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*
Roche Laboratories Inc., Nutley, New Jersey and
Hoffmann-La Roche Inc., Nutley, New Jersey
3To whom correspondence should be addressed at Roche Laboratories Inc., 340 Kingsland Street, Nutley, NJ 07110. E-mail: Daniel.Pace{at}Roche.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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33%
(P < 0.05). There were no significant differences
in mineral apparent absorption, urinary mineral loss or mineral balance
between the orlistat and placebo groups. Markers of bone turnover and
serum and urine electrolytes did not differ between the orlistat and
placebo groups. Orlistat was well tolerated; adverse events were of
mild or moderate intensity, and the majority of these events were
unrelated or remotely related to study treatment. In obese men
consuming a hypocaloric diet, the administration of orlistat had no
significant effect on the balance of six selected minerals. In
addition, biomarkers of bone turnover, as well as serum and urine
electrolytes, were not affected by orlistat treatment.
KEY WORDS: • weight loss • antiobesity drugs • mineral absorption • bone metabolism • fat malabsorption • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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,2)
. In
randomized, placebo-controlled trials, obese patients treated with
orlistat (120 mg three times daily) in combination with a
reduced-fat (30% of energy as fat), mildly [2092–3347 kJ/d
(500–800 kcal/d) deficit] hypocaloric diet, achieved mean weight loss
of 8–10% of their initial body weight after 1 y. This magnitude
of weight loss was significantly more than that achieved with dietary
intervention alone (3
,4)
. Thus, orlistat may be an
important pharmacotherapeutic adjunct in the long-term management
of obesity.
Weight loss may increase the risk of mineral loss and bone
demineralization (5
,6)
. Moreover, mineral deficiency could
theoretically occur, even with the consumption of a nutritionally
balanced hypocaloric diet used as an adjunct to orlistat therapy,
because of the drug-induced reduced fat absorption. Fat
malabsorption associated with various causes can result in increased
intestinal mineral loss (7)
. Therefore, inhibition of
dietary fat absorption subsequent to inhibition of intestinal lipase
activity during orlistat treatment could have an adverse effect on
dietary mineral absorption and balance due to formation of insoluble
mineral soaps within the intestine.
Thus, the primary aim of this study was to assess whether orlistat, used in combination with a mildly hypocaloric diet for 21 d, adversely affects mineral balance in obese men. The effects of orlistat treatment used in combination with a hypocaloric diet for 21 d on plasma and urinary electrolytes and biochemical markers of bone turnover were also assessed.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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18 y were recruited into the study. Subjects who had diarrhea
(more than two liquid stools per day) during the week before study
entry or constipation (3 d duration) within 2 wk before the study
entry were excluded. Subjects who required antacids in the 72 h
before the start of the study were also excluded.
A prestudy medical history was taken and a physical examination (also
repeated on d 22) was performed within 3 wk before the study.
Volunteers who met the inclusion criteria were matched for age (±5 y)
and randomly assigned to receive for 21 d either orlistat
(n = 14, 120 mg three times daily) or matching placebo
(n = 14) in conjunction with a daily menu that repeated
every 3 d. All subjects followed the same daily routine throughout
the 21-d period. The standardized hypocaloric diet was based on a food
composition table and prepared by the Harris Clinical Research
Division. A 3-d menu cycle of the hypocaloric diet (30% of energy from
fat, constant mineral content) is shown in Table 1
. The menu items were typical for food categories likely to be selected
by obese subjects during orlistat treatment (Table 2
). Subjects were permitted to drink deionized water ad libitum between
meals.
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In addition, to allow calculation of fecal recovery of minerals, all subjects received quantitative fecal markers consisting of one capsule containing 10 small radiopaque markers (Dunn Clinical Nutrition Unit, Cambridge, U.K.) concomitant with their medication (three times daily). Medication was administered with 100 mL of water with the three main meals. The use of any other medication or alcohol was prohibited during the study, with the exception of medication required to treat adverse events or intercurrent illness.
The initial 14 d of the study were considered to be an
equilibration period that allowed gastrointestinal clearance of
unabsorbed minerals from the prestudy diet, homogeneous distribution of
radiopaque markers in the gastrointestinal tract and steady-state
fecal fat excretion by orlistat. Mineral balance was assessed on d
15–21 (the balance period). The dietary concentrations of the minerals
under consideration in this study (calcium, phosphorus, magnesium,
iron, copper and zinc) were provided to meet the U.S. Recommended Daily
Allowance for adult men (8)
.
All urinary and fecal output was collected on a 24-h basis from d 10
through 21. Fecal and urine samples from d 15–21 were stored for
subsequent analysis (Nova Medical Medi-Lab, Copenhagen, Denmark) of
mineral and fecal fat concentration. On d 1 and 21, a fasting urine
sample was collected to analyze electrolytes and biochemical markers of
bone resorption, and fasting serum samples were collected to analyze
electrolytes and markers of bone formation. All fecal samples were
examined by flat plate radiography, and the number of radiopaque
markers were counted. The fecal mineral content was normalized using
the method of Cummings et al. to accurately determine mineral balance
(9
10
11)
. The fecal mineral content was corrected for
recovery by dividing fecal mineral content by the ratio of the actual
number of radiopaque markers counted in fecal samples to that expected
to be excreted (210 per person over the 7-d balance period). Apparent
mineral absorption was calculated as dietary mineral intake during the
balance period minus corrected fecal mineral content. Mineral balances
for each subject were calculated by subtracting urinary mineral loss
during the balance period from apparent mineral absorption. No
correction in mineral balance was made for unaccounted miscellaneous
mineral losses from sweat, semen, skin and hair sloughing, and so on.
Fecal mineral content was determined after ashing of the feces
(12)
. Fecal calcium, magnesium, iron and zinc were
determined by flame atomic absorption spectroscopy. Fecal copper was
determined by electrothermal atomic absorption spectroscopy. Fecal
phosphate was determined by UV-photometry. Urinary calcium, copper,
iron, magnesium and zinc were determined by flame atomic absorption
spectroscopy (Analytical Methods for Atomic Absorption Spectroscopy 1982; Perkin-Elmer Corporation,Norwalk,CT). Urinary phosphate was
determined by UV-photometry. Serum sodium and potassium were
analyzed with ion-selective electrodes. Urinary sodium and
potassium were analyzed with flame photometry. Serum total osteocalcin
was measured with an enzyme immunoassay
(EIA)4
(Metra Biosystems, Mountain View, CA). Serum intact osteocalcin was
measured with a luminescence specific assay (Heaning, Berlin, Germany).
Bone-specific alkaline phosphatase was measured with EIA (Metra
Biosystems, Mountain View, CA). Urinary hydroxyproline was determined
by a photometric method (13)
. Deoxypyridinoline (free and
total) and free pyridinoline was measured with enzyme-linked
immunosorbent assay (Metra Biosystems). Urinary
N-telopeptide was determined by EIA (Ostex Int
Seattle, WA). Fecal fat was determined (14)
.
A 24-h sample of meals (deboned) was collected for each menu. Each
sample was weighed and homogenized using automated homogenization
equipment. Meal calcium, iron, magnesium and zinc concentrations was
measured with flame atomic absorption spectroscopy (12)
.
Meal copper was measured with electrothermal atomic absorption
spectroscopy. Meal phosphate was analyzed with UV-photometry. The
meal total fat content was weighed after extraction, and the meal total
energy was calculated based on dry matter, fat and ashes. The
carbohydrates were determined by the difference (Nordic Committee on Food Analysis, no. 131, 1989; Fat Determination According to
Schmid-Bondzynski-Ratslaff in Meat and Meat Products). The accuracy and
precision of measurements for minerals and biochemical anylates were
determined.
Adverse events were monitored throughout the trial. Vital signs and standard laboratory tests (hematology, clinical chemistry and urinalysis) were performed at screening, before study entry on d 1 and at the end of the study.
The trial protocol was approved by the local ethics committee, and the trial was conducted in accordance with the Declaration of Helsinki (as amended in Tokyo, Venice and Hong Kong). All volunteers provided written informed consent before study participation.
Statistical analyses.
Descriptive statistics (mean, median, standard error, minimum and maximum) were calculated. Treatment groups were compared using descriptive statistics with respect to adverse events and vital signs. The mean apparent mineral absorption and balance determined during the last 7 d of treatment was used as the primary between-group comparisons to test the influence of orlistat on mineral metabolism. An unpaired t-test was used to determine significant treatment differences. A paired t-test was used to determine significant differences within treatments. A sample size of 28 was initially chosen based on an anticipated dropout rate of 15% (there were no dropouts) and to ensure that the width of 95% confidence intervals of treatment difference is <2 SD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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All men completed the study. As expected, groups did not differ in age,
because the subjects who were assigned to the placebo and treatment
groups were initially matched for age. In addition, none of the other
subject characteristics, including initial body mass index (30
kg/m2), differed between groups.
Fecal excretion.
During the balance period, d 15–21, dietary fat intake was 36 g/d
in both groups (Table 3
). Fecal fat content was 12 g/d in the orlistat-treated group and
2 g/d in the placebo-treated group (P < 0.05).
During the balance period, dietary fat was absorbed more efficiently in
the placebo-treated group compared with the orlistat-treated
group (P < 0.05).
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No significant difference between the placebo and orlistat groups in the observed-to-expected radiopaque marker ratios was seen during the balance period (0.92 and 0.95, respectively). Importantly, the high fecal marker recovery (93.5%) suggests that overall there was excellent recovery of fecal losses during the balance period.
The effect of orlistat treatment on apparent mineral absorption
corrected for fecal marker recovery and urinary loss of calcium,
phosphorus, magnesium, iron, zinc and copper are shown in Table 4
. Orlistat treatment had no significant effect on apparent mineral
absorption. There was an apparently greater, although not statistically
significant, difference between the placebo and orlistat groups
for zinc compared with the difference between groups for the other
minerals. This may be explained by one individual in the placebo group
who had a large amount of fecal zinc and an inordinate affect on the
group mean. When this subject was excluded from the analysis, apparent
zinc absorption in the placebo group was 22.12 ± 5.50 µmol/24
h, which did not differ from the orlistat group.
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). With the exception of iron, a positive mean fractional mineral
absorption was observed during the balance period in these obese men
consuming a mildly hypocaloric diet. No significant differences in the
efficiency of dietary mineral absorption were apparent between the
placebo and orlistat groups, despite significant differences in dietary
fat absorption caused by orlistat (Table 3)
.
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. Mineral balance.
Balance for most of the minerals studied was neutral or slightly
negative (Table 4)
.
Bone turnover markers.
The absence of important effects of orlistat on mineral metabolism is
further corroborated by the lack of treatment effects on bone turnover,
as measured with biochemical markers of bone formation and bone
resorption obtained at baseline and at the end of treatment
(Table 5
).
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Electrolytes were not affected by orlistat treatment, because baseline
and end-of-treatment serum and urine sodium and potassium
concentrations did not differ between treatment groups (Table 6
).
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Orlistat was well tolerated during the 21-d study period. Ten subjects in each group reported at least one adverse event, with a total of 14 events reported with placebo and 27 reported with orlistat. The incidence of adverse events was similar in orlistat and placebo groups for most body systems. However, a higher proportion of patients in the orlistat group had adverse events in the gastrointestinal system (orlistat, eight events in seven patients; placebo, seven events in five patients). Adverse events were of mild or moderate intensity and resolved without any subject discontinuing treatment. All cases of liquid stools (orlistat, five; placebo, two) and fatty/oily stools (one in each group) were considered to probably be related to treatment. However, the majority of adverse events were judged by the investigator to be unrelated or remotely related to study treatment. No serious adverse events were reported, and no unusual findings were noted in vital signs. Only two men (both in the placebo group) displayed marked abnormalities in laboratory tests (high alanine aminotransferase levels).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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,2)
, the amount
of fecal fat was significantly increased during treatment with
orlistat, resulting in a reduction of dietary fat absorption efficiency
by approximately one third. Although orlistat was well tolerated with a
similar safety profile as placebo, changes in fecal fat composition can
negatively affect mineral balance (e.g., with steatorrhea due to
various malabsorption syndromes). Because orlistat prevents a large
amount of dietary fat from being absorbed, this selective inhibition of
fat absorption could theoretically promote the formation of insoluble
mineral soaps and thereby alter mineral absorption and adversely affect
mineral balance. However, this study clearly showed that orlistat, in conjunction with a standardized hypocaloric diet administered for 21-d, did not alter mineral absorption or mineral balance in comparison with placebo treatment with the same standardized hypocaloric diet. Fractional absorption of minerals, the component of the overall mineral balance most likely to be affected by orlistat, was similar in both groups. Given the known relationship between fat malabsorption and intestinal mineral loss, our observations may seem at first questionable and counterintuitive. However, our findings may reflect the fact that orlistat was administered to our study subjects in the context of a low-fat diet, because orlistat is recommended as an adjunct to a weight loss–promoting hypocaloric diet. Under these circumstances, the quantitative loss of fecal fat is much reduced and the drug is clinically well tolerated. Errors in fecal mineral estimates have marked effects on derived measures of mineral balance. Moreover, some experimental treatments may affect fecal flow rates or influence the completeness of fecal collections and thereby systematically bias estimates of treatment effects on mineral absorption and balance. In the current study, particular attention was paid to verify the completeness of fecal collections and equivalency of recovery between treatment groups to improve the accuracy of the estimates of the effect of orlistat on mineral balance. The estimates of orlistat’s effects on mineral balance are accurate because 1) the observed fractional dietary mineral absorption efficiencies appear realistic across a wide range of evaluated minerals, 2) the mean recovery of a quantitative fecal marker was high (93.5%), suggesting excellent recovery of unabsorbed mineral, 3) no significant differences in marker recovery were found between placebo and treatment groups, suggesting that no systematic bias in fecal flow rates were confounding our estimates of fecal mineral loss and 4) estimates of apparent mineral absorption were corrected in each subject on the basis of individual recovery of the quantitative fecal marker.
The inherent experimental and measurement errors involved in estimating mineral balance can lead to a significant variability in its estimation. As explained earlier, special efforts were made to increase the accuracy of the estimates of dietary mineral absorption by using radiopaque pellets, an easily quantifiable fecal recovery marker. In addition, the balance period was preceded with a 14-d run-in period to allow for equilibration to the metabolic diet and drug treatment. However, despite a positive net fractional mineral absorption for almost all of the minerals studied, mineral balance was observed to be quite low or negative for most of the minerals studied. The apparent negative fractional iron absorption was not significantly different (P > 0.05, one-sample t-test) from zero.
Overall, the negative mineral balances observed in this group of adult
obese men may reflect a number of factors, including a true tendency of
obese men to lose body mineral stores during an initial readjustment
period after beginning a hypocaloric diet, an incomplete metabolic
adaptation to the experimental diet, a state of mineral equilibrium and
"zero" mineral balance in our adult subjects that cannot be
precisely determined given the inherent errors in determining mineral
balance or a combination of these factors. In any case, the important
observation in this study was that the administration of a therapeutic
dose of orlistat for 21 d, sufficient to reduce fat absorption
efficiency by one third, did not have a negative impact on mineral
metabolism, as judged by measurement of both mineral balance and
biomarkers of bone turnover. This absence of an effect of orlistat on
mineral balance in the current 3-wk study is consistent with a lack of
any reports of clinical conditions resulting from mineral deficiency
during long-term clinical trials of orlistat
(3
,4
,15
,16)
.
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FOOTNOTES |
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2 Supported by Hoffmann-La Roche Inc. (Nutley, NJ).
4 Abbreviation used: EIA, enzyme immunoassay.
Manuscript received September 7, 2000. Initial review completed October 24, 2000. Revision accepted February 24, 2001.
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