Table of Contents  

Hide and Wilding: Pharmacological treatment of obesity – present and future

Introduction

The chronic health condition known as obesity is caused by increased energy intake and/or reduced energy expenditure, leading to excess energy storage as adipose tissue. It is a major risk factor for diseases such as myocardial infarction, stroke, type 2 diabetes mellitus, osteoarthritis and some cancers.

Definition

Obesity is defined as a body mass index (BMI) of more than 30 kg/m2, calculated as an individual’s weight divided by their height squared; further BMI classifications are shown in Table 1.1 Most research behind the BMI classifications is based on European populations. However, evidence examined by the World Health Organization (WHO) expert consultation suggests that Asian populations are more likely to develop weight-related comorbidities at lower BMIs and may require different cut-off points. The consultation concluded that current BMI cut-offs should remain, but recommended that additional cut-off points (shown in Table 1) be added for reporting purposes in order to facilitate international comparisons.2 A crucial weakness of BMI measurements is that they do not differentiate between fat and muscle, and therefore may misclassify healthy muscular individuals, such as athletes, as overweight or obese. Therefore, it should be used in combination with other lifestyle factors and additional measurements such as waist circumference and waist-to-hip ratio.

TABLE 1

International classification of underweight, overweight and obese adults according to BMI

Classification BMI (kg/m2)
Principle cut-off points Additional cut-off points
Underweight < 18.5 < 18.5
Normal range 18.5–24.9 18.50–22.99
23.00–24.99
Overweight ≥ 25.0 ≥ 25.0
Pre-obese 25.00–29.99 25.00–27.49
27.50–29.99
Obese ≥ 30.0 ≥ 30.0
Class 1 30.0–34.9 30.00–32.49
32.50–34.99
Class 2 35.0–39.9 35.00–37.49
37.50–39.99
Class 3 ≥ 40.0 ≥ 40.0

Adapted from World Health Organization. BMI classification. URL: http://apps.who.int/bmi/index.jsp?introPage=intro_3.html.1

World Health Organization gender-specific waist circumference and waist-to-hip ratio measurement cut-offs are shown in Table 2, with an increased complication risk in men with waist circumferences more than 94 cm and more than 80 cm in women. As with BMI measurements, there is evidence to suggest that increased risk in South Asian, Chinese and Japanese populations occurs at waist circumferences more than 90 cm in men and more than 80 cm in women.3

TABLE 2

World Health Organization cut-off points and risk of metabolic complications

Indicator Cut-off points Risk of metabolic complications
Waist circumference > 94 cm (M); > 80 cm (W) Increased
Waist circumference > 102 cm (M); > 88 cm (W) Substantially increased
Waist-to-hip ratio ≥ 0.90 cm (M); ≥ 0.85 cm (W) Substantially increased

M, men; W, women.

Adapted from World Health Organization. Waist circumference and waist–hip ratio – report of a WHO Expert Consultation. Geneva, Switzerland: World Health Organization; 2008. Available from: http://apps.who.int/iris/bitstream/10665/44583/1/9789241501491_eng.pdf.3

Epidemiology

The overall increasing BMI trend is a global problem with the percentage of adult males with a BMI ≥ 25 kg/m2 increasing from 28.8% in 1980 to 36.9% in 2013, and the percentage of adult females with a BMI ≥ 25 kg/m2 increasing from 29.8% in 1980 to 38.0% in 2013.4

The map in Figure 1 illustrates the most recent estimated prevalence of obesity by country.5

FIGURE 1

Worldwide prevalence of obesity in adults. Adapted from World Obesity. World map of obesity. URL: www.worldobesity.org/aboutobesity/world-map-obesity/5 and showing the most recent data for each country as of November 2014 (countries without data are shown in grey).

8-1-15-fig1.jpg

Countries with a prevalence of obesity greater than 30% include South Africa, Libya, Egypt, Saudi Arabia, the United States of America (USA), Mexico and Venezuela. A closer look at the statistics shows that prevalence levels of obesity exceed 50% for men in Tonga and women in Kuwait, Kiribati, the Federated States of Micronesia, Libya, Qatar, Tonga and Samoa.4

In England, between 1993 and 2012, the proportion of obese men and women increased from 13.2% to 24.4% and from 16.4% to 25.1%, respectively.6

The negative impacts and health risks of obesity are well documented. A review in the New England Journal of Medicine7 pooled data from healthy, white adults and, looking specifically at the 687 000 who had never smoked, showed a linear relationship between BMI and mortality from cancer and cardiovascular disease (for BMIs between 25.0 and 40.0 kg/m2); the hazard ratio for death from any cause increased by 1.31 for every five-unit increase in BMI. Hazard ratios for BMI and mortality are shown in Table 3, illustrating that subjects with a BMI greater than 30.0 kg/m2 were more than 1.34 times more likely to die from cancer and more than 1.80 times more likely to die from cardiovascular disease than those with a BMI of 22.5–24.9 kg/m2.

TABLE 3

Estimated hazard ratios for death from specific causes among healthy subjects who have never smoked according to BMI

BMI (kg/m2) Cancer Cardiovascular disease
22.5–24.9 Reference group
25.0–27.4 1.05 1.19
27.5–29.9 1.12 1.43
30.0–34.9 1.34 1.80
35.0–39.9 1.47 2.63
40.0–49.9 1.70 3.56

Although Table 1 indicates that a normal BMI is between 18.5 and 24.9 kg/m2, for individuals with a BMI ≥ 25 kg/m2 even small amounts of weight loss (between 3% and 5%) probably reduce triglycerides, blood glucose and glycated haemoglobin and reduce the risk of developing type 2 diabetes mellitus.8

The high mortality, worldwide, from major non-communicable diseases – cardiovascular disease, cancer, type 2 diabetes mellitus – led to the formation of a global monitoring framework during the World Health Assembly in May 2013. Target number 7 of the nine voluntary targets set for member countries was to halt the rise in type 2 diabetes mellitus and obesity between 2015 and 2020.9

Non-pharmacological treatment of obesity

Management of obesity is multifactorial and complex. The main focus should be on lifestyle factors – diet and exercise – but often includes psychological aspects and behavioural support to help overcome barriers to change. Dietary advice to reduce energy intake is an essential part of any weight reduction strategy, but effectiveness is often limited.

Two long-term randomized controlled trials showed interesting results for non-pharmacological treatment of obesity. The first, the Diabetes Prevention Program (DPP), showed that lifestyle interventions aimed at reducing body mass and increasing activity levels were able to reduce the incidence of type 2 diabetes mellitus by 58%. Participants underwent regular individualized education sessions with a case manager in order to maintain a weight reduction of at least 7% of initial body weight through a low-calorie, low-fat diet combined with at least 150 minutes of moderate-intensity exercise per week. A total of 50% of participants were able to achieve the weight loss goal and 74% were able to meet the weekly activity goal by 24 weeks.10

The Look AHEAD (Action for Health in Diabetes)11 study in participants with type 2 diabetes mellitus and a BMI ≥ 25 kg/m2 looked at intensive weight loss counselling over 8 years. They found that with individualized structured calorie-controlled meal plans, more than 175 minutes/week of moderate-intensity exercise and a combination of individual and group behavioural sessions (more regular in the first year, but at least monthly). At the end of the 8 years, 50.3% of participants managed to lose ≥ 5% of initial weight, with an average weight loss of 4.7%. The intensive lifestyle intervention group was compared with the control group, which received support and education regarding type 2 diabetes mellitus; 35.7% of the control group lost ≥ 5% of their initial weight, with average weight loss of 2.1%, as illustrated in Figure 2.

FIGURE 2

Mean (± standard error) weight loss during the Look AHEAD study over 8 years for patients randomly assigned to an intensive lifestyle intervention (ILI) or their usual diabetes support and education (DSE) care group. Redrawn from Look AHEAD Research Group. Eight-year weight losses with an intensive lifestyle intervention: The look AHEAD study. Obesity 2014;22(1):5–13.11

8-1-15-fig2.jpg

Results from these randomized controlled trials, although positive, show that even with intensive individualized education and motivation, weight loss with lifestyle support alone has limited efficacy.

It is also worth mentioning bariatric surgery. Guidelines from the National Institute for Health and Care Excellence (NICE) recommend bariatric surgery only for individuals with a BMI ≥ 40 kg/m2 or ≥ 35 kg/m2 with any significant weight-related comorbidity, but with a lower threshold BMI of 30–35 kg/m2 for those with recent-onset diabetes.12

The Swedish Obese Subjects randomized controlled trial followed a group of obese participants who underwent bariatric surgery versus non-surgical usual treatment. They found that the mean weight loss after 2 years was 23% of initial weight in the surgical intervention group versus 0% in the control group. In participants followed up for 20 years the mean weight loss for the surgical intervention group was 18% of initial weight compared with a 1% weight gain in the usual treatment group.13

Pharmacological treatment of obesity

Broadly speaking, there are three ways that drugs may be used to assist with weight loss:

  1. reduce energy intake – medications used to reduce energy intake work by suppressing appetite and increasing satiety. These act on the central nervous system (CNS), including the appetite regulatory system of the hypothalamus, and other relevant brain sites, including the limbic system and higher centres;

  2. alter energy absorption or increase excretion – medication can also be used to reduce fat absorption through the gastrointestinal tract (e.g. lipase inhibitors) or potentially reduce absorption of carbohydrate or increase its excretion [sodium/glucose cotransporter 2 (SGLT2) inhibitors];

  3. increase energy expenditure – increasing energy expenditure through exercise is an important method to reduce weight both alone and used in combination with other strategies as mentioned above. Some medications, such as the sympathomimetics, which work primarily to reduce energy intake, may also have a small effect on energy expenditure.

This review will provide an overview of the pharmacological therapies available, their mechanisms of action, their advantages and their disadvantages. However, it is important to remember these medications work as an adjunct to a healthy lifestyle in individuals who are committed to reducing their weight and should be considered on an individual basis only after discussing risks and benefits.

The American Heart Association, American College of Cardiology and the Obesity Society guidelines14 advise the use of medication as an adjunct to lifestyle measurements in individuals with a BMI > 30 kg/m2, or > 27 kg/m2 with a weight-related comorbidity such as hypertension, dyslipidaemia and type 2 diabetes mellitus, and should be prescribed only by clinicians knowledgeable about the product label.

The National Institute for Health and Care Excellence offers similar guidance, recommending pharmacological therapy only after dietary, exercise and behavioural approaches have been started, evaluated and are alone deemed not sufficient. The guidelines mention only one medication by name, orlistat (Xenical®, Roche, Basel, Switzerland), which they recommend in patients with a BMI > 30 kg/m2, or > 28 kg/m2 with associated risk factors. They also recommend that orlistat should be continued only by individuals who lose more than 5% of their initial body weight by the end of 3 months.12

Previous therapeutic strategies

A large problem with antiobesity pharmacotherapy is the high rate of adverse events. A summary of these, together with previously withdrawn medications, is shown in Table 4.15

TABLE 4

Previously withdrawn antiobesity medications

Year of introduction/withdrawal Antiobesity drug Mechanism Serious adverse effect
1893/1949 Thyroxine Increase metabolic rate Thyrotoxicosis
1933/1935 Dinitrophenol Increase metabolic rate Cataracts, neuropathy and hyperthermia
1937/1971 Amphetamine and derivatives Appetite suppression:
Stimulate dopamine, noradrenaline and serotonin release
Tolerance, addiction and psychosis
1960/2000 Phenylpropanolamine
(stereoisomers – noradrenaline and norpseudoadrenaline)
Appetite suppression:
Acts as an alpha- and beta-adrenergic receptor agonist and partial dopamine receptor agonist
Haemorrhagic stroke
1965/1972 Aminorex Appetite suppression:
Chemical structure similar to adrenaline and amphetamine – stimulates release of catecholamines and noradrenaline
Pulmonary hypertension
1973/1997 Fenfluramine with Phentermine (combination drug) Appetite suppression:
Fenfluramine – stimulates serotonin release
Phentermine – stimulates noradrenaline release (and dopamine/serotonin to a lesser extent)
Pulmonary hypertension and cardiac valvular insufficiency problems
1997/2010 Sibutramine (Meridia®, Reductil®, Abbott, Chicago, IL, USA) Enhances satiety:
Serotonin/noradrenaline/dopamine neurotransmitter reuptake inhibitor
Myocardial infarction and stroke
2006/2009 Rimonabant (Acomplia®, Sanofi Aventis, Paris, France) Appetite suppression:
Selective cannabinoid-1 receptor blocker
Depression and suicidal ideation

Adapted from Astrup A. Is cardiometabolic risk improved by weight-loss drugs? Lancet 2010;376(9741):567–8.15

Amphetamines and their derivatives (phentermine, diethylpropion, phenylpropanolamine) were amongst the earliest medications used for weight reduction and appetite suppression. As sympathomimetics, they work by releasing noradrenaline from presynaptic vesicles in the lateral hypothalamus.

The amphetamine derivatives phentermine and diethylpropion are approved by the United States Food and Drug Administration (FDA) for short-term use as anorexic agents. These are still used in some countries, but in Europe, in August 1999, the Committee for Proprietary Medicinal Products (CPMP) recommended the withdrawal of the marketing authorizations for products containing phentermine, diethylpropion, clobenzorex, fenproporex, mefenorex, norpseudoephedrine, phendimetrazine, fenfluramine and dexfenfluramine based on the lack of therapeutic efficacy and unfavourable benefit/risk balance; this has been legally challenged, and phentermine and diethylpropion have limited availability in Europe for short-term use on a named patient basis despite not being recommended in guidelines. They remain controlled drugs in both the USA and Europe.16

Phenylpropanolamine, another synthetic sympathomimetic amine used as an appetite suppressant and also in cough and cold remedies, was approved by the FDA in 1960. However, a large case–control study, published in the New England Journal of Medicine, showed an increased risk of haemorrhagic stroke in individuals using phenylpropanolamine as an appetite suppressant; within 3 days before the focal time with an adjusted odds ratio of 15.92 [95% confidence interval (CI) 1.38 to 184.13; P-value = 0.03],17 resulting in its withdrawal in 2000.

The next promising group of weight reduction therapies were serotonin (5-HT)-releasing agents. Fenfluramine is a 5-HT reuptake inhibitor, used alone and in combination with phentermine, that has been shown in randomized controlled trials to promote weight loss18 and was on the market between 1973 and 1997. Dexfenfluramine, the selective d-isomer of fenfluramine, was also used from the mid-1990s. However, retrospective meta-analysis and case–control studies highlighted significantly increased risks of developing heart valvular regurgitation and pulmonary hypertension, particularly with the phentermine–fenfluramine combination.19

Sibutramine was approved as an antiobesity medication by the FDA in 1997 and the European Medicines Agency (EMA) in 1998. It works by inhibiting reuptake of serotonin and noradrenaline. Studies showed that, compared with a placebo, sibutramine resulted in mild weight loss.20 However, sibutramine was withdrawn in 2010, with marketing authorizations being withdrawn by the EMA, following concerns over adverse cardiovascular events.21 The Sibutramine Cardiovascular Outcome Trail (SCOUT) in overweight and obese individuals over 55 years of age with pre-existing cardiovascular disease and/or type 2 diabetes mellitus found that, in comparison with a placebo, sibutramine resulted in an increased risk (hazard ratio 1.16; 95% CI 1.03 to 1.31; P-value = 0.02) of the composite end point of non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest and cardiovascular death.22 It is thought that the increased risk of myocardial infarction may be because of the increase in sympathetic nervous system activity causing an increase in both heart rate and blood pressure. However, the design of this trial has been criticized, as most of the patients included in the trial had contraindications to the use of sibutramine (such as pre-existing ischaemic heart disease), and patients continued with treatment even if no weight was lost (which would have led to use of the drug being stopped in clinical practice); a separate analysis suggested that no increase in cardiovascular events occurred in patients who lost weight.23

Another investigated therapeutic route for weight loss involved the cannabinoid receptors in the CNS. Working on the basis that phytocannabinoids, such as cannabis, and endocannabinoids, such as anandamide, stimulate appetite via cannabinoid receptors in the brain and periphery;24 rimonabant was developed to block cannabinoid-1 receptors in the CNS and therefore reduce appetite. Although never approved in the USA, rimonabant was licensed by the EMA in June 2006.25 A Cochrane systematic review reported weight loss, compared with a placebo, and in addition with a hypocaloric diet, of 4.9 kg in 1 year for patients on 20 mg rimonabant, with improvements in waist circumference, high-density lipoprotein cholesterol, triglyceride levels and systolic and diastolic blood pressures. However, they also showed significant side effects such as psychiatric and gastrointestinal problems, leading to the suspension of marketing authorizations by the EMA in October 2008.25

Research into developing medications to improve weight loss by increasing energy expenditure has previously shown promise in animal models, although they do not seem to be effective in humans. For example, beta-3 receptor agonists were found to increase lipolysis, fat oxidation, energy expenditure and insulin action in rodent models. However, human trials have been largely unsuccessful because of pharmacological differences between the rodent and human beta-3 receptors, lack of sensitivity for the beta-3 over beta-1/beta-2 receptors and unsatisfactory oral bioavailability and pharmacokinetic properties.26

Another therapy previously investigated is use of the hormone leptin. Research conducted on leptin-deficient ob/ob mice showed a reversibility of their phenotypic abnormalities by administration of leptin. This was also extrapolated to humans with leptin deficiency, who showed beneficial effects on appetite, fat mass, hyperinsulinaemia and hyperlipidaemia with daily subcutaneous leptin therapy.27 Unfortunately, although a randomized controlled trial looking at recombinant leptin for weight loss in obese and lean adults found that a subset of obese patients lost a significant amount of weight, average weight loss was minimal.28 This led to the sponsor, Amgen (Thousand Oaks, CA, USA), suspending further research studies. Leptin is still an essential therapy for reducing weight and associated comorbidities in individuals with congenital leptin deficiency.

Current pharmacotherapy

The FDA has two criteria with which to judge the effectiveness of a weight management therapy. Over 1 year the treatment should show a statistically significant difference in mean weight loss of at least 5% compared with a placebo-treated group, and/or more than 35% of subjects (approximately twice the proportion in the placebo-treated group) should lose 5% or more of their baseline body weight, with a statistically significant difference between the groups.29 The EMA guidelines are slightly different, requiring weight loss of more than 10% of baseline weight, which is also statistically greater than that associated with a placebo.30

Weight reduction medications currently approved by the FDA are listed in Table 5, although the first two, phentermine and diethylpropion, are licensed only for short-term use and, as mentioned previously, are not approved for use in Europe.

TABLE 5

Weight loss therapies currently approved by the US FDA

Antiobesity drug (brand name) Mechanism
Phentermine Appetite suppression – stimulates noradrenaline release (and dopamine/serotonin to a lesser extent)
Diethylpropion Appetite suppression – stimulates noradrenaline release (and dopamine/serotonin to a lesser extent)
Orlistat (Xenical®, Roche, Basel, Switzerland; Alli®, GlaxoSmithKline, Brentford, UK) Decreased fat absorption from the gut
Lorcaserin (Belviq®, Arena Pharmaceuticals, Zofingen, Switzerland) Appetite suppression – selective 5-HT2C receptor agonist
Phentermine/topiramate (Qsymia®, Vivus, Inc., San Diego, CA, USA) Appetite suppression – topiramate is a drug approved for migraine prophylaxis and the treatment of seizure disorders
Naltrexone/bupropion (Contrave®/Mysimba®, Orexigen Therapeutics, Inc., La Jolla, CA, USA) Appetite suppression – naltrexone is an opioid receptor antagonist approved for treatment of opioid and alcohol dependency; bupropion is a dopamine and noradrenaline reuptake inhibitor used for the management of depression and smoking cessation

At the time of writing, orlistat and naltrexone/bupropion are the only weight loss medication licensed for long-term clinical use in Europe. Orlistat is a gastric and pancreatic lipase inhibitor and works by reducing fat absorption from the gut. At prescribed doses of 120 mg, three times daily, dietary fat absorption is reduced by ≈30%. Orlistat is also available over the counter at 60 mg, taken three times daily.

A large 4-year, double-blinded, randomized controlled trial investigated orlistat, 120 mg three times a day, compared with a placebo in 3305 obese participants, taken in combination with lifestyle changes.31 Weight loss at 1 year was 10.6 kg with orlistat (compared with 6.2 kg in the control group). After 4 years of follow-up the orlistat group had lost 5.8 kg of their baseline weight, compared with 3.0 kg in the control group. This is illustrated in Figure 3.

FIGURE 3

Mean weight loss during 4 years of treatment with orlistat plus lifestyle changes or placebo plus lifestyle changes in obese patients (last observation carried forward data). Redrawn from Torgerson JD, Hauptman J, Boldrin MN, Sjöström L. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27(1):155–61.31

8-1-15-fig3.jpg

A meta-analysis of randomized placebo controlled trials, evaluating 16 studies of at least 1 year duration (10 631 participants) showed orlistat to reduce weight by, on average, 2.9 kg more than the placebo.32

Further analysis by Rucker et al.32 showed that adverse gastrointestinal side effects occurred in 24% of patients. However, this led to discontinuation of treatment in only 2% of participants. Common gastrointestinal side effects included fatty/oily stools, faecal urgency and oily spotting. Concentrations of fat-soluble vitamins were also reported to be lower than in control groups, although no clinically relevant vitamin deficiency was reported. Patients taking orlistat were routinely advised to take daily multivitamins.

Orlistat was authorized for use by the EMA in July 1998. Marketed by Roche Registration Ltd, the EMA recommended Orlistat alongside a low calorie diet for:

the treatment of obese patients [BMI ≥ 30 kg/m²], or overweight patients (BMI > 28 kg/m²) with associated risk factors. Treatment with Orlistat should be discontinued after 12 weeks if patients have been unable to lose at least 5% of initial body weight

European Medicines Agency, Xenical (orlistat)33

The FDA approved lorcaserin in June 2012. Lorcaserin is a highly selective 5-HT2c receptor agonist, unlike fenfluramine and dexfenfluramine, which were non-specific 5-HT receptor agonists whose metabolites had a high binding affinity for the HT2b receptor, associated with cardiac valvulopathy.34

The Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial35 was a phase III randomized placebo-controlled trial involving 3182 adults (BMI 30–45 kg/m2 or 27–30 kg/m2 with weight-related comorbidities) who were all offered diet and exercise counselling. At 1 year, individuals taking lorcaserin, 10 mg twice daily, lost a mean of 5.8 kg compared with 2.2 kg in the placebo group. Of the participants in the lorcaserin group, 47.5% achieved more than 5% weight loss compared with 20.3% in the placebo group.35 Importantly, there was no statistical difference between rates of valvulopathy occurring in 2.7% of the lorcaserin group and 2.3% of the placebo group.

The Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial36 was a phase III randomized placebo-controlled trial to evaluate safety and cardiovascular risk factors with 10 mg of lorcaserin taken twice daily and 10 mg of lorcaserin taken once daily. Individual weight loss was shown to be related to dose with 47.2% taking lorcaserin twice daily compared with 40.2% taking lorcaserin once daily losing at least 5% of their baseline body weight. Common side effects included headache, nausea and dizziness.36

In order to further investigate the risk of valvulopathy results from the BLOOM, BLOSSOM and also the Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus (BLOOM-DM) study (a trial looking at lorcaserin specifically in participants with type 2 diabetes mellitus)37 were combined. The pooled relative risk of valvulopathy in individuals taking lorcaserin compared with the placebo group was 1.16 (95% CI 0.81 to 1.67), showing no significant difference.38 The use of lorcaserin is recommended with caution in patients with congestive heart failure, valvular disease and pulmonary hypertension because of the lack of data from these patient populations. There is a possibility that 5HT2b serotonin receptors are overexpressed in congestive heart failure, which could affect receptor-binding affinities.39

Phentermine/topiramate, a combination drug marketed by Vivus Inc. as Qsymia®, was described in Table 5. Phentermine is a sympathomimetic, acting on the CNS to stimulate noradrenaline release from the hypothalamus. Topiramate is a drug approved for migraine prophylaxis and the treatment of seizure disorders;40 it increases the activity of gamma-aminobutyric acid, antagonizes glutamate, blocks neuronal voltage-dependent sodium channels, receptors and inhibits carbonic anhydrase.41 Its mechanism to induce weight loss is unknown. Initial research investigated the use of topiramate on its own but this was stopped because of dose-dependent neuropsychiatric side effects. Combining phentermine and topiramate at low doses allowed for peak exposure of both drugs – phentermine in the morning and extended-release topiramate in the late afternoon/evening.40

The efficacy and safety of phentermine/topiramate was investigated in the phase III randomized placebo-controlled ‘CONQUER’ trial in overweight and obese individuals with two or more weight-related comorbidities.42 Participants taking phentermine 15 mg/topiramate 92 mg once daily lost, on average, 10.2 kg (70% achieved ≥ 5% weight loss) and participants taking phentermine 7.5 mg/topiramate 46 mg once daily lost, on average, 8.4 kg (62% achieved ≥ 5% weight loss), compared with the placebo group who lost, on average, 1.4 kg (21% achieved ≥ 5% weight loss).

Phentermine/topiramate, marketed initially as Qnexa, was rejected by the FDA in 2010 because of concerns regarding adverse side effects, as it was noted that participants given phentermine/topiramate had an increase in average resting heart rates compared with baseline, increased palpitations and increased mild to moderate arrhythmias. Vivus responded to this concern by pooling all available trial data and concluded that

the only significant predictor of heart rate increases was baseline heart rate, where the largest heart rate increases from baseline were observed in patients with the lowest baseline heart rate values

Vivus, Inc. VI-0521 (Qnexa®) Advisory Committee briefing document40

Vivus also concluded from the pooled trail data that in high-risk subgroups, blood pressure reductions tended to be higher, the combination showing, if anything, a less adverse pattern of change in heart rate and blood pressure. Importantly, hazard ratios for phentermine/topiramate versus the placebo, with regard to major cardiovascular outcomes (myocardial infarction cerebrovascular event and cardiovascular death), did not exceed 1.0.40 Consequently, the FDA approved phentermine/topiramate as Qsymia® in July 2012. Qsymia® is contraindicated in pregnancy because of an increased risk of teratogenicity, specifically the risk of cleft lip with or without cleft palate.43

More recently, in September 2014, the FDA approved another combination drug, naltrexone/bupropion marketed by Orexigen Therapeutics, Inc. as Contrave®.44 This was also approved by the EMA in December 2014, under the brand name Mysimba®.45 Naltrexone is an opioid receptor antagonist approved for treatment of opioid and alcohol dependency. Bupropion is a dopamine and noradrenaline reuptake inhibitor used for the management of depression and smoking cessation.46

Combined treatment with both medications was developed to stimulate pro-opiomelanocortin neurons in the hypothalamus with bupropion whilst at the same time blocking opioid mediated pro-opiomelanocortin autoinhibition with naltrexone. It is also suggested that this synergistic drug combination might also modulate mesolimbic reward pathways.46 Pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus integrate central and peripheral signals related to energy balance and produce a net anorexigenic output.47

The Contrave Obesity Research (COR)-I study was a phase III randomized placebo-controlled trial to assess the effect of this treatment in 1742 obese adults.48 Participants were split into three groups: the group given naltrexone 32 mg and bupropion 360 mg showed a mean reduction in body weight of 6.1% (48% achieved ≥ 5% weight loss), the group given naltrexone 16 mg and bupropion 360 mg showed a mean reduction in body weight of 5.0% (39% achieved ≥ 5% weight loss) and the placebo group showed a mean reduction in body weight of 1.3% (16% achieved ≥ 5% weight loss). Common side effects included nausea (in 27.2–29.8% of the treatment group versus 5.3% in the placebo group), headache (in 13.8–16.0% of the treatment group versus 9.3% in the placebo group), constipation, dizziness, vomiting and dry mouth.

The COR-II phase III randomized placebo-controlled trial49 was set up to assess the safety, tolerability and efficacy of naltrexone 32 mg and bupropion 360 mg versus a placebo in 1496 obese patients. The weight loss findings were similar to the COR-I study, with a mean reduction in body weight of 6.1 kg (53.1% achieved ≥ 5% weight loss), compared with the placebo group which showed a mean reduction in body weight of 2.3 kg (24% achieved ≥ 5% weight loss). Ambulatory blood pressure monitoring was undertaken in a subgroup of participants which showed no significant change in mean blood pressure or circadian pattern of blood pressure in the treatment group compared with the placebo group.

Future pharmacotherapy

A promising group of newly developed therapies are the glucagon-like peptides, initially developed to improve management of hyperglycaemia in individuals with type 2 diabetes mellitus. Synthetic glucagon-like peptide-1 (GLP-1), given by subcutaneous injection, mimics intestinally driven peptides usually released in the presence of glucose in the gut to increase postprandial insulin release.50

As well as improving blood glucose control in people with type 2 diabetes mellitus, significant weight loss was also noted. For the GLP-1 liraglutide, individuals with type 2 diabetes mellitus noted weight loss of 3.7 kg at 6 months.51

A study involving 564 obese, non-diabetic men and women compared the effect of liraglutide (at various doses) with that of orlistat and a placebo in combination with a hypocaloric diet.52 Mean weight loss over 20 weeks for liraglutide was dose dependent, ranging from 4.8 to 7.2 kg for once-daily doses of 1.2–3.0 mg, compared with weight losses of 2.8 kg in the placebo group and 4.1 kg in the orlistat group. Of those individuals taking 3.0 mg of liraglutide daily, 76% lost more than 5% of their initial body weight. The most common side effects, nausea and vomiting, were dose dependent.

The mechanisms for weight loss with GLP-1 analogues are unclear. However, literature reviews suggest that weight loss is caused by decreased food intake, rather than changes in energy expenditure, which is probably mediated by the action of GLP-1 in the hypothalamus and hindbrain.53

The Satiety and Clinical Adiposity – Liraglutide Evidence (SCALE) maintenance study was a large, phase IIIa randomized controlled trial conducted to compare subcutaneous liraglutide, 3.0 mg daily, with a placebo.54 Following low-calorie diet (1200–1400 kcal/day) run-in periods – varying from 4 to 12 weeks – participants who had lost more than 5% of their initial weight were recruited to the full 56-week study. During the run-in period, participants lost, on average, 6.0% (6.3 kg) of their initial weight. During the treatment period (from randomization to week 56) individuals taking 3.0 mg of liraglutide lost, on average, a further 6.0 kg, with 26.1% achieving weight loss of more than 10% of their weight, compared with the placebo group, which lost, on average, 0.1 kg, with 6.3% achieving weight loss of more than 10% of their weight. This is illustrated in Figure 4.

FIGURE 4

Mean percentage change in body weight with standard error bars. It shows the 14-week run-in period, the 56-week treatment period and the 12-week follow-up period. Redrawn from Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes 2013; 37(11):1443–51.54

8-1-15-fig4.jpg

The most common side effects with liraglutide were gastrointestinal disorders, reported by 74% of participants (in comparison with 45% of the placebo group). Of these disorders, 94.8% were rated as mild to moderate in severity.54 There are also two other SCALE studies looking at the potential of liraglutide to induce and maintain weight loss, which are not yet published at the time of writing.55 The first is looking at individuals with type 2 diabetes mellitus and the second, which is still ongoing, is also looking at the potential of liraglutide to delay the onset of type 2 diabetes mellitus in individuals diagnosed with pre-diabetes at baseline.

Following the SCALE studies, Novo Nordisk (Bagsvaerd, Denmark) submitted a New Drug Application to the FDA for the use of liraglutide 3.0 mg (Saxenda®) as a once-daily GLP-1 analogue for the treatment of obesity. This was approved by the FDA in December 2014.56 Cetilistat (Oblean®, Norgine BV, Amsterdam, the Netherlands), originally marketed by Norgine BV (Amsterdam, the Netherlands) and Takeda Pharmaceutical Company Ltd. (Osaka, Japan), was approved in September 2013 for use as an antiobesity drug in individuals with type 2 diabetes mellitus and dyslipidaemia in Japan only.57 Cetilistat is a lipase inhibitor and was the first therapy available to control lipid absorption to be approved in Japan. Phase II studies in individuals with type 2 diabetes mellitus and dyslipidaemia showed a mean reduction in body weight from a baseline of 2.8% compared with 1.1% in the placebo group after 52 weeks. Adverse events and discontinuation rates were suggested to be lower than with orlistat. However, further studies have not been performed. Currently, Norgine BV and Takeda Pharmaceutical Company Ltd are the only companies licensed to distribute cetilistat in Japan.57 Future research into other lipase inhibitors may be developed in the future with improved side effect profiles to those of orlistat.

Another possible future weight loss medication is canagliflozin (Invokana®, Janssen Pharmaceutica, Beerse, Belgium). Currently used to reduce hyperglycaemia in individuals with type 2 diabetes mellitus, canagliflozin is a sodium–glucose co-transporter 2 inhibitor which works by inhibiting glucose reabsorption by the kidney and increasing urinary glucose excretion.

A 12-week phase IIb randomized placebo-controlled trial published in April 2014 in participants without type 2 diabetes mellitus compared percentage weight change in individuals given canagliflozin 50 mg, 100 mg or 300 mg with a placebo given once daily. Changes in weight from baseline were –2.2% (canagliflozin 50 mg), –2.9% (canagliflozin 100 mg), –2.7% (canagliflozin 300 mg) and –1.3% (placebo). Overall, adverse events were similar across all groups. However, canagliflozin was associated with higher rates of genital mycotic infections in women.

There is currently an ongoing phase II randomized placebo-controlled study to investigate the effects of coadministration of canagliflozin 300 mg and phentermine 15 mg in non-diabetic overweight and obese participants.55

The favourable weight loss effects seen after gastric bypass surgery are thought, in part, to be related to changes in the gut hormones GLP-1, peptide tyrosine tyrosine (PYY), pancreatic polypeptide and oxyntomodulin and may be key to targets for future weight loss therapy, both alone and in combination.58 A small study of 12 healthy men given oral GLP-1 and PYY in conjunction with sodium N-caprylate led to a 21.5% reduction in energy intake and increased feeling of fullness during a meal served 15 minutes later. However, this study showed no difference in 24-hour energy intake and resulted in gastrointestinal side effects in two of the subjects.59 Combinations of other gut peptides in varying ratios (such as oxyntomodulin, PYY and GLP-1) and antagonism of the appetite-stimulating hormone ghrelin are also under consideration,55 and it will be interesting to see whether these approaches are successful as clinical trials progress.

Summary

Currently, the main long-term weight reduction pharmacotherapy with acceptable side effects has been limited to orlistat. However, it will be interesting to see how the four new drugs approved by the FDA over the past 2 years (lorcaserin, phentermine/topiramate, naltrexone/bupropion and liraglutide) are used and monitored for long-term side effects. Currently, only naltrexone/bupropion in this group is licensed for use in Europe, although liraglutide will hopefully be licensed in the near future.

Conflict of interest

John Wilding has acted as a consultant, received institutional grants and given lectures on behalf of pharmaceutical companies developing or marketing medicines used for the treatment of obesity and diabetes.

For the products discussed in this article, John Wilding has acted as a consultant and investigator for and given lectures on behalf of Novo Nordisk, the manufacturers of liraglutide, and in the past (>10 years ago) for Roche, manufacturer of orlistat.

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