Type 1 Diabetes Definition. The definition of type 1 diabetes is a state of absolute deficiency of insulin. In this scenario, the pancreas is unable to produce sufficient insulin to maintain proper glucose homeostasis in the body. As a result, individuals with type 1 diabetes must rely on insulin taken by injection to stay alive.

Why Does the Pancreas Fail? The exact cause of type 1 diabetes is not known for certain but the available evidence suggests that some type of autoimmune reaction is generally involved. This results in damage to the islet cells that produce insulin, and eventually cause failure of insulin production.

Is there a cure? One way to treat the disease is to have a pancreas transplant. This is a procedure where a whole pancreas is donated from a brain-dead organ donor and transplanted into a person requiring the pancreas. Someone who is living is not able to donate a whole or part of a pancreas as we each have a single pancreas that is required for our survival. A pancreas transplant is a major operation and requires that the individual stay in the hospital for a week or more and be on anti-rejection drug therapy for the rest of their life. Once a person receives a new pancreas that is functioning normally, they are no longer considered diabetic and no longer need to take insulin. Their blood glucose levels are regulated by the islet cells in their new transplanted pancreas.

More Recently. A new procedure has evolved that shows some promise as an alternative to a whole pancreas transplant. This procedure involves the isolation of islet cells from a donated pancreas and the transfer of those cells through a blood vessel to the liver where the cells will live and produce insulin in the recipient’s body. Although these individuals must also be on anti-rejection therapy there are several advantages to this procedure. These advantages include a less invasive procedure, a lower cost, and a much shorter hospital stay.

The Islet Cell Transplant Procedure. There are several steps in the islet transplant procedure that will be outlined as follows:

• The Donor. The islet cells used for the procedure are obtained from a brain-dead donor.
• Before the Transplant. The process prior to transplantation includes an assessment by the transplant physicians with a physical examination, eye examination, and blood work.
• The Transplant. The Transplant. The transplant is performed by a radiologist in the hospital. A catheter is placed in a vein in the abdomen. Islet cells are injected into the vein and end up in the liver where they will live. This procedure is performed using a local anesthetic in the skin of the abdomen, similar to the anesthetic in a dentist’s office. It is otherwise painless.
• After the Transplant. Recipients of a transplant will be seeing the transplant physicians and team on a regular basis after the transplant. They will be taking medications to keep the islet cells functioning and free of rejection. The exact medications used are currently being studied and are changing and improving with time and research.

How many transplants are required? From previous research, it appears that most people will require more than one islet transplant for successful treatment. Some people have required up to three transplants.

Risks of Transplantation. The risks associated with any transplant are infections and increased risk of developing cancers. These risks are side effects of the medications used to prevent transplant rejection. It is not clear at this point how common these risks will be in people receiving islet transplants. So far, there have been no reports of any such complications. However, this is a risk that all people who receive a transplant will be made aware of and will need to accept.

The Hypothesis for the Islet Cell Transplant Study Program. Intuitively we may assume that the islet cell transplant will definitely make a huge improvement in health and quality of life. That may not be true! Will it delay complications? What about the anti-rejection drugs? In terms of costs are the benefits to the patient really there? It may be found to be a great improvement in diabetes care, but we will not know if this in fact is true until studies are performed to look at this question.

Who is eligible for the research study? The trial population to be enrolled will include approximately 50 subjects, male and female, between 20 and 80 years of age who have Type 1 diabetes. Patients must also have some problems with their eyes and kidneys, related to diabetes, but those patients who have heart trouble or are considering pregnancy will be excluded. Patients must also reside in the greater Vancouver area.

How are patients evaluated for eligibility? Patients are evaluated by the islet transplantation physicians. Eye examination, urine tests, and blood work, will be monitored on a regular basis. Before transplantation, all patients will be treated with the best medical treatments for diabetes that we currently have which includes controlling blood sugars well with insulin injections, and treating any other medical problems such as high blood pressure or high cholesterol.

What is optimal medical therapy? Glycemic Control (blood sugars)

• Target fasting or pre-meal blood sugars by glucometer 4-7 mmol/L
• Target HbA1c <0.70 to be followed every 3 months.

These targets are based on the Diabetes Control and Complication Trial (DCCT), which demonstrated an approximately 50 percent reduction in eye, nerve, and kidney complications with intensive treatment for hyperglycemia.

Blood Pressure Control. Hypertension (blood pressure >140/90 mmHg) should be treated to attain target blood pressure <125/70 mmHg to prevent progression of renal disease.Treatment for high blood pressure is important because elevated diastolic blood pressure is a risk factor for the development of macular edema, and elevated systolic blood pressure is a risk factor for loss of vision.

Lipid Control (Blood fats). All patients will be treated to target values for the following fasting lipid profile:

• LDL-C level <2.5 mmol/L
• Total Cholesterol:HDL-C ratio <4
• Triglyceride level <2.0 mmol/L

Based on 10 year risk of coronary artery disease >30%, or a history of cardiovascular disease, or diabetes from the Recommendations for the Management and Treatment of Dyslipidemia , CMAJ, May 16, 2000; 162(10) 1441-1447.

Renal Protection (Kidneys). All patients with >300 mg/day of albumin in their urine and microalbuminuria (30-299 mg/day albumin in their urine) will receive ACE inhibitor treatment even in the absence of hypertension. Based on Should All Patients with Type 1 Diabetes Mellitus and Microalbuminuria Receive Angiotensin-Converting Enzyme Inhibitors? A Meta-Analysis of Individual Patient Data. Annals of Internal Medicine. March 2001, volume 134, pages 370-379.

Patients will be randomly selected from the group to receive an islet transplant.Of the group of 50, there will be 10 people at a time who will carry pagers so that they can be contacted in the case a transplant becomes immediately available.

Study Flow Chart

1. Meet Inclusion Criteria
2. Retinopathy Assessment
3. Cardiovascular Assessment
4. Transplantation Team Assessment
5. Exclusion Criteria and Assessment
6. Trial of Optimal Medical Therapy (3 months)
7. Collect Data on End Points on Optimal Medical Therapy
8. Await random selection for islet cell transplantation.

The Islet Cell Transplant Study (Blood fats). Despite medical treatment, complications related to diabetes still occur. This study will determine the rate of progression of complications related to type 1 diabetes in subjects with microalbuminuria and retinopathy on optimal medical therapy. The subjects will receive optimal medical treatment which includes: glycemic control, blood pressure control, lipid profile control, and all patients will be treated with an ACE inhibitor.

Trial Schedule

• Planned inclusion of first subject: started March 11, 2002
• Planned inclusion of last subject: When 50 patients have been recruited.

The study has started enrolling patients at this time. We anticipate that the first transplant will take place near the end of 2002 or early 2003.

Rationale for the Trial. These subjects will ultimately await random selection for pancreatic islet cell transplantion. The data collected in the first part of the study will ultimately be used to compare against data after islet cell transplantation.

The primary endpoints (key data measurements collected) are glycemic control, glycemia frequency, and progression of complications:

• rate of progression from microalbuminuria to proteinuria (kidney damage)
• rate of progression of diabetic non-proliferative retinopathy to proliferative retinopathy (eye damage).

The secondary endpoints of the study are:

• renal failure (elevated creatinine)
• end stage renal disease
• myocardial infarction (heart attacks).

Subjects will be randomly selected into the treatment arm or control arm. All subjects will be treated to the targets for optimal medical therapy (see previous page). Subjects in the treatment arm will randomly receive a transplant when there is a pancreas available. Randomization is similar to flipping a coin, and not controlled by the investigators. Both cohorts will be followed for primary and secondary endpoints (described earlier).

All study participants will be closely followed before the transplant as well as afterwards to determine whether the transplant has improved their quality of life as well as prevented progression of diabetes related problems.

Summary

Pancreatic islet cell transplantation is a potential new promising treatment for patients with type 1 diabetes. Currently, there are no clinical studies to show that pancreatic islet transplantation is better than the current optimal medical treatment for type 1 diabetes. There is also no long-term data on the effects of islet transplantation in the progression of complications related to diabetes. These complications include decrease in kidney function, diabetes-related eye disease, cardiovascular disease, and death. Currently, there is also no data on long-term safety of pancreatic islet transplantation. Studies to answer these questions have not yet been performed.

The study we are now starting will try to answer these questions. We will be comparing patients who receive optimal medical treatment for type 1 diabetes to patients who receive pancreatic islet cell transplantation. We hope to determine what differences in outcome and complications are seen between these two treatments. Should pancreatic islet transplantation be shown to be a superior treatment for type 1 diabetes than our current optimal medical therapy, we hope to be able to provide this treatment in improving the health of patients with type 1 diabetes.

Michelle Fung is a clinical fellow specializing in endocrinology and metabollism.

The post The Islet Cell Transplant Program appeared first on BC Diabetes Foundation.

The results of the Heart Protection Study were announced in November at the American Heart Association conference. This study was conducted in Britain and involved randomizing 20,500 volunteers, at high-risk for heart disease, to either 40 mg Zocor (a statin – one type of cholesterol lowering medication) or a placebo. They were then followed for 3-5 years and the incidence of heart attacks, strokes and re-vascularizations (procedures to open or by-pass blocked blood vessels) was assessed. There was also an additional part in the study where they randomized volunteers to a nutritional supplement containing 250 mg vitamin C, 600 IU vitamin E and 20 mg of beta carotene compared to those taking a placebo. The announcement of the results was a front page story in both the Vancouver Sun and the National Post last November. You can also find information on the study at www.hps.com.

What were they thinking?

The Zocor Arm. As a reminder Zocor is a member of the statin family of cholesterol lowering medications. It acts in the liver by inhibiting an enzyme involved in the synthesis of LDL, the ‘bad’ cholesterol. All of the statins on the market definitely work and typical LDL cholesterol reductions are in the order of 35 to 60% depending on the type and dose of statin used. LDL is believed to function as the ‘bad’ cholesterol in that it can contribute to the deposition of fat on arterials walls leading to narrowing and even blocking blood vessels. It follows therefore, that if we are able to lower the LDL cholesterol in a high-risk group of volunteers, then we should see a reduction in events such as heart attacks, strokes and revascularization procedures.

The Vitamin Arm

It is generally believed that antioxidants in the blood can reduce the activity of unstable free radicals which are thought to contribute to the progression of disease states such as heart disease and cancer. Therefore, by boosting the levels of the bloods antioxidants we would also hypothesize a reduction of events as mentioned above. With this in mind individuals were randomized to either placebo or a daily vitamin regimen of 250 mg vitamin C, 20 mg beta carotene, and 600 IU vitamin E.

The Findings In The Vitamin Arm

There was no significant effect of the vitamin intervention. While the investigators were disappointed with this result it really isn’t that surprising. They didn’t approach the vitamin arm from the same aggressive perspective that they did the statin arm. I spoke with a dietician who reviewed the doses of vitamins used and she made it clear that they did not approach the accepted safe upper limit. This was especially true for vitamin C as 250 mg daily is barely a supplemental level for most people, not a therapeutic dose. Doses of vitamin C in the 1000-2000 mg range are tolerated by most people, especially if taken as a slow release form. Given the doses for all three vitamins they used I don’t feel the protocol design allowed the vitamin supplement question to be properly addressed.

There are cardiologists and researchers in this field who feel differently. Vancouver’s Dr. Jiri Frohlich feels this study is ‘the nail in the coffin for antioxidants for people with heart disease’ and he is not alone. Many experts in this field of research feel this has once and for all answered the antioxidant question in terms of prevention of heart disease. Some of the experts do agree, however, that antioxidants started at an earlier age or in nutritionally deficient populations could theoretically provide some benefit although this has yet to be demonstrated.

The Zocor Arm Findings

The results of the Zocor arm of the study really were quite convincing. What was found was that all events including heart attacks, strokes and revascularization procedures were significantly reduced in those individuals taking Zocor compared to those individuals taking the placebo. This was found to be true regardless of age, sex, heart disease history or prior cholesterol levels. They found that risk was reduced even for people who had normal cholesterol at the start of the study.

The overwhelmingly positive results of this study are likely going to influence the prescribing habits of many physicians. This will not be a surprise given the scientific merit of this study and the strength of the conclusions. Unfortunately they may lose sight of what the study demonstrated. It showed that lower LDL and total cholesterol in a high-risk group reduced events and saved lives. We should use this information as incentive and as a catalyst for addressing the causes of elevated cholesterol and take a stronger preventative approach rather than accepting statin therapy as the first step.

Implications To Our Health Care System

Let’s consider the cost implications of putting people in BC on Zocor at 80 dollars a month. The newspaper quoted Dr. Rory Collins, the study’s lead investigator, as saying the results showed that treating 14 people for 5 years would prevent 1 heart attack/stroke/revascularization. The cost of Zocor for 14 people would be $67,200 and then we must consider the additional cost of GP visits and monitoring liver/muscle enzymes for safety purposes since not everyone tolerates statins. That’s the cost for 14 people to prevent one event. The study authors add that for every 40 individuals treated for 5 years we could save one life. The cost of saving one life therefore, would be approximately $192,000. In terms of BC let’s consider putting 100,000 Lower Mainland people (5% of 2 million) on Zocor since it estimated that about 5% of Canadian adults are on some statin and these numbers are likely to increase following the release of these study findings. That works out to almost 480 million dollars over five years to prevent an estimated 7140 events and 2500 deaths. Canada wide this could represent over 7 billion dollars. These are rough estimates but it is clear that it could represent a significant amount of our health budget and we must ask two questions. Is it worth it? Could these events and deaths have been prevented by other means?

Patents

It is true that when the patent on Zocor expires a cheaper generic form of Zocor should reduce the overall cost to the health care system. I contacted the local pharmacy to compare the cost of some of the generic statins currently available with the brand name original. The two generics available were 21% and 37% cheaper than their brand name versions and the cheapest was approximately half the cost of Zocor, the statin used in the Heart Protection Study. Be aware efficacy does vary between different statins and dosing.

The Savings

Will these expenses be offset by savings in hospitalizations and reduced burden on health care by the high risk individuals who would benefit the most from statin therapy? The care for patients with vascular disease is extremely expensive in terms of emergency visits, surgeries, rehabilitation etc and there is no doubt the savings would be substantial. Whether they would offset the costs is not known. I would suggest that a large scale cost-benefit assessment be performed before we put millions more Canadians on statins.

The New Aspirin?

Dr. Collins even went so far as to say that #39;statins are the new aspirin#39; based on their findings and the potential therapeutic applications. There are at least two major differences between aspirin and statins. Aspirin is only pennies a day and the cost is typically absorbed by the patient. Secondly, there is the safety issue and the cost associated with it. I don#39;t know any physicians who recommend blood safety tests for aspirin users. It isn’t required whereas typically a GP would arrange a blood test to check on a patient’s liver enzymes following initiation of statin treatment to make sure the patient is tolerating the medication. Referring to statins as the ‘new aspirin’ is misleading from a cost and safety perspective even though it may be true from the perspective of reduced events and deaths.

Not All Statins Are Created Equal

The study showed that Zocor does not appear to present a major safety risk based on the data in this study, the details of which were not provided. Dr. Salim Yusuf, Division of Cardiology at McMaster University, suggests that the safety profile for Zocor in this study was actually better than that for ASA. This is of course the best safety data we have yet on statins. For that reason many doctors will likely prescribe Zocor for patients just starting on a statin since safety has been demonstrated. It is not reasonable to assume that all other statins will have the same safety performance over the long term since they are all a little different. This is clear from the recent experience with cerivastatin (Baycol) which was removed from the market following a number of deaths and adverse experiences as a result of rhabdomyolysis, a potentially life-threatening condition which occurs when a large number of skeletal muscles die. Baycol may be unique in terms of some of it’s properties yet all statins present a potential danger. As the use of different statins becomes wide-spread it will be important to monitor patients who start taking them.

Our Unhealthy Heart Crisis

What was most sobering in the media articles that followed the HPS announcement was that there are so many high-risk people. Maybe some of the 7 billion dollars that may get spent on statins in Canada over the next 5 years could be spent on programs that try to address the underlying causes of the current Unhealthy Heart Crisis. The statin may do its prevention ‘thing’ regardless of lifestyle changes which is sad in a way. The statin doesn’t necessarily improve the health of any individual. What it does is reduce the risk of heart attack and stroke by 25%. We should think of good health as a sense of wellness and a high quality of life, not merely as a low-risk factor. High risk is often a function of being overweight, inactive, smoking and having a poor diet. We may have someone on a statin who is just as unhealthy as before or perhaps worse. They are simply at lower risk of heart attack and stroke and therefore represent less potential burden on the cardiovascular component of the health care system.

Could a degree of risk reduction have been accomplished by other means? I think the answer to that is yes. Lifestyle modification is one of the simplest ways to reduce your risk for the progression of heart disease and the eventual reduction of MIs and Stroke. The foundation is diet, exercise and stopping smoking. These changes lead to a major improvement in the quality of life, more energy and they empower the individual at the spiritual level giving them a sense of control over their life. One lifestyle convert is often enough to infect 10 others by example and through enthusiastic conversation. That can be a wonderful thing to witness and share in the ongoing cycle of healthy changed lives. Furthermore, if individuals do experience an MI or stroke the better fit individuals tend to have more rapid recoveries, shorter hospital stays and better long-term prognosis.

Reality

Could a lifestyle intervention arm have accomplished what this study accomplished with Zocor? With 100% compliance perhaps, but in the real world I don’t believe so as much as I would like to. The incredible amount of lowering of LDL cholesterol with statins is virtually impossible to achieve consistently with lifestyle intervention. In a group of 20,000 research volunteers compliance with pill taking is far more likely than compliance with a time consuming, energy demanding change in diet and activity. At the individual level however we can all make our own choices about changing our lives and LDL isn’t the only risk factor. Don’t let my earlier statement discourage you from making positive changes in your lifestyle because those changes will make a difference to your entire body, not just your heart disease risk profile.

Conclusions

Statins will undoubtedly play a key role in treating patients who are at high-risk for heart disease. There are people who will benefit from and who should be on statins. Given the recent findings of the Heart Protection Study there may be a trend to put a far greater number of lower-risk people on statins. If you are one of the low-risk individuals considering statins I would ask that you consider all your alternatives, and ask your doctor plenty of questions.

Eric Norman is a research scientist investigating heart disease.

The post The Benefits of Cholesterol Lowering: Reviewing the Heart Protection Study appeared first on BC Diabetes Foundation.

The Islet Cell Transplant Program is gearing up at Vancouver Hospital with the assistance of the BC Endocrine Research Foundation. The program which is described in detail in this issue will be conducted as a research study investigating whether having an islet cell transplant results in improved health/quality of life when compared to conventional non-surgical diabetes care.

The results of the large Heart Protection Study were released last fall and demonstrated the benefits of cholesterol lowering therapy using a statin. Now we should consider how this information can be incorporated into our approach to health and wellness, as an individual and as a society.

Enjoy this issue and feel free to check out our website and contact us if there is something you would like to see on the website that isn’t there.

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