Category Archives: Orlistat

Nutrition Disinformation III

but they actually get it right this time.   Big HT to George Henderson for bringing this ms to my attention.

In Nutrition Disinformation, Part I, the Mediterranean diets employed by Estruch & colleagues were discussed.  The study subjects’ need for antidiabetic drugs, insulin, and anti-platelets all increased over the course of 5 years.  The media and even the authors themselves reported the opposite, touting the benefits of Mediterranean diets.  Thus begat the Nutrition Disinformation series.

Nutrition Disinformation 2.0 was a follow-up to an older post on the Look AHEAD study, when the results were finally published.  The intensive lifestyle intervention consisted of a pharmaceutical-grade low fat diet (ie, LFD + a little bit of Orlistat), and exercise.  By the end of 10 years, medication use was modestly lower in the intensive lifestyle group compared to controls, but it was markedly increased from baseline.  Therefore, I deemed it egregious to say their intervention was “healthy.”  In the context of Nutrition Disinformation, “healthy” means you’re getting better.  The need for insulin, statins, and anti-hypertensives should decline if you’re getting better.

In part 3 of the series, Yancy must’ve been following the Nutrition Disinformation series :) and decided to conduct a subgroup analysis on the patients in his previous low carb vs. low fat + Orlistat study.  Weight loss was roughly similar, but all other biomarkers improved more on low carb.  In the new publication, Yancy analyzed data selectively from the diabetic patients in his original study to generate a “Medication Effect Score (MES).”  MES is based on what percentage of  the maximum dose was a patient given, and adjusted for the median decline in HbA1c experienced by patients on said drug.  A bit convoluted, but I’m on board (at least tentatively).

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April Fool’s day

Please forgive me in advance for the crass humor in this post.

Have obesity researchers given up?  Their most recent advice: shit your pants or eat shit.

Exhibit A. The drug formerly known as Zenical and Orlistat, currently marketed OTC as Alli, is one the only medications FDA approved for the treatment of obesity.  The results from Orlistat’s weight loss trials are unequivocal (figure below).

But the list of “Common Adverse Events” is horrendous.  “Common” means it happens in over 5% or 1 in 20 patients.  This was taken directly from the prescribing information.

Exhibit B.

The gut microbiota consists of millions of organisms that reside in the intestines and they are intricately associated with the health of its host.  The microbiota differs markedly between obese and lean people.  In animal studies, transfer of an obese mouse’s microbiota to a lean mouse makes the latter gain fat mass, suggesting a causal relationship.  (if your interested, check it this and this)  Recently, however, scientists have taken it to the next level.  The complete abstract is below.  Fecal transplants (from lean healthy donors) have remarkable effects on glucose tolerance and insulin sensitivity.  I shit you not.

Metabolic effects of transplanting gut microbiota from lean donors to subjects with metabolic syndrome (Vrieze et al., 2010 EASD)

Recent data in animal models revealed that obesity is associated with substantial changes in composition and metabolic function of gut microbiota. Moreover, colonization of germ-free mice with faeces harvested from obese mice resulted in a significantly greater increase in total body fat than colonization with a ‘lean microbiota’. However, data on the role of gut microbiota in human obesity are scarce. Thus, our aim was to examine the effect of faecal infusions derived from lean healthy donors on gut microbiota composition, glucose and lipids in metabolic syndrome.  This study was a double-blind, randomised controlled trial. A total of 18 male subjects with newly diagnosed metabolic syndrome (BMI?30 kg/m2, FPG>5.6mmol/L, TG>1,6 mmol/L with no medication use) underwent jejunum biopsies and subsequent polyethylene-glycol bowel lavage through duodenal tube followed by random assignment to either allogenic (from lean male donors with BMI<23 kg/m2, n=9) or autologous faecal transplantation (reinfusion of own collected faeces, n=9). We studied changes in sigmoidal microbiota composition and fasting lipid profiles at 0.5, 2, 6 and 12 weeks after faecal transplantation. Weight, jejunal gut microbiota (epithelial biopsy) and glucose metabolism (peripheral and hepatic insulin sensitivity as assessed by hyperinsulinemic euglycemic clamp with stable isotopes) were studied before and 6 weeks after transplantation.  Lean subjects were characterized by different sigmoidal gut microbiota compared to obese subjects (by HITChip phylogenetic microarray analysis). Fasting levels of TG-rich lipoproteins (TG/ApoB ratio) were significantly reduced following donor faeces (1.43 ± 0.21 to 1.11 ± 0.18, p<0.01) with no effect after autologous faeces infusion. Resting energy expenditure and basal endogenous glucose production (EGP) did not change in both groups after faecal infusion. Although weight remained stable, an improvement in both peripheral (Rd) and hepatic insulin sensitivity (suppression of EGP) was found 6 weeks after allogenic faeces (median Rd: from 26.2 to 45.3 ?mol/kg.min, p=0.02 and EGP suppression: from 51.5 to 61.6 %, p=0.08) while no significant changes were observed in the autologous treatment group (Rd: from 21.0 to 19.5 ?mol/kg.min and EGP suppression: from 53.8 to 52.4 %, ns). Changes in jejunal microbiota are currently analyzed. Lean donor faecal infusion improves hepatic and peripheral insulin resistance as well as fasting lipid levels in obese individuals with the metabolic syndrome underscoring the potential role of gut microbiota in the disturbances of glucose and lipid metabolism in obesity. Our data could provide pathophysiological insight in the metabolic deviations in obese subjects and a rationale for therapeutic intervention.

 

For the record, those changes in insulin sensitivity are fairly robust, especially compared to control.  And perhaps the title of this post was too crude; the fecal transplants were administered through a nasogastric tube that goes in through the recipient’s nose and down their throat, so they’re not technically “eating” it.  By the way, those infusions consisted of 300mL (1 ½ cups) infused slowly over the course of an hour, every day for 9 days.  The environment within: how gut microbiota may influence metabolism and body composition (Vrieze et al., 2010 Diabetologia).

 

calories proper

 

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Orlistat blog

Orlistat blog.

This post is a little long, but the conclusion was bold enough to warrant inclusion of enough studies to independently demonstrate each point.   Reducing calorie and dietary fat intake will help weight loss, but it’s not the only way.  The goal for this blog entry is to compare the results from studies on Orlistat, which pharmacologically inhibits dietary fat digestion, with the results from low fat and low carb diet studies.  In brief, yes, reducing dietary fat and calories pharmacologically via Orlistat or voluntarily via low fat diet causes weight loss, but the metabolic improvements that are usually associated with weight loss are considerably attenuated because of the reduced dietary fat.  IOW, for any given amount of weight loss, the metabolic improvements are greater for a diet that restricts carbohydrates (sugars, whole grains, refined grains, cereal fibre, etc.) than for a diet or drug that restricts fats (e.g., low-fat diet, Orlistat, etc.).

Note: Orlistat is biologically similar to a low fat diet.  With the low fat diet, dietary fat intake is reduced voluntarily; with Orlistat, dietary fat digestion is reduced pharmacologically.  With both, the amount of dietary fat that gets into the body is reduced.

These studies are relatively similar in study design, subject population, duration, and how the interventions were administered.  They all lasted at least one year, except the Yancy study, which was only 48 weeks but had to be included because it makes an important connection.

Orlistat (low fat) studies: Krempf, 18 months; Hauptman, 24 months.   Low carb vs. low fat: Stern, 12 months; Foster, 12 months.  Low carb vs. Orlistat: Yancy: 48 weeks.

Round 1. Orlistat vs. Placebo

Weight reduction and long-term maintenance after 18 months treatment with orlistat for obesity. (Krempf et al., 2003 International Journal of Obesity Related Metabolic Disorders)

700 obese subjects, baseline characteristics:

As expected, impressive weight loss in the Orlistat group:

Orlistat group lost 8% of their initial body weight, compared to 3% in the placebo group… Orlistat weight loss was 2.5x greater than placebo.

Important numbers: (Placebo vs. Orlistat)

Fasting glucose: -0.29 mM vs. -0.86 mM

HDL: +31.5% vs. +38.2%

TG: -15.6% vs. -24.4%

 

Orlistat in the long-term treatment of obesity in primary care settings. (Hauptman et al., 2000 Archives of Family Medicine)

Same basic outline as Krempf study (above). 600+ obese subjects, baseline characteristics:

results:

To compare directly with the Krempf study: by week 76 (18 months), Orlistat group lost 7% of their initial body weight compared to 3% in placebo, just over twice as much.  To compare with the rest of the data in this study: by week 104 (24 months), Orlistat group lost 5% of their initial body weight compared to 2% in placebo.  Orlistat group lost 2.5x more weight than placebo.

Important numbers: (placebo vs. 120 mg Orlistat [dose used by Krempf])

Fasting glucose: +0.24 vs. +0.16 (yes, fasting glucose actually increased in the Orlistat group)

HDL: +7.7 vs. +5.8%  (yes, HDL improved more in the placebo group compared to Orlistat)

TG: -3.0% vs. +13.5% (yes, TGs actually increased in the Orlistat group)

 

 

Round II. low carb vs. low fat.

The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. (Stern et al., 2004 Annals of Internal Medicine)

Weight loss:

Low fat dieters lost 2% of their initial body weight, and low carb dieters lost 4%.  Although this study was shorter (1 year, compared to 1.5 years in Krempf and 2 years in Hauptman).

Important numbers: (Low fat vs. low carb)

Fasting glucose: -1.11 vs. -1.55

HDL: -12.3% vs. -1.9%

TG: +2.7% vs. -28.2%

 

 

 

http://www.ncbi.nlm.nih.gov/pubmed/12761365

A randomized trial of a low-carbohydrate diet for obesity. (Foster et al., 2003 NEJM)

Baseline characteristics:

Weight loss:

and the data:

Important numbers: (Low carb vs. low fat)

Fasting glucose: ?

HDL: +11% vs. +6.0%

TG: -17% vs. -0.7%

 

Round III. Low carb diet vs. Orlistat

A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. (Yancy et al., 2010 Archives of Internal Medicine)

This study actually pitted a calorie unrestricted low carb diet directly against Orlistat.  Over 100 subjects were included, the details are in line with the above studies.

Body weight: Low carb group, 124 kg -> 113 kg, they lost 9 % of their initial body weight; Orlistat, 119 kg -> 109 kg, they lost 8 % of their initial body weight

Important numbers: (Low carb vs. Orlistat)

Body weight:   -9.2%   vs. -8.1%

Fasting glc:      -9.74    vs. -3.26

HDL:                +10.3% vs. +8.7%

TG:                   -19%    vs. -15.7%

 

 

Summary

Krempf:           placebo vs. Orlistat

Body weight:   -3%      vs. -8%

Fasting glc:      -0.29    vs. -0.86

HDL:                +32%   vs. +38%

TG:                   -16%    vs. -24%

 

Hauptman:      placebo vs. Orlistat

Body weight:   -2%      vs. -5%

Fasting glc:      +0.24   vs. +0.16

HDL:                +7.7     vs. +5.8%

TG:                   -3.0%   vs. +13.5%

 

Stern:               low fat vs. low carb

Body weight:   -2%      vs. -4%

Fasting glc:      -1.11    vs. -1.55

HDL:                -12.3% vs. -1.9%

TG:                   +2.7%  vs. -28.2%

 

Foster:             low fat vs. low carb

Body weight:   -3%      vs. -4%

Fasting glucose: ?

HDL:                +6%     vs. +11.0%

TG:                   -0.7%   vs. -17%

 

Yancy:              low carb vs. Orlistat

Body weight:   -9.2%   vs. -8.1%

Fasting glc:      -9.74    vs. -3.26

HDL:                +10.3% vs. +8.7%

TG:                   -19%    vs. -15.7%

1. In the Krempf Orlistat study, Orlistat caused more weight loss than placebo, and was modestly better at reducing fasting glucose and TGs and increasing HDL.

2. In the Hauptman Orlistat study, Orlistat caused more weight loss but fasting glucose actually increased relative to baseline, the increase in HDL was less than in placebo, and TGs actually increased relative to baseline and placebo.

3. In the Stern low carb study, the low carb diet caused more weight loss than the low fat diet, and the low carb diet lowered fasting glucose modestly better than low fat diet.  Changes in HDL and TGs were significantly better in the low carb group.

4. In the Foster low carb study, the low carb group lost modestly more weight than the low fat group, and the changes in HDL and TG were significantly better in the low carb group as well.

5. In the Yancy low carb vs. Orlistat study, the low carb group lost modestly more weight, fasting glucose decreased almost twice as much in the low carb group, and HDL and TG improved significantly more in low carb relative to Orlistat.

 

Reducing body weight by cutting calories and reducing fat intake (via Orlistat [Krempf, Hauptman, Yancy] or low fat diet [Orlistat studies, Stern, Foster]) consistently produces inferior changes in the metabolic landscape compared to reducing carbohydrate intake (Stern, Foster, & Yancy).  Orlistat caused more weight loss compared to placebo (Krempf, Hauptman), but not compared to a low carb diet (Yancy).

Dietary fat increases HDL.  Replacing carbs with dietary fat reduces TGs.  These things occur independently from weight loss, although weight loss is greater on a low carb diet compared to a low fat diet.   IOW, reducing carb intake causes more weight loss and superior changes in risk factor profiles compared to reducing calorie and fat intake regardless of whether fat is reduced via dieting (low fat diet) or pharmacologically (Orlistat).

 

 

 

 

Calories proper

 

 

 

 

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