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4.2 STUDY II: MAINTENANCE AND OBSTRUCTIVE SLEEP APNOEA
In the pooled observational study of maintenance of OSA improvements over one year, 58 of the 63
participants completed the VLED period and started the weight loss maintenance programme, with 44
completing the ful programme, and 49 with complete measurements at one year. In the main analysis,
data from al patients were analysed (baseline carried forward for missing data). At baseline mean AHI
was 36 events/hour, and mean weight was 113 kg. AHI changes after nine weeks of VLED were largely
maintained at one year (Table 16).
Table 16 Changes in weight and apnoea-hypopnoea index (AHI) during the one-year programme
Maintenance
Full programme
(0 to 9 weeks)
(>9 to 52 weeks)
(0 to 52 weeks)
Weight (kg)
BOCF (n=63)
Completers (n=44) AHI (events/h)
BOCF (n=63)
Completers (n=44) Data are mean (SD); P values from paired sample t test. BOCF=baseline carried forward for missing data. AHI=apnoea-hypopnoea index.
After one year, patients with severe obstructive sleep apnoea at baseline had greater improvements in
AHI (-25 events/h; -54%) compared with patients with moderate disease (-7 events/h; -30%; P<0.001).
In addition, a dose-response association between weight loss and AHI at fol ow-up were seen (β=0.50
events/kg, P=0.01; Figure 4).
After one-year, 48% (30/63) no longer required CPAP during sleep and 10% (6/63) had achieved ful
remission (AHI<5).
Figure 4 Relation between AHI and
weight (kg) for al participants with measured weight and index at baseline and follow-up (n=49). Lines indicate individuals. No participant gained weight, meaning that the right-most observation represents the baseline value Adapted from Johansson, K et al (2011). "Longer term effects of very low energy diet on obstructive sleep apnoea in cohort derived from randomised control ed trial: prospective observational fol ow-up study." BMJ 342: d3017. During the VLED period, 13 patients had an adverse event classified as probably causally linked with the VLED. Of the 13 adverse events three were constipation, six were increased ALAT activity, one was dizziness, two were gouts and one was dry lips. Al adverse events had disappeared by the visit two weeks after the VLED period. During weight loss maintenance there were five additional adverse events of which three were gallstones (all three resulting in cholecystectomy), one was gout and one was kidney stones. No patient discontinued treatment because of adverse events.
4.3 STUDY III: RISK OF GALLSTONES DURING VLED
After matching LED participants (n=4,588) with replacement to VLED participants (n=3,773) 1:1 by
age, sex, BMI category, waist circumference category, and gallstone history, 3,320 participants
remained in each group. At baseline mean age, weight and BMI were 46 years, 95 kg, and 33 kg/m2,
respectively, while 83% were women. The majority were class I obese (51%), while 23% were class II
obese, 8% class III obese, and 19% overweight.
82% of VLED participants and 78% of LED participants completed the one-year programme. Weight
loss after one year was greater in the VLED than the LED group (-11 vs -8 kg, baseline carried forward
for missing data, and among completers -14 vs -11 kg, both P<0.001; Figure 5).
Figure 5 Change in weight during the one-year
Figure 6 Risk of gal stones requiring hospital care
treatment programmes by weight loss programme LOCF=last observation carried forward VLED=very low energy diet BOCF=baseline observation carried forward LED=low energy diet
During 3,163 and 3,198 person-years in the VLED and LED groups, 48 and 14 gallstones requiring
hospital care occurred (152 vs 44 per 10,000 person-years; conditional hazard ratio 3.4, 95%CI 1.9
to6.1; P<0.001; Figure 6). The risk difference was 108 per 10,000 person-years (95%CI 59 to 157),
resulting in a number needed to harm of 92 (95%CI 63 to 168). That is, assuming a causal relationship,
one avoidable gallstone requiring hospital care would be caused for every 92 patients treated with
VLED instead of LED. Adjusting the analysis for weight loss during the first three months attenuated
the hazard ratio, but the risk remained statistical y significantly higher with VLED than LED (2.7, 95%CI
1.4 to 5.2).
Of the 62 participants with gallstones requiring hospital care, 39 (63%) resulted in cholecystectomy,
29 in the VLED and 10 in the LED group (conditional hazard ratio 3.1, 95%CI 1.5 to 6.5; P=0.003;
number needed to harm 151, 95%CI 94 to 377).
In a multivariable analysis including al subjects, the risk of developing gal stones requiring hospital care
was higher in women than men, in participants with a higher baseline BMI, among those who lost
≥10kg, and in those with a history of gallstones (irrespective of cholecystectomy status).


4.4 STUDY IV: TREATMENT DISCONTINUATION
A total of 28 randomised control ed trials met the inclusion criteria: 16 studies of orlistat (n=7,038), 7
of sibutramine (n=1,475) and 5 of rimonabant (n=4,944). All included studies were between 12 and 18
months duration. Patients had similar demographic profiles across trials of al three drugs, with
predominantly Caucasian subjects and a greater proportion of women than men in most of the studies.
The mean age ranged between 41 and 59 years and the mean BMI between 33 and 38 kg/m2.
The overall combined dropout rates in the included studies were high in drug and placebo arms, with
crude overal discontinuation rates of 30% for orlistat, 34% for sibutramine, 39% for rimonabant and
37% for placebo. In the overall pooled random effect model, the risk of dropout was marginal y but
statistical y significantly lower in the active drug compared to the placebo arms (pooled risk ratio 0.9;
95% 0.8 to 0.9; P=0.001; Figure 7).
Figure 7 Forest plot of the risk ratio (RR) of dropout from any cause in
the drug vs the placebo arms in rimonabant, sibutramine, orlistat and all In the drug arms, the most common reasons for withdrawal were adverse events, patient request and poor compliance. In the placebo arms, withdrawal due to patient request and poor compliance were most common. Lack of effectiveness, as reason for dropout was specified in 10 studies. Patients in the drug arms tended to drop out less frequently as a result of lack of effectiveness compared with placebo (pooled risk ratio 0.5; 95% 0.4 to 0.7; P<0.001). The risk ratios for discontinuation due to adverse events were significantly elevated for rimonabant (2.0; 1.7-2.4) and orlistat (1.6; 1.2-2.1), but not sibutramine (1.0, 0.7-1.4), compared to placebo. 5 DISCUSSION
The overal objective of this thesis was to evaluate effects and side-effects of VLEDs in different obesity
settings, and to characterise discontinuation in obesity treatment. Specific objectives were to evaluate
weight loss as treatment option for patients with OSA (Study I&II); to assess the risk of gal stones
requiring hospital care in a commercial weight loss programme using VLED or LED (Study I I); and to
characterise overal discontinuation in obesity treatment programmes by analysing data from anti-
obesity drug trials (Study IV).
5.1 MAIN FINDINGS
The studies in this thesis were carried out at a specialist outpatient obesity centre (hospital-based;
Study I&II), or in the commercial sector (Study I I). The hospital-based trial included only men with OSA
(Study I&I ), while the commercial study (Study I I) included both men and women with the majority
being women. Analyses included al starting patients (baseline observation carried forward for missing
data).
Initial weight loss after VLED in the hospital-based treatment was -16% (Study I&I ), and -14% in the
commercial weight loss programme (Study I I). Hence the men in the hospital-based treatment
programme lost slightly more weight during VLED, but regained more during the maintenance phase
than the participants in the commercial programme (32% vs 19% regain of lost weight). A similar
weight loss at one year in the hospital-based (-11%) and commercial programme (-12%) was therefore
found.
Dropout from both the hospital-based and commercial programme was lower compared to the
benchmark of 37% in placebo arms of anti-obesity drugs trials (Study IV), with 30% in the hospital-based
and 18% in the commercial programme after one year. In the clinical care treatment programme,
gallstones were reported in 5% (3/63; al three cholecystectomised; mean BMI 35) of the participants
over one year compared to 1.4% (48/3320; 29 of 48 cholecystectomised; mean BMI 33) of the VLED
participants of the commercial weight loss programme.
5.1.1 Weight Loss and Obstructive Sleep Apnoea
The findings of the randomised trial of obese men with moderate to severe OSA (Study I) indicated that weight loss induced by a VLED significantly improved OSA. The mean AHI was reduced by two-thirds from 37 to 12 in the intervention group compared with no change in the weight stable control group after nine weeks. The pooled observational fol ow-up study (Study I ) showed that the AHI changes after nine weeks of VLED (-58%) were largely maintained at one year (-47%) fol owing the initial weight loss of -16% (-18kg), and -11% (-12kg) at one-year. In addition, a significant effect modification by baseline AHI was observed with patients with severe OSA at baseline having larger AHI improvements than patients with moderate disease. Moreover, a dose response association between weight loss and AHI improvement was found. After one year, half of the men no longer required CPAP, and one out of ten had total remission of OSA. There were also marked improvements in metabolic risk and the physical dimension of quality of life.
5.1.2 VLED and Risk of Gallstones
The absolute risk of gallstones requiring hospitalisation in overweight and obese participants enrol ed
in a one-year commercial weight loss programme (Study I I), using either VLED or LED during the initial
three-months weight loss phase, was found to be low (1.4% vs 0.4%). However, the risk was three
times higher in the VLED than the LED programme with a number needed to harm of 92. That is,
assuming a causal relationship between weight loss treatment and gallstone problems, one additional
gallstone requiring hospital care would result per 92 patients on VLED instead of LED. The
corresponding number for an additional cholecystectomy was 151. While the risks were greater in the
VLED compared to the LED group, the benefit in terms of one-year weight loss was also greater -12%
(-11 kg) vs -9% (-8 kg) of initial body weight, respectively. Also, a larger proportion of the participants
in the VLED treatment programme completed one-year of treatment compared to participants in LED
(82% vs 78%). These completion rates can be compared with the 63% in the placebo arms of
randomised trials of anti-obesity drugs.
5.1.3 Dropout in Anti-Obesity Drug Trials
Attrition in anti-obesity drug trials including overweight and obese participants was found to be high in
both the drug and placebo group, with overal discontinuation of 37% in the placebo arms only
receiving diet and lifestyle modification (Study IV), and 30-39% in the drug arms, although slightly lower
in the drug arm (pooled risk ratio 0.9). In the drug arms, the most common reasons for withdrawal
were adverse events, patient request and poor compliance. In the placebo arms, withdrawal due to
patient request and poor compliance were most common. Overal , patients in the drug arms tended to
drop out less frequently as a result of lack of effectiveness compared with placebo (pooled risk ratio
0.5). The risk ratios for discontinuation due to adverse events were significantly elevated for
rimonabant and orlistat, but not for sibutramine, compared to placebo.
5.2 COMPARISON WITH PREVIOUS RESEARCH

5.2.1 Weight Loss and Obstructive Sleep Apnoea
Before 2009, no randomised trial had shown weight loss to improve OSA, while observational studies of both dietary and surgical interventions indicated that this was the case.155 In 2009, three randomised control ed trials were published,114-116 one of which is included in this thesis (Study I).114 All three trials found a positive effect of weight loss on OSA, but in different patient groups. A Finnish study by Tuomilehto et al115 found a 40% reduction in AHI in patients with mild OSA after -11% (-11kg) weight loss at one year, and a 46% AHI reduction with a -7% (-7kg) weight loss after two years.140 In a sub-sample of the American Look AHEAD study, Foster et al116 found a 24% AHI reduction at one year with -10% (-11kg) weight loss after an intensive lifestyle intervention in older (mean age 61y) patients with type 2 diabetes, while the AHI increased in control patients, resulting in a between group AHI difference of 42%. The dose-response association that was found in Study I&II between weight loss and OSA was also found by Foster et al and et Tuomilehto al115 116 Foster et al also found significantly greater improvements in patients with severe disease at baseline, as found in Study I&II.
In addition to dietary interventions, weight loss induced by bariatric surgery has also been shown in
observational studies to result in long-term improvements in OSA. In the SOS study including matched
controls, Grunstein et al120 found that 30% of the surgery group reported self-reported persistent
sleep apnoea at the two-year fol ow-up compared with 70% of the control group. Smal uncontrol ed
studies (n<20) have also found long-term improvements in OSA after weight loss surgery.124 125 132 135 137
5.2.2 VLED and Risk of Gallstones
Few randomised trials investigating the effect of VLED on weight loss report side-effects. In a meta-analysis comparing the long-term efficacy and safety of VLEDs and LEDs, Tsai and Wadden65 concluded that no symptomatic gallstones were reported among VLED participants in any of the included trials, but they also concluded that this may have been attributable to lack of assessment in the individual studies. The majority of studies specifical y investigating the risk of gal stones during VLED treatment have been conducted in the late 1980s and early 1990s with VLEDs containing low levels of fat (≈1 g/day).90-94 In a review of these studies,88 Everhart reported that 10-25% of VLED participants developed gallstones, one third of which were symptomatic. However, the studies were of short duration (8-36 weeks),90-94 and only one study included a weight stable control group.92 Later studies have investigated VLEDs containing higher fat content,95-98 including two randomized control ed trials,95 96 and found that fewer participants developed symptomatic gallstones. In a review, Festi et al89 concluded that adequate fat content is important in gal stone prevention, with 10 g/day as a threshold for obtaining efficient gal bladder emptying. A lower recommendation of 7 g/day has, however, been given by the European SCOOP-report on VLED use.60 In our register-linkage study of a commercial weight loss programme using a liquid formula diet containing 7-9 g/day, we found a higher, albeit low, risk of symptomatic gallstones requiring hospitalisation in the VLED compared to the LED group, suggesting that more fat may be needed to eliminate the excess risk of gallstones compared to LED (Study I I). Bariatric surgery, however, also increases the risk of gal stones probably as a result of the rapid weight loss. The postoperative incidence has been reported to be between 3 to 28%.156 This large span may be explained by different fol ow-up time and/or different methods of detecting gal stones. A Swedish population-based cohort study of bariatric surgery identified the risk of gallstones requiring hospitalisation by the use of the National Patient Register (that is, similar to the methodology in Study III), and found a fivefold increased risk of both gal stones requiring hospital care and cholecystectomy for the bariatric surgery group compared to that of the general population. In the SOS study the incidence of gallstones and cholecystectomy after 2 years was assessed using questionnaires.157 Compared to conventional treatment, bariatric surgery significantly increased the risk of self-reported gallstones in men (4.0% vs 1.2%, odds ratio 4.2; P<0.001), but not in women (5.5% vs 4.5%, odds ratio 1.1; P=0.33). However, in both sexes, a greater weight loss in the surgery group was related to an increased incidence of gal stones.
5.2.3 Weight Loss Programme Discontinuation
Weight loss treatment programmes in observational settings (hospital-based and commercial) as wel
as randomised trials are generally associated with high levels of attrition, although reported dropout
rates vary considerably. In a systematic review of weight loss studies addressing factors associated with
attrition,142 one-year dropout rates of diet and lifestyle modification studies ranged between 16-77%. In
comparison, low attrition rates were reported in the Look AHEAD trial after 1 year (3% in the
intensive lifestyle intervention and 4% in the diabetes support and education intervention),24 and at four
years (6% vs 7%, respectively).25

Lack of treatment effect is one of the most common reasons why participants discontinue treatment.
In anti-obesity drug trials, adverse events are also a common reason in the active drug arm for
withdrawal, as reported in Study IV. Identified predictors of dropout in weight loss intervention studies
in general include young age, previous dieting attempts, too high weight loss expectations, poor mental
health, body dissatisfaction, low self-efficacy, low social support, and low initial weight loss.142

Attrition has been reported as the major limitation of al weight loss trials.158 Although there are
several different statistical methods for addressing missing data, none of these have been deemed
sufficient replacement for measured data, and ultimately generate bias in one way or the other.154
When interpreting estimates of weight loss interventions it is important to consider how missing data
have been handled, especially when comparing treatment effects of different studies.

5.3 STRENGTHS AND LIMITATIONS
Study Design: Study I was a randomised control ed trial of nine week duration, fol owed by an
observational study of a total duration of one year (Study I ). The strengths of Study I was the
randomised study design with its low probability of selection bias and residual confounding.159 The
reason for not using a randomised design with a one-year fol ow-up was that our primary aim was to
show, in the short term, a treatment effect from weight loss with a VLED in moderate to severe OSA.
Our secondary aim was to see whether any improvements could be maintained in the long-term. We
therefore wanted to minimise non-compliance in the control group in the nine week randomised phase
by providing a strong incentive for controls to remain in the study by al owing patients to start the
VLED programme immediately after serving as controls. The limitation of the observational design
used for the one-year follow up means that our analysis is limited by the lack of comparison with
natural progression regarding AHI and weight.
Study I I was an observational cohort study with a large sample of participants in a commercial weight
loss programme in a real-life setting. Because the risk of gal stones is low, one strength was the large
sample which provided sufficient power for a comparison with LED. Also, by using a register-linkage
design for assessment of events, we could fol ow-up a large number of participants at a relatively low
cost. The main limitation was that participants were not randomised, but had self-selected to the VLED
and LED programmes. However, the ensuing baseline differences in age, sex, BMI, waist circumference,
and gal stone history were handled by performing a matched analysis. This design reduces the
likelihood and impact of confounding, but residual confounding may remain beyond the matching
factors.

Study IV was a meta-analysis which combined results from individual anti-obesity drug trials and
assessed the risk of treatment discontinuation. The strengths of the meta-analysis include: increased
statistical power, improved estimates of effect size and the ability to resolve controversies when
different studies report conflicting results regarding both overal discontinuation and discontinuation
due to adverse events.

Identification/measurement of main outcomes: In Study I&II the main outcome measure was
AHI derived from two consecutive nocturnal sleep studies in the home. Because of the reported night-
to-night variability,160 a strength was that duplicate sleep studies were performed. A limitation was the
use of a portable WatchPAT device instead of polysomnography, which is considered the gold
standard for diagnosing OSA. However, high costs, limited access to sleep laboratories, and the
increasing number of patients with OSA have led to the development of more accessible and cheaper
methods, such as the portable monitors used in this study. Validation studies show that the WatchPAT
device has high sensitivity and specificity for estimating sleep time and AHI compared with
polysomnography.161 162
In Study I I, the strength was the use of nationwide register data to identify the main outcome
(gal stones requiring hospital care), the secondary outcome (cholecystectomy), and co-morbidity
history and drug use of the cohort. The National Patient Register and the Prescribed Drug Register
contain prospectively reported data col ected routinely on a nationwide level in the universally
accessible Swedish health care system, with virtually complete fol ow-up. One limitation, however, is
that the National Patient Register only includes data on inpatient and non-primary outpatient visits and
not visits in primary care. Hence, symptomatic gallstones treated in primary care could not be
identified. However, our primary outcome was gallstones requiring hospital care, since symptomatic
gallstones treated in primary care, at home, or not at al , are likely to be both less serious for the
patient and less costly for society.
Study Populations: Study I&II included a patient group reported to have an increased risk for
mortality.110-112 However, since we only included obese men aged 30-65 years, our results might not be
generalisable to subjects outside the inclusion criteria of the study, that is women, younger (<30 years)
or older (>65 years) patients, overweight (BMI 25-29.9) or extremely obese patients (BMI ≥40), or
patients with mild sleep apnoea. The rationale for only including men was mainly to reduce risk of type
2 error, since we could not be certain that the effect of weight loss on OSA would be the same for
men and women. The reason for choosing men instead of women was that the prevalence of OSA is
much higher in men vs women (24% vs 9%, respectively).99 The strengths of Study I I included a large
sample of weight loss participants in a real-life setting. The results from this study may limit
generalisability to the wider overweight and obese population, since the participants had selected and
paid for the treatment themselves, and could therefore be considered as a highly motivated group of
higher socio-economic class.

5.4 CLINICAL IMPLICATIONS
The availability of obesity treatment is today limited mainly to lifestyle modification or bariatric surgery, since the withdrawal of two out of three previously approved anti-obesity drugs. Bariatric surgery is currently the most effective method for treating obesity and results in weight loss of about 14-25% after 10 years.52 However, it is not realistic to treat al obese patients with surgery. According to current guidelines, only class II and class III obese qualify, that is patients with a BMI >35. Furthermore, due to both presence of contraindications and capacity constraints, not al in the class II/III obese group would be operated upon either. Other non-surgical treatment options, with strict maintenance programmes, are therefore needed. VLED in combination with a strict maintenance programme has been found to be a strong non-surgical candidate for achieving one-year maintenance results of 10-15% weight loss.33 72 74-81 The long-term effects of the use of VLED in the treatment of obesity vs LED have however been questioned. In the meta-analysis of Tsai and Wadden, they concluded that VLEDs induced significantly greater short-term weight loss than LEDs (mean difference of initial weight loss -6.4%, p<0.001) during a mean initial 13 weeks, but similar losses after 2 years (-1.3%, p>0.02).65 They also concluded that VLEDs would be more attractive if sufficient weight loss maintenance programmes existed, but they did not recommend the use of VLEDs over LEDs. However, neither of the included studies of that meta-analysis included an extensive exercise programme,74 75 pharmaco-therapy,76-81 a prolonged re-feeding period72 75 or a low glycemic index diet in combination with high protein33 as a part of the maintenance programme, which have all been proven to limit weight regain or even reduce weight further. 33 74 76 80 81 In the VLED group of Study I I 81% of the initial weight loss was maintained up to one-year (98% among completers), although the adjusted mean difference between VLED and LED was reduced from -5 kg at 12 weeks to -3kg at one-year. In Study I&II 68% (82% among completers) of initial weight was maintained up to one-year. The larger maintained weight loss in Study I I could be explained by regular scheduled exercise as compared to Study II where increased exercise was emphasised but the programme did not include an exercise scheme. Also, Study I I included a highly motivated group that had sought and also paid for treatment themselves. Regarding the safety aspects of VLED, as shown in Study I I, there is an increased risk of symptomatic gallstones requiring hospital care as well as cholecystectomy when using VLED instead of LED, although the absolute risk was low. Increased risk for gal stones is, however, also seen after bariatric surgery, which currently is considered the most effective treatment for obesity. Whether the benefits of the additional weight loss in the VLED group compared to the LED group are worth the extra risk for gal stones and cholecystectomy, as well as the extra health care costs, may depend on patients' disease and risk factor status as well as their preferences. For some patients, VLED could however be difficult to adhere to and/or result in significant weight regain after the weight loss phase, while others will benefit from VLEDs both in the short and long-term. Although little is known about which patients are most likely to benefit from different treatments, a study by Gripeteg et al163 has investigated predictors of VLED outcome. The authors found that social support and walking capacity were important determinants of successful weight loss with VLED in men, whereas psycho-social function were important for VLED success in women. They also found that patients with low perceived health who lack a close social network may need extra support during treatment.

5.5 FUTURE RESEARCH
Weight loss maintenance after VLED: Further long-term randomised studies, including
comparison of the effect of different weight loss maintenance strategies after VLED or LED are
needed to optimise weight loss maintenance.
Composition of VLED: The effect of different fat contents of VLEDs has not been studied in detail
in long-term studies. Hence comparisons between products containing about 7 g/day of fat as
recommended by the European SCOOP-report on VLED use, and higher intakes (>12 g/day) are
needed to evaluate associated risk for gallstones with a lower fat intake of VLEDs.
Long-term effect of weight loss on OSA: Weight loss may have a long-term effect on OSA
despite a rebound in weight. Tuomilehto et al140 demonstrated in their two-year fol ow-up study
that AHI remained improved and did not relapse and fol ow the trend of modest weight gain. Also,
unpublished data of the four-year fol ow-up of the study by Foster et al116 demonstrated the same
trend. Further long-term studies of the effect of weight loss in OSA are therefore needed to
investigate this long-term response to weight loss.
Prevention of discontinuation: The majority of published weight loss studies focuses on the
effects of weight loss and/or the resolution of obesity-related co-morbidities, and reasons for
dropout are often either not reported, or not explored in any depth. The few studies that have
investigated reasons for dropout have been limited to data not col ected for the purpose of
evaluation of dropout.142 Studies are therefore needed to identify strategies to prevent dropout.
6 CONCLUSION
The overal conclusions of this thesis are:
I) VLED-induced weight loss resulted in a significant reduction of moderate to severe OSA in obese
men. Patients with severe OSA benefited most from the VLED-induced weight loss. II) In patients with moderate to severe OSA who had lost weight by a VLED, the majority of the initial improvement in AHI was maintained at one year. Almost half of the patients no longer required CPAP after one year, and one out of ten had total remission of OSA. III) Although VLED, compared to LED, is associated with a three times increased risk of gallstones requiring hospital care or cholecystectomy, the absolute risk was low (1.4% for VLED vs 0.4% for LED). While these risks were greater for VLED compared to LED, sustained weight loss reduction was approximately 30% greater at one year in the VLED group. IV) One-year treatment discontinuation was lower in both the sleep apnoea study using a hospital- based outpatient weight loss programme (30%) and in the commercial weight loss programme (18%) compared to the pooled data from placebo arms of anti-obesity drug trials (37%). 7 SVENSK SAMMANFATTNING
Bakgrund Förekomsten av fetma har ökat dramatiskt under de senaste decennierna, både i Sverige
och i övriga världen. Fetma är associerat med ökad risk för sjuklighet och dödlighet, vilket leder til stor
belastning för sjukvården. Den för närvarande mest effektiva fetmabehandlingen är fetmakirurgi.
Eftersom al a individer med fetma inte kan genomgå fetmakirurgi är behovet av icke-kirurgiska
behandlingsmetoder stort.
Syfte Det övergripande syftet med denna avhandling var att utvärdera effekter och bieffekter av "very
low energy diets" (VLEDs), men också att karakterisera avhopp från fetmabehandling. Specifika syften
var att utvärdera effekten av viktminskning med VLED som behandling för patienter med obstruktiv
sömnapné (OSA; Studie I&II) i ett kliniskt viktminskningsprogram, att utvärdera risken för sjukvårds-
krävande gallstensbesvär efter VLED el er "low energy" diet (LED, Studie III) i ett kommersiel t
viktminskningsprogram, och att karakterisera avhopp från fetmabehandling genom att analysera data
från fetmaläkemedelsprövningar (Studie IV).
Metoder Studie I&II bestod av en nio veckor lång randomiserad kontrol erad studie följd av 43
veckors observationel uppföljning. Män med fetma (n=63, BMI 30-40, 30-65 år) och måttlig til svår
OSA (apnea-hypopnea index (AHI) ≥ 15) behandlade med CPAP inkluderades. Interventionen bestod
av VLED (554 kcal/dag) under nio veckor. Efter den randomiserade fasen erhöl kontrol gruppen
samma intervention. VLED-perioden följdes av sedan av ett viktstabiliseringsprogram. Studie III var en
ettårig matchad kohortstudie, bestående av män och kvinnor som deltog i ett kommersiel t
viktminskningsprogram i Sverige mellan 2006 och 2009 (n=6,640; medelålder 46 år, 83% kvinnor, BMI
33). Programmet inkluderade en tremånaders viktminskningsperiod bestående antingen av VLED (500
kcal/dag) el er LED (1,200-1,500 kcal/dag). Viktminskningsfasen följdes av ett nio månaders
viktstabiliseringsprogram. Data om sjukvårdskrävande gal stensbesvär eller kolecystektomi under det
ettåriga programmet hämtades från patientregistret på Socialstyrelsen. Studie IV var en systematisk
genomgång och metaanalys som inkluderade publicerade randomiserade placebokontrol erade
läkemedelsprövningar av orlistat, sibutramin och rimonabant (n=13,457).
Resultat Studie I&II: Efter den nio veckor långa randomiserade fasen var interventionsgruppens
genomsnittliga kroppsvikt 20 kg lägre än kontrollgruppens, och medelvärdet för AHI var 23
uppehål /timme lägre. Totalt så fullföljde 70% (44/63) av al a deltagare den observationel a uppföljnings-
studien. Merparten av de initiala förbättringarna i AHI (-58%) efter ett år bibehöl s (-47%) efter den
initiala viktminskningen på 18 och 12 kg efter ett år. Studie III: Den absoluta risken för gallsten och
kolecystektomi var låg, men tre gånger högre i VLED än LED programmet (hasardkvot 3.4 och 3.1;
P<0.001). Medan riskerna för gal sten var större i VLED- jämfört med LED-gruppen så var
viktminskningen också större (11 vs 8 kg; P<0.001) och fler fullföljde studien (82% vs 78%). Studie IV:
Avhoppsfrekvensen från fetmaläkemedelsprövningar var hög både i läkemedels- (30-39%) och
kontrol grupperna (37%) men något lägre i läkemedelsgruppen (poolad riskkvot 0.9; P=0.001).
Slutsats VLED-inducerad viktnedgång resulterade i en signifikant reduktion av måttlig til svår OSA,
med majoriteten av den initiala förbättringen bibehål en efter ett år. Risken för gallsten var högre efter
VLED än LED, medan viktminskningen också var större i VLED-gruppen. Frekvensen behandlings-
avhopp var lägre i både det kliniska och det kommersiella viktminskningsprogrammet jämfört med
poolade data från kontrol grupperna i fetmaläkemedelsprövningar.
8 ACKNOWLEDGMENT

I would like to thank,

My supervisor, Martin Neovius, for everything you have taught me; for always being available regardless
the time of the day (and night); for the uncountable hours and endless commitment; for always pushing
me and for never letting me give up. Simply lots of thanks for being a fantastic main supervisor.
Erik Hemmingsson, co-supervisor, for al your support and encouragement; for never being further away
than a phone cal and for al the inspiring discussions.
Stephan Rössner, co-supervisor, for always believing in me; for always saying your opinion; for your
extremely rapid response in proof-reading; for making the OSA-study happen; and finally for your
humour and fun discussions.
Finally to al my supervisors for believing in me and al owing me to take responsibility; for placing high
expectations on me while at the same time giving me al the help I ever needed. Thank you for four
wonderful years.
Kristian Neovius for sharing the PhD-student time with me; for being a fantastic friend ever since we
shared office at the Obesity Unit; for al the fun discussions; for al your help and support with
everything from KI-forms to bicycle repairs to cooking.

Anna Laumann, Jenny Dygve and Sara Yl ö, for the fantastic years at the Obesity Unit; for all the laughter;
for showing the importance of having a calendar; for putting up with me when I did not have the time
for coffee breaks or anything else; for making work a wonderful place; and finally for being fantastic
friends ever since that time.
Lena Mannström for all the lovely discussions; for always having the time for me and helping me when
everything was new; for giving me a hand with everything from paper jams to study-planning and of
course for doing an excel ent job in the OSA-study.
Jonas Eriksson for al your SAS support. It is a true honour to share office with a human SAS-
encyclopaedia; and for al the inspiring cross-country skiing discussions.

Viveca Petré for help with everything from administration to study-planning and for al the nice chats
during the years at the Obesity Unit.

Mary Hyl for al the interesting discussions and for excellent proof-reading of manuscripts.

Richard Harlid for great collaboration in the OSA-study; for al your hard work with everything from
patient inclusion to manually reviewing al the sleep data; for delivering the data under time pressure;
and final y for all your help, guidance and patience with al my questions about sleep apnoea.
Ylva Trol e Lagerros for interesting research discussions and help with the OSA-study.
Al col eagues at the Obesity Unit, Huddinge, for making the time so fun and educational. A special thanks to Lena Mannström, Jenny Dygve, Mary Hyl , Ylva Trol e Lagerros, Viveca Petré, Anna Laumann and Sara Yl ö for your hard, dedicated and thorough work in the OSA-study. The staff at Aleris Fysiologlab, for performing the sleep studies. The study patients in the OSA-study for participating in the study. Fredrik Granath for statistical expertise. Birgitta Thörn, Itrim, for al the work with the data extraction in the commercial weight loss study. Johan Sundström and Claude Marcus for co-authorship, great comments and new ideas. Friends and Family, To Johanna, my oldest friend, for making me somewhat more spontaneous and for your support throughout al years. Astrid, my "big sister", for always guiding me and helping me see things from new perspectives; for your endless encouragement and support; and for always giving me your honest opinion. Anna for always being there for me; always supporting me; and for always reminding me to take care of myself when I become absorbed in work or other projects. Last but not least, to my family, to Björn for your patience, endless support and encouragement; for always believing in me and my abilities; and for putting up with al my ideas and projects. To my parents, Agneta and Svante, for always encouraging me to do what I believe in and for your everlasting support. 9 REFERENCES
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