Medical Education Library

CPT is a registered trademark^® of the American Medical Association.

CPT is a registered trademark^® of the American Medical Association.

CPT is a registered trademark^® of the American Medical Association.

The number of pharmacologic options available to treat type 2 diabetes mellitus (T2DM) has grown considerably over the past decade. With these options, health care providers have new opportunities to individualize treatment and provide better control of patients’ blood glucose levels. The “treat to failure” approach has been replaced by a “treat to target” approach, with the purpose of quickly achieving the A1C goal of <7.0% in most people, and then intensifying or changing therapy as needed to maintain glycemic control. At the same time, numerous questions have arisen, including where these new treatment options fit along the disease continuum, long-term safety, and how to treat T2DM from the time of diagnosis.

To better understand the questions and clinical challenges faced by primary care physicians, the Primary Care Education Consortium developed and distributed an online survey in February 2010 to primary care clinicians. The survey focused on the incretin class of glucose-lowering agents and was based on the results of reader surveys from 2 previous supplements of The Journal of Family Practice on incretin-based therapies, published in 2008 and 2009. The online survey was completed by 112 of the 1653 individuals (7% response) who received it.

The results of the online survey demonstrated a general understanding of the actions of incretin-based therapies—GLP-1 agonists and DPP-4 inhibitors—but uncertainty regarding their differences and roles in clinical management of patients with T2DM. These uncertainties are a concern because of the progressive nature of T2DM and the increasing importance of these agents in managing patients with T2DM, as reflected in guidelines and consensus statements issued in 2009 by the American Diabetes Association (ADA)/European Association for the Study of Diabetes¹ and the American Association of Clinical Endocrinologists/American College of Endocrinology.²

The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options, and from increasing experience not only from well-conducted clinical trials but also in clinical practice. Four incretin-based therapies are now available for use in the United States—exenatide and liraglutide, which are GLP-1 agonists, and sitagliptin and saxagliptin, which are DPP-4 inhibitors; liraglutide and saxagliptin were approved since publication of both guidelines in 2009. Although all are classified as incretin-based therapies, there are distinct differences between the GLP-1 agonists and DPP-4 inhibitors with respect to A1C reduction, effect on weight, and other nonglycemic parameters.

There are many issues with regard to providing comprehensive care to patients with T2DM that could be covered in this supplement. For example, as described in the ADA standards of care,³ the risks of other diseases, such as dyslipidemia, hypertension, and coronary heart disease, must also be considered in management of these patients. Glucose control remains a principal concern, however, and is the primary focus of this supplement.

Driven by results of the February 2010 online survey, this supplement builds upon the 2 previous supplements on incretin-based therapies to address 4 key areas:

• The pathophysiology of T2DM and the unique role of incretin hormones
• Glycemic control differences among available incretin-based agents
• Nonglycemic differences among available incretin-based agents
• Patient education regarding incretin-based therapies to promote patient self-management, with examples of patient cases for which incretin-based therapy is an option

The discussion will take a practical, problem-oriented approach by following 3 cases:

Case 1

A 53-year-old man was diagnosed with T2DM 6 weeks ago, at which time lifestyle intervention was recommended and treatment with metformin 500 mg twice daily was initiated. The patient began to experience severe diarrhea within a few days of beginning metformin. The diarrhea improved over the next 2 to 3 weeks, but he still experiences 1 or 2 episodes every few days. As a result, he does not want to continue taking metformin.

At diagnosis, the patient’s A1C level was 7.5% and his fasting plasma glucose was 158 mg/dL. He is 6-ft 2-in tall, 236 lb, with a body mass index of 30 kg/m² and blood pressure of 123/78 mm Hg. The patient works full-time as a building contractor, and he is a current smoker. He has hypertriglyceridemia (266 mg/dL), which is being treated with a fibrate.

Case 2

A 47-year-old man was diagnosed with T2DM 2.5 years ago. His A1C level was 8.8%. He had a good response with lifestyle intervention and metformin 1000 mg twice daily, losing 17 lb over 1.5 years. During that time, his A1C level dropped to 7.2%. Six months ago, treatment with pioglitazone 15 mg was started because his A1C level had risen to 7.8%. His current A1C is 7.0%. He is upset because he has since gained 6 lb, mostly edema, which has raised his blood pressure to 138/87 mm Hg. He refuses to take a diuretic, because hydrochlorothiazide, which was prescribed for essential hypertension, caused him to urinate more often. He wants to discontinue pioglitazone so he will lose weight and regain control of his blood pressure.

The patient is 5-ft 9-in tall, 237 lb, with a body mass index of 35 kg/m². He works full-time as an office manager. He has essential hypertension, which is being treated with lisinopril and metoprolol.

Case 3

A 68-year-old woman was diagnosed with T2DM 5 years ago. Her A1C value was 8.7%. She was initially managed with lifestyle intervention, but 1 year after diagnosis, treatment with metformin 500 mg twice daily was initiated, and the dose was titrated to 1000 mg twice daily a year later. On this regimen, her A1C level dropped to 7.1%, but 1.5 years later, it had increased to 8.3%. At that time, glyburide 5 mg once daily was added to her treatment regimen and titrated to 10 mg once daily. Mild renal insufficiency (CrCl_est, 58 mL/min) was identified at today’s visit. Her current A1C is 7.4%.

The patient is 5-ft 3-in tall, 148 lb, with a body mass index of 26 kg/m² and blood pressure of 122/76 mm Hg. She works part-time as a librarian. She has peripheral arterial disease, which is being treated with aspirin, clopidogrel, and atorvastatin. She also has osteoporosis, which is being treated with ibandronate.

These cases, which represent various stages of disease progression, present important decision points regarding how to initiate or modify therapy. For each of these decision points, many factors must be considered, including underlying pathophysiology, comorbidities, A1C-lowering ability, and previous treatment. Other factors to consider are the safety of available agents, including the risk of hypoglycemia; tolerability; and nonglycemic effects, such as on weight, lipids, and blood pressure.

The number of pharmacologic options available to treat type 2 diabetes mellitus (T2DM) has grown considerably over the past decade. With these options, health care providers have new opportunities to individualize treatment and provide better control of patients’ blood glucose levels. The “treat to failure” approach has been replaced by a “treat to target” approach, with the purpose of quickly achieving the A1C goal of <7.0% in most people, and then intensifying or changing therapy as needed to maintain glycemic control. At the same time, numerous questions have arisen, including where these new treatment options fit along the disease continuum, long-term safety, and how to treat T2DM from the time of diagnosis.

To better understand the questions and clinical challenges faced by primary care physicians, the Primary Care Education Consortium developed and distributed an online survey in February 2010 to primary care clinicians. The survey focused on the incretin class of glucose-lowering agents and was based on the results of reader surveys from 2 previous supplements of The Journal of Family Practice on incretin-based therapies, published in 2008 and 2009. The online survey was completed by 112 of the 1653 individuals (7% response) who received it.

The results of the online survey demonstrated a general understanding of the actions of incretin-based therapies—GLP-1 agonists and DPP-4 inhibitors—but uncertainty regarding their differences and roles in clinical management of patients with T2DM. These uncertainties are a concern because of the progressive nature of T2DM and the increasing importance of these agents in managing patients with T2DM, as reflected in guidelines and consensus statements issued in 2009 by the American Diabetes Association (ADA)/European Association for the Study of Diabetes¹ and the American Association of Clinical Endocrinologists/American College of Endocrinology.²

The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options, and from increasing experience not only from well-conducted clinical trials but also in clinical practice. Four incretin-based therapies are now available for use in the United States—exenatide and liraglutide, which are GLP-1 agonists, and sitagliptin and saxagliptin, which are DPP-4 inhibitors; liraglutide and saxagliptin were approved since publication of both guidelines in 2009. Although all are classified as incretin-based therapies, there are distinct differences between the GLP-1 agonists and DPP-4 inhibitors with respect to A1C reduction, effect on weight, and other nonglycemic parameters.

There are many issues with regard to providing comprehensive care to patients with T2DM that could be covered in this supplement. For example, as described in the ADA standards of care,³ the risks of other diseases, such as dyslipidemia, hypertension, and coronary heart disease, must also be considered in management of these patients. Glucose control remains a principal concern, however, and is the primary focus of this supplement.

Driven by results of the February 2010 online survey, this supplement builds upon the 2 previous supplements on incretin-based therapies to address 4 key areas:

• The pathophysiology of T2DM and the unique role of incretin hormones
• Glycemic control differences among available incretin-based agents
• Nonglycemic differences among available incretin-based agents
• Patient education regarding incretin-based therapies to promote patient self-management, with examples of patient cases for which incretin-based therapy is an option

The discussion will take a practical, problem-oriented approach by following 3 cases:

Case 1

A 53-year-old man was diagnosed with T2DM 6 weeks ago, at which time lifestyle intervention was recommended and treatment with metformin 500 mg twice daily was initiated. The patient began to experience severe diarrhea within a few days of beginning metformin. The diarrhea improved over the next 2 to 3 weeks, but he still experiences 1 or 2 episodes every few days. As a result, he does not want to continue taking metformin.

At diagnosis, the patient’s A1C level was 7.5% and his fasting plasma glucose was 158 mg/dL. He is 6-ft 2-in tall, 236 lb, with a body mass index of 30 kg/m² and blood pressure of 123/78 mm Hg. The patient works full-time as a building contractor, and he is a current smoker. He has hypertriglyceridemia (266 mg/dL), which is being treated with a fibrate.

Case 2

A 47-year-old man was diagnosed with T2DM 2.5 years ago. His A1C level was 8.8%. He had a good response with lifestyle intervention and metformin 1000 mg twice daily, losing 17 lb over 1.5 years. During that time, his A1C level dropped to 7.2%. Six months ago, treatment with pioglitazone 15 mg was started because his A1C level had risen to 7.8%. His current A1C is 7.0%. He is upset because he has since gained 6 lb, mostly edema, which has raised his blood pressure to 138/87 mm Hg. He refuses to take a diuretic, because hydrochlorothiazide, which was prescribed for essential hypertension, caused him to urinate more often. He wants to discontinue pioglitazone so he will lose weight and regain control of his blood pressure.

The patient is 5-ft 9-in tall, 237 lb, with a body mass index of 35 kg/m². He works full-time as an office manager. He has essential hypertension, which is being treated with lisinopril and metoprolol.

Case 3

A 68-year-old woman was diagnosed with T2DM 5 years ago. Her A1C value was 8.7%. She was initially managed with lifestyle intervention, but 1 year after diagnosis, treatment with metformin 500 mg twice daily was initiated, and the dose was titrated to 1000 mg twice daily a year later. On this regimen, her A1C level dropped to 7.1%, but 1.5 years later, it had increased to 8.3%. At that time, glyburide 5 mg once daily was added to her treatment regimen and titrated to 10 mg once daily. Mild renal insufficiency (CrCl_est, 58 mL/min) was identified at today’s visit. Her current A1C is 7.4%.

The patient is 5-ft 3-in tall, 148 lb, with a body mass index of 26 kg/m² and blood pressure of 122/76 mm Hg. She works part-time as a librarian. She has peripheral arterial disease, which is being treated with aspirin, clopidogrel, and atorvastatin. She also has osteoporosis, which is being treated with ibandronate.

These cases, which represent various stages of disease progression, present important decision points regarding how to initiate or modify therapy. For each of these decision points, many factors must be considered, including underlying pathophysiology, comorbidities, A1C-lowering ability, and previous treatment. Other factors to consider are the safety of available agents, including the risk of hypoglycemia; tolerability; and nonglycemic effects, such as on weight, lipids, and blood pressure.

The number of pharmacologic options available to treat type 2 diabetes mellitus (T2DM) has grown considerably over the past decade. With these options, health care providers have new opportunities to individualize treatment and provide better control of patients’ blood glucose levels. The “treat to failure” approach has been replaced by a “treat to target” approach, with the purpose of quickly achieving the A1C goal of <7.0% in most people, and then intensifying or changing therapy as needed to maintain glycemic control. At the same time, numerous questions have arisen, including where these new treatment options fit along the disease continuum, long-term safety, and how to treat T2DM from the time of diagnosis.

To better understand the questions and clinical challenges faced by primary care physicians, the Primary Care Education Consortium developed and distributed an online survey in February 2010 to primary care clinicians. The survey focused on the incretin class of glucose-lowering agents and was based on the results of reader surveys from 2 previous supplements of The Journal of Family Practice on incretin-based therapies, published in 2008 and 2009. The online survey was completed by 112 of the 1653 individuals (7% response) who received it.

The results of the online survey demonstrated a general understanding of the actions of incretin-based therapies—GLP-1 agonists and DPP-4 inhibitors—but uncertainty regarding their differences and roles in clinical management of patients with T2DM. These uncertainties are a concern because of the progressive nature of T2DM and the increasing importance of these agents in managing patients with T2DM, as reflected in guidelines and consensus statements issued in 2009 by the American Diabetes Association (ADA)/European Association for the Study of Diabetes¹ and the American Association of Clinical Endocrinologists/American College of Endocrinology.²

The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options, and from increasing experience not only from well-conducted clinical trials but also in clinical practice. Four incretin-based therapies are now available for use in the United States—exenatide and liraglutide, which are GLP-1 agonists, and sitagliptin and saxagliptin, which are DPP-4 inhibitors; liraglutide and saxagliptin were approved since publication of both guidelines in 2009. Although all are classified as incretin-based therapies, there are distinct differences between the GLP-1 agonists and DPP-4 inhibitors with respect to A1C reduction, effect on weight, and other nonglycemic parameters.

There are many issues with regard to providing comprehensive care to patients with T2DM that could be covered in this supplement. For example, as described in the ADA standards of care,³ the risks of other diseases, such as dyslipidemia, hypertension, and coronary heart disease, must also be considered in management of these patients. Glucose control remains a principal concern, however, and is the primary focus of this supplement.

Driven by results of the February 2010 online survey, this supplement builds upon the 2 previous supplements on incretin-based therapies to address 4 key areas:

• The pathophysiology of T2DM and the unique role of incretin hormones
• Glycemic control differences among available incretin-based agents
• Nonglycemic differences among available incretin-based agents
• Patient education regarding incretin-based therapies to promote patient self-management, with examples of patient cases for which incretin-based therapy is an option

The discussion will take a practical, problem-oriented approach by following 3 cases:

Case 1

A 53-year-old man was diagnosed with T2DM 6 weeks ago, at which time lifestyle intervention was recommended and treatment with metformin 500 mg twice daily was initiated. The patient began to experience severe diarrhea within a few days of beginning metformin. The diarrhea improved over the next 2 to 3 weeks, but he still experiences 1 or 2 episodes every few days. As a result, he does not want to continue taking metformin.

At diagnosis, the patient’s A1C level was 7.5% and his fasting plasma glucose was 158 mg/dL. He is 6-ft 2-in tall, 236 lb, with a body mass index of 30 kg/m² and blood pressure of 123/78 mm Hg. The patient works full-time as a building contractor, and he is a current smoker. He has hypertriglyceridemia (266 mg/dL), which is being treated with a fibrate.

Case 2

A 47-year-old man was diagnosed with T2DM 2.5 years ago. His A1C level was 8.8%. He had a good response with lifestyle intervention and metformin 1000 mg twice daily, losing 17 lb over 1.5 years. During that time, his A1C level dropped to 7.2%. Six months ago, treatment with pioglitazone 15 mg was started because his A1C level had risen to 7.8%. His current A1C is 7.0%. He is upset because he has since gained 6 lb, mostly edema, which has raised his blood pressure to 138/87 mm Hg. He refuses to take a diuretic, because hydrochlorothiazide, which was prescribed for essential hypertension, caused him to urinate more often. He wants to discontinue pioglitazone so he will lose weight and regain control of his blood pressure.

The patient is 5-ft 9-in tall, 237 lb, with a body mass index of 35 kg/m². He works full-time as an office manager. He has essential hypertension, which is being treated with lisinopril and metoprolol.

Case 3

A 68-year-old woman was diagnosed with T2DM 5 years ago. Her A1C value was 8.7%. She was initially managed with lifestyle intervention, but 1 year after diagnosis, treatment with metformin 500 mg twice daily was initiated, and the dose was titrated to 1000 mg twice daily a year later. On this regimen, her A1C level dropped to 7.1%, but 1.5 years later, it had increased to 8.3%. At that time, glyburide 5 mg once daily was added to her treatment regimen and titrated to 10 mg once daily. Mild renal insufficiency (CrCl_est, 58 mL/min) was identified at today’s visit. Her current A1C is 7.4%.

The patient is 5-ft 3-in tall, 148 lb, with a body mass index of 26 kg/m² and blood pressure of 122/76 mm Hg. She works part-time as a librarian. She has peripheral arterial disease, which is being treated with aspirin, clopidogrel, and atorvastatin. She also has osteoporosis, which is being treated with ibandronate.

These cases, which represent various stages of disease progression, present important decision points regarding how to initiate or modify therapy. For each of these decision points, many factors must be considered, including underlying pathophysiology, comorbidities, A1C-lowering ability, and previous treatment. Other factors to consider are the safety of available agents, including the risk of hypoglycemia; tolerability; and nonglycemic effects, such as on weight, lipids, and blood pressure.

Introduction

The comprehensive and long-term management of patients with type 2 diabetes mellitus (T2DM) requires that they assume primary responsibility for daily self-management. For this to occur, patient education is critical, yet it is time-consuming. Because our time as primary care physicians is limited, developing a diabetes care team, even informally, can be helpful in providing the comprehensive care that is needed. Beyond easing the amount of time we need to provide the patient education required, the patient is able to benefit from the specialized skills and knowledge of other team members, such as a nurse, pharmacist, dietitian, certified diabetes educator, or an exercise specialist. It is important, however, that as primary care physicians, we coordinate the care provided by the team so that treatment goals are clear, communication is maintained, and patient outcomes are optimal.

With this need for patient self-management supported by ongoing education in mind, let’s turn our attention to some issues of special importance with respect to the GLP-1 agonists and DPP-4 inhibitors.

Dosing and administration

There is considerable variability among the GLP-1 agonists and DPP-4 inhibitors with respect to their dosing and administration (TABLE).^1-4 This variability enables you and your patients to select a treatment that best meets their needs.

Case 2

As you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options for modifying his therapy, this 47-year-old office manager wants to know what side effects are likely and which, if any, might pose a problem at work.

You can begin by telling the patient that transient nausea has been a common occurrence in patients treated with a GLP-1 agonist and that a key factor regarding this side effect is how the medication is titrated (see accompanying article “Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Exenatide and liraglutide should be administered using the dose escalation strategy outlined in the TABLE. You tell him that nausea is typically mild and usually peaks within 8 weeks of commencing treatment with exenatide⁵ and within 4 to 6 weeks with liraglutide.^6,7 Should nausea persist and be troublesome, taking liraglutide with food has been helpful for some patients; otherwise, liraglutide can be taken at the same time each day irrespective of meals.² You also note that saxagliptin and sitagliptin can be taken with or without food.^3,4 While the prescribing information indicates that exenatide can be taken at any time within the 60-minute period before a meal,¹ exenatide can be administered during but not after the meal if necessary to reduce nausea, without sacrificing its glucose-lowering effects⁸; the satiety effect, however, may be blunted in some patients. Reduction in the postprandial glucose level has been shown to be greatest when exenatide is taken between 60 minutes before or by the end of the meal. Exenatide should not be taken after the meal, because transient low blood glucose levels may occur.⁸

In patients with renal dysfunction, the dose of sitagliptin and saxagliptin but not liraglutide needs to be adjusted (TABLE).^1-4 Exenatide should not be used in patients with a CrCl <30 mL/min. Exenatide and sitagliptin are contraindicated in patients with a known hypersensitivity reaction to the drug.^1,3 Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.² There are no contraindications listed for saxagliptin.⁴

TABLE

Dosing recommendations^1-4

Case 1

During your discussion with this building contractor, you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options. You begin to discuss the need to self-inject the GLP-1 agonist, when he interrupts you and tells you that he does not want to hear anything about insulin or other medications that would require him to self-inject, because his work environment and schedule would make this impossible.

While his feelings are understandable, open communication with this patient can do much to allay his concerns. Although concerns about injecting outside the home are common with insulin, the need for this with a GLP-1 agonist is unlikely because of the twice-daily exenatide and once-daily liraglutide dosing schedules and the lack of need to intensely monitor blood glucose levels. However, if the patient eats breakfast at work or doesn’t eat breakfast at all, this may become an issue with exenatide because of the need to eat within 60 minutes of taking a dose.

Concerns about self-injecting also can be addressed by showing patients the pen injection device and its small-gauge needle and instructing them in its use. Having a patient self-inject the first dose in the office can relieve much anxiety. Patients often comment about how easy and painless it is to inject themselves. One caution, however, is that if a patient self-injects a dose of exenatide in the office, he or she must be reminded of the need to eat within the next hour.

Talking about risks

Case 3

During your discussion with this 68-year-old woman about modifying her therapy, you include the GLP-1 agonists and DPP-4 inhibitors as treatment options. She replies, “Yes, I’ve seen information about them at my job at the library. They can cause cancer, can’t they?”

This comment highlights the importance of talking openly with patients to help them make good decisions about their health. Discussions often focus on the anticipated benefits of medications, but as we know, there are risks associated with every medication choice. Initially discussing risks with this patient could avoid having her return to the office angry with you for not warning her before she began taking the medication.

In this situation, as part of your discussion about liraglutide, you could refer her to the manufacturer’s Web site for information about the Risk Evaluation and Mitigation Strategy (REMS) program for liraglutide, sitagliptin, and saxagliptin. You also could provide her with the patient medication guide included with the program. REMS programs have been implemented for several glucose-lowering medications, since implementation of the REMS program by the US Food and Drug Administration (FDA) in 2007; these include exenatide, liraglutide, pioglitazone with or without glimepiride, rosiglitazone with or without glimepiride, and sitagliptin with or without metformin. Medication guides and other information are available online from the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Medication cost

Case 3

You continue your discussion with this 68-year-old part-time librarian about the benefits and risks of insulin, a thiazolidinedione, and a glinide, as well as a GLP-1 agonist and a DPP-4 inhibitor. Suddenly she asks you how much these medications cost.

The cost of health care in general and medications in particular continue to dominate discussions. This is especially true for medications that have arrived on the market more recently, including the GLP-1 agonists and the DPP-4 inhibitors, which range in cost from about $7 to $14 per day.^9-12 These agents, however, may be covered by health insurance, so cost to the patient may be limited to copays. The lower risk of hypoglycemia observed with the GLP-1 agonists and DPP-4 inhibitors compared with some other glucose-lowering therapies may make it possible to perform self-monitoring of blood glucose less frequently, but this is an individual patient issue.

Although it may be difficult or uncomfortable to talk about the costs of treatment, it has a great impact on medication adherence and overall treatment satisfaction. In this case, in addition to discussing insurance coverage and what she can afford, you should also talk with the patient about ways the cost of her medications might be reduced.

While no generic formulations are available for exenatide, liraglutide, saxagliptin, or sitagliptin, each manufacturer offers a prescription assistance program. Patients should also be encouraged to check manufacturers’ Web sites for available coupons or discount programs.

With this patient, you also might talk about how different medications can affect total cost of her diabetes treatment differently. Limited retrospective analyses suggest that compared with glimepiride, liraglutide reduces the total cost of care, including care for ocular events and neuropathy leading to amputation.¹³ Other studies indicate that the overall cost of care with exenatide is lower than with insulin glargine,¹⁴ including care for hypoglycemia-related events.¹⁵

Summary

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Introduction

The comprehensive and long-term management of patients with type 2 diabetes mellitus (T2DM) requires that they assume primary responsibility for daily self-management. For this to occur, patient education is critical, yet it is time-consuming. Because our time as primary care physicians is limited, developing a diabetes care team, even informally, can be helpful in providing the comprehensive care that is needed. Beyond easing the amount of time we need to provide the patient education required, the patient is able to benefit from the specialized skills and knowledge of other team members, such as a nurse, pharmacist, dietitian, certified diabetes educator, or an exercise specialist. It is important, however, that as primary care physicians, we coordinate the care provided by the team so that treatment goals are clear, communication is maintained, and patient outcomes are optimal.

With this need for patient self-management supported by ongoing education in mind, let’s turn our attention to some issues of special importance with respect to the GLP-1 agonists and DPP-4 inhibitors.

Dosing and administration

There is considerable variability among the GLP-1 agonists and DPP-4 inhibitors with respect to their dosing and administration (TABLE).^1-4 This variability enables you and your patients to select a treatment that best meets their needs.

Case 2

As you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options for modifying his therapy, this 47-year-old office manager wants to know what side effects are likely and which, if any, might pose a problem at work.

You can begin by telling the patient that transient nausea has been a common occurrence in patients treated with a GLP-1 agonist and that a key factor regarding this side effect is how the medication is titrated (see accompanying article “Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Exenatide and liraglutide should be administered using the dose escalation strategy outlined in the TABLE. You tell him that nausea is typically mild and usually peaks within 8 weeks of commencing treatment with exenatide⁵ and within 4 to 6 weeks with liraglutide.^6,7 Should nausea persist and be troublesome, taking liraglutide with food has been helpful for some patients; otherwise, liraglutide can be taken at the same time each day irrespective of meals.² You also note that saxagliptin and sitagliptin can be taken with or without food.^3,4 While the prescribing information indicates that exenatide can be taken at any time within the 60-minute period before a meal,¹ exenatide can be administered during but not after the meal if necessary to reduce nausea, without sacrificing its glucose-lowering effects⁸; the satiety effect, however, may be blunted in some patients. Reduction in the postprandial glucose level has been shown to be greatest when exenatide is taken between 60 minutes before or by the end of the meal. Exenatide should not be taken after the meal, because transient low blood glucose levels may occur.⁸

In patients with renal dysfunction, the dose of sitagliptin and saxagliptin but not liraglutide needs to be adjusted (TABLE).^1-4 Exenatide should not be used in patients with a CrCl <30 mL/min. Exenatide and sitagliptin are contraindicated in patients with a known hypersensitivity reaction to the drug.^1,3 Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.² There are no contraindications listed for saxagliptin.⁴

TABLE

Dosing recommendations^1-4

Case 1

During your discussion with this building contractor, you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options. You begin to discuss the need to self-inject the GLP-1 agonist, when he interrupts you and tells you that he does not want to hear anything about insulin or other medications that would require him to self-inject, because his work environment and schedule would make this impossible.

While his feelings are understandable, open communication with this patient can do much to allay his concerns. Although concerns about injecting outside the home are common with insulin, the need for this with a GLP-1 agonist is unlikely because of the twice-daily exenatide and once-daily liraglutide dosing schedules and the lack of need to intensely monitor blood glucose levels. However, if the patient eats breakfast at work or doesn’t eat breakfast at all, this may become an issue with exenatide because of the need to eat within 60 minutes of taking a dose.

Concerns about self-injecting also can be addressed by showing patients the pen injection device and its small-gauge needle and instructing them in its use. Having a patient self-inject the first dose in the office can relieve much anxiety. Patients often comment about how easy and painless it is to inject themselves. One caution, however, is that if a patient self-injects a dose of exenatide in the office, he or she must be reminded of the need to eat within the next hour.

Talking about risks

Case 3

During your discussion with this 68-year-old woman about modifying her therapy, you include the GLP-1 agonists and DPP-4 inhibitors as treatment options. She replies, “Yes, I’ve seen information about them at my job at the library. They can cause cancer, can’t they?”

This comment highlights the importance of talking openly with patients to help them make good decisions about their health. Discussions often focus on the anticipated benefits of medications, but as we know, there are risks associated with every medication choice. Initially discussing risks with this patient could avoid having her return to the office angry with you for not warning her before she began taking the medication.

In this situation, as part of your discussion about liraglutide, you could refer her to the manufacturer’s Web site for information about the Risk Evaluation and Mitigation Strategy (REMS) program for liraglutide, sitagliptin, and saxagliptin. You also could provide her with the patient medication guide included with the program. REMS programs have been implemented for several glucose-lowering medications, since implementation of the REMS program by the US Food and Drug Administration (FDA) in 2007; these include exenatide, liraglutide, pioglitazone with or without glimepiride, rosiglitazone with or without glimepiride, and sitagliptin with or without metformin. Medication guides and other information are available online from the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Medication cost

Case 3

You continue your discussion with this 68-year-old part-time librarian about the benefits and risks of insulin, a thiazolidinedione, and a glinide, as well as a GLP-1 agonist and a DPP-4 inhibitor. Suddenly she asks you how much these medications cost.

The cost of health care in general and medications in particular continue to dominate discussions. This is especially true for medications that have arrived on the market more recently, including the GLP-1 agonists and the DPP-4 inhibitors, which range in cost from about $7 to $14 per day.^9-12 These agents, however, may be covered by health insurance, so cost to the patient may be limited to copays. The lower risk of hypoglycemia observed with the GLP-1 agonists and DPP-4 inhibitors compared with some other glucose-lowering therapies may make it possible to perform self-monitoring of blood glucose less frequently, but this is an individual patient issue.

Although it may be difficult or uncomfortable to talk about the costs of treatment, it has a great impact on medication adherence and overall treatment satisfaction. In this case, in addition to discussing insurance coverage and what she can afford, you should also talk with the patient about ways the cost of her medications might be reduced.

While no generic formulations are available for exenatide, liraglutide, saxagliptin, or sitagliptin, each manufacturer offers a prescription assistance program. Patients should also be encouraged to check manufacturers’ Web sites for available coupons or discount programs.

With this patient, you also might talk about how different medications can affect total cost of her diabetes treatment differently. Limited retrospective analyses suggest that compared with glimepiride, liraglutide reduces the total cost of care, including care for ocular events and neuropathy leading to amputation.¹³ Other studies indicate that the overall cost of care with exenatide is lower than with insulin glargine,¹⁴ including care for hypoglycemia-related events.¹⁵

Summary

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Introduction

The comprehensive and long-term management of patients with type 2 diabetes mellitus (T2DM) requires that they assume primary responsibility for daily self-management. For this to occur, patient education is critical, yet it is time-consuming. Because our time as primary care physicians is limited, developing a diabetes care team, even informally, can be helpful in providing the comprehensive care that is needed. Beyond easing the amount of time we need to provide the patient education required, the patient is able to benefit from the specialized skills and knowledge of other team members, such as a nurse, pharmacist, dietitian, certified diabetes educator, or an exercise specialist. It is important, however, that as primary care physicians, we coordinate the care provided by the team so that treatment goals are clear, communication is maintained, and patient outcomes are optimal.

With this need for patient self-management supported by ongoing education in mind, let’s turn our attention to some issues of special importance with respect to the GLP-1 agonists and DPP-4 inhibitors.

Dosing and administration

There is considerable variability among the GLP-1 agonists and DPP-4 inhibitors with respect to their dosing and administration (TABLE).^1-4 This variability enables you and your patients to select a treatment that best meets their needs.

Case 2

As you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options for modifying his therapy, this 47-year-old office manager wants to know what side effects are likely and which, if any, might pose a problem at work.

You can begin by telling the patient that transient nausea has been a common occurrence in patients treated with a GLP-1 agonist and that a key factor regarding this side effect is how the medication is titrated (see accompanying article “Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Exenatide and liraglutide should be administered using the dose escalation strategy outlined in the TABLE. You tell him that nausea is typically mild and usually peaks within 8 weeks of commencing treatment with exenatide⁵ and within 4 to 6 weeks with liraglutide.^6,7 Should nausea persist and be troublesome, taking liraglutide with food has been helpful for some patients; otherwise, liraglutide can be taken at the same time each day irrespective of meals.² You also note that saxagliptin and sitagliptin can be taken with or without food.^3,4 While the prescribing information indicates that exenatide can be taken at any time within the 60-minute period before a meal,¹ exenatide can be administered during but not after the meal if necessary to reduce nausea, without sacrificing its glucose-lowering effects⁸; the satiety effect, however, may be blunted in some patients. Reduction in the postprandial glucose level has been shown to be greatest when exenatide is taken between 60 minutes before or by the end of the meal. Exenatide should not be taken after the meal, because transient low blood glucose levels may occur.⁸

In patients with renal dysfunction, the dose of sitagliptin and saxagliptin but not liraglutide needs to be adjusted (TABLE).^1-4 Exenatide should not be used in patients with a CrCl <30 mL/min. Exenatide and sitagliptin are contraindicated in patients with a known hypersensitivity reaction to the drug.^1,3 Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.² There are no contraindications listed for saxagliptin.⁴

TABLE

Dosing recommendations^1-4

Case 1

During your discussion with this building contractor, you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options. You begin to discuss the need to self-inject the GLP-1 agonist, when he interrupts you and tells you that he does not want to hear anything about insulin or other medications that would require him to self-inject, because his work environment and schedule would make this impossible.

While his feelings are understandable, open communication with this patient can do much to allay his concerns. Although concerns about injecting outside the home are common with insulin, the need for this with a GLP-1 agonist is unlikely because of the twice-daily exenatide and once-daily liraglutide dosing schedules and the lack of need to intensely monitor blood glucose levels. However, if the patient eats breakfast at work or doesn’t eat breakfast at all, this may become an issue with exenatide because of the need to eat within 60 minutes of taking a dose.

Concerns about self-injecting also can be addressed by showing patients the pen injection device and its small-gauge needle and instructing them in its use. Having a patient self-inject the first dose in the office can relieve much anxiety. Patients often comment about how easy and painless it is to inject themselves. One caution, however, is that if a patient self-injects a dose of exenatide in the office, he or she must be reminded of the need to eat within the next hour.

Talking about risks

Case 3

During your discussion with this 68-year-old woman about modifying her therapy, you include the GLP-1 agonists and DPP-4 inhibitors as treatment options. She replies, “Yes, I’ve seen information about them at my job at the library. They can cause cancer, can’t they?”

This comment highlights the importance of talking openly with patients to help them make good decisions about their health. Discussions often focus on the anticipated benefits of medications, but as we know, there are risks associated with every medication choice. Initially discussing risks with this patient could avoid having her return to the office angry with you for not warning her before she began taking the medication.

In this situation, as part of your discussion about liraglutide, you could refer her to the manufacturer’s Web site for information about the Risk Evaluation and Mitigation Strategy (REMS) program for liraglutide, sitagliptin, and saxagliptin. You also could provide her with the patient medication guide included with the program. REMS programs have been implemented for several glucose-lowering medications, since implementation of the REMS program by the US Food and Drug Administration (FDA) in 2007; these include exenatide, liraglutide, pioglitazone with or without glimepiride, rosiglitazone with or without glimepiride, and sitagliptin with or without metformin. Medication guides and other information are available online from the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

Medication cost

Case 3

You continue your discussion with this 68-year-old part-time librarian about the benefits and risks of insulin, a thiazolidinedione, and a glinide, as well as a GLP-1 agonist and a DPP-4 inhibitor. Suddenly she asks you how much these medications cost.

The cost of health care in general and medications in particular continue to dominate discussions. This is especially true for medications that have arrived on the market more recently, including the GLP-1 agonists and the DPP-4 inhibitors, which range in cost from about $7 to $14 per day.^9-12 These agents, however, may be covered by health insurance, so cost to the patient may be limited to copays. The lower risk of hypoglycemia observed with the GLP-1 agonists and DPP-4 inhibitors compared with some other glucose-lowering therapies may make it possible to perform self-monitoring of blood glucose less frequently, but this is an individual patient issue.

Although it may be difficult or uncomfortable to talk about the costs of treatment, it has a great impact on medication adherence and overall treatment satisfaction. In this case, in addition to discussing insurance coverage and what she can afford, you should also talk with the patient about ways the cost of her medications might be reduced.

While no generic formulations are available for exenatide, liraglutide, saxagliptin, or sitagliptin, each manufacturer offers a prescription assistance program. Patients should also be encouraged to check manufacturers’ Web sites for available coupons or discount programs.

With this patient, you also might talk about how different medications can affect total cost of her diabetes treatment differently. Limited retrospective analyses suggest that compared with glimepiride, liraglutide reduces the total cost of care, including care for ocular events and neuropathy leading to amputation.¹³ Other studies indicate that the overall cost of care with exenatide is lower than with insulin glargine,¹⁴ including care for hypoglycemia-related events.¹⁵

Summary

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Introduction

The GLP-1 agonists and DPP-4 inhibitors have important benefits beyond lowering glycosylated hemoglobin, fasting plasma glucose, and postprandial glucose. Although an important treatment goal for type 2 diabetes mellitus (T2DM) is to reduce the risk of other diabetes-related diseases, eg, cardiovascular disease, many glucose-lowering agents cause weight gain, thereby adding to the burgeoning problem of obesity and related long-term consequences, as shown in our 3 case studies. In addition, cardiovascular risks associated with thiazolidinediones have become a major concern.

Side effects and their impact on patient tolerability are also important considerations when selecting and titrating therapy. Concerns about hypoglycemia can affect patient adherence to a medication regimen and a patient’s willingness to continue and intensify therapy, especially with insulin and sulfonylureas.^1-3 As seen in Cases 1 (metformin-related diarrhea) and 2 (pioglitazone-related edema), patient adherence and willingness to continue therapy can be jeopardized by medication-related side effects.

Given these issues, the use of glucose-lowering medications that reduce related risk factors and have a favorable safety profile is advantageous. The GLP-1 agonists and DPP-4 inhibitors are desirable options, based on these considerations.

Reducing risk

The importance of weight

It is well recognized that weight gain is a major risk factor for T2DM and other disorders. It is also clear that concerns about weight gain adversely affect a patient’s willingness to begin treatment with glucose-lowering medications such as thiazolidinediones (TZDs), insulin, and sulfonylureas.^1-3 The other side of the story is probably less appreciated—that is, weight loss can be a significant motivating factor for patients with T2DM that, in our experience, can improve adherence to lifestyle intervention and a medication regimen. In fact, improved quality of life, as assessed by physical and emotional domains, has been reported as a result of liraglutide-associated weight loss.⁴ In addition, multidimensional assessment of patient satisfaction generally has shown similar improvement with liraglutide 1.2 mg once daily and sitagliptin 100 mg once daily, and significantly greater improvement with liraglutide 1.8 mg once daily.⁵ Consequently, the ability of GLP-1 agonists to promote weight loss in most patients and of DPP-4 inhibitors to be weight neutral offers important benefits. Weight is an issue in all 3 of our patient cases, especially in Cases 1 and 2, where the patients’ body mass indices (BMIs) are ≥30 kg/m².

Either as monotherapy or when added to glucose-lowering therapy, twice-daily exenatide or once-daily liraglutide generally promotes a 1 kg to 4 kg weight loss.^4,6-11 The addition of exenatide or liraglutide to metformin, a sulfonylurea, or both resulted in a mean 2.9 kg weight loss with exenatide and a 3.2 kg loss with liraglutide after 26 weeks.¹² Patients who continued liraglutide for an additional 14 weeks lost an additional 0.4 kg, while patients switched from exenatide to liraglutide lost an additional 0.9 kg.¹³ The amount of weight lost is greater with a higher baseline BMI.^14,15 It is important to note, however, that 16% of patients did not experience any weight loss,¹⁴ possibly because no specific caloric restriction was required.^14,16 Slight increases to slight decreases in weight have been observed in clinical trials with sitagliptin and saxagliptin.^17-23 Comparison of liraglutide with sitagliptin showed a mean weight loss of 2.9 kg and 3.4 kg for liraglutide 1.2 mg and 1.8 mg once daily, respectively, over 26 weeks and a 1.0 kg weight loss with sitagliptin 100 mg once daily.⁵ Analysis of a large cohort database that followed patients for up to 1 year showed that patients treated with exenatide lost a mean of 3.0 kg, while patients treated with sitagliptin lost 1.1 kg and those treated with insulin gained 0.6 kg.²⁴ Accordingly, the DPP-4 inhibitors are considered weight neutral.

The reason for the difference between GLP-1 agonists and DPP-4 inhibitors with respect to weight remains unclear, but may result from the direct action of GLP-1 agonists on the GLP-1 receptor compared to the indirect action of DPP-4 inhibitors, which slow the clearance of endogenous GLP-1.²⁵ This may explain the ability of GLP-1 agonists—but not DPP-4 inhibitors—to promote satiety and reduce caloric intake.^26,27 In a crossover comparison of exenatide with sitagliptin, caloric intake during a standardized meal decreased with exenatide (–134 kcal) and increased with sitagliptin (+130 kcal) (P=.0227).¹⁶

The possibility that the nausea associated with GLP-1 agonists but not DPP-4 inhibitors is the reason for the difference in weight effects has been investigated. Analyses have shown, however, that the weight loss observed with GLP-1 agonists is independent of nausea.^4,10,28 For example, in a study by Garber et al,⁴ there was no difference in the amount of weight lost among patients who experienced liraglutide-associated nausea for >7 days, for 1 to 7 days, or not at all. The finding that nausea generally resolved within the first few weeks of liraglutide treatment, while weight loss was maintained over the 52 weeks of the trial, provides further evidence that nausea is not the cause of weight loss (FIGURE 1).⁴ Similar long-term weight loss has been observed with exenatide: weight loss was achieved through 30 weeks (–3.0 kg; P<.05 vs baseline) of double-blind treatment and maintained during an additional 52 weeks of open-label treatment (–5.3 kg; P<.05 vs baseline).²⁹

FIGURE 1 Change in body weight (kg) over 52 weeks with liraglutide 1.2 mg and 1.8 mg vs glimepiride 8.0 mg⁴

cardiovascular benefits

The effects of incretin therapy on markers of cardiovascular disease have been assessed in several clinical trials (TABLE 1).^{4,8-12,17,22,30,31} In general, these trials demonstrate small but significant reductions in systolic blood pressure (1 to 7 mm Hg) with the GLP-1 agonists; diastolic blood pressure, however, is not significantly affected.^4,8-12,30,31 There are insufficient data regarding the DPP-4 inhibitors.^17,22

Effects on the lipid profile also have been investigated,^{4,5,8-12,17,22,30,31} but differences among the agents are difficult to assess because of different baseline lipid levels and the limited number of direct comparative studies. In general, clinical studies show that low-density lipoprotein (LDL) cholesterol is reduced by 1 to 17 mg/dL with the GLP-1 agonists and increased by 3 to 9 mg/dL with the DPP-4 inhibitors. Changes in high-density lipoprotein (HDL) cholesterol are generally small for both GLP-1 agonists and DPP-4 inhibitors, ranging from an increase of 5 mg/dL to a decrease of 2 mg/dL. The greatest change in the lipid profile is in the triglyceride level, with a reduction of 12 to 40 mg/dL with the GLP-1 agonists, while the triglyceride changes observed with the DPP-4 inhibitors range from a reduction of 35 mg/dL to an increase of 16 mg/dL.

Two studies have directly compared the effects on the lipid profile of 2 incretin agents over 26 weeks. In the first study, exenatide and liraglutide showed similar changes in LDL cholesterol (–7 vs –8 mg/dL, respectively) and HDL cholesterol (–1 vs –1 mg/dL, respectively) levels, but liraglutide showed a significantly greater reduction in triglyceride levels than exenatide (–36 vs –20 mg/dL, respectively; P=.0485).¹² The second study compared liraglutide 1.2 mg and 1.8 mg once daily and sitagliptin 100 mg once daily.⁵ LDL cholesterol increased by 1 mg/dL in both liraglutide groups and by 2 mg/dL in the sitagliptin group, while there was no change in HDL cholesterol with either dose of liraglutide or sitagliptin. The triglyceride level decreased by 17 mg/dL in the liraglutide 1.2 mg group, 38 mg/dL in the liraglutide 1.8 mg group, and 35 mg/dL in the sitagliptin group. None of the differences between either liraglutide group and sitagliptin were statistically significant.

Effects on the lipid profile appear to be durable. Klonoff et al showed that the effects of exenatide on the lipid profile were sustained over 3.5 years of follow-up (in a 30-week randomized, double-blind trial followed by a 3-year open-label extension).¹⁴ In patients younger than 65 years, changes from baseline were as follows: total cholesterol, –10 mg/dL (P=.0056); LDL cholesterol, –11 mg/dL (P=.0012); HDL cholesterol, +8 mg/dL (P<.0001); and triglycerides, –44 mg/dL (P=.0042). Similar changes were observed in those 65 years and older.

The cardiovascular benefits of incretin therapy may extend beyond blood pressure and the lipid profile. An exploratory subanalysis of a randomized controlled trial with liraglutide showed a significant decrease in plasminogen activator inhibitor-1, an inflammatory biomarker, and B-type natriuretic peptide, a marker of left ventricular dysfunction.³² No significant effect on high-sensitivity C-reactive protein, interleukin-6, or tumor necrosis factor-α was observed.

While not appropriate as primary therapy, the effect of the GLP-1 agonists on blood pressure and of the GLP-1 agonists and DPP-4 inhibitors on the lipid profile could be an added benefit for all patients with T2DM because of the strong association between T2DM and cardiovascular disease. This can be seen in all 3 of our cases: Case 1 (hypertriglyceridemia), Case 2 (essential hypertension), and Case 3 (peripheral arterial disease).

TABLE 1

Selected studies with GLP-1 agonists and DPP-4 inhibitors assessing cardiovascular end points^{4,8-12,17,22,30,31}

Favorable safety profile

Overview

In general, GLP-1 agonists and DPP-4 inhibitors are well tolerated. Because of concerns about hypoglycemia with glucose-lowering agents, signs and symptoms of hypoglycemia have been closely monitored in clinical trials. The low incidence and mild to moderate severity of hypoglycemia are important attributes of the GLP-1 agonists and DPP-4 inhibitors.

Other than hypoglycemia, the most common adverse reaction reported in ≥5% of patients and more commonly than with placebo are shown in TABLE 2.^33-36 Other medication-specific side effects are seen infrequently but bear mentioning. An increased international normalized ratio, sometimes with bleeding, has been noted with combined use of exenatide and warfarin.³³ Immune-related events (eg, urticaria) have been reported with exenatide³³ and have been observed to occur more frequently with liraglutide than with comparator agents.³⁴ Peripheral edema is more common when a thiazolidinedione is administered with saxagliptin than with placebo.³⁶

While experience with GLP-1 agonists and DPP-4 inhibitors indicates that they have favorable safety profiles, some concerns have surfaced with 1 or more of these agents during clinical trials or from postmarketing reports. These include gastrointestinal side effects (principally nausea), acute pancreatitis, and hypersensitivity reactions. In addition, new standards recently adopted by the US Food and Drug Administration (FDA) are requiring further investigation of several issues for newly approved glucose-lowering drugs and those in development. These issues are discussed next.

TABLE 2

Most common side effects^a of the GLP-1 agonists and DPP-4 inhibitors^33-36

Hypoglycemia

In contrast to other glucose-lowering drugs that stimulate insulin secretion, incretin-based therapies have a glucose-dependent mechanism of action that minimizes the risk of hypoglycemia. Preclinical investigation showed that GLP-1 acts on islet α-cells to strongly inhibit postprandial glucagon secretion.^37,38 These observations were subsequently supported by early clinical investigations showing that administration of GLP-1 to healthy volunteers and people with T2DM augmented insulin secretion and decreased glucagon secretion in a glucose-dependent manner.^39,40 Similar effects were also observed with a DPP-4 inhibitor.²⁵ At the same time, GLP-1 has been shown not to suppress glucagon secretion at a plasma glucose level <65 mg/dL.⁴¹ This mechanism is believed to maintain the counterregulatory hormone response that serves to prevent hypoglycemia.

Accordingly, severe hypoglycemia has not been observed in monotherapy trials of exenatide,^6,30 liraglutide,^4,42 sitagliptin,^17,19 or saxagliptin.²¹ Mild to mod erate hypoglycemia has been observed in 4% to 9% of patients treated with exenatide monotherapy^6,30 and 0% to 12% of patients treated with liraglutide monotherapy^4,42; by comparison, the incidence was 24% in patients treated with glimepiride monotherapy.⁴ Mild to moderate hypoglycemia has been found to be less frequent with sitagliptin and saxagliptin. In monotherapy and combination studies, 0% to 4% of patients treated with sitagliptin and 0% to 2% administered placebo experienced mild to moderate hypoglycemia.^17,18,43-45 Mild to moderate hypoglycemia has not been observed in patients treated with saxagliptin monotherapy at doses of 2.5 mg to 40 mg.²¹ When saxagliptin was added to metformin, hypoglycemia was reported by 5.7% of patients compared with 5.0% of patients who added placebo to metformin.⁴⁶

It is important to note that the incidence of mild to moderate hypoglycemia is increased in patients treated concomitantly with a GLP-1 agonist or DPP-4 inhibitor and a sulfonylurea. In 1 trial, 14% to 36% of patients treated with a combination of exenatide and a maximally effective dose of a sulfonylurea (glimepiride, glipizide, glyburide, chlorpropamide, tolazamide) reported mild to moderate hypoglycemia compared with 3% of those administered a placebo and a sulfonylurea.⁴⁷ A trial involving the addition of saxagliptin to glyburide found that 13% to 15% of patients treated daily with glyburide 7.5 mg and saxagliptin 2.5 mg or 5 mg reported mild to moderate hypoglycemia compared with 10% of patients treated with glyburide 10 mg to 15 mg alone.²³ For this reason, consideration should be given to reducing the dose of a sulfonylurea or secretagogue when combined with a GLP-1 agonist or DPP-4 inhibitor.^33-35

Because of their low incidence of hypoglycemia, the American Diabetes Association/European Association for the Study of Diabetes panel recommends GLP-1 agonists for patients for whom hypoglycemia is particularly undesirable, such as those who perform manual labor, drive a vehicle for a living, or operate heavy or dangerous machinery.⁴⁸ In fact, the US Federal Aviation Administration lists the GLP-1 agonists and DPP-4 inhibitors as allowable medications for aviators.⁴⁹ This recommendation is particularly appropriate for the building contractor in Case 1.

Nausea

Transient nausea is the most common GI side effect associated with GLP-1 agonists, occurring in up to 57% of patients treated with exenatide in clinical trials^6,30 and 29% treated with liraglutide.⁴ Diarrhea and vomiting also occurred, although rates were similar to rates with initiation of metformin. The high occurrence of transient nausea in these trials prompted investigators to implement a dose escalation strategy^33,34 (see “Patient education and self-management” article in this supplement). Since adoption of this strategy, a comparative trial of exenatide and liraglutide found that nausea occurred in 28% of patients treated with exenatide and in 26% treated with liraglutide.¹² Nausea was generally transient, so that by Week 6 of therapy, 16% of patients treated with exenatide and 8% with liraglutide experienced nausea,¹² and by Week 26, 9% of exenatide-treated patients and 3% of liraglutide-treated patients continued to experience nausea.¹²

Of patients treated with the DPP-4 inhibitor sitagliptin, nausea has occurred in 1% to 2% com pared with 1% of those receiving placebo.^18,43 In patients treated with saxagliptin, nausea has occurred in 2% to 4% compared with 8% of those receiving placebo.²¹

Acute pancreatitis

Acute pancreatitis has been observed in clinical trials and/or identified in postmarketing reports involving exenatide,³³ liraglutide,³⁴ and sitagliptin.³⁶ Determining whether there is a true association of these agents with acute pancreatitis or this is just coincidental has been difficult, partly because patients with T2DM have a 2.8-fold greater risk of pancreatitis compared with nondiabetic subjects.⁵⁰ A review of health insurance transactions with 1-year follow-up (June 2005 through June 2008) involving approximately 88,000 patients (exenatide, n=27,996; sitagliptin, n=16,276; approximately equal numbers of matched comparators) showed that the relative risk of pancreatitis was statistically the same with exenatide, sitagliptin, metformin, and glyburide.⁵¹

In its ongoing review, the FDA has required the manufacturers of exenatide and sitagliptin to modify product labeling regarding the risk of acute pancreatitis and to conduct additional animal studies.⁵² As part of the January 2010 approval of liraglutide, the FDA required the manufacturer to perform mechanistic studies in animals and to conduct an epidemiologic evaluation using a large insurance claims database.⁵² In the interim, exenatide, liraglutide, and sitagliptin should be used cautiously,^34,35 if at all, in people with a history of pancreatitis.³³ Furthermore, educating patients about the signs and symptoms of pancreatitis, including how to differentiate it from the transient nausea commonly observed with these agents, is critical. Patients at risk of developing acute pancreatitis (eg, due to excess alcohol consumption or gallstones) should not receive an incretin-based therapy. Therapy should be changed if a patient develops acute pancreatitis while using a GLP-1 agonist or DPP-4 inhibitor.

Hypersensitivity

Hypersensitivity reactions have been experienced by some patients treated with exenatide,³³ liraglutide,³⁴ sitagliptin,³⁵ or saxagliptin.³⁶ Postmarketing reports have described serious hypersensitivity reactions (anaphylaxis, angioedema) with exenatide.³³ In clinical trials, 0.8% of patients treated with liraglutide and 0.4% treated with comparator agents experienced an immunogenic reaction, generally urticaria.³⁴ With sitagliptin, anaphylaxis, angioedema, or exfoliative dermatitis, including Stevens-Johnson syndrome, typically occurs within 3 months but may occur after the first dose. Hypersensitivity events, such as urticaria and facial edema, were shown to occur in 1.5% of patients treated with saxagliptin 2.5 mg, 1.5% of those treated with saxagliptin 5 mg, and 0.4% of those receiving placebo. None of the events necessitated hospitalization or were life-threatening.³⁶ If a hypersensitivity reaction occurs, treatment should be discontinued.

additional safety investigations

The FDA has required additional safety investigations for liraglutide, saxagliptin, and sitagliptin. These investigations will address observations made during preclinical and clinical evaluation, as well as the new standards adopted by the agency in December 2008 regarding cardiovascular safety for all new glucose-lowering agents.⁵³

Thyroid cancer

Rodent studies have suggested that liraglutide in doses many times those utilized in humans is associated with an increased risk of preneoplastic lesions that can lead to C-cell hyperplasia and medullary thyroid cancer, which occurs rarely in humans.⁵² Thyroid tumors have also been observed in rodents administered native GLP-1⁵⁴ or exenatide³³ but not sitagliptin³⁵ or saxagliptin.³⁶ A slight increase in calcitonin, a marker for medullary cancer, which remained well within the normal reference range, was observed during Phase 3 clinical trials in patients treated with liraglutide compared with controls. There were no cases of medullary thyroid cancer in the liraglutide trials, including one that involved more than 2 years of follow-up. Based on this evidence, the FDA determined that the risk of thyroid cancer among humans treated with liraglutide is low. The effects may be due to species-specific differences in GLP-1 receptor expression and action in the thyroid, as 20 months of liraglutide at >60 times the human exposure level did not lead to C-cell hyperplasia in monkeys.⁵⁵ The FDA has required the manufacturer to conduct additional animal studies, however, and to establish a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years.⁵² In addition, the prescribing information for liraglutide carries a boxed warning describing the rodent findings and the risk of medullary thyroid cancer.³⁴ Liraglutide is also contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.³⁴

Cardiovascular risk

The clinical evaluation of liraglutide and saxagliptin was completed prior to December 2008, when the FDA adopted the new cardiovascular safety standards for new antidiabetic drugs. Analyses of data from Phase 2 and 3 clinical trials indicate that liraglutide meets the new 2008 standard for ruling out an unacceptable increase in cardiovascular risk.⁵² While the overall rates of cardiovascular events were low in preapproval clinical trials, the more stringent criteria for postapproval evaluations were not met. Consequently, the FDA has required postapproval clinical trials of cardiovascular safety with liraglutide⁵² and saxagliptin.

Summary

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Introduction

The GLP-1 agonists and DPP-4 inhibitors have important benefits beyond lowering glycosylated hemoglobin, fasting plasma glucose, and postprandial glucose. Although an important treatment goal for type 2 diabetes mellitus (T2DM) is to reduce the risk of other diabetes-related diseases, eg, cardiovascular disease, many glucose-lowering agents cause weight gain, thereby adding to the burgeoning problem of obesity and related long-term consequences, as shown in our 3 case studies. In addition, cardiovascular risks associated with thiazolidinediones have become a major concern.

Side effects and their impact on patient tolerability are also important considerations when selecting and titrating therapy. Concerns about hypoglycemia can affect patient adherence to a medication regimen and a patient’s willingness to continue and intensify therapy, especially with insulin and sulfonylureas.^1-3 As seen in Cases 1 (metformin-related diarrhea) and 2 (pioglitazone-related edema), patient adherence and willingness to continue therapy can be jeopardized by medication-related side effects.

Given these issues, the use of glucose-lowering medications that reduce related risk factors and have a favorable safety profile is advantageous. The GLP-1 agonists and DPP-4 inhibitors are desirable options, based on these considerations.

Reducing risk

The importance of weight

It is well recognized that weight gain is a major risk factor for T2DM and other disorders. It is also clear that concerns about weight gain adversely affect a patient’s willingness to begin treatment with glucose-lowering medications such as thiazolidinediones (TZDs), insulin, and sulfonylureas.^1-3 The other side of the story is probably less appreciated—that is, weight loss can be a significant motivating factor for patients with T2DM that, in our experience, can improve adherence to lifestyle intervention and a medication regimen. In fact, improved quality of life, as assessed by physical and emotional domains, has been reported as a result of liraglutide-associated weight loss.⁴ In addition, multidimensional assessment of patient satisfaction generally has shown similar improvement with liraglutide 1.2 mg once daily and sitagliptin 100 mg once daily, and significantly greater improvement with liraglutide 1.8 mg once daily.⁵ Consequently, the ability of GLP-1 agonists to promote weight loss in most patients and of DPP-4 inhibitors to be weight neutral offers important benefits. Weight is an issue in all 3 of our patient cases, especially in Cases 1 and 2, where the patients’ body mass indices (BMIs) are ≥30 kg/m².

Either as monotherapy or when added to glucose-lowering therapy, twice-daily exenatide or once-daily liraglutide generally promotes a 1 kg to 4 kg weight loss.^4,6-11 The addition of exenatide or liraglutide to metformin, a sulfonylurea, or both resulted in a mean 2.9 kg weight loss with exenatide and a 3.2 kg loss with liraglutide after 26 weeks.¹² Patients who continued liraglutide for an additional 14 weeks lost an additional 0.4 kg, while patients switched from exenatide to liraglutide lost an additional 0.9 kg.¹³ The amount of weight lost is greater with a higher baseline BMI.^14,15 It is important to note, however, that 16% of patients did not experience any weight loss,¹⁴ possibly because no specific caloric restriction was required.^14,16 Slight increases to slight decreases in weight have been observed in clinical trials with sitagliptin and saxagliptin.^17-23 Comparison of liraglutide with sitagliptin showed a mean weight loss of 2.9 kg and 3.4 kg for liraglutide 1.2 mg and 1.8 mg once daily, respectively, over 26 weeks and a 1.0 kg weight loss with sitagliptin 100 mg once daily.⁵ Analysis of a large cohort database that followed patients for up to 1 year showed that patients treated with exenatide lost a mean of 3.0 kg, while patients treated with sitagliptin lost 1.1 kg and those treated with insulin gained 0.6 kg.²⁴ Accordingly, the DPP-4 inhibitors are considered weight neutral.

The reason for the difference between GLP-1 agonists and DPP-4 inhibitors with respect to weight remains unclear, but may result from the direct action of GLP-1 agonists on the GLP-1 receptor compared to the indirect action of DPP-4 inhibitors, which slow the clearance of endogenous GLP-1.²⁵ This may explain the ability of GLP-1 agonists—but not DPP-4 inhibitors—to promote satiety and reduce caloric intake.^26,27 In a crossover comparison of exenatide with sitagliptin, caloric intake during a standardized meal decreased with exenatide (–134 kcal) and increased with sitagliptin (+130 kcal) (P=.0227).¹⁶

The possibility that the nausea associated with GLP-1 agonists but not DPP-4 inhibitors is the reason for the difference in weight effects has been investigated. Analyses have shown, however, that the weight loss observed with GLP-1 agonists is independent of nausea.^4,10,28 For example, in a study by Garber et al,⁴ there was no difference in the amount of weight lost among patients who experienced liraglutide-associated nausea for >7 days, for 1 to 7 days, or not at all. The finding that nausea generally resolved within the first few weeks of liraglutide treatment, while weight loss was maintained over the 52 weeks of the trial, provides further evidence that nausea is not the cause of weight loss (FIGURE 1).⁴ Similar long-term weight loss has been observed with exenatide: weight loss was achieved through 30 weeks (–3.0 kg; P<.05 vs baseline) of double-blind treatment and maintained during an additional 52 weeks of open-label treatment (–5.3 kg; P<.05 vs baseline).²⁹

FIGURE 1 Change in body weight (kg) over 52 weeks with liraglutide 1.2 mg and 1.8 mg vs glimepiride 8.0 mg⁴

cardiovascular benefits

The effects of incretin therapy on markers of cardiovascular disease have been assessed in several clinical trials (TABLE 1).^{4,8-12,17,22,30,31} In general, these trials demonstrate small but significant reductions in systolic blood pressure (1 to 7 mm Hg) with the GLP-1 agonists; diastolic blood pressure, however, is not significantly affected.^4,8-12,30,31 There are insufficient data regarding the DPP-4 inhibitors.^17,22

Effects on the lipid profile also have been investigated,^{4,5,8-12,17,22,30,31} but differences among the agents are difficult to assess because of different baseline lipid levels and the limited number of direct comparative studies. In general, clinical studies show that low-density lipoprotein (LDL) cholesterol is reduced by 1 to 17 mg/dL with the GLP-1 agonists and increased by 3 to 9 mg/dL with the DPP-4 inhibitors. Changes in high-density lipoprotein (HDL) cholesterol are generally small for both GLP-1 agonists and DPP-4 inhibitors, ranging from an increase of 5 mg/dL to a decrease of 2 mg/dL. The greatest change in the lipid profile is in the triglyceride level, with a reduction of 12 to 40 mg/dL with the GLP-1 agonists, while the triglyceride changes observed with the DPP-4 inhibitors range from a reduction of 35 mg/dL to an increase of 16 mg/dL.

Two studies have directly compared the effects on the lipid profile of 2 incretin agents over 26 weeks. In the first study, exenatide and liraglutide showed similar changes in LDL cholesterol (–7 vs –8 mg/dL, respectively) and HDL cholesterol (–1 vs –1 mg/dL, respectively) levels, but liraglutide showed a significantly greater reduction in triglyceride levels than exenatide (–36 vs –20 mg/dL, respectively; P=.0485).¹² The second study compared liraglutide 1.2 mg and 1.8 mg once daily and sitagliptin 100 mg once daily.⁵ LDL cholesterol increased by 1 mg/dL in both liraglutide groups and by 2 mg/dL in the sitagliptin group, while there was no change in HDL cholesterol with either dose of liraglutide or sitagliptin. The triglyceride level decreased by 17 mg/dL in the liraglutide 1.2 mg group, 38 mg/dL in the liraglutide 1.8 mg group, and 35 mg/dL in the sitagliptin group. None of the differences between either liraglutide group and sitagliptin were statistically significant.

Effects on the lipid profile appear to be durable. Klonoff et al showed that the effects of exenatide on the lipid profile were sustained over 3.5 years of follow-up (in a 30-week randomized, double-blind trial followed by a 3-year open-label extension).¹⁴ In patients younger than 65 years, changes from baseline were as follows: total cholesterol, –10 mg/dL (P=.0056); LDL cholesterol, –11 mg/dL (P=.0012); HDL cholesterol, +8 mg/dL (P<.0001); and triglycerides, –44 mg/dL (P=.0042). Similar changes were observed in those 65 years and older.

The cardiovascular benefits of incretin therapy may extend beyond blood pressure and the lipid profile. An exploratory subanalysis of a randomized controlled trial with liraglutide showed a significant decrease in plasminogen activator inhibitor-1, an inflammatory biomarker, and B-type natriuretic peptide, a marker of left ventricular dysfunction.³² No significant effect on high-sensitivity C-reactive protein, interleukin-6, or tumor necrosis factor-α was observed.

While not appropriate as primary therapy, the effect of the GLP-1 agonists on blood pressure and of the GLP-1 agonists and DPP-4 inhibitors on the lipid profile could be an added benefit for all patients with T2DM because of the strong association between T2DM and cardiovascular disease. This can be seen in all 3 of our cases: Case 1 (hypertriglyceridemia), Case 2 (essential hypertension), and Case 3 (peripheral arterial disease).

TABLE 1

Selected studies with GLP-1 agonists and DPP-4 inhibitors assessing cardiovascular end points^{4,8-12,17,22,30,31}

Favorable safety profile

Overview

In general, GLP-1 agonists and DPP-4 inhibitors are well tolerated. Because of concerns about hypoglycemia with glucose-lowering agents, signs and symptoms of hypoglycemia have been closely monitored in clinical trials. The low incidence and mild to moderate severity of hypoglycemia are important attributes of the GLP-1 agonists and DPP-4 inhibitors.

Other than hypoglycemia, the most common adverse reaction reported in ≥5% of patients and more commonly than with placebo are shown in TABLE 2.^33-36 Other medication-specific side effects are seen infrequently but bear mentioning. An increased international normalized ratio, sometimes with bleeding, has been noted with combined use of exenatide and warfarin.³³ Immune-related events (eg, urticaria) have been reported with exenatide³³ and have been observed to occur more frequently with liraglutide than with comparator agents.³⁴ Peripheral edema is more common when a thiazolidinedione is administered with saxagliptin than with placebo.³⁶

While experience with GLP-1 agonists and DPP-4 inhibitors indicates that they have favorable safety profiles, some concerns have surfaced with 1 or more of these agents during clinical trials or from postmarketing reports. These include gastrointestinal side effects (principally nausea), acute pancreatitis, and hypersensitivity reactions. In addition, new standards recently adopted by the US Food and Drug Administration (FDA) are requiring further investigation of several issues for newly approved glucose-lowering drugs and those in development. These issues are discussed next.

TABLE 2

Most common side effects^a of the GLP-1 agonists and DPP-4 inhibitors^33-36

Hypoglycemia

In contrast to other glucose-lowering drugs that stimulate insulin secretion, incretin-based therapies have a glucose-dependent mechanism of action that minimizes the risk of hypoglycemia. Preclinical investigation showed that GLP-1 acts on islet α-cells to strongly inhibit postprandial glucagon secretion.^37,38 These observations were subsequently supported by early clinical investigations showing that administration of GLP-1 to healthy volunteers and people with T2DM augmented insulin secretion and decreased glucagon secretion in a glucose-dependent manner.^39,40 Similar effects were also observed with a DPP-4 inhibitor.²⁵ At the same time, GLP-1 has been shown not to suppress glucagon secretion at a plasma glucose level <65 mg/dL.⁴¹ This mechanism is believed to maintain the counterregulatory hormone response that serves to prevent hypoglycemia.

Accordingly, severe hypoglycemia has not been observed in monotherapy trials of exenatide,^6,30 liraglutide,^4,42 sitagliptin,^17,19 or saxagliptin.²¹ Mild to mod erate hypoglycemia has been observed in 4% to 9% of patients treated with exenatide monotherapy^6,30 and 0% to 12% of patients treated with liraglutide monotherapy^4,42; by comparison, the incidence was 24% in patients treated with glimepiride monotherapy.⁴ Mild to moderate hypoglycemia has been found to be less frequent with sitagliptin and saxagliptin. In monotherapy and combination studies, 0% to 4% of patients treated with sitagliptin and 0% to 2% administered placebo experienced mild to moderate hypoglycemia.^17,18,43-45 Mild to moderate hypoglycemia has not been observed in patients treated with saxagliptin monotherapy at doses of 2.5 mg to 40 mg.²¹ When saxagliptin was added to metformin, hypoglycemia was reported by 5.7% of patients compared with 5.0% of patients who added placebo to metformin.⁴⁶

It is important to note that the incidence of mild to moderate hypoglycemia is increased in patients treated concomitantly with a GLP-1 agonist or DPP-4 inhibitor and a sulfonylurea. In 1 trial, 14% to 36% of patients treated with a combination of exenatide and a maximally effective dose of a sulfonylurea (glimepiride, glipizide, glyburide, chlorpropamide, tolazamide) reported mild to moderate hypoglycemia compared with 3% of those administered a placebo and a sulfonylurea.⁴⁷ A trial involving the addition of saxagliptin to glyburide found that 13% to 15% of patients treated daily with glyburide 7.5 mg and saxagliptin 2.5 mg or 5 mg reported mild to moderate hypoglycemia compared with 10% of patients treated with glyburide 10 mg to 15 mg alone.²³ For this reason, consideration should be given to reducing the dose of a sulfonylurea or secretagogue when combined with a GLP-1 agonist or DPP-4 inhibitor.^33-35

Because of their low incidence of hypoglycemia, the American Diabetes Association/European Association for the Study of Diabetes panel recommends GLP-1 agonists for patients for whom hypoglycemia is particularly undesirable, such as those who perform manual labor, drive a vehicle for a living, or operate heavy or dangerous machinery.⁴⁸ In fact, the US Federal Aviation Administration lists the GLP-1 agonists and DPP-4 inhibitors as allowable medications for aviators.⁴⁹ This recommendation is particularly appropriate for the building contractor in Case 1.

Nausea

Transient nausea is the most common GI side effect associated with GLP-1 agonists, occurring in up to 57% of patients treated with exenatide in clinical trials^6,30 and 29% treated with liraglutide.⁴ Diarrhea and vomiting also occurred, although rates were similar to rates with initiation of metformin. The high occurrence of transient nausea in these trials prompted investigators to implement a dose escalation strategy^33,34 (see “Patient education and self-management” article in this supplement). Since adoption of this strategy, a comparative trial of exenatide and liraglutide found that nausea occurred in 28% of patients treated with exenatide and in 26% treated with liraglutide.¹² Nausea was generally transient, so that by Week 6 of therapy, 16% of patients treated with exenatide and 8% with liraglutide experienced nausea,¹² and by Week 26, 9% of exenatide-treated patients and 3% of liraglutide-treated patients continued to experience nausea.¹²

Of patients treated with the DPP-4 inhibitor sitagliptin, nausea has occurred in 1% to 2% com pared with 1% of those receiving placebo.^18,43 In patients treated with saxagliptin, nausea has occurred in 2% to 4% compared with 8% of those receiving placebo.²¹

Acute pancreatitis

Acute pancreatitis has been observed in clinical trials and/or identified in postmarketing reports involving exenatide,³³ liraglutide,³⁴ and sitagliptin.³⁶ Determining whether there is a true association of these agents with acute pancreatitis or this is just coincidental has been difficult, partly because patients with T2DM have a 2.8-fold greater risk of pancreatitis compared with nondiabetic subjects.⁵⁰ A review of health insurance transactions with 1-year follow-up (June 2005 through June 2008) involving approximately 88,000 patients (exenatide, n=27,996; sitagliptin, n=16,276; approximately equal numbers of matched comparators) showed that the relative risk of pancreatitis was statistically the same with exenatide, sitagliptin, metformin, and glyburide.⁵¹

In its ongoing review, the FDA has required the manufacturers of exenatide and sitagliptin to modify product labeling regarding the risk of acute pancreatitis and to conduct additional animal studies.⁵² As part of the January 2010 approval of liraglutide, the FDA required the manufacturer to perform mechanistic studies in animals and to conduct an epidemiologic evaluation using a large insurance claims database.⁵² In the interim, exenatide, liraglutide, and sitagliptin should be used cautiously,^34,35 if at all, in people with a history of pancreatitis.³³ Furthermore, educating patients about the signs and symptoms of pancreatitis, including how to differentiate it from the transient nausea commonly observed with these agents, is critical. Patients at risk of developing acute pancreatitis (eg, due to excess alcohol consumption or gallstones) should not receive an incretin-based therapy. Therapy should be changed if a patient develops acute pancreatitis while using a GLP-1 agonist or DPP-4 inhibitor.

Hypersensitivity

Hypersensitivity reactions have been experienced by some patients treated with exenatide,³³ liraglutide,³⁴ sitagliptin,³⁵ or saxagliptin.³⁶ Postmarketing reports have described serious hypersensitivity reactions (anaphylaxis, angioedema) with exenatide.³³ In clinical trials, 0.8% of patients treated with liraglutide and 0.4% treated with comparator agents experienced an immunogenic reaction, generally urticaria.³⁴ With sitagliptin, anaphylaxis, angioedema, or exfoliative dermatitis, including Stevens-Johnson syndrome, typically occurs within 3 months but may occur after the first dose. Hypersensitivity events, such as urticaria and facial edema, were shown to occur in 1.5% of patients treated with saxagliptin 2.5 mg, 1.5% of those treated with saxagliptin 5 mg, and 0.4% of those receiving placebo. None of the events necessitated hospitalization or were life-threatening.³⁶ If a hypersensitivity reaction occurs, treatment should be discontinued.

additional safety investigations

The FDA has required additional safety investigations for liraglutide, saxagliptin, and sitagliptin. These investigations will address observations made during preclinical and clinical evaluation, as well as the new standards adopted by the agency in December 2008 regarding cardiovascular safety for all new glucose-lowering agents.⁵³

Thyroid cancer

Rodent studies have suggested that liraglutide in doses many times those utilized in humans is associated with an increased risk of preneoplastic lesions that can lead to C-cell hyperplasia and medullary thyroid cancer, which occurs rarely in humans.⁵² Thyroid tumors have also been observed in rodents administered native GLP-1⁵⁴ or exenatide³³ but not sitagliptin³⁵ or saxagliptin.³⁶ A slight increase in calcitonin, a marker for medullary cancer, which remained well within the normal reference range, was observed during Phase 3 clinical trials in patients treated with liraglutide compared with controls. There were no cases of medullary thyroid cancer in the liraglutide trials, including one that involved more than 2 years of follow-up. Based on this evidence, the FDA determined that the risk of thyroid cancer among humans treated with liraglutide is low. The effects may be due to species-specific differences in GLP-1 receptor expression and action in the thyroid, as 20 months of liraglutide at >60 times the human exposure level did not lead to C-cell hyperplasia in monkeys.⁵⁵ The FDA has required the manufacturer to conduct additional animal studies, however, and to establish a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years.⁵² In addition, the prescribing information for liraglutide carries a boxed warning describing the rodent findings and the risk of medullary thyroid cancer.³⁴ Liraglutide is also contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.³⁴

Cardiovascular risk

The clinical evaluation of liraglutide and saxagliptin was completed prior to December 2008, when the FDA adopted the new cardiovascular safety standards for new antidiabetic drugs. Analyses of data from Phase 2 and 3 clinical trials indicate that liraglutide meets the new 2008 standard for ruling out an unacceptable increase in cardiovascular risk.⁵² While the overall rates of cardiovascular events were low in preapproval clinical trials, the more stringent criteria for postapproval evaluations were not met. Consequently, the FDA has required postapproval clinical trials of cardiovascular safety with liraglutide⁵² and saxagliptin.

Summary

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Introduction

The GLP-1 agonists and DPP-4 inhibitors have important benefits beyond lowering glycosylated hemoglobin, fasting plasma glucose, and postprandial glucose. Although an important treatment goal for type 2 diabetes mellitus (T2DM) is to reduce the risk of other diabetes-related diseases, eg, cardiovascular disease, many glucose-lowering agents cause weight gain, thereby adding to the burgeoning problem of obesity and related long-term consequences, as shown in our 3 case studies. In addition, cardiovascular risks associated with thiazolidinediones have become a major concern.

Side effects and their impact on patient tolerability are also important considerations when selecting and titrating therapy. Concerns about hypoglycemia can affect patient adherence to a medication regimen and a patient’s willingness to continue and intensify therapy, especially with insulin and sulfonylureas.^1-3 As seen in Cases 1 (metformin-related diarrhea) and 2 (pioglitazone-related edema), patient adherence and willingness to continue therapy can be jeopardized by medication-related side effects.

Given these issues, the use of glucose-lowering medications that reduce related risk factors and have a favorable safety profile is advantageous. The GLP-1 agonists and DPP-4 inhibitors are desirable options, based on these considerations.

Reducing risk

The importance of weight

It is well recognized that weight gain is a major risk factor for T2DM and other disorders. It is also clear that concerns about weight gain adversely affect a patient’s willingness to begin treatment with glucose-lowering medications such as thiazolidinediones (TZDs), insulin, and sulfonylureas.^1-3 The other side of the story is probably less appreciated—that is, weight loss can be a significant motivating factor for patients with T2DM that, in our experience, can improve adherence to lifestyle intervention and a medication regimen. In fact, improved quality of life, as assessed by physical and emotional domains, has been reported as a result of liraglutide-associated weight loss.⁴ In addition, multidimensional assessment of patient satisfaction generally has shown similar improvement with liraglutide 1.2 mg once daily and sitagliptin 100 mg once daily, and significantly greater improvement with liraglutide 1.8 mg once daily.⁵ Consequently, the ability of GLP-1 agonists to promote weight loss in most patients and of DPP-4 inhibitors to be weight neutral offers important benefits. Weight is an issue in all 3 of our patient cases, especially in Cases 1 and 2, where the patients’ body mass indices (BMIs) are ≥30 kg/m².

Either as monotherapy or when added to glucose-lowering therapy, twice-daily exenatide or once-daily liraglutide generally promotes a 1 kg to 4 kg weight loss.^4,6-11 The addition of exenatide or liraglutide to metformin, a sulfonylurea, or both resulted in a mean 2.9 kg weight loss with exenatide and a 3.2 kg loss with liraglutide after 26 weeks.¹² Patients who continued liraglutide for an additional 14 weeks lost an additional 0.4 kg, while patients switched from exenatide to liraglutide lost an additional 0.9 kg.¹³ The amount of weight lost is greater with a higher baseline BMI.^14,15 It is important to note, however, that 16% of patients did not experience any weight loss,¹⁴ possibly because no specific caloric restriction was required.^14,16 Slight increases to slight decreases in weight have been observed in clinical trials with sitagliptin and saxagliptin.^17-23 Comparison of liraglutide with sitagliptin showed a mean weight loss of 2.9 kg and 3.4 kg for liraglutide 1.2 mg and 1.8 mg once daily, respectively, over 26 weeks and a 1.0 kg weight loss with sitagliptin 100 mg once daily.⁵ Analysis of a large cohort database that followed patients for up to 1 year showed that patients treated with exenatide lost a mean of 3.0 kg, while patients treated with sitagliptin lost 1.1 kg and those treated with insulin gained 0.6 kg.²⁴ Accordingly, the DPP-4 inhibitors are considered weight neutral.

The reason for the difference between GLP-1 agonists and DPP-4 inhibitors with respect to weight remains unclear, but may result from the direct action of GLP-1 agonists on the GLP-1 receptor compared to the indirect action of DPP-4 inhibitors, which slow the clearance of endogenous GLP-1.²⁵ This may explain the ability of GLP-1 agonists—but not DPP-4 inhibitors—to promote satiety and reduce caloric intake.^26,27 In a crossover comparison of exenatide with sitagliptin, caloric intake during a standardized meal decreased with exenatide (–134 kcal) and increased with sitagliptin (+130 kcal) (P=.0227).¹⁶

The possibility that the nausea associated with GLP-1 agonists but not DPP-4 inhibitors is the reason for the difference in weight effects has been investigated. Analyses have shown, however, that the weight loss observed with GLP-1 agonists is independent of nausea.^4,10,28 For example, in a study by Garber et al,⁴ there was no difference in the amount of weight lost among patients who experienced liraglutide-associated nausea for >7 days, for 1 to 7 days, or not at all. The finding that nausea generally resolved within the first few weeks of liraglutide treatment, while weight loss was maintained over the 52 weeks of the trial, provides further evidence that nausea is not the cause of weight loss (FIGURE 1).⁴ Similar long-term weight loss has been observed with exenatide: weight loss was achieved through 30 weeks (–3.0 kg; P<.05 vs baseline) of double-blind treatment and maintained during an additional 52 weeks of open-label treatment (–5.3 kg; P<.05 vs baseline).²⁹

FIGURE 1 Change in body weight (kg) over 52 weeks with liraglutide 1.2 mg and 1.8 mg vs glimepiride 8.0 mg⁴

cardiovascular benefits

The effects of incretin therapy on markers of cardiovascular disease have been assessed in several clinical trials (TABLE 1).^{4,8-12,17,22,30,31} In general, these trials demonstrate small but significant reductions in systolic blood pressure (1 to 7 mm Hg) with the GLP-1 agonists; diastolic blood pressure, however, is not significantly affected.^4,8-12,30,31 There are insufficient data regarding the DPP-4 inhibitors.^17,22

Effects on the lipid profile also have been investigated,^{4,5,8-12,17,22,30,31} but differences among the agents are difficult to assess because of different baseline lipid levels and the limited number of direct comparative studies. In general, clinical studies show that low-density lipoprotein (LDL) cholesterol is reduced by 1 to 17 mg/dL with the GLP-1 agonists and increased by 3 to 9 mg/dL with the DPP-4 inhibitors. Changes in high-density lipoprotein (HDL) cholesterol are generally small for both GLP-1 agonists and DPP-4 inhibitors, ranging from an increase of 5 mg/dL to a decrease of 2 mg/dL. The greatest change in the lipid profile is in the triglyceride level, with a reduction of 12 to 40 mg/dL with the GLP-1 agonists, while the triglyceride changes observed with the DPP-4 inhibitors range from a reduction of 35 mg/dL to an increase of 16 mg/dL.

Two studies have directly compared the effects on the lipid profile of 2 incretin agents over 26 weeks. In the first study, exenatide and liraglutide showed similar changes in LDL cholesterol (–7 vs –8 mg/dL, respectively) and HDL cholesterol (–1 vs –1 mg/dL, respectively) levels, but liraglutide showed a significantly greater reduction in triglyceride levels than exenatide (–36 vs –20 mg/dL, respectively; P=.0485).¹² The second study compared liraglutide 1.2 mg and 1.8 mg once daily and sitagliptin 100 mg once daily.⁵ LDL cholesterol increased by 1 mg/dL in both liraglutide groups and by 2 mg/dL in the sitagliptin group, while there was no change in HDL cholesterol with either dose of liraglutide or sitagliptin. The triglyceride level decreased by 17 mg/dL in the liraglutide 1.2 mg group, 38 mg/dL in the liraglutide 1.8 mg group, and 35 mg/dL in the sitagliptin group. None of the differences between either liraglutide group and sitagliptin were statistically significant.

Effects on the lipid profile appear to be durable. Klonoff et al showed that the effects of exenatide on the lipid profile were sustained over 3.5 years of follow-up (in a 30-week randomized, double-blind trial followed by a 3-year open-label extension).¹⁴ In patients younger than 65 years, changes from baseline were as follows: total cholesterol, –10 mg/dL (P=.0056); LDL cholesterol, –11 mg/dL (P=.0012); HDL cholesterol, +8 mg/dL (P<.0001); and triglycerides, –44 mg/dL (P=.0042). Similar changes were observed in those 65 years and older.

The cardiovascular benefits of incretin therapy may extend beyond blood pressure and the lipid profile. An exploratory subanalysis of a randomized controlled trial with liraglutide showed a significant decrease in plasminogen activator inhibitor-1, an inflammatory biomarker, and B-type natriuretic peptide, a marker of left ventricular dysfunction.³² No significant effect on high-sensitivity C-reactive protein, interleukin-6, or tumor necrosis factor-α was observed.

While not appropriate as primary therapy, the effect of the GLP-1 agonists on blood pressure and of the GLP-1 agonists and DPP-4 inhibitors on the lipid profile could be an added benefit for all patients with T2DM because of the strong association between T2DM and cardiovascular disease. This can be seen in all 3 of our cases: Case 1 (hypertriglyceridemia), Case 2 (essential hypertension), and Case 3 (peripheral arterial disease).

TABLE 1

Selected studies with GLP-1 agonists and DPP-4 inhibitors assessing cardiovascular end points^{4,8-12,17,22,30,31}

Favorable safety profile

Overview

In general, GLP-1 agonists and DPP-4 inhibitors are well tolerated. Because of concerns about hypoglycemia with glucose-lowering agents, signs and symptoms of hypoglycemia have been closely monitored in clinical trials. The low incidence and mild to moderate severity of hypoglycemia are important attributes of the GLP-1 agonists and DPP-4 inhibitors.

Other than hypoglycemia, the most common adverse reaction reported in ≥5% of patients and more commonly than with placebo are shown in TABLE 2.^33-36 Other medication-specific side effects are seen infrequently but bear mentioning. An increased international normalized ratio, sometimes with bleeding, has been noted with combined use of exenatide and warfarin.³³ Immune-related events (eg, urticaria) have been reported with exenatide³³ and have been observed to occur more frequently with liraglutide than with comparator agents.³⁴ Peripheral edema is more common when a thiazolidinedione is administered with saxagliptin than with placebo.³⁶

While experience with GLP-1 agonists and DPP-4 inhibitors indicates that they have favorable safety profiles, some concerns have surfaced with 1 or more of these agents during clinical trials or from postmarketing reports. These include gastrointestinal side effects (principally nausea), acute pancreatitis, and hypersensitivity reactions. In addition, new standards recently adopted by the US Food and Drug Administration (FDA) are requiring further investigation of several issues for newly approved glucose-lowering drugs and those in development. These issues are discussed next.

TABLE 2

Most common side effects^a of the GLP-1 agonists and DPP-4 inhibitors^33-36

Hypoglycemia

In contrast to other glucose-lowering drugs that stimulate insulin secretion, incretin-based therapies have a glucose-dependent mechanism of action that minimizes the risk of hypoglycemia. Preclinical investigation showed that GLP-1 acts on islet α-cells to strongly inhibit postprandial glucagon secretion.^37,38 These observations were subsequently supported by early clinical investigations showing that administration of GLP-1 to healthy volunteers and people with T2DM augmented insulin secretion and decreased glucagon secretion in a glucose-dependent manner.^39,40 Similar effects were also observed with a DPP-4 inhibitor.²⁵ At the same time, GLP-1 has been shown not to suppress glucagon secretion at a plasma glucose level <65 mg/dL.⁴¹ This mechanism is believed to maintain the counterregulatory hormone response that serves to prevent hypoglycemia.

Accordingly, severe hypoglycemia has not been observed in monotherapy trials of exenatide,^6,30 liraglutide,^4,42 sitagliptin,^17,19 or saxagliptin.²¹ Mild to mod erate hypoglycemia has been observed in 4% to 9% of patients treated with exenatide monotherapy^6,30 and 0% to 12% of patients treated with liraglutide monotherapy^4,42; by comparison, the incidence was 24% in patients treated with glimepiride monotherapy.⁴ Mild to moderate hypoglycemia has been found to be less frequent with sitagliptin and saxagliptin. In monotherapy and combination studies, 0% to 4% of patients treated with sitagliptin and 0% to 2% administered placebo experienced mild to moderate hypoglycemia.^17,18,43-45 Mild to moderate hypoglycemia has not been observed in patients treated with saxagliptin monotherapy at doses of 2.5 mg to 40 mg.²¹ When saxagliptin was added to metformin, hypoglycemia was reported by 5.7% of patients compared with 5.0% of patients who added placebo to metformin.⁴⁶

It is important to note that the incidence of mild to moderate hypoglycemia is increased in patients treated concomitantly with a GLP-1 agonist or DPP-4 inhibitor and a sulfonylurea. In 1 trial, 14% to 36% of patients treated with a combination of exenatide and a maximally effective dose of a sulfonylurea (glimepiride, glipizide, glyburide, chlorpropamide, tolazamide) reported mild to moderate hypoglycemia compared with 3% of those administered a placebo and a sulfonylurea.⁴⁷ A trial involving the addition of saxagliptin to glyburide found that 13% to 15% of patients treated daily with glyburide 7.5 mg and saxagliptin 2.5 mg or 5 mg reported mild to moderate hypoglycemia compared with 10% of patients treated with glyburide 10 mg to 15 mg alone.²³ For this reason, consideration should be given to reducing the dose of a sulfonylurea or secretagogue when combined with a GLP-1 agonist or DPP-4 inhibitor.^33-35

Because of their low incidence of hypoglycemia, the American Diabetes Association/European Association for the Study of Diabetes panel recommends GLP-1 agonists for patients for whom hypoglycemia is particularly undesirable, such as those who perform manual labor, drive a vehicle for a living, or operate heavy or dangerous machinery.⁴⁸ In fact, the US Federal Aviation Administration lists the GLP-1 agonists and DPP-4 inhibitors as allowable medications for aviators.⁴⁹ This recommendation is particularly appropriate for the building contractor in Case 1.

Nausea

Transient nausea is the most common GI side effect associated with GLP-1 agonists, occurring in up to 57% of patients treated with exenatide in clinical trials^6,30 and 29% treated with liraglutide.⁴ Diarrhea and vomiting also occurred, although rates were similar to rates with initiation of metformin. The high occurrence of transient nausea in these trials prompted investigators to implement a dose escalation strategy^33,34 (see “Patient education and self-management” article in this supplement). Since adoption of this strategy, a comparative trial of exenatide and liraglutide found that nausea occurred in 28% of patients treated with exenatide and in 26% treated with liraglutide.¹² Nausea was generally transient, so that by Week 6 of therapy, 16% of patients treated with exenatide and 8% with liraglutide experienced nausea,¹² and by Week 26, 9% of exenatide-treated patients and 3% of liraglutide-treated patients continued to experience nausea.¹²

Of patients treated with the DPP-4 inhibitor sitagliptin, nausea has occurred in 1% to 2% com pared with 1% of those receiving placebo.^18,43 In patients treated with saxagliptin, nausea has occurred in 2% to 4% compared with 8% of those receiving placebo.²¹

Acute pancreatitis

Acute pancreatitis has been observed in clinical trials and/or identified in postmarketing reports involving exenatide,³³ liraglutide,³⁴ and sitagliptin.³⁶ Determining whether there is a true association of these agents with acute pancreatitis or this is just coincidental has been difficult, partly because patients with T2DM have a 2.8-fold greater risk of pancreatitis compared with nondiabetic subjects.⁵⁰ A review of health insurance transactions with 1-year follow-up (June 2005 through June 2008) involving approximately 88,000 patients (exenatide, n=27,996; sitagliptin, n=16,276; approximately equal numbers of matched comparators) showed that the relative risk of pancreatitis was statistically the same with exenatide, sitagliptin, metformin, and glyburide.⁵¹

In its ongoing review, the FDA has required the manufacturers of exenatide and sitagliptin to modify product labeling regarding the risk of acute pancreatitis and to conduct additional animal studies.⁵² As part of the January 2010 approval of liraglutide, the FDA required the manufacturer to perform mechanistic studies in animals and to conduct an epidemiologic evaluation using a large insurance claims database.⁵² In the interim, exenatide, liraglutide, and sitagliptin should be used cautiously,^34,35 if at all, in people with a history of pancreatitis.³³ Furthermore, educating patients about the signs and symptoms of pancreatitis, including how to differentiate it from the transient nausea commonly observed with these agents, is critical. Patients at risk of developing acute pancreatitis (eg, due to excess alcohol consumption or gallstones) should not receive an incretin-based therapy. Therapy should be changed if a patient develops acute pancreatitis while using a GLP-1 agonist or DPP-4 inhibitor.

Hypersensitivity

Hypersensitivity reactions have been experienced by some patients treated with exenatide,³³ liraglutide,³⁴ sitagliptin,³⁵ or saxagliptin.³⁶ Postmarketing reports have described serious hypersensitivity reactions (anaphylaxis, angioedema) with exenatide.³³ In clinical trials, 0.8% of patients treated with liraglutide and 0.4% treated with comparator agents experienced an immunogenic reaction, generally urticaria.³⁴ With sitagliptin, anaphylaxis, angioedema, or exfoliative dermatitis, including Stevens-Johnson syndrome, typically occurs within 3 months but may occur after the first dose. Hypersensitivity events, such as urticaria and facial edema, were shown to occur in 1.5% of patients treated with saxagliptin 2.5 mg, 1.5% of those treated with saxagliptin 5 mg, and 0.4% of those receiving placebo. None of the events necessitated hospitalization or were life-threatening.³⁶ If a hypersensitivity reaction occurs, treatment should be discontinued.

additional safety investigations

The FDA has required additional safety investigations for liraglutide, saxagliptin, and sitagliptin. These investigations will address observations made during preclinical and clinical evaluation, as well as the new standards adopted by the agency in December 2008 regarding cardiovascular safety for all new glucose-lowering agents.⁵³

Thyroid cancer

Rodent studies have suggested that liraglutide in doses many times those utilized in humans is associated with an increased risk of preneoplastic lesions that can lead to C-cell hyperplasia and medullary thyroid cancer, which occurs rarely in humans.⁵² Thyroid tumors have also been observed in rodents administered native GLP-1⁵⁴ or exenatide³³ but not sitagliptin³⁵ or saxagliptin.³⁶ A slight increase in calcitonin, a marker for medullary cancer, which remained well within the normal reference range, was observed during Phase 3 clinical trials in patients treated with liraglutide compared with controls. There were no cases of medullary thyroid cancer in the liraglutide trials, including one that involved more than 2 years of follow-up. Based on this evidence, the FDA determined that the risk of thyroid cancer among humans treated with liraglutide is low. The effects may be due to species-specific differences in GLP-1 receptor expression and action in the thyroid, as 20 months of liraglutide at >60 times the human exposure level did not lead to C-cell hyperplasia in monkeys.⁵⁵ The FDA has required the manufacturer to conduct additional animal studies, however, and to establish a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years.⁵² In addition, the prescribing information for liraglutide carries a boxed warning describing the rodent findings and the risk of medullary thyroid cancer.³⁴ Liraglutide is also contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2.³⁴

Cardiovascular risk

The clinical evaluation of liraglutide and saxagliptin was completed prior to December 2008, when the FDA adopted the new cardiovascular safety standards for new antidiabetic drugs. Analyses of data from Phase 2 and 3 clinical trials indicate that liraglutide meets the new 2008 standard for ruling out an unacceptable increase in cardiovascular risk.⁵² While the overall rates of cardiovascular events were low in preapproval clinical trials, the more stringent criteria for postapproval evaluations were not met. Consequently, the FDA has required postapproval clinical trials of cardiovascular safety with liraglutide⁵² and saxagliptin.

Summary

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.