1. ANTI OBESITY PRESCRIBING 19 th November 2013 V.Welch

2. 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2001, Dec 2006) Rimonabant - Acomplia ® licensed June 2006 (NICE – June 2008) – licence suspended October 2008, Licence withdrawn September 2009 Sibutramine –Reductil® - Abbott – Licensed Jan 2004 (NICE -Oct 2001, Dec 2006), EU Licence withdrawn Feb 2010.

3. 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

4. Orlistat

5. 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).

6. 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

7. 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.

8. SIGN 115 - Feb 2010 (GPP) Orlistat should only be used where diet, physical activity and behavioural changes are supported. NHSGGC – prescribed only within GCWMS

9. 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

10. 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.

11. 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.

12. 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.

13. 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.

14. 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).

15. 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).

16. Cochrane Review 2009 4 orlistat weight maintenance studies* Continuations of weight loss trials Weight maintenance diet during 2 nd Year Orlistat and placebo Similar amounts of weight regain Weight differential preserved. *(Davidson 1999;Hauptman 2000; Rossner 2000; Sjostrom 1998).

17. 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.

18. 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).

19. 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.

20. 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)

22. 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

23. 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

24. 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

25. New Drugs Qnexa (Qsiva) - Phentermine / topiramate (Oral Tablet) Vivus US licence, EU and UK –not recommended for approval - issues relating to cardiac safety.

26. 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

27. New Drugs Sodium Deoxycholate –Bayer HC Adipolytic agent Reduction of submental fat Phase III clinical trials Ref: UKMI