In the past few months, I bet you’ve seen at least one ad like these. When I first saw these ads, I was impressed.

Most direct-to-consumer drug advertising is loathsome, filled with moronic non sequiturs–what does kayaking have to do with a nucleoside analog used to treat herpes–or simply build up anxiety about a problem, offering no explanation as to how the drug helps.

These ads, for a combination pill meant to treat high cholesterol, are actually quite clever in explaining how the drug should work–a combination of blocking cholesterol production by your liver (a gift of your parent’s genes) and blocking the absorption of cholesterol you eat.

Memorable, clear, informative; too bad the drug doesn’t work.

The results of our study showed that the addition of ezetimibe to the highest recommended dose of simvastatin did not reduce the intima–media thickness of the carotid-artery wall in this cohort of patients with familial hypercholesterolemia, despite significant incremental reductions in levels of both LDL cholesterol and C-reactive protein. The primary outcome, the change in the mean intima–media thickness, did not differ significantly between the two study groups, nor did the secondary outcome measures.

In plain English, this combo pill didn’t stop the arteries from getting clogged with cholesterol any better than the older drug alone. In fact, the older statin drugs–available as much cheaper generics now–do a better job on what you, as a patient, would care about.

The vast majority of people exposed to these ads probably don’t know this, and will never know that the drugs didn’t work, that you’re better off with a vastly cheaper drug, that the company that makes Vytorin sat on the negative results in this study while racking up billions of dollars in sales. My suspicion is that many people will continue to ‘ask your doctor about Vytorin,’ as the ad suggests. And this is why even exemplary direct-to-consumer drug advertising is so damn irritating.

A few things to note:

1. Day-to-day variation in my weight is somewhat typical. The churn is probably from water. Hence, the seven day moving average as a more accurate measure.

2. Each pound of fat contains 3500 (kilo) calories. Therefore, the half pound gain over the week represents about 250 extra calories a day. (Hey, it was the holidays.)

So, how many calories did I average on a given day? About 2126. Subtract the 250 or so extra a day, and we’ll say that 1875 calories a day would be about right for me to just maintain weight. To lose a pound-a-week, I need to eat no more than about 1400 calories a day. A half-pound-a-week? 1625 calories a day.

1875 calories a day is an interesting number. Per the USDA charts, a typical person of my height, age, gender, activity level and weight would need 2858 just to maintain weight. I do it with a third fewer calories. Here is some empiric evidence that I’m an energy sparing person–with the combination of genes, epigenetics and microflora that is more efficient than most at extracting and saving energy from food.

If I ate as many calories as a typical person like me ate, their weight would stay the same; I’d gain about a hundred pounds a year, two pounds a week.

I’ve known this qualitatively for a while, coming from a family of big people and always being prone to gaining weight. Still, seeing the numbers is pretty startling. If I wish to lose weight, I have to eat less, much less, than the average person.

Now I know the number to target. I’m starting at a goal of a half-pound a week, or about 1625 calories.

On my slight five-foot-ten frame, that represents about a fifth more of me since 2001. How did that happen? Very slowly, and with both fat and muscle gains contributing.

Arriving at 135 pounds to Seattle, I was close to being underweight, my BMI above 18.5. Now at 165, I’m not officially overweight, my BMI is still below 25.

BMI isn’t the greatest measure of health. According to the Met Life tables, my ideal body weight is about 155 pounds. Putting aside the numbers for a moment, it’s where I’ve gained fat that matters more from a health perspective. Belly fat, like many men gain as they exit their twenties, is the most worrisome, with negative effects upon blood sugar, lipid profiles and general health.

At some point in the near future, I’m sure to find myself telling a patient to lose weight–ten, twenty, thirty, fifty pounds. How hard is it? By many of the measures I’d use with patients, I could stand to lose ten. Using the best available scientific data, can I do it?

Well, let’s try.

The first step: for the next week, each day I’ll carefully record what I eat and my weight. The goal is to stay about as close as possible to a “typical” week of eating for me, in an attempt to figure out my particular equilibrium between the calories I consume and use in a given day.

This public health triumph has arisen, Unicef officials said, partly from campaigns against measles, malaria and bottle-feeding, and partly from improvements in the economies of most of the world outside Africa.

So, with more babies surviving through early childhood, will there be a population boom? Maybe not.

If you live in a culture where children are the only feasible retirement plan–i.e. most of the world–it’s really important one child survives through your retirement, right? And if there is about a one in three chance that any given child won’t survive to see his or her fifth birthday (where Sub-Saharan Africa was a few decades ago), you better have several children.

Here comes some math to back up this notion. If your only willing to risk a one in a hundred chance of ending up destitute in old age, and there is a thirty percent chance than any given child will perish, the math tells us you’ll need to have four kids. Drop the mortality to fifteen percent–where Sub-Saharan Africa is today–and three kids will cut it. Five percent chance of perishing before five, like present day North Africa? Two kids will cut it. Magic. Smaller families through better survival.

Logic like this helps us understand why people in economically marginal areas of the world continue to have large families–further stretching resources, resulting in higher childhood mortalities, causing larger yet families–and how this pattern can be broken by public health.

While the new therapy started in 1996, it was on September 11th 1997 when the first report was published in the New England Journal of Medicine. Here is a lovely manuscript–a proper randomized double-blind and controlled study.

The trial patients were grouped by CD4 T cell counts, and then randomized to triple drug therapy or the controls of single or double drug therapy. Initially, the study was to last 52 weeks. When the results started to roll in, the blinding was ended and everyone allowed access to the triple drug cocktail.

At the time the language both cautious and astounded,

The three-drug combination of indinavir, zidovudine, and lamivudine reduced the viral load in serum to less than 500 copies per milliliter for up to one year in more than 80 percent of the HIV-infected patients we studied, all of whom had prior antiretroviral therapy. Most patients in the three-drug group whose HIV RNA levels were reduced to less than 500 copies per milliliter also had less than 50 RNA copies per milliliter when the ultrasensitive investigational assay was used. The sustained response in HIV RNA levels with the three-drug therapy was superior to that with either indinavir monotherapy or the combination of zidovudine and lamivudine. No prior antiretroviral regimen has produced the marked, sustained decreases in viral load achieved with this three-drug combination.

Finally, physicians were able to reduce viral loads to near undetectable levels. The researchers didn’t even consider this a cure, rather a path to “delayed progression to AIDS and prolonged survival.” At the time, it wasn’t clear if reducing HIV viral loads would really help patients avoid AIDS; by the end of the short study, CD4 T cell levels had only started to increase.

The dissociation between the marked decreases in viral load and the incomplete restoration of CD4 cell counts in the three-drug group remains unexplained. Some patients may have ongoing, slower increases in CD4 cell counts after six months of therapy. In patients with autoimmune disease or cancer who receive intensive radiation therapy or chemotherapy, CD4 cell counts recover slowly and may take three years or more to reach normal levels.30,31 Further study is needed to determine what level of restoration of CD4 cell number and function can ultimately be attained with the three-drug regimen. It remains to be seen whether the immune system can be fully reconstituted even when regimens that achieve maximal HIV suppression are used.

The scientists ended with a prescient thought. “Without complete viral suppression, antiretroviral regimens will probably select for drug-resistant mutants, leading to the failure of therapy,” they cautioned.

Swoon.

So, happy ten years of highly effective anti-retroviral therapy.

Weight is an intrinsic trait, determined mostly by our genes. Yet, globally the number of obese people has nearly doubled since 1980–faster than alleles can redistribute in the population.

The amount we eat is strictly controlled by regulatory systems. Each of us is endowed with an energy set-point; forced overeating makes people feel ill, until their weight drops back down. Unless, of course you are obese, where the setpoint is somehow reset to much higher than it should be; eating fewer calories to dip below the new setpoint results in a starvation response from the body, even for people who are massively overweight.

The more overweight you are, the higher your risk for heart attacks, strokes, diabetes, sleep apnea, high blood pressure and even some cancers. Unless you are active and obese; for at least some of these maladies, you’d statistically have a similar risk to sedentary skinny folk.

Confused yet? Mix in all the high emotions that come from questioning who or what is responsible for our increasingly zaftig culture, and it’s a real mess.

So, let’s add one more piece: Your bone and fat cells are talking to one another.

We’ve known for a while that being obese protects you from osteoporosis. A protein made by fat cells called leptin–also essential for regulating feeling full when you’ve had enough to eat–stimulates the bone making osteoblast cells.

The authors of a recent Cell study figured that if fat cells can stimulate bone-producing cells, the bone cells should signal back to the fat, creating a tidy negative feedback loop, where the fat cells stimulate bone producing cells (”We need stronger bones to carry around all this fat!”), and the bone cells inhibit fat formation (”Too. Much. To. Carry. Stop making fat!”)

So, what could be this signal? Bone producing cells create only a handful of distinct proteins, one of which deemed Osteocalcin. Mice lacking the Osteocalcin gene have fat bellies. Very interesting.

In this most recent study, the scientists followed this trail, and found that mice without Osteocalcin are not only fat, but are also glucose intolerant — just like people with type-II diabetes. So, less Osteocalcin, more diabetes-like symptoms.
Don’t take my word for it, here is are some snippets from figure 5 of the paper.

The mice lacking Ostocalcin (in blue) have bigger abdominal fat pads than normal mice (gray).

Compared to normal friends, the Osteocalcin-lacking mice drop their blood sugar much less after being injected with insulin.

And Osteocalcin-lacking mice do a much poorer job of cleaning up after sugar is injected into them.

Ok, great. But how are the bone cells figuring out how much Osteocalcin to release? The scientists went on to knock out a signal receptor only in bone forming cells, Esp. Mice without the Esp receptor have more insulin producing cells (left is normal, right is from a mouse lacking Esp),

more insulin production (gray normal mouse as compared to green or red mice lacking Esp),

and increased sensitivity to insulin (gray normal mouse as compared to green or red mice lacking Esp)

– the anti-diabetes.

So, maybe signaling through the Esp receptor blocks Osteocalcin release; remove Esp and you’d get a flood of anti-fat Osteocalcin, right? The authors tested this idea by also getting rid of only one copy of the Osteocalcin gene in mice already without Esp.

It worked. Mice lacking both were more or less normal. (Holy double negatives, batman.)

So, who knows. Now for some wild speculation: Perhaps stimulating your skeleton is key in preventing diabetes. Certainly bone producing cells in mice can pump out a powerful signal that blocks belly fat, and keeps the blood sugar regulating system humming along. Next time you think about spending the whole weekend on the couch, think about the conversation between your bone and fat cells. Next time you think about spending the whole weekend on the couch, think about the conversation between your bone and fat cells.

Our selections:

1. Staphylococcus Aureus (from snot)

2. Bacillus cereus (from improperly cooked and refrigerated starches)

Snot or rot. Snot or rot? Which is less nauseating to you?