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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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suggest discontinuing the medication if a certain amount of
weight loss has not been achieved after 12 to 16 weeks.
Table 11.2
Most Commonly Used Medications for Obesity Approved by the Food
and Drug Administration
Medication Mechanism, Dosage,
Available Formulation
Total
Body
Weight
Loss (%)
Initial
FDA
Approval
Phentermine
(Adipex, 43 Ionamin,
44
Lomaira, 46 Suprenza 45 )
Adrenergic agonist
8-37.5 mg daily
(8 mg dose can be
prescribed up to TID)
Capsule, tablet
15 mg/d:
6.06
7.5 mg/d:
5.45
Placebo:
1.71
28 wk
42
1959
Schedule
IV
controlled
substance
Approved
for shortterm use
Orlistat
(Alli, 51 Xenical 50 )
Lipase inhibitor
60-120 mg TID with
meals
Capsule
120 mg
TID: 9.6
Placebo:
5.61
52 wk
49
1999
Phentermine/topiramate
extended release
(Qsymia 54 )
Adrenergic
agonist/neurostabilizer
3.75/23-15/92 mg daily
Capsule
15/92 mg
daily: 9.8
7.5/46 mg
daily: 7.8
Placebo:
1.2
56 wk
53
2012
Schedule
IV
controlled
substance
Lorcaserin
(Belviq, Belviq XR 56 )
Serotonin (5-HT)
2C
receptor agonist
10 mg BID or 20 mg XR
daily
Tablet
10 mg
BID: 5.8
Placebo:
2.2
52 wk
59
2012
Schedule
IV
controlled
substance
Naltrexone/bupropion
sustained release
(Contrave
110
)
Opioid receptor
antagonist/dopamine and
norepinephrine reuptake
inhibitor
8/90 mg daily to
16/180 mg BID
Tablet
16/180 mg
BID: 6.1
8/180 mg
BID: 5.0
Placebo:
1.3
56 wk
61
2014
Liraglutide 3.0 mg
(Saxenda 64 )
GLP-1 receptor agonist
0.6-3.0 mg daily
Prefilled pen for
subcutaneous injection
3.0 mg
daily: 8.0
Placebo:
2.6
56 wk
63
2014
Adapted from Saunders KH, Umashanker D, Igel LI, et al. Obesity
pharmacotherapy. Med Clin North Am. 2018;102(1):135-148. Copyright © 2017
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Elsevier. With permission. BID, twice daily; GLP-1, glucagon-like peptide-1;
TID, three times daily; XR, extended release.
Phentermine
Phentermine was approved by the FDA in 1959 and is the
most commonly prescribed antiobesity medication in the
United States. It is an adrenergic agonist that suppresses
appetite and increases resting energy expenditure. Phentermine
is indicated for short-term use (up to 3 mo), as there are no
long-term safety trials of phentermine monotherapy; however,
it was approved in combination with topiramate ER for longterm therapy, so many providers prescribe phentermine for
longer durations as off-label therapy. In a 28-week randomized
controlled trial comparing phentermine, topiramate ER, and
the combination of the two medications, participants taking
phentermine 15 mg daily lost an average of 6.0 kg compared
with 1.5 kg among those assigned to placebo.
42
The recommended dosage of phentermine is up to 37.5 mg
daily, but dosage should be individualized to achieve adequate
response with the lowest effective dose.
43-45
In 2016, the FDA
approved an 8-mg formulation, which can be prescribed up to
three times per day. 46 Administration of the last dose late in
the day should be avoided to prevent insomnia. Phentermine is
a schedule IV controlled substance. There seems to be no
advantage of continuous compared with intermittent
phentermine treatment. 47 The most common treatment-
emergent adverse events (TEAEs) include dry mouth,
headache, insomnia, dizziness, irritability, nausea, diarrhea,
and constipation. Contraindications include pregnancy,
nursing, history of drug abuse or cardiovascular disease,
hyperthyroidism, glaucoma, and agitated states.
Orlisat
Orlistat was approved by the FDA in 1999 for long-term
weight management. It promotes weight loss by inhibiting
pancreatic and gastric lipases, thereby reducing fat absorption
from the gastrointestinal tract. At the recommended
prescription dose, orlistat blocks absorption of approximately
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30% of ingested fat. 48 In a double-blind, prospective study
that randomized 3305 patients with a BMI of 30 kg/m2 or
higher to lifestyle changes with either orlistat 120 mg or
placebo three times per day, the mean weight loss was
significantly greater with orlistat (5.8 kg) than with placebo
(3.0 kg) after 4 years.
49
The recommended dosage of orlistat is one 120-mg capsule
(Xenical, prescription strength) or one 60-mg capsule (Alli,
over the counter) three times a day with each main meal
containing fat.
50,51
Orlistat is not often prescribed for weight
management because of the TEAEs of fecal urgency, oily
stool, and fecal incontinence; however, it may have a role as
an additional agent for patients who are constipated on other
antiobesity pharmacotherapy. Side effects can be reduced by
the addition of a psyllium fiber supplement. Orlistat should not
be used in patients who are pregnant or those who have
cholestasis or chronic malabsorption syndromes. Orlistat can
decrease the absorption of certain medications such as
levothyroxine and warfarin.
Phentermine/Topiramate Extended
Release
Phentermine/topiramate ER was approved in 2012 for longterm weight management. As appetite regulation involves
multiple pathways, targeting different mechanisms
simultaneously with a combination of two low-dose
medications can have an additive or synergistic effect on body
weight while reducing the risk of TEAEs. Topiramate, which
was approved for epilepsy in 1996 and migraine prophylaxis
in 2004, reduces caloric intake through inhibition of carbonic
anhydrase, antagonism of glutamate, and modulation of
gamma-aminobutyric acid receptors. 52 In a double-blind,
placebo-controlled trial that randomized 2487 patients with a
BMI of 27 to 45 kg/m2 and two or more weight-related
comorbidities (dyslipidemia, hypertension, diabetes or
prediabetes, or abdominal obesity), participants taking
phentermine/topiramate ER 15/92 mg lost significantly more
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weight (9.8 kg) than those assigned to the 7.5/46-mg dosage
(7.8 kg) or placebo (1.2 kg) after 56 weeks.
53
Phentermine/topiramate ER is available in four doses (3.75/23,
7.5/46, 11.25/69, and 15.0/92 mg), which should be prescribed
using a dose-escalation protocol. 54 Phentermine/topiramate
ER is a schedule IV controlled substance. The FDA requires a
risk evaluation and mitigation strategy to inform women of
reproductive potential and prescribers about the potential
increased risk of orofacial clefts in infants exposed to the
medication during the first trimester of pregnancy. 55 The most
common TEAEs include dry mouth, paresthesias, dizziness,
dysgeusia, insomnia, and constipation. Contraindications
include pregnancy, hyperthyroidism, glaucoma, and
monoamine oxidase inhibitor (MAOI) use.
Lorcaserin
Lorcaserin was the second medication approved by the FDA in
2012 for long-term treatment of obesity. It is a selective
agonist of the serotonin-2C receptor in the hypothalamus. It
increases satiety and reduces appetite by targeting the POMC
neurons in the hypothalamus. In a randomized, double-blind,
placebo-controlled trial, 3182 patients received lorcaserin
10 mg twice daily or placebo for 52 weeks. 56 Mean weight
loss in the lorcaserin group was 5.8% compared with 2.2% in
the placebo group. In the recently published CAMELLIATIMI 61 trial, which enrolled a high-risk population of
subjects with obesity and overweight, lorcaserin facilitated
sustained weight loss without a higher rate of major
cardiovascular events compared with placebo.
57
The recommended dosage of lorcaserin is either 10 mg
immediate-release twice daily or 20 mg extended-release
tablet once daily.
58,59
Lorcaserin is a schedule IV controlled
substance. The most common TEAEs are dry mouth,
dizziness, headache, fatigue, nausea, and constipation.
Coadministration with other serotonergic drugs could
potentially lead to the development of serotonin syndrome or
neuroleptic malignant syndrome-like reactions; however, none
have been reported.
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Naltrexone Sustained Release/Bupropion
Sustained Release
Naltrexone SR/bupropion SR was approved for the treatment
of obesity in 2014. Bupropion, a dopamine and norepinephrine
reuptake inhibitor, was approved as an antidepressant in 1989
and as an aide for smoking cessation in 1997. Naltrexone, an
opioid antagonist, was approved to treat opioid dependence in
1984 and alcohol abuse in 1994. The combination reduces
both appetite and food cravings by targeting two areas of the
brain, the arcuate nucleus of the hypothalamus and the
mesolimbic dopamine reward circuit. 60 In a double-blind,
placebo-controlled trial that enrolled 1742 subjects who were
obese or overweight with at least one weight-related
comorbidity, mean change in bodyweight was 6.1% in the
group assigned to naltrexone 32 mg + bupropion 360 mg daily
compared with 5.0% in the group assigned to naltrexone
16 mg + bupropion 360 mg daily and 1.3% in the placebo
group after 56 weeks.
61
Each tablet of naltrexone SR/bupropion SR contains 8 mg of
naltrexone and 90 mg of bupropion. The initial prescription is
one tablet daily with instructions to increase by one tablet
weekly to a maximum dosage of two tablets twice daily
(32/360 mg). 62 The most common TEAEs include headache,
dizziness, insomnia, nausea, and constipation.
Naltrexone/bupropion is contraindicated in pregnant patients,
those taking chronic opioids or MAOIs, and in patients with
uncontrolled hypertension, history of seizures, or conditions
that predispose one to seizure. Similar to all antidepressants,
bupropion carries a black box warning related to a potential
increase in suicidality among younger patients during the early
phase of treatment.
Liraglutide 3.0 mg
Liraglutide 3.0 mg was also approved by the FDA in 2014 for
chronic weight management. It mimics the incretin hormone,
glucagonlike peptide-1, which is released following food
ingestion. In addition to reducing hunger and energy intake, it
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delays gastric emptying. Liraglutide was initially approved in
2010 for the treatment of type 2 diabetes under the brand name
Victoza at doses up to 1.8 mg daily. In a 56-week, randomized,
placebo-controlled, double-blind trial of patients who were
overweight or obese, the mean weight loss was 6.0% with
liraglutide 3.0 mg daily, 4.7% with 1.8 mg daily, and 2.0%
with placebo.
63
Liraglutide is administered as a subcutaneous injection once
per day. 64 The starting dose is 0.6 mg daily for 1 week with
instructions to increase by 0.6 mg weekly to a therapeutic
dosage of 3.0 mg daily. The most common TEAEs include
nausea, dyspepsia, diarrhea, constipation, and abdominal pain.
Liraglutide is contraindicated in patients who are pregnant as
well as patients with personal or family history of medullary
thyroid carcinoma or multiple endocrine neoplasia syndrome
type 2. Thyroid C-cell tumors were found in rodents given
supratherapeutic doses of liraglutide, but there have been no
reports of liraglutide causing C-cell tumors in humans.
Bariatric Surgery
Bariatric surgery is the most effective of the treatments
available for obesity. 65 Not only is it associated with
significant and sustained weight loss, but it has also been
shown to reduce obesity-related comorbidities and improve
quality of life. 66 In addition, bariatric surgery is associated
with lower incidence of cardiovascular events, a decreased
number of cardiovascular deaths, and a reduction in overall
mortality compared with usual care.
67-69
The three most
common bariatric procedures in the United States are the
sleeve gastrectomy (SG), the Roux-en-Y gastric bypass
(RYGB), and the and laparoscopic adjustable gastric band
(LAGB). 70 Table 11.3 provides an overview of the three
procedures. SG and RYGB are performed more frequently
than LABG because of greater efficacy and a lower
complication rate.
Table 11.3
Most Commonly Performed Bariatric Surgeries
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Procedure Description Total
Body
Weight
Loss at
1 y
(%)
Procedures
Performed
in 2013
(%)
Procedure Description Total
Body
Weight
Loss at
1 y
(%)
Procedures
Performed
in 2013
(%)
Sleeve
gastrectomy
(SG)
∼70% of the stomach removed along
the greater curvature
25 43
Roux-en-Y
gastric
bypass
(RYGB)
A small pouch (∼<50 mL) is created
from the proximal stomach and attached
to the jejunum, thus bypassing 95% of
the stomach, duodenum, and most of
the jejunum
30 49
Laparoscopic
adjustable
gastric band
(LAGB)
An inflatable silicone band is placed
around the fundus of the stomach to
create a small pouch (∼30 mL). The
size of the pouch can be adjusted to
regulate food intake by increasing or
decreasing the amount of saline in the
band via a subcutaneous access port
15-20 6
Data from Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and
management of obesity. N Engl J Med. 2017;376:254-266.
The 2013 American College of Cardiology/American Heart
Association/The Obesity Society’s guideline for the
management of overweight and obesity in adults recommends
considering bariatric surgery in patients with a
BMI ≥ 40 kg/m2 or a BMI ≥ 35 kg/m2 who have weight-related
comorbid conditions and are motivated to lose weight but have
not achieved sufficient weight loss for target health goals
following behavioral treatment, with or without
pharmacotherapy. 37 The American Association of Clinical
Endocrinologists and American College of Endocrinology
clinical practice guidelines for comprehensive medical care of
patients with obesity recommend considering surgery in an
expanded population: patients with a BMI ≥ 40 kg/m2, a
BMI ≥ 35 kg/m2 with one or more severe obesity- related
complications, or a BMI 30 to 34.9 kg/m2 with diabetes or
metabolic syndrome. 71 Evidence for bariatric surgery among
patients with a BMI < 35 kg/m2 is limited.
Long-term lifestyle changes, adherence to a vitamin regimen,
and medical follow-up are critical to the success of bariatric
surgery; however, some patients have difficulty maintaining
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weight loss and regain at least some of the lost weight.
37
Contraindications to bariatric surgery include poor cardiac
reserve, chronic obstructive pulmonary disease or respiratory
dysfunction, severe psychological disorders, and nonadherence
to medical treatment.
72
Sleeve Gastrectomy
Sleeve gastrectomy is a procedure in which approximately
70% of the stomach is removed along the greater curvature.
The remaining stomach is shaped like a tube or a sleeve. The
pyloric valve and the small intestine remain intact. The fundus
of the stomach, which secretes ghrelin, a hormone that
stimulates appetite, is removed. SG is associated with
approximately 25% total body weight loss (TBWL) after
1 year. 73 As this procedure is mainly restrictive (vs. RYGB,
which is also malabsorptive), there is a lower risk of
nutritional deficiencies. In general, SG is associated with
fewer complications than both RYGB and LAGB. Early
adverse events include leaking along the staple line, bleeding,
stenosis, gastroesophageal reflux, and vomiting due to
excessive eating. 72 Late complications include stomach
expansion, leading to decreased restriction. Unlike the other
two procedures, SG is not reversible.
Roux-en-Y Gastric Bypass
The Roux-en-Y gastric bypass is a procedure that attaches a
small pouch created from the proximal stomach to the
jejunum, thus bypassing the remainder of the stomach,
duodenum, and most of the jejunum. In addition to the
resulting restriction and malabsorption, other potential
mechanisms for weight loss associated with the procedure
include alteration in levels of endogenous gut hormones,
which promote postprandial satiety, and increased bile acids,
which affect the gut microbiome intestinal hypertrophy.
74
RYGB is associated with approximately 30% to 35% TBWL
at 2 years and greater improvements in comorbid disease
markers compared with the two other procedures.
68,73
RYGB
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is associated with a lower rate of gastroesophageal reflux than
SG and can even alleviate gastroesophageal reflux in patients
who have the disease. RYGB is often recommended over SG
for patients with mild or moderate type 2 diabetes, as it leads
to greater long-term remission; however, both RYBG and SG
have low efficacy for type 2 diabetes remission among patients
with limited pancreatic beta cell reserve.
Early adverse events associated with RYGB include
obstruction, stricture, leak, and failure of the staple partition of
the upper stomach. 72 Late adverse events include nutritional
deficiencies and anastomosis ulceration. Dumping syndrome
can develop at any time. Early dumping results in abdominal
cramping and osmotic diarrhea, and late dumping results in
reactive hypoglycemia. RYGB is technically a reversible
procedure; however, it is generally only reversed in extreme
circumstances.
Laparoscopic Adjustable Gastric Band
The laparoscopic adjustable gastric band is an inflatable
device that is placed around the fundus of the stomach to
create a small pouch. The size of the pouch can be adjusted to
regulate food intake by increasing or decreasing the amount of
saline in the band. Saline can be added or removed through a
subcutaneous access port. LAGB is associated with 15%
TBWL at 2 years. 75 As the procedure is purely restrictive,
there is a lower risk of nutritional deficiencies compared with
RYGB. LAGB is reversible and less invasive than the other
two procedures but is associated with more complications than
SG and RYGB. The most common adverse events include
nausea, vomiting, obstruction, band erosion or migration, and
esophageal dysmotility leading to acid reflux. 66 LAGB often
requires more postoperative visits than the other procedures to
optimize band tightness. A large number of bands are
eventually removed because of adverse events, difficulty
tolerating the device, and/or inadequate weight loss.
75,76
Antiobesity Devices
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Patients who cannot achieve clinically meaningful weight loss
with antiobesity medications and who do not undergo bariatric
surgery (because they are not surgical candidates, they do not
meet eligibility criteria, or they choose not to) fall into a
“treatment gap.” Devices and endoscopic procedures are
emerging options to address this significant treatment gap in
the management of obesity. 77 Not only are these devices and
procedures reversible and minimally invasive, but they are
also potentially more effective than antiobesity medications,
possibly less expensive than bariatric surgery, and often safer
for poor surgical candidates. The five FDA-approved devices
include three intragastric balloons (Orbera, ReShape, and
Obalon), the AspireAssist aspiration device, and the Maestro
Rechargeable System intermittent vagal blockade device
(vBloc). Table 11.4 provides an overview of the devices. There
are also many investigational devices and endoscopic bariatric
therapies being developed.
Table 11.4
Devices Approved for Obesity by the Food and Drug Administration
Device Description Total
Body
Weight
Loss
(%)
FDA
Approval
Orbera
Intragastric
Balloon
78
Endoscopically placed intragastric
balloon filled with 400-700 mL
saline, removed endoscopically
after 6 mo
10.2
Sham:
3.3
6 mo
81,82
2015
BMI 3040 kg/m
2
ReShape
Integrated Dual
Balloon (IDB)
System
79
Endoscopically placed balloons (2)
attached via a silicone tube and
filled with 750-900 mL of saline
(total), removed endoscopically
after 6 mo
6.8
Sham:
3.3
6 mo
83,84
2015
BMI 3040 kg/m2
+ at least
one
weight- related
comorbid
condition
Obalon Balloon
System
80
Sequentially swallowed balloons
(3) filled with 250 mL of gas each,
removed endoscopically 6 mo after
1st balloon placed
6.6
Sham:
3.4
6 mo
85,86
2016
BMI 3040 kg/m
2
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