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


Diabetic Microvascular Complications: Examining the Underlying Mechanisms and Understanding the Implications for Patient Care


GOAL
To provide endocrinologists, diabetologists, and primary care physicians with up-to-date information on the management and latest therapeutic trends for diabetic microvascular complications.

TARGET AUDIENCE
This activity is designed for endocrinologists, diabetologists, and primary care physicians. 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:

  • Review current theories that explain the etiology of diabetic microvascular complications.
  • Recognize the importance of aggressive glycemic control strategies in preventing diabetic microvascular complications.
  • Explain the theories underlying the pathology for different diabetic microvascular complications and understand the metabolic link between them.
  • Understand the rationale and approach for screening and early detection.
  • Describe the specific pathogenic targets that might attenuate microvascular disease and the current and potential approaches to affecting these pathologies.

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, 2004. Expiration date: December 15, 2006.

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 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 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 DIRECTOR

Christopher D. Saudek, MD
Hugh P. McCormick Family Professor of Endocrinology and Metabolism
Johns Hopkins University School of Medicine
Director, Johns Hopkins Diabetes Center
Program Director, General Clinical Research Center
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Saudek reports serving as a consultant to Eli Lilly and Company, Novartis, Novo Nordisk, and Aventis; and receiving honoraria from Eli Lilly and Company, Novartis, Novo Nordisk, and Aventis.

PARTICIPATING FACULTY

Paul M. Dodson, MD, FRCP, FRCOphth
Consultant Ophthalmic Physician
Departments of Diabetes and Ophthalmology
Undergraduate Centre
Birmingham Heartlands Hospital
Birmingham, UK
Dr Dodson reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Richard Donnelly, MD, PhD, FRCP, FRACP
Professor and Associate Dean
University of Nottingham
Director of Research and Development
Southern Derbyshire Acute Hospitals Trust
The Medical School
Derby, UK
Dr Donnelly reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Solomon Tesfaye, MD, FRCP
Consultant Physician and Diabetologist
Sheffield Teaching Hospitals
Sheffield, UK
Dr Tesfaye reports serving as a consultant and receiving honoraria from Eli Lilly and Company.

Jiten Vora, MA, MD, FRCP
Consultant Physician and Endocrinologist
Royal Liverpool University Hospital
Liverpool, UK
Dr Vora reports having no significant financial or advisory relationships with corporate organizations related to this activity.


Notice: In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. The following faculty members have disclosed that their articles have referenced the following unlabeled/unapproved uses of drugs or devices:

Dr Dodson, Dr Donnelly, Dr Tesfaye, Dr Vora—ruboxistaurin.

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.

Diabetic Microvascular Complications: Examining The Underlying Mechanisms And Understanding The Implications For Patient Care
Christopher D. Saudek, MD*

This issue of Advanced Studies in Medicine features the proceedings of a satellite symposium held in conjunction with the 12th International Congress of Endocrinology (ICE) in Lisbon, Portugal, on August 31, 2004.

The symposium, Diabetic Microvascular Complications: Examining the Underlying Mechanisms and Understanding the Implications for Patient Care, featured a distinguished international faculty with expertise in neuropathy, nephrology, retinopathy, endocrinology, and molecular biology, and a commitment to improving care for all patients with diabetes.

The microvascular complications of diabetes are major contributors to morbidity, mortality, and cost of type 1 and type 2 diabetes mellitus. Damage to the small vessels of the kidney can lead to end-stage renal disease; destruction of the smaller vessels that supply nutrients and oxygen to peripheral nerves contribute to lower-limb amputation; and damage in the microvasculature of the eye is the leading cause of loss of vision in working-age adults.

The manifestations of microvascular disease are so pathognomonic of diabetes mellitus that diabetes itself is defined primarily by that level of hyperglycemia which causes microvascular complications.

The management of diabetes mellitus has improved enormously over the 80+ years since the discovery of insulin. Even in the past 10 years, the options for controlling diabetes have proliferated. Yet the epidemic incidence of diabetes suggests that we will be seeing more, not less, of its ravages. Although we are theoretically in a position to reduce the microvascular complication rates, the currently available approaches are unacceptably difficult on the patient and treating professional alike. We need better tools, more effective and more specifically targeted at the prevention of diabetic complications.

Although primary care physicians and internal medicine physicians are fully qualified to screen for, diagnose, and initiate therapy of diabetes, endocrinologists and diabetologists are often called upon for their expertise in the finer points of controlling diabetes and treating its complications once diagnosed. Endocrinologists and diabetologists also translate basic science and research findings on pathogenesis and metabolic control into clinical practice.

In keeping with the objective of the symposium (ie, to examine the underlying mechanisms of diabetic microvascular complications and understand the implications of these mechanisms for patient care) this issue of Advanced Studies in Medicine focuses on scientific investigations as they relate to clinical intervention, patient care, and prevention.

Dr Paul M. Dodson reviews the pathogenesis of diabetic retinopathy, which results from vessels that leak edematous fluid into the macula or from the formation of new and fragile vessels. He focuses on the role of protein kinase C (PKC), vascular endothelial growth factor (VEGF), growth hormone, and other factors involved in the development of diabetic retinopathy and on several new therapies directed at these targets.

In particular, he discusses the results of clinical trials evaluating the PKC b inhibitor ruboxistaurin, in addition to smaller studies evaluating VEGF aptamers that block VEGF at the cellular level, growth factor antagonists, and intravitreal steroids. He also emphasizes the importance of glycemic control and reduction of blood pressure, proteinuria, and elevated cholesterol levels in managing diabetic retinopathy, in addition to the need for regular eye examinations to detect changes in the retinal vessels.

Dr Richard Donnelly reviews the molecular mechanisms involved in the pathogenesis of diabetic microvascular complications and explains how these mechanisms point to potential therapeutic targets. He focuses on PKC, its b1 and b2 isoforms that appear to be particularly involved in hyperglycemia-induced vascular injury, and the deleterious effects of PKC and its b isoforms on the endothelium in the retina and glomerulus. He also presents experimental and clinical data demonstrating the beneficial effects of PKC b1 and PKC b2 inhibition with ruboxistaurin on the retinal vessels.

Dr Solomon Tesfaye notes in his presentation on the epidemiology and etiology of diabetic peripheral neuropathy (DPN) that DPN is characterized by painful symptoms and/or Òstocking-gloveÓ sensory loss. It affects up to 50% of patients with type 1 or type 2 diabetes mellitus, and at least 50% of foot ulcerations that develop in approximately 15% of patients with DPN could be prevented. Control of elevated glucose, blood pressure, and cholesterol levels and proper foot care are essential.

Although promising newer agents, such as a-lipoic acid and the PKC b inhibitor ruboxistaurin, have been shown to improve DPN symptom scores and composite neurologic examination scores, Dr Tesfaye emphasizes that the key to prevention is early detection of nerve damage, followed by early treatment to prevent further nerve damage.

In his presentation on diabetic nephropathy, Dr Jiten Vora reviews the epidemiology of nephropathy in patients with type 1 and type 2 diabetes mellitus, the progression of microalbuminuria to nephropathy, various interventions to reduce albumin excretion and to halt or slow disease progression, and the management of overt nephropathy. He emphasizes the importance of annual screening for albuminuria, glycemic control, reduction of blood pressure and proteinuria levels, and aggressive management of cardiovascular risk factors in treatment and prevention.

Dr Vora also presents data demonstrating the importance of reducing proteinuria by more than 30% below baseline levels, in addition to data on interruption of the renin-angiotensin-aldosterone system and the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in reducing blood pressure and proteinuria levels.

A case presentation illustrating the challenges of managing diabetes mellitus and its complications in clinical practice rounds out the issue. We hope the information presented in this publication eventually will lead to better treatment of retinopathy, nephropathy, and neuropathy and to better overall care of patients with diabetes.

*Hugh P. McCormick Family Professor of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Director, Johns Hopkins Diabetes Center, Program Director, General Clinical Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address correspondence to: Christopher D. Saudek, MD, Johns Hopkins University School of Medicine, Osler 576-Endocrinology, 600 North Wolfe Street, Baltimore, MD 21287. E-mail: csaudek@jhu.edu.





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