The new NICE Technology Appraisal on Rimonabant for the treatment of overweight and obese adults1 represents a thorough and robust assessment of the clinical evidence surrounding the benefits to health versus the risks of taking rimonabant. The guidance approves rimonabant as an appropriate drug for use in obesity or overweight in particular groups of patients. In fact, this is an extremely positive appraisal that is both exciting and reassuring, paving the way for rimonabant to be used much more widely by clinicians.
The recommendations from NICE are that:1
- rimonabant should be used as licensed for adults who are overweight or obese, in addition to exercise and dietary modification, if orlistat and sibutramine have not induced an adequate response or are contraindicated, or if the patient is intolerant to those drugs
- response to treatment with rimonabant should be assessed at 6 months and should only continue beyond that period provided the patient has lost at least 5% of his or her initial body weight
- if weight loss stops and the person receiving treatment returns to their original weight, rimonabant should be stopped
- continued treatment with rimonabant depends on a formal clinical assessment being carried out within 2 years and the patient should be advised of the risks and benefits of the treatment.
The guidance reports the results of randomised controlled trials, which demonstrated the benefits of the drug over and above weight loss alone: ‘At 1 year, rimonabant had a statistically significant beneficial effect on systolic blood pressure, high density lipoprotein cholesterol, triglycerides and fasting plasma glucose in the diabetic and non-diabetic groups, and glycosylated haemoglobin (HbA1c) in the diabetic group.’
Discussion of side-effects
The NICE appraisal is particularly reassuring because it lays to rest some of the controversies surrounding rimonabant and the potential for serious psychiatric side-effects, partly by balancing them against the undoubted benefits of actively managing obesity, and partly by emphasising and assessing changes in the summary of product characteristics (SPC), which narrow the field of patients who are deemed appropriate for treatment with the drug. Patients with current depression, or a history of significant mental health problems are those most likely to run into problems with side-effects, and rimonabant is contraindicated in these cases. The inclusion of these contraindications in the SPC will flag up these patients in advance, thereby avoiding many of the most serious side-effects. Other less severe effects include possible nausea and vomiting, irritability, sleep disorders, and adverse effects on memory and attention.
Additional roles of rimonabant
Abdominal obesity is the key driver behind insulin resistance, metabolic syndrome, and type 2 diabetes, as well as being an important factor in heart disease, hypertension, and other serious chronic diseases. The modern generation of weight loss drugs should not be considered alongside their obsolete and discredited ancestors, not least because, rather than being mere reducing agents, drugs such as rimonabant have been shown to improve other cardiometabolic risk factors, including glycaemic control and lipid profile, over and above that which would be expected from weight loss alone.2
It is known that risk factors and disease processes cluster together under the umbrella of the metabolic syndrome, so it makes perfect sense to use this ‘smart bomb’ technology to modify these risks simultaneously. Obesity is the underlying cause, and therefore the obvious primary target. Obese individuals tend to have multiple risk factors, which are multiplicative rather than additive, therefore global risk modification in obese or overweight patients is one reason for therapy with rimonabant.
Another important role for rimonabant is in the management of diabetes in patients with a body mass index greater than 27. Three major studies were presented at the American Diabetes Association Conference in San Francisco in June 2008: Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT). Between them they concluded that:
- overintensive and too rapid reduction of glycosylated haemoglobin (HbA1c), using drugs such as insulin has its dangers. The intensive arm of ACCORD was stopped because of excess deaths,3 and the VADT and subsequent discussions with diabetologists have warned that significant hypoglycaemic episodes are the second biggest predictor of cardiovascular events, after age4
- careful reduction of HbA1c to lower targets is beneficial4
- no significant reduction in macrovascular risk was demonstrated,5 highlighting the importance of vigorous management of associated risk factors including cholesterol, waist circumference, smoking, and blood pressure
- reduction in microvascular risk was supported by evidence from the ADVANCE trial6
- intensive treatment was only seen to make a difference if it was started early in the course of disease.7
Step forward rimonabant to join the other anti-obesity agents and the newer hypoglycaemic agents such as sitagliptin and exenatide. Rimonabant fits exactly with the messages drawn from these trials, because it:
- rarely induces hypoglycaemia, (avoiding the pitfalls associated with insulin and insulin secretagogues)
- reduces HbA1c significantly,1 and is not contraindicated with other oral hypoglycaemic agents, allowing it to become part of a diabetes care pathway aimed at vigorous, but responsible lowering of HbA1c to stricter targets
- can be used early in the onset of disease, as it is licensed for use in obese patients over 30 kg/m2 or over 27 kg/m2 in the presence of other risk factors,1 even before diabetes develops, also in impaired fasting glucose1 and at any stage in the insulin resistance pathway associated with overweight or obesity
- helps to improve other risk factors associated with macrovascular risk—in particular abdominal obesity, systolic blood pressure, high density lipoprotein cholesterol, and triglycerides.1,2
Anti-obesity pharmacotherapy will never replace lifestyle measures, and nutrition and physical activity will always be the cornerstones of obesity management. However, there are many individuals, who have genuinely failed to lose weight through first-line measures, whose global risk is increasing and driving them towards overt disease. In addition, there are patients already suffering from overt co-morbidities of obesity for whom the management of obesity is logical and cost effective, and others whose excess weight is caused by drugs such as insulin8 and sulphonylureas.9
The Irishman Denis Burkitt, who described Burkitt’s lymphoma, likened the progression of disease to the fall off a cliff. As more and more people fall off cliffs, he hypothesised, the obvious answer is to provide more ambulances at the foot of the cliff to pick up the dead and injured, but the best answer is to build a fence at the top of the precipice.10 As people become more obese, we can observe them approaching the cliff edge; furthermore according to the QOF, primary care professionals are even incentivised to record their presence in the danger zone (by their inclusion on the obesity register) but not to stop them falling. We should use all appropriate measures to prevent overweight and obese individuals from dropping over the ‘cliff edge’ into diabetes, heart disease, stroke, cancer, and more, and these recommendations from NICE for the use of rimonabant will assist clinicians to do that.
- National Institute for Health and Care Excellence. Rimonabant for the treatment of overweight and obese adults. Technology Appraisal 144. London: NICE, 2008.
- Van Gaal L, Rissanen A, Scheen A et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365 (9468): 1389–1397.
- National Heart, Lung, and Blood Institute. For safety, NHLBI changes intensive blood sugar treatment strategy in clinical trial of diabetes and cardiovascular disease. http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2551
- Patel A; ADVANCE Collaborative Group, MacMahon S et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370 (9590): 829–840.
- ADVANCE Collaborative Group, Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358 (24): 2560–2572.
- Russell-Jones D, Khan R. Insulin-associated weight gain in diabetes—causes, effects and coping strategies. Diabetes Obes Metab 2007; 9 (6) 799–812.
- British National Formulary. March 2008. London: BMJ Publishing Group Ltd, Royal Pharmaceutical Society, 2008.
- Burkitt D. An approach to the reduction of the most common Western cancers. The failure of therapy to reduce disease. Arch Surg 1991; 126 (3): 345–347.G