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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Is HDL Always "Good Cholesterol"? | Main | The Genetic Diversity of Cancer Cells »

May 18, 2012

Strangely Good Results in Diabetes and Cardiovascular Disease

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Posted by Derek

I've read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn't something you'd necessarily think would do much good - it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong:

In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.

A note to the conspiratorially minded, should any such come across this: it's worth noticing that this "maybe everyone should take statins" result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn't (and probably couldn't have, since we didn't have as much data as we do now).

Now to another (often related) disease, type II diabetes. It's been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense - obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent:

Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.

Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it's something to do with secretion of hormones from the gut itself, and you'd also have to think that nutrient sensing gets profoundly altered. It's not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you'd imagine:

Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned.

Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer's, the subject of yesterday's post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it's a death sentence. Good to know that things can work in the other way once in a while.

Comments (14) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Diabetes and Obesity


COMMENTS

1. exGlaxoid on May 18, 2012 9:14 AM writes...

If someone could figure out how to create the same gastric hormone changes via a drug or other simple treatment as gastric bypass surgery produces will be a very wealthy person or company. I know someone who studied this area and also saw dramatic changes in insulin and sugar levels within days of the surgery, even after the patient was eating again.

It would be worth seeing if just the effects of the surgery and anesthesia of other invasive surgeries affect diabetic patients in a similar manner, to see if just having major surgery is enough to promote the changes in metabolism. Of course that would be a very drastic step for weight loss. Surgery makes rimonabant look very safe.

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2. Morten G on May 18, 2012 10:55 AM writes...

*post-doc sulk, pout, and eye-roll*

Well, the SOS study showed large improvements against diabetes for anyone who cut 5 points off their BMI, no matter if it was achieved with surgery or dietary changes and no matter if they were still obese after dropping 5 BMI points.
tl;dr eating below maintenance calories rolled back diabetes. Eating above maintenance probably promoted it.

Statins reduce inflammation. The majority of Westerners have too high inflammation.
tl;dr another nail in the coffin of the cholesterol hypothesis.

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3. luyss on May 18, 2012 12:32 PM writes...

The improvement in type II diabetes within 2 weeks after bariatric surgery and before significant weight loss has occurred is quite noteworthy. Type I diabetics usually need MORE insulin with trauma and/or surgery (which is inherently traumatic), and sugar usually rises with these events in type IIs. Usually by the second postop week things have settled down. So when was the improvement noted, the first or the second postop week (or both)?

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4. NoDrugsNoJobs on May 18, 2012 12:35 PM writes...

#2 - There are multiple genetic studies that clearly link LDL abnormalities (too high) with adverse heart events, the paper Derek cited about HDl in the Lancet clearly reiterates this point - Now, if you want to make the argument that high ldl numbers are strongly correlated with inflammation (e.g. crp) and that by lowering cholesterol you lower inflammation and therefore the cholesterol is an indirect cause, you might be on to something interesting.

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5. Todd on May 18, 2012 2:02 PM writes...

I agree with #4. While inflammation is an important factor with regard to heart disease (and why some people's heart attack is higher or lower in proportion to their cholesterol level), cholesterol is definitely the biggie. You can say direct or indirect, but it's far from irrelevant.

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6. Anon on May 18, 2012 3:04 PM writes...

"This benefit greatly exceeds any known hazards of statin therapy"

Anecdata about memory loss concerns me greatly.

I'm Late 30s, no coronary problems, otherwise healthy but LDL=190 and total chol=275

I would rather have a year off my life statistically than have memory problems.....


Are there any good peer reviewed studies about this? This boston.com article seems to suggest not yet.....

href="http://www.boston.com/Boston/dailydose/2012/03/statin-side-effects-how-common-are-memory-loss-diabetes-and-muscle-aches/jjSsnfRshNt7TWQHbSsxJP/story.html

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7. Anonymous on May 18, 2012 5:17 PM writes...

Laparoscopic Roux-en-Y gastric bypass may work better than traditional open Roux-en-Y surgery. A number of people - friends and acquaintances - who had the open surgery failed, regaining any weight lost as early as six months post-surgery, in spite of up to 18 months of behavioral modification and counseling with registered dieticians.

These people became more obese than they had been prior to the surgery, all the conditions they had prior to the surgery (diabetes, high cholesterol, high blood pressure, et al) returned, and they needed more drugs at higher doses than they did before.

Also anecdotal, but something like that might make an interesting study.

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8. Rick Wobbe on May 18, 2012 5:34 PM writes...

#3 Luyss, interesting point. Since I'm too cheap and cranky to fork over the $18 to get the article or drive to the library, I don't know whether the authors looked for this effect post-op for other surgical procedures on obese patients. Did they? Seems like an obvious, easy thing to do.

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9. luysii on May 18, 2012 6:18 PM writes...

It is a truism that the fatter you are, the worse you do with any surgery. Whether this is because of the associated conditions (diabetes, hypertension, cardiac problems, vascular disease, hyperlipidemia) or obesity per se is hard to know. It's not easy to find obese people having surgery with none of the above.

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10. jonb on May 18, 2012 8:22 PM writes...

Double blind studies show insomnia and memory loss associate with statin use in aggregate. I see patients all the time with delayed statin side effects...possibly (not proven) as a result of decreased coenzyme Q10 synthesis affecting intracellular energy production and/or free radical signaling. These drugs are not for everyone.

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11. Marilyn Mann on May 20, 2012 8:17 AM writes...

The CTT meta-analysis seems like old news. I think we have known for quite some time that statins benefit low risk patients, or at least the kinds of low risk patients that were enrolled in the statin trials.

Moreover, in the U.S., our current cholesterol guidelines suggest statins for people with LDL-cholesterol levels above certain cutpoints even if they are low risk, and millions of low risk Americans are already on statins. Heck, there are lots of Americans on statins whose baseline LDL is below the cutpoints in the guidelines. On the NHS, in contrast, statins are only suggested for people with 10-year risk above 20 percent. So you have to read the article and editorial in that context. To make things even more confusing, I note that the CTT defines "low risk" as 5-year risk below 10 percent (10-year risk below 20 percent). In the U.S., "low risk" is usually 10-year risk below 10 percent, while "intermediate risk" is 10-year risk between 10-20 percent.

The real issue is not whether there is a benefit for low risk people who have risk factors for cardiovascular disease. The issue is what benefit is large enough to make taking a statin for years or potentially decades of your life worthwhile. That is not a question that can be answered by CTT or by anyone else other than the patient. It depends on what value the patient puts on the kind of small reductions in absolute risk (NNT 167 in the lowest risk category) we are talking about here and whether that value outweighs the burden and possible side effects of taking a pill every day. Some people don't like taking pills. Some people don't mind taking a pill if there is a chance of benefit. It is a personal decision.

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12. Norman Yarvin on May 20, 2012 1:15 PM writes...

With the gastric surgery, my guess is that the one thing it enforces -- eating less at each meal -- is the important thing: smaller meals mean less of a spike in blood sugar and/or other metabolic variables. This improved metabolism then leads to weight loss. (It's generally acknowledged, I believe, that gastric surgery doesn't limit the total amount you can eat; you can still eat as many calories as before. It just limits the amount that can be eaten at a single sitting.)

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13. Morten G on May 24, 2012 7:29 AM writes...

4. NoDrugsNoJobs

Yes, abnormal LDL particles are engulfed by macrophages that somehow become overwhelmed and become foam cells which causes artherosclerotic plagues.
To treat do you:
reduce LDL
reduce abnormal LDL
reduce macrophage activity
reduce macrophage > foam cell conversion
reduce foam cell activity
?

Statins both reduce LDL and macrophage activity. LDL reduction therapy is called cholesterol hypothesis (sometimes expanded to the hypothesis that cholesterol intake leads to artherosclerotic plaques) and the macrophage activity relates to the systemic inflammation hypothesis.

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14. Morten G on May 24, 2012 7:56 AM writes...

That wasn't even what I wanted to post about!

Bariatric surgery is preceded by numerous health interventions and if the patient fails to implement them the surgery cannot go forward.
First of all they can't smoke for a month before the surgery.
Second of all they must adhere to a high-protein, moderate calorie diet for two weeks (UK - one week US).
More here: http://www.dukehealth.org/services/weight_loss_surgery/care_guides/patient_manual/preparation_instructions_for_surgery
I just wanted to point out that their results are biased towards people who gave up smoking and reduced their calorie intake (particularly their carbohydrate intake). Because the others weren't operated on.

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