Mike,* a 43-year-old school bus driver, was diagnosed with Type 2 diabetes 11 years ago. His most recent lab work reveals that his control is worsening. His fasting glucose level was 211 mg/dL, and his glycosylated hemoglobin (A1c) level was 9.2%. (A1c is a measure of blood glucose control over the past three months.) Mike is 40 pounds overweight, and despite his long-standing use of an angiotensin converting enzyme inhibitor (ACEI), his blood pressure remains elevated, and his renal function has declined. His diabetes-related medications include 1000 mg of metformin (Glucophage) twice daily, 45 mg of pioglitazone (Actos) daily, and 10 mg of glyburide (Micronase) twice daily. He drinks one or two cans of beer watching Sunday football and is a former smoker, having quit four years ago.

Despite poor control, Mike is reluctant to start the long-acting insulin therapy his primary care nurse practitioner has suggested. He hesitates not so much because of a fear of needles but because of his job: Treating diabetes with injectable insulin raises the risk of hypoglycemic reactions, which could pose a safety concern that he is not willing to risk while driving children. He asks you, his sister-in-law, the “family nurse,” what other options are available. Would you be able to discuss new treatment options that he may be a candidate for?

More than 20.8 million Americans have Type 2 diabetes, and most have difficulty controlling their blood glucose levels.¹ The slow, progressive decline in function and eventual death of pancreatic insulin-producing beta cells present healthcare providers an often nearly impossible task of matching treatment options to patient needs to maintain desirable blood glucose levels yet avoid hypoglycemic episodes. The traditional approach is for the patient to progress from diet and exercise changes alone to the use of oral antidiabetic agents, and finally, and usually as a last option, to insulin therapy. But many patients and providers view the use of insulin as a “failure” of the other therapies or as an indication of patient nonadherence rather than a natural and often unavoidable step as the disease progresses.

A new way of thinking

Fortunately, evidence has emerged that may change this negative mind-set and give providers and patients the upper hand in managing Type 2 diabetes. One of the important factors to remember is that diabetes as a progressive disease requires progressive treatment. (View clinical practice guidelines at www.guideline.gov/summary/summary.aspx?doc_id=9659.)

While pancreatic beta cell dysfunction is a key culprit in abnormal glucose homeostasis, new discoveries are continually emerging that point to other biochemical processes as coconspirators. The biotechnical race is on to discover these processes and create unique disease-modifying treatment options and alternatives to long-standing treatment options, such as new classes of oral diabetes medications and inhaled insulin therapy.

To understand how the new oral diabetes treatment options work, it’s important to understand how the synthesis and release of insulin works. When we eat, glucagonlike peptide-1 (GLP-1) — an incretin (GI) hormone released by the small intestine in response to ingested carbohydrates — helps regulate the synthesis and release of insulin from the pancreatic beta cells. GLP-1 is also responsible for initiating neuropeptide reactions that reduce hepatic glucose production after meals, induce satiety by crossing the blood-brain barrier to reduce appetite, and slow down gastric emptying. Studies have also shown that GLP-1 may also play a role in stimulating beta-cell regrowth and repair. This has been called the “pancreatic-sparing effect.”^2,3

For every reaction in the body, there is a corresponding counterreaction to return the body to a state of homeostasis. When GLP-1 is released, an enzyme, dipeptidyl-peptidase 4 (DPP-4), is released to stop the action of GLP-1. If GLP-1 were left completely uninhibited by DPP-4, we would have blunted appetites, risk malnutrition, and inadequately store nutrients and energy from digested foods. But all too often, when enough GLP-1 isn’t released or if DPP-4 inhibits GLP-1 too quickly, a person may not feel satisfied and will continue to eat despite having taken in more nutrition than the body requires. In addition, glycogen stores in the liver may be inappropriately released, and gastric emptying may occur more rapidly, placing a rapid demand on the pancreas for insulin.

A newly discovered class of oral medications, DPP-4 inhibitors, has been shown to help lower blood glucose levels by increasing and prolonging the action of GLP-1. This is the first class of diabetes treatment drugs to address this metabolic defect as a means to control blood glucose levels. DPP-4 inhibitors are also called “incretin enhancers” because by prolonging the action of GLP-1 they enhance the effect of the natural incretin hormones present in the small intestine.⁴

Sitagliptin (Januvia) is the first DPP-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with Type 2 diabetes. Patients with Type 2 diabetes use sitagliptin alone or with the traditional oral medications metformin or thiazolidinediones, such as pioglitazone, when sitagliptin alone does not provide adequate glycemic control. Sitagliptin is available in 25-mg, 50-mg, and 100-mg tablets and is typically administered as a 100-mg dose taken once daily with or without food. The recommended starting dose of 100 mg can be titrated down depending upon the patient’s renal status.⁵

Patients with Type 1 diabetes or diabetic ketoacidosis shouldn’t use sitagliptin. Patients with moderate, severe, or end-stage renal disease will require dosage reductions to 25 or 50 mg daily.⁵

Another DPP-4 inhibitor, vildagliptin (Galvus), is in the final phases of FDA approval, and other DPP-4 inhibitors are not far behind. Clinical trials have shown that it may not be necessary to reduce the dose of vildagliptin in patients with renal disease and that vildagliptin is associated with an improvement in pancreatic beta cell function when used for at least 12 weeks.^3,6

Weighing in

Because many people with Type 2 diabetes are overweight, promoting weight loss — or at least avoiding weight gain — is important. Some traditional Type 2 oral diabetes medications, including insulin therapy, sulfonylureas, and thiazolidinediones, are associated with weight gain while no weight gain or some weight loss is typically seen with metformin. Sitagliptin is a “weight neutral” drug, neither promoting weight loss nor gain. Similar to exenatide (Byetta), sitagliptin promotes pancreatic secretion of insulin and improves carbohydrate metabolism (the “gut hormone” aspect of diabetes). Sitagliptin, however, is not associated with the often-significant initial GI discomfort that can accompany injectable exenatide therapy.^4,7

Unfortunately, sitagliptin and incretin mimetics, such as exenatide, are now approved only for adults. Ongoing research to evaluate the safety of these agents among pediatric patients may, in time, lead to the same therapeutic treatment options for children, an important healthcare concern because overweight and obesity have also risen dramatically among the pediatric population. The incidence of Type 2 diabetes among adolescents has increased significantly, necessitating diverse treatment plans that may involve medication combinations used not only to reduce glucose levels, but also to combat obesity and reduce future cardiovascular risks. Regardless of approval status, nurses may care for pediatric patients placed on sitagliptin and incretin mimetics in an off-label fashion, requiring cautious observation for adverse events, even beyond those reported already in the adult population.⁸

What to look for

Adverse reactions to monitor for with sitagliptin therapy include upper respiratory tract infection, nasopharyngitis, diarrhea, and headache. In patients taking digoxin, sitagliptin can potentially increase the levels of that drug. Patient monitoring includes initial and periodic assessment of renal status before beginning sitagliptin to determine the appropriate dose. Patient teaching should stress the importance of following the prescribing healthcare professional’s recommendations for periodic laboratory monitoring of renal function.⁵

As monotherapy, sitagliptin will not cause hypoglycemia. Studies have not been conducted to evaluate the risk for hypoglycemia when sitagliptin is administered with a sulfonylurea, such as glipizide (Glucotrol) or glimepiride (Amaryl).⁵ While this combination is currently considered an off-label use, some prescribing professionals may recommend it to their patients, and nurses must provide guidance to patients so that they can recognize and treat hypoglycemic episodes. Patients who are using sitagliptin and a sulfonylurea should use caution and have their blood glucose meter and a rapidly absorbed source of carbohydrate on hand to monitor for and treat hypoglycemia.

Some patients with diabetes are deficient in GLP-1 to begin with, and many of these are overweight or obese. In fact, the term diabesity has been coined to describe the coexistence of diabetes and obesity in epidemic proportions that presents a therapeutic challenge to caregivers.⁹ For those people, oral GLP-1 inhibitors may not be effective; injection therapy with exenatide may be more appropriate. Weight loss combined with a 1% reduction in A1c levels make injectable incretin mimetic therapy more desirable than oral therapy with DPP-4 inhibitors, which has demonstrated only a 0.5% to 1% reduction in A1c in clinical trials. While associated with more adverse GI symptoms that taper with continued use, exenatide injections do promote weight loss, which can be quite significant. But again, exenatide injections may not be an option for a “needlephobic” person.⁴

Needle-free has arrived

Clearly, many people with diabetes view daily subcutaneous insulin injection therapy as a tremendous burden. The lack of alternative insulin delivery methods has contributed to poor diabetes control as many people are hesitant to start and providers are hesitant to prescribe injection therapy.¹⁰

Injection therapy has improved over the years, with needles and devices becoming smaller and disposable and even aided by automated insulin pumps. Clinical practice guidelines are available for nurses caring for patients requiring insulin therapy (www.guideline.gov/summary/summary.aspx?doc_id=5736).

A welcome alternative

But now, some patients have an alternative to daily subcutaneous insulin injection therapy: inhaled insulin. It is the first nonsubcutaneous insulin delivery option available to adults since insulin was discovered in the 1920s. Newly discovered pulmonary insulin delivery is not only a more comfortable route, but it is actually a therapeutic improvement because it mimics the activity of biological insulin more closely than does insulin injected subcutaneously.¹¹

The first inhaled form of insulin, Exubera (insulin human [rDNA origin] inhalation powder), received approval in early 2006, and numerous others are in the research and development pipeline. Exubera is available as 1-mg or 3-mg dry powder blister packs that are inserted into a handheld oral inhaler for administration. Exubera is indicated for adults with Type 1 or Type 2 diabetes mellitus as an alternative to mealtime injections of insulin. The 1-mg blister packs deliver roughly 3 units of insulin. The 3 mg blister packs deliver roughly 8 units.¹² The inhaler weighs about 4 ounces and does not require electricity or batteries. It is about the size of an eyeglass case when it is closed. Adverse reactions include dry mouth, chest discomfort, and decreased lung capacity. A dry cough, which often diminishes with continued use, is common immediately after Exubera administration. The decrease in lung capacity is minimal and is seen as an early decrease in forced expiratory volume measured by spirometry at 1 second (FEV1) by 1% to 1.5% from baseline. This decrease does not progress during two years of continuous therapy and reverses after the drug is discontinued.¹³

With Exubera, as well as all injected insulins, some patients may develop insulin antibodies, but they have no clinical significance. Testing for the presence of antibodies isn’t routine, because they have no impact on postprandial glucose tolerance or the action of inhaled insulin.¹⁴

While patients already using insulin therapy may be excited about needle-free therapy, patients with COPD and patients who have smoked within the last six months are not candidates for Exubera.^12,13

Starting Exubera involves additional work for patients and their healthcare professionals. A baseline spirometry reading must be obtained before therapy can be considered and be repeated after six months of therapy and yearly thereafter.

Nurses must reinforce the need for close blood glucose monitoring when patients start Exubera therapy. And while it has been hailed as way of introducing preprandial (before meal) insulin to needle-shy patients, Exubera will not replace the need for all injectable insulins. Most people with Type 1 diabetes and many with Type 2 will continue to need basal insulin injections, such as glargine (Lantus), to mimic the continual slow release of insulin that the pancreas normally releases. Depending on the patient’s response to Exubera, oral diabetic medicines may also require adjustment or discontinuation. During certain times, including hospitalization, injectable insulin may be required instead.^12,13

Patients who administer mealtime insulin based on carbohydrate counting may find inhaled insulin difficult to titrate precisely to achieve desired blood glucose control.

Blister packs must be stored in a dry place at room temperature, between 59 F and 86 F. They are to be inserted unopened directly into the inhaler. The mouthpiece and inhalation chamber must be cleaned weekly. A removable cartridge that pierces the blister packs must be replaced every two weeks to ensure accurate dosing.¹²

Stress to patients that three 1-mg blisters must not be used in place of a 3-mg blister. To help patients distinguish between the two doses, the 1-mg blister pack is labeled in green ink and the 3-mg pack in blue. To help people who have limited vision or are colorblind, the 1-mg blister packs have one Braille bump, the 3-mg blister packs three. Patients can also use a black marker to write 1 or 3 on the individual blisters to reduce confusion, but not over the foil area where the medication is released.

To avoid hypoglycemic episodes, remind patients that Exubera is a rapid-acting insulin that should be administered at least 10 minutes before eating because it rapidly passes through the aveoli to the bloodstream and starts lowering blood glucose within 10 minutes after use. Remind patients that they must not smoke at all while using Exubera; smoking can increase the risk of hypoglycemic reactions. It may be wise for patients to avoid secondhand smoke as much as possible. Passive exposure to smoke has a reverse effect on Exubera absorption and availability, making hyperglycemia possible.¹⁶

Additional inhaled insulin products are in development or available outside the United States. More information is available at the following websites:

• AERx Diabetes Management System www.aradigm.com/tech/aerx.html
• Technosphere Insulin System www.mannkindcorp.com/technology/diabetes/pulmonary.cfm
• Ora-lyn inhaled insulin www.generex.com/products/oral-lyn

Research is under way to evaluate other novel noninvasive insulin delivery routes. In the not-too-distant future, nurses may see transdermal insulin delivery, via patch, or oral delivery methods, including sprays absorbed into the buccal mucosa and coated delivery pills that do not open until they reach the intestines.¹⁷

Customized care

Despite advances in understanding diabetes pathophysiology and new treatment options, many patients still experience poor control. Inadequate diabetes management education is a big part of the problem. Some prescribing professionals do not keep up-to-date on the emerging treatment options, and others remain reluctant to aggressively treat patients with all available options — especially if this means introducing injection therapy.¹⁸

The future promises to include many new treatment options for diabetes. These options, often used in combination, will require careful patient instruction and follow-up. Because endocrinologists and certified diabetes educators are in short supply, the responsibility for much of the education will be placed on registered nurses and general practitioners. To learn about diabetes education as a nursing career option, visit the American Association of Diabetes Educators website at www.diabeteseducator.org

What happened to Mike?

Mike’s still driving a school bus — and has more energy and better control of his diabetes now. He attended a diabetes education program, where he learned dietary modifications (such as giving up his Sunday beers) and the importance of controlling his blood glucose levels. His NP continued metformin and pioglitazone therapy, initiated therapy with 25 mg of sitagliptin, and discontinued glyburide to reduce chances of hypoglycemic reactions. After three months of dietary modifications and medication changes, Mike has lost 23 pounds, his renal function has improved, and his A1c has dropped to 6.4%.

Beverly Dyck Thomassian, RN, MPH, CDE, a reviewer of this module, has disclosed that she has been a consultant to Pfizer. Nursing Spectrum Continuing Education guarantees that this educational activity is free from bias.

*The patient’s name has been changed.