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


Practical Applications of Emerging Data on Diabetic Microvascular Complications


GOAL
To provide endocrinologists, diabetologists, and primary care physicians with up-to-date information on the pathogenesis and management of diabetic microvascular complications.

TARGET AUDIENCE
This activity is designed for endocrinologists, diabetologists, managed care professionals, 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 the 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 behind them.
  • Understand the rationale and approach for screening and early detection.
  • Describe the specific pathogenic targets that might ameliorate microvascular disease and the current and potential approaches to affecting these underlying 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: March 15, 2005. Expiration date: March 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 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 Director 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.

PARTICIPATING FACULTY

Eva L. Feldman, MD, PhD
Professor of Neurology
Director, JDRF Center for the Study of  Complications in Diabetes
University of Michigan Health System
Ann Arbor, Michigan
Dr Feldman reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Rayaz A. Malik, MB.ChB, PhD, MRCP
Senior Lecturer and Consultant Physician
Academic Department of Medicine
Manchester Royal Infirmary
Manchester, United Kingdom
Dr Malik reports receiving grants/research support from AstraZeneca and Eli Lilly and Company; serving as a consultant for Eli Lilly and Company and Pfizer Inc; and receiving honoraria from Aventis Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, and Pfizer Inc.

Andreas F. H. Pfeiffer, MD
Professor of Internal Medicine and Chairman
Department of Endocrinology
Diabetes and Nutrition
Campus Benjamin Franklin-Charit University Medicine
Berlin, Germany
Director
Department of Clinical Nutrition
German Institute of Human Nutrition Potsdam
Nuthetal, Germany.
Dr Pfeiffer reports receiving grants/research support from Eli Lilly and Company; serving as a consultant to Eli Lilly and Company; and receiving honoraria from Eli Lilly and Company.

Massimo Porta, MD, PhD
Associate Professor of Medicine
Department of Internal Medicine
Diabetic Retinopathy Centre
University of Turin
Turin, Italy
Dr Porta reports receiving grants/research support from Eli Lilly and Company; and serving as a consultant for AstraZeneca.

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

Dr Malik—ruboxistaurin mesylate.
Dr Porta—benfotiamine, candesartan, octreotide, ruboxistaurin mesylate, and thiamine.

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.

Practical Applications Of Emerging Data On Diabetic Microvascular Complications
Christopher D. Saudek, MD*

This issue of Advanced Studies in Medicine features the proceedings of a satellite symposium held on the occasion of the 40th Annual Meeting of the European Association for the Study of Diabetes in Munich, Germany, on September 4, 2004.

The symposium titled "Diabetic Microvascular Complications: New Concepts of Pathogenesis and New Strategies for Clinical Practice" featured a distinguished international faculty with expertise in the overall clinical management of patients with diabetes and the pathogenesis, diagnosis, and treatment of diabetic peripheral neuropathy, diabetic retinopathy, and diabetic nephropathy. Although diabetic macrovascular complications continue to garner attention because they are the major cause of death in persons with type 2 diabetes mellitus, microvascular complications are pathognomonic of diabetes. In fact, the glycemic thresholds that define diabetes and impaired glucose tolerance were selected because they are the levels of blood glucose at which the specific microvascular complications occur.
Therefore, the microvascular complications are important causes of the morbidity and mortality associated with diabetes mellitus, in addition to the societal and economic burden of the disease.

The detection and treatment of diabetes mellitus and its microvascular complications rest on a multispecialty approach involving primary care physicians, internists, neurologists, nephrologists, ophthalmologists, endocrinologists, diabetologists, and other healthcare professionals, such as diabetes nurses, diabetes educators, pharmacists, and nutritionists. Within this framework, the role of the endocrinologist is central to the management of diabetes mellitus to prevent microvascular complications and manage these complications when they do occur.

Control of blood glucose and blood pressure levels is a proven preventive strategy, as are secondary treatments such as laser photocoagulation and therapeutic footwear to prevent further progression of the disease. However, because each of these treatments has limitations, even their combined use is not the whole answer to prevention of diabetic microvascular complications. Additional therapies are needed. In that regard, recent research into the pathogenesis of diabetic peripheral neuropathy, diabetic nephropathy, and diabetic retinopathy has suggested several new therapeutic possibilities that may prove effective.

In keeping with the objectives of the symposium to review how and why diabetic microvascular complications occur and evaluate newer therapies based on the etiology of these complications, the contents of this publication include the research findings, the clinical application of new therapies, and the bridges between them. In other words, the contents translate research findings into clinical practice and patient care.

Eva L. Feldman, MD, PhD, notes in her article the major impact of the microvascular and macrovascular complications of diabetes mellitus. Dr Feldman then explores the various pathways and mechanisms by which abnormal glucose metabolism leads to oxidative stress and explains why oxidative stress is the unifying mechanism underlying glucose-mediated damage to the eyes, kidneys, and nerves. She also reviews the current status of several classes of drugs that have been developed to target individual oxidative stress pathways.

In his article, Rayaz A. Malik, MB.ChB, PhD, MRCP, extends the concept of a unifying mechanism with epidemiologic, pathologic, pathophysiologic, and molecular evidence to support the hypothesis that damage to the microvasculature is the underlying cause of diabetic peripheral neuropathy.

He reviews the key pathways involved in endothelial cell dysfunction and tissue damage and describes in detail the functional abnormalities, which are driven by oxidative stress, that precede structural abnormalities such as basement membrane thickening and microvascular sclerosis. He also points out that these abnormalities, which are clearly present in late-stage diabetic peripheral neuropathy, are also present in patients with impaired glucose tolerance and early stage diabetic peripheral neuropathy, a finding that underscores the need for early detection and treatment.
Dr Malik concludes his article with a review of recent and ongoing studies of angiotensin II receptor blockade (ARB), angiotensin-converting enzyme (ACE) inhibition, and protein kinase C (PKC) inhibition in patients with diabetic neuropathy.

Massimo Porta, MD, PhD, provides an overview of the natural history of diabetic retinopathy and the clinical features of each stage in its progression. He then describes the factors that may be involved in the progression of retinopathy. These include pericyte loss, increased capillary permeability caused by PKC-mediated release of vascular endothelial growth factor (VEGF), retinal ischemia and new vessel formation, and endothelial cell death and capillary occlusion.

Dr Porta concludes with a review of current treatment options—glycemic control, blood pressure control, and photocoagulation—and newer therapies for retinopathy, which include the PKC-b inhibitor ruboxi-staurin, ACE inhibitors, ARBs, statins, somatostatin analogues, growth hormone-receptor blockers, VEGF-receptor blockers, advanced glycation end product-receptor blockers, intravitreal steroids, and thiamine.

In the final article, Andreas F. H. Pfeiffer, MD, notes that early detection of diabetic microvascular complications is the key to improving outcomes, particularly because 50% of all patients with type 2 diabetes mellitus already have signs of at least 1 microvascular or macrovascular complication at diagnosis.

He focuses first on prevention and early detection of diabetic nephropathy, which hinge on monitoring and screening for hypertension, poor glucose control, microalbuminuria, and cardiovascular risk factors (because patients with diabetes and nephropathy are also at increased risk for cardiovascular disease).

Dr Pfeiffer closes with a review of newer therapies for diabetic nephropathy, noting that these therapies may provide a novel means of reducing complications because they target early pathophysiologic events occurring before clinical signs and symptoms develop.

It is hoped that the information presented in this issue provides some valuable insights regarding pathogenesis and therapy and will eventually lead to the improved treatment of diabetic microvascular complications and better overall management of patients with diabetes mellitus.

*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 at Johns Hopkins, 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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