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Where are we now: Treatments for obesity

GPs have been bombarded with new obesity treatments in recent years. Now the evidence has had time to bed in, Dr David Haslam gives an overview of what they can do

The controversy

Some of the most toxic compounds known to man have been used as drugs to combat excess weight: mercury, arsenic, strychnine and the metabolic poison dinitrophenol. In the 1930s, following the introduction of benzadrine to treat narcolepsy, similar compounds – amphetamines – were introduced to manage obesity. Undoubtedly effective as reducing agents, and backed by massive advertising campaigns, amphetamine use and abuse soared. In the 1950s they were even given as combination drugs alongside barbiturates, introduced to offset amphetamine-induced ‘jitters'.

It eventually became clear that the drugs were addictive, abusable, and had potentially fatal side-effects including heart valve defects and primary pulmonary hypertension. The weight loss they induced was short term, and rapidly regained, and even those related drugs that can still be used on a named-patient basis in the UK (by dodgy and outrageously expensive slimming clinics), have no place in the long-term management of obesity.

Unfortunately, however, modern anti-obesity agents have been tainted by the memory of their discredited predecessors even though a huge portfolio of major trials proves their tolerability and efficacy, not only as weight loss agents, but also as cardiometabolic risk modifiers.

Differing expectations

There is a major discrepancy between the patient's expectations surrounding obesity drugs and those of their physician. Obese individuals may be desperate to lose weight for a holiday or wedding, and require quick-fix remedies that take away the need to diet or be physically active, resulting in ‘ideal body weight'.

Many quack remedies, including those sold over the internet, assure users that excess fat will simply ‘melt away', and amphetamine-related agents achieved exactly that, but only in the short term, and with horrific consequences.

Physicians prefer slow, gradual weight loss, at 1-2lb per week, with the aim of 5-10% weight loss, for reasons of health improvement, and risk modification – precisely what modern drugs confer.

Who to treat – and why

First-line treatment of overweight and obesity will always centre upon nutritional and activity advice. Drugs are only appropriate when initial remedies have proved inadequate, and should always be an adjunct to lifestyle changes, and prescribed according to NICE guidelines.

The ideal candidate for weight loss drugs is an overweight or obese individual with co-existent diseases or risk factors; the person whose cardiometabolic risk is raised, and can be successfully modified by treatment. Recent JBS guidelines remind primary care that a person without overt disease, but with multiple borderline risk factors equates to a high-risk individual.

It is not acceptable to manage a patient with borderline blood pressure conservatively, by repeated measurements, if they also have borderline cholesterol, glycaemic control or abdominal obesity.

Visceral fat is a risk factor in its own right, and, in combination with the classical risk factors such as smoking and hypercholesterolaemia, especially hypertriglyceridaemia, identifies the individual who should be targeted with drugs.

The diabetes context

The other group of patients for whom anti-obesity drugs are strongly indicated is those with obesity in association with overt comorbidities. There is a strong argument to be made that, rather than adding another hypoglycaemic agent, antihypertensive, or cholesterol lowering drug, that obesity itself – often the underlying cause of disease – should be targeted.

For example, once metformin has been prescribed for newly diagnosed type 2 diabetes, the race for second-line treatments is close-run. Sulphonylureas induce rapid but brief improvements in glucose metabolism: thiozoledinediones and insulin induce impressive glycaemic benefits, but cause significant weight gain: GLP mimetics induce weight loss alongside impressive glycaemic improvements, but require injections, and induce nausea, at high financial cost: and DPP-4s, while modestly improving glucose control, are weight neutral. Orlistat, sibutramine and rimonabant all induce weight loss alongside improvements in glycaemic control.

Viewed with an eye towards GMS QOF targets, HbA1c reduction is important in achieving audit targets, but more importantly, reducing HbA1c to below 7% reduces the risk of microvascular complications of diabetes; blindness and renal disease.

Orlistat

Orlistat, a pancreatic lipase inhibitor, was the first modern agent to be introduced, and acts by preventing the absorption of 30% of the fat ingested in the diet. The major trial is the Xendos study1, which demonstrated, in addition to weight loss, a 37% reduction in the cumulative incidence of type 2 diabetes over four years in patients with impaired glucose tolerance.

Sibutramine

Sibutramine – a centrally acting drug affecting the serotonin-noradrenaline system – was the next to be introduced, and like orlistat, shows benefits over and above weight loss alone. The major sibutramine weight loss study is the STORM trial2, which also demonstrated improvements in lipid profile and HbA1c.

The results of the sibutramine SCOUT trial are eagerly awaited, to see for the first time whether the assumed reduction in cardiovascular events and premature mortality actually occurs with weight loss. Contrary to popular opinion, the preliminary results from the lead-in to the study reveal that, in hypertensive patients, blood pressure is reduced with sibutramine.

Rimonabant

Rimonabant relied on a series of RIO (rimonabant in obesity) trials to prove its efficacy and tolerability prior to its launch in July 2006. The RIO trials demonstrated effective weight loss, and reduction in waist circumference, alongside improvements in lipid profile and glycaemic control.

According to the Serenade study, rimonabant reduces HbA1c by 0.9% – the amount expected by the introduction of any new hypoglycaemic agent. Furthermore, in the cohort of individuals whose HbA1c at baseline was 8.5% or more, the reduction was an impressive 1.9%.

Rimonabant has recently hit the headlines because concurrent antidepressant use and mental health disorders have been upgraded from warnings to contraindications. There is no question that rimonabant causes mood alteration in a small minority of cases; sometimes described by patients as irritability or boredom; but overt depression is rare, suicidal ideation much rarer still. However, it is perfectly reasonable to exclude such individuals from treatment, as they were excluded from most of the trials, and it is inappropriate to induce mood changes in an already depressed individual.

Each person should be considered on their own merits, both in terms of the possible benefits in cardiometabolic risk they may derive from treatment, but also the risk profile they offer.

Long-term management

As with traditional hypoglycaemic agents, and other drugs that manage chronic conditions, weight loss agents only work while the drug is being continued. On stopping, weight regain will tend to occur, unless sustainable lifestyle changes have occurred during the spell on medication, but rather than implying some inadequacy in the drug, the opposite is true; however successful a drug may be, it only works if it is being taken.

There is a valid argument to be made that treatment should be long term, especially in those individuals with overt disease such as type 2 diabetes, and in the cases of orlistat and rimonabant, this is allowed for in the drug's licence.

It is extremely difficult to ensure that patients adhere to long-term lifestyle change, as they live in an environment that promotes the exact opposite. All three anti-obesity agents have excellent patient support programmes, which use literature, web-based material and phone lines to promote lifestyle change.

As many members as possible of the primary care team should be involved in promoting and maintaining healthy living.

Surgery

Bariatric surgery – the collective name for operations intended to induce weight loss – is among the most clinically effective and cost-effective procedures in any field of medicine. About 90% of patients with type 2 diabetes who undergo bariatric surgery have their diabetes cured. Procedures pay for themselves within three years, due to reduced prescribing costs associated with the reduction in comorbidities.

NICE has deemed the procedures, including laparoscopic banding and gastric bypass operations, to be appropriate, and even recommends that for patients with a BMI of >50, surgery should be first line, ahead of even diet and lifestyle measures.

There is therefore a legal obligation for PCTs to provide funding for surgery, although the vast majority of PCTs still attempt to ban procedures. Primary care should be aware of the massive and permanent health benefits resulting from surgery, alongside the huge financial savings induced, and should be prepared to remind PCTs in emphatic terms of their legal requirements.

Dr David Haslam is a GP in Watton-at-Stone, and clinical director of the National Obesity Forum.

Competing interests Dr Haslam does advisory work for Roche, Abbott, Sanofi, GSK, Pfizer and MSD, as well as other companies including those in the surgery, food and activity industries. He has also provided submissions for QOF, NICE, Department of Health and health select committees

Key points

• Recent JBS guidelines remind primary care that a person without overt disease but with multiple borderline risk factors equates to a high-risk individual.
•There is a strong argument to be made that, rather than adding another hypoglycaemic agent, antihypertensive or cholesterol-lowering drug, that obesity itself – often the underlying cause of disease – should be targeted.
•The results of the sibutramine SCOUT trial are eagerly awaited, to see whether the assumed reduction in cardiovascular events and premature mortality actually occurs with weight loss. Contrary to popular opinion, the preliminary results from the lead-in to the study reveal that, in hypertensive patients, blood pressure is reduced with sibutramine.
•There is no question that rimonabant causes mood alteration in a small minority of cases; sometimes described by patients as irritability or boredom; but overt depression is rare and suicidal ideation much rarer still.
•For patients with a BMI of >50, NICE recommends surgery should be first line, ahead of even diet and lifestyle measures.

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