ADVANCE and NAVIGATOR

The Internet is abuzz with the latest results from a couple of those massive trials that physicians who practice "evidence-based medicine" require before they'll believe in any treatment.

Although I understand why such studies are needed, I hate them, because they're studying a huge, diverse population of patients who may differ a lot in their baseline characteristics, even though the mean is usually all you can see.

Unless the outcome is black and white, for example, 100% of the patients who took the new drug dropped dead within 2 weeks, you need statistics to evaluate the study. Quite often, individual patients may be harmed or helped, but the published conclusion refers only to the average impact, as I noted here. Then physicians apply these average results to everyone.

A good example of this is the blood glucose (BG) arm of the ACCORD study, which was stopped early a couple of years ago because it appeared that the patients who used intensive treatment with a lot of drugs and lowered their A1cs to a mean of 6.5% had higher mortality than those who used standard treatment and had A1cs of about 7.3%.

This was despite the fact that patients in both groups had mortality rates lower than those of most people with diabetes.

In fact, the patients in the ACCORD study were older, had had type 2 for at least 10 years, had other risk factors for heart disease, and started with mean A1cs of 8.3. This means they had probably had poor control for years. Yet doctors are applying the conclusions to everyone.

Many patients are now reporting that their doctors tell them that their excellent A1c levels in the 5s are too low and they should increase them until they're over 7!

Furthermore, like most patients, the ACCORD patients were told to follow an ADA-type diet with less than 30% total fat and less than 10% saturated fat. This means they undoubtedly increased their consumption of carbohydrates, most likely the kind most Americans eat: potatoes, rice, white bread, processed fat-free foods. Yet a recent meta-analysis showed that there is no significant evidence to conclude that saturated fat causes heart disease. Some studies showed an increase when saturated fat was reduced, and others showed an increase. This averaged out to no effect.

The authors suggested that it might depend on what you substitute for the saturated fat, as studies with substitution of unsaturated fat tended to reduce heart disease and mortality and studies with substitution of carbohydrate tended to increase it, although no studies have been done that would actually prove this.

Yet replacing saturated fat with carbohydrate is undoubtedly what people in ACCORD were told to do, and those in the intensive treatment arm of the study got more intensive nutritional counseling and hence probably ate more carbohydrate.

Now the other two arms of the ACCORD study have been published. The blood pressure arm showed that reducing the systolic blood pressure below 120 resulted in no better cardiovascular outcomes than using fewer drugs to keep the systolic blood pressure below 140. The lower blood pressures did result in fewer strokes.

This is the same patient population as the BG arm of the study, and the same caveats apply: longstanding diabetes in an elderly population with coexisting medical problems (34% had already had a cardiovascular event), relatively high starting A1cs and fasting BG levels over 170, and multiple blood pressure drugs given to reach the goal. Also, twice as many of the intensively treated patients gained more than 10 kg during the study.

The final arm of the study was designed to see whether adding a fibrate drug to the treatment of patients already taking a statin would reduce cardiovascular events. The fibrates (they used fenofibrate) reduce triglycerides and increase HDL levels.

Again, they found no significant effect but a suggestion that the drug might help in patients who began with triglyceride levels over 204 and HDL levels under 34. Men appeared to do better and women appeared to do worse on the fibrate. Such studies can show differences that appear to be real but aren't statistically significant.

Again: same population and same caveats.

Another study, the NAVIGATOR study, was reported at the same time. This study started with patients who had prediabetes, with mean A1cs of 5.8 and also either preexisting heart disease or cardiovascular risk factors. They tested whether using valsartan (Diovan), an angiotensin-receptor inhibitor that lowers blood pressure, would reduce progression from prediabetes to diabetes. Similar drugs had been shown in the past to do so.

Again, all the patients were given "lifestyle modification" advice, although the papers don't specify exactly what that was other than the usual ADA line of reducing total and saturated fat and increasing exercise. You have to go to an Appendix, which most people won't read, and then to a reference to a Finnish study they cite to see what type of dietary advice was given.

It turns out to be the usual low fat with "lots of whole grains, fruits and vegetable." Many Americans told to eat lots of whole grains are apt to eat whole-wheat bread (which isn't whole grain) and to drink more orange juice and eat more apples and bananas, and maybe more peas and corn. Very few will up their intake of kale and broccoli and other low-carb veggies.

It turned out that the low-fat high-carb diet plus increased exercise plus the drug reduced the progression to type 2 diabetes from 36.8% to 33.1%, which they calculate is a 13% reduction in the "absolute hazard difference using an exponential model," but a pretty small absolute reduction. It didn't affect the rate of cardiovascular events.

The second arm of the NAVIGATOR trial involved the same patient population and the drug nateglinide (Starlix), which is a sulfonylurea-type drug that increases insulin secretion by the beta cells but for a shorter period than the traditional sulfs.

The rationale was that high postprandial BG levels are said to lead to beta cell deterioration, and higher A1cs are associated with increased heart disease. They tested whether or not this drug would reduce progression from prediabetes to diabetes and whether it would affect cardiovascular events.

They found it did neither.

Do these studies mean there's no point in trying to control our diabetes?

Not at all. What they really show is that you can't give people with longstanding diabetes or even a diabetic tendency and either preexisting heart disease or a lot of heart disease risk factors a low fat, and hence very high carbohydrate, diet, try to control the resulting high BG levels with a lot of drugs, and expect the heart disease to go away.

Furthermore, even though you tell people to eat lots of vegetables and whole grains, you know that in the general population, most of them -- if they modify their diet at all -- will eat high-glycemic foods, low-fat processed convenience foods, and sugary fruits. If they show the dietician that their fat consumption is down, the dietician will probably tell them they're doing great.

No one has tested whether or not trying to control diabetes with lower-carb diets and fewer drugs would reduce heart disease rates.

But I'm afraid that the results of these trials will make a lot of people simply throw up their hands and give up, figuring that heart attacks are inevitable, no matter what they do.

Even if the results from a lower-carb study showed fewer cardiovascular events, I'm afraid most Americans wouldn't make significant changes in their diets. An intelligent woman with type 2 once told me she had trouble eating just a couple of potato chips. I asked why she bought potato chips (she lived alone). She said, "Because I like potato chips."

Well, who doesn't. I also used to like blueberry pie (I probably wouldn't like it now, because it would seem overwhelmingly sweet with relatively little taste) and homemade bread slathered with butter and homemade jam. But I don't eat those things now.

What we need to learn to do is to become gourmets, seeking out foods with a lot of taste and not a lot of carbohydrate, like berries, or exotic fresh vegetables from a farmers market. This is a lot more fun and cheaper than paying $500 a month for a lot of pills to try to cover the damage from eating ho-hum potato chips and packaged snack cakes.

The intelligent people who read this blog will understand this. I worry about the other millions of people in the country who don't have access to good information. I worry about the overworked GPs who don't have time to slog through long statistical studies and try to figure out what an "absolute hazard difference using an exponential model" is.

Many of the details, like the actual dietary advice, in these papers are difficult, if not impossible, to find. If you make an effort to download the full study protocol of the ACCORD study, you find that patients were taught carb counting but it doesn't say how many carbs they were supposed to eat. They were taught self-monitoring of BG, and how to titrate their drugs according to the results. They were apparently not taught how to "titrate" their carb consumption according to the results.

And the authors are often sloppy. For example, sometimes they give both mean and median A1c. Sometimes they give only one. Sometimes they don't indicate which one they calculated.

I worry that the busy physicians will just read the headlines in medical magazines and the New York Times ("Diabetes Heart Treatments May Cause Harm") and conclude that they shouldn't try to treat diabetic patients with high blood pressure, high BG levels, or high lipid levels. Why bother, because they might be sued if they caused harm.

As studies become old, people who write about them tend to simplify, ignoring the many caveats that apply to the studies. For example, Gina Kolata wrote in the recent New York Times story, "It was discovered 2 years ago that rigorously controlling blood sugar did not prevent heart disease or deaths in people with type 2 diabetes." What that study actually showed was that "rigorously controlling blood sugar with a lot of drugs to cover a high-carb diet did not prevent heart disease or death in elderly patients with preexisting heart disease or at least two cardiovascular risk factors and long-standing poorly controlled diabetes."

But how many physicians have retained Kolata's interpretation? I suspect a lot. I've mentioned the many patients whose doctors told them that their diet-controlled A1cs of 5.6 were too low and they should try to get them up to 7!

I would agree that if someone had an A1c of 5.6 only because they were on 7 different expensive medications with a lot of potential side effects, it would make sense to stop several of the drugs and let the A1c go up a bit, especially if the patient was elderly with several other medical problems treated with even more drugs.

But if someone has an A1c of 4.8 because of strict diet control and a lot of exercise, and if that person doesn't go low (after all, nondiabetics don't go low when they have low A1cs), there's absolutely no reason to tell that person to increase the A1c.

Applying a "rule" for the wrong reasons is the type of faulty logic that has caused harm in a lot of diabetic patients. I know some who have been told by registered dieticians that they should put raisins in their oatmeal "to get the carb counts up."

The reason for the high-carb ADA diet is not to eat a lot of carbohydrate; it's to eat less fat. The idea is that when you eat more carbohydrate, you'll eat less fat. But adding carbohydrate to a meal instead of substituting carbohydrate for fat won't reach the ADA goals (which many people today don't agree with anyway). It will just add calories, increase insulin levels, and promote even more fat gain.

So will patients with type 2 diabetes soon be told to get their blood pressure up, not worry about lipid levels, and pay no attention to postprandial BG levels?

I certainly hope not.

The full texts of the New England Journal of Medicine articles cited are available free here.

Ancient Bacteria

It's generally agreed that low-grade chronic inflammation is related to metabolic syndrome, cardiovascular disease, and type 2 diabetes. But no one knows what causes this generalized inflammation.

Acute, localized inflammation is a good thing. It's what walls off an infection, "eats" the offending organism, and then digests it with the help of heavy-duty oxidants. Then, when things are working right, the body repairs the damage, and the cells that have been doing all this leave the scene.

Chronic inflammation, on the other hand, is not a good thing, and the more scientists can find out about it, the better.

Hence I was intrigued by a recent paper in Nature that proposed a totally new idea and confirmed an old idea. You can read a popularized description here, or a link to the original paper here.

When we are invaded by pathogens, the body mounts what is called the innate immune response. This is a nonspecific response triggered by certain chemicals on the surface of many organisms that are unique to them and are not found on our own cells. The body sends out cells called macrophages to engulf the offending organisms and sends chemical signals to recruit other cell types to help rid the body of the organisms and then repair any damage that occurred.

This response is more primitive than the adaptive immune response that uses antibodies and is more specific than the innate immune response.

Usually, the cause of the response is clear, as bacteria or viruses or other pathogens can be found in the blood. But sometimes people seem to have such a response when no pathogens can be found. This puzzled scientists for a long time.

But Carl Hauser and colleagues, the authors of the Nature paper, came up with a fascinating hypothesis. It is generally accepted that mitochondria, known as the "powerhouses of the cell" because they are where most of the cell's energy is produced, were originally bacteria that invaded the cells of other organisms and adapted to the benefit of both.

Mitochondria have their own DNA, which comes only from the mother.

Hauser and colleagues wondered if perhaps trauma that destroys cells could release mitochondria from the damaged cells into the bloodstream. Then, because the mitochondria are descended from bacteria, they might have surface molecules that our bodies would interpret as foreign, so we would mount an innate immune response, just as we do to other bacteria.

His researched suggested that this does indeed happen.

It explains why severe trauma patients sometimes get reactions that look like severe infections when no signs of infecting organisms can be found.

And I wonder if less severe chronic trauma could cause just enough of an innate immune response to trigger chronic disease. For example, we know that chronic gum disease can increase blood glucose levels, along with various signs if inflammation. Could this be because the gum disease is causing gum cells to break down and release mitochondria?

Could other hidden infections be doing the same? By reducing various chronic infections, could we reduce people's chance of getting type 2 diabetes?

I find this research exciting, not because it offers an immediate chance for a cure of type 2 diabetes, but because it's a new idea and I find new paradigm-shifting ideas much more fascinating than huge studies of drugs that rely on statistics to prove anything. Even then, although the statistics can show that the drug worked on average, it can never show whether or not it will help you in particular, as I discussed here.

Creative new ideas can suggest new research paths that may some day lead to real cures.







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Slow Progress

One thing that annoys me is how long it takes for new ideas and new research results to filter down to practitioners. At this rate I will have died of old age before they figure out a better way to treat type 2 diabetes.

When I was first diagnosed in 1996, because I had been a biology major and had done some research in biochemistry, I wanted to learn more about the science of type 2 diabetes.

I was puzzled because the nurse practitioner who diagnosed me told me to follow the American Diabetes Association (ADA) diet, which was chock-a-block full of carbohydrates. I knew that diabetes was caused by an inability to process carbohydrates. So why were they telling me to eat more of them? It made no sense.

So I went to the library. Remember libraries? They were places with books and preceded Internet searches and Google and all that. The library didn't have much of interest, so I searched the interlibrary loan catalogs and found and ordered a book called Insulin, edited by F. M. and S. J. H. Ashcroft. It was published in 1992, which means it was probably written around 1990, as the publishing process does take time.

The book was very interesting. A chapter author named Erol Cerasi said he and others had done a study of a large group of obese and nonobese subects both with and without diabetes and studied insulin resistance (IR) and insulin secretion.

They found that only beta-cell responsiveness could distinguish the diabetic from nondiabetic subjects. The IR could only distinguish obese from nonobese subjects.

In other words, if you're obese, you'll have IR, but you won't necessarily have diabetes. If you have diabetes, your beta cells won't secrete enough insulin, whether or not you're overweight.

They concluded that "the diabetic state is much more closely related to a failure of the secretion of insulin than to diminished efficiency of the circulating hormone level," that is, beta cell defects are more important than IR in causing type 2.

Another group did a similar study and found that those who progressed from prediabetes to diabetes had decreased insulin responses to glucose at the beginning of the study.

Yet people with type 2 diabetes continued to be told that their obesity had caused IR and the IR had caused the diabetes.

Recently, 23 years after the research published by Cerasi and others, there was a report of a study of 13 new genes increasing the risk of type 2 diabetes. The authors of the study said they were "intrigued" by the finding that most of these genes affect beta cell secretion rather than insulin resistance.

"Beta cell impairment may play a larger role in type 2 diabetes than previously recognized," the authors said, as if this was a totally new idea.

It is true that there's so much diabetes research published that no researcher can have read all of it. One report or one person's opinion isn't considered proof of anything, but it should suggest something, so researchers shouldn't be stunned 23 years later to discover the same thing.

Why is it that an amateur researcher, a newly diagnosed patient, can find information a professional apparently cannot? I'm sure the Cerasi papers were not the only ones to come to the same conclusion, and the other researchers had 23 years in which to look.

Cerasi also recommended using insulin in type 2 patients right from the beginning, to normalize blood glucose levels and reduce glucotoxicity, which he felt contributed to the IR. "Present therapeutic approaches based on initial dietary restriction followed after a period of up to several months by oral diabetic agents, seem rather unsuited" for returning the patient to mild diabetes or prediabetes.

"I propose initial, short-term (one to a few weeks) intensified insulin treatment aimed at achieving euglycemia very rapidly, in order to block down-regulation of glucose transport and inprove beta-cell function." He showed in a pilot study that when patients in whom the oral drugs had stopped working were given insulin to maintain normal BG levels for two weeks, they could then maintain good control on oral agents alone after the insulin was stopped.

Again, a recent proposal suggests essentially the same thing. Ralph DeFronzo proposed starting newly diagnosed patients with type 2 on an intensive drug regimen of metformin, a TZD, and exenatide. And he and 15 other diabetes experts proposed the same at the 2008 ADA meeting.

The ADA's response: Prove it. They just now started a 3-year study to see if early normalization of BG levels with drugs helps. But what is taking them so long? And why use drugs instead of insulin?

Other research has shown that early intensive insulin treatment is more effective than drugs in maintenance of beta cell function. So why mess around with expensive drugs that can have serious side effects when a simpler, cheaper treatment has already been shown to work?

It boggles the mind.

Another example is a 2007 paper by Frank Q. Nuttall and Mary C. Gannon. They showed in 1996 that fasting caused normalization of BG levels in people with type 2 diabetes and wondered, "Could merely a reduction in carbohydrate mimic the effect of a reduced fuel-energy diet or short-term starvation on blood glucose in people with type 2 diabetes mellitus?"

They published the results of using l0w-carb diets (20 and 30% carbohydrate), showing that BG levels and HbA1c levels were much lower. However, their request for further funding was rejected by the National Institutes of Health, which said their sample sizes were too low to show anything and "it is difficult to conceive of the diet as producing larger improvements than metformin or rosiglitazone, for example, especially if the subjects are maintaining their body weight."

"So much for open mindedness," wrote Nuttall and Gannon. The health authorities cling to their old views even in the face of new evidence. They seem to have made up their minds, and there's no more room in their tiny minds to consider alternatives.

But wait a minute. For decades, Richard K. Bernstein has been proposing low-carbohydrate diets for both type 1 and type 2 patients. His first book was published in 1984. But almost no one in the professional world listened to him either. Why did Nuttall and Gannon have to "wonder" in 1996 if the idea of reducing carbohyrate would work?

Research has been done, and it has been published, but other researchers don't seem to pay a lot of attention.

Why must the patients be the ones to ferret out the facts?