Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Bariatric surgery and its impact on sleep architecture,

sleep-disordered breathing, and metabolism
Silvana Pannain, MD, Assistant Professor of Medicine a, *,
Babak Mokhlesi, MD, M.Sc, Associate Professor of Medicine b,1
a
Section of Endocrinology, Diabetes and Metabolism, The University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue,
Chicago, IL 60637, USA
b
Sleep Disorders Center and Sleep Medicine Fellowship Program, Section of Pulmonary and Critical Care Medicine, The University of
Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, Chicago, IL 60637, USA

Keywords:
Over the last several decades, the prevalence of obesity has
Obesity increased significantly worldwide. This has translated into an
Obstructive sleep apnea increased prevalence of obesity-associated morbidities including
Sleep sleep-disordered breathing and metabolic disorders. While the
Bariatric surgery medical management of obesity is relatively ineffective, bariatric
Sleep architecture surgery is the most successful method for sustained weight loss
Diabetes and markedly reduces obesity-related morbidity and mortality.
Cytokines
The anatomical changes created with different types of procedures
lead to variable weight loss and improvement of co-morbidities;
however the latter does not appear to be exclusively dependent on
the amount of weight loss. Bariatric surgery does not always lead
to complete resolution of obstructive sleep apnea and age, gender
and severity of the obstructive sleep apnea predict the residual
disease after peak weight loss. Metabolic disorders and specifically
diabetes often improve dramatically early after the procedure,
before any significant weight loss has occurred. The modified
gastrointestinal anatomy and physiology may explain this
phenomenon.
Ó 2010 Published by Elsevier Ltd.

* Corresponding author. Tel.: þ1 773 702 3275; fax: þ1 773 834 7205.
E-mail addresses: spannain@uchicago.edu (S. Pannain), bmokhles@medicine.bsd.uchicago.edu (B. Mokhlesi).
1
Tel.: þ1 773 702 2181; fax: þ1 773 702 6113.

1521-690X/$ – see front matter Ó 2010 Published by Elsevier Ltd.

doi:10.1016/j.beem.2010.07.007
746 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

Introduction

In the United States, a third of the adult population is obese (body mass index or BMI  30 kg/m2)
and the prevalence of extreme obesity (BMI  40 kg/m2) has increased dramatically. From 1986 to
2005,the prevalence of individuals with BMI  40 kg/m2 has increased 5-fold from 1 in every 200
adults to 1 in every 33 adults. Similarly, the prevalence of BMI  50 kg/m2 has increased 10-fold from
affecting 1 in every 2,000 adults to 1 in every 230 adults.1 The obesity epidemic is not only
impacting adults in the United States, it is a global phenomenon that also affects children and
adolescents.2 Associated health care expenditures in obese individuals are 36% higher than in
normal weight persons, and it has been estimated that up to 7% of annual health care expenditures
are related to obesity.3,4 Obesity is a well-recognized risk factor for a variety of medical conditions
such as obstructive sleep apnea (OSA), type 2 diabetes (T2DM), cardiovascular diseases, dyslipide-
mia, metabolic syndrome, and nonalcoholic fatty liver disease.2 The majority of large population-
based epidemiologic studies have consistently shown that obesity is associated with increased
mortality.5–10 It has been estimated that life expectancy is reduced by 5–20 years in severely obese
individuals.11
Unfortunately medical management is relatively ineffective in the long-term treatment of obesity.
Therefore in 1991 the National Institutes of Health established guidelines for the surgical therapy of
morbid obesity (BMI  40 kg/m2 or BMI  35 kg/m2 in the presence of significant co-morbidities), now
referred to as bariatric surgery. Today bariatric surgery is the best established and most successful
method for sustained weight loss in the morbidly obese 12,13 and irrespective of the specific procedure
performed, surgical weight loss markedly reduces morbidity and mortality 14,15 and improves quality of
life.16 However the procedures available today differ with regard to their effectiveness in causing
weight loss and resolving or significantly improving many common obesity-related morbidities,
including OSA, T2DM, and dyslipidemia.17

Bariatric surgery

Types of bariatric procedures and their effects on weight

Bariatric surgery was first introduced in 1950 and involves surgical manipulation of the gastroin-
testinal tract. Bariatric surgical procedures have been traditionally classified in three categories:
(a) restrictive, in which the gastric volume is reduced to decrease energy intake; (b) malabsorptive, in
which portions of the small intestine are bypassed to reduce energy absorption; and (c) combined
restrictive and malabsorptive.
In most patients, these procedures are performed through a laparoscopic approach. In this section
we will review the procedures most commonly performed today. The effect on weight loss varies
among the procedures and has been best analyzed in the Swedish Obese Subjects study, a large
prospective, control matched surgical intervention trial which enrolled approximately 4000 subjects.14
In general the maximum weight loss occurred at 1–2 years. A weight regain was observed for all types
of surgery, but it leveled off after 8–10 years. Since the publication of the Swedish study the surgical
techniques have advanced and some of the procedures included in that study have become less
popular and newer procedures are performed more routinely.

Restrictive procedures

Laparoscopic adjustable gastric band (LAGB). The LAGB is a purely restrictive procedure (Fig. 1a) in
which the upper part of the stomach is encircled with a band-like saline–filled tube immediately
below the gastro-esophageal junction to limit the luminal diameter. The amount of restriction can
be adjusted by injecting or withdrawing saline solution from the band through a subcutaneous
port similar to that used for long-term venous access. The maximum weight loss is variable with
an average of 20  10% of total body weight (TBW), weight loss at 10 years averages 13  14% of
TBW.14
 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761 747

Fig. 1. Most commonly performed bariatric procedures. (a) Laparoscopic adjustable gastric banding; (b) Roux-en Y gastric bypass;
(c) biliopancreatic diversion; (d) duodenal switch; (e) sleeve gastrectomy. (Adapted from Rubino, F.et al. Metabolic Surgery: the role
of the gastrointestinal tract in diabetes mellitus. Nat Rev Endocrinol (2010) 6; p. 102–109.123)

Vertical banded gastroplasty (VBG). The VBG is also a purely restrictive procedure, which consists of con-
structing a vertically oriented pouch based on the lesser curvature of the stomach, and restrict its outlet
with a prosthetic band. The maximal weight loss is 25  9% of TBW; the weight loss at 10 years is 16  11%.14

Malabsorptive procedures

Biliopancreatic diversion (BPD). In the original BPD procedure designed by Scopinaro in the late 1970s18
(Fig. 1c), a horizontal subtotal gastrectomy is performed leaving a 400 cc gastric pouch. The small
748 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

bowel is then divided 250 cm proximal to the ileocecal valve and the alimentary limb is connected to
the gastric pouch while the biliary limb is then connected to the alimentary limb 50 cm proximal to the
ileocecal valve. This ultimately creates a short 50 cm distal common channel where bile and nutrient
mix, which limits fat and starch absorption.

The duodenal switch (DS). The DS is a modification of the Scopinaro’s procedure (Fig. 1d). A sleeve
vertical gastrectomy is performed with a maximum reservoir of 150–200 cc. The duodenum is divided
immediately beyond the pylorus and is connected to the alimentary limb while the biliary limb is
connected to the ileum as in BPD, creating a longer common channel up to 100 cm from the ileocecal
valve as opposed to the 50 cm of the original Scopinaro’s procedure.
These types of malabsorptive procedures are more often used to treat extreme obesity (BMI 50–
60 kg/m2). To date there are no large controlled studies on the long-term weight loss with BPD or DS. A
meta-analysis of 17 studies with 4000 patients who underwent BPD or DS reported a mean maximal
weight loss of 39% TBW.17 One recent head to head study of Roux-en Y Gastric Bypass vs. DS in the
extremely obese (BMI 50–60 kg/m2) showed greater weight loss with the DS at 1 year.19

Combined restrictive/malabsorptive procedures

Roux-en Y gastric bypass (RYGB). The RYGB is the most widely performed bariatric operation today and
combines both a restrictive and malabsorptive procedure (Fig. 1b). At first a surgical stapler is used to
create a small and vertically oriented 30 cc gastric pouch. The pouch is then divided from the distal
gastric remnant and is anastomosed to the jejunum (gastrojejunostomy) 30 and 75 cm distally to the
ligament of Treiz through a narrow gastrojeunal anastomosis in a so called Roux-en Y fashion. Bowel
continuity is restored by an entero-entero anastomosis between the excluded proximal limb, which
carries the bile and pancreatic secretions (biliary limb) and the distal limb (alimentary limb) usually
75–100 cm distal to the gastrojejunostomy. The result is that the ingested food bypasses approximately
95% of the stomach, the entire duodenum and a portion of the jejunum. This procedure is associated
with a maximal weight loss of 32  8% of TBW at 1–2 years and 25  11% of TBW at 10 years.14

Sleeve gastrectomy. This procedure has been proposed as a step procedure in high-risk patients, fol-
lowed by a second step Roux-en Y gastric bypass or biliopancreatic diversion and duodenal switch
(Fig. 1e). More recently it has been used as a standalone bariatric surgery technique. At this time only
preliminary data are available on weight loss using sleeve gastrectomy as a single procedure, including
a report of 20% of TBW loss at 1 year,20 and 30% of TBW loss in a small follow-up study at 5 years.21
Clearly there is a need for larger series with long-term follow up.

Safety of bariatric surgery

While the popularity of bariatric surgery grows and its benefits for diabetes, cardiovascular disease
and overall mortality are becoming better documented,14,22,23 concerns about safety have also grown.
A meta-analysis of 361 studies and 85,048 patients showed an overall mortality of 0.28% within 30 days
and 0.35% between 30 days and 2 years after surgery.24 The Longitudinal Assessment of Bariatric
Surgery (LABS) consortium conducted the first large multi-centric prospective observational study of
the 30-day safety outcomes in 4776 patients undergoing a first time bariatric procedure from March
2005 to December 2007.25 As expected in that time period, RYGB was the most frequently performed
procedure (more than 60% of the cases), while BPD and DS were performed in less the 1% of the cohort.
The overall 30-day mortality was 0.3% across all procedures. Patients (4.1%) experienced a major
adverse event, which included death, deep vein thrombosis (DVT) or venous thrombo-embolism,
re-intervention or failure to be discharged at 30 days.25 A prior history of DVT or venous thrombo-
embolism or a history of obstructive sleep apnea (OSA) independently predicted the adverse event
regardless of the baseline BMI and after controlling for functional status of the patient and type of
surgical procedure. Overall, these data do not support the common notion that bariatric surgery may be
unduly risky, particularly given the potential benefit of the procedure (see below). Indeed, the
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mortality of bariatric surgery in the US is equivalent to that of laparoscopic cholecystectomy,

a commonly performed abdominal surgery.26

Effect of obesity on sleep

Impact of obesity on sleep-disordered breathing

Overview of obstructive sleep apnea

The most common type of sleep-disordered breathing (SDB) is OSA which is characterized by
recurrent episodes of complete (apnea) or partial obstruction (hypopnea) of the upper airway during
sleep associated with progressive respiratory effort to overcome the obstruction. These obstructive
respiratory events are associated with cortical microarousals and oxygen desaturation leading to sleep
fragmentation, chronic sleep loss, and increased sympathetic neural activity.27 Clinical symptoms
suggestive of OSA include loud snoring, breathing pauses witnessed by a bed-partner, choking or
gasping during sleep, morning headaches, insomnia, and daytime sleepiness. Obstructive apneas are
defined as complete or near complete cessation of airflow due to upper airway collapse lasting at least
10 s. Obstructive hypopneas are characterized by either a 30% decrease in airflow from baseline
lasting at least 10 seconds associated with a 4% oxygen desaturation or a decrease in flow by 50% of
baseline for at least 10 s associated with either a 3% oxygen desaturation or electroencephalographic
criteria for a cortical microarousal from sleep.28 A number of health related conditions have been
associated with OSA including diminished neurocognitive function, increased risk of motor vehicle
accidents, reduced quality of life, hypertension, insulin resistance, and cardiovascular diseases.
The standard diagnostic test for OSA is an overnight polysomnogram. This study involves several
measured physiologic recordings such as electroencephalogram, electrooculogram, electrocardiogram,
chin and leg electromyograms, body position, finger pulse oximetry, measurements of airflow, and
measurements of thoracic and abdominal respiratory effort. The apnea-hypopnea index (AHI) is
commonly used to categorize the severity of OSA and it represents the average number of apneas and/
or hypopneas per hour of recorded sleep. In adults, an AHI less than 5 events per hour is considered
normal. Mild OSA is defined as an AHI between 5 and 15 events per hour, moderate OSA between 15
and 30 events per hour, and severe OSA as greater than 30 events per hour. Other measures of severity
used in both clinical practice and research settings include oxygen saturation nadir, percent of sleep
time with oxygen saturation below 90%, and the severity of daytime symptoms. OSA, however, can be
present without any significant symptomatology. When OSA is accompanied by symptoms, most
commonly excessive daytime sleepiness (EDS), it has been labeled as the OSA syndrome.

Epidemiology of OSA
Despite methodologic differences, comparisons of several epidemiologic studies have yielded
similar high prevalence rates of OSA and OSA syndrome in various geographic regions and amongst
a range of ethnic groups (Table 1).29 This “epidemic” of OSA is closely related to the obesity epidemic.
A large proportion of individuals with OSA remain unrecognized. In fact, up to 80% of cases of moderate
or severe OSA have gone undiagnosed despite adequate access to health care.30–32
The most rigorous population-based study of OSA is the Wisconsin Sleep Cohort Study.33 Using
in-laboratory polysomnography, the prevalence of OSA (AHI  5) in 602 middle-aged adults between
30 and 60 years of age was 9% for women and 24% for men. The OSA syndrome, characterized by both
an AHI  5 along with EDS was present in 2% of women and 4% of men.

Obesity as a risk factor for OSA

Several risk factors have been identified in the development of OSA but undoubtedly, the strongest
risk factor is obesity reflected by several markers including BMI, neck circumference, and waist-to-hip
ratio.34,35 Other risk factors include aging (up to age 65), male gender, menopause, craniofacial
abnormalities, upper airway anatomy, smoking, alcohol, and genetic predisposition.30
Obesity has been well established as a risk factor for OSA in multiple population-based studies and in
fact there is a direct relationship between the OSA epidemic and the obesity epidemic (Table 2).33,34,36,37
These studies have demonstrated an increase in the prevalence of OSA that is proportionate to an
750 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

Table 1
Population-based studies reporting the prevalence of OSA and OSA syndrome.

Study Number of AHI  5 AHI  15 OSA

subjects syndrome
Wisconsin, U.S.A.33, Men: 352; Men: 24%; Men: 9%; Men: 4%;
1993a Women: 250 Women: 9% Women: 4% Women: 2%
(age 30–60)
Pennsylvania, U.S.A.38,39, Men: 741; Men: 17%; Men: 7%; Men: 3.3%;
1998, 2001b Women: 1000 Women: 5% Women: 2% Women: 1.2%
(age 20–100)
Spain116, 2001b Men: 325; Men: 26%; Men: 14%; Men: 3.4%;
Women: 235 Women: 28% Women: 7% Women: 3%
(age 30–70)
117
Australia , 1995a Men: 294 Men: 25.9% Men: 10%; Men: 3.1%;
(age 40–65) (AHI  10) Women: n/a
Hong Kong, China118,119, Men: 153; Men: 8.8%; Men: 5.3%; Men: 4.1%;
2001, 2004a Women: 106 Women: 3.7% Women: 1.2% Women: 2.1%
(age 30–60)
Korea120, 2004a Men: 309; Men: 27% Men: 10.1% Men: 4.5%;
Women: 148 Women: 16% Women: 4.7% Women: 3.2%
(age 40–69)
India121, 2004a Men: 250 Men: 19.5% Men: 8.4% Men: 7.5%;
(age 35–65) Women: n/a
India122, 2006a Men: 88; Men: 19.7%; n/a Men: 4.9%;
Women: 63 Women: 7.4% Women: 2.1%
(age 30–60)
a
OSA syndrome defined as: AHI  5 þ excessive daytime sleepiness.
b
OSA syndrome defined as: AHI  10 þ excessive daytime sleepiness.

increase in any measure of body habitus (BMI, waist-to-hip ratio, or neck girth). Moreover, more than
half of the prevalence of OSA is attributable to excess body weight.33,36 Indeed, for each unit increase in
BMI the adjusted odds ratio for developing OSA is 1.14 (95% CI 1.10–1.19). However, the impact of BMI on
OSA becomes much less significant after age 60.34 It has been shown that BMI has a smaller influence on
AHI in the elderly as compared to middle-aged individuals and that changes in BMI, particularly weight
gain, have a lesser impact on the severity of OSA in the elderly.34,37–39 There is also a sexual dimorphism
in OSA prevalence. This has been attributed to the fact that compared to men, women with similar degree
of obesity have a less collapsible upper airway.40 This pathophysiologic difference in the upper airway
anatomy could explain the overall lower prevalence of OSA in premenopausal women.41
Weight changes have also been associated with the progression or regression of OSA.37 In subjects
with no OSA or mild OSA at baseline (AHI < 15), a 10% weight gain increases the odds of developing
moderate or worse OSA (AHI  15) by 6-fold (95% CI, 2–17).42

Effect of obesity on sleep architecture in the absence of OSA

The prevalence of OSA in severe obesity (BMI  40 kg/m2) is very high and has been estimated to
range from 50 to 98%.43–46 Thus, up to 50% of severely obese subjects do not suffer from OSA and yet,
complaints of fatigue, daytime sleepiness and non-refreshing sleep are very common despite the
absence of sleep-disordered breathing in this group.47
The excessive daytime sleepiness in the severely obese without OSA could be due to a disruption of
sleep homeostasis due to obesity per se which occurs as a consequence of poor sleep quality. Pro-
inflammatory somnogenic cytokines released by the adipose tissue such as Il-6 and TNF-alpha have
been hypothesized to cause daytime sleepiness and fatigue in obese subjects who do not suffer from
OSA48,49 and one possible mechanism could be a direct deleterious effect on overall sleep homeostasis.
The increased daytime sleepiness is thought to partly dissipate sleep pressure, resulting in a lower
intensity of NREM sleep and poorer sleep quality.
To date, three studies have assessed sleep architecture in obese subjects without OSA.47,49,50 Taken
together these studies have reported lighter and more fragmented sleep, longer sleep latency and less
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Table 2
Prevalence of OSA by body mass index in population-based studies utilizing polysomnography.

Study n Age (years) Definition BMI (kg/m2) Prevalence of OSA

of OSA (percentage)
Pennsylvania, U.S.A., 1741 20–100 AHI  15 Women Women
Bixler et al. 38,39 <32.3 1.1%
32.3 7.2%
Men Men
<32.3 2.0%
32.3 13.8%

Sleep Heart Health, 5615 40–98 AHI  15 Quartiles

U.S.A., 16–24 10%
Young et al.35 24–28 13%
28–32 17%
32–59 32%

Hong Kong, China, 259 30–60 AHI  5 Women Women

Ip et al. 118,119 <23 0.9%
23 14.5%
Men Men
<23 0.9%
23 8.8%

OSA: obstructive sleep apnea; BMI: body mass index.

rapid eye movement (REM) sleep compared to lean controls. Preliminary data from our group confirm
that severely obese patients without OSA have higher scores of subjective daytime sleepiness and
disruption of sleep homeostasis with markedly reduced amounts of the deepest non-REM sleep (stage
4) and markedly decreased slow wave activity compared to lean controls.51
In conclusion, severe obesity appears to be associated with marked sleep disturbances, even in
individuals who do not have OSA. Further studies are needed to establish that these sleep disturbances
are causing increased fatigue and daytime sleepiness in these individuals.

The effect of weight loss on sleep architecture and OSA

Impact of surgical weight loss on the sleep architecture

Four studies with a total of 124 patients have reported changes in sleep architecture assessed by
polysomnography before and after surgically induced weight loss.52–55 Table 3 provides a summary of
the findings. Despite the significant reductions in BMI, arousal index, and AHI, the impact of weight loss
on sleep architecture was mixed and is difficult to interpret, particularly given the fact that the subjects
were still obese at the time of re-assessment. Only one study showed a significant improvement in
sleep efficiency and latency to REM sleep.52 Two studies reported an increase in the duration of stage 3
and 4 of non-REM sleep (i.e. slow wave sleep).52,53 REM sleep, on the other hand, increased in three out
of the four studies.52,53,55 Taken together, it is difficult to quantify what proportion of improvement in
sleep architecture is due to the improvement in OSA or simply to weight loss. These studies also lacked
an habituation night, and therefore an impact of the “first night effect” in the sleep laboratory – which
can decrease sleep efficiency and the duration of REM sleep and slow wave sleep – cannot be excluded.

Impact of nonsurgical weight loss on OSA

Two recent randomized controlled trials examined the effect of weight loss on OSA. Tuomilehto and
colleagues enrolled 72 consecutive overweight and obese patients with mild OSA.56 The intervention
group was randomized to a very low caloric diet and lifestyle modification and the control group
received routine lifestyle counseling. At one-year follow-up, the BMI in the intervention group was
reduced by 3.5 kg/m2 vs. 0.8 kg/m2 in the control group. Although the difference in AHI reduction was
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Table 3
Changes in sleep architecture after surgical weight loss.

Variables Charuzi52 Dixon53 Lettieri54 Valencia-Flores55

mean  SD (n ¼ 47)a (n ¼ 25) (n ¼ 24) (n ¼ 28)b
Interval between pre-and 9.7  7.2 17.7  10 13.9 (range 13.7  6.6
post-operative PSG, 10.9–22.5)
months

BMI, kg/m2
Baseline n/a 52.7  9.5c 51  10.4c 56.5  12.3c
At time of repeat PSG n/a 37.2  7.2 32.1  5.5 39.2  8.5

AHI, events per hour of sleep

Preoperative 60.8  35.5c 61.6  31.9c 47.9  33.8c 52.3  42.5c
After surgical weight loss 8.0  11.8 13.4  13 24.5  18.1 14.3  13.4

Arousal index
Preoperative NR 48.2  34c 42.8  17.3c 20.1  16.9c
After surgical weight loss NR 18.4  13 23.3  8.1 12.1  9.1

Sleep efficiency, %
Preoperative 83  13c 71  18 92.8  27.5 85.6  8.9
After surgical weight loss 87.4  7.3 79  10 83.6  10.8 87.6  10.6

Sleep latency, min

Preoperative 14.1  25.6 NR 31  25.6 7.0  6.6
After surgical weight loss 9.1  7.3 NR 34.4  33.2 6.5  9.7

REM sleep latency, min

Preoperative 161.1  93.9c NR NR 129.5  79.3
After surgical weight loss 82.9  41.0 NR NR 118.5  66

Stage 1 non-REM sleep, %

Preoperative 1.8  2.8 NR 18.6  8.6c 18.5  12.6c
After surgical weight loss 1.8  2.3 NR 5.8  4.4 11.5  5.9

Stage 2 non-REM sleep, %

Preoperative 69.7  15.8 NR 44.4  13.8 NR
After surgical weight loss 53.2  12.3 NR 58.6  12.9 NR

Stage 3 and 4 non-REM sleep, %

Preoperative 10.9  11.6c 15  14c 11.0  10.7 10.7  7.1
After surgical weight loss 21.8  11.5 26  10 8.5  8.6 11.4  5.7

REM sleep, %
Preoperative 10.5  7.2c 8.7  7.5c 8.0  6.1 10.4  5.8c
After surgical weight loss 19.1  7.5 16.3  5.8 11.5  2.6 14.8  6.5

PSG: polysomnogram; AHI: apnea-hypopnea index; BMI: body mass index; REM: rapid eye movement; NR: not reported; n/a:
not available.
a
BMI not reported by Charuzi et al. Baseline weight was 138.9  24.6 kg and the % excess body weight was reduced from
117.4  36.4 to 44.4  35.1.
b
Mean and SD calculated from data.
c
p < 0.05 comparing preoperative results to after surgical weight loss.

approximately 4 events per hour, the improvements were proportionate to the degree of weight loss.
The proportion of patients with AHI < 5 events per hour was significantly larger in the intervention
group (63% vs. 35%, p ¼ 0.019).
In the other study, Foster and colleagues randomized 264 patients with OSA and type 2 diabetes to
an intensive lifestyle modification with a behavioral weight loss program or effective diabetes
management through routine diabetes support and education.57 They found that at one-year follow-up
those patients randomized to the intensive intervention lost more weight than those randomized to
routine care (10.8 kg vs. 0.6 kg, p < 0.001). In patients randomized to intensive lifestyle modification
the AHI decreased from 22.9  18.0 to 18.3  15.3. In contrast, patients randomized to routine diabetes
support and education had an overall increase in the mean AHI from 23.5  15.0 to 28.3  20.7. The
adjusted mean decrease in the AHI between the two groups was 9.7 events per hour (95% CI, 13.6 to
 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761 753

5.7; p < 0.001). In fact, OSA remission was achieved in 3 times as many participants in the intensive
intervention group. Taken together, these findings suggest that lifestyle modifications leading to
significant weight loss can be an effective intervention in patients with mild to moderate OSA.
However, both studies provide only one year of follow-up and it is conceivable and even likely, that
weight regain may occur over time, thereby attenuating the benefits on OSA severity.

Impact of surgical weight loss on OSA symptoms

Bariatric surgery has variable long-term efficacy in treating OSA. Its impact on the severity of OSA has
been documented in a meta-analysis that compiled several studies evaluating bariatric surgery
outcomes.17 However, several studies that had not performed polysomnograms pre- and post-
maximum weight loss and had relied instead on patient symptoms were included in this meta-analysis.
Dixon and colleague assessed sleep symptoms before and after surgically induced weight loss in 313
consecutive patients.58 After 1 year this cohort had lost a mean (SD) of 48  16% of excess weight. With
this degree of weight loss, the prevalence of habitual snoring had decreased from 82% to 14% and
observed apneas decreased from 33% to 2%. Excessive daytime sleepiness was measured with the
validated Epworth Sleepiness Scale (ESS), an 8-item questionnaire in which 0 is the lowest score and 24 is
the highest score and scores equal or above 10 are consistent with hypersomnolence. The ESS decreased
from a mean of 9.1  5.7 to 4.0  3.4. In another prospective non-randomized study, Grunstein and
colleagues compared the improvement in sleep apnea symptoms in the Swedish Obese Subjects cohort
that had undergone bariatric surgery (n ¼ 1592) to the cohort that was treated conservatively
(n ¼ 1431).59 At two year follow up, BMI in the surgical group had decreased by 9.7  5 kg/m2 while that
in the control group had not changed significantly. The significant weight loss seen in these patients led
to dramatic improvements in self-reporting of frequent apneas, snoring, and EDS (Table 4). Moreover,
the degree of improvement in sleep apnea symptoms was related to the degree of weight loss achieved. It
should be pointed out that despite the dramatic weight loss and improvement in symptoms, a propor-
tion of patients remained symptomatic. Therefore, the general perception that bariatric surgery cures
OSA in 70–80% of patients may be inaccurate since in most studies the resolution of OSA has been
established by subjective symptom resolution and not systematically by polysomnography.17 Such
a high cure rate based on subjective symptom improvement can be notoriously unreliable since there is
a poor correlation between symptoms of OSA and severity of the disease based on the AHI.

Impact of surgical weight loss on polysomnographic measures of OSA

To better understand the impact of surgical weight loss on OSA, Greenburg and colleagues per-
formed a meta-analysis of twelve studies including a total of 342 patients in whom pre- and post-
maximum weight loss sleep assessments by polysomnography were available.60 They found that

Table 4
Improvement in OSA symptoms after surgical weight loss compared to controls.59

Symptoms Surgical weight loss Control p-Value

(n ¼ 1592) (n ¼ 1431)
BMI, kg/m2
Baseline 42.2  4.4 40.1  4.6 <0.001
Change in BMI at 2 years 9.7  5 03 <0.0001

Frequent apneas, %
Baseline 24 22 0.15
Two year follow up 8 21 <0.001

Frequent snoring, %
Baseline 45 36 <0.001
Two year follow up 11 30 <0.001

Frequent daytime sleepiness, %

Baseline 26 20.4 <0.001
Two year follow up 13 18 <0.001
754 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

bariatric surgery led to significant weight loss with a mean reduction in BMI from 55.3 kg/m2 to
37.7 kg/m2. This robust weight loss was accompanied by a 71% reduction in the AHI from baseline
values of 55 events per hour (95% CI 49–60) to 16 events per hour (95% CI 13–19). Only 38% achieved
cure defined as AHI < 5. In contrast, 62% of patients had residual disease with the mean residual AHI of
16 events per hour. Many of these patients had persistent OSA of moderate severity (AHI  15 events
per hour). Thus, although improvements should be anticipated, OSA will not resolve in all patients after
surgically achieved weight loss but it should be noted that, despite weight loss, the majority of patients
were still obese at the time of the second sleep assessment. While there is a drastic reduction in OSA
severity, some patients still have moderate OSA after maximum weight loss and could therefore benefit
from continuous positive airway pressure (CPAP) therapy.55,61 Only one study has prospectively per-
formed polysomnography several years after maximum weight loss.61 These authors reported that
approximately half of the patients who had mild OSA after bariatric surgery developed severe OSA 7
years post-operatively despite no significant change in their weight. It is also known that in the 6–8
years after weight reduction surgery, patients experience a weight gain averaging 7%.23 This weight
gain compounded by aging could significantly increase the severity of OSA.30,35,62
Only one study has examined the impact of bariatric surgery in patients with the obesity hypo-
ventilation syndrome 63 a condition that is associated with severe OSA, obesity and daytime hyper-
capnia.64 In 31 patients, preoperative partial pressure of arterial oxygen (PaO2) increased from 53 to
73 mm Hg one year after surgery, and the partial pressure of arterial carbon dioxide (PaCO2) decreased
from 53 to 44 mm Hg. In the 12 patients in whom arterial blood gas measurements was available 5
years after surgery, values had worsened with the mean PaO2 dropping to 68 mm Hg from 73 mm Hg
and PaCO2 increasing from 44 mm Hg to 47 mm Hg. In these 12 patients, BMI had hardly increased
from 1 to 5 years post-operatively (38  9 to 40  10 kg/m2). The worsening in daytime blood gases is
likely due to the redevelopment of OSA.
Adherence with CPAP therapy after bariatric surgery was evaluated in 3 studies.53,54,65 Adherence
with CPAP therapy is very low in the first few months after bariatric surgery. In one study, the
investigators reported that only 26% of patients with residual OSA after surgery (mean residual AHI
24  18) were adherent with CPAP at 1 year.54 Such poor adherence with CPAP therapy in patients who
have undergone bariatric surgery is significantly lower than the 50% adherence rates previously
reported in patients with OSA.66 This could be due to the post-surgical improvement of subjective
symptoms (daytime sleepiness and snoring) or to intolerance to the pre-surgical CPAP pressure
settings. In fact, the pressure requirements decrease with significant weight loss from an average of
11 cm H2O to 7 cm H2O.54,65 There are no published studies that have systematically assessed whether
adherence with CPAP therapy would improve with an auto-PAP device that can adjust pressures as
patients experience weight loss after bariatric surgery.
Taken together, the limited studies that have objectively assessed the degree of improvement of OSA
pre- and post-surgical weight loss demonstrate a significant improvement in OSA severity and
symptoms. However, a significant proportion of patients will continue to have moderate and in some
cases severe OSA and could therefore benefit from CPAP therapy. Since subjective symptom
improvement can be unreliable, we recommend a formal reevaluation of OSA severity with poly-
somnography after maximum weight loss. It is also important to note that with time there is a risk of
gradual worsening of OSA that is related to both weight gain and aging.

Surgical weight loss and impact on metabolism

Obesity is a risk factor for multiple metabolic abnormalities and the common pathophysiologic
pathway for metabolic disorders may be due, at least in part, to an overall increase in inflammation
associated with obesity.67 We review here the effect of bariatric surgery on obesity-related metabolic
diseases such as T2DM, dyslipidemia, and on inflammation.

Type 2 diabetes mellitus (T2DM)

With the increased prevalence and severity of obesity worldwide, an epidemic of T2DM is also
developing. T2DM is a relentless and progressive disease and conventional therapeutic modalities
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cannot achieve a cure. However, there is a growing body of evidence demonstrating remission of T2DM
after bariatric surgery.68–70 In a large meta-analysis which examined 136 studies and included 222,094
patients who underwent bariatric surgery (LAGB, VBG, RYGB and BPD), diabetes resolution, defined as
ability to maintain euglycemia after discontinuing all diabetes–related medications, was achieved in
more than 75% of the patients across all procedures, while up to 85% of patients experienced
demonstrable improvement.17
In general the purely restrictive bariatric surgeries induce an improvement of diabetes that is
proportional to the degree of weight loss71; complete resolution of diabetes has been estimated to be
around 50% with gastric banding.17 The most effective procedures in leading to resolution or significant
improvement of T2DM are the BPD and the DS curing 99% of cases, followed by RYBP with a 83.7% rate
of resolution.17 All these procedures share a malabsorptive component created via a major anatomic
rearrangement of the small intestine. The sleeve gastrectomy has also been shown to dramatically
improve T2DM as reported in a 12-month prospective study, in which 84.6% of patients achieved
complete remission.72
Resolution of T2DM often occurs in the first few days following surgery, before marked weight loss is
achieved,70 suggesting that weight loss alone cannot entirely explain why these procedures improve
T2DM. Recent experimental data suggest that the improvement of beta-cell function may be a main
mechanism of the short-term effect of bariatric surgery and point toward the rearrangement of the
gastrointestinal anatomy as a primary mediator of this phenomenon, independently of the weight loss and
the diminished caloric intake after surgery.73 The leading hypothesis is that the intestinal rearrangement
may modulate a mechanism responsible for the abnormal beta-cell function seen in T2DM. It is
conceivable that different anatomical changes in the gut anatomy may have different effects on glucose
homeostasis. Specifically for RYGB two hypotheses have been proposed, both bearing on the role of the
incretins, gastrointestinal hormones that stimulate insulin secretion after a meal.74 The “proximal bowel”
hypothesis holds that bypassing the proximal portion of the small intestine reduces the secretion of
a “diabetes inducing factor” with possible anti-incretin effect. Such a mediator is yet to be identified.
According to the “distal bowel” hypothesis, the expedited delivery of undigested nutrients to the distal
intestine may enhance the secretion of an antidiabetes peptide, possibly of incretin nature. Indeed, several
studies to date have shown that the levels of meal- or glucose-stimulated incretins, i.e. glucagon-like
peptide (GLP-1) and gastric inhibitory peptide (GIP), increase after RYGB.75–78 GLP-1 and GIP are secreted
by the endocrine cells of the intestinal mucosa in response to food and are responsible for 50–60% of insulin
secretion after meals.79–81 In patients with T2DM, GLP-1 levels are blunted 82 but the effect of administered
GLP-1 on insulin secretion persists.83 GIP levels in T2DM patients are usually normal but the effect of
administered GIP on insulin secretion is blunted,84 although it can be restored under normal glycemic
conditions.85 The most rigorous studies have been provided recently by Leferrere et al. 86 who showed that
GLP-1 and GIP levels and their effects increase 4 weeks after RYGB. In contrast, a diet intervention with
similar weight loss tended to decrease GLP-1 and did not show a comparable increase in GIP levels.86
The effect of bariatric surgery on insulin sensitivity independently of the weight loss is more
controversial. In morbidly obese with severe insulin resistance, Pereira et al. demonstrated that bariatric
surgery improved insulin-dependent glucose uptake in proportion to the degree of weight loss.87 Few
studies have investigated insulin sensitivity after RYGB as measured by glucose tolerance tests (intra-
venous and oral). Two earlier studies in non-diabetics88,89 showed that the area under the curve for
insulin after an oral glucose load was lower after RYGB versus weight matched non-surgical controls,
which points to improved insulin sensitivity in the post surgery group. A prospective study in 19 severely
obese women before and 1 month after RYGB reported a 10% weight loss and a significant decrease in
fasting HOMA-IR, which is a measure of insulin resistance.90 A cross-sectional study by Bikman et al. 91
compared post-RYGB patients (weight stable at 1 year with mean BMI of 30 kg/m2) to weight matched
obese (BMI 25–35 kg/m2), more severely obese (BMI > 35 kg/m2) and lean individuals (BMI < 25 kg/m2).
Insulin sensitivity as assessed by intravenous glucose tolerance testing was higher in surgical patients
than in the weight-matched subjects and not different from the lean subjects; muscle glucose transport
was similar to that assessed in lean subjects and IRS-1 protein phosphorylation in muscle (which inhibits
insulin signaling) was decreased after surgery and tended to be lower than in weight-matched subjects.
Leferrere and colleagues also showed that RYGB improves peripheral glucose disposal more significantly
than a comparable diet only induced weight loss.86 A study in non-diabetic morbidly obese subjects
756 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

demonstrated that insulin sensitivity was markedly improved within a few days after BPD.92 After BPD in
severely obese patients with insulin resistance, whole-body glucose uptake is not only normalized
compared with the normal weight healthy individuals, but often exceeds the normal levels.93
What are the mechanisms that may explain enhanced insulin sensitivity early post bariatric surgery
before significant weight loss? One possibility is a decreased accumulation of fatty acids in the myo-
cytes which could be enhanced by surgery compared with diet induced weight loss. This could be the
case for BPD which induces an extreme fat malabsorption. The acute lipid “ starvation” would lead to
intramyocellular fat depots normalization even when the extracellular muscle fat and whole-body fat
stores are still abundant.94 The mechanisms by which lipid withdrawal depletes intramyocellular fat
depots are not yet uncovered but as been suggested that they could involve a decrease in leptin gene
expression and an increase in leptin sensitivity.94,95 Alternatively changes in gut hormone release after
the surgery could directly affect peripheral glucose disposal independently of insulin action . While
specific GLP-1 receptors have not been found to be expressed in either muscle or liver, the insulin
independent extra-pancreatic effects of GLP-1 on glucose disposal in the liver and muscle have been
previously well described in animal models,96,97 although the supra-normal values of glucose uptake
after BPD cannot solely be explained by an increase in the incretin effect.
Recent work in rodents suggests another mechanism for how the intestine might modulate insulin
sensitivity.98,99 This work proposes the intestine as a neuroendocrine organ that regulates food intake
as well as insulin secretion and action to improve glucose tolerance and favors a seamless transition
from fuel catabolism to storage of nutrients. The hypothesis is that lipid- and carbohydrate-based
neurocircuits from the intestine to the hindbrain and back down to the liver influence hepatic glucose
production in response to ingested nutrients. This circuit operates in concert with established post-
prandial actions of the intestine to generate incretins that facilitate insulin secretion, as well as satiety
factors that promote meal termination. The proximal and distal bowel hypotheses are also compatible
with this theory that altered nutrient flow may trigger neural signals from the gut to the brain rather
than hormonal signals. This more recent hypothesis opens novel questions on how these pathways
might be affected by the intestinal bypass operations to help ameliorate T2DM.
In summary, the evidence available at this time seems to support a paradigm shift in the application
of bariatric surgery from the treatment of excess weight to the treatment of T2DM. As a result a new
term has been introduced which refers to bariatric procedures as “metabolic” surgeries.

Dyslipidemia

In addition to substantially reducing hyperglycemia, bariatric surgery has been shown to improve
dyslipidemia. Results of the meta-analysis published in 2004 showed that dyslipidemia improved in at
least 70% of the patients who underwent bariatric surgery.17 Across all procedures, levels of total
cholesterol, low-density lipoprotein, and triglycerides were reduced while there was not a significant
increase in high-density lipoprotein except with two procedures, gastric banding and gastroplasty. The
effect on resolution or improvement of dyslipidemia is also seen early after surgery.100

Systemic inflammation and the metabolic syndrome

Obesity is thought to induce a state of chronic low-grade inflammation101 as the adipose tissue is
a remarkable endocrine organ releasing numerous cytokines (adipokines), including pro-inflammatory
molecules such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). These adipokines
have been shown to have an impact on glucose homeostasis, vascular biology, tumor development and
lipoprotein metabolism, and on the inflammatory process.102 Inflammatory markers are elevated in the
co-morbid conditions associated with obesity and it has been postulated that they may have a path-
ogenetic role in obesity-related diseases. Indeed, systemic low-grade inflammation is critical for the
appearance of the metabolic syndrome.103 IL-6 stimulates the hepatocytes to produce acute-phase
proteins including C-reactive protein (CRP), which has received the most attention as a potential
marker of atherosclerotic risk. IL-6 is secreted by the adipocyte in proportion to the volume of fat
tissue; therefore weight loss may directly impact metabolism via a decrease of IL-6 and an improve-
ment of the inflammatory status.
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The data on the effect of bariatric surgery on inflammatory markers are scattered and pertain
almost exclusively to the long-term (1 year) effect of RYGB. Several studies have shown that CRP was
decreased 12 months after RYGB 90,104,105–108 in proportion to the degree of weight loss.108 In one study,
the CRP level after bariatric surgery was directly correlated to HgA1C, insulin level, and the HOMA
index,106 a measure of insulin resistance, supporting the hypothesis of a direct link between a reduction
in the inflammatory process and the lower peripheral resistance to insulin after RYGB.
While marked reductions in the prevalence of the metabolic syndrome have been observed at 1
year following RYGB,109,110 most of the improvement of the metabolic syndrome may occur shortly
after the surgical procedure, similar to what has been seen with glucose homeostasis111 and blood
pressure.112 It remains to be elucidated whether the early metabolic changes are also mediated by
a change in the inflammatory status. Very few studies have evaluated the short-term effects of RYGB on
inflammation and have reported either no change or no association between inflammatory markers
and changes in the metabolic parameters,113,114 suggesting that the early changes in the metabolic
syndrome following RYGB may be better explained by changes in insulin sensitivity possibly directly
mediated by the changes in gut hormone physiology115 derived from the surgical manipulation of the
gastrointestinal tract, rather than an improvement of the inflammatory status.

Summary

With the global obesity epidemic, there has been a significant surge in the number of bariatric
surgeries performed worldwide. Surgical techniques that include malabsorptive procedures have
proven to be safe and very effective in both the amount and maintenance of weight loss. The dramatic
weight change after bariatric surgery can lead to improvement in OSA. The impact of weight loss on
sleep architecture, independent of improvement in OSA, has not been well studied. Despite
improvement in OSA severity, it is important to recognize that in a significant proportion of patients,
OSA persists after maximum weight loss. Moreover, OSA can worsen as patients age and regain weight
over time. Although the impact of bariatric surgery on OSA appears to be related to the degree of
weight loss, the metabolic benefits occur very early after surgery, before patients experience any
weight reduction. This suggests that weight loss alone cannot entirely explain improvement in T2DM
following bariatric procedures. The purely restrictive bariatric surgeries induce an improvement of
which is proportional to the degree of weight loss but procedures that include a malabsorptive
component have a more dramatic and earlier effect on T2DM. The mechanisms behind improvement in
T2DM following bariatric malabsorptive surgeries have not been fully elucidated, however, one of the
major effects appears to be an improvement in beta-cell function. This may be primarily related to
the rearrangement of the gastrointestinal anatomy, specifically the bypass of the proximal portion of
the small intestine. Such anatomical rearrangement could also be responsible for an improvement in
insulin sensitivity, independent of weight loss and diminished caloric intake.

Practice points

 Bariatric surgery is the most effective treatment for obesity; in most of the patients these
procedures are performed through a laparoscopic approach, which has significantly
improved the safety of the procedures.
 Despite improvement of subjective OSA symptoms, some degree of OSA persists even after
maximal surgical weight loss and therefore patients should be retested for OSA once their
weight has stabilized after bariatric surgery.
 Obesity may affect sleep even in the absence of clinically significant OSA. The impact of
weight loss on sleep architecture in the absence of OSA remains unknown.
 Improvement of T2DM occurs early after malapsorptive bariatric procedures, before any
significant weight loss has occurred. The mechanism behind this phenomenon is still not
fully elucidated.
758 S. Pannain, B. Mokhlesi / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 745–761

Research agenda

 Additional studies are needed to identify predictors of OSA persistence after surgical weight
loss.
 The effect of obesity per se on sleep architecture in the absence of OSA should be better
investigated.
 More research is needed to better elucidate the mechanism of the improvement of T2DM
after bariatric surgery. Such research may uncover novel pharmaceutical targets for the
treatment of T2DM.
 Trials are needed to compare the effect of various bariatric procedures on T2DM and examine
the individual predictors of improvement of T2DM. Results from such studies may in the
future assist patients in deciding whether to undergo bariatric surgery and selecting the most
appropriate procedure.

Conflict of interest

The authors do not have any financial or other potential conflicts of interest to declare.

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