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

The recent buzz about hyperinsulinemia being at the root of obesity (whatever the mechanism) has had me thinking again about the insulin lowering drugs.   Studies in this regard were referenced in the recent article in Cell from Dr. James Johnson's research group at UBC.   If this is really all there is to it, why not just treat obesity with such drugs?  Or at least give them to the reduced-obese so they won't regain the weight, and/or the so-called pre-obese who start gaining at some point in life before they become obese.  This is really the bottom line of studies like the recent one from UBC.  Because if all we need to do is suppress the hyperinsulinemia (however it is caused) to prevent obesity it would be done.  There is a relatively rare condition, called by many names, but most descriptively neo-natal or infant hyperinsulinism.  These children must be treated ASAP to avoid the consequences of hypoglycemic episodes.  I surmise the drugs octreotide and diazoxide were developed at least in part for treating this condition, though often partial removal of the pancreas is required.

So anyway, these drugs are around.  And they have been used by a "name" most of you recognize:  endocrinologist Dr. Robert Lustig.  Here he is investigating octreotide in real, live human beings, and this study made the references of the Mehran/Johnson paper:  Lustig, R.H. et al. (2006). 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. Int J Obes (Lond) 30, 331–341.   Here is another earlier study (published Feb 2003 in the same journal) bearing his name:  Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults (emphasis mine).  And the abstract shows it's right up the alley of what we're looking at:

Hyperinsulinemia is a common feature of many obesity syndromes. We investigated whether suppression of insulin secretion, without dietary or exercise intervention, could promote weight loss and alter food intake and preference in obese adults.

Now this was an interesting study, as is the fact that the lead author and Lustig are authors on an August  2004 paper published in Nature: Obesity, leptin resistance, and the effects of insulin reduction   The results of that study:

... support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

Now here is where the annoyingly freakish memory of your resident blogstress comes into play.  Because I read these studies and I'm like this is deja vu all over again.  In the 2004 paper I read:

This study was approved by the University of Tennessee Institutional Review Board and the Scientific Advisory Committee of the University of Tennessee General Clinical Research Center (UT GCRC), and all subjects gave informed consent prior to participation. A total of 17 obese subjects underwent 6 months of experimental weight loss therapy using octreotide-LAR, 40 mg i.m. every month.12

Ahh, yes, and do you want to guess what reference 12 is?  Do we have a free Lustig-inspired cocktail here at the Asylum for me to give out??    It's that 2003 IntJOb study.  Now, the 2003 study involved 53 subjects initially, 9 dropped out (more later on that) leaving 44 subjects (89% female, 61% Caucasian, avg. age 39) .   So was the 2004 study merely an analysis of a subset of the 2003 cohort ... or did they actually repeat 6 months of octreotide with 17 more subjects?    I'm going to presume they did and all 17 remained in the study, or I'm going to call foul here, because there's no indication of any sort of random selection from the full 2003 cohort for inclusion in what amounts to additional tests in the 2004 cohort.  

In any case .....

What happens when you take real-live obese humans, give them injections of an insulin suppressing drug, and do not counsel dietary or activity intervention?  Some lose weight!  Yay!   But not so fast .... Some neither gain nor lose, and some even gain.  In addition to that, the weight loss (or gain) is not entirely fat or necessarily compares favorably to proportional fat v. lean losses in various weight loss studies. Remember those 9 dropouts?  Well, four of them dropped out because of "lack of weight loss during the first 4–20 weeks".   Oh ... OK.  So these recruits were apparently signing up for a weight loss drug study, and when weight loss didn't occur, they dropped out.  I'll add them to the non-responders count then.  But this means the subjects knew they were trying out something to lose weight.  Where is the control?  There is none ... and thus no randomization either since all participants got the octreotide.   We'll come back to the placebo effect in a bit, because in 2006 Lustig and colleagues got around to testing placebo and different octreotide doses (20, 40 and 60 mg) in "the multicenter" paper cited by Johnson.

Responders were defined as patients who lost ≥5% of their baseline body weight during the study. By this definition, five (11.4%) patients in the placebo group, three (7.3%) patients in the octreotide LAR 20 mg group, five (12.5%) patients in the 40 mg group, and nine (20.5%) patients in the 60 mg group responded to the study medication.

So ... the "responder" rate for treatment in this study was roughly equal for placebo vs. 40 mg octreotide which is the dose used in the other studies.  Further:

After 6 months of treatment, patients receiving 40 or 60 mg of octreotide LAR experienced statistically significant weight loss compared to baseline, with mean differences from placebo in percent weight change of −1.98 and −1.87%, respectively.

So at the therapeutic and higher dose the subjects lost, on average, less than 2% more body weight than those getting the placebo.  Also:

Post hoc analysis revealed a 3.5–3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIRgp (corrected insulin response at the glucose peak) ≥1.43.

Wait ... What's this CIRgp? I blogged on this separately here, based on this paper. This is cited to in yet another study bearing Lustig's name, 

This study used the CIRgp which meant it used glucose and insulin levels at peak glucose level.  In comparing these ratios to those in the study defining the CIR, I would note that:

• We only had up to 30 min glucose levels, so CIR's reported are not CIRgp for several of the subjects.  
• A dose of 100g glucose was used in the CIR development paper while most studies referenced in the studies currently being addressed use the more standard 75g OGTT.  My best guess is that a 75g test was used here as well.  
• I am having difficulty finding average OGTT data to calculate a "normal" CIRgp, but here is one study that reported average OGTT glucose and insulin levels.  Using 8.2 mmol/L as peak BG and 400 pmol/L as insulin at "gp", converting to proper units (glucose * 18.02, insulin * 0.144), I calculate a CIRgp of around 0.5.  
• How this 75g OGTT results compare to a 100g test is unknown.

But as I was trying to find some CIR info in the paper, I noted the following:

To be included in this study, patients had to be 18–70 years of age, have at least moderate obesity (defined as BMI>30 kg/m2), and demonstrate insulin hypersecretion (defined as CIRgp≥1.0) on a screening OGTT.

Patients attended eight study visits. An initial screening OGTT and laboratory tests documented CIRgp>1.0, and excluded patients with asymptomatic diabetes mellitus, pregnancy, and renal or hepatic disease. [There were some other exclusions such as recent weight loss, etc.]

Initial screening of 756 obese patients yielded 216 (28%) who exhibited a CIRgp≥1.0. Of these, 172 passed the other inclusion criteria.

Got that?  Just over 1 in 4 obese patients qualified as an insulin hypersecreter.  Leaving aside the recent Mehran/Johnson study that looked at basal insulin levels, and focusing on hypotheses that float about this community, this information in and of itself is pretty damning for TWICHOO.  Because that means that nearly three-quarters of the obese are NOT postprandial insulin hypersecreters.  And now I'll repeat the initial quote regarding the results of this study:

Post hoc analysis revealed a 3.5–3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIRgp (corrected insulin response at the glucose peak) ≥1.43.

What is interesting -- perhaps a topic for another day -- is that Caucasians seem to have a higher prevalence of insulin hypersecretion vs. non, as well as a higher "response rate" to octreotide.  And yet looking at the "best case scenario" -- the top half of the hypersecreting Caucasians) -- for the effectiveness of octreotide/lowering insulin in treating obesity, we see pretty paltry results:  under 4% body weight in 6 months.  We'll get to the reason weight is italicized in a moment.  But to put this in context, 11% of the placebo group lost ≥ 5% of their body weight in the same 6 months.  Or in head-to-head competition of roughly equal sized groups of subjects, the mean %BW changes for placebo, 20, 40 and 60 mg respectively were 0.09 ± 3.21, −0.96 ± 3.32,  −1.89 ± 3.3, and −1.79 ± 3.92.  I note that the standard deviations (variability) are quite large compared to the means!  It seems the 40 mg dose is required for effectiveness, but the 60 mg dose  is not more effective on average.  Still I would be remiss were I not to stress that the greatest percentage (20.5%) of  ≥ 5% were in the 60 mg group.  They also report the difference in weight loss from placebo and we're not talking a lot folks.  For 20, 40 and 60 respectively these amount to -1.03, -1.98 and -1.87% -- 1 to 2 percent body weight on average over 6 months.

Before addressing another study and "weight" loss with octreotide, I want to address glycemic control.  Here is what happened here:

Mean changes of blood glucose AUC_{0–180 min} during an oral glucose tolerance test in patients taking octreotide LAR were 39–40 mg/dl-h higher than those on placebo.  

... the mean peak blood glucose concentrations after oral glucose challenge were significantly elevated in patients receiving octreotide LAR

... Mean HbA1c levels in patients receiving octreotide LAR rose by 0.2% and were independent of dose while they were essentially unchanged in the placebo group.

Unfortunately we aren't given the peak BG data, but  we are given the AUC data to put that ~40 mg/dL-hr into context.   The AUC is the glucose "exposure" in the 3 hrs post OGTT.   The data are shown in the table I constructed at right.  (* I used baseline = 6-mo - mean change, and calculated percent change from baseline).  Those changes are rather significant to me, even if they  may not have taken the participants into diabetic range. 

In comments on my analysis of the Johnson paper, Stephan brought up the topic of insulin lowering drugs, though he only mentioned diazoxide, and discussed hyperglycemia.  Jim responded that Stephan's claims were countered by Alemzadeh, presumably this study:  Beneficial Effect of Diazoxide in Obese Hyperinsulinemic Adults.  I discussed this study over a year ago in:  Diazoxide, Insulin & Obesity.    That study took 24 obese adults (12 each to each group, 10F/2M per group, age ~ 30, avg weight 110-120 kg, BMI 40-42) and gave them either DZ (2 mg/kg/day divided to 3 doses) or placebo for 8 weeks.  Unlike the octreotide studies, the groups were put on a calorie restricted shake/meal (Opti plan) diet of 1260 cal/day (F) or  1570 cal/day (M).  Results:  the DZ group lost more weight (9.8 ± 1.0 kg vs. 5.0 ± 1.0 kg) and more fat mass (−9.3 ± 1.0 kg vs.−3.6 ± 0.9 kg), whereas the FFM loss was similar in both groups (−1.3 ± 0.3 vs. −1.9 ± 0.5 kg).  But, "there were no significant changes in the REE values of either group" and "substrate use, as derived from indirect calorimetry, did not reveal any significant change in carbohydrate or fat metabolism in either group".   I discussed some of the issues with this study in more detail in my other post.  But what of glycemic control?  Well, it wasn't bad, but considering this was a calorie restricted diet (that normally reduces FBG if even only slightly), the placebo group saw a slight decrease (0.1 mmolar) while the DZ group saw a slight increase (0.17 mmolar).  I would note that this cohort had normal fasting glucose  (5.4 placebo, 5.4 DZ, average 5.3 mmolar = 95 mg/dL) with fasting levels of insulin in the low range for hyperinsulinemia:  204 pmol/L = 29 µU/ml for placebo and 168 pmol/L = 24 µU/ml for DZ.  Unfortunately, actual insulin levels are not reported for the octreotide study.  We're not given comparable information in these two studies.  

So I will say this.  Even with nominal weight/fat losses, insulin levels and glycemic parameters tend to improve.  In the case of both octreotide and diazoxide, the glycemic parameters changed unfavorably, if not deleteriously so within the time frames tested.   This aspect is probably a wash, with non-diabetics, but I expect we would see a greater worsening with obese with borderline glycemic control (aka those with elevated FBG and/or IGT).  I'll address that at some future point if I find studies in such populations to discuss.

OK ... This is getting long ... and I have much more to discuss about the other octreotide studies.  So I'm going to end this now, and post a follow-up within the next week or so.  

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