotrol XL), or glimepiride (Amaryl); metformin (Glucophage, Glucophage XR, Glucovance); or a thiazolidinedione drug, such as pioglitizone (Actos) or rosiglitizone (Avandia). Exenatide rarely causes low blood glucose (hypoglycemia), and it tends to cause a gradual weight loss due to decreased calorie intake.

How to take exenatide. Exenatide comes in prefilled pens that deliver fixed, 5-microgram or 10-microgram doses. (Unlike insulin pens, exenatide pens do not require dialing in the desired dose.) Exenatide is typically taken twice daily, once before breakfast, and once before the evening meal. Each pen has 60 doses to provide 30 days of twice-daily injections. The usual starting dose is 5 micrograms (µg) twice a day. If the drug is well tolerated during the first 30 days of use, the dose may be increased to 10 µg twice a day. Exenatide must be given by injection because it is a protein. If it were taken by mouth, the drug would be digested before it could begin working.

When an exenatide pen is used for the first time, a “new pen setup” procedure must be done to prime the pen and to help remove any large bubbles that may be in it. However, the setup procedure needs to be done only once per pen; it should not be done each time a new needle is attached to the pen. Doing the new pen setup procedure more than once per pen will cause you to run out of medicine before 30 days are up.

The timing of exenatide doses is very important. It must be taken between 1 to 60 minutes before a meal. The drug reaches peak effectiveness in about three hours, and its effects taper off by about five hours after injection. If a dose of exenatide is missed or forgotten before starting to eat, it should not be taken during or after the meal. The missed dose should be skipped entirely and the next dose taken as scheduled.

Exenatide is injected just under the skin of the outer thigh, stomach area, or upper arm. Once the needle has been inserted under the skin, the injection button of the pen must be pushed in completely to deliver the drug. To ensure that the full dose of medicine has been delivered, keep the needle inserted and continue pressing the button while counting slowly to five. Because the volume of an exenatide injection is very small, it is unlikely that you would be able to feel when an entire dose had been delivered.

A separate prescription is needed for the pen needles (which can also be used with insulin pens). The following pen needle sizes from various manufacturers are compatible with the exenatide pen: 31 gauge, 3/16 inch; 31 gauge, 1/4 inch; 31 gauge, 5/16 inch; 29 gauge, 1/2 inch. A new needle is needed for each injection. After use, it should be removed and discarded in a puncture-resistant sharps container.

Exenatide pens must be stored in the refrigerator prior to first use. After that, they can be stored at room temperature no higher than 77°F and must be protected from light when not in use. If you need to use your pen away from home in hot weather, carry it in an insulated container to keep it cool. Each pen should be discarded 30 days after first use, even if there is some medicine left in it. A pen should also be discarded if it has been frozen.

You will get the most benefit from exenatide if you use it exactly as prescribed by your health-care provider. In research studies, people who used a 5 µg dose saw an average decrease in glycosylated hemoglobin level (HbA1c) of 0.4% to 0.6%. People who used a 10 µg dose saw an average HbA1c decrease of 0.8% to 0.9%. The HbA1c test is a measure of blood glucose control over 2–3 months. Each 1% drop in HbA1c level reduces the risk of microvascular complications (such as nerve, kidney, and eye disease) by 20% to 30% and reduces the risk of cardiovascular disease by 15% to 20%.

Work with your diabetes care team to be properly trained on how to inject exenatide. Your team can offer suggestions on which pen needle length and gauge is best for you.

Potential side effects. The most common side effect experienced with exenatide is mild to moderate nausea. Nausea is most common when first starting exenatide, but it decreases over time in most people. Other possible side effects include vomiting, diarrhea, feeling jittery, dizziness, headache, and heartburn.

When exenatide is used with a sulfonylurea, mild to moderate hypoglycemia may occur. Often, to reduce the risk of hypoglycemia, health-care providers reduce a person’s dose of the sulfonylurea when starting exenatide.

Precautions. Exenatide may decrease the absorption of some oral medicines such as antibiotics and birth control pills. These medicines should generally be taken at least one hour before the exenatide dose to avoid such an interaction.

Exenatide is not recommended for use in women who are pregnant or breast-feeding. It should not be used by people with severe kidney disease or gastroparesis (slow stomach emptying usually caused by nerve damage). Exenatide does not work the same way as insulin does and should not be used to treat Type 1 diabetes or diabetic ketoacidosis.

Tips for use. Your response to exenatide and to all other diabetes medicines will be better if you eat well-balanced meals, watch portion sizes, and stay physically active.

You will need to continue to monitor your blood glucose levels when taking exenatide. Varying the times at which you monitor, and monitoring both before meals and after meals on some days may be useful to evaluate any changes in blood glucose control. Work with your diabetes care team to determine a monitoring schedule that is right for you.


A healthy pancreas releases both insulin and amylin in response to food intake. However, people with Type 1 diabetes and many with Type 2 diabetes do not make enough insulin, with the result being that glucose from food stays in the bloodstream rather than entering muscle, fat, and other body cells. In general, people who do not produce enough insulin also do not make enough amylin at mealtimes. Without enough amylin, glucose from food enters the bloodstream more quickly than normal, causing blood glucose levels to rise.

Pramlintide, a synthetic analog of human amylin, helps to reduce the rise in blood glucose after meals in the following ways:

  • It slows the speed with which food leaves the stomach.
  • It suppresses the secretion of glucagon after meals, which decreases the amount of glucose released from the liver.
  • It decreases appetite, so that less food is eaten. This can also lead to a small weight loss in some people.

Pramlintide is approved for use in adults with Type 1 diabetes and adults with Type 2 diabetes who have not achieved adequate blood glucose control when using intensive insulin therapy.

How to take pramlintide. Like exenatide, pramlintide must be injected, but unlike exenatide, it is not yet available in a pen device. (The SymlinPen 60 and SymlinPen 120, pen-injector devices that can delivered fixed doses of pramlintide, and are expected to be available by December 2007.) Currently, a standard, U-100 insulin syringe is used to administer pramlintide. However, pramlintide is dosed in micrograms (µg), while insulin is dosed in units. To see how micrograms correspond with units, check out the table “Pramlintide: Drawing Up the Right Dose.” Your health-care provider will tell you what size doses to take and should also demonstrate how to measure doses and inject them. Pramlintide should not be mixed with insulin or any other injectable drug in the same syringe.

Pramlintide should be injected just under the skin of the stomach area or upper thigh more than 2 inches away from insulin injections given at the same time. Pramlintide should be at room temperature when injected. A new, unused syringe and needle should be used for each pramlintide injection and then discarded in a sharps container.

Pramlintide is to be taken just before any meal that contains at least 250 calories or 30 grams of carbohydrate. Peak action is reached in approximately 20 minutes and diminishes over three hours. Unlike insulin, doses of pramlintide do not need to be adjusted for the amount of carbohydrate in meals or for physical activity. However, if you skip a meal, the dose of pramlintide should also be skipped.

Generally, pramlintide is started at very low doses, and the doses are increased gradually depending on how well it is tolerated. When you first start taking pramlintide, your physician may decrease your mealtime insulin doses to account for the effects of pramlintide and to decrease your chances of developing low blood glucose. Your physician should direct any changes to your doses of insulin and/or pramlintide as you find what works best for you.

Pramlintide vials should be stored in the refrigerator until opened. Opened vials can be refrigerated or kept at room temperature for up to 28 days. Using an insulated container that is kept cool is recommended when traveling. Do not freeze vials of pramlintide, and discard any that are accidentally frozen. Vials should be discarded 28 days after first use, even if there is some medicine left. Do not use a vial of pramlintide if it looks cloudy.

Potential side effects. The most common side effect experienced with pramlintide is mild to moderate nausea. Starting pramlintide at a low dose and gradually increasing it once the nausea subsides (often after about three days) can enable a person to work up to a therapeutic dose. Nausea may also occur in people who continue to eat beyond the point of fullness. Other possible side effects include vomiting, upset stomach, decreased appetite, headache, tiredness, and dizziness. As mentioned earlier, use of pramlintide may cause some weight loss.

By itself, pramlintide does not cause low blood glucose. However, when used along with insulin, there is a risk of low blood glucose occurring, generally about three hours after the two drugs are administered. You and your diabetes care team should work together to find a dose of insulin and pramlintide that does not cause low blood glucose.

Precautions. Pramlintide should not be used by people with hypoglycemia unawareness (the inability to sense early signs of low blood glucose) or gastroparesis. It should also not be used by people who are allergic to pramlintide acetate, metacresol, D-mannitol, acetic acid, or sodium acetate.

Because pramlintide can slow the absorption of some oral medicines, it is good idea to discuss with your physician all the prescription drugs, over-the-counter drugs, and herbal or other supplements you may take. If you use any type of pain medicine, it is best to take it either one hour before or two hours after your pramlintide injection.

The safety of taking pramlintide during pregnancy is unknown. It is also not known whether pramlintide passes into breast milk. For these reasons, any women who becomes pregnant (or is considering becoming pregnant) while taking pramlintide should talk to her health-care provider about whether to continue taking the drug. Pramlintide has not been evaluated for use in children.

Helpful tips. If you miss a dose of pramlintide, do not take it during or after your meal. Wait until the next meal, then take your usual dose of pramlintide at that meal.

The manufacturer of pramlintide recommends monitoring blood glucose before meals, two hours after starting meals, and at bedtime when using pramlintide. If your health insurance plan does not cover enough testing supplies to follow this schedule, speak to your diabetes care team about an individualized monitoring schedule.

To get the most benefit out of using pramlintide, it is important to follow the instructions for taking it exactly. Your diabetes care team should direct any necessary adjustments to your pramlintide and insulin doses. Research studies have shown that adding pramlintide to insulin for the treatment of diabetes results in a lowered HbA1c level.

Recent arrivals and on the horizon

Other incretin mimetics besides exenatide continue to be studied. Another, known as liraglutide, is currently being investigated in clinical trials. It is being developed for once-daily administration. A long-acting release formulation of exenatide is also being investigated in clinical trials. The early trial results suggest that the long-acting release formulation of exenatide may be administered once weekly or once every other week.

A drug that may become available soon, pending FDA approval, is vildagliptin (Galvus). Sitagliptin (Januvia), a similar medicine, was recently released. These drugs represent a new class of drugs that also target the incretins, or gut hormones, such as GLP-1. In your body, GLP-1 is rapidly broken down by enzymes called dipeptidyl peptidase IV (DPP-IV). The new drugs act by inhibiting DPP-IV, which prolongs the level of GLP-1 in your body. This improves insulin production and suppresses glucagon secretion, effects that signal the liver to stop producing glucose and reduce blood glucose levels after meals. Sitagliptin is taken by mouth once daily; if approved, vildagliptin will be taken in the same manner.

The most commonly reported side effects of sitagliptin were stuffy or runny nose and sore throat, headache, diarrhea, and joint pain. The most common side effect of vildagliptin is hypoglycemia if a person has missed a meal or exercised strenuously. Fluid retention has occurred with vildagliptin in some people, but nausea has not been reported. Neither sitagliptin nor vildagliptin has been associated with weight gain. People who have taken vildagliptin while participating in research studies have experienced an average decrease in HbA1c of 0.6%. Large studies will help in evaluating the long-term safety information of DPP-IV inhibition.

Changing with the times

In 2004, despite the availability of numerous options for treating diabetes, studies showed that only 33% of people with Type 2 diabetes were meeting established targets for blood glucose control. Optimal blood glucose control is important to prevent or minimize the chronic complications that can be caused by diabetes, including nerve, kidney, eye, and heart disease.

If you are unable to keep your blood glucose levels in target range with your current diabetes plan, talk to your diabetes care team about other available treatment options, including those newly on the market. Work together with your team to achieve the best possible blood glucose control for you.