Overweight and obesity are the second leading risk factors for ill health and death in Australia, second only to tobacco use. Excess weight is linked to 30 diseases, including some cancers, cardiovascular disease, and type 2 diabetes. It is responsible for 8.4% of the total disease burden and contributed to around 16,400 deaths in Australia in 2018.
The body mass index (BMI) is one tool that can be used to measure general adiposity. The BMI can be quickly calculated by dividing a person’s weight (kg) by their height (m). Some general classifications of weight according to BMI are shown in Table 1.
Table 1. Classification of weight according to BMI
|18.5 to 24.9||Healthy|
|25 to 29.9||Overweight|
|30 to 34.9||· Class I|
|35 to 39.9||· Class II|
|≥ 40||· Class III|
Some caution is required when interpreting BMI figures in individuals. The BMI is intended to be used in conjunction with other assessments to evaluate an individual’s health status appropriately. However, based on the latest available data, 67% of all Australian adults are living with overweight or obesity and 31% are obese. In addition, 60% of men and 66% of women have a waist circumference that indicates a substantially increased risk of metabolic complications.
Studies suggest that even modest weight loss (5-10% body weight) is associated with a significant improvement in overall health in people with obesity. While lifestyle modification is the cornerstone of weight loss strategies, this may be supplemented with weight loss medications in some cases. Medicines that are currently approved in Australia solely for the purpose of weight loss are orlistat, phentermine, naltrexone with bupropion, and liraglutide.
Orlistat is registered for the treatment of obese patients with a BMI of at least 30 in conjunction with a mildly hypocaloric diet. Orlistat may also be used in overweight patients with a BMI of at least 27 if other risk factors are present.
Orlistat is a selective and reversible inhibitor of gastric and pancreatic lipase activity. Lipases are important in the digestion of dietary fat, catalysing the hydrolysis of ester bonds in triglycerides. This leads to the production of free fatty acids and monoglycerides that can be absorbed. This process is impaired in the presence of orlistat, and the undigested triglycerides are not absorbed. At recommended doses, orlistat prevents the absorption of around 30% of dietary fat
Orlistat is available as 120mg tablets, which can be taken up to three times daily with meals. Doses should be administered during or up to one hour after the meal. Doses should be omitted if a meal is skipped or contains no fat.
As systemic exposure to orlistat is minimal, adverse effects are predominantly gastrointestinal in nature. Owing to its mechanism of action, orlistat leads to increased fat in the stool, which can produce diarrhoea and faecal urgency or incontinence. These effects can be minimised by reducing the fat content of the diet.
A vitamin supplement should be considered as orlistat may reduce the absorption of fat-soluble vitamins. If a supplement is used, it should be taken at least two hours before or after an orlistat dose.
Phentermine is a sympathomimetic amine that acts as an appetite suppressant. It is a central nervous system stimulant with major effects on the noradrenergic and dopaminergic nervous systems. The appetite suppressant effects are thought to be mediated through the hypothalamus.
Due to its stimulatory effect on the sympathetic nervous system, phentermine has a number of contraindications, including:
- Pulmonary artery hypertension;
- Existing heart valve abnormalities or heart murmurs;
- Moderate to severe arterial hypertension;
- Cerebrovascular disease;
- Severe cardiac disease including arrhythmias, advanced arteriosclerosis;
- Agitated states or a history of psychiatric illnesses including anorexia nervosa and depression;
- History of drug/alcohol abuse or dependence; and
- Concomitant treatment with a monoamine oxidase (MAO) inhibitor or within 14 days following their administration.
Common adverse effects include central nervous system (CNS) overstimulation, which may present as insomnia, restlessness, nervousness, or agitation. Cardiovascular effects are also common and may include arrhythmia, tachycardia, and hypertension.
Phentermine is administered as a once-daily dose. Due to its stimulatory effects, doses should be taken in the morning to prevent insomnia. Phentermine has a limited role in the long-term management of obesity and is recommended for short-term treatment.
Naltrexone with bupropion
Naltrexone is available in a fixed-dose combination with bupropion for the management of weight in adults with an initial BMI of 30 kg/m2 or more. It may also be initiated in adults with a BMI of 27 kg/m2 or more if a weight-related comorbidity is present, such as type 2 diabetes, dyslipidaemia, or controlled hypertension. It should be used as an adjunct to a reduced-calorie diet and increased physical activity.
The precise mechanism of action that leads to weight loss is not completely understood for this combination. Naltrexone is a mu-opioid antagonist that may block the effects of endogenous opioids. The pro-opiomelanocortin (POMC) cells of the hypothalamus produce melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, an endogenous opioid. Alpha-MSH activates the melanocortin-4 receptor (MC4R), which leads to reduced appetite and increased energy expenditure. Beta-endorphin inhibits the activity of POMC cells by binding to the inhibitory mu-opioid receptor.
Bupropion is a weak inhibitor of dopamine and noradrenaline reuptake. In vitro, it has been shown to enhance POMC cell production and release of alpha-MSH and beta-endorphin. When taken with naltrexone, the beta-endorphin inhibitory feedback on POMC cells is blocked. Therefore, this combination has synergistic effects on POMC signalling, producing greater effects on weight loss than either agent on its own.
Treatment is usually initiated with one tablet in the morning. The dose is then escalated over the following four weeks to a maintenance dose of two tablets twice daily.
Due to the opioid-antagonist properties of naltrexone, this medication should not be used in patients who are currently dependent on chronic opioids or patients in acute opioid withdrawal.
Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue. Other medications in this class are dulaglutide and semaglutide. In Australia, these medications are all registered for the treatment of type 2 diabetes, while liraglutide is also registered for weight management.
Glucagon-like peptide-1 has a range of actions in the body, including the glucose-dependent stimulation of insulin secretion, inhibition of glucagon secretion, delayed gastric emptying, and inhibition of food intake. As the half-life of GLP-1 is less than two minutes, modification of the peptide is required to allow an appropriate dosing interval. Liraglutide has an amino acid sequence that is 97% homologous to endogenous human GLP-1. Modifications of the liraglutide molecule slow its absorption and make it more stable against metabolic degradation. This increases its half-life to 13 hours following subcutaneous administration.
Liraglutide is administered once daily with an initial dose escalation period to improve tolerability. Gastrointestinal adverse effects are common, with up to 50% of patients experiencing nausea or vomiting at the start of therapy. Other common adverse effects include diarrhoea, constipation, dyspepsia, and injection site reactions. Hypoglycaemia may also occur, particularly if the patient is also taking insulin or a sulfonylurea.
Singh et al. (2020) conducted a meta-analysis to investigate the effect of anti-obesity medications on weight loss and other cardio-metabolic parameters. Medications compared included orlistat, phentermine plus topiramate, naltrexone plus bupropion, and liraglutide. In this study, phentermine was administered as part of a fixed-dose combination with topiramate. This product is not registered for use in Australia.
The meta-analysis found that the weight-lowering potential of these agents was greatest for phentermine plus topiramate, followed by liraglutide, then naltrexone plus bupropion, and lowest for orlistat. Compared to placebo, the weight reduction for each agent is shown below (all p < 0.00001):
- Phentermine plus topiramate 9.77 kg (95% CI: 11.73 to 7.81);
- Liraglutide 5.25 kg (95% CI: 6.17 to 4.32);
- Naltrexone plus bupropion 4.39 kg (95% CI: 5.05 to 3.72); and
- Orlistat 3.07 kg (95% CI: 3.76 to 2.37).
While the weight-lowering potential of orlistat is considered modest, its simple dosing and better tolerability are potential advantages.
These agents may have other benefits in addition to their effect on weight, such as glycaemic control and effects on lipid profiles.
Effects on glycaemic control noted by Singh et al. include:
- Associated with a reduction in HbA1c of 0.4% and fasting blood glucose of 18mg/dl.
- In patients with impaired glucose tolerance, orlistat was associated with a reduced rate of progression to diabetes (3.0% compared to 7.6%).
- Phentermine plus topiramate
- Associated with a 0.4% reduction in HbA1c in patients with diabetes.
- A significant reduction in the required dose of antihyperglycaemic medications was also seen.
- The SEQUEL trial showed a 78.7% reduction in the development of diabetes in patients with pre-diabetes or metabolic syndrome.
- Naltrexone plus bupropion
- Change in HbA1c ranged from no change to a 0.5% reduction in the COR trials.
- No data was available on the rate of diabetes progression.
- Associated with a reduction in HbA1c of 0.33% to 1.85% in patients with type 2 diabetes (doses up to 1.8mg).
- Associated with a reduction in HbA1c of 0.2% to 0.9% in patients without diabetes.
The overall effect of these medicines on cardiovascular outcomes is uncertain. However, Singh et al. observed the following effects:
- Small but significant reductions in total cholesterol and low-density lipoprotein (LDL)
- Small but significant reduction in systolic blood pressure
- Phentermine plus topiramate
- Reduction in triglycerides and increased high-density lipoprotein (HDL), but no effect on HDL
- Naltrexone plus bupropion
- Small but significant reduction in triglyceride and LDL and a small increase in HDL.
- Unfavourable effects on systolic blood pressure and heart rate.
- Reduced triglycerides but no significant improvement in LDL or HDL.
- Small but significant reduction in systolic blood pressure plus a small increase in heart rate.
- Australian Institute of Health and Welfare. Overweight and obesity: web report. Canberra: AIHW; 2023. Accessed 25/9/2023.
- Saxenda® (Liraglutide) Australian approved product information. North Sydney: Novo Nordisk. Approved July 2023.
- Sherman MM, Ungureanu S, Rey JA. Naltrexone/bupropion ER (Contrave): newly approved treatment option for chronic weight management in obese adults. Pharmacy and Therapeutics 2016; 41(3): 164.
- Singh AK, Singh R. Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs. Expert Rev Clin Pharmacol. 2020; 13(1): 53-64.
- Wang Y, Wang W, Yang Y, Yang W, Li R, Jin Y, et al. GLP−1 receptor agonists for the treatment of obesity: role as a promising approach. Front Endocrinol. 2023: 14; 1085799.
- Xenical® (Orlistat) Australian approved product information. Chatswood: Pharmaco. Approved August 2022.
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