More Hyperinsulinemia, Insulin-Suppressive Drugs & Obesity (and Lustig)

Building on my last post on this topic ...

So far I've spent most of the blogging on a study comparing 3 doses of octreotide, an insulin suppressing drug, vs. placebo in a subset of obese people pre-tested and determined to be insulin hypersecreters as defined by a corrected ratio for insulin to glucose levels.  This post will focus more on two other studies using this drug, perhaps just the first ... let's see how long this gets ;-)    I think it will be easiest to number the 3 studies, all bearing Lustig's name:

• Study 1: Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults (2003)
• Study 2: Obesity, leptin resistance, and the effects of insulin reduction  (2004)
• Study 3: A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion.  (2006)

I've already discussed the rather unimpressive performance of octreotide in Study 3.  While the highest dose group had the highest "response" rate (20.5% losing ≥5% initial weight), the rates were similar between the placebo group (11.4%) compared to the 40mg octreotide group (12.5%), which is important as this is the dose used in Studies 1&2.   Additionally, mean losses for the entire 40 & 60 mg groups were less than 2%, and even the most promising responders, Caucasian hypersecreters with above median CIR, only lost an average of less than 4% over 6 months.

Studies 1 and 2 give us some more information that I think is relevant to looking into the role of insulin in obesity.  Let's refresh on the low carb theories shall we?  Because one of the premises Mr. Taubes is clinging desperately to is the fact that humans tend to lose weight rapidly on a low carb diet.  He and various LC advocates attribute this to the reduction in insulin levels, releasing fatty acids from their adipose prisons ... not caloric deficit.   The length of these two studies is right along the lines of when we see the greatest losses for low carb diets, time and again, in diet comparison studies.   

• For example, in the infamous Shai et.al. study, the LC group averaged roughly 6.4 kg lost at 6 months (14 lbs, about 7% initial weight).   These participants were mostly men, average starting weight just over 90 kg (~200 lb) BMI around 30, with normal fasting insulin (around 14 µU/mL).  Yes, you read that right.  We are not given how much their insulin levels changed at the 6 month mark (at the 2 year mark it averaged a reduction of 3.7 µU/mL in non-diabetics, 2.2 µU/mL in diabetics), but it's likely not a huge amount.   
• In another study by Westman et.al. -- 6months 20g/day VLC -- Subjects lost 10.1 kg in 6 months from a starting weight averaging 108.4 kg (9.3% body weigh).  This cohort of mostly women (14F/7M), and at BMI averaging almost 38, quite a bit more obese.  Yet fasting insulin began at 20.4 µU/mL and dropped to 14.4 µU/mL.
• One last one, not LC but I have the data next to that Westman study, is that "crash diet" study -- This cohort lost 15.3 kg in 2 months, 12.2 kg at 5 months from 103.7 kg avg starting weight for almost 15% and 12% respectively.  Fasting insulin went from 16.6 to 9.4 µU/mL.  

If it is all about the insulin levels and not about the calories/energy balance, why do we see such anemic weight loss with more significant reductions in insulin (octreotide) than we do with relatively minor diet-induced reductions in insulin in conjunction with calorie reduction (deliberate or spontaneous)?  

One of the looming questions all along has been, if it is just the insulin, why is not a drug like octreotide the hottest thing around?  Sure, as Dr. JD Johnson and others have pointed out, there's the nasty side effects.   But heck, if a drug like Xenical can make it to OTC (as Alli) with such open recommendations as "wear dark clothes lest an oily rectal emission spoil your day" (OK, I took a little poetic license there), what's a little discomfort amongst a population where a significant percentage would trade just about anything to be thin?

Well, here's where these octreotide studies really "shine" ... only not in the way one Dr. Robert Lustig had apparently hoped.   You see, in looking for these studies, I happened across a very interesting document ... thanks Google Scholar!  Lookie here, it's a US Patent application from Oct. 2002:  Method of treating obesity in adult patients exhibiting primary insulin hypersecretion.  This is based on Study #1 published in 2003.    Was the doc hoping to cash in on octreotide in some sort of weight loss clinic setting?  This was the reason I asked about patenting dosing protocols a while back.  What is interesting about the patent app is that it contains scatter plots of the individual data that the peer-review article does not.

First, let's look at the study:

• 44 "severely obese" individuals
• 39F/5M  89% female
• 26 Caucasian, 17 Minorities (39%)

If we're going to see an effect of insulin on obesity, 

we really ought to see it for the severely obese!!

• Received 40 mg octreotide/day for 24 weeks = approx 6 months.
• Metabolic Parameters Measured:  β-cell activity (Corrected Insulin Response @ peak glucose, CIRgp -- blogged on/defined here) , insulin sensitivity (Composite Insulin Sensitivity Index from this reference), and insulin clearance (compares c-peptide to insulin AUCs), leptin.
• Group divided into subsets for analysis by "response":  High responders (HR; ΔBMI < −3 kg/m2) , Low responders (LR; ΔBMI between −3 and −0.5) , and Nonresponders  (NR; ΔBMI > −0.5).

Here are the Results:  (I re-tabulated this with a few additional calcs and converted weights to pounds).  I note that the upper limit of DEXA reliability is 300 lbs and so body composition data was only obtained from 75% of the subjects.  Thus fully one-quarter of the participants were over 300 lbs, and since we're talking an 89% female group, this is indeed quite severe obesity as compared to the obese subjects used in many studies.  Obesity is defined generally as BMI over 30, and many studies involve BMI's in the 30's if even on the high end.  Average BMI at baseline was 44.3.

• Out of 44 subjects, only 8 (18%) were high responders losing an average of 28 lbs in 6 months.  This is not too shabby, but this amounted to less than an average of 10% initial body mass in 6 months.  A solid majority (25 = 57%) were considered low responders losing an average of only 3% of body mass at under 8 lbs on average.  The term non-responder used for the remaining quarter of the participants (11 = 25%) is misleading as this group gained an average of 6.6 lbs or 2% body weight over the six month course.

• Half of the "Biggest Losers" were over the 300lb DEXA limit and did not have body composition measured. For the four that did, on average:
• Less than one third (31%) of the weight lost was fat.
• Body fat percentage INCREASED from 53% to 56%!!

• The news was better for the Low Responders.  They did lose an average of 5.5 lbs body weight and 5.7 lbs body fat, which means they essentially lost all fat and maintained or even gained a tad of lean mass.  The bad news is that after 6 months on this drug, all of the LR's lost a whopping 8 lbs off an average of almost 260 lbs, and the DEXA subset lost under 6 lbs body fat starting at just over 225 lbs.  I don't know about you, but I'm not impressed.  

• For the "Non-Responders", matters are pretty bad.  Of the 11 total, 9 (82%) were eligible for DEXA.  These nine gained 4 lbs!  Not only that, it was all fat and then some, because they gained 6.8 lbs fat and only 4.2 lbs total weight ... that means they managed to lose 2.6 lbs of lean mass in the process.  Yay insulin-lowering drug!  NOT!  

I'm thinking that it might be difficult to market this unpredictable drug for weight loss if a quarter of those who take it actually tack on more fat mass!  To recoup ... If you respond well to the drug, expect to lose a bit of weight, but more than two-thirds of it will be lean mass.  If you are a lucky low responder, you can expect to lose under a pound a month but at least it will all be fat.  But .... If you are a non responder, and the odds are greater for this than for being a high responder, you can expect to gain over a pound a month of fat and lose about a half pound of lean tissue.  

We get some more info from the scatter plots and time plots from the patent application.  First up the time course for change in weight and BMI for the three response groups.  I don't know that there's anything to the slopes for the NR and LR being roughly equal and opposite, but the HR's clearly follow a different trajectory.  But this is less than 1 in 5 subjects, the rest would average out to a pretty pathetic loss trajectory.  And I'll keep reminding you that those high responders are losing more than twice as much lean mass as they are losing fat mass.  With that in mind, look at the LR v. HR on the left and recall that pretty much all of the weight lost by the LR group is fat.  Eyeballing it, it would appear that if one really responds to octreotide, the extra response is almost entirely lean mass.   That's not good!

Next, all of these studies have identified a differential response for caucasians vs. non-whites.  This is interesting as it would imply insulin works differently along racial lines.  But it's not really in the way one would expect.  One reason for our increased incidence of obesity as a population is the increased proportion of non-whites.  Additionally we would expect more hyperinsulinemia in the non-white populations that are at higher risk for diabetes.  Here was the weight loss along racial lines.  It seems whatever nominal effect octreotide has on non-whites it levels off rather quickly and no further weight is lost.  The caucasians, on the other hand, drop weight for the full 6 months and does not appear to be leveling off.   How much of that is fat loss though?  

From the numbers given on the plots in the patent app, we learn that of the 33 under 300 lb DEXA eligible participants, 11 (33%) were minorities, 22 caucasians (67%).    I could also determine the number of HR, LR and NR in each group.  There is only one minority HR who did make it into the DEXA group.  

I've highlighted a few things on the select plots below for ΔIAUC (insulin area under curve) vs. ΔBMI, and ΔFatMass vs. ΔBMI.  Minorities are on top, caucasians on the bottom.  Let's discuss the minorities -- there are no statistically significant correlations in this group for any measurements compared.  In "b" we see that there are 4 (red squares) participants with reductions in ΔIAUC greater than all but one of the caucasians, yet the three largest ΔIAUCs correspond with no change in BMI or slight increase.  One could comment all day here on various observations.  Of the NR by BMI group (accidentally highlighted an extra one in blue), you have quite significant differences in the insulin response to octreotide, however.  Put another way, in the minorities, we could not attribute a lack of response to a lack of insulin suppression.   The horizontal blue line is just one iso-insulin line for which you see a range of ΔBMI, and the vertical red line is sort of iso-BMI where you see a wide variety of insulin suppression responses.   Looking next door to "d", we see that only 2 of 11 lost any significant fat mass, and these were in the LR group losing about 1 and 2 BMI points.  

So now let's look at the caucasians.  While there's a correlation line here, I would point out that this is likely more shallow if just the 3rd quadrant (-ΔIAUC, -ΔBMI) and I drew another horizontal line just to illustrate the wide range of ΔBMI for a given reduction in insulin.  As pointed out previously, however, all but one one participant had insulin suppression greater than 10 (around 13), while 4 minorities had insulin suppressions of around 13, 19, 20 and 25.  I have a hard time seeing any real correlation between insulin and BMI here ... how about you?   Lastly, 5 of 22 (23%) caucasians gained fat mass by DEXA, of which 2 (LRs) gained fat mass despite losing body weight/BMI.  There are also one or two (not highlighted) on the -1 on the x-axis that would represent total lean mass losses from the LR group.   {I have linked to the PDF containing the other parameters measured, I don't think they bail out TWICHOO here, feel free to comment if I've missed something here}

So.  It looks like the Merry* Weight Loss Centers featuring octreotide would have been a bad deal.  I find it interesting that Lustig & Co. proffered up the individual data in the patent application, but not in the journal article.  And ahh, sometimes things are just a little too coincidental ... I came across this around the time of the JimKKKins Scandal, and isn't it interesting that the "LC pill" would disproportionately "benefit" the white race!  Sometimes you just gotta chuckle.  Still, by just presenting means and describing "non-response" as BMI loss of less than 0.5, some key results are obscured in the peer review paper -- namely,  that there were considerable weight and fat mass gains in a considerable proportion of the subjects.  Why they would show this in an attempt to patent a weight loss drug/methology, I don't know, but it really looks quite bad.  

So, I'll leave you with one last graphic.  Below left is ΔIAUC (insulin suppression) vs. ΔFatMass (n=26 of 33) and below right is ΔCSIS (insulin sensitivity) vs. ΔFatMass (n=30 of 33), recalling that DEXA involved 33 participants and presumably there is just some missing data for the IAUC and CSIS.  

Folks ... forget high response low response.  Of the 26 folks on the left, 11 gained some fat mass and 13, or 50%  could be said to have either not lost or gained fat mass.   At least that percent out of 30 gained fat mass according to the plot on the right.  Of those who gained any fat mass, as many had reductions in insulin response as increases, and w/o counting up, roughly the same could probably be said for insulin sensitivity on the right plot.  

Now tell me again, how it is that insulin is causing obesity in the American human population.

*Richard Feinman is fond of calling Lustig "Merry" as that apparently is what his name means in German.

Oh, and I see I'll have to leave Study 2 for another day if ever.