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Dec 2006) • Rimonabant - Acomplia ® licensed June 2006 (NICE – June 2008) – licence suspended October 2008, Licence withdrawn September 2009 • Sibutramine –Reductil® - Abbott – Licensed Jan 2004 (NICE -Oct 2001, Dec 2006), EU Licence withdrawn Feb 2010.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
Improved Neurodevelopmental Outcomes Associated With Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula: A Randomized, Controlled Trial