Orlistat/Xenical Info: Possible AGE inhibitor?


http://tinyurl.com/fsz7k

"Exogenous advanced glycation endproducts (AGEs, known atherogenic
molecules) abundant in everyday precooked, rich in fat, overheated
meals can possibly contribute to the increased risk for diabetes and
cardiovascular disease in women with polycystic ovary syndrome
(PCOS).......Thirty-six women were studied, 15 controls (mean age,
28.80 ¡Ó 5.47 years; body mass index, 25.85 ¡Ó 6.73 kg/m2) and 21 with
PCOS (mean age, 25.29 ¡Ó 5.06 years; body mass index, 30.40 ¡Ó 7.51
kg/m2) (University Hospital, Athens, Greece, institutional
practice). Serum AGE levels, on day 1, were significantly increased
both in the control group and in the PCOS group as compared with
basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The
corresponding rise was significantly lower on day 2 when the same
meal was combined with orlistat (control group, 4.1%; PCOS group,
2.0%; P < .01). A limitation of the study is that it is a
nonplacebo, nonrandomized therapeutic trial where each subject is con
sidered
as its own control. In conclusion, this study demonstrated the
beneficial effect of orlistat on the absorption of food glycotoxins."

[The problem with orlistat (also called Xenical) is similar to the problem of
using chitosan or any other fat blocker. All of them also inhibit the absorption
of all fat soluble vitamins and good fats. These would include all carotenoids,
retinol (vit A), all E vitamers, vit K, ascorbyl palmitate, CoQ10, GLA, EPA and
DHA. These would need to be all taken separately from the meal with which
orlistat is taken. My view is that it is best to avoid all high temperature
cooking and eat mostly either raw foods or foods cooked in moist heat only. I
know this is hard to take because so many of the most enjoyable flavors come
from higher temperature cooking. The only thing that I can suggest is that,
since all flavor likes and dislikes are based on habits, one can always change
such likes and dislikes so that they are more consistent with what is healthy
and unhealthy respectively. Finally, if there is some unhealthy lifestyle action
that one finds is not conducive to one's overall happiness to go without, then
at the least minimize how often one does it.

BTW, fat blocking is quite different from a drug like acarbose which does not
block the digestion of sugars and starches but simply lowers the rate of
digestion, thereby preventing glucose blood spikes and effectively lowering the
overall glycation rate. --Paul]

[For Chris and others, a page on Acarbose was uploaded a few days ago -
http://morelife.org/prescripdrugs/acarbose.html **Kitty]


and

http://www.rocheusa.com/newsroom/current/2002/pr2002052401.html

About the Study
A total of 535 patients (56% female/44% male) at 43 sites in the
United States participated in the double-blind study. Subjects were
randomised to receive either insulin and Xenical 120 mg three times
a day plus diet (n = 274) or insulin plus placebo plus diet (n =
276). The diet was reduced in calories, consistent with the ADA
dietary recommendations. At enrollment, the two groups were similar
in terms of gender, race, body weight, mean daily insulin dose,
serum HbA1c, fasting glucose and use of oral diabetes medications.
Fifty-one percent of the Xenical group (137) and 47% of the placebo
group (128) completed 52 weeks of treatment.
At the end of the study, participants treated with Xenical
experienced greater weight loss compared to patients receiving
placebo (-3.76% of baseline body weight vs. ¡V1.22%). In addition,
more patients treated with Xenical lost 5% or more of their body
weight (33% vs. 13%). And in the Xenical group, three times more
patients achieved a 10% weight loss compared to the placebo group.
Patients in the Xenical group also had, on average, twice as great a
reduction in serum HbA1c levels at the study¡¦s conclusion compared
to the placebo group (ƒ{ 0.62% vs. ƒ{ 0.27%). More over, the
improvement in HbA1c was ¡V1.0% for patients on Xenical plus insulin
plus diet and ¡V0.57% for patients on placebo plus insulin plus diet
in individuals whose value for HbA1c was equal to or greater than 9%
before treatment was begun. Notably, the greater reduction in HbA1c
seen with Xenical treatment was not entirely dependent on weight
loss. After adjusting for differences in weight loss, the mean
change in HbA1c remained significantly different between groups (ƒ{
0.56% vs. ¡V0.32% for the Xenical and placebo treatment groups,
respectively).
Xenical therapy was also associated with a reduced need for insulin
and oral diabetes medicines. On average, Xenical patients saw a
significant reduction in daily insulin dose when compared to the
placebo treated group (-8.1 units per day reduction for the Xenical
group vs. -1.6 units per day reduction for the placebo group). More
Xenical-treated patients (41.3%) decreased or discontinued at least
one oral diabetes medication during the study compared to placebo
(30.9%).
At 52 weeks, Xenical-treated patients had greater improvements in
total cholesterol, LDL-cholesterol, and ratio of LDL to high-density
lipoprotein (HDL) ¡V or good ¡V cholesterol than placebo-treated
patients. However, changes in serum triglycerides and HDL-
concentration did not differ significantly between the treatment
groups.

[It is interesting that the Xenical group required less insulin and had lower
HbA1c. It is too bad there was no mention of any effect on serum glucose levels,
although the lower HbA1c level implies that the serum glucose was also lower. My
guess about the reason for this occurring is that the Xenical reduced absorbed
fat and calories sufficiently that those patients converted more of their
glucose into triglycerides (which was why the level of triglycerides remained
the same with less fat intake even with similar weight reduction). In any case,
the HbA1c level was only very slightly lower in the Xenical group than the
placebo group and the article does not even state whether this small amount was
statistically significant.


[I have another possible explanation for this. Saturated fat reduces insulin
sensitivity and raises cholesterol (PMID: 16357064, PMID: 15479216, PMID:
12842493, PMID: 1529707). If the patients in the study generally ate a diet
high in saturated fat (which isn't unlikely since the typical american diet is
fairly high in saturated fat), the beneficial effects on HbA1c and cholesterol
in the Xenical group might be explained partly by the reduction in absorption of
saturated fat. The reason the triglycerides were not lower in the Xenical
group, despite the reduced fat absorption and improved insulin sensitivity,
might be that a patient in the Xenical group would've gotten more energy from
carbs compared to a patient in the placebo group that lost the same amount of
weight (and therefore absorbed the same amount of calories). Since
carbohydrates raise triglycerides moreso than fat does, this might have caused
their triglycerides to remain as high as in the placebo group despite the
improved insulin sensitivity. -°Olafur]

[Additional note after Olafur's comment: Except for his first point about
saturated fat reducing insulin sensitivity, I think that Olafur's proposed
explanation of the observed reduction of HbA1c without change in triglycerides
is actually the same as mine, but with a more detailed explanation of the
mechanism. Both relate to the increased ratio of carb:fat calories absorbed in
the Xenical group. It is good to have Olafur commenting, because I sometimes
state only a conclusion without sufficiently explaining the reasoning behind it
for many people to be able to see how I reached my conclusion. --Paul]

Of course, this was a study in overweight and obese diabetics, so it may not
apply at all to already slim healthy people who have no cholesterol problems
that need to be fixed. Most certainly no healthy person should be using insulin
to decrease hir glucose, because low insulin levels are life extending.

As I stated above, the answer is not to try to block the digestion of something
one ingests since what one ingests is under one's control. Instead the answer is
to not ingest it in the first place!

So my answer to the question posed as the subject of this message is yes,
orlistat could benefit healthy people if they use it only with fatty high
temperature cooked meals, and if they take fat soluble vitamins and fat
supplements with meals where they do not take orlistat. However, it seems to me
even better to not eat high temperature cooked meals or at least do so very
seldom. Actually, if you can get it easily, it might be useful to have some
orlistat around just for those times when, for some reason, you need to eat a
higher temperature cooked fatty meal. --Paul]