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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Targeting the Pathophysiology of Type 2 Diabetes: The Emerging Role of Incretin-Based Therapies


GOAL
To provide cardiologists, internists, and endocrinologists with up-to-date information on the treatment and management of patients with type 2 diabetes.

TARGET AUDIENCE
This activity is designed for cardiologists, internists, and endocrinologists. No prerequisites required.

LEARNING OBJECTIVES
At the conclusion of this activity, the participant should be able to:

  • Summarize challenges to meeting glycemic targets in patients with type 2 diabetes.
  • Identify the mode of action of the incretin-based therapies in the treatment of type 2 diabetes.
  • Discuss the clinical effectiveness and safety of incretin-based therapies for the treatment of type 2 diabetes.
  • Evaluate the appropriate clinical application of incretin-based therapies, including proper patient selection based on clinical need and current glycemic control.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide CME for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 2 hours. After reading this monograph, participants may receive credit by completing the CE test, evaluation, and receiving a score of 70% or higher.

Release date: December 31, 2008. Expiration date: December 31, 2010.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This activity is supported by an educational grant from Novo Nordisk, Inc.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of The Johns Hopkins University School of Medicine to require the disclosure of the existence of any relevant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Course Director and Participating Faculty reported the following:

COURSE DIRECTOR

Annabelle Rodriguez, MD
Associate Professor of Medicine
Director, Diabetes Management Service
The Johns Hopkins Bayview Medical Center
The Johns Hopkins University School of Medicine
Division of Endocrinology
Baltimore, Maryland
Dr Rodriguez reports having no relevant financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Vivian A. Fonseca, MD, FRCP
Professor of Medicine
Tullis-Tulane Alumni Chair in Diabetes
Chief of the Section of Endocrinology
Tulane University Medical Center
New Orleans, Louisiana
Dr Fonseca reports receiving research support grants (to Tulane) from the American Diabetes Association, AstraZeneca, Daiichi-Sankyo, Inc, Eli Lilly and Company, GlaxoSmithKline, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc, Pfizer Inc, Sanofi-Aventis, and Takeda Pharmaceuticals North America, Inc; and receiving honoraria for consulting and lectures from Daiichi-Sankyo, Inc, Eli Lilly and Company, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc, Pfizer Inc, Sanofi-Aventis, and Takeda Pharmaceuticals North America, Inc.

Jack Leahy, MD
Professor of Medicine
Endocrinology, Diabetes and Metabolism
University of Vermont
Burlington, Vermont
Dr Leahy reports serving as a consultant for Merck & Co, Inc, Sankyo, and Sanofi-Aventis; and holding stock in Schering-Plough Corporation.

Richard E. Pratley, MD
Professor of Medicine
Director of the Diabetes and Metabolism
Translational Medicine Unit
University of Vermont College of Medicine
Burlington, Vermont
Dr Pratley reports receiving grants/research support from Eli Lilly and Company, GlaxoSmithKline, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc, Roche Pharmaceuticals, Sanofi-Aventis, and Takeda Pharmaceuticals North America, Inc; serving as a consultant for and receiving honoraria from GlaxoSmithKline, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc, and Takeda Pharmaceuticals North America, Inc; holding stock in Novartis Pharmaceuticals Corporation; and serving on the speakers' bureau for Merck & Co, Inc, Novo Nordisk, Inc, and Takeda Pharmaceuticals North America, Inc.

Notice: The audience is advised that an article in this CME activity contains reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Pratley—glucagon-like peptide-1 for the treatment of type 2 diabetes mellitus

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Targeting the Pathophysiology of Type 2 Diabetes: The Emerging Role of Incretin-Based Therapies
Annabelle Rodriguez, MD*

Cardiometabolic disease, characterized by type 2 diabetes and excessive cardiovascular risk, has become an important challenge to healthcare providers in the United States as an increasing number of individuals present with this complex pathophysiology. The American Diabetes Association estimated that 20.8 million Americans suffered from diabetes in 2007, and 41 million exhibited symptoms consistent with prediabetes. The US economic impact of the disease is staggering, as evidenced by the $174 billion in total costs stemming from diabetes in 2007.1 Diabetes also exerts an important impact on health worldwide, especially in developing countries that are in the process of introducing diets and lifestyles from the developed world.2

The important public health impact of type 2 diabetes and cardiometabolic disease has been matched by a wealth of research into the pathophysiology that underlies these conditions. As a result, researchers are now recognizing a potential shift from the traditional paradigm of type 2 diabetes as a sole problem of insulin resistance. Although insulin resistance, as a result of excessive body weight, is a critical factor in type 2 diabetes, it is now widely accepted that type 2 diabetes is often part of a more complex process that ultimately results in premature atherosclerosis and heightened cardiovascular risk.3 In addition, many individuals exhibit insulin resistance without developing type 2 diabetes, thus it is clear that a more complex pathophysiology underlies the disease.

Despite the availability of established oral antidiabetic agents (OADs) to address glucose control in individuals with type 2 diabetes who fail to control the disease with lifestyle modifications, many individuals do not achieve recommended treatment goals. The most recent data from the National Health and Nutrition Examination Survey found that only 50% of patients with diabetes achieved a target glycosylated hemoglobin (A1c) of less than 7%, only 36% achieved the recommended low-density lipoprotein cholesterol target of less than 100 mg/dL, and only 40% achieved a blood pressure of less than 130/80 mm Hg.4 The inadequate control of A1c, in addition to the dyslipidemia and hypertension that directly contributes to cardiovascular risk, signals the need for new treatment options in type 2 diabetes.

The role that β-cell function plays in effective glucose control is now receiving attention as a therapeutic target because it is known that β cells have a direct impact on glucose control, and individuals with type 2 diabetes exhibit a steady decline in β-cell function. In addition, individuals with early diabetes exhibit a compensation in β-cell mass and function to maintain normal glucose levels, but this process gradually declines with long-standing disease.5 It is now thought that certain individuals may have an increased risk of developing type 2 diabetes due to a genetic predisposition to β cells that are more susceptible to decline when challenged by the factors that result in insulin resistance.

As researchers have increasingly focused on the role of β cells in type 2 diabetes, new agents have come to the forefront that have the potential to offer a targeted response to this aspect of type 2 diabetes pathophysiology. For example, glucagon-like peptide-1 (GLP-1) is released in response to food intake and causes a glucose-dependent release of insulin from β cells, in addition to a suppression of glucagon production, resulting in decreased glucose output from the liver.6,7 Exenatide, an incretin mimetic that exerts a physiologic effect similar to GLP-1, has been introduced to augment insulin release from β cells and improve postprandial glucagon suppression. Exenatide has been shown to improve glucose control without a risk of hypoglycemia, when used as monotherapy.8 Unlike traditional OADs, exenatide does not result in weight gain, and has actually been associated with weight loss,9-11 including sustained weight loss after long-term administration.12 Exenatide and liraglutide, another GLP-1 mimetic that is currently under development, have been shown to improve cardiovascular risk in patients with type 2 diabetes, including improvements in blood pressure,13-19 as well as improvements in lipid profile.11 Both exenatide and liraglutide are delivered by subcutaneous injection.

The development of dipeptidyl peptidase-4 (DPP-4) inhibitors has also resulted from increased interest in the role that β-cell function plays in type 2 diabetes. These agents increase the levels of circulating GLP-1 by blocking DPP-4, the enzyme responsible for GLP-1 breakdown. These agents include sitagliptin, which has been approved by the US Food and Drug Administration, in addition to investigational agents, such as vildagliptin, saxagliptin, and alogliptin. Preliminary research suggests that sitagliptin may offer a synergistic effect on glucose control when administered with metformin in type 2 diabetes.20 All of the DPP-4 inhibitors are oral agents and have demonstrated a weight-neutral effect in individuals with type 2 diabetes.

This issue of Johns Hopkins Advanced Studies in Medicine includes proceedings from an educational symposium held during the 2008 Cardiometabolic Health Congress in Boston, Massachusetts, on October 16, 2008. Jack Leahy, MD, Professor of Medicine from the University of Vermont in Burlington, Vermont, opened the symposium with a review of current type 2 diabetes treatment goals; the limitations of current agents in helping patients and clinicians achieve these goals; the role of β cells and incretins, including GLP-1, in the pathophysiology of type 2 diabetes; and new agents that address these targets. Vivian A. Fonseca, MD, FRCP, Tullis-Tulane Alumni Chair in Diabetes and Chief of the Section of Endocrinology at Tulane University Medical Center in New Orleans, Louisiana, provided a detailed review of incretin mimetic agents and DPP-4 inhibitors, including those in development, that have the potential to improve type 2 diabetes care while avoiding some of the unwanted effects of traditional OADs. Finally, Richard E. Pratley, MD, Professor of Medicine and Director of the Diabetes and Metabolism Translational Medicine Unit at the University of Vermont College of Medicine, completed the symposium with a discussion of the evolving theories behind type 2 diabetes management, and emerging research that supports a role for GLP-1 in appetite and satiety, weight loss, the modification of cardiovascular risk, and neuroprotection. As cardiovascular risk has come to the forefront of type 2 diabetes management, clinicians are considering these new targets and moving beyond a sole focus on tight glucose control. This monograph should help clinicians recognize the role that incretins play in the pathophysiology of type 2 diabetes and the potential for targeted therapies in patient management.

REFERENCES

1. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care. 2008;31:596-615.
2. Diabetes Atlas Committee. Diabetes Atlas 2nd Edition. Brussels, Belgium: International Diabetes Federation; 2003.
3. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28:629-636.
4. Resnick HE, Foster GL, Bardsley J, Ratner RE. Achievement of American Diabetes Association clinical practice recommendations among US adults with diabetes, 1999-2002: the National Health and Nutrition Examination Survey. Diabetes Care. 2006;29:531-537.
5. Kendall DM, Bergenstal RM. 2005. International Diabetes Center, Minneapolis, MN.
6. Larsson H, Holst JJ, AhrŽn B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand. 1997; 160:413-422.
7. Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239-1246.
8. Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741-744.
9. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-2635.
10. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
11. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286.
12. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091.
13. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-na•ve patients with type 2 diabetes: a randomized double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30:1448-1460.
14. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care. 2008. [Epub ahead of print].
15. Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analog, added to a sulfonylurea (SU) offers significantly better glycemic control and favorable weight change compared with rosiglitazone and SU combination therapy in subjects with type 2 diabetes. Diabetes. 2008; 57(suppl 1):A4 (abstract 13-OR).
16. Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267.
17. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 mono): a randomized, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2008. [Epub ahead of print].
18. Zinman B, Gerich J, Buse J, et al. Effect of the GLP-1 analogue liraglutide on glycaemic control and weight reduction in patients on metformin and rosiglitazone: a randomized double-blind placebo-controlled trial. Diabetologia. 2008; 57(suppl 1):5359 (abstract 898).
19. Russell-Jones D, Vaag A, Schmitz O, et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes. Diabetes. 2008;57(suppl 1):A159 (abstract 536-P).
20. Migoya EM, Miller J, Larson P, et al. Sitagliptin, a selective DPP-4 inhibitor, and metformin have complementary effects to increase active GLP-1 concentrations. Diabetes. 2007; 56(supp 1):0286-OR.

*Associate Professor of Medicine, Director, Diabetes Management Service, The Johns Hopkins Bayview Medical Center, The Johns Hopkins University School of Medicine, Division of Endocrinology, Baltimore, Maryland.

Address correspondence to: Annabelle Rodriguez, MD, Associate Professor of Medicine, Director, Diabetes Management Service, The Johns Hopkins Bayview Medical Center, Endocrinology MFL 4300 Center Tower, 5200 Eastern Avenue, Baltimore, MD 21224. E-mail: arodrig5@jhmi.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his or her article and all its contents.





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