Sheila* has been using mealtime insulin for three years and desires better blood glucose control. Despite her latest three-month blood glucose level being 7.5 (near the target), her readings after meals often are above 300 mg/dL. (Most experts agree that at or below 150 mg/dL denotes good control.) Since adding pramlintide acetate (Symlin) to her medication regimen last week, Sheila has experienced nausea and has had several hypoglycemic episodes. She wants to quit the drug because she is scared. If Sheila were your patient, could you provide the information she needs to adjust to this new therapy?

Out of control

Only 37% of people with diabetes have well-controlled blood glucose levels, defined by the American Diabetes Association as a three-month target blood glucose level [hemoglobin A1c] of less than 7% or by the American Association of Clinical Endorcinologists as less than 6.5%. Let’s restate that: The majority of patients with diabetes are walking around with poorly controlled blood glucose levels, placing them at increased risk for a host of complications including blindness, renal failure, amputation, stroke, and death; in fact, 63% of patients with diabetes have an A1c above 9.5%.¹ Sounds like it’s about time for a major breakthrough to get more people with diabetes at or below the goal of 7%. There’s also an unequal incidence of diabetes among ethnicities — with a two-fold incidence among Blacks and Mexican Americans.²

For some people with diabetes, help may already be here in the form of exenatide (Byetta, the “lizard spit” drug), and pramlintide. Nurses may be asked about these new options and should be able to educate patients and steer them to reliable sources of information. And many nurses who work with patients with diabetes will have the responsibility of educating and monitoring patients who are using these important new treatments.

Insulin’s new accomplices

These new treatments stem, in part, from our new understanding that insulin is not the only hormone involved in poor blood glucose regulation. To think that all these years we’ve been placing the blame for poor blood glucose regulation on a lack of insulin. We know that physical activity, food intake, and hepatic glucose production play important roles, but from a hormonal standpoint, insulin may have been getting a bad rap. Truth be told, two other hormones with totally different origins and mechanisms of action have now been discovered to play significantly important roles in blood glucose regulation.³

The first hormone, amylin, is a pancreatic beta-cell secreted hormone that regulates glucose balance in conjunction with insulin and glucagon in response to food intake. It’s secreted with insulin and contributes more significantly to glucose lowering after meals (the postprandial period), especially during the three hours immediately after eating.⁴ Amylin slows the hepatic production of glucose and also serves as a satiety signal, sending the message of fullness across the blood-brain barrier to encourage us to stop eating.⁴

In people with Type 1 diabetes, amylin, like insulin, is not produced. With Type 2 diabetes, secretion of both insulin and amylin are deficient. When beta cells are destroyed or improperly functioning, supplementation with insulin injections can provide better, yet not physiologically identical, glucose control because serum amylin levels are often deficient.⁵ Compound this with the lack or reduction of insulin with an accelerated gastric emptying rate that often ensues, and you have a formula for ever-rising and difficult-to-manage blood glucose levels.

The second hormone, the human incretin hormone glucagon-like-peptide-1 (GLP-1), is released from the cells lining the ileum and the colon. GLP-1 is also called a “gut peptide” that promotes pancreatic secretion of insulin and improves carbohydrate metabolism.⁶

Get tight … get right!

“Tight” control of blood glucose levels is desirable for people with either Type 1 or Type 2 diabetes to reduce the risk for long-term complications, including neuropathy, nephropathy, retinopathy, amputations, and cardiovascular disease and stroke.^1,7 To review recommended clinical guidelines, go to The National Quality Measures Clearinghouse at www.qualitymeasures.ahrq.gov/summary/summary.aspx?ss=1&doc_id=4067 or to the American Diabetes 2007 Clinical Practice Recommendations at http://care.diabetesjournals.org/cgi/content/full/30/suppl_1/S3. Achieving tight control, however, can be difficult despite a multitude of medication options and readily accessible, easy-to-operate home glucose monitoring meters. Patients may fear episodes of hypoglycemia, may dislike testing their blood glucose as often as necessary (or not have the time or resources to test), and may not understand the benefits of tight control. In addition, achieving tight control using insulin is associated with an increased risk of hypoglycemia and weight gain for most patients.⁸ Even as patients get closer to target A1c goals of 7%, the importance of controlling postprandial glucose levels and achieving glucose homeostasis becomes more significant. Patients with hyperglycemia associated with diabetes may be able to use exenatide and pramlintide when insulin or oral therapy alone is insufficient for adequate blood glucose control.⁹ 

Pramlintide — a copycat

Classified as an antihyperglycemic, pramlintide is a synthetic analog, a laboratory-created compound that is structurally similar to human amylin. Clinical studies have shown that patients with Type 1 or Type 2 diabetes who take pramlintide in addition to insulin have better postprandial and long-term glucose control in addition to weight reduction. Pramlintide also enables patients to reduce their mealtime insulin dosages necessary to achieve target blood glucose levels.¹⁰

Pramlintide is not a replacement for insulin but an adjunctive medication to be administered at the same time with mealtime insulin to enhance clinical outcomes.¹⁰ One study evaluated the impact of adding pramlintide to insulin therapy for 296 patients with Type 1 diabetes for 29 weeks. Half of the study participants added pramlintide to their daily insulin therapy, and the other half did not. The study results revealed that while all patients experienced equal reductions in A1c levels, the patients who received escalating dosages of pramlintide had lower mealtime insulin use, reductions in postprandial glucose levels, and weight loss than those who received insulin therapy alone.¹¹

Exenatide — lizard what?

Patients with Type 2 diabetes experiencing difficulty controlling blood sugar despite oral antihyperglycemic therapy with metformin, a sulfonylurea such as glyburide, or a combination of the two drugs may benefit from an addition of exenatide injections. Some patients may be taken back when they discover exenatide was synthesized from the saliva of a large desert lizard, the Gila monster. These large lizards typically eat only a few times each year, and extendin-4 (a substance in their saliva similar to human GLP-1) allows nutrients to be stored and the pancreas “turned off” until they eat again.¹² Scientists studied extendin-4 and were able to synthesize a compound in the lab that behaves in humans the way extendin-4 does in the Gila monster.

Patients administer exenatide subcutaneously in the thigh, abdomen, or upper arm twice daily, within one hour before morning and evening meals. It’s only available in disposable prefilled injection pens delivering 5 mcg and 10 mcg per dose and must never be placed in an insulin pump device. The dose starts at 5 mcg twice daily before meals and may be increased to 10 mcg twice daily after one month if necessary. Dosage adjustment is not necessary based on meal size or physical activity levels.¹² Exenatide, unlike other pen-delivered diabetes injectabless, must be kept refrigerated.

The first drug in a new classification of medications known as incretin mimetics, exenatide improves blood glucose control by significantly lowering postprandial blood glucose levels and moderately lowering fasting blood glucose levels by closely regulating insulin secretion and restoring first-phase secretion of insulin — the release of insulin the first 10 minutes after eating. Its action is directly related to glucose levels: When exenatide is administered to a patient with very high glucose levels, a significant amount of insulin secretion is stimulated. When glucose levels are lower, less insulin secretion is stimulated.¹² Incretin mimetics have glucose-regulating actions on the stomach, liver, pancreas, and brain. Research has shown that in addition to lowering A1c levels, exenatide in combination with metformin and sulfolylureas can promote weight loss and help improve beta cell function and restore normal Phase 1 and 2 insulin release.^13,14,15 In fact, researchers are investigating the usefulness of exenatide and pramlintide therapy as a treatment for obesity.¹⁶

For exenatide to work, the pancreas must be able to secrete insulin; therefore, it is not indicated for patients with Type 1 diabetes or for treatment of diabetic ketoacidosis. It’s approved for use in conjunction with metformin. with the thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia), and with the sulfonylureas glimepiride (Amaryl), glipizide (Glucatrol, Glucatrol XR), glyburide (Micronase or DiaBeta), chlorpropamide (Diabinese), and tolazamide (Tolinase).¹²

Researchers are investigating the use of exenatide with other medications. To date, however, exenatide has not been approved to be used in combination therapy with insulin, the D-phenylalanine derivative nateglinide (Starlix), the meglitinide repaglinide (Prandin), or the alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset). Patients taking these medications who are also prescribed exenatide off-label should be closely monitored for adverse effects, especially hypoglycemia.¹²

The downside

Both pramlintide and exenatide have drawbacks. Because patients must be injecting insulin to be prescribed pramlintide, the drawback to this dual injection therapy is that the medications may not be combined in the same syringe, necessitating two injections for every meal. At the very least, patients would expect to administer six individual injections and check their blood glucose levels seven times daily. Those using basal insulin and consuming more frequent, smaller meals would test and inject themselves even more. Pramlintide may not be administered through insulin pump delivery devices.¹⁰

With pramlintide, patients may experience nausea and profound hypoglycemia, especially if dosages are miscalculated proportionately to dietary intake and physical activity, making some tasks unsafe. People with Type 1 diabetes tend to experience more adverse effects with pramlintide than do people with Type 2 diabetes. Until patients determine whether they will experience these adverse effects, encourage them not to drive or operate machinery. Patients typically will be titrating their dose of pramlintide up while titrating their insulin dose down.¹⁰ While medication titration, multiple injections, and additional blood glucose monitoring may sound complex, time-consuming, and uncomfortable, research indicates that patients using pramlintide therapy report satisfaction with therapy and enhanced blood glucose control.¹⁷

Patients transitioning to combination therapy with mealtime insulin and pramlintide benefit from referral to a certified diabetes educator and a registered dietitian for guidance on dosing, titration, and administration of the two medications in conjunction with balanced meals and periods of physical activity. Meals covered with insulin and pramlintide must contain at least 250 calories or 30 grams of carbohydrates.¹⁰

When pramlintide therapy begins, the prescribing healthcare provider will set target goals for blood glucose levels before and after meals. The initial recommended dose with Type 1 diabetes is 2.5 units and with Type 2, 10 units before meals. The dosage of pramlintide is titrated upward provided nausea has subsided for three days. The insulin dosage is titrated downward as needed to achieve desired target blood glucose goals. Presently, pramlintide is not available in an injectable pen and must be drawn up from a vial into a standard insulin syringe. Patients using rapid-acting insulin in pen form may need instruction on proper technique with drawing up medication from a vial with a syringe. They must also be reminded to select two sites that are at least 2 inches apart.¹⁰

With exenatide, common adverse effects include vomiting, diarrhea, headache, jitteriness, and acidic stomach. Nausea is especially common when exenatide therapy begins, but tends to decrease with time in most patients. Up to 39% of patients receiving the 5 mcg dose and 49% of patients receiving the 10 mcg dose experienced nausea when exenatide therapy was initiated.¹²

Additional points to remember about exenatide: Women who are breastfeeding, pregnant, or planning conception should not take exenatide, nor should children.¹² Exenatide is a clear solution; if it appears cloudy, it must not be used. Missed doses should be skipped entirely as exenatide should never be taken after a meal is completed.

Some like it … NOT!

While replacement of naturally occurring hormones may sound ideal, pramlintide and exenatide are not intended for all patients with diabetes. Patients with gastroparesis, a condition that slows down the absorption of food from the digestive tract; patients who have had gastric bypass surgery; and those who have difficulty recognizing the warning signs of hypoglycemia are not candidates for pramlintide or exenatide therapy.^10,12

One major barrier in persuading patients to start exenatide or pramlintide therapy is the fact that these medications must be injected to work. In addition, patients must be willing to intensively monitor their blood glucose and follow up regularly with their prescribing professionals. Intensive monitoring recommended for patients prescribed pramlintide includes testing blood glucose levels before and after every meal and at bedtime. Patients also must understand how to adjust insulin and pramlintide doses simultaneously.¹⁰

Patients tend to lose weight when prescribed exenatide and pramlintide, a desired effect for many but not all patients with diabetes.¹² The weight loss is slow and gradual, apparently unrelated to the incidence of nausea — patients who do not experience nausea have been shown to experience weight loss similar to those who do experience nausea that initially subsides with continued therapy.^14,15

Essential education, close monitoring

Exenatide and pramlintide require extensive education and close monitoring. Nurses caring for patients who take exenatide and pramlintide should monitor for hypoglycemia, especially when therapy begins or dosages are titrated upward. Because exenatide slows gastric emptying, it’s also important to monitor for the effectiveness of medications that may depend on rapid GI absorption, such as pain relief medications. Administration of medications may need to be adjusted to times when exenatide is not used to cover a meal (such as at lunchtime or during a snack). Medications dependent on specific threshold levels, such as contraceptives, should be taken at least one hour before exenatide injection; in this instance, a backup contraceptive method might be a good idea, especially if nausea and vomiting occur.

Remind patients that exenatide may cause hypoglycemia, especially when used in conjunction with a sulfonylurea, requiring the dosage of the sulfonylurea to be decreased. Patients combining insulin and pramlintide therapy may also experience profound hypoglycemia, typically within three hours after dosing.¹⁰ Patients prescribed either of these new medications should always keep their blood glucose meter nearby and carry a rapidly absorbing source of glucose. Convenient tablets containing exactly 15 grams of carbohydrate are available at most drugstores and are preferred to the indiscriminate use of hard candy or other sources of sugar. The “rule of 15” is easy to remember for treating hypoglycemic episodes: Take 15 grams of carbohydrate, wait 15 minutes, and if still symptomatic, take 15 more. Advise patients not to drive, operate machinery, or perform activities requiring their full attention until they see how they respond to the medication.

Episodes of hypoglycemia and nausea may be less bothersome when patients become more familiar with how their body responds and how to adjust the timing of medication. Often patients experience a lack of desire to complete their meal, a real problem when medications are given at the start of a meal. Remember that nausea may affect the amount of food consumed during a meal, so the timing of fast-acting insulin and pramlintide may need to be delayed to avoid hypoglycemia. It may be best delivered when the patient has nearly completed the meal and is better able to calculate his or her actual carbohydrate intake and make necessary dosage adjustments. Delivering mealtime insulin near the end of a meal may sound unorthodox, but since gastric emptying will be delayed with pramlintide, this strategy may reduce the risk for hypoglycemic episodes.

Often, patients focus on desirable medication benefits and grow discouraged when they are slow to experience them. Remind patients that the weight loss associated with exenatide and pramlintide is slow and gradual. Encourage them to endure nausea that often accompanies the start of therapy.

On the horizon

Extended-release versions of pramlintide and exenatide are already undergoing research trials. The extent to which nurses will see patients taking these two medications depends on many factors, including patient acceptance and prescribing providers’ comfort levels in encouraging aggressive and tight glucose control. Cost may also be a factor. However, the short-term expense for medication most assuredly will be justified by the postponement or elimination of the complications of poorly controlled diabetes.