Current and emerging medications for the management of obesity in adults

Abstract

The prevalence of obesity among adults has nearly tripled worldwide since 1975 to more than 650 million in 2016,1 including 31% of adults in Australia.2 Obesity is the second leading contributor to Australia's burden of disease due to its complications, which include cardiovascular disease, type 2 diabetes, chronic kidney disease, fatty liver, obstructive sleep apnoea, and several cancers.2 Many of these complications can be prevented or mitigated with a loss of as little as 5% of total body weight (Box 1), with greater weight loss usually resulting in progressive improvements in obesity-related complications and quality of life.4-6 HFpEF = heart failure with preserved ejection fraction; NAFLD = non-alcoholic fatty liver disease; PCOS = polycystic ovary syndrome; QOL = quality of life. Lifestyle interventions that incorporate reduction in energy intake, improved diet quality and increased physical activity are the foundation of obesity management. However, obesity is chronic and relapsing, and most people who lose weight with lifestyle interventions alone will regain weight over time.7 Long term maintenance of weight loss is very challenging for most people because of complex interactions between biology, behaviour and the obesogenic environment. Weight loss leads to numerous long-lasting biological changes, including a reduction in total energy expenditure greater than expected for the amount of lean mass lost, an increase in appetite, alterations in several hormones (including adipocyte, thyroid and gut hormones) involved in hunger, satiety and energy expenditure, and alterations in neural activity in several brain areas that mediate food intake.8, 9 Although direct links with weight regain have not been shown, many of these changes would appear to favour regain of lost weight. Lack of understanding of the biology of obesity perpetuates the misconception that it is simply due to lifestyle factors and inadequate motivation for behaviour change. This stigma is common, even in the health care sector, and can lead to reluctance by people with obesity to seek treatment, as well as compromise the quality of care provided (eg, incomplete discussion of treatment options).10 Clinical practice guidelines for obesity management recommend consideration of very low energy diets, medications and bariatric surgery when lifestyle interventions alone have not achieved therapeutic goals.11, 12 Growing recognition of the pathophysiology of obesity12, 13 has led to considerable advances in obesity pharmacotherapies over the past decade. This narrative review provides an overview of current and emerging medications for obesity management, including recommendations and knowledge gaps regarding their use in clinical practice. We searched the MEDLINE (Ovid) online database and the ClinicalTrials.gov registration to identify relevant studies, using the search terms “obesity”, “morbid obesity”, “overweight”, “body weight”, “weight loss”, “weight gain”, “adiposity”, “adipose”, “medication”, “pharmacotherapy” and “weight management”. We considered for inclusion human studies published in English before 22 August 2022 based on relevance, originality and impact (eg, number of citations), and screened the reference lists of relevant articles. Publications reporting outcomes of phase 3 clinical trials of obesity medications were preferentially included, along with any article otherwise known to the authors relevant to the topic and not identified through the search or reference list screen. In Australia, medications, in conjunction with lifestyle interventions, are indicated for weight management in adults (≥18 years of age) with obesity (body mass index ≥ 30 kg/m2) or those who are overweight (body mass index ≥ 27 kg/m2, or ≥ 25 kg/m2 for phentermine) with at least one weight-related complication. Five agents are currently approved by the Therapeutic Goods Administration (TGA) for obesity management: orlistat, phentermine, naltrexone–bupropion, and the glucagon-like peptide 1 (GLP-1) receptor agonists liraglutide and semaglutide. Their mechanisms of action, dosing, effects, and costs are summarised in Box 2. All currently approved medications, apart from orlistat, act centrally in brain regions involved in appetite regulation to increase satiety, reduce hunger, and, in some cases, reduce the rewarding properties of high calorie food. At present, the Pharmaceutical Benefits Scheme does not subsidise medications indicated for obesity management. In Australia, at the time of writing, semaglutide 2.4 mg weekly is indicated for chronic weight management but is not yet available. Orlistat reduces the absorption of dietary fats by preventing their digestion through the inactivation of gastric and pancreatic lipases, leading to an increase in excretion of up to 35% of ingested fat in the faeces.29 In clinical trials with at least 12 months’ follow-up, the use of orlistat leads to weight loss of around 4–10 kg over 12 months (~3% in excess of placebo).7, 30 Gastrointestinal adverse effects such as steatorrhea (30% in clinical trials15), faecal urgency and oily leakage31 are common and related to the fat content of the meal. It is recommended that people taking orlistat also take a multivitamin supplement due to reduced absorption of fat-soluble vitamins,32 although clinically significant vitamin deficiency is rarely reported.30 There are also reports of acute kidney injury in association with orlistat use due to hyperoxaluria and oxalate nephropathy.33 In Australia, orlistat is available from pharmacies without a prescription. Phentermine is a sympathomimetic agent. Studies in rats show that it stimulates the release of noradrenaline, dopamine and serotonin in several areas of the brain, including the hypothalamus.34, 35 Phentermine reduces hunger and reward-related eating.21 It has been in use for more than 60 years (approved by the United States Food and Drug Administration [FDA] in 1959), and is the subject of few randomised controlled trials. Phentermine is indicated as a short term adjunct in the management of overweight and obesity (duration unspecified, often interpreted as < 12 weeks). A clinical trial of phentermine 30 mg daily reported weight loss of 12.2 kg (v 4.8 kg with placebo) in participants who completed 36 weeks of treatment.14 Common adverse effects of phentermine include insomnia, dry mouth, and increased blood pressure and heart rate. Cardiac valvular regurgitation was reported in people who took phentermine in combination with fenfluramine or dexfenfluramine (no longer available) for weight loss. Even though there are no reported cases to date of valvular heart disease associated with phentermine monotherapy, the combination of phentermine with selective serotonin reuptake inhibitors is not recommended due to the theoretical risk of cardiac valvular disease.36 The combination of the antidepressant bupropion and the opioid antagonist naltrexone was developed for obesity management based on the synergistic effects of these agents in central appetite and reward regions. Bupropion is a dopamine and noradrenaline reuptake inhibitor that stimulates the activity of anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus.24 Naltrexone blocks endogenous opioid-mediated inhibition of POMC neurons, leading to sustained POMC stimulation.24 Clinical trials report weight loss of 5–6 kg (3–5% above placebo) over one year.17, 37, 38 The adverse effects most commonly reported in clinical trials of naltrexone–bupropion are nausea (30%) and constipation (16%), particularly during dose escalation.37 Increased blood pressure and heart rate are also potential adverse effects. The label contains a warning about an increased risk of depression and suicidal behaviour based on these effects with bupropion monotherapy, although clinical trials have not reported increased depression or suicidality with the naltrexone–bupropion combination compared with placebo.17, 37, 38 Clinicians should be aware of several potential drug interactions when prescribing naltrexone–bupropion. Concomitant treatment with certain cytochrome P450 2B6 (CYP2B6) inhibiting agents (eg, clopidogrel) can increase bupropion exposure. Conversely, CYP2B6 inducers (including human immunodeficiency virus antivirals and some anticonvulsant medications, such as carbamazepine and phenytoin) may reduce efficacy by increasing bupropion metabolism. Bupropion inhibits cytochrome P450 2D6 (CYP2D6) thereby reducing metabolism of some antidepressant (selective serotonin reuptake inhibitors and tricyclics), antipsychotic (eg, haloperidol, risperidone) and cardiac medications (eg, metoprolol, flecainide). Extreme caution is advised when combining naltrexone–bupropion with drugs that lower the seizure threshold (including some antipsychotic and antidepressant agents). In addition, central nervous system toxicity has been reported with concomitant use of bupropion with dopaminergic drugs such as levodopa.39 GLP-1 is a hormone secreted by L cells in the distal small intestine and colon in response to ingestion of nutrients. Its numerous metabolic actions are mediated via GLP-1 receptors, which are widely distributed, including in the brain, pancreas, stomach, kidney, heart, and adipose tissue.40 GLP-1 receptor agonists reduce food intake by acting at GLP-1 receptors in appetite- and reward-related regions of the brain, including the hypothalamus, hindbrain and mesolimbic pathway, to promote satiation and reduce hunger and food reward.40 Additional effects of GLP-1 include stimulation of insulin secretion under conditions of hyperglycaemia, reduction in glucagon secretion, and slowing of gastric emptying.41, 42 Endogenous GLP-1 has a short half-life of one to two minutes, as it is rapidly inactivated by the enzyme dipeptidylpeptidase-4 (DPP-4) and cleared from the circulation by the kidneys. GLP-1 receptor agonists have been developed to promote the favourable metabolic effects of native GLP-1 with longer duration of action and greater bioavailability. Several GLP-1 receptor agonists are available in Australia for the treatment of type 2 diabetes, of which two, liraglutide and semaglutide, are also indicated for obesity treatment at higher doses (liraglutide 3.0 mg daily and semaglutide 2.4 mg weekly for obesity, and up to 1.8 mg daily and 1.0 mg weekly, respectively, for type 2 diabetes). When used at recommended doses for obesity management in people without type 2 diabetes, mean weight losses in clinical trials are 6–8 kg (~6% placebo-subtracted) for liraglutide16 and 15–18 kg (~13% placebo-subtracted) with semaglutide.18, 19 The adverse effects of GLP-1 receptor agonists are predominantly gastrointestinal. Nausea (40%) and diarrhoea (21%) are the most common adverse effects for liraglutide 3.0 mg,16 with a similar adverse event profile for semaglutide 2.4 mg.43 A gradual dose escalation is recommended to minimise these effects. Nausea is usually transient and mild and is most common shortly after treatment initiation and during dose escalation.16, 18 In people with type 2 diabetes, the 1 mg dose of semaglutide for type 2 diabetes treatment was associated with a higher risk of complications of diabetic retinopathy in patients with a history of retinopathy at the time of treatment initiation.44 This might be related to rapid improvement in glycaemic control, which is known to be associated with transient worsening of diabetic retinopathy.45 Hence, retinopathy-related risks are likely to be much lower in people without diabetes. The effect of semaglutide (up to 1 mg weekly) on the development and progression of diabetic retinopathy over five years will be examined in a dedicated trial (ClinicalTrials.gov, NCT03811561). Some epidemiological studies have suggested an increased risk of acute pancreatitis and pancreatic cancer in people using GLP-1 receptor agonists. However, a meta-analysis of more than 55 000 participants from cardiovascular outcome trials in people with type 2 diabetes using GLP-1 receptor agonists (including semaglutide and liraglutide) at doses used to treat type 2 diabetes did not detect a signal for these events over 175 000 patient-years of observation.46 Topiramate is a carbonic anhydrase inhibitor indicated for the treatment of epilepsy and as prophylaxis against migraines. When used in the treatment of epilepsy, anorexia and weight loss are common adverse effects. The mechanism by which topiramate decreases appetite is not known. In Australia, topiramate is not approved by the TGA for an obesity indication, but it is inexpensive and commonly used “off-label” for obesity management, either as monotherapy or in combination with medications, particularly phentermine.47 The combination of phentermine with an extended-release formulation of topiramate is approved for chronic weight management in the United States but not in Australia. Of note, the recommended dose of this combination contains 7.5 mg phentermine and 46 mg of topiramate (half of the minimum available capsule size of phentermine in Australia), with a maximum dose of 15 mg phentermine plus 92 mg topiramate. Gradual dose escalation of topiramate is recommended to improve tolerability, starting with 12.5 mg once a day and increasing to a maximum of 50 mg twice a day. Common adverse effects include paraesthesia, dysgeusia (taste distortion), somnolence, memory, attention and concentration difficulties, and mood disturbances.48 Rare adverse effects include kidney stones and angle closure glaucoma. Topiramate is contraindicated in pregnancy due to an association with congenital malformations. A meta-analysis of randomised trials examining the effect of topiramate use for 16 weeks or more on weight loss reported a mean placebo-subtracted weight loss of 5.3 kg.48 Medications indicated for obesity management are consistently associated with lower weight losses in people with type 2 diabetes than in those without diabetes.16, 18, 49, 50 The reasons for this are not known but might include concomitant use of glucose-lowering agents that promote weight gain, increased food intake to prevent or treat hypoglycaemia, and reduction in glycosuria (due to glycaemic improvement) offsetting weight loss.51 Although mean weight loss with current obesity medications (with the exception of semaglutide) is in the range of 3–6% in excess of placebo, it is important to note that individual responses vary widely for all agents, with 25–69% of participants achieving at least 10% weight loss over one year of treatment. All obesity medications are associated with improvements in cardiovascular risk factors, although these benefits differ between medications even if similar mean weight loss is achieved. For example, low-density lipoprotein cholesterol lowering is greater with orlistat than other agents, which is likely due to its effect on reducing fat absorption.20, 52, 53 Weight loss induced by naltrexone–bupropion is not associated with the expected improvement in blood pressure.24, 37, 38 As anticipated from their pancreatic actions, GLP-1 receptor agonists are associated with greater glycaemic improvements than other agents after a similar amount of weight loss.17, 50 Orlistat54 and GLP-1 receptor agonists55, 56 appear to reduce liver fat content and markers of liver injury in people with non-alcoholic fatty liver disease, but this effect is of weight loss There is a of on the effects of other obesity medications on non-alcoholic fatty liver As there are no completed cardiovascular outcome trials of medications currently indicated for obesity management. trials have not been for phentermine and orlistat, and a cardiovascular outcome trial of naltrexone–bupropion was due to a of regarding In people with type 2 diabetes, who have a higher cardiovascular risk than the liraglutide and semaglutide have in adverse cardiovascular outcomes compared with doses used for the treatment of type 2 liraglutide 1.8 mg semaglutide mg and 1.0 mg In people without type 2 diabetes, an of from five trials that liraglutide 3.0 mg did not reduce cardiovascular events compared with = A cardiovascular outcome trial of semaglutide 2.4 mg weekly in people is in people with obesity without type 2 who have cardiovascular approved obesity medications have been to improve or weight-related quality of life. Orlistat might not improve quality of compared with and quality of outcomes have not been reported for All obesity medications orlistat are associated with improvements in behaviour compared with (Box is a of receptors for GLP-1 and these two gut hormones insulin secretion via GLP-1 and receptors on pancreatic thereby blood for hormones are also in regions of the brain that food intake, although studies are in their on the of receptor to food intake and body reduces body weight as well as blood It is approved by the and the TGA for the treatment of type 2 diabetes at a dose of mg and 15 mg and is clinical trials for the management of obesity at the as well as other such as heart failure with preserved ejection and non-alcoholic from a phase 3 clinical trial for obesity = that mg and 15 mg in mean placebo-subtracted weight loss over weeks of and weight loss of than of participants in the mg and 15 mg lost or more of body and improvements were in blood and physical The adverse effect profile similar to GLP-1 receptor with predominantly effects At the time of writing, is indicated for type 2 diabetes but is not yet available in Australia. is a hormone with insulin from pancreatic in response to It the absorption of the circulation by gastric and at receptors in the hindbrain and mesolimbic dopamine system to increase satiation and reduce the rewarding of is a in development for the management of obesity as a once weekly from a phase 2 weight loss of up to kg greater than and greater than liraglutide 3.0 mg over A combination of and semaglutide is also for obesity is a receptor developed for the treatment of obesity by in the are by and is approved for use in the and but not currently Australia, for patients years or with 1 or receptor is also trials for use in other associated with obesity, such as and are the most common adverse effects in clinical trials. is a human that to the type receptor the of that and, in adipose and In a small phase 2 trial in adults with type 2 diabetes and obesity, up to in loss of fat mass of compared with in the kg kg and a in lean mass of compared with loss of in the kg kg as well as improved glycaemic The increase in lean mass is as energy and weight loss are associated with lean mass The mechanism for fat mass reduction is and were the most common adverse effects. 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