Introduction

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 The “treat to failure” approach has been replaced by a “treat to target” approach, with the purpose of quickly achieving the A1C goal of 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.