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FDA Rethinks Type 2 Diabetes
Drug Approval Rules, May Require
Heart Disease Risk Assessments

When the FDA approves a drug for type 2 diabetes, should risks of heart disease be added to judgements about a drug's ability to help control blood sugar and A1C levels?

For the first time in history, an impressive panel of experts will meet in Washington, D.C. beginning July 1st to vote on this important question. What they conclude may decide the fate of many thousands of diabetics throughout the USA for decades to come. If you're a diabetic, your own life may hang in the balance...

Released June 27, 2008 by Leve1Diet.com -- The U.S. Food and Drug Administration has finally announced that it is studying whether to require new standards for all type 2 diabetic drugs.

Almost one full year has lapsed since the controversial announcement linking the diabetic drug Avandia to deaths from heart disease, in July of 2007. Now the FDA is convening a panel of experts to look at questions about whether heart disease risks should be investigated for all present or future diabetic drugs.

The meeting will happen at the Hilton Hotel in Silver Springs, Maryland, for two full days from Tuesday, July 1st through Wednesday, July 2nd, 2008. A combined panel has been assembled consisting of the medical and health experts listed at the bottom of this page. It's an impressive list. It should be, since the issues being studied may affect the lives of many thousands, even millions of diabetic patients.

The new standards may examine whether any diabetic drug may increase risks of heart disease or fatal heart attacks for patients suffering from type-2 diabetes, also called adult-onset or NIDDM diabetes. This form of diabetes is often associated with a condition called insulin resistance or the metabolic syndrome.

The diabetic metabolic syndrome includes a broad spectrum of conditions that appear to be linked together in type-2 diabetics:

Signs of the Metabolic Syndrome or "Syndrome X"

  • Elevated waist circumference:
    • Men — Equal to or greater than 40 inches (102 cm)
    • Women — Equal to or greater than 35 inches (88 cm)
  • Elevated triglycerides: Equal to or greater than 150 mg/dL
  • Elevated levels of fibrinogen clotting factors, above 150-300 mg/dL
  • High proportions of smaller, more dense LDL particles under 26nm in diameter (appears linked to high triglyceride levels)
  • Reduced HDL (“good”) cholesterol:
    • Men — Less than 40 mg/dL
    • Women — Less than 50 mg/dL
  • Elevated blood pressure: Equal to or greater than 130/85 mm Hg or use of medication for hypertension
  • Elevated fasting glucose: Equal to or greater than 100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia
  • Microalbuminuria: urinary albumin excretion ratio ≥ 20 mg/min or albumin:creatinine ratio ≥ 30 mg/g
  • High levels of C-Reactive Protein, Tumor Necrosis Factor-Alpha TNFa, interleukin 6 IL-6, and other markers of systemic persistent inflammation
Patients often suffer from both high blood sugar and high levels of insulin at the same time. As a result of all of these problems, diabetics suffer extraordinarily high risks for heart disease. In fact, heart disease accounts for between 65% and 80% of all diabetic deaths. This compares to only 28% deaths from heart disease for the total US population (which includes diabetics). Non-diabetic Americans dying from heart disease would be somewhere around 20% or so -- diabetics are about 2-1/2 times more likely to die from heart disease as a non-diabetic. Since their heart disease risks are already high, any drug that raised heart disease risks even higher still would be especially bad for diabetics.

Of course this is exactly what is bothering the FDA. In fact, is it possible that anti-diabetic drugs may be making matters worse -- increasing the diabetic's already high chances of dying from a heart attack or stroke? Some experts argue that this is precise the case. Others don't think so. And, there are billions of dollars in drug company profits at stake. So you can bet the controversy is heated.

Drugs like Avandia (rosiglitazone), Glucophage (metformin) and Actos (pioglitazone) are given to reduce a patient's resistance to insulin, as well as reducing their tendency to produce unneeded sugar in the liver, and uptake too much sugar in the gut. As their insulin resistance decreases, their ability to process sugar in organs like the liver, the pancreas and muscles significantly improves. This makes their diabetes much more manageable.

Further, benefits to taking Avandia include reduced levels of some "bad" cholesterol, and modest improvements in the patients' inflammation profile.

One would think that these benefits would DECREASE the risks for heart disease. But, even drug proponents and Avandia defenders do not claim an actual decrease in risks for cardiovascular disease from taking the drug. This lack of CVD risk reduction seems very, very strange.

However, FDA experts point out that while the approved diabetic drugs do reduce average blood sugar levels and A1C, there is not one single diabetic drug that has been proven to decrease or improve heart disease risks. This is a remarkable fact. Wouldn't you think that improving blood sugar control would reduce risks of dying from heart disease, too? After all, if you're improving your blood sugar management, you are in fact improving your diabetes, right?

Evidently not. Not with respect to dying from heart attacks or strokes.

This is very strange. Something else must be going on, if a drug lowers our blood sugar, improves our A1C scores, improves insulin resistance and many factors related to the metabolic syndrome -- all while NOT improving our risks for heart attack.

This is why many experts believe that there is a mechanism involved with these drugs that does something BAD all the while they are doing other things that are GOOD.

That's why these experts insist on beginning an expensive, long term, and possibly very unprofitable testing program. These experts want all future diabetes drugs tested for their possible effects on heart disease. Plus, they want today's already approved drugs (like metformin, rosiglitazone, pioglitazone, etc.) tested too. This will cost hundreds of millions of dollars, maybe billions. Because heart disease develops over many years or decades, it will take many years or decades to complete.

Further, the added costs of testing for heart disease risks will discourage many if not most companies from new diabetes drug development. They may spend their cash reserves on less expensive and more profitable diseases. Diabetes research, and diabetics patients, may be left out in the cold as far as new research goes.

These are complex and interesting questions, to be sure.

Avandia Pills, GlaxoSmithKline(tm)However, some drugs like Avandia do cause some undesirable side effects in many patients -- swelling of the feet and legs, accumulation of fluid in the lungs, made obvious by fits of coughing. There is a general puffiness called "edema". This is fluid retention that is related to the heart becoming less efficient -- a condition doctors call "congestive heart failure". As the body becomes filled with large amounts of extra water, the heart becomes congested... The heart does not seem to have enough strength to fully pump the blood volume to enable the kidneys to remove fluids properly. In some individuals who already have existing heart disease as many diabetics do, this added load on a damaged heart and circulatory system could be fatal. These developments appear to help cause a very significant increased risk of fatal heart failure or "adverse events" (as the professionals prefer to call them). In addition the side effects also may sometimes include other serious heart disease related problems, such as strokes.

Last year the world took note of dangers linked to certain diabetes drugs, when the FDA began publishing new data that the popular drug Avandia (rosiglitazone) is linked to 43% increased risks for heart attacks, and a 64% risk to overall deaths from all cardiovascular related diseases.

Actos Pills, by Takeda(tm)The maker of Avandia -- GlaxoSmithKline -- protested immediately that their drug was no more dangerous than other type 2 diabetes drugs that patients might have taken as an alternative. Such other drugs include Actos (pioglitazone) made by Takeda, metformin, sulfonylurea, and possibly others. These drugs do have similar reported side effects in some studies, or do no better than rosiglitazone.

However, some experts argue that the side effects of Avandia are especially pronounced. This continues to be very controversial.

Avandia, like many other diabetes drugs, is primarily aimed at reducing the patient's blood sugar levels, and at lowering their resistance to insulin. Until now, heart disease was not considered a major concern for Avandia's enthusiastic defenders.

An Incidental Question: Do people who take Rosiglitazone for diabetes live longer than those who don't? Do they live longer than people taking different combinations of competing drugs -- without Avandia?

It would seem a simple question to answer. Aside from the controversial heart disease question, who lives longer -- those taking Avandia, or those who don't? Enquiring minds want to know.

Over the last year, things have changed. Now the FDA is using their experience with Avandia to question whether heart disease testing needs to be included BEFORE any future drug is approved. And, they are also wondering if new studies ought to be done on already-approved diabetes drugs to include heart disease risk assessments. These new tests would be expensive, and take years to complete. Since millions of patients are now taking drugs like Avandia, billions of dollars in total drug sale revenues are at stake.

The Questions the Panel Will Consider

From the FDA Points for Discussion Document

1. "What specific cardiovascular assessments should be required as part of the approval process for drugs and biologics developed for the treatment of type 2 diabetes, and why?"

2. "Should these cardiovascular assessments occur prior to approval of new treatments for type 2 diabetes or during the post-approval setting?"

3. "Should these cardiovascular assessments apply to every new treatment for type 2 diabetes or only to those treatments that have a scientific basis for these assessments?"

4. "Should these cardiovascular assessments be applied to already marketed treatments for type 2 diabetes?"

5. "Design considerations for a cardiovascular trial:
  • Should the trial’s objective be to show cardiovascular benefit or rule out an increase in cardiovascular risk? If the objective is to rule out a pre-specified magnitude of increase in cardiovascular risk, what is an acceptable magnitude of increased risk?
  • What should the primary endpoint be?
  • What type of patient population should be enrolled?
  • Which treatment comparator(s) should be used?
  • How will deteriorating glycemic control be handled?
  • Should investigators be encouraged to manage blood pressures, lipid profiles, aspirin use, and other cardiovascular factors to current guidelines (which will not necessarily ensure comparability across treatment groups) or should algorithms be used post-randomization to ensure that these risk factors are equalized across treatment groups?
  • Are there other critical features that should be considered when designing these trials?"
6. "Should cardiovascular endpoints be blindly and independently adjudicated in phase 2 and 3 clinical trials of all treatments developed for type 2 diabetes?"

Endocrinologic and Metabolic Drugs Advisory Committee meeting

A briefing document was prepared for the paneled committee members. From the FDA briefing background document linked below:

"The role of cardiovascular assessment in the pre-approval and post-approval settings for drugs and biologics developed for the treatment of type 2 diabetes mellitus."

"All drugs that are approved by the Food and Drug Administration (FDA) for the treatment of diabetes mellitus are indicated to improve glycemic control. FDA has been basing approval of anti-diabetic drugs on the surrogate of hemoglobin A1c (HbA1c), which is a well-validated measure of glycemia. However, questions have been raised as to whether long-term cardiovascular trials should be part of the approval process for pharmacological therapies developed for the treatment of diabetes. There are 2 categories of cardiovascular trials, one that evaluates whether a treatment has cardiovascular benefit (i.e., reduces cardiovascular events) and another that evaluates whether a treatment is likely to increase cardiovascular risk. A requirement for demonstrating cardiovascular benefit will likely have major implications on the availability of new treatments for type 2 diabetes, because conclusive evidence of a reduced risk of macro-vascular complications in type 2 diabetes has not yet been established for any of the currently available anti-diabetic medications, including insulin. In addition, a requirement for long-term cardiovascular benefit would prompt questions as to why currently marketed therapies (all lacking evidence of such benefit) should remain available."

"Establishing a hurdle of long-term, costly trials to exclude cardiovascular harm may also affect drug development for type 2 diabetes, particularly if this mandate applies to every product, even those that have no suggestion of cardiotoxicity."

"To further explore these complex issues, we have convened the current advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for drugs and biologics developed for the treatment of type 2 diabetes mellitus. The purpose of this briefing document is to provide introductory material to prepare the advisory committee members for the scheduled presentations and ensuing discussion."

"The advisory committee meeting is scheduled for 2 full days. The panel will be populated by the Endocrinologic and Metabolic Drugs Advisory Committee, diabetologists, cardiologists, statisticians, and members of the Drug Safety and Risk Management Committee (DSARM)."

"During the first day, experts in the field of diabetes and cardiology will present background information that will lay the foundation for extensive discussion among committee panel members (Table 1). Most of the second day of the advisory committee meeting will be reserved for an extensive discussion among the advisory committee members."
  • Introduction, including current basis of approval of drugs/biologics for type 2 diabetes
  • Natural history of type 2 diabetes and diabetes-related macrovascular complications
  • Hemoglobin A1c as a surrogate for glycemic control and diabetes-related complications
  • Cardiovascular outcome trials: Statistical considerations
  • Clinical macrovascular outcomes with antidiabetic drugs: What we already know
  • Clinical macrovascular outcomes with antidiabetic drugs: Ongoing studies
  • Need for cardiovascular assessment during the approval process for antidiabetic drugs
  • Challenges in designing a cardiovascular outcomes trial in patients with type 2 diabetes

Diabetes Drug Assessment Panel Members

Voting Panelists

  1. Kenneth D. Burman, M.D. (Acting Chair) Chief, Endocrine Section Washington Hospital Center Washington, District of Columbia

  2. Katherine M. Flegal, Ph.D. Senior Research Scientist Distinguished Consultant National Center for Health Statistics Centers for Disease Control and Prevention Hyattsville, Maryland

  3. Thomas P. Bersot, M.D., Ph.D. Associate Investigator Gladstone Institute of Cardiovascular Disease San Francisco, California

  4. Jessica W. Henderson, Ph.D. Associate Professor Division of Health and Physical Education Western Oregon University Monmouth, Oregon

  5. Michael A. Proschan, Ph.D. Biostatistician Biostatistics Research Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland

  6. Clifford J. Rosen, M.D. Senior Staff Scientist Maine Center for Osteoporosis St. Joseph Hospital Bangor, Maine

  7. Allison B. Goldfine, M.D. Assistant Director of Clinical Research Joslin Diabetes Center, Research Division Boston, Massachusetts
  8. Eric Felner, M.D. Emory University School of Medicine Department of Pediatrics Division of Endocrinology Atlanta, Georgia

  9. Thomas Fleming, Ph.D. (Discussant + Speaker) Professor of Biostatistics University of Washington Seattle, Washington Rebecca W. Killion Patient Representative Bowie, Maryland

  10. Eric S. Holmboe, M.D., F.A.C.P. Vice President for Evaluation Research Director, Clinical Performance Services American Board of Internal Medicine Philadelphia, Pennsylvania

  11. Ruth S. Day, Ph.D. Director, Medical Cognition Laboratory Duke University Durham, North Carolina

  12. Marvin A. Konstam, M.D. Tufts-New England Medical Center Boston, Massachusetts

  13. Timothy S. Lesar, Pharm.D. Director of Pharmacy Albany Medical Center Albany, New York

  14. Judith Fradkin, M.D. Director Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK, National Institutes of Health Bethesda, Maryland

  15. Peter Savage, M.D. Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK, National Institutes of Health Bethesda, Maryland

Non-Voting Panelists

  1. Enrico P. Veltri, M.D. Group Vice President Global Clinical Development Cardiovascular and Metabolic Diseases Shering-Plough Research Institute Kenilworth, New Jersey

  2. Saul Genuth, M.D. Case Western Reserve University Cleveland, Ohio

  3. Steve Nissen, M.D. (Limited to Speaking Only) Medical Director, Cleveland Clinic

  4. Robert Califf, M.D. (Limited to Speaking Only) Vice Chancellor for Clinical Research Duke University Durham, North Carolina

  5. David Nathan, M.D. Director of the General Clinical Research Center and of the Diabetes Center at Massachusetts General Hospital, and a Professor of Medicine at Harvard Medical School.

  6. Robert E. Ratner, M.D. Vice-President of Scientific Affairs MedStar Research Institute Hyattsville, Maryland

  7. Professor Rury Holman, Professor of Diabetic Medicine Diabetes Trials Unit Director OCDEM, University of Oxford

  8. Hertzel C. Gerstein M.D. MSc FRCPC McMaster University Dept. of Medicine, Hamilton, Ontario, Canada

  9. Gerald Dal Pan, M.D., M.H.S. Director Office of Surveillance and Epidemiology CDER, FDA

  10. Robert Temple, M.D. Director Office of Medical Policy CDER, FDA

  11. John Jenkins, M.D. Director Office of New Drugs CDER, FDA

  12. Curtis Rosebraugh, M.D., M.P.H. Acting Director Office of Drug Evaluation II CDER, FDA

  13. Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products CDER, FDA

  14. Hylton Joffe, M.D. Lead Medical Officer Division of Metabolism and Endocrinology Products CDER, FDA

Related Official FDA Document Downloads in PDF Form

1. Download the list of the Panel of Experts -- The Panel of ExpertsMore..., 4 pages, PDF.

2. Download the official FDA Agenda for the meeting -- The Agenda for the MeetingMore..., 1 page, PDF.

3. Download the full PDF document, including 61 pages of background, details of the science, medicine and history of the drug assessments involved - The FDA Briefing DocumentMore..., 61 pages, PDF

©2008 Level1Diet.com, Rights granted for unlimited duplication and dissemination as long as the references to Level1Diet.com are left unchanged, and a working link is provided pointing back to our home page: /

* All information on Level1Diet.com is for educational purposes only. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. Before changing your diet, or adding supplements to your diet, or beginning an exercise program, everyone should consult a qualified and licensed health practitioner; a physician, dietician or similar professional.

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