Cut the Waist

Cut the Waist

Illustrative photo for 'Cut the Waist'
The philosophy of Cut the Waist is to prevent obesity related ill health through education resources

Tailored approach to management: Pharmacotherapy

Introduction

Pharmacotherapy should be considered part of a comprehensive strategy of obesity management. Although it is clear that the key to long term weight management success is significant and sustained lifestyle modification, it is evident that even with the best professional support, a significant proportion of at-risk patients are unable to achieve significant weight loss to improve health. For these patients the choice of medical treatment versus surgical treatment of overweight and obesity should depend upon treatment goals and individual patient preference.

Following the European Medicines Agency (EMA) recommendation to suspend the marketing licence of sibutramine (Reductil) in January 20101, Orlistat (Xenical) is the only anti-obesity medication available for treatment of obesity in the European Union.

Anti-obesity pharmacotherapy should be used to support weight reduction following commitment to an ongoing lifestyle and behavioural change approach for those patients whose weight has reached a plateau or for those who are in need of adjunctive treatment to reach and their 5 or 10% weight loss target.

Pharmacotherapy may not be considered appropriate for extreme obesity BMI >50 where weight loss surgery is considered to be the treatment of choice. Similarly for people whose BMI is greater than 40, particularly in cases where there are associated co-morbidities such as type 2 diabetes, a surgical approach may be considered preferable to pharmacotherapy in view of more significant loss of excess body fat and higher rate of resolution of associated co-morbidities.

It is useful to consider the medical management of overweight and obesity using orlistat within the context of the following objectives:

  1. Evidence of effectiveness of treatment supporting clinically significant 5-10% weight loss
  2. Evidence of effectiveness of treatment to prevent obesity co-morbidities
  3. Evidence of effectiveness of treatment to improve patient outcomes
  4. Evidence of effectiveness of treatment to resolve obesity co-morbidities

1 Evidence of medical treatment supporting significant weight loss

Pooled data from 16 clinical trials lasting one year or longer and involving a total of 10,631 patients reported that orlistat reduced weight by an average of 2.9kg more than placebo. Orlistat was demonstrated to increase the percentage of patients achieving 5% weight loss by 21% and those achieving and 10% weight loss by 12%2.

2 Evidence of medical treatment preventing co-morbidities

The Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) trial involved randomising over three thousand people at risk of developing type 2 diabetes with BMI >30 to either orlistat or placebo.

Of the 1410 people who completed the four-year trial, the average weight loss for people in the orlistat treated group was 2.8kg greater than those in the placebo treated group.

Graph: Orlistat effect on body weight: Completers (XENDOS)

At the end of the trial period, the risk of developing type 2 diabetes was significantly lower in the orlistat treated group than in the placebo treated group (6.2% versus 9.0% incidence of type 2 diabetes respectively). This represents a 37% reduction in risk of progression to type 2 diabetes over 4years following treatment with orlistat in patients at risk of developing this condition.

Graph: Effect of orlistat on development of type 2 diabetes (XENDOS)

The XENDOS trial results should be considered within the context of other Type 2 diabetes prevention trials such as the American Diabetes Prevention Programme (DPP). The DPP randomised patients with pre-diabetes to either placebo or to the diabetes medication metformin 850mg twice daily, or to lifestyle. Metformin reduced risk of progression to Type 2 diabetes by 31% over 2.8 years – making metformin slightly less effective at diabetes prevention in the DPP than orlistat in the XENDOS trial. However, the most effective intervention in the DPP was lifestyle rather than drug therapy. A lifestyle approach reduced risk of progression by 58%3. This significant 58% reduction in progression with lifestyle intervention was replicated in the Finnish Diabetes Prevention Study over a four year period4.

Neither Orlistat nor metformin has a licence for diabetes prevention. However, following the XENDOS study results, orlistat may be considered for obese patients who have pre-diabetes/non-diabetic hyperglycaemia in order to reduce the risk of progression to frank type 2 diabetes. Clinicians and patients should be aware that lifestyle intervention is more effective than medication in reducing risk but mindful that many at-risk patients have significant difficulties with weight management.

3 Evidence of medical treatment improving patient outcomes

Orlistat

Other than the XENDOS trial which demonstrated a reduction in progression to type 2 diabetes in at-risk patients treated with Orlistat, there are no other outcome data to demonstrate reduced morbidity or mortality with Orlistat treatment. Although we can hypothesize that weight loss reduced risk of many chronic diseases, we cannot say for sure whether an average weight reduction of 2.9kg achieved at one year with orlistat would translate into a reduction in cardiovascular events such as heart attack over a longer time frame as this specific outcome data for orlistat does not exist.

We are able to report that Orlistat treatment is associated with significant reductions in several markers of cardiovascular disease such as total cholesterol, LDL-cholesterol, BMI and waist circumference which would suggest a potential benefit in reducing cardiovascular disease. However concentrations of protective HDL cholesterol are slightly lower with Orlistat treatment. This may be considered an adverse effect of treatment making it difficult to predict whether Orlistat might have cardiovascular benefit with longer term use.

Orlistat treatment is associated with significant reductions in fasting plasma glucose and HbA1c, in keeping with the XENDOS diabetes prevention results and may suggest a place for Orlistat in the management of the overweight or obese patient with type 2 diabetes.

4 Evidence of medical treatment resolving obesity related co-morbidities such as Type 2 diabetes and Obstructive Sleep Apnoea (OSA)

Anti-obesity medications such as orlistat are not efficacious enough to have a significant impact in resolving obesity-related co-morbidities such as type 2 diabetes, and obstructive sleep apnoea.

Resolution of established type 2 diabetes generally requires weight loss in excess of 15% body weight. Weight loss in the order of magnitude necessary to resolve obesity related co-morbidities such as type 2 diabetes is difficult to achieve with medication.

In contrast to anti-obesity medication, weight loss surgery is known to have a significant impact in resolving type 2 diabetes and other obesity-related co-morbidities.

Weight loss surgery is associated with a 50-60% reduction in excess body fat and as a direct result of this more significant reduction in body weight, weight loss surgery resolves type 2 diabetes in 70% of cases. In addition, weight loss surgery is now known to be associated with a 50% reduction in mortality when comparing outcome data for those patients who made the decision to opt for surgery, in relation to age and weight-matched controls who made the decision to decline surgical treatment offered as a potential weight management strategy.

There is presently no direct evidence that a reduction in mortality is associated with any medical treatment for obesity.

Prescribing considerations:

BMI cut-off criteria

Orlistat is licensed for use in adults who have a BMI>28kg/m2 with associated risk factors such as type 2 diabetes or dyslipidaemia, or adults who have a BMI>30 g/m2.

Mechanism of action & appropriate patient selection

Orlistat

Orlistat reduces dietary fat absorption in the small intestine by 30% by blocking the fat-digesting enzyme intestinal lipase. Orlistat is prescribed as 120mg capsules to be taken three times daily with (or up to one hour after) meals. A 60mg capsule is now available for over the counter purchase from pharmacies.

Prior to considering Orlistat, patients should demonstrate commitment to a low fat diet (less than 30% of calories taken as fat). This will allow patients to tolerate orlistat. Failure to adhere to a low fat diet whilst taking this medication will lead to side effects such as faecal urgency, oily spotting and anal leakage as a result of passing an excess of unabsorbed dietary fat in the stool. 15-30% of people report experiencing these symptoms in most studies.

Orlistat may be considered particularly suitable for patients who have gained excess weight as a result of difficulty controlling portion sizes, exhibiting a tendency to eat three large regular meals each day. Fat absorption can be reduced from these three meals by taking Orlistat. It follows that Orlistat is less suitable for patients who gain weight as a result of grazing throughout the day. Orlistat can be useful in helping patients to identify high fat foodstuffs which generate “biofeedback” as a result of increased faecal fat excretion. Patients should then be aware of the high fat foodstuffs to avoid whilst taking this medication.

Failure to counsel patients adequately regarding the need to reduce fat intake whilst taking orlistat can lead to discontinuation of treatment or variable compliance as a result of unacceptable side effects as a result of ongoing excess dietary fat ingestion. Some patients will decide not to take medication when going on holiday or going out for a meal to enable them to tolerate a rather more rich diet on these occasions.

It is important that patients are appropriately supported following the introduction of Orlistat as a therapeutic strategy for weight management. The MAP programme (Motivation Advice and Proactive Support) offered as a free service by Roche to support patients prescribed Orlistat is felt by many patients to be of great benefit.

Length of treatment

When considering licensed use of anti-obesity mediation it is important to consider that obesity is recognised as a chronic disease by the World Health Organisation.

Orlistat

The product license for Orlistat does not specify a maximum duration of treatment. It is recommended that the decision to continue use orlistat for greater than one year should be made following re-assessment to determine appropriateness of continued use, usually for weight loss maintenance at this stage.

Contra-indications

Orlistat

Chronic malabsorption, cholestasis and pregnancy and lactation are contraindications.

For further information and full list of cautions and contraindications, see the Electronic Medicines Compendium entry.

Initiation and Monitoring requirements

Orlistat

Orlistat should commence at a dose of one 120mg capsule three times daily with meals.

An over the counter 60mg capsule (alli) is available for use at a dose of 60mg three times daily with meals.

Reduced fat absorption with orlistat does increase the risk of fat-soluble vitamin deficiency (vitamin D, E and beta-carotene). Daily fat soluble vitamin supplementation is therefore recommended. Supplements should be taken between meals (2hours before of after orlistat ingestion).

Failure to respond and discontinuation of treatment

Orlistat

Treatment should be discontinued after 3 months if patients have been unable to lose at least 5% of their body weight as measured at the start of therapy.

Patient support

Following the prescription of orlistat it is important that patients are made aware of the associated support programme provided by Roche. The programme provides good practical advice and support designed to help patients achieve their weight management goals.

Many patients find these free services very helpful.

Orlistat (Xenical)
www.xenicalmap.co.uk

References

1. Further details regarding the EMA decision may be accessed via the following links: Press release and Questions and answers on the suspension of medicines containing sibutramine

2. Rudcker D, Padwal R, Lis SK, et al. Long term pharmacotherapy for obesity and overweight; updated metaanalysis. BMJ 2007; 335: 1194-9.

3. Diabetes Prevention Program Research G. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403

4. Tuomilehto J, Lindstrom J, Erriksson J, Valle T, Hamalainen H. Prevention of type 2 diabetes mellitus by changes in lifestyle amongst subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343-1350