Ruminations on the halted ACCORD study
A few days ago the National Heart, Lung, and Blood Institute (NHLBI), the organization coordinating the ACCORD study (Action to Control Cardiovascular Risk in Diabetes), pulled the plug on the glucose lowering part of it. Why? Because in a stunning mid-trial finding, subjects in the arm of the study who were edging their glucose levels closer to normal were dying in significantly greater numbers than those whose glucose levels remained elevated.
What the heck is going on? Conventional wisdom has it that the lower (toward the normal range) the blood sugar the better. It has been the goal of diabetic management to reduce blood sugar levels as close as possible to the normal range; now comes this disastrous study presenting dramatic evidence to the contrary. Amazingly, those subjects who died in the lowered-blood-sugar group succumbed to some form of cardiovascular disease, the very condition the more aggressive blood-sugar lowering was crafted to prevent. Do these tragic deaths invalidate the sugar hypothesis of heart disease?
I don’t think so, but before we get into why, let’s summarize this experiment.
If you want specific details on the trial itself, you can check out the ACCORD website where you can find the study purpose, protocol, etc.
In short the study personnel selected diabetic patients who had pretty well established type II diabetes. All were on some kind of medication, many were on insulin injections as well. All had HbA1c levels in the range of 7.5% to 11% (the upper limit of normal is 5.9%) and all had either a history of cardiovascular disease (CVD) or a number of risk factors for CVD. Researchers wanted to find out if aggressive therapy to reduce HbA1c levels to under 6% in these subjects would reduce CVD events more than less aggressive therapy designed to reduce HbA1c to an average of 7.5% (still pretty high). The conventional wisdom was that the lower the blood sugar the better, so when it was discovered that the subjects in the lower-blood-sugar group were dropping like flies as compared to their peers with higher sugar levels, the study was halted, and the head scratching began.
Here is a sampling of what many well-known physicians had to say about the results:
Said Dr. William Friedewald, chair of the ACCORD steering committee:
The simple and honest answer is that we have done extensive analyses and not identified a cause for the increased mortality. We will now do even more extensive analyses with all of our investigators, who are now unblinded to the results, and prepare a paper with the data and our best impressions of the possible causes.
Dr. John Buse, a member of the ACCORD steering committee, suggested (as paraphrased by Heartwire):
…three basic possibilities that would explain the higher mortality rate in the intensively treated group: it could have been a spurious observation, and it might have disappeared with further follow-up; it could have been due to adverse effects of a particular drug or drug combination that has not yet been teased out; or it could be that the observation is true, that lowering blood-sugar levels too much in older diabetics with heart disease is a bad thing.
He also said
The patients enrolled in this study were quite vulnerable in that they were relatively old (average age 62) and had heart disease or at least two or more other risk factors for heart disease. Maybe we just flogged them too hard to get their sugar levels down. The intensive group had extremely rigorous treatment, with some patients taking four shots of insulin and three pills and checking their blood-sugar levels four times a day. Perhaps this was just too many drugs at too high a dosage, and the effort required just stressed them out too much. I think our conclusion is therefore that we should not be zealots about lowering blood sugar at all costs. We must understand that there are risks and benefits and one size probably does not fit all patients.
As reported by Heartwire, our old friend Dr. Steve Nissen commented:
“This result really does defy conventional wisdom.” Noting that benefit has been seen in lowering blood sugar in terms of diabetic complications but the effect on major cardiovascular events and mortality is not known, he added: “I suppose it wouldn’t have been a major surprise if there was no effect, but to show harm is really a big surprise. This effect could have been due to some of the drugs being used to lower glucose levels, which may have other effects that cause harm. We know that rosiglitazone increases MI risk, so others may do this too.” He said not enough data on rosiglitazone use in ACCORD had been released to establish whether it could have played a role in the adverse outcome. “We don’t even know what percentage of people in each group were on rosiglitazone. So we can’t answer that question yet. All in all, this trial has raised a lot more questions than it has answered.”
These comments pretty much summarize the thinking of all the diabetes experts I’ve heard opine on this study. Let me give you my views. Before I do, though, you’ve got to understand that just as is true of those commenting above, my views are speculative. And just like the others, I haven’t been able to dig into the actual data to see what makes sense. My views are derived from looking through the lens of my own years of experience, my reading and analysis of a lot of medical literature, my knowledge of how most doctors go about treating their diabetic patients (which I think borders on malpractice) and my experience with big-name, mainstream physicians and their thought processes.
First, I think the lowered blood sugar levels are a red herring.
To see why, let’s look at how the typical doc treats his/her type II diabetic patients.
The patient gets a diagnosis of type II diabetes, is scared to death, and needs help. Most docs put these newly diagnosed patients on a low-fat, low-calorie diet. And they give them some kind of drug to help lower blood sugar. They make an appointment for a recheck in a month or six weeks.
The patient comes back and gets a retest of his/her HbA1c. If the HbA1c is lower, the doc says, You’re looking good. Keep it up. If – as is more common – the HbA1c is the same (it’s already elevated or the patient wouldn’t be a diabetic), the doc increases the medication dose.
The patient leaves, takes the higher dose of meds, which usually drops the blood sugar. A falling blood sugar is a strong stimulus to eat. The patient (if trying to be compliant) eats from the low-fat, high-carb list of foods given by the doc. The patient’s blood sugar comes back up, the patient feels better, and this cycle repeats.
On the next visit, the patient’s HbA1c is the same or higher than before. The doc views this as failure of the medication to lower the patient’s blood sugar. The doc raises the dose and/or adds another medication. The patient takes the increased dose/added drug and repeats the above cycle. Lowered blood sugar, feeling lousy, eating more carbs to compensate.
The next visit finds the HbA1c the same or higher, and the doc increases or adds medications, sometimes even insulin injections. And on and on and on.
Patients on this regimen typically gain weight, feel like crap, and don’t control their sugars all that well. And that’s the standard treatment for type II diabetes in this country today. These patients are actually ‘treating’ their over medication with carbohydrates. I’m confident that many commenters who have undergone this regimen will back me up.
Happily, there is a better way.
Newly diagnosed type II diabetic comes in. Doc says, Let’s give this diet a try before we fool with medications. Doc gives patient instructions on how to follow a low-carb diet.
Patient comes back in a month or six weeks, finds HbA1c is lower than before. Doc says, Good job, let’s keep on the diet and see what happens. Patient comes back in a couple of months, weighs less, sleeping better, and HgbA1c is almost normal. Doc says, Good job, let’s keep working with the diet.
Ultimately, the patient’s HbA1c is normal on diet alone. Doc tells the patient, Your type II diabetes is gone, but the propensity for it is still there, so it’s important to remain on your diet, although you can lighten up a little on the carbs now and then. But if you go back to your old way of eating, your diabetes will return.
(Unfortunately, sometimes in certain patients with type II diabetes, a low-carb diet isn’t enough. Small doses of medications are required to normalize blood sugar. But it’s typically one medication only and in fairly low doses.)
Sadly, only one patient gets treated this second, more effective, less harmful way for every thousand patients (if not more) who get treated the first way.
In my opinion, here’s what happened in the ACCORD study.
The doctors running the study tried to aggressively lower blood sugar levels by increasing dosage levels or by adding more drugs to the patients’ regimens. The goal was to treat the HbA1c, not to treat the patient. The docs taking care of the patients in the aggressive treatment group pulled out all the stops to get HbA1c into the normal range using drugs and insulin, which was the study protocol.
All the strategies used to aggressively lower HbA1c – whether increased insulin dosing or using medications designed to wring the last drop of insulin from the pancreatic beta cells – ends up increasing insulin levels in these patients. And insulin itself is a major risk factor for heart disease.
I think that in their focus on reducing blood sugar in an effort to decrease risk for CVD, these researchers ran insulin levels up and increased another more potent risk factor for CVD. In other words, researchers traded one risk factor (high blood sugar) for an even more potent one (elevated insulin). The result was that more people died in the aggressively treated group.
Had the aggressive treatment been with a rigorous low-carb diet instead of a rigorous drug/insulin therapy, I believe the results would have been the opposite. But that is simply speculation on my part. But it’s speculation seasoned with a dose of good sense. And I think it solves the conundrum of what happened to these unfortunate victims.
I have just had an AH! moment while reading various articles about the most overlooked historical mysteries, including the Tarim Mummies of China and all the government suppression of information that has occurred in China regarding them. (For those of you who don’t know about them, the Tarim Mummies are caucasian mummies found in China dating at least as far back as 4000 years. You’ve probably seen pictures of them in the news sometime, white mummies with blonde or red hair wearing colorful wool clothing, a female mummy with a very tall “witches hat”, etc…)
Getting back to my Ah!, I just realized the fatal flaw in the formation of the U.S Constitution. Our Founding Fathers neglected to include separation of Science and Medicine and The State! Just think, if the government stayed out of the realms of science and medicine how much healthier we all might be. No lobbying by drug companies, no spending on studies that are pointless, no food pyramid…
Maybe while we’re at it, for archeology’s sake we should add separation of Church and Science too. So many ancient artifacts and so much ancient information have been lost because of religions.
I’m with you whole heartedly in both ideas.
Cheers–
MRE
Reading the ACCORD web site, it appears to me as though the “Lipid Trial” portion of the study is comparing the use of fibrate plus statin to the use of statin (alone), with no “untreated” control group. That seems… odd. Or maybe I am misunderstanding?
I haven’t read this part of the study critically, but in my once over that seems to be the case. It’s a trial comparing more aggressive therapy to less aggressive therapy. But both arms get therapy.
There has just been another study reported in the BMJ “Sugary drinks, fruit and increased risk of gout: dietary fructose could be a contributing factor.”
Martin Underwood BMJ 2008;336:285-6
doi:10.1136/bmj.39479.667731.80
Some excerpts:
Consuming two or more glasses of fruit juice each day increased the risk of gout by 81% and eating an apple or an orange a day increased the risk by 64%…..free fructose has an adverse effect on urate metabolism. This in turn might have a causal effect on the development of the metabolic syndrome. …..on the other hand increased fruit and vegetable intake is generally thought to reduce the risk of cardiovascular disease.
Another little nail in the high carb/low fat coffin?
A little one, maybe, But a whole lot of little ones can ultimately do the job.
Hey Dr. E.,
No need to post this comment as it adds nothing to the discussion. I have a question regarding your RSS feed. It looks like you’ve gone to using the “More” link, which forces subscribers to come to the site to read the entire post. I generally try to stay in my reader as much as possible unless I have a comment to make. Is there any chance you can go back to running the entire post in your RSS feed?
Thanks
Scott Kustes
Modern Forager
I’m working on it. Thanks for the feedback.
Dr Eades
The protocol for the ACCORD study included giving the patients both fibrates and statins.
http://www.accordtrial.org/web/public/documents/Protocol%20All%20Chapters.pdf
(page 3)
Your comments?
The combination of fibrates and statins has been shown to cause rhabdomyolisis. This fact isn’t unknown or unusual – in fact, it is listed in the PDR as a warning. Yet physicians persist in frequently putting their patients on this combo. Rhabdomyolisis is the breakdown of muscle protein, a situation that can over task the kidneys and, not uncommonly, bring about kidney failure. Either Statins or fibrates alone, in my opinion, are pretty much worthless, but together, can be disastrous.
Hi Mike,
Great post that helped me work through some of the confusion I was having with these results. Dave Dixon has a similar post about these results that goes more deeply into the effects of insulin at Spark Of Reason: http://sparkofreason.blogspot.com/2008/02/insulin-insanity.html
Like other commenters here, I get very frustrated with all the stupidity, special interests, and blind dogma that the medical community seems so infected with of late. Although with information that you provide it really is kind of fun to irritate my GP when he tries to instruct me in a “healthy” diet.
As always, I appreciate the work you do.
Any way I can talk you into switching your blog feed from partial back to full posts? I usually read your articles from Google Reader and just as I’m getting into your post I run into the “(more)” link and I have to come to to the website to finish the story.
I’ve been subscribed to your feed for a while now and have really been enjoying it. It was quite surprising when the feed changed recently to partial.
Thanks for listening.
Hey Mark–
My web guy did all kinds of things late one night. I woke up the next morning, and I had banner ads and all kinds of stuff. I haven’t been able to get in touch with him since to figure out exactly what he did and why. I’ll pass along your complaint.
My internist has prescribed four medications for me as preventative measures and I could not tolerate any one of them. At one point I was on Actos, and a few days after having started it, I found myself in front of a client discussing a large sale involving many products. All of a sudden, I had to excuse myself very quickly and practically run to the restroom to avoid an embarrasing situation.
Nobody in business can afford to interrupt a client in the middle of ironing out details, and no human being should be put through such pain as I was. Every med prescribed has had the same result. I have discontinued every one of them. Without low carb and paying attention to every starch and sugar that gets put into my system, I have no way to prevent the onset of full blown diabetes. I fear that my doctor prescribes these meds as much to cover her liability as to try to help me. It’s too bad she has no incentive to try low carb as a measure.
It doesn’t surprise me that these meds would contribute to worsening CVD considering how much pain they caused me. I can’t believe that anything with such terrible side effects can be good in the long run.
I might add this is a good place to link to Adam Campbell’s very informative article:
A CURE FOR DIABETES in menshealth.com
http://www.menshealth.com/cda/article.do?site=MensHealth&channel=health&category=other.diseases.ailments&conitem=4a935e4e40fae010VgnVCM20000012281eac____
I almost missed that there was 5 pages, so be sure to click NEXT at the bottom to view all the other sections of that article, including:
-Eliminate Foods that Raise Blood Sugar
-In Favor of Vegetables
-Our Data-Driven World
-Stay Off the Starch
Thank you, Dr(s) Eades
Another great article. Thank you.
Just wanted to mention that when I click on the section of your website that says “About” Dr Eades, I always get a 404-Page not found message. Could this be corrected on your end?
It says that because the theme of the blogging software has that section, and I haven’t gone to the trouble to fill it in. I’ll do it sooner or later.
Cheers–
MRE
Hi Dr. Mike,
Thanks for all of the great information. I check in everyday and enjoy reading your posts.
I was wondering if you have ever written a post on arthritis medications such as Humira (Adalimumab) or Enbrel (Etanercept).
-Paul
Not yet.
Another thought: If you try to lower the average blood sugar down to the “normal” range when the body’s natural regulating mechanisms have been put out of action, how low do the inevitable low levels go? Do those sudden deaths come at times when the blood sugar levels are just too low? what if an infarction hits at an unnaturally low bg – will it be deadlier than otherwise?
Usually the lower levels are into the normal range – they typically don’t fall drastically. I don’t think these lowered blood sugars have anything to do with sudden death from heart attacks. Sudden death is usually caused by the infarct hitting an area of the heart that is important in the conduction of the electrical impulse that stimulates the heart to beat in a rhythmic and coordinated fashion. When this impulse is short circuited, the heart fails to beat properly (ventricular fibrillation), leading to loss of blood to the brain and everywhere else and often death
I saw that same article about this study in the paper, and when I got to the “we used lots of drugs” part, I knew that was probably the problem.
My fiance introduced me to Protein Power last June, and since then, I’ve lost weight, I’m sleeping better, my nails are stronger, my skin is better … low-carb is such good medicine! And I would not be diagnosed as diabetic, either, even though I have a family history of it. I’ve given away 4 sets of PP and Lifeplan to people I love who need to read them … and none of them have. (sigh) I’ll just have to go on being a good example, along with my fiance. Thanks for disseminating all the good info, Dr. Eades.
And thank you for buying all the books.
Cheers–
MRE
Dr. Mike, Something hit me after reading this. The doctors don’t believe their patients will make a life style adjustment or stay on the adjustment. So why not give them a pill that a sales rep has told them will work? Generally, I bet they are right, lifestyle change is difficult to do and maintain, especially in the US (Sugar is everywhere!). I don’t want to switch the blame here, I think I want to add more, there is enough to go around. The Gov., food industry, lawyers, doctors, advertising… How can the common man survive?!
By using his brain.
Dr: Eades:
I posted a comment earlier, but it has not shown up. It says “awaiting moderation,” but other comments have appeared since then. I’d like to be a commenter and contribute, but I’d like to have some confidence I won’t be wasting my time.
Hi Richard–
I wrote a post a couple of weeks or so ago stating that I wasn’t going to be able to answer comments individually as I had been doing. The time commitment is too much now that I’ve got a book contract to deal with. What I’ve started doing is posting comments that are comments as they come in. Questions go to the back of the line until I have the time to deal with them. I could simply post all comments, whether comments or questions, as they come in without a response to either. Which would you prefer?
Cheers–
MRE
I’ll ditto what Dave Dixon says. After reading Taubes’ book, I say that the answer to the “surprising” results of the ACCORD study lies in Chapter 10 about the role of insulin. Insulin in and of itself can be a harmful substance. What I don’t understand is why so few people seem to be aware of this…especially in the media. I just read an article in the Economist discussing the ACCORD study (usually they are a fairly serious bunch) and not one mention was made regarding insulin as the culprit. Wonder what the explanation of these results will be in 6-8 weeks after they get a chance to write up their hypotheses.
I wonder myself.
Dr. Eades
I do respect the fact that you are a real doctor and have to deal with the stresses of giving patients answers and quickly.
I’m sorry for the trolling. Some things are too serious to troll about. I don’t know enough to comment about the existence of a Metabolic Advantage.
Also I wish they would make progress as to the REAL cause of CHD. I certainly don’t want to get it. I wish the corruption of the national health organizations agendas would stop preventing the doctors who have something to offer to get their message out and the real results of these trials out.
The real cause of CHD could be something Anthony is missing, Orthodoxy is missing , and the Taubes camp is missing.
My trolling before was all in good fun. I’m sorry.
No problem. Apology accepted.
Cheers–
MRE
Of course: ACCORD wan’t testing just the effects on CHD deaths of normal or near normal bloodsugar it was equally testing the effects on CHD deaths of the ACCORD program for lowering bloodsugar.
What is stunning is that I hadn’t seen the hyper-insulin hypothesis before I arrived here while hunting for explanations for what went wrong in ACCORD.
But my impression is that none of the posters here had panicked about ACCORD, that no one had decided they’d better raise their A1c to ADA levels AND that no one here has reached normal through ACCORD-like measures.
What I wonder is, on the one hand, WILL anyone “out there” be frightened away from normalizing by ACCORD, especailly those following a non-ACCORD path and, on the other hand, do many people reach normal using ACCORD-like measures who weren’t in ACCORD? In other words, is ACCORD likely to have a real effect on real people’s goals and methods?
Ironically, I didn’t know this site before my search for ACCORD explanations brought me here, because I have been low carb only since late October, so the ACCORD debacle has at least that as a silver lining — but we can hope that it shakes up the paradigm (in the right direction).
I don’t think there is a big worry about the vast unwashed masses of people being put off by the ACCORD results. Most will never hear of them. I’m more worried about physicians being put off of helping their patients work to achieve closely controlled blood sugars.
Cheers–
MRE
Please do not blame the dietitian for high carb diets. Most people forget that a diet order is a legal prescription and dietitians have to follow the doctors order. Not all dietitians believe in the high carb diet approach to diabetes. It is however hard to buck the system when insurances and Medicare will only pay for the “evidence based diabetic protocol”.
I understand. Point taken.
Cheers–
MRE
Wow, I give firm Kudos to the censors who deleted the statistics from this article:
First: THREE out of ONE THOUSAND people died. This number was ONE-THIRD LESS then what ACCORD expected. Real epidemic on our hands.
Second: For those THREE people who died we do NOT know what their blood sugar numbers were because this is a BLIND study.
Lastly: For those people who claim that Insulin is harmful, it may be for people WITHOUT diabetes, but for those people with diabetes…READ MY LIPS: THEY CANNOT MAKE ENOUGH INSULIN TO LIVE. They have TWO Choices: A. Die without Insulin or B: Live a normal life WITHOUT any problems due to insulin because they are not taking excess of it.
And your point is?