The Doctor Weighs In

By Dov Michaeli MD, Ph.D

So you don’t exercise. And you like your six pack. And you have a bit of a pot belly. But you are not overweight. In fact, your BMI is in the normal range. Do you feel pretty smug? Read on, and I think you’ll get shaken up a bit, as you should.

Central Obesity

The correlation between obesity and diabetes and heart disease is well known. In fact, we now know that people should be concerned not only about body fat, but importantly: where this fat is located. Waistline fat is a major risk factor of diabetes and heart disease, deceptively cute names like “love handles” not withstanding. But did you know that being a Michelin Man may end up in dementia?

The Kaiser study

I certainly did not suspect it. And I dare say,I don’t know anybody in the medical community who has.

Now comes a wonderful study, led by Rachel A. Whitmer of the famed Research Division of Kaiser Permanente in Oakland , CA , and tells us a very disturbing tale.

The investigators took advantage of the extensive medical records kept by Kaiser about their members. They conducted a longitudinal study of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later (!), January 1, 1994 , to June 16, 2006 . Where else, with the possible exception of the Scandinavian countries, could you get such a long follow-up? And who else would pay for sagittal sections of the abdomen to carry out such a study? Only Kaiser Permanente, which is a non-profit HMO, with “non-profit” being the operative word. Before I go on, sagittal sections divide the body into left and right portions. Rather than waste a thousand words, check out this picture.

Bottom line: sagittal sections allow the determination of a pot belly size with great accuracy.

And the surprising resuls

A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72). Now, you’d think that obesity in general could explain this astonishing finding. But when the BMI (body mass index) was taken into account the hazard ratio, or risk of dementia, was 1.92, or about twofold.Those with high SAD (>25 cm, or 10 inch) and normal BMI had an increased risk (hazard ratio, 1.89) vs those with low SAD (<25 cm) and normal BMI (18.5–24.9 kg/m²), whereas those both obese (BMI >30 kg/m²) and with high SAD had the highest risk of dementia (HR, 3.60). In other words, if you are not obese, but have those cute love handles, your risk is double that of “normal”, and if you are obese and blessed with central obesity, than your risk of developing dementia increases 4 fold! Food for thought, while you still can. Even more alarming: these subjects had central obesity since middle age. And you can’t find refuge in your good numbers; the association held after correcting for high cholesterol, high blood pressure, diabetes, heart disease, stroke, and other variables. And if you think that your sex will shield you, it won’t: the results were the same for men and women.

As far as I know, this is the first time that anybody studied the correlation between central obesity and dementia. Nobody has a clue how this works on the physiological or molecular level, but rest assured: researchers will rush in to investigate this surprising finding.

But for now, all I can say is: thank you Kaiser Permanente for this great study.

William Bestermann, MD

The intensive glucose lowering arm of the ACCORD trial was just shut down because of an increased number of deaths in that portion of the study.  That finding has created a great deal of confusion on the long-held belief that aggressive treatment of blood sugar should protect patients from vascular events and death.  That belief, like many that prevailed in the practice of medicine, made perfect sense.  Virtually all of the bad things that happen to diabetics are the result of vascular disease.  Blindness, kidney failure, and nerve injury are the result of small vessel disease.  Heart attack, stroke and amputation are the result of large vessel disease.  For a long time, we have known that lower sugar reduces the damage to small vessels.  Very aggressive care should therefore lower heart attacks and strokes due to large vessel disease.

Glucose lowering-per se-does not prevent heart attack, stroke, or death.  I think the ACCORD trial did establish that fact, but this finding is now commonplace in vascular medicine.  Let not your heart be troubled.  There is a place for aggressive glucose control in optimal medical therapy for disease of the large vessels.  We have learned that certain drugs lower the risk factor, but do not protect the patient from events or death.  ACCORD is no different.  Treating hypertension  prevents heart attack and stroke.  Alpha blockers lower blood pressure.  Alpha blockers are inferior to other treatments in preventing events.  Rosiglitazone lowers blood sugar.  Rosiglitazone is associated with increased cardiovascular events.  The very first trial that looked at glucose lowering using tolbutamide was shut down early because of an increased death rate.  For decades estrogen was prescribed for its cardioprotective effects.  That practice ended when a controlled clinical trial showed that estrogens combined with progesterone were associated with increased numbers of heart attacks.  We have known for decades that higher HDL lowers vascular risk-yet a clinical trial for a medication that dramatically raised HDL had to be shut down because of increased events.  In fact, our whole system functions as if bypass surgery and angioplasty are the ultimate answer in heart attack prevention.  These treatments do nothing to prevent heart attack in the stable patient.  There is therefore, a long list of treatments that make sense but when subjected to clinical trials offer no benefit or actually cause harm.

The ACCORD trial was not a vascular trial but a sugar trial.  The trial was designed to test the hypothesis that lowering the sugar, taking precedence above all other considerations would lower events.  The interventions section from the ACCORD protocol states: “Both the intensive and the standard therapy groups will utilize all currently available glucose-lowering therapies.  The two treatment groups will have different glycemic targets and will have different thresholds of glycemic control at which therapeutic changes will be considered.

To achieve these glycemic targets, participants  will require self-management education and dietary and lifestyle interventions, as well as pharmacologic therapy.  They will also require different drug choices and treatment intensities.  For example, within 6 months of randomization, most intensive group participants will likely be on 3 or more injections of insulin a day in addition to two or 3 oral agents.  Conversely, standard therapy participants are less likely to be on insulin, will be on less than or equal to 2 injections per day if insulin is used, and will be taking fewer oral agents.  Moreover, the frequency with which self-management behavior is applied and participants are contacted will vary between the two levels of glycemic control.”  Later, in the Dietary and Lifestyle Interventions section there is the following guidance for investigators: “All participants will be provided with the same dietary and lifestyle recommendations to optimize their glucose control.  These will include : a) advice that blood glucose control may be more critical than weight control in reducing the risk of complications of diabetes.”
The investigators could use metformin, thiazolidinediones (TZDs), insulins, sulfonylureas, exanatide, and acarbose.  

There have been serious questions raised in the past about the adverse effects of certain drugs for diabetes on vascular events and survival.  These questions have been raised for rosiglitazone and sulfonylureas.  Diabetes is itself a weight-related illness.  Most type 2 diabetics have blood pressure and cholesterol problems that are both made worse by increased weight.  All diabetic treatments except for metformin, exanatide, and acarbose are associated with weight gain.  If you compare twice daily insulin with metformin and a single long-acting insulin shot, the metformin-insulin people gain no weight and the twice daily insulin patients gain an average of 10 pounds in one year.  This is no small matter in a weight-driven illness.  The ACCORD trial allowed a number of medical interventions that would be expected to produce weight gain.

On the very same day that the intensive glucose-lowering arm of ACCORD was shut down, the Steno-2 investigators reported their 13 year follow-up for aggressive treatment of high-risk type 2 diabetic patients.  They found that early intensive intervention with multiple drug combinations and behavior modification leads to reduced rates of death and cardiovascular disorders.  There was a 20% absolute risk reduction in the primary end-point of  all-cause mortality.  There was also a 13% absolute risk reduction for cardiovascular death.   In Steno-2, cholesterol, hypertension, glucose were all treated in an intensive and structured way.  The conservatively treated patients in the Steno-2 trial had a 50% death rate over 13 years-a shocking mortality rate.

The big difference in the glucose management compared with ACCORD was that Steno-2 provided an evidence-based protocol consistent with best practice.  Overweight diabetics in Steno 2 were given metformin.  Gliclazide was added to the medical therapy of obese patients who did not achieve goal glucose reduction.  If the glicazide-metformin combination did not result in reduction of A1c to 7.0, then gliclazide was dropped and long-acting insulin added to the metformin.  This is a critical difference.

The insulin-metformin regimen does not cause weight gain.  Metformin is the only diabetic drug with powerful evidence of reduction of incidence of myocardial infarction (39%) and all cause mortality (42%) compared with diet and exercise.  Pioglitazone has some evidence of a less potent effect in this regard.  If metformin fails, it is because the patient is not making enough insulin and so simply replacing the insulin that the patient cannot make should result in preservation of the protective effects of metformin regarding heart attack and death.  Steno 2 seems to bear that out.

Metformin is a drug that has powerful vascular effects on a par with a statin or ACE inhibitor.  Metformin is associated with modest weight loss, decreased total cholesterol, decreased triglycerides, decreased LDL cholesterol, improved endothelial function (increased ability of the artery to dilate) and positive effects on the increased tendency to clot formation found in diabetics.  Metformin cuts to the center of the metabolic syndrome and diabetes by upregulating AMPK-its only site of action.  A study abstract that has just been published by David Lefer’s group shows that a single dose of metformin reduces myocardial infarction size in lab animals by 50% by upregulating AMPK and nitric oxide activity.  A single dose of statin does the same thing.  These are powerful effects.  The National Registry of Myocardial Infarction showed that  the patient entering an emergency room with a heart attack was one third as likely to develop CHF or die if a statin was started in the ER and continued during the hospitalization.  These effects are due most likely to a reduction in myocardial infarction size.

These two studies, ACCORD and Steno 2 teach us a great deal about the way that we should manage the epidemic of type 2 diabetes.  It is not about the sugar.  Simply driving the sugar lower may well be harmful.  The Institute of Medicine in 2001 recommended evidence-based protocols consistent with best practices in the treatment of chronic conditions.  Steno 2 fits that recommendation and ACCORD clearly does not.  Steno 2 should provide us with the model of the future- that is a coordinated-integrated attack on global cardiovascular risk using medications that have been shown to reduce the risk of heart attack and death.  ACCORD has shown us that aggressive care using any modality that lowers the risk factor may be dangerous and a premium should be placed on medications that have been shown to reduce events and death.  The ADA treatment guidelines say that metformin should be started at diagnosis in the absence of contraindication and these results underscore that recommendation.  Long-acting insulin should be used sooner as in Steno 2 rather than later.  

Over a 10-year period in South Carolina ending in 2007, I personally treated 450 type 2 diabetic patients with an average age of 65 and multiple comorbidities.  By using metformin, a self-adjusted long-acting insulin shot and the South Beach diet, I was able to maintain an A1c in that patient population that ranged from 6.8-7.0 over a the entire 10-year period.  These patients did very well with nothing approaching a 50% mortality.  Most of these patients had hypertension and cholesterol problems.  They were treated in a systematic protocol-driven manner.  Pharmaceutical interventions were chosen using the following cascade of priorities. 

1. event reduction
2. effect on weight
3. beneficial effects on other risk factors
4. effects on endothelial function and arterial structure
5. convenience
6. side effect profile
7. reduction of insulin resistance

The basic protocol used looked like this:

Most of these drugs are now available at Walmart for $4 a month.  Most of the patients actually lost weight and kept it off.  The patients could be seen at a reasonable rate of speed and for relatively little cost.  Aggressive diabetes management can be an important part of vascular risk reduction.

The last message anyone should take away from the ACCORD shut-down is that aggressive treatment is a bad idea.  Evidence of event reduction is king and other treatments should only be used when the patient cannot take the evidence-based therapy.

Dr. Bestermann leads the Center for Cardiovascular and Diabetes Management at the Holston Medical Group in Kingsport TN. He is a regular contributor to The Doctor Weighs In.

By Pat Salber

When I was a practicing Emergency Physician, I always used to volunteer to work Super Bowl Sunday. Two reasons: 1) I could care less about football, and 2) It is the one day of the year when no one, and I mean no one, comes to the ER. Whole families on their second week of a cold show up on Christmas Eve. Folks drop by to have their skin rashes checked out on Thanksgiving Day. New Years Eve and New Years Day – busy, busy, busy. But Super Bowl Sunday, while the Super Bowl is on, is dead quiet.

If you talk to emergency physicians, they all have stories about the guy who got chest pain during the first quarter, but held out, sweating and breathing hard, until the game was over. By the time this fellow actually showed up in the ED, his heart muscle had been starved for oxygen for quite some time and the damage was worse than it would have been if he had shut off the TV and dialed 911.

Turns out, according to a study presented at last year’s American College of Emergency Physicians’ 37^th annual scientific session, that some guys (and it is mostly guys), do delay seeking emergency care if they are watching a game. Dr. David Jerrard of the University of Maryland Medical Center in Baltimore and colleagues tracked ER visits over a three year period during and immediately after 800 postseason professional football games, major league baseball games, or Division l college football or basketball games. They found that on the days that games were televised, more men were seen in the 4 hours following the event than were seen during the same 4-hour period on nongame days.

An internet report on the study published on Daily News Central quoted Dr. Jerrard as saying, “Men should not risk their health by putting off going to the emergency room because they want to see the final results of a football game. It could be the last game they ever see."

A more recent article, titled “Super Bowl Could Be Heart Health Hazard,” describes the results of another research study. The investigators looked at cardiac events in Germany (greater Munich area) during the World Cup competition in Germany in the summer of 2006. They analyzed results from 4,279 patients. The results showed that cardiac emergencies were more than double the norm on the seven days when the German team played – it was triple for men. The effect was the strongest for people with known heart disease. Ok, this study looked at soccer fans soccer…I believe we can extrapolate the results to American football fans as well...are they any less rabid?

Considering the learnings of these two studies together, leads me to make two recommendations:

• If you have known heart disease, be sure you take your cardiac meds (including aspirin if prescribed) and have your nitroglycerin handy.
• If you get chest pain (or any other serious symptoms) during the game, get yourself to the ER.

Chances are the game is going to be on all of the TV sets in the hospital anyway so you probably won’t miss much. Besides, you can always record it or watch the recaps on ESPN. I am willing to bet that if your problem turns out to be serious, you probably won’t really care who won or lost the game anyway.

By Dov Michaeli MD, Ph.D

Stem cell research is hot, and getting hotter. Big deal, you might think. This esoteric topic may be important for some scientists, or maybe a few politicians—but what’s in it for me? Let me tell you right off: a lot more than you can imagine. Just consider the statistics, and do the math of your odds requiring one day stem cell therapy.

Heart disease:

• Almost 1 out of every 2.4 deaths in the USA result from cardiovascular disease, or CVD.
• Since 1900, CVD has been the leading cause of death in every year but one - 1918. In that year, the main cause of death was the Spanish Flu pandemic.
• About every 29 seconds an American will suffer a coronary event.
• About every 60 seconds, someone dies from one.
• At least 250,000 people die of heart attacks each year before they reach a hospital.
• It is a myth that heart disease is a man's disease. In fact, cardiovascular diseases are the number one killer of women (and men). These diseases currently claim the lives of more than a half a million females every year - more than the next 16 causes of death put together.

Diabetes (type 2):

· As of 2005, 20.8 million people—7.0% of the population—had diabetes; According to recent CDC figures, there are approximately 798,000 new cases of type 2 diabetes annually in USA, most are Type 2 diabetes.

· According to the WHO figures, there were 173 million cases of type 2 diabetes worldwide in 2002.

· Type 2 diabetes confers a two to four-fold greater risk of coronary heart disease among men and a three to five-fold increased risk among women.

· Diabetes also magnifies the effect of raised cholesterol levels, raised blood pressure, smoking and obesity and so influences coronary heart disease risk indirectly.

· Number of deaths with diabetes as underlying cause of death climbed form 34,500 in 1980 to 62,000 in 1996—an increase of over 44% in 16 years.

· Diabetics use medical resources at a higher rate than average nationwide. Diagnosed diabetics constitute about seven percent of the total population, but diabetes costs account for about 13-14% of all health care expenditures. Diabetes treatment costs about $113 billion a year - more than three and a half times as much as the care for non-diabetic patients.

Alzheimer’s disease:

· There are now more than 5 million people in the United States living with Alzheimer’s. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer's disease and other dementias. This is a 10 percent increase from the previous prevalence nationwide estimate of 4.5 million.

· Every 72 seconds, someone develops Alzheimer’s.

· Without a cure or effective treatments to delay the onset or progression of the Alzheimer's, the prevalence could soar to 7.7 million people with the disease by 2030. By mid-century, the number of people with Alzheimer's is expected to grow to as many as 16 million, more than the current total population of New York City, Los Angeles, Chicago and Houston combined.

· As the prevalence impact of Alzheimer's grows, so does the cost to the nation. The direct and indirect costs of Alzheimer's and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart.

Parkinson’s disease

· There are about 1.1 million people in the U.S. diagnosed with Parkinson’s disease. This is a rate of about 360/ 100,000 people. The rate for people over 65 is about 3%.

· The most detailed report on the economic impact of PD was prepared in 1998 for the Parkinson's Disease Foundation. This study estimated the per-individual yearly cost of PD in 1997 at $24,041 ($24,425 in 1998). Based on a prevalence of one million affected individuals, the total economic burden was calculated at $24 billion.

So there you have it. I listed only four diseases that may be amenable to stem cell therapy. The reason I included the costs of these diseases is to highlight the cost to you, in the form of health-care insurance and direct costs, before you die.

What is a stem cell?

Just think of it as the stem of a plant, which gives rise to the branches and leaves. The developing embryo is formed by a few cells that have the potential to develop into any of the body’s almost 200 cell types. We call such cells ‘pluripotential’, and when their origin is from an embryo they are called ‘embryonic pluripotential cells’. It turns out that every fully formed tissue-- be it blood, neurons, heart—maintains a small reservoir of pluripotential cells, albeit less “pluri” than the embryonic ones, because they are destined to develop into only one or a few specific tissues. This is biology’s form of insurance, in case a certain tissue is in need of repair or regeneration. Alas, in the course of evolution we lost our capacity to regenerate new heart muscle or new brain cells, although the cells are still there, dormant.

The big debate the country went through was over the use of cells derived from a (discarded) blastula (an early stage of embryonic development, consisting of a spherical layer of around 128 cells surrounding a central fluid-filled cavity). Some people saw it as tantamount to murder; others saw the tilting of the moral balance in favor of a discarded agglomeration of 128 cells over the suffering of millions of living people as incomprehensible, if not unconscionable.

The new discovery: genetically manufactured stem cells

Last week Shinya Yamanaka of the University of Kyoto reported that his team has created pluripotent cells from human skin cells, or fibroblasts. On the same day, a team of researchers led by James Thompson at the University of Wisconsin, Madison, reported the same. Do you get the sense that there must have been a fierce race underway to reach this goal? You are absolutely right. Here is what happened.

Last year Yamanaka discovered that introducing four proteins called transcription factors into mouse skin cells ‘reprogrammed’ the cells into embryo-like state. There are thousands of different transcription factors in every cell nucleus, and their function is to regulate gene expression. The discovery that only four transcription factors can induce such a profound change in the character of a cell is astounding. But this was in mouse, and there are basic differences between human and mouse cells. Yamanaka knew that his publication would trigger an intense race to accomplish the same feat in human cells. He worked 16 hour a day, seven days a week, and reported last week that the same four factors produced the same results in humans. The cells were taken from the face of a 36-year-old Caucasian woman. He repeated the exercise with cells from joint fluid from a 69-year-old man with similar results.

Back in Madison James Thompson read Yamanaka’s mouse experiment with more than passing interest. After all, he was the discoverer of the method to propagate human embryonic stem cells. He immediately set out to repeat Yamanaka’s experiments in human cells, with two differences. The first was the source of the skin cells: he obtained them from foreskin, which is fertile ground for a lot of internet jokes but is otherwise of no import. The other difference is important; he used four transforming factors, but only two of the ones used by Yamanaka. He avoided one factor, c-myc, because it is associated with cancer. The fact that he could use different transforming factors suggests that in the future, scientists will have great latitude in the formation of ‘induced pluripotent stem (iPS) cells’, maybe of different traits and capabilities.

The future is bright

These were the first two teams to reach the finish line. Many more are still racing. With researchers crowding into the field rapid advancements are certain. As several scientists ecstatically stated, this is a paradigm shift in reprogramming cells, and will relatively soon result in patient-specific pluripotent cell therapy. Many obstacles remain, but all are surmountable; the big breakthrough has been accomplished. The grim statistics of heart disease, diabetes, neurological diseases, and probably cancer, will become a lot less menacing.

Dov Michaeli MD, Ph.D is in the biotech industry

By Dov Michaeli MD, Ph.D

In 2005, a team of investigators at the Center for Disease Control and Prevention, or CDC, published a paper that shook the foundations of our long-held beliefs; they found that death rates due to overweight (BMI 25-30) and obesity (BMI >30) were actually lower than death rates due to underweight. The paper came under withering criticism by scientists and nutritionists who had been preaching the gospel of weight control. “Libertarian” organizations funded by the food industry, such as “Food Freedom”, piled on with glee. Their basic message: you can’t trust those scientists; just let the consumer beware (and, I presume, let Darwin and the forces of the “free” market weed out those who did not).

The most serious criticism of the study was that it was not even a prospective study, let alone a controlled one. It had a retrospective design, the least reliable of epidemiological studies. Furthermore, it relied on death certificate reports, notoriously inaccurate and many times misleading. Just as one example, a patient dying of a heart attack would normally have his cause of death listed as myocardial infarction, without mention of the underlying type 2 diabetes. It also flew in the face of a huge body of literature showing excess mortality due to obesity and its link to type 2 diabetes and its cardiac and kidney complications, as well as some of the biggest cancer killers such as colon, breast, esophageal, uterine, ovarian, kidney and pancreas—all obesity related cancers. I might add that recently prostate cancer was added to the list.

In a paper published in the Nov 7 issue of JAMA, the authors of the 2005 study went back to the same data bases they had used, in order to determine which causes of death are associated with underweight and which are associated with overweight and obesity.

The envelope, please…

The group with normal weight (BMI 20-25) were considered the baseline and the groups over or below this range were compared to them.

The diseases associated with overweight and obesity were not surprising; the usual suspects were identified, again: heart disease, kidney disease, type 2 diabetes and cancers related to excess weight.

What is intriguing is the relationship of underweight (BMI less than 18.5) to disease; to my knowledge, this kind of information has not been available before this study was published. These people suffered excessive mortality rates from acute and chronic respiratory disease, injury, as well as some cancers that are not related to excess weight, and miscellaneous other diseases (Alzheimer’s, Parkinson’s).

Critique

The study is revealing, especially in its identification of underweight as not healthy. Jewish and Italian mothers, please stand up and say in unison: I TOLD YOU SO.

What could explain the lower rate of mortality associated with overweight than that associated with underweight? No answer is offered by the survey, but what comes to mind is that modern medicine is simply too good at warding off death. We can now keep patients with heart disease and kidney disease alive with all kinds of wonderful drugs and procedures. Even colon and breast cancers, major killers in the not-too-distant past, are now more like chronic diseases, thanks to early detection, chemo- and biological therapy. And bear in mind: the study measured death rates only; it did not attempt to measure the prevalence of disease that has not resulted in death during the study period. 

What could explain the underweight association with disease? A study of this kind cannot establish causality, but one can speculate (especially when not subjected to the jaundiced eyes of peer reviewers). Two things come to mind: muscle mass and immunity. BMI below 18.5 almost by definition means that some of the lost weight comes from loss of muscle. One of the most important muscles, when it comes to infectious diseases, is the diaphragm. When this muscle is weak, respiration is weak, lungs are not ventilated completely, and before long pneumonia ensues. Bedridden patients, elderly people, patients with AIDS, cachectic (wasted) patients with advanced cancer—all are susceptible to respiratory infections. In fact, this is the most common cause of death in such patients. Likewise, low nutritional status is associated with defective immunity to infectious diseases. But, as I said, this is sheer speculation.

What about the validity of the study as a whole? None of the deficiencies that plagued the original paper, namely retrospective design and reliance on death certificates, have been cured. The methodology is identical, the data base is identical—the only difference is that here we get an analysis of the diseases associated with out- of- the- normal body weights.

Dr, Flegal, the senior author of the study, was quite cautious in her assessment of the study . According to Dr. Flegal, "The take-home message is that the relationship between fat and mortality is more complicated than we tend to think." On the other hand, experts like Walter Willett, professor of epidemiology and nutrition at the Harvard School of Public Health, "dismissed the findings as fundamentally flawed, saying [that] an overwhelming body of evidence has documented the risks of being either overweight or obese." He called the findings "rubbish."

Well, well, I wouldn’t go that far. The study did contribute some valuable information on underweight and its relationship to disease. And it provoked controversy—which is great; this is how science is done and how progress is made.

"Most heart attacks in women are preventable," is the headline of an article posted on NBC.com.  The article describes a study, published in the Archives of Internal Medicine, that was done by the researchers at the Karoinska Institute in Sweden.  Dr. Agneta Akesson and colleagues looked at the diet and lifestyle patterns of almost 25,000 postmenopausal women.  At the time of enrollment none of the women had heart disease, diabetes or cancer.

The researchers asked the women to fill out "food frequency" questionnaires to identify how often they ate 96 different foods.  The researchers analyzed the data and found four major dietary patterns:

• Healthy - vegetables, fruits, and legumes
• Western/Swedish - red meat, processed meat, poultry, rice, pasta, eggs, fried potatoes, and fish
• Alcohol - wine, beer and some snacks
• Sweets - sweet baked goods, candy, chocolate, jam, and ice cream

Other information collected included family history of heart disease, education level, physical activity, and body measurements.

The women were followed for an average of 6 years.  During that time, 308 women had heart attacks.  The investigators found that two of the dietary patterns (healthy and alcohol) were associated with a decreased risk of heart attack.  Women who drank less than a quarter ounce of alcohol daily (that is just a splash in the bottom of your glass) and ate lots of veggies, fruit, whole grains, legumes, and fish had a 57% lower risk of having a first heart attack.  That is a whopping big difference.

If women added three other healthy lifestyle habits into the mix (not smoking, being physically active, and avoiding too much weight gain), they had a 92% lower risk of heart attack.  In other words, most heart attacks in women are preventable by making healthy lifestyle choices.

Now, it is one thing to say, eat healthy, drink in moderation, exercise and maintain a healthy weight.  It is quite another thing to actually do all of those things over the course of an entire lifetime.  On the other hand, if you look at the amount of money the US (and, indeed, the entire world) spends to treat cardiovascular disease, I believe you would find there is enough there to buy each and every person a personal cook and a personal trainer (I believe this is the secret to Oprah's weight loss and maintenance).

I say this tongue in cheek, but it does make the point that we aren't spending our "health" care dollars on the right things.  We spend generously to fix disease, but we are very stingy when it comes to funding health.   It is time to get this right.  There aren't enough dollars in any treasury to treat all of the heart disease we are going to see as a result of the global epidemic of obesity and physical inactivity.  This must be  a top priority of policy makers and health reformers.  Studies, like the Karolinska study, should be used to promote changes in public policy - such as healthy school foods, ensuring that all neighborhoods have access to fresh fruits and vegetables and that they have safe places where kids and adults can move their bodies (without worrying about getting shot in the process).

Every politician, health reformer, and policy wonk ought to know about this study and others that prove that healthy lifestyles mean fewer heart (expensive) attacks - not just in women, but in men as well.  The bottom line is most heart attacks are preventable!

By Dov Michaeli MD, Ph.D

Tis the season of the Nobel, and we, ordinary mortals, should rejoice. Global warming was acknowledged as real yet again, sneering antediluvian conservatives notwithstanding. The prize for Chemistry was given for discovery of reactions occurring of the surface of solids—which enabled the invention of none other than the iPOD, among others. The prize for Economics was give for something that I really don’t understand, despite my earnest efforts. And the prize for Physiology and Medicine was given for something that sounds straight out of the boxing ring: the knockout mouse. But this is something too important to dismiss with a shrug and rolled eyes. This technology is already giving us something far more important than the iPOD—it’s a huge step forward in understanding everything about us—normal and abnormal. Sounds like a bit of a stretch? Stay tuned.

What is homologous recombination?

Chromosomes, which package DNA, exist in pairs — one inherited from each parent — and during homologous recombination fragments of DNA can be exchanged between the two. Mario Capecchi (you'll catch him without his tie on)  and  silver-haired Oliver Smithies ( two of the three winners of the prize) found that artificial DNA of known sequence could engage in homologous recombination with mouse DNA, and exploited this to target specific mouse genes.

  Oliver Smithies                          Mario Capecchi                                  Martin Evans

   AP photo/Karen Tam           AP Photo/Douglas C. Pizac

An artificial (synthetic) gene can do one of two things: it can be designed to knock out (or silence) a natural, also called wild type, gene. It can also be added to the genome without knocking out an existing gene.

Now this gives us a powerful tool: by knocking out a wild type gene we can learn about its function by observing which physiological functions are dirupted. By adding an artificial gene we can introduce a human gene (for example, the one causing Parkinson’s disease) into a mouse, and then learn how this mutation causes the disease.

MartinEvans, the third winner of the prize  (and still manning his microscope), worked out the technique that allowed the synthetic gene to be heritable. This in essence enabled us to create strains of mice that carried any human disease we wish to study. Thousands of strains of knock-out mice have been generated since use of the technique was first reported in 1989. More than 500 of these are models for specific human disorders such as cardiovascular and neurodegenerative diseases, and cancer.

There is literally no field of Biology and Medicine that hasn’t benefitted from this powerful technology. And it brought about the new field of Genomic Medicine.

What can Gnomic Medicine do for us?

The implications are almost limitless. One day we will be able to knock out the gene causing ALS (Lou Gherig disease), or the genes predisposing to heart disease, or diabetes, or rheumatoid arthritis, or cancer. Or we’d be able to add a normal growth hormone gene to children whose short stature is genetically determined, or a normal gene to infants suffering from metabolic diseases due some genetic deficiency.

And it doesn’t stop with Medicine. We are already creating plants that are resistant to diseases, or pests, or have nutritional values that promise to wipe out hunger and malnutrition. These are the much-maligned GM (Genetically Modified) foods.

This indeed is revolutionary, and exciting. We do live in interesting times, and I for one, feel extremely lucky.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

Here is some exciting news from the Biotech world: the time is fast approaching when your personal DNA sequence will be readily available.

So what’s the big deal? Read on.

The human genome project

In 2003, the first complete genetic blueprint was published with great fanfare (President Bush, believe it or not, was present at the announcement). At the time, scientific pundits, journalists, and self-appointed crystal ball-gazers, fell over each other proclaiming the benefits of this scientific feat. Indeed, the possibilities were, and still are, simply huge. People expected the advances to come tumbling down almost immediately; it did not happen. Why? Money! It cost about 3 billion dollars to complete the first sequencing in 2003. At that price, it would have cost about $900 billion to sequence everybody's DNA in the US. Come to think of it, that’s not that much more than the Iraq war is costing us…

Fortunately, bright and competent people are engaged in this enterprise. The J. Craig Ventner Institute announced two months ago that it had completed the sequencing of, well, J. Craig Ventner’s genome. Cost: $60 million, or 2% of the cost of the original Human Genome Project’s DNA sequence.

Want more? There are now at least four companies that are racing to develop machines that will sequence a person’s genome for $10,000, or 0.017% of the cost for the Ventner sequence. In fact, the first one to reach the mark will win a $10 million prize offered by the X Prize Foundation. At this price we could have everybody’s DNA sequenced for a total national cost of $3 billion—chump change, about 2 week’s worth of a dirty little war.

What’s the big deal about sequencing everybody’s DNA?

For this you have to understand what DNA is made of. It is made of 4 chemicals, or bases, A, T, G, and C, strung together. Every three bases code for an amino acid, and those, strung together, make up the proteins that carry out all the functions that keep us alive and well. The sequence of these bases, and hence the equence of the amino acids they code for, is highly variable.  So, to be able to read the genomic blueprint, you have to determine the sequence in which they appear. The number of possible permutations in the order in which the bases, and amino acids, is arranged  is essentially infinite.There are about 100 million bases in a chromosome, and there are 23 chromosomes—so you can appreciate the enormity of the task.

But you can appreciate another fact. No system is 100% error-free. As they say in Washington, mistakes have been made. The mistakes in the formation of the DNA, for instance T instead of a G in a particular place, are actually quite common. They are called single nucleotide polymorphisms or SNP (pronounced ‘snips’, aka ‘point mutations’), and they are responsible for our individuality. This is why my daughter and son share a lot of traits with me and their mother, but are not identical to either one of us, and are not even ‘an average’ between the two of us. They are truly unique. This is also the reason why the fear that people will clone their offspring, or the DNA of some famous people, in order to obtain a perfect replica, is misplaced—they will never get it thanks to SNPs (and thank God, or evolution, for that). The first and last individual to come close was Narcissus—and look what happened to him: he became something else—a flower (called narcissus). Not even close.

As part of our personality/ individuality SNPs determine something important: our susceptibility to various diseases and our tolerance of different drugs. For instance, Ventner discovered from his DNA that he has a certain gene variant that increases his susceptibility to Alzheimer’s disease. Other variants are associated with cardiovascular disease, diabetes, basically all human diseases. Mind you, we are not saying that people with SNPs predisposing them to obesity will become obese. But they are predisposed to obesity, and most likely will have to work harder to ward it off.

Now you can begin to see the revolutionary importance of having a complete map of your DNA.

• You, and your physician, will know ahead of time what incipient diseases are lurking in the dark recesses of your genome. You can then take action. To avoid type 2 diabetes you can control your diet. To avoid heart disease you could adhere to a diet and exercise regime, get more frequent checkups, maybe even start on low dose aspirin as a preventative measure. The same goes for cancers, psychiatric disorders, etc, etc.
• Or consider this: we'll be able to tell which child really suffers from ADHD or bipolar disorder, and who is just ' being a kid'; no more fuzzy and subjective diagnoses, especially in psychiatry.
• We now know, from a field called pharmacogenomics, that people respond differently to different drugs. This too is controlled to a large extent by your SNPs. Some people take a drug called methotrexate for treatment of their cancer or rheumatoid arthritis and tolerate it without much of a problem. Others experience extreme fatigue, nausea, vomiting, anemia, infections and other unpleasant side effects. The answer my friend is written in the SNPs.
• There are certain drugs that work in some people and not at all in others. One of those is a cancer drug called 5FU, another is the anti acid drug Zantac. I still remember that many years ago the Japanese government refused to approve it in Japan unless the drug company conducted extensive clinical trials in Japan, because "the Japanese GI tract is different". We attributed it to plain old protectionism. It turned out that many Japanese indeed react to the drug differently—because of a unique combination of SNPs.
• Psychiatric drugs are currently prescribed on a hit or miss basis. Some patients go through four or five drugs, different doses of each, combinations of drugs etc. until the desired effect is achieved. Why is this great variability? you guessed it. Knowing the patient’s genetic makeup ahead of time could avoid this terrible process of trial and error.

I could go on and on, because the list is endless. But you get the idea.

The Pharmaceutical Industry

The business model of the drug industry depended on the discovery of blockbuster drugs, selling for billions of dollars a year. The industry is now changing its collective thinking. They realize that to make money they don’t have to treat millions and millions of people; they could make it by focusing on a much smaller population, and deliver a drug that is essentially tailor-made for it. The up front expense of clinical trials is enormous. The reason is that if the drug works on say, 50% of the people, you need many thousands of subjects enrolled in the trial in order to show a significant effect of the drug. But if you knew ahead of time the genetic makeup of the people who are likely to respond to the drug- then you’ll need only dozens, or a few hundred at most, to show the effect. The tremendous reduction in the cost of such a trial would make even a drug that is effective in only10% of the population highly profitable.

This is not a theoretical model anymore, it actually happened. A small percentage of patients with chronic myelogenous leukemia (CML) have a certain constellation of SNPs in an enzyme that is central to the disease. The drug company, Novartis, decided to develop a drug that would be specific for these people. They saw it as a public service rather than a commercial undertaking. The drug, called Imatinib, was tested in the first phase of the trial in about 25-30 patients, to prove its safety. But lo and behold, it was also 100% effective. On this basis the FDA quickly approved it. The company did not have to spend hundreds of millions of dollars and 15 years to bring it to market. This made it a very profitable drug.

The sociological effect

Without getting too deeply into the implications of these developments, here is a thought: we faithfully repeat the mantra that we are all unique individuals. Some truly believe in it, others (especially people in power) pay lip service to the concept, but in reality expect everybody to behave the same. Just ask any teacher who has to deal with a bright, but restless, child. Or the police officer who has no time or patience for idiosyncratic behavior. Or the despot who brooks no dissent. But once the concept of uniqueness of the individual ceases to be just a philosophical idea and becomes rooted in our Biology, maybe, just maybe, we’ll learn to accept our fellow humans as uniquely individual, deserving of all the legitimacy and respect we’d accord to ourselves.

Now that would be a paradigm shift!

by Bill Bestermann, MD

In my last post, I discussed the untimely death of Wake Forest Basketball coach Skip Prosser and the relationship of vulnerable plaque to sudden cardiac death and myocardial infarction. Only 14% of heart attacks are caused by a fixed artery blockage of 70% or greater. For 70% of heart attack patients, the blockage in the coronary artery is less than 50% (non-obstructive). A non-obstructive plaque causes no symptoms and usually would not produce a positive stress test. Since the 50% blockage typically causes no symptoms, for 70% of myocardial infarction patients, the heart attack or sudden death is their first symptom.

We try to overcome this by using the Framingham risk score, assigning points for risk factors including HDL cholesterol, systolic blood pressure, age, total cholesterol, and smoking status. This is useful, and helps to identify some high-risk patients, but still we frequently miss people who go on to infarction. Our current system, based on risk scores, stress tests, coronary angiography, bypasses and stents has simply failed to identify too many patients with substantial risk.

Since the vast majority of heart attacks are not occurring at sites of fixed stenosis but rather at the site of a vulnerable plaque rupture, the question becomes-how do we identify these high-risk patients and treat them aggressively. Patients who have established atherosclerotic arterial disease at any site should be treated as if they have coronary artery disease. Arterial disease is a diffuse process and any blockage anywhere indicates that most of the arteries are involved with atherosclerotic plaque. There is a dramatic correlation between type 2 diabetes and arterial disease. The same holds true for patients with kidney damage. Both of these patient classes should be treated with the same level of aggression as the patient with established vascular disease. Patients with a high Framingham Risk Score should be aggressively managed. The risk factor management targets for these patients are lower than those we normally are aiming for. The blood pressure should be less than 130 systolic (top number). The LDL cholesterol should be less than 70. The hemoglobin A1c should be under 6.5.

There are many patients at risk who fit none of these categories and currently they are not being treated aggressively enough. Patients with strong family histories but low to intermediate risk scores are an example. Some people have intermediate risk scores but in actuality are very high risk—how do we identify them? Since the fundamental risk is the extent of plaque in the artery—specifically the amount of unstable plaque—the ideal way to identify high-risk patients would be to develop a methodology that allows us to identify patients with unstable plaque. The higher the amount of unstable plaque, the higher the risk.

The gold standard for directly examining the amount of plaque in the artery is coronary catheterization using intravascular ultrasound technology. This is an invasive technique that carries some risk and substantial expense. It is not routinely used even in patients having a heart catheterization. It is impractical for intermediate risk screening.

More studies are now available to help us understand the role of coronary artery calcium scoring. The American College of Cardiology and the American Heart Association have just published an expert consensus document on this technology. Atherosclerotic plaques are dynamic deposits in the arterial wall that go through progressive and predictable stages. Plaque “instability and rupture can be followed by calcification, perhaps to provide stability to an unstable plaque.” The authors state: “Radiographically detected coronary calcium can provide an estimate of total coronary plaque burden. The authors go on to provide a further rationale for the use of this technology: “Patients who have calcified plaque are also more likely to have non-calcified or “soft-plaque” that is prone to rupture and acute coronary thrombosis….coronary artery calcium scoring may be able to globally define a patient’s CHD (coronary heart disease) event risk by virtue of it’s strong association with total coronary atherosclerotic disease burden, as shown by correlation with pathologic specimens. Perhap even more convincing is the following:

“ Pathology studies have shown that the extent of coronary calcium within plaques tends to be related to healed plaque ruptures.” We cannot identify the vulnerable plaque but we can quantify ruptured plaque history which tells us his risk for future plaque rupture and thrombotic obstruction. We cannot identify the vulnerable plaque, but we can identify the “vulnerable patient.”

Even more impressive, when we combine the Framingham Risk Score and the Coronary Calcium Score, we have a system that is able to predict coronary risk in a very robust fashion as shown in the figure below. Any patient with a coronary calcium score over 100 should be considered to have coronary disease and should have risk factors reduced to those same aggressive targets.

Women are a special case here and for them this technology may be even more important. Women are less likely to form focal narrowings in the arteries and so they are even more likely to have an infarction with a non-obstructive plaque (narrowing less than 50%) Women tend to deposit their plaque in a concentric, symmetrical fashion up and down the artery. In fact, women with recurrent chest pain and a normal heart catheterization still have a 20% six-year risk of sudden death, myocardial infarction, stroke or congestive heart failure (WISE study). For this reason, I would not consider any woman’s cardiac workup to be complete until she had a calcium score. Too many women are told they have nothing to worry about after a normal heart catherterization. The woman with recurrent chest pain is still often high risk and in need of aggressive risk-factor management.

Here is the really amazing part. In spite of the extensive literature on the new science of risk assessment and the importance of vulnerable plaque, almost no insurance companies pay for the calcium score. In our group practice, we offer this test for $249.00. When you consider the information to be gained from the study, that seems very reasonable. This technology should be much more widely applied to identify high-risk patients and we should press the payors to allow this test in intermediate-risk patients.

Bill Bestermann

The Wake Forest University School of Medicine is my alma mater and earlier in the week I came upon our quarterly alumni magazine.  I was at first struck by the wonderful cover photo and then chagrined as it began to dawn on me what the picture meant.

You can see this warm, engaging man relating to the students at a Wake Forest basketball game and the love these young people felt for him is plainly seen in their happy expressions.  The photo speaks volumes about head basketball coach Skip Prosser.  It is a painfully tragic scene because the coach came in after a jog this summer and died suddenly at the age of 56.  The great game was the life he lived.

Athletic Director Ron Wellman said “Prosser’s life wasn’t about championships—although he won the ACC regular season championship in 2003—but about relationships and friends.  ‘Skip tried to know everyone.  Once you met him, you considered him a friend and he considered you a friend.  On campus, he seemed to be everywhere.  When he said hi, that made your day.”  Somehow, looking at this haunting picture, that is believable.

Events like this weigh heavily on my heart because most of them could be avoided.  Medical science has advanced to the point that the number of sudden deaths related to heart attack could be dramatically reduced.  Leading cardiologists like Peter Libby, Erling Falk, and Steven Nissen have helped us to understand that a heart attack does not come from a fixed blockage.  Myocardial infarction and cardiac sudden death almost always are the result of a ruptured vulnerable plaque.  A 1995 article by Erling Falk documents that only 14% of heart attacks occur at a point in the artery where the obstruction exceeds 70%.  Seventy percent of myocardial infarctions occur where the fixed obstruction is 50% or less.  Since a 50% blockage seldom produces symptoms, for 70% of patients, the heart attack is the first symptom.  Unfortunately, for many patients the first symptom is fatal.

In fact, the new science of arterial disease goes back nearly twenty years. The Falk article summarized findings from 4 previous studies.  The summation of the data from those studies helped us understand that chronic obstruction is not the cause of a heart attack, most heart attacks occur when a newer, less obstructive plaque ruptures.  The unstable plaque contains LDL cholesterol or “bad” cholesterol.  That LDL cholesterol is oxidized—chemically changed—in the wall of the artery and then it is recognized as foreign by the body.  The human body deals with foreign material by attacking it with white cells or pus cells.  The unstable plaque is a microabscess or a tiny boil in the wall of the artery.  When that boil ruptures, a toxic, inflamed gruel with the consistency of toothpaste comes in contact with the blood in the artery and sets off the clotting process.  If the clot partially blocks the artery, unstable angina or an acute coronary syndrome is the result.  If it totally blocks the artery, myocardial infarction is the result.  The blocked artery causes death of the heart muscle downstream.

Only a few heart attacks occur as the result of severe chronic obstruction of the artery because the more obstructive plaques are much more stable.  They have been present longer.  The body reacts to those lesions by producing a thick cap over the cholesterol plaque and the inflammation produced by the white cells (pus) causes scar tissue formation.  The inflamed cholesterol is bound up and rupture is more difficult.

This scientific understanding ties the new critical facts of arterial disease together.  It explains the fact that the anticoagulant aspirin cuts the risk of heart attack by a third.  It helps us understand why the clot dissolver TPA (tissue plasmin activator) aborts the heart attack process.  It helps us understand why statins have power beyond cholesterol lowering in that they dramatically reduce inflammation and quickly stabilize plaque to prevent rupture.  Other medications like ACE inhibitors for blood pressure and metformin for diabetes have beneficial effects on the metabolism of the arterial wall to improve arterial function and diminish plaque instability.  The highest risk patients---type 2 diabetics—have an 80% life-time risk of heart attack or stroke.  Treating pressure, glucose, and cholesterol to aggressive goals lowers the risk by roughly half for each risk factor.  Dr. Steven Nissen and others have shown that aggressive lowering of the LDL cholesterol with statin therapy stabilizes the plaque and actually reverses the buildup of LDL cholesterol and pus in the wall of the artery.  So, we really have a very solid understanding of how arterial disease works and the ability to produce a tremendous  reduction in the risk of heart attack with medical treatment.

It is somehow ironic that one of the first two articles of the four cited in the Falk study came from Wake Forest.  Dr. WC Little and his team wrote in Circulation in 1988:

”Acute myocardial infarction is usually produced by the sudden total occlusion of a coronary artery by thrombus (clot), usually occurring at the site of an atherosclerotic lesion.  Our study indicates that the lesion that will be the site of the thrombotic occlusion frequently is not severe when evaluated by coronary angiography weeks to years before the infarct in patients with mild-to-moderate coronary artery disease; thus, coronary angiography was not able to accurately predict the time or location of the subsequent myocardial infarction.  (my italics) In the majority (66%) of patients in this study, the myocardial infarction occurred because of the occlusion of a coronary artery that did not contain an obstructive (more than 50% diameter narrowing stenosis) on a previously performed coronary angiogram.  A high-grade stenosis (more than 79% diameter narrowing) was initially present in the infarct related artery in only one patient.  Furthermore, the myocardial infarction did not  occur because of occlusion of the previously patent artery with the most severe stenosis in two thirds of the patients.”

Dr. Little and his colleagues went on to conclude:

“Because it was difficult to predict the site of the subsequent occlusion in our patients from the initial coronary angiogram, coronary bypass surgery or angioplasty appropriately directed only at the angiographically significant lesions initially present in almost all our patients would not have been effective in preventing the majority of myocardial infarctions.  This does not indicate that arteries that do not have obstructive lesions should be bypassed or dilated.  Instead, effective therapy to prevent myocardial infarction may need to be directed at the entire coronary tree, not just at obstructive lesions.  Such therapy to prevent myocardial infarctions might rationally include avoiding smoking, reducing serum cholesterol, administering agents that alter platelet function…(my italics)"

In 1988, Dr. Little was saying that bypass surgery and angioplasty did not prevent heart attack in stable patients and could not be expected to prevent heart attack in stable patients.  He predicted the results of the COURAGE trial (New England Journal-2007) nearly 20 years ago.  The COURAGE trial compared optimal medical therapy with optimal medical therapy plus appropriate stenting in patients with angina, most of whom had two and three vessel coronary disease.  There was no difference in heart attack or sudden cardiac death in the two groups after 5 years of therapy.  In other words, the stent added nothing but pain relief.  Additionally, in the COURAGE trial, 70% of the patients were pain-free at 5 years on medical therapy alone.

The new science of vascular disease tells us that we are doing too many catheterizations, bypasses, and stents.  We are doing a miserably inadequate job of identifying high-risk patients like Skip Prosser and providing optimal management for all risk factors.  We have known or should have known that for almost 20 years.  Let us call it what it is—a failure of leadership.  How many good men like Skip Prosser have to go down before we get this right?

By William H. Bestermann Jr. MD

Type 2 diabetes is a condition that costs Americans terribly in terms of death, disability, and health care expenditures. This chronic condition is a vicious cycle type of illness. Glucose control tends to deteriorate over time. Most of these patients also have problems with blood pressure and cholesterol. Only about a third of type 2 diabetics have their pressure, sugar, or cholesterol under control as individual risk factors. Only 7% have all three risk factors controlled simultaneously to conservative goals. This sad fact has dramatic consequences. The lifetime risk of a diabetic having a heart attack or a stroke is 80%. For each risk factor that is controlled to goal using the right medication, the risk is reduced by roughly half—so when we control pressure, sugar, and cholesterol the risk is reduced from 80% to 40% to 20% to 10%. Now maybe the risk is not really 10%, but it is very dramatically reduced and in 10 years of experience with 450 diabetics, I believe that I have seen a very important reduction in vascular events that has been achieved by aggressively controlling these risk factors..

Everything bad that happens to a diabetic is fundamentally arterial or vascular. Obviously the heart attacks, strokes and amputations are vascular, but even the kidney, nerve and eye damage relate to arterial damage as well. So the target here is not just the sugar or the cholesterol. The fundamental question is “how do we lower the sugar, cholesterol and pressure with the maximum benefit on the artery?” Furthermore, how do we accomplish this in such a way that the patient’s life is minimally altered and this is sustainable.

In this post, I will focus on sugar control. Everyone agrees that type 2 diabetes is at its core a life-style illness. As one of my colleagues in South Carolina said: “There is nothing that we can do for diabetes that you cannot outrun with a spoon.” In other words, if the patient does not make some effort with diet and exercise, it is difficult and perhaps impossible to get risk factors to goal. I have controlled the sugar in disabled patients, but it is more difficult. Type 2 diabetes is a disease of elevated blood sugar. It is self-evident that sugar consumption must be limited. Less widely appreciated is the impact of starch or carbohydrate consumption. Processed starch becomes sugar in 2 minutes once it is consumed. When a person eats 100 calories of white rice, in 2 minutes it is just as if he took a spoon and ate 100 calories of sugar out of the sugar bowl. The less processed a carbohydrate, the more slowly it is consumed.

Some understanding of nutrition is vital. Formal dietary instruction by a certified diabetic instructor is helpful but I see substantial variation in what patients are told. As a practical matter I have found the South Beach diet to be very useful and just bought the book for a friend at Walmart for $12.00. I have recommended that diet for patients and found it very effective with sustainable effects on weight and sugar control. Dr Agatson, the author, is a cardiologist famous for developing the cat scan calcium score we use to determine cardiac risk. He teaches two very important concepts. First, we have to learn to limit starch and to eat our starch in the form of whole foods. Second, we need to limit fats, especially animal fats and trans fat. This program is attractive because it is effective, widely available, and supported by recipe books and pre-packaged items.

Next we come to drug therapy. Doctors are trained in the treatment of diabetes with medication by learning about all of the medications that are available, and then they are left to decide which of these many medications they will use and in what order. There are several different classes of oral drugs with multiple drugs in each class. There are multiple types of insulin with differing durations of action. There is no real protocol that is universally agreed upon as best practice.

Type 2 diabetes is the later stage of the metabolic syndrome. Most type 2 diabetics have been metabolically abnormal for decades. They have been resistant to the effects of insulin for years and just before they become diabetic they have been maintaining their normal sugar by producing levels of insulin in the blood that are three times normal. As time goes on they are unable to sustain that level of insulin production and when insulin levels fall the sugar begins to rise. At the time of diagnosis, insulin production has fallen by 50% and the loss of the ability to produce insulin is aggravated by poor sugar control—a built-in vicious cycle. When it comes to diabetes, we just do too little too late.

In recognition of this fact, there was a recent consensus algorithm published in Diabetes Care. This is a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. They emphasized the importance of diet and exercise as first therapy. Most notably in my view the authors went on to say, “The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain metabolic goals, either because of failure to lose weight, weight regain, progressive disease, or a combination of factors. Therefore, our consensus is that metformin therapy should be initiated concurrent with lifestyle intervention at diagnosis.” Most medications for diabetes cause weight gain. Metformin has modest effects in assisting with weight reduction and it is the only medical treatment for diabetes that is proven to lower the incidence of heart attack and stroke by 40%. That effect is on a par with the best cholesterol and pressure treatments.

If treatment with metformin fails, it is generally because insulin production is at least relatively inadequate. The most effective and rational next step is to instruct the patient in a self-adjusted insulin shot using Lantus or Levemir. In the protocol I use, the patient is able to rapidly bring the sugar safely down and most patients are at goal with this reasonably simple approach. It seems to me that the proven vascular benefits of metformin would be preserved in these patients since all we are doing is replacing insulin that they cannot make themselves. Most patients are really surprised at how easy this is to work with and how much better they feel when their sugar is controlled.

Brian Klepper

This week TDWI is delighted to take our turn hosting Health Care Wonk Review, a collection that highlights some of health policy's best observers. The quality of these 14 posts is very high, and well worth your time.

As HWR has gained visibility and popularity, the number of submissions has risen. We couldn't publish them all, so chose the ones we thought were must-reads across industry sectors. (Apologies to those we didn't include this time.)

Before we begin, a quick announcement. Envision Solutions, LLC and Trusted.MD Network have launched the second annual global survey of healthcare bloggers.  The companies are producing this poll to shed additional light on why people blog about health-related subjects.  Click on the link to learn about and take the survey.  The study will close on October 15.

Now onto the show!

Physician Temper Tantrums. Over at Managed Care Matters, Joe Paduda picks a scab and elicits a (deliciously) minor furor. He argues that when payors use the results of claims data analysis to encourage patients to see better performing doctors, they are well within their rights as purchasers. He also notes (and I agree) that when doctors reject out-of-hand claims data as inherently flawed and inappropriate to provide quality analysis, they may not appreciate the progress in the available tools and methods, and may be simply defensive. Actually, he says "their actions look more childish than professional from here." A provocative piece.

No Docs in This Box. Retail medical clinics are popping up all over as an inexpensive alternative to a full-blown practice or the ER. Traditional providers are crying foul, but InsureBlog's Bob Vineyard suggests this is the pot calling the kettle black.

Abusing The Orphan Drug Law To Rip Off Customers. In a damning indictment of a drug company's business