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Posted: Sun May 22nd, 2005 01:40 |
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Diabetes is a Th1 inflammatory disease
Diabetes is a Th1 disease. It is caused when monocytes and macrophages permeate the outer tissues of the pancreas and shut down production of isulin, and then inulin. Although we don't have confirming clinical data yet, I have little doubt that as folk recover on the MP, their Diabetes will also vanish.
There is no doubt that Diabetes Type1 and Type 2 are both Th1 diseases, and that they both have an L-form infectious pathogenesis.
The VDR is responsible for transcribing the gene which creates insulin receptors. When the VDR is messed up (by 1,25-D from Th1 disease) insulin receptor expression (manufacture) can be affected. But there are other factors to consider as well, including direct effects of the bacterial inflammation in the pancreas.
Diabetes is caused by a Th1 immune reaction which affects the pancreas, and not necessarily following a family history of Diabetes etc.
See I thought I had a genetic defect. What is successive infection?
..Trevor..
Last edited on Mon Mar 17th, 2008 20:23 by Foundation Staff
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Posted: Mon May 23rd, 2005 06:12 |
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Tests to monitor diabetes
Please see Suggested tests to monitor your progress on the MP.
You will want to monitor serum glucose levels at home. Doc will test HbA1C periodically.
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Aussie Barb
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Posted: Sat May 28th, 2005 01:17 |
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Member's with diabetes
Interview with Chris Eastlund, a long-time MPer who has now essentially recovered from diabetes, sarcoidosis, and irritable bowel syndrome thanks to the MP.
captkirk: Bree: summary of improvements: A1C, weight, hearing etc
44 years of Diabetes Debbie Y
rc45guy: Type1 Diabetes Jan89, insulin pump, improvements.
Reported lapse in Benicar blockade results in ocular hemorrhage
-I was on prednisone for two years before starting the MP. Before I was on prednisone, I had little to no retinopathy. In the timespan of those two years on prednisone, I went from little to severe.
I had a hemmorhage in my right eye about 6wks ago. I was very lax in taking my Benicar over a period of 2 days (like twice a day, 16h apart), and on the 2nd day I got the hemmorhage.
It wasn't a conscious risk, I was 4h away from the hotel and my wife didn't have her normal purse carrying it. A total mistake on my part - not making that one again!
-I am a MPer in phase 3 who is on an insulin pump and have had diabetes type 1 for 46 years. My blood sugar levels have consistently dropped on the day I take my Z and for a few days after. Several things have changed since being on the MP: I can feel my hypoglycemia more now where before MP I could not feel any signs of hypoglycemia due to longstanding diabetes, at times I have had unexplained high glucose levels for no reason other than an IP event and taking extra Benicar straightened it out, my A1C has lowered to normal when it had not been for awhile, I have had no diabetic problems with my eyes since on antibiotics and Benicar, I have had no diabetic problems with infections and or healing. Taking the antibiotics and Benicar, along with the proper diabetic diet, checking glucose levels regularly and recording them and having regular A1C levels checked, have helped my diabetes status and has allowed me to see the effects from the MP meds. ~debbie y
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Barb: Dx Inflammatory Disease Endocrine Imbalance 2003| Depression| 24+ years not Dx| MP Aug04| ABC of MP| MP Search|
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Aussie Barb
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Posted: Tue May 31st, 2005 21:32 |
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Infectious cause of diabetes
Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.
The association of metabolic syndrome and Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus type 1: the Persian Gulf Healthy Heart Study.
Diabetes clusters suggest infectious cause
Thu Jul 13, 2005
NEW YORK (Reuters Health) - Results of a new study support the notion that common infections may trigger type 1 diabetes in children and young adults.
Specifically, UK researchers uncovered evidence of clustering among young diabetes patients.
A relative high number of cases in a small area and within a limited period -- space-time clustering --is "consistent" with an environmental component in disease development, "possibly linked to infections," Dr. Richard J. Q. McNally, of the University of Newcastle upon Tyne, and colleagues explain in the journal Diabetologia.
The team used data from a population-based register in Yorkshire to look for evidence of space-time clustering of diabetes among subjects younger than age 30.
Included in the analysis were two data sets of patients diagnosed with type 1 diabetes: 3019 children up to 14 years of age who resided in Yorkshire between 1978 and 2002; and 989 patients between 15 and 29 years who resided in West Yorkshire between 1991 and 2002.
In the first group, significant space-time clustering, based on place and time of diagnosis, was confirmed for the children between 10 and 14 years old. In the second group, space-time clustering was observed for those between 15 and 19 years old.
"These findings suggest that infections may precipitate type 1 diabetes in a limited number of susceptible people," McNally commented to Reuters Health. "Other environmental factors are also likely to be involved."
Although the findings suggest an environmental cause, the investigators note that the study cannot confirm if the environmental effects are direct or if they merely unmask latent diabetes.
SOURCE: Diabetologia, July 2006.
BCG vaccine and diabetes
It is well documented, over several decades, that the BCG vaccine causes Sarcoidosis, eg
"Juvenile sarcoidosis after BCG vaccination (2006)"
http://www.ncbi.nlm.nih.gov/pubmed/12734491
"Juvenile sarcoidosis after BCG vaccination (1989)"
http://www.ncbi.nlm.nih.gov/pubmed/2602688
"Incidence of Intrathoracic Sarcoidosis among young adults participating in a trial of Tuberculosis vaccines (1965)"
http://www.ncbi.nlm.nih.gov/pubmed/14321221
The use of BCG vaccine has been banned in several countries , as being unsafe. Its use in Diabetes is not even a new idea, having been first mooted in 1991
http://www.ncbi.nlm.nih.gov/pubmed/1833072
Anybody who is researching the use of live vaccines, and who doesn't know about the terrible track record of BCG, needs to have their researchers' licenses stripped from them, in my opinion. ..Trevor..
See also Infections linked to Type 1 diabetes
Last edited on Mon Mar 17th, 2008 20:22 by
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Barb: Dx Inflammatory Disease Endocrine Imbalance 2003| Depression| 24+ years not Dx| MP Aug04| ABC of MP| MP Search|
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Aussie Barb
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Posted: Tue Jun 14th, 2005 20:36 |
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Diabetes and the Marshall Protocol
I have no data whether the damage causing Type 1 diabetes can be reversed. Certainly it will take a long time for the body's normal insulin production to start up again. ..Trevor..
How much resolution of your type I diabetes you will achieve on the MP is impossible to say since this is relatively uncharted territory. You will want to follow your doctors recommendations for monitoring your blood sugar levels.
Immunopathology may reveal inflammation in delicate tissues that are commonly damaged by high blood sugar and high insulin levels. Therefore, your doctor may want to monitor your kidney function, liver enzymes and eye inflammation. He will know what tests to order. You can expect some exacerbation of inflamed tissues and may see some labwork temporarily elevated. Adjusting the MP medications to reduce the Herx reactions will keep the inflammation under control.
See BENICAR AMELIORATES INSULIN RESISTANCE
Here is good news for those who are looking for recovery from Type 1 Diabetes:
Insulin cells persist in long-standing diabetes by Megan Rauscher
I have suspected that recovery was possible right from my early days studying Diabetes in the early 80s, and it is nice to see studies which confirm my suspicion ..Trevor..
We are confident that benicar, plus the 1,2 and 3 abx combos we now have available, will get all of the species, or at least enough to get a patient to 'cure.' But different folks have different species dominant, and will need slightly different abx combos as they progress through the MP.
..Trevor..
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Barb: Dx Inflammatory Disease Endocrine Imbalance 2003| Depression| 24+ years not Dx| MP Aug04| ABC of MP| MP Search|
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Posted: Wed Sep 14th, 2005 02:05 |
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Diabetic diet
What diabetics should eat is controversial these days. The American Diabetic Association recommends carb counting but allows a pretty high amount of carbohydrates. They admit that a diet very low in carbohydrates will succesfully maintain low blood sugar levels but they will not endorse a low carb diet claiming it would be too hard to follow.
Other experts recommend various low carbohydrate diets. Dr. Richard Bernstein, MD, a type one diabetic himself, follows a diet extremely low in carbohydrates. It is described online and in his book The Diabetic Solution.
Like most other issues in medicine, you have options. Do some reading on your choices and talk it over with your doctor or diabetic educator.
Diabetics Improve Health With Very High-Fat, Low Carb Diet
By Cameron Johnston
SAN DIEGO, CA -- June 15, 1999 -- A very high-fat, low-carbohydrate diet has been shown to have astounding effects in helping type 2 diabetics lose weight and improve their blood lipid profiles.
The results of three studies involving such a diet, which is similar to, but has a few key differences from the famous "Dr. Atkins Diet", were presented today at the annual meeting of the Endocrine Society.
Dr. James Hays, an endocrinologist and director of the Limestone Medical Center in Wilmington, DE, admitted that the concept of a high-fat diet in people who are already at higher risk of cardiovascular disease might seem incongruous. Nonetheless, this study of 157 men and women with type 2 diabetes showed an impressive benefit in body mass index (BMI) triglycerides, HDL, LDL and HbA1c.
Most people are encouraged to reduce the amount of fat in their diets, particularly saturated fats, and diabetics in particular are advised to reduce their overall caloric intake, Dr. Hays explained in an interview in San Diego during the conference.
Whereas a normal diet would be in the order of 1800 to 2100 calories, with 60 percent of calories coming from carbohydrates and 30 percent from fat, patients in this diet were restricted to 1800 calories per day and were encouraged to get 50 percent of their caloric intake from fat, and just 20 percent from carbohydrates. The balance of 30 percent would come from proteins.
A whopping 90 percent of the fat content in their diets was saturated fat, compared with just 10 percent that was monounsaturated fat.
"I think this is at least worth considering for any diabetic," Dr. Hays said in an interview. "The thing many diabetics coming into the office don't realize is that other forms of carbohydrates will increase their sugars, too. Dieticians will point them toward complex carbohydrates ... oatmeal and whole wheat bread, but we have to deliver the message that these are carbohydrates that increase blood sugars, too."
Higher-fat diets, on the other hand, seem to make the person feel full faster so they eat less; higher-fat diets also tend to reduce postprandial hypoglycemia so the patients feel better after eating.
"Every diabetic comes home from the doctor with instructions as to what their diet should consist of, but they're not getting the information from dieticians about what complex carbohydrates they should eat," Dr. Hays said.
"The important thing here is no ketosis. We absolutely don't want people to become ketotic, and so we said they had to have so many exchanges of fresh fruits and vegetables and we specified the ones they could eat."
They were able to eat all the meat and cheese they wanted, but as for carbohydrates, they are restricted to eating unprocessed foods, mainly fresh fruit and vegetables, he added.
Subjects recruited into the study (84 men, 73 women) were all type 2 diabetics and were required to undergo a standard American Diabetes Association modified diet for one full year before entry into the trial. Over the course of one year, the subjects achieved a mean decline in total cholesterol of between 231 and 190 mg/dl. Triglycerides declined from 229 to 182 mg/dl.
Low-density lipoproteins (LDL cholesterol) fell from 133 to 105 mg/dl, while HDL increased from 44 to 47 mg/dl.
HbA1c, which at the start of the study averaged 3.34 percent above normal, declined to the point that at one year, the mean was just 0.96 percent above normal. The average weight loss among subjects in the study was in the order of 40 pounds, Dr. Hays said.
By the end of the one-year study, he added, 90 percent of the patients had achieved ADA (American Diabetes Association) targets for HbA1c, HDL, LDL and triglycerides.
Even among juvenile diabetics, he said, they might not be overweight and they might have more or less normal lipid levels, but when they are on this kind of diet it is possible to treat them with lower doses of insulin and make their lives a little safer, he said.
As for the response from cardiologists who see a high-fat diet as anathema to what they have been instructing their patients for years now, Dr. Hays said he has three cardiologist patients who are now on the diet.
"If you have a diet that results in weight loss, lower cholesterol, and a better lipid profile, eventually, everybody will be eating that way. It's going to come whether we like it or not."
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Posted: Wed Sep 14th, 2005 02:05 |
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Eye problems are common in diabetics
The renin-angiotensin-aldosterone system and the eye in diabetes.
http://tinyurl.com/67ldp
Immuno-localization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye.
http://tinyurl.com/552tv
Retinopathy
Retinopathy, in general, is a very common occurrence in Type 1 Diabetics, many of whom end up blinded by it.
A similar process, macular degeneration, is an inflammatory process (see http://tinyurl.com/yjthzk ).
Reduction of retinopathy during the course of the MP (in others) would tend to indicate it is also an inflammatory process. However, several of my Diabetes-research colleagues were convinced it was caused by the body failing to assimilate exogenous insulin correctly. see diagram summarizing some of the key relationships between the body's hormones and 1,25-D. You can access it at http://autoimmunityresearch.org/hormones.pdf
Be careful of the lasers. Th1 tissues don't heal as easily, and certainly not when a lot of incident radiation has been focused on them (excess Vit D production).
There is no effective treatment for Diabetic Retinopathy, so I would doubt that it "could be prevented with early detection." I would like to see real data to back up that assertion
Peripheral blood vessels are profoundly affected during Th1 disease, usually by increased vascular permeability, but I am not sure how that translates to the retina. Blood flow takes a while to return to normal, maybe 3-5 years, depending on how sick you were in the first place.
The disease mechanisms are complex, I wouldn't even venture to fully characterize them. Blood flow is a very small part of it, as the changes that influence blood flow are the critical factors.
Dr. Trevor Marshall, Ph.D
See Pubmed: a common antibiotic called minocycline may slow or prevent diabetic retinopathy
Members' experiences
-I am a type 1 diabetic on MP, on an insulin pump. I have had DM for 46 years. Since being on MP, I have not experienced any negative issues with my diabetes. In fact, my A1C has improved, my eyes show no signs of retinopathy and I am checked every 6 months - she even took photos of my retinas they were so perfect! ~debbie y
As was sorting through the genes transcribed by the VDR I noticed that several of them were involved with retinal structure. I suspect the improvements in your eyes are not just due to reduced inflammation, but also increased transcription of these retinal structure proteins. ..Trevor..
Adequate eye protection is essential
See Protecting Your Eyes
-I started wearing my Bolle 100s around the house, and stayed inside until I get my 2% NoIRs 207s. WOW - just by wearing the Bolle's inside, the spots in my eyes went down about 80% in about 8hrs! After 4-5 days of wearing Bolle's inside, I'd say my spots are about 10%-20% of what they were (yay!). I just recv'd my 207s so now I can go outside. btw, Trevor said it was essential that I wear Bolle's inside and 2%'s outside, especially because of my retinopathy. ~rc45guy
Numerous anecdotal reports confirm the effects of increased and decreased light on the eyes of patients with Th1 inflammation.
See also:
Eye Inflammation
Eye inflammation, vision, and bacteria
Testimonials to the need to wear adequate eye protection.
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Posted: Fri Sep 23rd, 2005 06:47 |
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Pancreatic transplants have high failure rate
I just attended a conference on Autoimmune Clinical Research and one of the papers was on Diabetes Type 1. It was reporting failures of pancreatic transplants, as they lost the ability to generate insulin after about 7 months.
The speaker was very insistent that this was due to an unknown cause, as they specifically looked to make sure (by biopsy) that there was no organ rejection. When they showed the biopsy slides with monocytes invading the new pancreas I knew we had a winner here
The monocytes had started to infiltrate the new pancreas by about 7 months, which is a very similar time to that it takes for granuloma to start to form in lungs transplanted into Sarc patients (granuloma are 90% monocytes). Glycogen was still being accreted by the islet cells, but the insulin secretion had already shut down.
..Trevor..
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Posted: Sun Sep 25th, 2005 01:08 |
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HbA1c
HgA1c is a long-term measure of blood-sugar control. It is useful because it measures the average control over a long period of time. I would not be surprised if it elevated mildly, due to herx,while the pathogens were being killed.
Remember that an untreated diabetic would expect a gradual increase in hgA1c as their condition worsened over their lifetime. At some point, however, you should expect yours to start dropping, but probably not until most of the herx is behind you.
..Trevor..
The Hemoglobin A1C test is not directly related to the CBC hemoglobin. It is used to get an idea of what your blood sugars have been over the last two to three months.
There is some information on it here… Hemoglobin A1C
When your fasting blood sugar has "jumped" on a lab test, your Dr may order the Hemoglobin A1C to check if there is any reason to run further tests.
You should request the Hemoglobin A1C test before going through a glucose tolerance test which requires multiple blood samples.
Low Blood Sugar (Hypoglycemia)
Low blood sugar can make you feel:
-shaky
-weak
-confused
-irritable
-hungry
-tired
-you may sweat a lot
-you may get a headache
If you have these symptoms, check your blood sugar.
If it is 70 or lower, have one of the following right away:
· 3 or 4 glucose tablets
· 1 serving of glucose gel (check the label—you’ll want the amount equal to 15 grams of carbohydrate)
· 1/2 cup (4 ounces) of any fruit juice
· 1/2 cup of a regular (not diet) soft drink
· 1 cup (8 ounces) of milk
· 5 or 6 pieces of hard candy (jelly beans are convenient to carry with you)
· 1 tablespoon of sugar or honey
After 15 minutes, check your blood sugar again.
If it is still too low, have another serving.
Repeat until your blood sugar level is 70 or higher.
If it will be an hour or more before your next meal, have a snack.
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Posted: Thu Dec 8th, 2005 03:09 |
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ARBs and diabetes
Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus.
Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.
From The British Journal of Diabetes and Vascular Disease
Dual Blockade of the Renin Angiotensin System in Diabetes
Angiotensin II receptor blockers decreased blood glucose levels: a longitudinal survey using data from electronic medical records.
Cardiovasc Diabetol. 2007 Sep 29;6(1):26 [Epub ahead of print]
PMID: 17903269 [PubMed - as supplied by publisher]
Clinical and experimental aspects of olmesartan medoxomil, a new angiotensin II receptor antagonist.
Cardiovasc Drug Rev. 2004 Winter;22(4):285-308.
PMID: 15592575 [PubMed - in process]
Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models.
ARBs are being used prophylactically in diabetes to prevent retinopathy and nephropathy.
Here are a few references:
Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes.
PMID: 15716329 [PubMed]
J Am Soc Nephrol. 2005 Apr;16(4):1135-40. Epub 2005 Feb 16.
Pharmacological and pharmacokinetic study of olmesartan medoxomil in animal diabetic retinopathy models.
Eur J Pharmacol. 2005 Apr 11;512(2-3):239-46.
PMID: 15840410 [PubMed]
The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics.
J Renin Angiotensin Aldosterone Syst. 2005 Mar;6(1):25-32.
PMID: 16088848 [PubMed - indexed for MEDLINE]
The angiotensin II receptor antagonist candesartan cilexetil (TCV-116) ameliorates retinal disorders in rats.
Diabetologia. 2001 Jul;44(7):883-8.
PMID: 11508274 [PubMed - indexed for MEDLINE]
Insulin Resistance, Inflammatory Biomarkers, and Adipokines in Patients with Chronic Kidney Disease: Effects of Angiotensin II Blockade.
Last edited on Wed Mar 5th, 2008 07:10 by Foundation Staff
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Posted: Mon Jul 31st, 2006 01:53 |
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Link Between Diabetes and Alzheimer’s Deepens
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Posted: Tue Dec 5th, 2006 07:03 |
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(filelink)
Interview with Dr Randall Wolcott, bacterial biofilm wound specialist:
http://bacteriality.com/2008/04/13/wolcott/
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Posted: Tue Feb 20th, 2007 04:34 |
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The Renin-Angiotensin system and insulin resistance.
Curr Diab Rep. 2007 Feb;7(1):34-42. Liu Z. Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, PO Box 801410, Charlottesville, VA 22908-1410, USA.
Insulin resistance upregulates the renin-angiotensin system (RAS), which contributes to the pathogenesis of hypertension, heart failure, and atherosclerosis. RAS inhibition decreases cardiovascular and renal morbidity and mortality and the incidence of new-onset type 2 diabetes. To the same degree, angiotensin II impairs insulin signaling, induces inflammation via the nuclear factor-kappaB pathway, and reduces nitric oxide availability and facilitates vasoconstriction, leading to insulin resistance and endothelial dysfunction. Thus, the RAS, insulin resistance, and inflammation perpetuate each other and coordinately contribute to endothelial dysfunction, vascular injury, and atherosclerosis.
PMID: 17254516 [PubMed - in process]
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Posted: Sun Aug 19th, 2007 05:32 |
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Angiotensin II Receptor Blockade Expert Column
Angiotensin Receptor Blockers: Benefits Beyond Blood Pressure Lowering?
Michael A. Weber, MD
Medscape Cardiology. 2007; ©2007 Medscape
Posted 06/26/2007
Editor's Note
Michael A. Weber, MD, is Professor of Medicine in the Cardiology Division at the State University of New York (SUNY) Downstate Medical College of Medicine (Brooklyn, New York). Dr. Weber's main areas of interest are hypertension and preventive cardiology, and he has been involved in numerous clinical trials in patients with hypertension and those at high risk for cardiovascular events or recurrent strokes. He is also an active participant in trials involving patients with diabetic and nondiabetic nephropathy. Dr Weber currently serves on the steering committees of several national and international clinical outcomes trials. He has published numerous research articles and has authored/edited 16 books. He was one of the founders of the American Society of Hypertension (ASH) and has served as President of the Society. He has also served on the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration.
ARBs vs ACE Inhibitors
Medscape: What do we currently know about the effects of angiotensin receptor blockers (ARBs) beyond blood pressure lowering? Do we know that they differ from angiotensin-converting enzyme (ACE) inhibitors, or are ARBs just ACE inhibitors without the side effects of cough, etc?
Dr. Weber: To date it has been difficult to fully separate ARBs from ACE inhibitors. ACE inhibitors have been around almost 15-20 years longer than ARBs, so they have built up a strong list of credentials in terms of cardiovascular and metabolic effects. For example, we know that ACE inhibitors, beyond their ability to lower blood pressure, improve outcomes and survival in patients with heart failure, people with prior myocardial infarction (MI), and patients with type 1 diabetes and kidney disease. With ARBs we expect that there might be similar but potentially also different results when we analyze outcomes, because of their different mechanism of action. They act very specifically by blocking the renin-angiotensin system, and particularly by preventing angiotensin II from having its effects at the so-called AT1 receptor. ACE inhibitors, on the other hand, have a mechanism of action that is not as precise. In fact, they may only partly prevent formation of angiotensin II and so not completely block the renin-angiotensin system. On the other hand, ACE inhibitors reduce breakdown of bradykinin, which may have beneficial effects. So from a pharmacologic point of view, it is very reasonable to assume that the 2 drug classes -- ACE inhibitors and ARBs -- may produce different outcomes.
Having said all that, we now know that ARBs have very comparable beneficial effects to ACE inhibitors in patients with heart failure,[1-5] and almost identical benefits in patients who have had an MI with residual left ventricular dysfunction.[6] We also have very strong data with ARBs in patients with diabetic nephropathy, where we see, quite independent of their blood pressure effects, significant protection for those patients in preventing progression to end-stage renal disease.[7-10] That is a subtle but potentially interesting difference between ACE inhibitors and ARBs: The data with ACE inhibitors were obtained in patients with type 1 diabetes and kidney disease, and now for the first time we have compelling data in patients with type 2 diabetes and kidney disease, but only in studies with ARBs.
Medscape: The studies that demonstrate the non-blood-pressure-lowering effects of ARBs have usually only been carried out with 1 or 2 drugs. Would the results of these studies hold for the entire ARB drug class?
Dr. Weber: We always assume the possibility that what is true for one ARB will be true for others. For instance, in heart failure we have definitive data with valsartan and candesartan. Valsartan was used in the Valsartan Heart Failure Trial (Val-HeFT)[1] and candesartan in the Candesartan in Heart Failure -- Assessment of Mortality and morbidity (CHARM) trial.[2-5] In both studies, the ARB showed significant benefits and both of these ARBs are now indicated for the treatment of heart failure. Valsartan was also shown in the Valsartan in Acute Myocardial Infarction Trial (VALIANT)[6] to be at least as good as the ACE inhibitor captopril in patients with left ventricular dysfunction following an MI. That was really a major study; and at this point valsartan is the only ARB able to claim that kind of benefit in those patients. Other ARBs might have the same effect, but we do not have any data as of yet. So it is tempting always to talk about class effects, but at the same time one ought to be cautious.
Slowing the Progression of New-Onset Diabetes
Medscape: One effect of antihypertensive drugs that always gives rise to a lot of debate is the one on new-onset diabetes mellitus. Do ARBs really have a better protective effect than other drug classes, as suggested in a recent meta-analysis?[11] Do we know anything about the mechanism of this effect?
Dr. Weber: I would say that at this time, both ACE inhibitors and ARBs can be said to be useful in preventing or delaying progression of nondiabetic patients into type 2 diabetes. So far, neither drug class, nor any single drug, has stood out. Most of the studies in which an ACE inhibitor or an ARB has appeared beneficial have been in comparison with drugs known to have potentially deleterious effects on progression to diabetes such as diuretics and beta-blockers. However, in a substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,[12] valsartan was shown to be superior to the calcium channel blocker (CCB) amlodipine at preventing new-onset diabetes. This is interesting, because amlodipine itself is somewhat beneficial in terms of improving glucose metabolism, so for valsartan to be superior to amlodipine is quite noteworthy. Whether other ARBs could do the same remains to be examined.
It is important, though, that when we talk about preventing new-onset diabetes, we face the rather sad truth that these drugs are not completely preventing new-onset diabetes. It is more accurate to think of them as slowing down the rate of progression to true diabetes. So in the end, most patients destined to become diabetic will still become diabetic, but if they are taking valsartan they will do so at a later time, which, of course, is very useful, clinically and economically. The longer we can delay diabetes, the better off are our patients, and ARBs are very effective in that way.
Medscape: What will the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial tell us about ARBs and incident diabetes?
Dr. Weber: NAVIGATOR is using the oral antidiabetic agent nateglinide and the ARB valsartan in high-risk patients with impaired glucose tolerance. The primary endpoint of the trial is the occurrence of a major cardiovascular outcome, and I think we are all hoping to be pleased by what we might see. But a key secondary endpoint of NAVIGATOR is new-onset diabetes, and that will allow us to learn whether valsartan performs the way we predict. We expect to hear the first results of NAVIGATOR in 2008.
The Importance of Long-term Follow-up
Medscape: In the recently reported Diabetes Reduction Approaches With Ramipril and Rosiglitazone Medications (DREAM) study,[13] the use of ramipril for 3 years did not significantly reduce the incidence of diabetes in patients with impaired fasting glucose or impaired glucose tolerance over 3 years. Does this result have any implications for ARBs?
Dr. Weber: Every clinical trial inevitably seems to create its own cluster of controversies, and in the case of DREAM some people at first sight felt that the ramipril arm was something of a disappointment. There was actually a significant improvement in the patients brought into the study with so-called prediabetes (impaired glucose tolerance) back into normoglycemia; so quite a few people who appeared to have been on the brink of diabetes were rescued and returned to normal status. As far as preventing new-onset diabetes was concerned, although there was no significant benefit associated with ramipril, there was a trend in that direction. It was unfortunate that for the first year or two of the study, ramipril had no effect whatsoever in preventing new-onset diabetes; but as the study continued, the effect appeared and was getting stronger and wider with each passing month. When the study was finally stopped, the effect of the drug was not yet statistically significant, but the investigators running the study are now being criticized for stopping it too early. So there is always a story and there is always a controversy with trials; but having seen the data, I remain confident that ramipril is a useful antidiabetes drug. It may not be the best, however; there may be others, perhaps some of the ARBs, that are more effective.
Medscape: How long would a clinical trial with an ARB, or another drug, need to run to show when the effects on new-onset diabetes, diabetic nephropathy, etc, would start translating into a reduction of events?
Dr. Weber: That is such a difficult question. There was an Italian study of new-onset diabetes, not the most robust or authoritative of studies, but it indicated that the effect of new-onset diabetes on clinical events did not emerge for at least 5 years.[14] It was only because these patients were followed for 15 years that the investigators were able to get some sense of the importance of drug-induced diabetes in hypertension in leading to events.
So I believe there is a benefit in terms of event reduction if you can prevent new-onset diabetes, but it will not be apparent within 3-5 years; it may take a long time. This is a very long-term investment and I do not think that many clinical trialists could get the support or, frankly, would have the patience to follow patients for 12-15 years to see whether preventing new-onset diabetes really does prevent events. Most of us accept that preventing diabetes will have long-term benefits, but we are not likely to see authoritative proof.
Animal Studies
Medscape: What do animal studies tell us about how ACE inhibitors or ARBs prevent diabetes? For instance, there have been studies in mice suggesting that blockade of the renin-angiotensin system affects pancreatic beta cells, etc.
Dr. Weber: That is fascinating. The renin-angiotensin system seems to mediate a number of adverse events in the islets of the pancreas, and there are at least 2 ways in which angiotensin could predispose to diabetes. First, angiotensin stimulates growth factors in the islets, such as transforming growth factor beta-1 (TGF- beta 1), that increase fibrosis in the islets, which in time has the effect of damaging and engulfing the beta cells that actually produce the insulin. Second, there seems to be a direct effect of angiotensin within the islets on the beta cells themselves, and this effect seems to hasten so-called apoptosis, the permanent death of those cells. So there are several reasons to assume that effective blockade of the renin-angiotensin system would directly support the function of the pancreas, and it has been demonstrated in animal models. It would be more difficult, obviously, to show it in humans.
Medscape: A recent animal study has suggested that another benefit of ARBs might be to prevent diabetes-associated sexual dysfunction.[15]
Dr. Weber: That is something that needs to be explored. There have been some superficial clinical studies, including one in which valsartan was compared with atenolol. The people on valsartan reported better sexual activity, with atenolol having a negative effect.[16]
Protecting Against Myocardial Infarction
Medscape: There has recently been a lot of discussion, some of it contentious, about the effect of ARBs and MI.
Dr. Weber: The discussion has been about whether blockers of the renin-angiotensin system are as good at preventing MIs as we would have predicted based on our knowledge of the renin-angiotensin system and our belief that it is a major contributor to coronary events. The most recently published meta-analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC)[17] concluded that ACE inhibitors are truly efficacious at preventing MIs and perhaps superior to other drug classes in doing so. Usually there are so many variables in this sort of statement, because blood pressure reductions and many other factors that could affect the likelihood of MIs must be accounted for. In the hands of this very experienced group, however, there seemed to be evidence that the ACE inhibitors are truly beneficial and perhaps more so than other classes.
So where does this leave the ARBs? There has been some concern, perhaps driven by poorly understood data from a few of the major trials, that ARBs may be less efficacious than other drug classes in preventing heart attacks.[18-21] This has now been firmly refuted, and in their latest review the BPLTTC says quite categorically that there is no evidence whatsoever to justify any concern about ARBs, but rather that they are just as effective as any other classes of antihypertensive drugs in protecting against MIs. The group even adds that there are not yet enough data to take the analysis further and examine whether ARBs could even be superior to certain other drug classes used for treating hypertension. It is again important to recognize that the data are not yet strong enough and the experience not yet broad enough for any conclusion along those lines to be properly examined; but even so, it is promising, and ongoing studies may reveal more about this.
Important additional information in this discussion will come from the results of a very large trial, scheduled to finish at the end of 2007, which will probably be announced in March 2008. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)[22] is a perfect study to answer the questions that we are considering here. It is a head-to-head comparison of a well-established ACE inhibitor, ramipril, which was very effective in providing survival and endpoint benefits in high-risk cardiovascular patients in the Heart Outcomes Prevention Evaluation (HOPE) trial,[23] vs telmisartan, which is a powerful, long-acting ARB. ONTARGET is basically a repeat of the HOPE study in high-risk cardiovascular patients, but now comparing an ARB and an ACE inhibitor. That will give us fascinating information and should resolve many of these issues once and for all. ONTARGET is also examining the combination of the ACE inhibitor and the ARB, and that may turn out to be most effective at improving survival and reducing major endpoints. If so, then this sort of combination treatment may become a standard approach for people with high-risk cardiovascular status.
Medscape: With respect to the HOPE trial, there was some discussion as to whether the risk reduction seen for stroke and cardiovascular endpoints in the HOPE study were really greater than could be accounted for by the small reduction in measured blood pressure.[24-27]
Dr. Weber: That is a very relevant point, because many people did believe and still do believe that some of the benefit of ramipril in the HOPE study was because it had a blood pressure-lowering effect, and even the authors of the study themselves have acknowledged that as much as 50% of the supposed benefit of the ACE inhibitor could be attributed to its blood pressure- lowering effects.[28-30] Of course, there are many people who say that they do not care whether there was a blood pressure effect or not. The point is, the trial asked whether -- on top of all the other treatments that patients with high cardiovascular risk were supposed to be taking -- would adding an ACE inhibitor provide a benefit compared with adding placebo? The answer was, yes, it provided a very strong benefit. Perhaps blood pressure lowering was a part of that, but there was nothing to stop people in the placebo arm from getting whatever antihypertensive drugs they needed to help reduce their blood pressure. So if you take the point of view that this was a true intent to treat, a full exposure of patients to the best available therapies, then however ramipril worked, and however it achieved its results, it did so. The same question will come up with the ONTARGET trial, because telmisartan is probably a better blood pressure-lowering drug than ramipril. All the ONTARGET investigators have been told to ensure that they treat any hypertension effectively, so hopefully there will not be a blood pressure story to confound the results. If there is, however, I would take the view that it is largely irrelevant if there is a blood pressure inequality, because investigators were told to do everything they could to prevent this inequality. Frankly, at this point, we have to put blood pressure behind us and see what the real results are.
Expanding Indications
Medscape: What is the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trial?
Dr. Weber: TRANSCEND is a trial being done in parallel with ONTARGET, and it is an important study. It is a comparative study of an ARB, again telmisartan, vs placebo in patients who are intolerant of ACE inhibitors. So this is a situation where it was perfectly ethical in high-risk cardiovascular patients to compare an ARB with placebo. That study is also well advanced, and I believe the results will be announced later in 2008.
Medscape: What is your opinion about the effect of ARBs on diastolic dysfunction? The results of the Valsartan In Diastolic Dysfunction (VALIDD) trial,[31,32] announced at the recent American College of Cardiology meeting, did not show any benefit for an ARB-based regimen over aggressive blood pressure lowering with a regimen of non-renin-angiotensin system-inhibiting drugs in prehypertensive adults with diastolic dysfunction, as measured by tissue Doppler imaging.
Dr. Weber: Diastolic dysfunction in difficult to study. A long-term study is needed if it is going to be events-driven, rather than just depending on studies of function. There was an intriguing finding in the CHARM-Preserved study of a borderline benefit in preventing hospitalizations for heart failure compared with placebo on top of all other treatments, although there was no mortality benefit.[5] The currently ongoing Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE)[33] trial, a true large-scale, robust, well-designed comparison of irbesartan with all other drugs that are not renin-angiotensin system blockers in patients with diastolic dysfunction, will be the definitive study in this area. However, the fact that diastolic dysfunction has not responded particularly well to ACE inhibitors or to ARBs up to this point leads me to suspect that the etiology of the dysfunction, which is obviously related to the abnormal tissue properties of the left ventricle, is not being driven primarily by the renin-angiotensin system. I think we are going to have to wait for some rather innovative pharmacologies to truly address what is happening in those left ventricles.
Medscape: ARBs have also been reported to have a benefit in preventing stroke.
Dr. Weber: There have been several studies on ARBs and stroke, including the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES)[34] trial, the Study on Cognition and Prognosis in the Elderly (SCOPE)[35] trial, and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)[36,37] study. In all of these trials, an ARB was better than other drugs at preventing strokes. In the LIFE study, the ARB was compared with the beta-blocker atenolol; but even if one is skeptical about a beta-blocker as a comparator, the MOSES study, which was a small but well-conducted, relatively rigorous trial, compared an ARB with a CCB, nitrendipine, which is widely used in Europe, and which has powerful antistroke credentials of its own. Nitrendipine was the drug used, for example, in the Systolic Hypertension in Europe (Syst-Eur)[38] trial, in which it showed dramatic benefits in stroke prevention.[38] In MOSES, nitrendipine and the ARB eprosartan achieved identical blood pressure effects in patients who had had previous ischemia; but by the time the study was over, eprosartan was associated with a 25% relative reduction in new strokes. That raises an issue as to whether there is something special about ARBs.
Pharmacologists have hypothesized that the ARBs do not just block the renin-angiotensin system, but they do it in such a selective way that they actually enhance the effect of angiotensin on the AT2 receptor, which may have a protective effect on nerve tissue. This has been shown in animals, but whether that is a mechanism for why these drugs may have a stroke benefit in humans is another question that has yet to be explored. Of course, the ONTARGET study will address that question as well. It will be fascinating to see whether the ARB and the ACE inhibitor combination have the same stroke effects or whether one is better than the other.
Medscape: ARBs have also been associated with a reduced risk of developing new-onset atrial fibrillation.
Dr. Weber: We are tantalized at the moment by the atrial fibrillation story. We know, particularly from meta-analyses,[39-41] that ACE inhibitors can be shown to prevent new-onset atrial fibrillation, and the same is true for ARBs.[42-45] There were some very nice data from the LIFE study,[42] and even though people are a little critical now of that study -- because atenolol is not regarded as an optimal comparator -- you would nonetheless assume that a beta-blocker should be effective at protecting against atrial fibrillation. Yet in that particular study, the patients who received losartan had about a one-third reduction in the incidence of new-onset atrial fibrillation. To me that was compelling information, and there are now some exciting mechanistic studies being done by electrophysiologists that seem to show that there are angiotensin receptors that activate -- or at least in some ways regulate -- the flow of cardiac electrical impulses. Such findings lead one to believe that drugs that block the renin-angiotensin system, perhaps particularly ARBs, could potentially be good anti-atrial fibrillation drugs. We are a long way off from making such a strong assertion, but it is a beguiling thought.
Dosing and Future Outlook
Medscape: If patients were to benefit from all these non-blood-pressure-lowering effects of ARBs, would the highest approved dose be sufficient, or do you think that they would need an even higher dose?
Dr. Weber: This is a difficult issue. With all these drugs, not only the ARBs, but also the ACE inhibitors, the CCBs, etc, we tend to achieve some sort of a belief in doses based on the first major indication for which these drugs are tested, which is often hypertension. So we learn what the best doses for ACE inhibitors and ARBs are for treating high blood pressure, and we assume that when we have reached a dose of drug beyond which you get no further reduction in blood pressure, that we have maximized the dose range. That is correct, but only for high blood pressure. There may be a totally different dose range needed to protect the kidney or to protect the myocardium. For instance, as far as the kidney is concerned, if we use the so-called maximum dose of an ARB and measure its effect on proteinuria, we will typically see about a one-third reduction in proteinuria. With so-called super doses, however, such as valsartan 640 mg instead of 160 mg or 320 mg, even though there is no further reduction in blood pressure, there is a significant further reduction in proteinuria. Likewise with irbesartan: Instead of stopping at 300 mg, if we go to 600 mg and 900 mg we see better and better proteinuria effects. So this is teaching us that just because we have reached the maximum dose for blood pressure, it does not mean that we have reached the maximum dose for what these drugs might do at other tissues, regulating other cardiovascular outcomes of interest.
Medscape: How will physicians prescribing for blood pressure control feel about these additional benefits? Maybe they do not have enough time to worry about them because they just want to get the blood pressure down to targets with the approved doses?
Dr. Weber: Your statement is absolutely accurate at the moment. The doctor treating high blood pressure will be satisfied when the blood pressure is brought under control. If there is some reason to suspect that other things are going on, such as kidney involvement or heart failure, then there might be a reason to think about alternatives. No one has done definitive studies with "super dosing" of the ARBs or the ACE inhibitors. It is a pity, because these drugs are well tolerated and it would probably be possible to go up to 2, 4, 8, or even 12 times what is now regarded as the top dose without producing major adverse effects. However, we do not have that information as yet, and so it is not possible to advise administering any dose in excess of what is currently the maximum recommended dose.
Medscape: When do you think we will have answers about these benefits beyond blood pressure lowering with ARBs?
Dr. Weber: It is an exciting time at the moment and a good time to raise these questions. I predict that by the end of 2008 we will know a lot more about these effects of ARBs.
Supported by an independent educational grant from Novartis
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Michael A. Weber, MD, Professor of Medicine, Cardiology Division, State University of New York (SUNY) Downstate Medical College of Medicine, Brooklyn, New York
Disclosure: Michael Weber, MD, has disclosed that he has served as a consultant for Boehringer Ingelheim, Daiichi-Sankyo, Forest, Gilead, Merck & Co., Inc., Novartis, and Takeda. Dr. Weber has also disclosed that he was a speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Forest, GlaxoSmithKline, Merck & Co., Inc., Novartis, Pfizer, and sanofi-aventis.
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