Obesity: The Disease Burden and Current Treatment Landscape
Obesity is a chronic relapsing disease defined as abnormal or excessive fat accumulation resulting from an interplay of genetic and behavioral factors. Its prevalence is widespread on a global scale, with an estimated incidence of 1.9 billion overweight and 650 million obese adults as of 2016. In Singapore, the prevalence of obesity across all ages rose from 8.6 per cent in 2017 to 10.5 per cent in 2020 and is expected to surpass 15% by 2024.
Despite clinical and scientific advancements that have led to a better understanding of the disease and its management, its burden has been unabating and pervasive across clinical, humanistic and economic fronts. Obesity is linked to multiple health complications including an increased risk of stroke, cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and the development of certain cancers such as pancreatic, colon and breast cancers. The 2017 Global Burden of Disease Study observed that high body mass index (BMI) and its consequent complications caused over 4 million deaths and 70.7 million disability adjusted life years (DALYs). CVD, T2DM and kidney diseases were among the leading causes of high-BMI-related death and DALYs worldwide. In 2016, the economic impact of obesity, in terms of healthcare spending and lost productivity, to the local economy was estimated at US$400 million.
Local clinical practice guidelines on tackling obesity, developed by the Ministry of Health (MOH) and Health Promotion Board (HPB), were last revised in 2016. Pharmacotherapy was considered a second-line strategy and adjunct to lifestyle as well as behaviour modification. Drug therapy was recommended only when BMI≥30kg/m2 or when BMI is between 27.5 to 29.9kg/m2 in Asians with specific comorbidities (e.g. hypertension (HTN) and T2DM). Further, the guidelines outlined the limited handful of pharmacotherapeutics available locally – phentermine and mazindol for short term weight management (6-12 months); liraglutide for weight management up to 2 years; and orlistat as an anti-obesity drug for longer-term therapy of up to 4 years.
In January 2022, the Health Sciences Authority (HSA) approved the use of Contrave, a prolonged-release (PR) fixed dose combination tablet containing 8mg naltrexone, an opioid antagonist, and 90mg buproprion, an aminoketone antidepressant. Contrave dosing should be escalated progressively over 3 weeks, culminating in a total daily dosage of two Contrave 8mg/ 90mg tablets twice daily (i.e. 32mg/ 360mg) at the start of Week 4. The drug is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in obese adults or overweight adults with weight-related comorbidities. Critically however, its use is limited by the lack of cardiovascular morbidity and mortality safety data and must thus be used with caution in higher risk groups. Notwithstanding, local market authorization of the new anti-obesity drug marks a regulatory push to provide more effective strategies for preventing and managing the public health crisis.
Contrave: Its Efficacy and Safety Profiles
The known effects of naltrexone and bupropion (NB) on addiction (alcohol and nicotine, respectively) informed its development as a pharmacotherapeutic combination for weight loss. Nonclinical studies suggest that naltrexone and bupropion have effects on two distinct areas of the brain: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The NB combination is thus hypothesized to reduce food intake and induce weight loss through sustained modulation of the various central nervous system pathways.
Its successful regulatory approval was based on the Contrave Obesity Research (COR) clinical program, comprising four pivotal 56-week Phase III randomized controlled trials (RCTs) – COR-I, COR-II, COR-DM and COR-BMOD.
- COR-I, COR-II and COR-BMOD enrolled adult patients who were obese (BMI of 30-45 kg/m2) or overweight (27-45 kg/m2) with at least one comorbidity (hyperlipidemia (HLD) or HTN).
- COR-DM further evaluated patients with T2DM.
Collectively, the Phase III trials recruited over 4,536 individuals, of which 24% had HTN, 54% had HLD, and 10% had T2DM. The co-primary endpoints at the end of 56 weeks were percentage change in body weight and proportion of patients who achieved at least 5% of weight loss. Other secondary endpoints investigated include impact on waist circumference, lipid levels, HRQoL, as well as blood sugar levels in COR-DM. A brief overview of the trial populations, outcomes and safety data are presented in Table 1.
Efficacy
Overall, the clinical program demonstrated an average weight loss of 4.1% over placebo among non-diabetics. The percentages of patients who achieved at least 5% or at least 10% body weight loss from baseline were greater among those assigned Contrave, compared with placebo, in all four obesity trials. The average weight loss from baseline across the four studies was approximately 5 to 9kg. Secondary endpoints met across the COR program include significant improvements in measures of CV and metabolic risk factors (e.g. waist circumference, visceral fat, triglycerides), food cravings, as well as HbA1c in the COR-DM trial.
Safety
From a safety perspective, Contrave was observed to be generally well tolerated, with an overall safety profile that was consistent with its individual constituents. Notably, a substantial proportion withdrew from the trials prior to Week 56 (45% among the placebo group and 46% among CONTRAVE groups). Approximately 24% of subjects treated with Contrave and 12% of subjects treated with placebo discontinued treatment due to an adverse reaction. Adverse events reported by more than 5% of Contrave-treated subjects and at least twice the rate of placebo-exposed subjects were nausea, constipation, vomiting, dizziness and dry mouth.
Notably, its regulatory approval is accompanied by a warning that the effect of Contrave on cardiovascular mortality and morbidity has not been established. In 2011, the FDA stalled its regulatory approval citing statistically significant higher mean systolic and diastolic blood pressure (SBP, DBP) and heart rate among NB treated subjects compared to placebo treated subjects. In addition, more adverse events related to HTN were observed in the NB groups, particularly among subjects with T2DM.
Concerns about the CV safety profile were thus raised surrounding the long-term use of NB in a population of overweight and obese individuals. A multicenter cardiovascular outcomes trial, LIGHT (N=8,910), was subsequently conducted to investigate these safety concerns. The LIGHT study was a noninferiority trial assessing time to first confirmed occurrence of a major adverse cardiovascular event (MACE) using a noninferiority margin of 1.4 for the hazard ratio (HR) to rule out increased risk of MACE with NB versus placebo. At the first planned interim analysis (25% of planned events), both the on-study and on-treatment analysis of NB vs placebo yielded an estimated HR for MACE with an upper bound 95% CI that was less than 2.0. However, the data was prematurely released via a patent publication submission which compromised the integrity of the scientific study. The trial was thus terminated early precluding assessment of non-inferiority for the prespecified upper limit of 1.4. To date, CV safety remains a matter of uncertainty and evaluation in a new adequately powered outcome trial is required.
| Trial, Population | Intervention/ Comparator | Primary Efficacy Outcome | Safety |
| COR-I
N=1,742 + reduced calorie diet (est. 500kcal/day decrease in caloric intake), behavioral counselling and physical activity involving 30 min walks three days/ week 56 weeks |
Randomized 1:1:1 to receive:
|
Mean change in BW: -1.3% (placebo) vs -6.1% (N32+B) vs -5.0% (N16+B); p<0.0001 for all active treatments vs placebo
≥5% BW decrease: 16% (placebo), 48% (N32 + B), 39% (N16+B); p<0.0001 for all active treatments vs placebo |
Most frequent AE was nausea: 29.8% (N32+B), 27.2% (N16+B), 5.3% (placebo)
Occurring more frequently in N+B groups vs placebo: headache, constipation, dizziness, vomiting, dry mouth No increase in depression or suicidality events in N+B vs placebo |
| COR-II
N=1,496 + reduced calorie diet (est. 500kcal/day decrease in caloric intake), behavioral counselling and physical activity involving 30 min walks three days/ week 56 weeks |
Randomized 2:1 to received:
From Week 28 to 44, patients who did not lose at least 5% of BW were re-randomized to continue or receive N48+B |
Week 28 results:
LSMD: – 3.28 (p<0.001 for NB vs placebo) ≥5% BW decrease: 13.9% (placebo), 42.1% (N32+B) |
AEs occurred in 75.2% of the placebo arm and 85.9% of NB arm. Notable AEs that occurred more frequently in the NB arm were: GI disorders (53.6% vs 26.6%) and HTN (1.9% vs 1.6%) |
| COR-DM
N=505 + reduced calorie diet (est. 500kcal/day decrease in caloric intake), behavioral counselling and physical activity involving 30 min walks three days/ week Obese T2DM patients with Hba1c > 7% despite diet, exercise and/or oral antidiabetic agents |
Randomized 2:1 to receive
|
Week 56 results:
LSMD: -1.72 (p<0.001 for NB vs placebo) ≥5% BW decrease: 14.1% (placebo), 28.1% (N32+B) |
AEs occurred in 85.2% of the placebo arm and 90.4% of the NB arm.
Notable AEs that occurred more frequently in the NB arm were: GI disorders (64.6% vs 31.4%) and HTN (9.9% vs 4.1%) |
| COR-BMOD
+ intensive behavioral modification program consisting 28 group counselling sessions and a prescribed diet and exercise regimen |
Randomized 3:1 to received:
|
Week 56 results:
LSMD: -1.91 (p<0.001 for NB vs placebo) ≥5% BW decrease: 33.2% (placebo), 50.2% (N32+B) |
AEs occurred in 88.0% of the placebo arm and 93.7% of the NB arm.
Notable AEs that occurred more frequently in the NB arm were: GI disorders (65.1% vs 39.0%) and HTN (2.4% vs 2.0%) |
| Abbreviations: N: Naltrexone, B: Bupropion, SR: sustained release, BW: bodyweight, MACE: major adverse cardiovascular events, CVRF: cardiovascular risk factors, CVOT: cardiovascular outcomes trial, LSMD: least squares mean difference | |||
Table 1. Phase III COR Clinical Trial Program – Study Details
Final thoughts and clinical practice implications
Contrave represents the first treatment for obesity to target reward centers in the central nervous system. The bottom-line is that the drug results in greater weight loss versus placebo in obese or overweight adults in the presence of at least one weight-related comorbidity. However, clinically meaningful benefit remains unclear as the improvement in, or prevention of, weight-related complications were either not assessed or could not be statistically evaluated. Treatment discontinuation was also common in the RCTs, often due to adverse effects. There is also insufficient evidence to demonstrate weight loss maintenance with Contrave beyond one year of treatment, which can be a major limitation considering the progressive nature of the disease. Further, patient access also remains uncertain given the presently unknown local pricing and reimbursement pathways.
Notwithstanding, as the burden of obesity continues to burgeon, appropriate solutions to manage obesity and achieve better health outcomes are urgently needed to relieve the strain on our local healthcare system. Intersectoral action is needed to support access to programs and drug therapies that can help to reverse current epidemic trends. There are limited treatment options presently available for obesity in Singapore and Contrave will ultimately provide relief in a disease landscape plagued by heterogeneity and high unmet need.
