Download Orlistat

ANTI OBESITY PRESCRIBING
19th November 2013
V.Welch
Reduction in choice of medicines
• Orlistat - Xenical® - Roche - licensed July 1998
Patent finished 2007(NICE -March 2001, Dec
2006)
• Rimonabant - Acomplia ® licensed June 2006
(NICE – June 2008) – licence suspended
October 2008, Licence withdrawn September
2009
• Sibutramine –Reductil® - Abbott – Licensed Jan
2004 (NICE -Oct 2001, Dec 2006), EU Licence
withdrawn Feb 2010.
Orlistat
• Xenical® ( Roche) 120mg
• Orlistat – 120mg (Generic)
• 84 tablets in blister pack - 28 days
£31.63 BNF Sept 2013
• Alli ® P – OTC 60mg (GSK) April
2009
Orlistat
Orlistat -intestinal fat absorption
inhibitor
• Orlistat - lipase inhibitor ( pancreatic and
other) , active ingredient lipostatin.
• Reduces the absorption of dietary fat ~ 30%
• It is the only agent currently available in this
class.
• Side effects are related to malabsorption of
fat.
• Faecal incontinence and malabsorption of fat
soluble vitamins, such as vitamin A, D, E, and
K, have also been reported (McNeely 1998).
Safety of Orlistat
• MHRA monitoring since licensed in 1998
• 1,295 suspected adverse drug reactions
(ADRs)
• 20 reports linked to alli® (UK April 2009).
• MHRA - 137 suspected hepatic ADRs – 2
fatal
• Alli® - 1 x abnormal liver function tests
SIGN 115 - Feb 2010
A grade recommendation
• Orlistat should be considered as an
adjunct to lifestyle interventions in
the management of weight loss.
Patients with BMI ≥28 kg/m2 (with
comorbidities) or BMI ≥30 kg/m2
should be considered on an
individual case basis following
assessment of risk and benefit.
SIGN 115 - Feb 2010 (GPP)
•
Orlistat should only be used where
diet, physical activity and behavioural
changes are supported.
•
NHSGGC – prescribed only within
GCWMS
SIGN 115 - Feb 2010
• Used NICE 2006 guideline Data- TA
• Meta-analysis of 15 RCTs
• Orlistat (120 mg x 3 /day) with a weightreducing diet - more effective for weight loss
maintenance than placebo and diet at 12
months.
• Median weight loss
• 5.4 kg (range –3.3 kg to –10.6 kg) orlistat
• 2.7 kg (range –0.9 kg to –7.6 kg) for placebo
• 2.7Kg net weight loss orlistat
SIGN 115 - Feb 2010
Orlistat
▼ total cholesterol (0.3-0.4 mmol/l vs
diet alone at 12 months)
▼ %Hb1Ac (0.23% vs diet alone at 12
months)
▼systolic and diastolic blood pressure
compared to diet alone.
SIGN 115 - Feb 2010
Orlistat (120 mg 3 x day) (& lifestyle)
1) Significantly decreased the progression to
type 2 diabetes compared with placebo (&
lifestyle)
2) 37.3% decrease in the risk of developing
diabetes at four years - In people with
impaired glucose tolerance at baseline
3) 45% decrease in the risk of developing
diabetes at four years.
SIGN 115 - Orlistat (GPP)
• Therapy with orlistat beyond 12 weeks only if
the patient has lost at least 5% of their initial
body weight since starting drug treatment.
• Therapy should then be continued for as long
as there are clinical benefits (eg prevention of
significant weight regain).
• This may involve medication use outside
current licence.
• Ongoing risks and benefits should be
discussed with patients.
SIGN 115 - 2010
• less strict goals may be appropriate for
people with type 2 diabetes.
• Continue prescribing for longer than 12
months (usually for weight
maintenance) only after discussing
potential benefits and limitations with
the patient.
• Co-prescribing with other drugs for
weight reduction is not recommended.
Long-term pharmacotherapy for obesity and
overweight - Cochrane Review 2009
Padwal RS, Rucker D, Li SK, Curioni C, Lau DCW
• Review - long-term benefits and risks of antiobesity drugs
• Clinical trials of 1 to 4 years
• Sixteen orlistat trials included (n = 10,631),
• Compared with placebo, orlistat reduced wt
by 2.9 kg (2.9%)
• In patients with diabetes, orlistat reduced
weight by 2.3 kg (2.6%) compared to placebo
therapy*
*(Berne 2004; Hollander1998; Kelley 2002; Lindgarde 2000; Miles 2002).
Cochrane Review 2009
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The 16 trials * 10 631 participants (50 – 3305)
Average:-BMI 36.3 kg/m2
Weight 104 kg
Age 47 years
66% female
89% Caucasian.
In the XENDOS trial, the largest study, 21%
of patients had impaired glucose tolerance
*( Bakris 2002; Berne 2004; Broom 2002; Davidson 1999; Derosa
2003; Finer 2000; Hauptman 2000; Hollander 1998; Kelley 2002;
Krempf 2003; Lindgarde 2000;Miles 2002; Rossner 2000; Sjostrom
1998; Swinburn 2005; XENDOS).
Cochrane Review 2009
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4 orlistat weight maintenance studies*
Continuations of weight loss trials
Weight maintenance diet during 2nd Year
Orlistat and placebo
Similar amounts of weight regain
Weight differential preserved.
*(Davidson 1999;Hauptman 2000; Rossner 2000; Sjostrom
1998).
Cochrane Review 2009
• XENDOS - Largest and longest trial, 60%of
patients dropped out over the four year
follow-up period
• Most common reasons for premature
withdrawal - treatment refusal, loss to follow
up and adverse effects.
• Orlistat reduced the incidence of type 2
diabetes from 9.0% to 6.2% (XENDOS).
• This benefit was primarily observed in the
patients with impaired glucose tolerance at
baseline.
Fat Soluble Vitamins
• Levels of fat-soluble vitamins (A,D, E) and
beta-carotene were lowered by orlistat
therapy
• vitamin D most frequently affected*.
• No study reported the occurrence of clinically
significant vitamin deficiency, although
patients were routinely advised to take a
multivitamin pill daily.
*(Finer 2000;Hauptman 2000;Hollander 1998;
Sjostrom1998).
Is pharmacotherapy effective?
• The average amount of weight lost with
orlistat modest 2.9 Kg ( 2.3Kg if Diabetic)
• Realistic minimum weight loss goals of 5% to
10% should be set
• A minority of patients (10 - 20%) achieve
weight loss >10%
• ? predict which patients will lose >10%
• Drug therapy should be used in conjunction
with lifestyle modification.
Cost effective?
• Near-maximal weight loss was achieved by
three to six months in most trials
• Therapy should be discontinued at this point
if significant weight loss and/or improvement
in co morbidity has not occurred.
• NICE and SIGN – 5% wt loss at 3 month
period or therapy should be discontinued.
• Orlistat 120 mg Tid (£31.63 per 28 days) vs
simvastatin 20mg (91p per 28 days)
New Drugs
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Liraglutide (Victoza) Novo-Nordisk
Injectible GLP-1 receptor agonist
3 Phase III trials (SCALE)
1- Overweight and Obese patients
2 -Overweight & Obese T2DM patients
3 – Obesity patients with moderate to
severe obstructive sleep apnoea
Liraglutide
• Liraglutide is about £183/month vs.
£32/month for orlistat (120mg 3 times a
day)
• To file liraglutide 3 mg for regulatory
review as a treatment for obesity in the
US and EU around the turn of the year
• If successful: UK launch plans Q4 2014
New Drugs
• Lorqess – Venseca, selective serotonin
2C receptor agonist.
• Appetite suppressant ( Oral tablet)
• US licence (Schedule IV controlled
substance)
• EU and UK – company withdrew
submission for marketing approval
New Drugs
• Qnexa (Qsiva) - Phentermine /
topiramate (Oral Tablet) Vivus
• US licence,
• EU and UK –not recommended for
approval - issues relating to cardiac
safety.
New Drugs
• Contrave –(Naltrexone & Bupropion),
Orexigen
• Opioid receptor antagonist plus a selective
inhibitor of neuronal re-uptake of
noradrenaline and dopamine
• Oct 2013 Filed for EU and UK Licence
• ‘Light’ study interim analysis due Dec 13
• April 2011- 7.5% weight loss vs 2.5%
placebo over 1 year period
New Drugs
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Sodium Deoxycholate –Bayer HC
Adipolytic agent
Reduction of submental fat
Phase III clinical trials
• Ref: UKMI