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• Rimonabant - Acomplia ® licensed June 2006 (NICE – June 2008) – licence suspended October 2008, Licence withdrawn September 2009

• Sibutramine –Reductil® - Abbott – Licensed Jan 2004 (NICE -Oct 2001, Dec 2006), EU Licence withdrawn Feb 2010.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 weight-

reducing 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 anti-obesity 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

• 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

• 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

• 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

• Sodium Deoxycholate –Bayer HC

• Adipolytic agent

• Reduction of submental fat

• Phase III clinical trials

• Ref: UKMI