ACCORD/ADVANCE/VADT/ORIGIN/TECOS – T2D 39

//ACCORD/ADVANCE/VADT/ORIGIN/TECOS – T2D 39

Tired of all the controversy, and still confident of the benefits of blood glucose lowering, the National Institutes for Health in the United States funded a huge, ambitious randomized controlled trial involving over 10,000 patients called the Action to Control Cardiac Risk in Diabetes (ACCORD) study to assess the benefits of intensive glucose control. After all, this was the standard diabetes advice of virtually every doctor in the world. Every medical school student had been indoctrinated to believe that this was the ‘best’ treatment approach.

Intensive medical therapy certainly reduced the A1C from 7.5% to 6.5%, a large and meaningful reduction. Great, but that’s not the question we are interested in. Did this make any difference to health? It sure did. When the trial results broke in 2008, there was a media firestorm.

Why? Intensive treatment was killing people!

The safety committee forced a premature end to this trial. It was unethical to continue a treatment that was potentially lethal. Completely contrary to expectations, intensively treated patients were dying faster at a rate 22% higher than the standard treatment group despite, or perhaps because of the intervention. This equaled one extra death for every 95 patients treated. It could not be ethically allowed to continue, although this trial could not specify the reasons for the increased mortality.

At the same time, the randomized double blind controlled ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial results were published. Once again, this blood glucose reducing strategy failed to deliver cardiovascular benefits, although at least there was no increase in mortality.

Not all interventions were futile. The ADVANCE trial revealed that blood pressure lowering medications reduced cardiovascular disease, as expected. Certain medications did truly benefit patients, but those that reduced blood glucose did not.

Two further randomized controlled trials quickly followed to confirm these disappointing results. The Veterans Affair’s Diabetes Trial (VADT) found that medications to lower blood glucose produced no significant benefits to heart, kidney or eye disease.

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial treated pre-diabetic with early initiation of insulin, with the hope of reducing heart disease. Unfortunately, the answer is no. There was no reduction in heart disease, stroke, eye disease, or peripheral vascular disease. There were no measureable health benefits. Further experience with a new class of agents, the DPP4 inhibitors only confirmed the futility of blood glucose lowering as a therapeutic strategy.

TECOS/ SAVIOR

In 2006, the FDA approved a new class of blood glucose lowering medication called the dipeptidyl peptidase 4 (DPP4) inhibitors. . Incretins are hormones released in the stomach, which increased the insulin secretion in response to food. The DPP4 inhibitors blocked the breakdown of the incretin hormones thus boosting levels. However, the insulin response was not sustained and thus, these drugs did not cause weight gain.

There were high hopes for the new DPP4 inhibitors. These drugs could lower blood glucose, with a low risk of hypoglycemia and no weight gain. The SAVIOR study was published in 2013 and the TECOS study was published in 2015, evaluating two new medications for the treatment of type 2 diabetes.

While there were no safety concerns, hopes were soon dashed that they would save lives. There were no protective effects, despite blood glucose lowering. Cardiovascular disease was not affected one way or the other.

The ACCORD, ADVANCE, and VADT trial all continued longer term follow up and published extended results (15,16, 18), but this yielded little new information. All trials agreed that intensive treatment did not save lives and had marginal benefits if any. Furthermore, there were adverse health consequences. Medications often increased weight gain and hypoglycemic reactions. Using more medications to lower blood glucose was obviously not beneficial.

The glucotoxicity paradigm, which formed the bedrock of medical treatment of type 2 diabetes was entirely, and irrevocably shattered. What was going on?

Inflammation

Atherosclerosis, the buildup of plaque in the arteries that contributes to heart disease and strokes is an inflammatory process, rather than simply cholesterol clogging up the artery like sludge in a pipe. This ‘hardening’ of the arteries is caused by injury to the lining of the blood vessel, which sets off the inflammatory response. Inflammatory mediators such as high sensitivity C-Reactive Protein (hsCRP), interleukin 6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFr2) are measurable blood markers of this process and all independent predictors of cardiovascular disease.

Treatments that reduce blood vessel injury also reduce inflammation, a more easily measured marker. Does lowering blood sugars lower inflammation? Not so much. In the LANCET metformin trial, treatment reduced blood glucose but left inflammatory markers essentially unchanged. The insulin group raised hsCRP and IL-6, indicating more, not less inflammation. Yeah, that’s bad. Insulin is making things worse, not better. While insulin made blood sugars better, it made the diabetes worse. Drugs could not reduce the inflammation, and therefore could not prevent atherosclerosis, an inflammatory disease.

Likewise, the coronary artery calcification score, an indication of the burden of atherosclerotic plaque in the heart, is not correlated to measures of blood glucose control such as the A1C. But what was the problem?

Tradeoff

Standard medications for type 2 diabetes represent a tradeoff between glucotoxicity and insulin toxicity. Both insulin and SUs increase insulin to reduce hyperglycemia. The effect of the increased insulin becomes clinically obvious as weight gain, as hyperinsulinemia is the main driver of obesity. The price of better glucose control was higher insulin dosage, and there is no net benefit. These medications simply trade lower glucotoxicity for higher insulin toxicity.

Metformin and DPP4 medications use mechanisms other than raising insulin to lower blood glucose. But they do not lower insulin either. Once again, this manifests clinically with neither weight gain nor weight loss. Reducing glucotoxicity by itself produces minimal if any benefits. The hyperinsulinemia is the dominant feature of type 2 diabetes. Medications that do not lower the elevated insulin do no have benefits. Clinically, it becomes obvious that medications that lower blood glucose but do not lower body weight have no benefits.

Epidemiologic studies had shown a clear correlation between lower blood sugars and better health outcomes. Every 1% increase in the hemoglobin A1C was associated with an 18% increase in risk of cardiovascular events, 12-14% increase risk of death and a 37% increased risk of eye disease or kidney disease. But this was far from proof and made no distinction between medications and lifestyle measures.

Consider two type 2 diabetic patients with an identical A1C of 6.5%. One takes no medications and the other uses 200 units of insulin daily. Are these identical situations? Hardly. The first situation reflects mild diabetes while the other reflects severe diabetes requiring heavy doses of insulin. The cardiovascular risks are completely different and the use of medications does not reduce that risk.

The Hisayama Study compared A1C levels to risk of cardiovascular events. Importantly, this study differentiated between patients taking mediation versus those that did not. In those patients not taking medication, cardiovascular risk increased as the A1C increases. This is logical, since this reflects more severe type 2 diabetes.

What is telling though is the complete inability of the addition of diabetic medications to lower the risk of disease. This concurs with the evidence obtained through randomized controlled trials.

Recent research confirms the utter ineptitude of standard diabetic medications. Including all relevant trials up to March 2016, none of the drug classes considered, including metformin, SUs, TZDs and DPP4 inhibitors reduced cardiovascular disease or other complications despite the proven ability to lower blood glucose.

The results for insulin, when considered separately, came out even worse. Reviewing all available literature up to 2016, including twenty randomized controlled trials, researchers could only conclude that, “there is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D (type 2 diabetes). However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain.” In other words, insulin treatment carries no discernible benefits, but significant risks of adverse side effects. Insulin is “significantly more harmful than other active treatments”.

While the evidence is crystal clear, most diabetes guidelines have failed to reflect this new reality. Dr. Montori, of the Mayo Clinic reviewed published guidelines to find that 95% unequivocally endorsed benefit despite their non-existence.

The fact that insulin, SUs, metformin and DPP4 medications are proven to have no clinical impact on type 2 diabetes is of singular importance. Why would you take medications that have no benefits? Worse, why would you take medications that have no benefits and make you fat? These treatments should only be used when no other alternative is available for short-term reduction of blood glucose. But this situation never exists. As we shall see, there is always an available therapeutic lifestyle strategy. No, these medications are best described as “How NOT to treat type 2 diabetes”.

2017-10-12T19:48:57+00:00 40 Comments

About the Author:

Dr. Fung is a Toronto based kidney specialist, having graduated from the University of Toronto and finishing his medical specialty at the University of California, Los Angeles in 2001. He is the author of the bestsellers ‘The Obesity Code’ and ‘The Complete Guide to Fasting’. He has pioneered the use of therapeutic fasting for weight loss and type 2 diabetes reversal in his IDM clinic.

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40 Comments on "ACCORD/ADVANCE/VADT/ORIGIN/TECOS – T2D 39"

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Dawn Hudson-Taylor
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Yesterday a friend – a science graduate – told me that fat increases insulin resistance! The day before I was informed by a neighbour that eating sweet potatoes lowers the blood sugars!! Her husband died of a heart attack on a plane – he was a diabetic so she believed she was well informed about diet. And not long ago friends told me that if you have a lot of risk factors that will cause a disease or condition. They too are science graduates and have a son who is a doctor and a daughter who is a pharmacist. I… Read more »
Sean Raymond (Dietitian)
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Sean Raymond (Dietitian)
Dawn Hudson-Taylor – diets are complicated, comprised of different macronutrients in different ratios however studies that have looked at the immediate metabolic effects of saturated fat have shown it to induce an acute insulin resistant effect. In short – sat fat does seem to reduce insulin sensitivity so your friend was correct. The issue I take with these studies was that an isolated fat bolus was administered – this is not how we eat so a meal of saturated fat, protein and carbohydrate may have a buffering effect on the insulin resisting effect of the lipid. Transient glucose intolerance is… Read more »
Lori
Guest

Please cite your studies rather than making blanket statements. I would prefer to access them myself. Since this website is based on standing mainstream medicine on its head and seeing what shakes out, to quote others, please show me the science

Sean Raymond (Dietitian)
Guest
Sean Raymond (Dietitian)
Lori – Cite studies for what blanket statement? This is a comments forum, not a PHD thesis. Whatever it is I have said that you challenge or disagree with please state what and why – we can take it from there. I do not have the time to write such elegant posts that incorporate citations unfortunately but if you are more specific in what you are unsure of I will certainly post a link to a study or two when I can which will support everything I say. But I will do that upon request when the issue is more… Read more »
sten bjorsell
Guest
As I ointed out here before, most studies with diabetic-2 mice or rats start out make the animals diabetic-2. This is accomplished n a special high fat chow that makes the animals insulin resistant… But if you stop there, you are being lied to. Checking the chow gives two things. 1/ To the fat is 20% (!!!) sugar added 2/ Suppliers comments: Without the sugar, the animals won’t eat it. How many of today’s academics that went through that education found out about the insulin raising sugar and liver damaging fructose in that fat? Very few it seems to me.… Read more »
Dana
Guest

PUFA in excessive amounts in human beings has a longer-term effect on insulin resistance, making it worse. Dr. Michael Eades wrote about this recently; look him up.

And the idea that making your own glucose causes hyperglycemia is just absurd. Especially since you yourself admit that hyperglycemia is more strongly associated with high glucose intake. Way to argue with yourself in just one overly-long and convoluted sentence.

If you ever wonder why more and more people are trusting dietitians less and less, read your own comment.

Sean Raymond (Dietitian)
Guest
Sean Raymond (Dietitian)
Dana – not absurd. It is insulins failure to shut down endogenous glucose production post prandially which is the major cause of hyperglycaemia. The failure of insulin to promote GLUT 4 translocation in muscle cells does not inhibit whole body glucose disposal it just reduces it. Simply put, when we eat – the non insulin mediated pathway of glucose uptake seems to be able to adequately compensate for the failure of our insulin mediated pathway of glucose disposal. If you disagree with the role of hepatic glucose production in hyperglycaemia I am VERY interested for you to explain to me… Read more »
Sean Raymond (Dietitian)
Guest
Sean Raymond (Dietitian)

EDIT: I meant ” it is insulins failure to shut down endogenous glucose production post prandially in diabetics which is the major CONTRIBUTOR to hyperglycaemia”.

Stephen T
Guest

English clearly isn’t your first language. Learning to punctuate and write clearly would help the reader.

Sean Raymond (Dietitian)
Guest
Sean Raymond (Dietitian)

How are my posts unpunctuated to make them unreadable? English is my first language – thank you for informing me of your pointless assumption though.

thebigpicture
Guest
I’m an internal medicine physician. I’m begging you people to understand that hospitals, IT systems, etc. are putting in place the use of metrics in which we actually have to get hba1c within target parameters by using whatever meds necessary, including insulin. Read that again if you have to. It is now part of the doctor’s job description to treat type II diabetes in this fashion, which as we know will only make the problem worse. In fact, sometimes we even outsource the problem to pharmacists and nurse practitioners who just blindly follow the protocol. Also, when we refer patients… Read more »
Rodrigo Brzezinski
Guest

Dr. Fung,
Why did Empaglifozine (EMPAREG study) and Liraglutin (LEADER study) lead to a decrease in cardiovascular mortality in diabetics? Would not it be a counterpoint to your analysis?

Stephen T
Guest

Rodrigo, I can’t answer your question, but I always prefer a none drug solution, if at all possible, and it certainly is with type 2 diabetes. Why? Because trials funded by pharma are always designed to find the best possible outcome. They are the best case scenario and then some more. Drugs later found to killing people have trials showing benefit. Are there trials supporting metformin, insulin and all the best? No doubt.

Pharma has destroyed its own credibility with its short term greed, cynicism and manipulation of published results.

Ernest
Guest

Empaglifozine is an SGLT2 inhibitor – a kind of “low carb by peeing out Glucose” drug – it is expected to get better results with low carb (However be aware of the side effects of the SGLT2 inhibitors).
Liraglutin is a GLP1 drug which is compared against Sulfonylurea and Insulin. Therefore it is easy o show a better results.

It supports Dr. Fung’s analysis.

Guy Bedard
Guest

That entirely depends on who wrote the ‘studies’ doesn’t it? I would trust that Dr. Fung is correct thereby making the ‘studies’ indicate a confirmation bias for the drugs EMPAREG and Liraglutin.

Christina Walsh
Guest
Brilliant! Thanks Jason..am gonna email this article to my doctor who’d just love to stick me on metformin! Am doing intermittent fasting daily (sometimes a day off here n there) and love it! Makes so much sense..I feel better, can see weight,(waist size and belly going down) and am much happier.I grow a few organic veges.. still eat some processed foods but am working at trying to minimise them, but not totally banish them.. They have a place when you have a small income! Many thanks for the work you and your team do in brinigng us this much needed… Read more »
sten bjorsell
Guest
Reducing food intake can be done in a very simple way, using a little-known know-how about our digestive system! I am sure you can apply it to those processed bits! When we eat fat, best pure fat like butter or lard or coconut oil, our digestive system “halts” for a while. It allows the fat down out of the stomach into the small intestine. Then it closes the down side outlet of the stomach to enable preparing the fat with bile and enzymes to enable the later absorption of it. Eat the fat 20 -30 minutes before dinner, and then… Read more »
Andrew Miller, PharmD
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Andrew Miller, PharmD

Thoughts on the UKPDS study from 1998 that showed cardiovascular benefit in T2DM for metformin and has been the go to paper for defending metformin’s 1st line status in the guidelines? The study appears to be missing from the proposition above.

By the way, I fully support your position. I promote and follow a low-carb, 16/8 intermittent fasting diet myself.

Dr Leon Greeff
Guest

Thanks Jason, this gives some useful ammunition to reply to medical reps when they produce useless fodder about diabetic drugs.

Mary
Guest

I am very curious about a more in depth discussion around the usefulness of Metformin and the UKPDS study from 1998 that Andrew Miller’s post cites. Since many folks are on this, are you saying that that is worthless for diabetes care?

Becky
Guest

Does the body continue to produce as much insulin in T2D when Metformin and DPP4 medications reduce blood sugars. Am I correct in assuming that a T2D’s insulin production is not based on high blood sugars? I know I am missing a major point and I really want to understand. Help!

Ken Stephens
Guest
The first thing we need to be aware of is that you can’t take correlations with blood sugar and then claim that lowering blood sugar reduces the incidence. This is part of the trickery they use but this sure does fool a lot of people. You really have to measure the difference between treatments to see and when we do, then we see that this is really a smoke and mirror job. It’s not even a case of manipulating statistics here, the flaw here is a logical one. So what these general numbers do tell us is that the worse… Read more »
sten bjorsell
Guest
It seems mainstream has set out to use the same method to “prove” that their medications work among diabetics as among the rest of us. Pushing medications to lower blood sugar in just the same way as they still push statins to lower cholesterol. Both types medications are effective in their primary marketed senses, lowering blood sugar, lowering cholesterol. Since most of us are not familiar with studies like above, they can present the overall effect of these “treatments” in terms of how well they act on their respective -actually loosely correlated – primary target, talking often exclusively about that,… Read more »
Stephen T
Guest

Well said, Sten. Glucose and cholesterol are selected ‘surrogate’ end points instead of meaningful end points, such as heart attacks. So, they hit a target that suits them and doesn’t help us.

As you suggest, lower cholesterol should be avoided, particularly in the elderly. The conclusions in the attached BMJ paper are easy to read.

http://bmjopen.bmj.com/content/6/6/e010401

sten bjorsell
Guest
Stephen, thank you! Also for the link! Crystal clear that it is not safe but life-risking to take statins over 60, judging from all those studies! Moreover, small dense LDL particles create the damage in our blood vessel walls and they are often caused by excess low-fat foods. I will never again start the day with cereal and low-fat milk, eat one bowl of it and hardly be able to resist the second one like it often used to be before I got heart problems. Bt most doctors refuse to check LDL particle size. The pharma-reps never tell them anything… Read more »
Hap
Guest

Hmm……..lowering basal insulin (genetic)resulted in healthspan benefit.
http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30862-8

sten bjorsell
Guest
Very interesting link to study that lowering insulin by means of manipulation increased mouse life span! Since these researchers apparently are (2017 study!) stuck in the belief that high-fat diets induce insulin resistance in mice, natural tools to reduce insulin may not even exist in their minds! Because they do not yet know that what they buy as “high-fat chow” from their suppliers contain about 20% SUGAR!. The manufacturers reply to a different researcher about the sugar was: “the mice won’t eat the chow without the sugar”. Dietary fat is one of the few foods that raises neither blood glucose… Read more »
Dana
Guest
Fats inappropriate to the eater’s biology may increase insulin resistance by a process I still don’t understand. Dr. Michael Eades wrote about this recently. It explains soybean oil’s contribution to metabolic syndrome and it explains why mice fed lard don’t do so well. (Frankly, they don’t seem to deal with corn and soybean oil very well either.) In humans, however, animal fat is innocuous if you don’t have an allergy to any of the animal sources they come from. Plus, unlike Free The Animal’s claim to the contrary, animal fats in particular have some vitamins riding along that you might… Read more »
Richard
Guest
All of this is easy to understand, but painful, and therefore difficult, to read. Big Pharma looks like the villain here, and perhaps that is the truth. But really, shouldn’t we be talking about the customers of Big Pharma as the villains, and not the drug companies? Big Pharma is simply reacting to a perceived need provided by the medical profession, who have in general endorsed the concept of sugar numbers “being” diabetes or causing diabetes. The Big Pharma customers are the MDs, and not the patients. The MDs are not doing their job. This reality is of course about… Read more »
Dana
Guest
MDs are also constrained by professional and licensing standards. You can be a little bit of a maverick as a doctor but go too far and they lower the banhammer. Even if you help 999 people reverse the diabetic process back to normal glucose and insulin numbers, if 1 person seemingly has an adverse reaction to your protocol, it might all be over. I think there IS a place for regulation of medical practice IF it is science-based. Problem is, it’s often not, because when you get into doctoring research to get the outcome you want and you rely on… Read more »
Lori
Guest
They do not know any better! Plus low fat approaches CAN work, they just usually do not. Here is a very interesting article https://deniseminger.com/2015/10/06/in-defense-of-low-fat-a-call-for-some-evolution-of-thought-part-1/ Diet these days is about belief not science. It should not be but there are so many manipulated studies out there. The AHA tells doctors that dietary fat will kill their patients. The AHA is a prestigious organization, why should they not believe them! ? Bottom line the AHA and ADA sets the standard of care and regulates the continuing medical education. Doctors seeing 70 patients a day do not have time to read studies, they… Read more »
Balazs
Guest
Hi Dr. Fung! Read every post of your blog. Really outstanding material, most of the time. I fully agree that a dietary disease should be addressed by dietary intervention. However, I have some question related to metformin in your last 2 posts. You wrote: “Overweight type 2 diabetic patients were randomly assigned to either metformin or diet control… Metformin reduced diabetes-related death by a jaw-dropping 42% decrease and the risk of heart attack by a whopping 39%… Metformin could save lives, where SUs and insulin could not.” And then in this article: “The fact that insulin, SUs, metformin and DPP4… Read more »
Dana
Guest

I just want to point out that metformin interferes with the absorption of several B vitamins that also play roles in the methylation process. Even if it’s a miracle drug that decreases both circulating insulin and circulating glucose, doctors don’t tend to warn their patients about this one unwanted effect, and it’s going to come back and bite them in the butt in the long run. Especially as you get older, interfering with methylation is a BAD idea.

Sue
Guest

We would be very interested in Dr. Fung’s response as well. Thank you for all your hard work and dedication Jason. Where would we all be without you?

johnny
Guest

According to this article fasting leads to lower levels of circulating glucose, causing the body to start producing insulin-like growth factor (IGF-1), which has been linked to cancer.

http://www.jhunewsletter.com/2017/03/02/new-diet-reduces-risk-of-age-related-diseases/

Is this true?

Dana
Guest

IGF-1 is triggered by protein intake. Even if there are other triggers (I don’t know everything), if you’re fasting then by definition you’ve taken one trigger of IGF-1 off the table. But your body is supposed to produce IGF-1 sometimes, even though you’re not growing anymore. Sometimes you want to break down old cells but sometimes you want to preserve younger ones.

And if you want cancer, your surest shot is to *increase* circulating glucose. Many cancers love the stuff.

Mary
Guest

I found this video below of an analysis of studies of diabetes drugs and outcomes. What an eye openner! It seems to reinforce Dr Fung’s message in the above blog and addresses my previous curiosity about the UKDPS study around metformin and its designation as first line treatment raised by Andrew Miller’s post. I owe my lower blood sugar readings to Dr. Fung and so grateful for his insights and posts! Keeps me questioning the why of diabetic medical care.
https://youtu.be/pUOC5d0Siws
Thoughts?

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Sean Raymond (Dietitian)
Guest
Sean Raymond (Dietitian)
Sten Bjorsell – I am unable to reply to your comment directly however I am not sure what the comment was trying to say. Were you saying that the high fat diets used to make animals diabetic only accomplished his because of the added sugar the chow contained? Sugar does not cause diabetes directly. Also – fructose is not damaging to the liver, it does appear to behave different to glucose metabolically which may be damaging beyond glucose equivalents but many studies have shown this to only be the case at supra-physiological quantities. In short – studies that have shown… Read more »
sten bjorsell
Guest
Sean Raymond There are multiple studies showing that sugar per se causes fatty liver /insulin resistance https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880768/ http://matzav.com/israeli-study-soda-drinks-cause-liver-damage/ https://www.sciencedaily.com/releases/2016/09/160926221442.htm Tables sugar is 50(50 glucose & fructose. Sodas are usually sweetened with HFSC which is more fructose and less glucose, usually. The soda drink trials above, and there are much more, employ amounts that many young people today normally drink, and they are causing the damage. One trial on kids in Israel with 2 daily soda tins combined with regular liver scans was stopped prematurely due to that fatty liver was being detected increasingly in the test group after only 4-6… Read more »
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