Download Current drugs for weight loss

Short report
Current drugs for weight loss
Orlistat is the only weight loss drug
currently licensed in the UK. Outside
the UK, there are now four other
agents approved for weight loss.
Dr Kate Millar and Dr Ruth
Poole here review the evidence
regarding the comparative efficacy
and adverse effects of the five
different drug treatments.
Background
According to WHO data, the global
prevalence of obesity has doubled
between 1980 and 2014. By 2014, 39%
of the world’s adults (1.9 billion indiv­
iduals) were overweight and 18% were
obese (600 million individuals).1 As
well as being a major risk factor for
type 2 diabetes (T2DM), overweight
and obesity contribute to morbidity
and mortality from cardiovascular dis­
ease, osteoarthritis and some cancers
such as endometrial, breast and colon.
Excess weight now leads to more deaths
than malnutrition worldwide.1 The
reasons for this increase are complex.
Easy access to energy rich foods and
decreased activity have been recog­
nised for many years2 but more recent
evidence suggests that gut microbia,
epigenetic mechanisms, increasing
maternal age, greater fecundity among
people with higher adiposity, and endo­
crine disrupting chemicals may all be
having some effect.3
Lifestyle modifications are gener­
ally ineffective for weight loss in the
long term due to the body’s adapta­
tions to lower energy expenditure in
response to reduced calorific intake
and the high levels of motivation
needed to sustain significant changes.
Even in clinical studies where patients
are highly motivated, initial weight
loss is followed by gradual weight
regain.4 Equally, bariatric surgery is
invasive and potentially dangerous. As
more research has allowed a greater
understanding of the pathways and
signalling involved in regulating
metabolism and appetite, this has
fuelled interest into new potential
therapeutic targets. The use of phar­
macological agents for weight loss has
historically been associated with sig­
nificant side effect burden and safety
concerns. Fenfluramine, a serotonin
increasing anorectic, was withdrawn
from the market in 1997 after being
PRACTICAL DIABETES VOL. 33 NO. 7
shown to cause potentially fatal pul­
monary hypertension and cardiac
valvulopathy. Rimonabant, a selective
cannabinoid receptor blocker, was
withdrawn in 2008 because of serious
psychiatric side effects including risk
of suicide. Sibutramine, a serotonin–
norepinephrine reuptake inhibitor,
was withdrawn in 2010 because of its
association with increased cardiovas­
cular events and strokes.
Orlistat is the only weight loss drug
currently licensed in the UK. It works
by inhibiting pancreatic lipases and
thereby decreasing dietary fat absorp­
tion and increasing faecal fat excre­
tion. Weight loss in the first year of
treatment is around 5–10kg,5 and this
has been shown to be maintained over
four years with continued use.6 Orlistat
reduces the risk of developing diabetes
in obese patients with impaired
glucose tolerance by around a third.6
In patients with diabetes, orlistat has
been demonstrated to reduce HbA1c
by 0.6% (7mmol/mol) over 52 weeks.7
It has also been shown to improve
blood pressure and serum lipids
beyond expected levels from weight
reduction alone.8,9 Between 15–30%
of patients experience gastrointestinal
(GI) side effects associated with
orlistat; generally these improve as
patients learn to avoid high fat diets.
Absorption rates of fat soluble vitamins
A, D, E and K are lowered with orlistat
therapy (vitamin D in particular) and
supplements should be considered.
Here we review four new weight loss
drugs: lorcasarin (Belviq), high dose
liraglutide (Saxenda), naltrexone/
bupropion (Contrave or Mysimba) and
phentermine/topiramate (Qsymia).
We review their efficacy and their
adverse effects. Saxenda is adminis­
tered by subcutaneous injection while
Belviq, Contrave and Qsymia are all
oral tablets.
or obstructive sleep apnoea. It is not
currently licensed in the UK.
A multicentre placebo-controlled
trial of lorcaserin found that at one
year 47.5% of patients in the lorcaserin
group had lost 5% or more of their
body weight compared to 20.3% in the
placebo group (p<0.001) This corre­
sponds to a 3–4kg difference in weight
loss between the two groups. They also
showed that in year two weight loss was
more likely to be maintained if they
continued on lorcaserin rather than
switching to placebo.10
A trial looking at the efficacy of
lorcaserin for weight loss in patients
with T2DM randomised patients to
lorca­serin 10mg once a day, 10mg twice
a day or placebo. Patients were being
treated with metformin, a sulphonyl­
urea or both. At one year, there was no
difference in weight loss between the
two active treatment groups, but both
had lost three times more weight than
the placebo group (6% vs 2%) and
significantly more patients lost more
than 5% of their body weight on
lorcaserin (44.7% once-daily dose and
37.5% twice-daily dose) compared to
placebo (16.1%). There was also a sig­
nificant improvement in glycaemic
control with HbA1c decreasing 0.9% to
1.0% (10–11mmol/mol) in the lorca­
serin groups and 0.4% (4mmol/mol)
in the placebo group.11
Adverse effects of lorcaserin are
generally mild with headache, back
pain and naso-pharyngitis occurring
with greater frequency than compared
to the placebo group. Neuropsychiatric
effects were not significantly increased
in any of the trials. With regard to
concerns of serotonin-associated valvu­
lopathy, pooled analysis of the phase 3
trials showed that the rates of FDA
defined valvulopathy were 2.3% and
2.2% for patients taking lorcaserin or
placebo respectively.12
Lorcaserin (Belviq)
Lorcaserin is a selective agonist of the
serotonin 2C receptor which reduces
food intake by increasing satiety. It
was approved by the US Food and
Drug Administration (FDA) in 2012
as an adjunct to lifestyle interventions
for patients with BMI above 30kg/m2
or above 27kg/m2 with at least one
medical comorbidity such as T2DM
Liraglutide (Saxenda)
Liraglutide is an analogue of the
incretin hormone glucagon-like pep­
tide 1 (GLP-1) and has dual thera­
peutic benefits in terms of glycaemic
control and weight loss due to
enhanced postprandial insulin secre­
tion, delayed gastric emptying and
decreased food intake. Liraglutide is
established in Europe and America
COPYRIGHT © 2016 JOHN WILEY & SONS
229
Short report
Current drugs for weight loss
as a treatment option for patients
with T2DM with BMI above 30kg/m2
or above 27kg/m2 with at least one
weight-related comorbidity at doses
of 0.6mg to 1.8mg daily, and is linked
to a significant reduction in weight
(2–3kg) when compared to placebo
or glimepiride.13 In the UK, liraglu­
tide can only be prescribed for
patients with a BMI above 35kg/m2
unless there are comorbidities, and
the maximum dose is 1.2mg daily.14
High-dose liraglutide (3mg) has
been licensed as a treatment for
weight loss in people without diabe­
tes in the US since September 2014
under the trade name Saxenda, but
is not yet licensed for this indication
in the UK.
There is evidence that liraglutide,
at the doses licensed for patients
with diabetes, is being used in the
UK for obese patients without dia­
betes. Twenty-two obese individuals
without diabetes attending a special­
ist obesity service were enrolled in a
12-month study to see if liraglutide
1.8mg could avoid bariatric surgery.
Fourteen completed the study
with a mean weight loss of 12.1kg.
Two participants withdrew because
of lack of efficacy, two because of
GI side effects and the rest failed
to complete the study as their
primary care funding of the treat­
ment was withdrawn.15
Other studies of the efficacy of
liraglutide for inducing weight loss
in those without diabetes have used
higher doses. In a 56-week dou­
ble-blind trial, 63.2% of patients
receiving 3mg liraglutide lost at least
5% of their body weight compared
to 27.1% in the placebo group.
Additionally, HbA1c, quality of life
and cardio-metabolic risk factors
all improved.16 A randomised con­
trolled trial comparing the efficacy
of liraglutide with that of orlistat
showed that patients taking the two
highest doses of liraglutide (2.4 and
3.0mg) lost significantly more weight
than those taking orlistat (6.3, 7.2
and 4.1kg, respectively).17
The SCALE diabetes trial looked
at the efficacy and safety of the higher
liraglutide 3.0mg dose in patients
with T2DM and found that at 56
weeks weight loss was 6.0% (6.4kg)
with 3.0mg dose, 4.7% (5.0kg) with
1.8mg dose and 2% (2.2kg) with
placebo. HbA1c significantly improved
230
PRACTICAL DIABETES VOL. 33 NO. 7
compared to placebo with treatment
difference of -0.93% (10mmol/mol)
in the 3.0mg dose group. Mean
systolic blood pressure was signifi­
cantly decreased (treatment differ­
ence -2.6mmHg) in the liraglutide
dose compared to placebo without a
dose effect. Liraglutide 3.0mg also
significantly improved levels of total
cholesterol, VLDL, HDL and triglyc­
erides compared with placebo.
Liraglutide was associated with a
mean heart rate increase of 2.0 beats
per minute compared to a reduction
of 1.4 beats per minute for placebo.
Given the improvements in the
other cardiovascular risk factors, the
long-term clinical relevance of this
is unclear.18
The higher dosages of liraglutide
are, however, associated with a higher
incidence of GI side effects. The 3mg
dose caused GI side effects in 77% of
participants and was the most com­
mon cause for cessation of treat­
ment. There were eight people in
the liraglutide groups who withdrew
(2.2%) because of nausea, and five
(1.3%; in the 2.4mg and 3.0mg
groups) because of vomiting. Nobody
in the placebo or orlistat groups
withdrew because of such events.17
Naltrexone/bupropion
(Contrave/Mysimba)
The combination of naltrexone and
bupropion was approved by the
FDA in September 2014 under the
trade name Contrave and in some
European countries in March 2016
as Mysimba. It is not currently
licensed in the UK. Bupropion stim­
ulates hypothalamic proopiomel­
anocortin (POMC) neurons while
naltrexone blocks opioid-mediated
POMC neurone auto-inhibition,
inducing satiety. Given their estab­
lished uses in addiction, it is also
postulated that this combination
may help modulate central nervous
system reward pathways.
Efficacy and safety of naltrexone/
bupropion combination therapy
were tested in the Contrave Obesity
Research (COR) studies. COR-I com­
pared two different doses of naltrex­
one (16 and 32mg) combined with
bupropion against placebo in 1742
participants.19 COR-II compared
naltrexone/bupropion 32/360mg
against placebo in 1496 partici­
pants.20 Primary endpoints in each
trial were percentage weight loss and
proportion of subjects achieving
more than 5% weight loss. All part­
icipants were either obese (BMI
30–45kg/m2) or overweight (27–
45kg/m2) with dyslipidemia and/or
hypertension. Both trials were con­
ducted over 56 weeks.
In COR-1, 48% of participants
assigned to naltrexone 32mg plus
bupropion had a decrease in body
weight of 5% or more compared
with 16% of participants assigned to
placebo. Mean reduction in body
weight was 6.1% in the naltrexone
32mg plus bupropion group versus
1.3% in the placebo group.19 Similar
results were seen in COR-II with a
6.1% weight reduction by week 56
in the naltrexone/bupropion group
against 1.2% in the placebo group,
and 50.5% achieved a 5% weight loss
compared to 17.1% of participants
on placebo.20
Side effects were common, par­
ticularly nausea, headache and con­
stipation. Drop-out rates were high
with only 54% of participants in
COR-II completing the study. In the
active treatment arm, this was due to
side effects while, in the placebo
arm, the same proportion of patients
withdrew due to insufficient weight
loss.20 Pulse and blood pressure were
not adversely affected.
The LIGHT study was conducted
to establish the cardiovascular safety
of Contrave. More than 8000 partici­
pants were randomised either to
naltrexone/bupropion or to placebo.
However, the trial was stopped early
after public release of confidential
interim data by the sponsor suggesting
a 40% reduction in major cardiovascu­
lar events in the naltrexone/bupro­
pion group.21 This was not confirmed
after further analysis, but cardiovascu­
lar safety was not established and
further evaluation is required.
Phentermine/topiramate
(Qsymia)
Phentermine is a centrally-acting sym­
pathomimetic and acts as an appetite
suppressant. As a single agent it is the
most frequently prescribed drug for
weight loss in the US where it is
approved only for short-term (up to
12 weeks) use because of its addictive
potential. Topiramate is an anti-epi­
leptic drug, also licensed for migraine
prophylaxis which has been noted to
COPYRIGHT © 2016 JOHN WILEY & SONS
Short report
Current drugs for weight loss
Weight loss
treatment
Current UK
licence
Mode of action
Weight loss
potential
Metabolic benefits
Side effects
Orlistat6,27
Yes
Inhibition of pancreatic lipase;
decreased absorption of
ingested fat
10.2% over
1 year
Reductions in total and LDL
cholesterol
Gastrointestinal
Lorcaserin10
No
Selective serotonin agonist;
increased satiety; reduced
food intake
5.8% over
1 year
Reduction in HbA1c in
patients with diabetes
Headache, back pain
and naso-pharyngitis
Liraglutide16,18,26
No
GLP-1 agonist; increased
satiety; reduced food intake
8% over
56 weeks
Reduction in HbA1c in
patients with diabetes;
reduction in blood pressure
and improved lipid profile
Gastrointestinal
Naltrexone/
bupropion19
No
POMC (proopiomelanocortin)
modulation; increased satiety;
reduced food intake
6.1% over
56 weeks
–
Nausea, headache
and constipation
Phentermine/
topiramate22
No
Centrally-acting
sympathomimetic; reduced
appetite; reduced food intake
9.8% over
56 weeks
HbA1c in patients with
diabetes; reduction in blood
pressure
Gastrointestinal,
neurological and
psychiatric
Table 1. Comparison of currently available weight loss treatments
have some weight loss effects. Qsymia
was approved as a combination treat­
ment in the US in 2012 but is not
licensed in the UK.
The benefits of low-dose Qsymia
were assessed in the CONQUER
trial. A total of 2487 patients
were randomised to phentermine/
topiramate at either 7.5/46mg or
15/92mg daily or to placebo; 20%
of participants had T2DM at study
entry. At 56 weeks, participants tak­
ing Qsymia had lost 8–10kg while
those on placebo had lost 1.4kg. Five
percent weight loss was achieved by
62% and 70% of participants in the
two active arms and in 21% of partic­
ipants taking placebo. There was a
mean decrease in systolic blood
pressure of 2.3mmHg compared to
placebo in the 7.5/46mg dose and
3.2mmHg in the 15/92mg group
following one year of treatment.
Among the 388 subjects with T2DM,
reductions in HbA1c from baseline
were 0.1% (1mmol/mol) for pla­
cebo compared to 0.4% (4mmol/
mol) with both doses of Qsymia.22
The SEQUEL trial was an exten­
sion of the CONQUER trial with par­
ticipants continuing on the same dose
of Qsymia or placebo for a further
52 weeks. Weight loss during the first
56 weeks in the Qsymia group was
maintained over a further 52 weeks.
Blood pressure was not different
between the groups although 13.1%
and 15.6% of patients in the two
PRACTICAL DIABETES VOL. 33 NO. 7
active treatment groups had reduc­
tions in their antihypertensive medi­
cations while 11% of participants
taking placebo had their antihyper­
tensive medications increased.23
The most common adverse effects
were dry mouth, constipation and
paraesthesia as well as a dose-related
increase in incidence of depression,
anxiety and attention difficulties. This
is further underlined as a study exam­
ining its use in the real world environ­
ment of a multidisciplinary weight
loss clinic noted an adverse event
cessation rate of 40% with neurologi­
cal side effects predominating.24
Discussion
As the prevalence of obesity and
related comorbidities continues to
climb, pharmacological interventions
for weight loss remain limited.
Overall, the usefulness of weight loss
medications are limited by side effects
which result in high drop-out rates
in medical trials as well as poor
compliance in real world prescribing.
In a population-based cohort, at one
year after prescription of orlistat or
sibutramine, less than 10% of patients
were still on their medication and
by two years only 2% continued on
either medication.25 A further diffi­
culty is that weight loss tends to slow
and then plateau with continued
treatment and the majority of patients
regain weight when their weight loss
drugs are stopped. However, it is of
interest that trials have shown that a
good initial response predicts longterm response and this underlines
not only the importance of assessing
responses within six months and
discontinuing treatment in those with
no measurable benefit, but also the
potential value of further investigat­
ing the characteristics/phenotype
associated with a good response. This
may allow for more personalised
treatments in the future.
Belviq, Saxenda, Contrave and
Qsymia have all been shown to be
effective for weight management
with the potential for weight loss of
between 5.8–9.8% of starting weight
over the first year of treatment (see
Table 1). However, none are more
effective than orlistat. There is also at
this stage a lack of long-term data
(more than two years) available for
the new medications discussed in
contrast to the established long-term
safety profile of orlistat.
These new weight loss drugs need
to be considered with caution. Each
has demonstrated significant bene­
fits for weight reduction but none
is without significant side effects.
Weight loss alone may be beneficial
for patient self-esteem and for
reduction in weight-related joint
disease and thrombo-embolic risk.
An ideal drug would also reduce the
metabolic complications of obesity
including glycaemia, blood pressure
and lipid profile and demonstrate
COPYRIGHT © 2016 JOHN WILEY & SONS
231
Short report
Current drugs for weight loss
significant reductions in cardiovascu­
lar endpoints. At this stage, some of
the new weight loss treatments have
demonstrated reductions in HbA1c,
blood pressure and cholesterol (see
Table 1), but until recently none
have shown reduction in myocardial
infarction (MI), stroke or mortality.
This has changed with the recent
publication of the LEADER trial.
In all, 9340 patients with T2DM and
high cardiovascular risk were ran­
domised to 1.8mg of liraglutide or
placebo. Over 3.8 years of follow up,
the primary outcome of death from
cardiovascular disease, non-fatal MI
or non-fatal stroke was 13% in the
liraglutide arm and 14.9% in the
placebo arm. Cardiovascular mortal­
ity was lower in the liraglutide group
than in the placebo group (4.7% vs
6.0%) as was total mortality (8.2% vs
9.6%). Differences in non-fatal MI
and stroke did not reach statistical
significance.26
Arguably the most exciting and
promising line of new pharmacolog­
ical treatments are those targeted at
gut hormones, given that research
has proven their role in regulating
appetite, metabolism, gut motility,
secretion and even acting as neuro­
transmitters. GLP-1 analogues have
paved the way towards developing
gut hormones as therapeutics but
have limited efficacy and dosedepend­
ent side effects. However,
other gut hormone pathways are also
yet to be exploited and new combi­
nations of hormone analogues are
currently being developed. This
includes peptide YY and pancreatic
polypeptide analogues which are
currently in phase 1 trials and hold
potential to deliver better appetite
suppression with fewer dose-depend­
ent side effects. Furthermore, the
use of agents to increase energy
expenditure alongside appetite sup­
pression is also under development
which would represent a big step
forward given that the body normally
counter regulates weight loss by
reducing energy expenditure and
thus limiting weight loss. The poten­
tial use of glucagon receptor agonists
in combination with GLP-1 in this
way could therefore lead to a much
greater weight loss than either pep­
tide could achieve alone. New com­
binations of gut hormone analogues
could thus mimic physiological
232
PRACTICAL DIABETES VOL. 33 NO. 7
processes to provide safe weight loss
at a comparable level to surgery and
this represents an exciting area of
investigation for pharmacological
agents in the future.
Conclusion
In the UK, orlistat remains the only
licensed weight reduction treatment
although, for patients with T2DM,
GLP-1 agonists such as liraglutide
already used for treatment of hyper­
glycaemia also benefit patients in
terms of weight loss. Whether the
increased side effects with the higher
dose as Saxenda will outweigh the
additional weight loss benefits in
clinical practice remains to be seen.
The possibility of alternative oral
medications such as Belviq, Contrave
or Qsymia in the UK will depend on
future studies of long-term efficacy
and any long-term harms found
during real world prescribing in the
US and Europe.
Kate Millar, MBChB, MRCP,
Speciality Registrar, Royal
Hampshire County Hospital,
Winchester, UK
Ruth Poole, DM, FRCP, Consultant,
Poole Hospital NHS Foundation
Trust, Poole, UK
Correspondence to: Dr Ruth Poole,
Poole Hospital NHS Foundation
Trust, Poole BH15 2JB, UK;
email: [email protected]
Declaration of interests
There are no conflicts of interest
declared.
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COPYRIGHT © 2016 JOHN WILEY & SONS