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 Issue No 26
January 2007         

Rimonabant▼ for obesity
A cholesterol target of <5mmol/l is national policy for statin prescribing
New from the National Prescribing Centre

Rimonabant▼ for obesity

Rimonabant▼ is an oral selective cannabinoid CB1 receptor antagonist that was recently licensed as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.¹ Earlier this year, the NPC published a New Medicine Alert on rimonabant.² Since, then two more studies have been published, which further define the evidence base.^3,4

RIO-diabetes was a one-year randomised controlled trial (RCT) that compared rimonabant with placebo in 1,047 overweight or obese patients (mean weight 96kg) with type 2 diabetes who had been taking metformin or a sulphonylurea for at least six months.³ After a two-week screening period, and four-week placebo run-in period, participants took rimonabant 5mg, rimonabant 20mg or placebo once daily. In addition, they reduced their dietary intake by 600kcal/day and were advised to increase their physical activity from the start of the run-in period to the end of the study. One of the inclusion criteria for this study was poor diabetic control (i.e. HbA1C 6.5% to 10%). However, on average, patients were relatively well controlled at the end of the run-in period (mean HbA1C 7.3%).

At one year, patients taking rimonabant 20mg lost 3.9kg more weight (the primary endpoint) than those on placebo (P<0.0001). Also, 16.4% of patients on rimonabant 20mg lost >10% of their body weight compared with 2.0% of those taking placebo (P<0.0001). There were also some improvements in secondary endpoints, such as waist circumference, HbA1C and some other metabolic variables, with rimonabant 20mg. At one year, HbA1C fell by 0.6% with rimonabant 20mg, compared with a 0.1% increase in the placebo group (P<0.0001). The authors suggest that over half of this improvement was unrelated to the weight loss seen, and could be due to direct peripheral metabolic effects of the drug. However, the accompanying editorial suggests closer scrutiny of the data is necessary to confirm this.^3,5

A Cochrane Review of the one-year data from the four main obesity RCTs of rimonabant in addition to diet and exercise (including RIO-diabetes) has also been published.⁴ Patients (n=6,625) were overweight or obese and had additional cardiovascular risk factors (not necessarily type 2 diabetes). Each RCT followed a similar design to RIO-diabetes. The authors of the review concluded that rimonabant produces modest weight loss of approximately 5%, but they were concerned about the quality of studies; for example, the high drop-out rates (40% at one year when the trials were pooled).⁴ However, high drop-out rates are common in obesity studies.

The efficacy and safety of rimonabant has not been evaluated beyond two years. Pooled data from studies indicate that almost twice as many people discontinue rimonabant, compared with placebo, because of adverse events (13.8% vs. 7.2%). These consistently involved psychiatric disorders (8.5% vs. 3.2%), including depressed mood disorders and anxiety. Other common adverse events included insomnia, nausea, vomiting, diarrhoea and fatigue. All trials excluded people with a history of psychiatric disorders or with severe depression. Therefore, rimonabant is not recommended for patients with uncontrolled psychiatric disease, including major depression, or those on antidepressant medication.^1,2

Our previous conclusions about rimonabant still stand.² Obesity is a long-term problem and patients will need continued support to manage their condition. The manufacturer is providing a patient support programme for those initiated on rimonabant. However, it is still unclear whether weight loss is maintained in the long-term with, or without, ongoing rimonabant. Also, it is not clear whether the improvements seen with this drug translate into significant reductions in morbidity or mortality. The results from ongoing long-term outcome studies of rimonabant may help to clarify this issue further. In the meantime, as outlined in the recently published NICE guideline on obesity,⁶ lifestyle changes, such as diet and exercise are still the mainstay of obesity management.

References

1. Acomplia▼. Summary of Product Characteristics, June 2006. Accessed from www.medicines.org.uk on 20/11/06
2. National Prescribing Centre. Rimonabant (Acomplia▼). New Medicine Alert No. 2, July 2006. Accessed from www.npc.nhs.uk/new_drugs.htm on 10/11/06 (requires NHSnet connection)
3. Scheen AJ, Finer N, Hollander P, et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368:1660–72
4. Curioni C, André C. Rimonabant for overweight or obesity. Cochrane database of systematic reviews 2006, Issue 4. Art No.: CD006162. DOI: 10.1002/14651858.CD006162.pub2
5. Cleland SJ. Does rimonabant pull its weight for type 2 diabetes? Lancet 2006;368:1632–4
6. National Institute for Health and Clinical Excellence. Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children. NICE Clinical Guideline 43. December 2006. Accessed from www.nice.org.uk on 14/12/06

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A cholesterol target of <5mmol/l is national policy for statin prescribing

A recent statement from Professor Boyle, National Director for Heart Disease and Stroke,¹ points out that current national policy for lipid management and current targets for cholesterol levels are those recommended in the National Service Framework (NSF) for Coronary Heart Disease (CHD),² and not those recommended by the Joint British Societies' Guidelines (JBS2).³

The NSF for CHD (2000) laid down standards of care for the prevention and treatment of CHD.² It set a target for total cholesterol lowering of <5mmol/l (low-density lipoprotein cholesterol [LDL-C] <3mmol/l), or by 20–25% (LDL-C by 30%), whichever results in the lowest absolute level.^2,4

In December 2005, JBS2 recommended an optimal total cholesterol target level of <4.0mmol/l (<2.0mmol/l LDL-C).² However, NICE has yet to issue its guidance on lipid modification (due December 2007).⁵ Until then, the Healthcare Commission will expect the current NSF and NICE guidance to be delivered — not that of JBS2. The Quality and Outcomes Framework for 2007/2008 will continue to include a 5mmol/l target for total cholesterol.¹

The current cardiovascular disease (CVD) risk threshold for treatment of patients with statins is given in the NICE technology appraisal on statins (January 2006).⁶ Statins are recommended for all patients with existing CVD, and for primary prevention in those who have a >20% 10-year risk of developing CVD (equivalent to a >15% 10-year CHD risk). JBS2 guidelines recommend a similar threshold.²

NICE recommends initiating statin therapy with a drug with a low acquisition cost (taking into account required daily dose and product price per dose).⁶ Most patients will achieve the NSF target with a standard dose of simvastatin, and the evidence for more aggressive therapy is inconsistent. In the 4S study,⁷ total cholesterol levels were reduced by 28% on average with simvastatin 20mg daily over a 6-week period, and more than 70% of patients achieved a level of <5.2mmol/l using a dose of 20mg or 40mg daily within one year.⁷ In the IDEAL study,⁸ only 21% of patients receiving simvastatin 20mg daily had a total cholesterol level >5mmol/l after 24 weeks and required an increase in dose to 40mg daily. Over a median of 4.8 years, simvastatin 20/40mg was not associated with significantly more major coronary events than aggressive lipid lowering with atorvastatin 80mg (see MeReC Extra No. 21, March 2006). The future NICE guideline on lipid modification,⁵ which will include an analysis of clinical effectiveness and heath economics, should clarify the most appropriate lipid-lowering strategy for the NHS.

References

1. Boyle R. National policy on statin prescribing. Department of Health. November 7th 2006. Accessed from www.heart.nhs.uk on 15/11/06
2. Department of Health. National service framework for coronary heart disease: modern standards and service models. March 2000. Accessed from www.dh.gov.uk on 15/11/06
3. Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. JBS 2. Heart 2005;91(Suppl V):v1–v52
4. Boyle R. Letter. BMJ 2000;321:1083
5. National Institute for Health and Clinical Excellence. Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Scope. August 2005. Accessed from www.nice.org.uk on 15/11/06
6. National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events. Technology Appraisal 94. January 2006. Accessed from www.nice.org.uk on 15/11/06
7. Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–9
8. Pedersen TR, Faergeman O, Kastelein JJP, et al. JAMA 2005; 294:2437–45

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New from the National Prescribing Centre

Two new MeReC Bulletins are available on the NPC website at www.npc.co.uk/merec.htm. The first looks at current issues in contraception, including information on the effectiveness of different methods, and the risks associated with use of combined oral contraceptives. The newer contraceptives, Evra▼, Yasmin and Cerazette, are also discussed, as is the recent NICE guidance on long-acting reversible contraception.

The second Bulletin looks at the management of common infections in primary care (common cold, sinusitis, acute otitis media, sore throat, cough, and urinary tract infection). It considers which patients may benefit from antibiotic therapy, either because their symptoms are probably due to bacterial infection rather than viral infection, or because they are at risk of complications from the infection. The evidence to support antibiotic treatment, symptomatic treatment, and delayed prescriptions is discussed.

A New Medicines Alert on varenicline▼ is also available at www.npc.nhs.uk/new_drugs.htm. This provides a brief summary of relevant information on this smoking cessation aid, and can be used to inform practitioners, commissioners and others of key issues. NHSnet connection is required to access this publication.

To provide support for continuing professional development and local implementation of the evidence base, a range of education and implementation resources, such as slide sets, case studies and learning quizzes, are being produced by the NPC. The first materials cover statin prescribing and are now available at www.npc.co.uk/statins.htm. Hypertension resources will also be published shortly.

Register at www.npc.co.uk/merec.htm to receive an email alert when a new MeReC resource is added to the NPC website.

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The National Institute for Health and Clinical Excellence (NICE) is associated with MeReC Publications published by the NPC through a funding contract. This arrangement provides NICE with the ability to secure value for money in the use of NHS funds invested in its work and enables it to influence topic selection, methodology and dissemination practice. NICE considers the work of this organisation to be of value to the NHS in England and Wales and recommends that it be used to inform decisions on service organisation and delivery. This publication represents the views of the authors and not necessarily those of the Institute.

NPC materials may be downloaded / copied freely by people employed by the NHS in England for purposes that support NHS activities in England. Any person not employed by the NHS, or who is working for the NHS outside England, who wishes to download / copy NPC materials for purposes other than their personal use should seek permission first from the NPC.
Email: copyright@npc.nhs.uk Copyright 2006

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