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


Type 2 Diabetes Management in the 21st Century: The Role of Incretin-Based Therapies


GOAL
To provide diabetologists and endocrinologists with the latest information on incretin hormones in the treatment of type 2 diabetes.

TARGET AUDIENCE
This activity is designed for diabetologists and endocrinologists. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, participants should be able to:

  • Discuss the use and physiologic effect of incretin hormones in the treatment of type 2 diabetes.
  • Assess the developing therapeutic strategies that are based on the glucagon-like peptide-1 pathway and the impact of this new treatment.
  • Examine clinical trial results and evidence of the effectiveness of incretin hormone therapies.
  • Distinguish the potential benefits and risks associated with incretin-based therapies from the patient’s perspective.

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

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. The estimated time to complete this educational activity: 2 hours.

Release date: December 15, 2005.
Expiration date: December 15, 2007.

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 program is supported by an educational grant from Amylin Pharmaceuticals, Inc and Eli Lilly and Company.

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 significant 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 Program Directors and Participating Faculty reported the following:

PROGRAM DIRECTORS

Josephine M. Egan, MD
Senior Investigator
Chief, Diabetes Section
Laboratory of Clinical Investigation
National Institute on Aging
Intramural Research Program
Baltimore, Maryland
Dr Egan reports having no financial or advisory relationships with corporate organizations related to this activity.

Simeon Margolis, MD, PhD
Professor of Medicine and Biological Chemistry
Division of Endocrinology and Metabolism
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Margolis reports having no financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Lawrence Blonde, MD, FACP, FACE
Director, Ochsner Diabetes Clinical Research Unit
Section on Endocrinology
Diabetes and Metabolic Diseases
Associate Residency Program Director
Department of Internal Medicine
Ochsner Clinic Foundation
New Orleans, Louisiana
Dr Blonde reports receiving grants/research support/honoraria from and serving as a consultant for Amylin Pharmaceuticals, AstraZeneca, Aventis, BD, Bristol-Myers Squibb, Eli Lilly and Company, EMD, GlaxoSmithKline, Merck & Co, Inc, Novo Nordisk, Novartis Pharmaceuticals Corporation, Pfizer Inc, and Sanofi-Aventis; serving as a consultant for and receiving honoraria from Abbott Laboratories, Lifescan, and Merck/Schering-Plough; and receiving honoraria from Takeda Pharmaceuticals of America and Wyeth Pharmaceuticals. Dr Blonde also reports his spouse owning shares of Amylin Pharmaceuticals and Pfizer, Inc in an inherited account that is not part of their community property.

Daniel J. Drucker, MD
Director
Banting and Best Diabetes Centre
University of Toronto
Toronto General Hospital
Toronto, Ontario, Canada
Dr Drucker reports receiving grants/research support from Amylin Pharmaceuticals, Inc, Eli Lilly and Company, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, and Novo Nordisk; and serving as a consultant to Abbott Laboratories, Amylin Pharmaceuticals, Inc, ConjuChem, Eli Lilly and Company, GlaxoSmithKline, Merck & Co, Inc, Novartis Pharmaceuticals Corporation, Pharmaceutical Product Development, Inc, Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Transition Therapeutics Inc, and Triad Group, Inc.

Robert R. Henry, MD
Professor of Medicine
University of California, San Diego
Director, Center for Metabolic Research
Chief, Section of Diabetes, Endocrinology & Metabolism
VA San Diego Healthcare System
San Diego, California
Dr Henry reports serving as a consultant to and receiving honoraria from Amylin Pharmaceuticals, Inc and Eli Lilly and Company; and holding stock in Amylin Pharmaceuticals, Inc.

Deborah Hinnen, ARNP, BC-ADM, CDE, FAAN
Diabetes Nurse Specialist
Mid-America Diabetes Associates
Wichita, Kansas
Ms Hinnen reports serving as a consultant to and on the advisory board for Abbott Laboratories and Eli Lilly and Company; and receiving honoraria from Abbott Laboratories, BioCentric, Eli Lilly and Company, Sanofi- Aventis, and Vox Medical, Inc.

Notice: The audience is advised that articles in this CME activity contain no reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Blonde—CJC-1131, liraglutide, MK-0431, vildagliptin.
Dr Drucker—CJC-1131, albugon, liraglutide, sitagliptin, vildagliptin.

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

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. 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.

Type 2 Diabetes Management in the 21st Century: The Role of Incretin-Based Therapies
Josephine M. Egan, MD,* and Simeon Margolis, MD, PhD†

According to 2005 prevalence estimates issued by the Centers for Disease Control and Prevention, 20.8 million people in the United States (7.0% of the total population) have diabetes. Of that number, most patients—90% to 95% of all diagnosed cases of diabetes—have type 2 diabetes. Type 2 diabetes is often underdiagnosed. The American Diabetes Association estimates that for every diagnosed case, there are 2 more cases of prediabetes that will inexorably go on to diabetes. The cost of diabetes in the United States is staggering, accounting for approximately 16% of all expenditures made for healthcare.

Type 2 diabetes presents as abnormal carbohydrate, lipid, and protein metabolism with insulin resistance and impaired insulin secretion, making it a chronic disease requiring daily management. Several metabolic events occur over a period of years, causing the elevated blood glucose levels to put patients at an increased risk of developing serious diabetes-related complications, such as stroke, heart attack, blindness, kidney failure, and foot and leg amputations. Long-term, prospective studies have shown that near-normal or improved glycemic control may stop or slow the progression of the complications of the disease; data from an epidemiologic analysis of the United Kingdom Prospective Diabetes Study showed that in patients with type 2 diabetes, reduction of hemoglobin A1c (HbA1c) is associated with a marked reduction in the occurrence of complications. Yet, near-normal glycemic control is difficult to attain. Most patients require initiation of pharmacologic therapy, beginning with oral agents as a rule, to achieve better glycemic control.

In spite of many advances made in diabetes care during the past several years, most patients today who have type 2 diabetes are not adequately controlling their blood sugar levels. The American Association of Clinical Endocrinologists collected data on HbA1c levels in more than 157 000 patients with type 2 diabetes in the United States during 2003 and 2004; their report showed that 66% of the individuals studied had HbA1c levels above the American College of Endocrinology target goal of 6.5% or less. If a combination of 2 oral agents fails to provide adequate glycemic control, the current approach is to then begin insulin therapy. Clinicians also continue to stress the nonpharmacologic approaches of diet modification, weight control, and regular exercise.

Because the oral agents currently used to treat type 2 diabetes (ie, sulfonylureas, metformin, peroxisome proliferators-activated receptor-g inhibitors, and a-glucosidase inhibitors) often fail to adequately control glycemia as measured by HbA1c levels, a substantial amount of research has been undertaken to identify ways to help patients who still can produce endogenous insulin and are not yet taking exogenous insulin. Incretins, hormones produced by the gastrointestinal tract in response to nutrient entry that then stimulate insulin secretion, have been 1 such research target. The incretin glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino acid peptide secreted by L cells in the gastrointestinal tract. In people with type 2 diabetes the insulin secretory response to GLP-1 is preserved. This significant observation underlies its therapeutic potential. Studies have shown that GLP-1 stimulates insulin secretion, and in cell culture models and rodent islets, it stimulates b-cell proliferation. GLP-1 is metabolized very rapidly by dipeptidyl peptidase-IV (DPP-IV), thus native GLP-1 is not a satisfactory treatment for type 2 diabetes. Oral DPP-IV inhibitors and incretin mimetics (analogs of GLP-1 and GLP-1 receptor agonists) are currently being developed. Exenatide (exendin-4), a GLP-1 receptor agonist naturally produced in the salivary glands of the Gila monster lizard, was approved by the US Food and Drug Administration (FDA) in April 2005 as an adjunctive therapy to improve glycemic control in patients with type 2 diabetes who also are taking metformin or a sulfonylurea, or a combination of the 2 drugs, and who have not achieved adequate glycemic control.

This issue of Advanced Studies in Medicine covers highlights from a satellite symposium presented at the American Diabetes Association’s 65th Annual Scientific Sessions held June 10-14, 2005, in San Diego, Calif. The symposium featured experts in the field of type 2 diabetes, each having presented information on incretin hormones in the treatment of type 2 diabetes.

In this issue, Robert R. Henry, MD, Veterans Affairs San Diego Healthcare System, San Diego, Calif, discusses information on the physiologic effects of incretin hormones. Dr Henry defines the incretin hormones and describes the history that led to the use of incretin-based therapies. He also discusses the role of GLP-1 in the central regulation of feeding and its effects on b cells. He explains how the effects of GLP-1 on b cells are broken down into 3 categories: acute, to enhance glucose-dependent insulin secretion; subacute, to stimulate transcription of proinsulin and biosynthesis of insulin; and chronic, to stimulate proliferation and neogenesis of b cells from precursor ductal cells and to increase expression of GLUT-2 transporters and glucokinase. He further explains how GLP-1 has been shown to stimulate b-cell replication in a number of model systems.

Daniel J. Drucker, MD, continues the discussion by exploring the therapeutic strategies based on GLP-1 pathways. He describes how GLP-1 directly affects b cells and explains that activated GLP-1 receptors signal a transduction pathway that leads to an increase in insulin biosynthesis and secretion. He further notes that none of the oral agents used for the treatment of diabetes directly activate this pathway. Dr Drucker cites the Zander study and notes its importance for demonstrating that GLP-1 not only stimulates insulin secretion from b cells but also reprograms defective b cells to “reawaken” and become more sensitive to glucose. He offers information on several treatment approaches currently being studied that are based on the activation of GLP-1 receptors on b cells, including exenatide, liraglutide (NN2211), CJC-1131, and albugon.

Lawrence Blonde, MD, FACP, FACE, discusses recent clinical trial results of various GLP-1–based agents. His paper includes a review of results from 2 recent clinical trials of GLP-1 analogs: a 12-week, double-blind, randomized, placebo-controlled trial of liraglutide in patients with type 2 diabetes, in addition to a 12-week, randomized, double-blind, placebo-controlled phase II clinical study of CJC-1131. He also describes results from a 12-week, placebo-controlled study of the oral DPP-IV inhibitor vildagliptin (NVP LAF237) in metformin-treated patients with type 2 diabetes. Dr Blonde’s review concludes by describing the results of several phase II and phase III clinical trials involving the naturally occurring peptide exenatide, including 52-week open-label extensions of each of the 3 phase III trials.

Deborah Hinnen, ARNP, BC-ADM, CDE, FAAN, outlines 2 case studies to illustrate which patients are most likely to benefit from treatment with GLP-based agents. She primarily focuses on exenatide, the first of these GLP-based agents approved by the FDA, and notes that this is a potential therapy option for patients with type 2 diabetes who have not achieved the desired level of glycemic control with metformin or sulfonylurea monotherapy or with a metformin-sulfonylurea combined therapy. Through the vehicle of the case studies, she describes the issues and thought processes behind the decision to treat with a GLP-based agent.

Summaries of 2 posters, 2 oral presentations, and an abstract presented at the American Diabetes Association’s 65th Annual Scientific Sessions also are included in this issue of Advanced Studies in Medicine.

Researchers continue to seek new antidiabetic regimens to better manage this complex condition in its many stages. With so many agents under investigation, clinicians may look forward to an increased pharmacologic armamentarium with which to treat type 2 diabetes.

*Senior Investigator, Chief, Diabetes Section, Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, Baltimore, Maryland.
†Professor of Medicine and Biological Chemistry, Division of Endocrinology & Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address correspondence to: Simeon Margolis, MD, PhD, Division of Endocrinology & Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 336, Baltimore, MD 21205. E-mail smargoli@jhu.edu.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.