Weight Loss Study: Genetics and Response to Naltrexone/Bupropion

Weight loss can improve or prevent many obesity-related co-morbidities, yet time and again the cornerstone of obesity therapy - diet, physical activity and behavioral modification - fails to produce sufficient long-term weight loss in most individuals. In such cases, clinical guidelines recommend the addition of anti-obesity medication (AOM) when conservative methods are less than optimal. Yet even with the use of AOM, there is a wide range of inter-individual weight loss suggesting that there are "responders" and "non-responders." The variability in response to AOMs underscores the heterogeneity of obesity and the need for more personalized treatment that accounts for individual differences in etiologic factors. Given the strong heritability of obesity, it is possible that genetic factors play a role in an individual's response to a given pharmacotherapy.

This proposal focuses on the FDA-approved AOM, Contrave, which is a combination of two medications, naltrexone 32 mg and bupropion 360 mg (NB). Naltrexone is a µ-opioid receptor (MOPR) antagonist and bupropion inhibits the reuptake of dopamine and norepinephrine. Clinical trials of NB demonstrate a mean weight loss of 6.1% after 56 weeks of treatment; however, only 48% of patients achieved a clinically significant reduction in body weight of at least 5%. Knowledge of the likely mechanisms of action of NB makes it possible to address what might underlie the variability in response. The bupropion component of NB activates the proopiomelanocortin (POMC) neuron, a key regulator in decreasing food intake and stimulating energy expenditure, through stimulation of dopamine D2 receptors (DRD2). Naltrexone also activates POMC neurons by binding MOPR.

The investigators postulated that some of the variability in response to NB may be due to the Taq1A genetic variant (rs1800497) located in the ankyrin repeat and kinase domain-containing protein 1 (ANKK1) gene, adjacent to the DRD2 gene. Individuals carrying at least one minor allele of the rs1800497 polymorphism (termed Taq1A A1+) represent about 45% of the population and have 30-40% fewer brain DRD2. Carriers of the minor allele likely have a relative deficiency in dopaminergic activation of POMC neurons and, therefore, might receive the greatest benefit from a drug that activates POMC neurons. With this hypothesis in mind, the investigators conducted a retrospective proof-of-concept pilot study reviewing charts of patients treated with NB and found that individuals with the Taq1A A1+ genotype had a greater response compared with non-carriers, suggesting that this genotype could be used to predict successful weight loss.

In Aim One, the investigators propose to rigorously test the hypothesis that presence of the Taq1A A1+ polymorphism is associated with greater weight loss with NB compared with the A1- genotype. In Aim Two, the investigators will explore other genetic polymorphisms that might influence the efficacy of NB such as the fat mass and obesity-associated (FTO) gene which modulates DRD2 signaling, as carriers of risk alleles in both the FTO and ANKK1 gene demonstrate altered responses to reward-learning tasks associated with negative outcomes. Functional polymorphisms within genes that influence the metabolism of bupropion and naltrexone will also be examined in relation to weight loss outcomes. The ultimate goal is to incorporate pharmacogenetics into obesity medicine in order to maximize positive results and limit unnecessary cost and exposure to side effects of medications that provide minimal benefit to the individual patient.

Inclusion criteria

• Men and women ages 18-65 years
• BMI 30-50 kg/m2 or
• BMI 27-29.99 kg/m2 with at least one weight-related comorbidity including controlled hypertension, dyslipidemia, obstructive sleep apnea, or osteoarthritis of a weight-bearing joint.

Exclusion criteria

• Obesity of known endocrine or hypothalamic origin
• HbA1c > 6.5%
• Cerebrovascular, cardiovascular, hepatic or renal disease
• History of seizures, serious psychiatric illness or suicide attempts, drug or alcohol misuse within prior 24 months
• Glaucoma
• Current tobacco use on a regular basis
• Use of dopamine agonists, opioid analgesics, antipsychotics, antidepressants, neuroleptics, naltrexone, diabetes medications
• Use of Monoamine oxidase (MAO) inhibitors < 14 days prior to screening
• Concomitant use of CYP2B6 inhibitors
• History of anorexia nervosa or bulimia
• Previous surgery for obesity
• Weight loss device intervention within prior 2 years
• Currently pregnant or lactating, planning pregnancy or refusal to use birth control when appropriate (Women of childbearing potential will be required to use effective contraception.)
• Blood pressure > 145/95 (use of anti-hypertensives will be allowed with the exception of verapamil, which can cause hyperprolactinemia)
• Clinically significant thyroid disease
• Triglycerides > 499 mg/dl
• Current use or use of weight loss medication within prior six months
• Any lifetime weight change deemed significant by Principal Investigator
• An affirmative answer to any question in the Columbia-Suicide Severity Rating Scale