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Patient education and monitoring recommendations for the use of glucagon-like peptide-1 receptor agonists.

UNLIKE MOST DISEASES, diabetes requires extensive patient self-management. Educating patients with type 2 diabetes mellitus (T2DM) about self-management skills is essential to improving health outcomes. (1) To achieve the greatest benefit and efficiently use resources, self-management education should be specific and relevant to each patient's needs. Beginning at the time of diagnosis, individualizing patient education is accomplished through an assessment process that identifies the needs, concerns, and capabilities of the patient, including barriers to learning. Since the patient's educational needs will change over time, this assessment process should be done at regular intervals, ideally with each visit. (See "A checklist approach to selecting the optimal treatment regimen for a patient with type 2 diabetes" on page S21 of this supplement.)

An education program that includes behavioral and psychological strategies that are both culturally sensitive and age-appropriate should be developed. (1) Because T2DM is often asymptomatic in its early stages, patients often feel that lifestyle recommendations and treatments have a negative impact on their quality of life. For these reasons, having an honest discussion about the benefits and risks of various treatment options and involving the patient in the therapeutic decision-making process can improve treatment adherence. It is equally important to ask patients to establish short-term goals and priorities and to congratulate themselves when they have met their goals.

Establishing glycemic goals at the outset is important for patient self-management and acceptance of treatment modifications when necessary. To guide management, the American Diabetes Association (ADA) recommends self-monitoring of blood glucose (SMBG) based on the particular needs and goals of the patient. The ADA, however, acknowledges that the optimal timing and frequency of SMBG for patients with T2DM on non-insulin therapy is unclear. (2)

The primary care provider can use the results of patient SMBG to enhance treatment adherence and goal attainment. For example, having the patient occasionally monitor postprandial glucose (PPG) levels and reflect on what he or she has recently eaten, how much he or she has exercised, and the medication(s) taken can provide an important link between behavior and results.

The primary care provider should ask patients about their home glucose monitoring results at every visit, encourage them to formulate personal strategies they can adopt to improve glycemic control, and affirm their appropriate behaviors and decisions. Regular encouragement and feedback from health care providers about self-monitoring activities is a strong motivator and an essential ingredient to success.

There are several key patient education issues specific to the use of the glucagon-like peptide-1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) in the treatment of T2DM. Let's examine these issues more closely by continuing the case study from "Practical applications of therapy with a glucagon-like peptide-1 receptor agonist" that begins on page S35 of this supplement.


ML is a 53-year-old African American female diagnosed with T2DM 6 months ago. Her glycosylated hemoglobin (A1C)level has decreased from 8.5% at baseline to 7.5% as a result of treatment with lifestyle management and metformin, 1000 mg twice daily. Pioglitazone was added 3 months ago but was discontinued at this (24 week) visit because of a weight gain of 2.5 kg. After a discussion of her needs, concerns, and capabilities, as well as the clinical evidence supporting the use of GLP-1 receptor agonists, ML and her physician agree to add exenatide, 5 mcg twice daily, to her present regimen of lifestyle management and metformin and increase the dose of exenatide to 10 mcg twice daily 1 month later.

Although exenatide was selected in this case because it is currently the only approved GLP-1 receptor agonist, the concepts that should be discussed with the patient during an initial education session would be similar for any GLP-1 receptor agonist. Liraglutide is a once-daily GLP-1 receptor agonist that has recently been approved in the European Union and is in late-stage review with the US Food and Drug Administration (FDA). When initiating therapy with any antihyperglycemic agent, including a GLP-1 receptor agonist, it is important to address the 3 P's: purpose, potential side effects, and proper use.



What are the potential benefits of taking a GLP-1 receptor agonist?

In order to make an informed decision about using a GLP-1 receptor agonist, patients should have a basic understanding about how this class of medications works. Using terminology the patient can understand, the health care provider should explain that most people with T2DM do not produce enough insulin immediately after eating food and release too much glucagon. GLP-1 receptor agonists improve blood glucose control primarily by restoring a proper balance of these 2 hormones. Health care providers should be careful not to make claims about the long-term benefits of GLP-1 receptor agonists, because long-term studies on the impact of these agents on microvascular and macrovascular outcomes have not been completed. However, early research with animals, as well as patients with T2DM, indicates that these drugs have promising effects on [beta]-cell function which, in turn, may have long-term health benefits. When coupled with healthy eating habits and regular physical activity, many people lose weight when taking a GLP-1 receptor agonist. For patients who are overweight, it is important to clearly state that weight loss has several health benefits, including improved control of blood glucose, blood pressure, and blood lipids and, for many patients, an increased sense of self-worth and well-being.

Potential side effects


What are the potential risks of taking a GLP-1 receptor agonist?

Noting that all drugs have potential side effects, the health care provider should clearly state to patients that the most common side effect from a GLP-1 receptor agonist is nausea. This symptom is sometimes described as a bloated feeling after eating, and it is generally mild and transient. Vomiting and more severe symptoms also may occur. These symptoms are most common during the first few weeks of treatment and generally go away with continued use. Some patients have loose stools or diarrhea. These adverse gastrointestinal (GI) effects are similar to those experienced by some patients when initiating metformin.

Because of the glucose-dependent action of GLP-1 receptor agonists, hypoglycemia is uncommon when a GLP-1 receptor agonist is used as monotherapy (not currently indicated) or in combination with metformin. However, when added to a sulfonylurea or any therapy that increases insulin concentration, the frequency and severity of hypoglycemia may increase, thereby necessitating a reduction in the dose of the sulfonylurea. Health care providers should encourage patients to monitor blood glucose and to report hypoglycemic symptoms and episodes confirmed by SMBG so that appropriate dose adjustments can be made in a timely manner.

Acute pancreatitis is a serious problem that has been reported in a very small number of people who have taken exenatide. It is not yet known whether exenatide is the cause of this rare problem or whether it is coincidental. (3) However, it is known that patients with diabetes do have an increased background risk for developing pancreatitis, as compared with a healthy population. (4) If the patient has risk factors such as excessive alcohol use and/or gallstones, he or she should be monitored carefully; if persistent abdominal pain continues, instruct the patient to seek immediate medical attention for careful evaluation. Should this or any other unexpected adverse event occur with an incretin-based therapy, it is important for physicians to file a report with the FDA via the MedWatch program (

Proper use


How is treatment with a GLP-1 receptor agonist initiated?

Both exenatide and liraglutide are started at a low dose, which is increased over a period of a few weeks to reduce the likelihood and severity of nausea.

Exenatide. Start at 5 mcg twice a day for 1 month, then increase to 10 mcg twice a day. The 5 mcg twice-daily dose is the minimum effective dose. Based on fasting plasma glucose (FPG) and/or PPG levels, the dose is generally increased to the maximum dose of 10 mcg twice a day as tolerated. (5) Exenatide is administered twice daily within 60 minutes before the 2 main meals of the day (generally breakfast and dinner) and at least 6 hours apart. (5)

Liraglutide. In clinical trials, liraglutide was started at 0.6 mg once daily for 1 week, then increased to 1.2 mg once daffy for 1 week, and finally increased to 1.8 mg once daily as tolerated. This regimen is under review by the FDA and has been approved by the European authorities. (6) The 1.2 mg dose appears to be the minimum effective dose. Based on FPG and/or PPG levels, the dose is generally increased to the maximum dose of 1.8 mg once daily as tolerated. In clinical trials, liraglutide was administered once daily at approximately the same time each day without regard to meals. (6-10)


How are exenatide and liraglutide administered?

GLP-1 receptor agonists are administered subcutaneously in the abdominal fat, upper thigh, or arm. Although many patients will readily agree to administer an injectable medication that will help them lose weight, some patients will express reluctance or fear. It's important to explore the patient's feelings.

Many patients have had a previous negative experience with an injectable medication or vaccination given intramuscularly and requiring a large-gauge needle. Many assume that all injections are painful. Some patients believe that injectable therapies are only used as a last resort and are reserved for patients who have a severe or fatal illness. Many patients lack the self-confidence to administer injectable medications, worry about making errors, or believe that it requires years of training. Many patients associate injectable medication with drug dependency and addiction.

These misconceptions are often reinforced or promulgated through depictions of people using injections on television and in movies. The health care provider should avoid making assumptions but, rather, explore the patient's fears by asking open-ended questions and addressing any misconceptions in an empathetic manner. The vast majority of patients are able to self-administer these medications after they've had an opportunity to handle the injection device and self-administer the medication with supervision. The health care provider should explain that pen delivery devices and fine-gauge needles make injection therapy relatively simple and painless.


What can be done to reduce the incidence and severity of nausea?

Although adverse GI events (ie, nausea, vomiting, and/or diarrhea) are the most common side effects with GLP-1 receptor agonist therapy, these symptoms are generally mild and subside within several weeks. These adverse events are probably related to reduced gastric emptying. Only 7% of patients treated with exenatide (vs 3% with placebo) (5) and 4% of patients who took liraglutide as monotherapy discontinued treatment due to these side effects. (6) When used in combination with metformin--another drug that can cause GI side effects--only 8% stopped taking liraglutide. (11) In patients treated with the combination of exenatide and metformin, only 1.8% of patients stopped taking exenatide due to GI side effects. (12)

Two strategies can reduce the likelihood and severity of nausea and vomiting. The first approach, as described above, is to start therapy with a low dose and increase the dose over a few weeks. Should nausea or vomiting occur after the maximum daily dose is given, the dose can be reduced, or in the case of exenatide, a 5 mcg dose can be given prior to one meal and a 10 mcg dose can be given prior to another meal for a few weeks.

Adverse GI events, including nausea, peak in the first 4 weeks with liraglutide, (6,11) and within 8 weeks with exenatide. (12) If a patient is initially unable to tolerate the maximum dose, a second attempt to increase the dose should be made if the patient tolerates the lower dose for 4 to 8 weeks. Another strategy that may reduce the likelihood and severity of nausea is to administer the agent immediately before or during, but not after, a meal. However, the effectiveness of exenatide may be diminished if this strategy is used. (13) Therefore, after 4 to 8 weeks, the patient should attempt to administer the dose 10 to 15 minutes before a meal and then, if tolerated, 30 to 45 minutes prior to a meal.


At a follow-up visit 5 weeks after initiating treatment with exenatide (29 weeks after diagnosis), ML's physician notes that her blood glucose levels and body weight have improved and her leg swelling has resolved. ML reports no symptoms of hypoglycemia, but states that she experienced mild nausea for a few days after increasing her dose to 10 mcg twice a day. The report from the certified diabetes educator to whom the physician referred ML notes that ML has improved her eating habits but skips lunch 1 or 2 times a week.


What if the patient doesn't eat as planned or forgets to take the dose?

If a patient takes exenatide but the meal is delayed more than 1 hour after the injection, the patient has a small risk of experiencing hypoglycemia. (13,14) Consequently, it is prudent to advise the patient to be vigilant for symptoms of hypoglycemia if he or she does not eat when planned and to avoid driving or performing other dangerous tasks until after eating.

On the other hand, if the patient eats and realizes he or she forgot to take exenatide before that meal, that dose should be skipped and the next dose should be taken at the scheduled time. The patient should be advised not to double the dose, because this will increase the risk for GI side effects and will not lower blood glucose any better than a standard dose. (5,14)

Liraglutide can be administered at any time of day without regard to meals, but it should be taken at the same time each day. In clinical trials, liraglutide was administered once daily in the morning or the evening with no apparent difference in blood glucose response. (7-9) If a patient forgets to eat a meal or a meal is delayed, the patient should be advised to eat as soon as he or she remembers and to watch for symptoms of hypoglycemia. The patient should not drive or perform other dangerous tasks until he or she eats.


Are there any clinically important drug interactions with GLP-1 receptor agonists?

The combined use of a GLP-1 receptor agonist and a sulfonylurea increases the risk for hypoglycemia. As a consequence, it is recommended that the sulfonylurea dose be reduced when the 2 drugs are used in combination. (5) Exenatide is cleared by glomerular filtration (and is thus contraindicated in patients with severe renal disease), whereas liraglutide is metabolized by endopeptidases and undergoes hepatic or renal metabolism.

GLP-1 receptor agonists slow gastric emptying and may slow or reduce the absorption of orally administered medications. Studies evaluating the potential interactions between exenatide and acetaminophen, lovastatin, and oral contraceptives found that the absorption of these drugs was reduced or delayed and the time to peak concentration was delayed significantly. (5)

The clinical significance of these findings is unclear, but they suggest that the effectiveness of these medications may be reduced. For example, pain relief with acetaminophen may be reduced or delayed if a dose is taken soon after taking exenatide. Until more is known about the clinical significance of these interactions with GLP-1 receptor agonists, the most prudent strategy is to advise the patient to administer acetaminophen, lovastatin, or oral contraceptives 1 hour before or 4 hours after administering exenatide whenever possible. (5)

However, these gastric effects do not uniformly impair the oral absorption of all medications. Studies evaluating the potential for drug-drug interactions between exenatide and digoxin or lisinopril did not demonstrate any clinically significant effect on pharmacokinetic and pharmacodynamic parameters. (5) Although the concurrent use of exenatide and warfarin did not significantly alter the pharmacokinetics of warfarin in prospective studies, there have been case reports of an increase in the international normalization ratio (INR) and bleeding. (5)

Numerous theoretical pharmacodynamic interactions may occur between GLP-1 receptor agonists and other medications that impact blood glucose, blood pressure, and lipids. Since exenatide and liraglutide lower blood pressure and some blood lipids, appropriate monitoring should be performed when either of these drugs is initiated. Similarly, medications or nutritional supplements that alter glucose levels (eg, steroids, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, protease inhibitors, atypical antipsychotics, cinnamon) may alter the response to GLP-1 agonists.

At each office visit, it is important to inquire about the patient's use of prescription and nonprescription drugs, as well as nutritional supplements and alternative healing practices, because of the possibility of drug interactions. It is also prudent to encourage the patient to use the same pharmacy for all of his or her medication needs.


At her 33-week follow-up visit, ML's physician congratulates her on achieving the target A1C goal of <7.0%. ML seems pleased but confides that her life has changed quite a bit since she was diagnosed. ML felt fine before diagnosis, and although she follows a routine of taking her medications, eating better, exercising regularly, and monitoring her blood glucose level every day, she just isn't sure all the effort is worth it. The physician empathizes with ML. He acknowledges that she has made significant changes in her lifestyle behaviors, but that she may be having difficulty with motivation. He reminds ML of the long-term health benefits of controlling her diabetes and engaging in healthy lifestyle behaviors. He also points out that she:

* Lost 3 kg since diagnosis.

* No longer needs to monitor her blood glucose daily and recommends that she do so only 2 or 3 times a week and whenever she's not feeling well.

* Has had positive changes in blood pressure and lipids that will reduce her risk of heart disease. ML appreciates her physician's support and reaffirms her commitment to improve her diabetes self-management.


Ongoing patient education and feedback is critical to successful self-management for patients with T2DM. The patient's individualized program is based on an ongoing needs assessment, involves an interprofessional approach with a team of qualified health care professionals, and supports the patient by using positive feedback and motivational strategies at each visit.


(1.) Funnell MM, Brown TL, Childs BP, et al. National standards for diabetes self-management education. Diabetes Care. 2009;32(suppl 1):S87-S94.

(2.) American Diabetes Association. Standards of medical care in diabetes--2009. Diabetes Care. 2009;32(suppl 1):S13-S61.

(3.) Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.

(4.) Noel RA, Braun DK, Patterson RE, et al. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2009;32:834-838.

(5.) Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals, inc.; 2008.

(6.) Garber A, Henry R, Ramer R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase

III, double-blind, parallel-treatment trial. Lancet. 2009;373:473-481.

(7.) Vilsboll T, Zdravkovic M, Le Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30:1608-1610.

(8.) Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, doubleblind, randomized, controlled trial. Diabetes Care. 2004;27:1335-1342.

(9.) Harder H, Nielsen L, Tu DT, et al. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004;27:1915-1921.

(10.) Degn 103, Juhl CB, Sturis J, et al. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha-and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004;53:1187-1194.

(11.) Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84-90.

(12.) DeFronzo RA, Ranter RF, Han J, et al.. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.

(13.) Linnebjerg H, Kothare PA, Skrivanek Z, et al. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med. 2006;23:240-245.

(14.) Amylin Pharmaceuticals, Inc. Byetta--Meal-time jsp?reqNavId=5.4. Accessed April 21, 2009.

Stuart T. Haines, PharmD, BCPS, BC-ADM

Professor and Pharmacotherapy Specialist

Department of Pharmacy

Practice and Science

University of Maryland School

of Pharmacy

Baltimore, Maryland

Clinical Pharmacy Specialist--Primary Care Patient Services

West Palm Beach VA

Medical Center

West Palm Beach, Florida


Dr Haines has disclosed that he has common stock ownership in Merck & Co., Inc.
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Author:Haines, Stuart T.
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Sep 1, 2009
Previous Article:Practical applications of therapy with a glucagon-like peptide-1 receptor agonist.
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