Role of Bupropion Plus Naltrexone for the Management of Obesity

Obesity has been and still is a concern among the American population.  By the American Medical Association, obesity is a recognized disease state and is a risk for chronic diseases such as diabetes and osteoarthritis.  Lifestyle modifications including exercise and healthy diet are pertinent in treatment, however, if obesity is not cured which includes a high BMI of at or above 30 kg/m2, intervention of pharmacologic treatment may be necessary.  One of such treatments is branded as Contrave, which is bupropion plus naltrexone and is FDA indicated for chronic weight management.  This article reviews the clinical evidence in that regard.

There is evidence that suggests bupropion may help with weight loss by itself, however, working in conjunction with naltrexone, naltrexone can increase bupropion’s effect on the POMC neurons in the hypothalamus to cause appetite suppression.  It blocks the mu-receptors and results in an increased activity of POMC neurons leading to weight loss.

Five articles were included in this study as a data source.  In the clinical trials evaluated, it can be noted that there is substantial evidence that supports the efficacy of bupropion plus naltrexone, compared to placebo, in obesity management.  Results from these trials show that the average weight loss was 6.8% from baseline and 4.3% from baseline with the placebo subtracted.  About 66% and 42% of patients randomized to treatment also respectively lost 5% and 10% of weight from baseline.  Adverse effects which include nausea and constipation were the most common reason patients stopped the medication during the trials.  Dry mouth, vomiting, dizziness, and heartache were also experienced.  A limitation is that this drug’s efficacy hasn’t been studied in the Hispanic, African American, and Asian populations.

Since weight management medications are becoming more popular in the treatment of obesity, it is valuable that this review was done on these clinical trials to show the efficacy.  This also may lead to the possibility of a generic formulation.  In the future I hope to see an established efficacy of the drug in other racial populations.

J Pharm Technol. doi:10.1177/8755122515624220 (published 11 January 2016).

An Association Between Liraglutide Treatment and Reduction in Excessive Daytime Sleepiness in Obese Subjects with Type 2 Diabetes

A study was conducted to see whether liraglutide helped with improving excessive daytime sleepiness for those with Type II diabetes who were also obese. This included 158 obese adults with a body mass of over 30kg/m2 and Type II diabetes who had begun liraglutide therapy at the start of the study. A significant amount of data was collected, including data from the Epworth Sleeping Scale (ESS), anthropometric parameters, glucose-control, and metabolic parameters. This data was collected at baseline and at both one month and three months after baseline.

The results showed major reductions in ESS score with the study participants at both months 1 and 3 (-1.3±2 p <0.001 and -1.5 ± 3.0 p<-.001, respectively). Significant reductions were also seen after 3 months in body weight, BMI, waist and neck circumferences, HbA1c, mean blood glucose, fasting blood glucose, triglycerides, and total cholesterol levels.

Overall, 3 months of liraglutide treatment proved effective in reducing excessive daytime sleepiness in obese participants with Type II diabetes. More research is required to see if liraglutide could improve other abnormal sleep pattern disorders and obstructive sleep aponea. I am wondering if liraglutide does one day prove to be effective in improving these disorders, would it be able to be indicated for patients without diabetes or obesity but with sleep disorders?

BMC Endocr Disord. 2015 Dec 4;15:78

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669657/

Effect of Metformin Added to Insulin on Glycemic Control Among Obese Adolescents with Type 1 Diabetes

Studies currently show that 24% of children and adolescents with Type 1 Diabetes are overweight and 15% are obese. The need for high doses of insulin may further promote weight gain. Additionally, insulin resistance has been associated with increased risk for cardiovascular risk factors. Metformin lowers glucose and was associated with low insulin doses without having an effect on A1C.

A trial was conducted using patients aged 12 to 19 diagnosed with Type 1 Diabetes for at least one year who had an insulin pump or administered at least 3 injections of insulin each day. The patients had an A1C between 7.5% and 9.9% and were in the 85th percentile for BMI. The patients were given 500 mg of metformin that was titrated over 4 weeks to reach 2000mg daily. The rest of the patients were given a placebo.

The baseline A1C was 8.8% in each both groups. At 13 weeks, the mean change in the metformin group was -0.2% and 0.1% in the placebo group. However at 26 weeks, the mean change in the metformin group was 0% and 0.3% in the placebo group. There was no significant difference for glycemic control. However, the patients in the metformin group used less insulin throughout the 26 weeks than the patients on the placebo and more patients in the metformin group maintained or lost weight.

In conclusion, metformin did not improve glycemic control in children or adolescents with Type 1 Diabetes. A few outcomes were favored but not significantly. Additionally, taking metformin increases the risk of GI adverse effects. Therefore, it is not indicated to prescribe metformin to this patient population.

This is interesting because many people do not fully understand the difference between Type 1 and Type 2 Diabetes and the medications to treat each. It is important to know what medications are indicated for each to educate children and parents. Thoughts on another oral medication that may be better suited for this patient population?

JAMA. 2015;314(21):2241-2250. 

A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

Obesity is a serious problem in the United States.  Obesity increases a person’s risk for a multitude of health problems, including diabetes mellitus type 2.  However, it is sometimes extremely difficult for individuals to lose weight through lifestyle changes alone, especially as they get older.  In this study, the use of 3.0 mg of liraglutide daily for weight loss was studied to determine whether or not it is efficient and safe.

The study was a placebo-controlled, double-blind trial that lasted 56 weeks.  3731 patients were involved.  No participant had type 2 diabetes and every person had a BMI of 30 or more or a BMI of 27 or more and dyslipidemia or hypertension.  Each participant received either a daily dose of 3.0 mg liraglutide or a placebo.  At the end of the trial the primary end points were change in body weight and percentage of patients that lost at least 5% or 10% of their body weight. The results of the study showed that the group assigned liraglutide lost a mean of 8.4 ± 7.3 kg while the group assigned a placebo lost only 2.8 ± 6.5 kg.  Additionally, participants in the liraglutide group 63.2% lost at least 5% of their body weight and 33.1% lost at least 10%.  In the placebo group only 27.1% lost at least 5% and 10.6% lost at least 10%.  All of the differences between the groups were statistically significant.

I found this study interesting because I was unaware of any prescription medications currently being tested to help weight loss.  I believe if a medication can be determined to help weight loss without serious side effects then it should be used to help the country’s obesity problem.  However, a medication cannot be the sole technique used.  People on the medication should also restrict their diet and exercise regularly.  Even if the medication is approved for weight loss, it should only be temporary.  Patients need to learn how to maintain a healthy lifestyle so that they can eventually succeed without it and not take the medication permanently.

Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 Mg of Liraglutide in Weight Management. N Engl J Med. 2015; 373(1): 11-22.

http://www.nejm.org/doi/full/10.1056/NEJMoa1411892#t=abstract

Prevalence of Sugar-Sweetened Beverage Intake Among Adults — 23 States and the District of Columbia, 2013

The 2015-2020 Dietary Guidelines for Americans states that only 10% of a person’s daily calories should come from added sugar. They identified sugar-sweetened drinks as one of the most significant sources of sugar in the U.S., and frequently consuming these types of beverages is associated with many health conditions such as Type 2 diabetes, obesity, and cardiovascular disease. In an NHANES study, it was found that 50.6% of U.S. adults drink at least one sugar-sweetened beverage per day, and in certain regions of the country, such as the Northeast and South, this intake was even higher, reaching 68.4% and 66.7%, respectively. When looking at specific states, Louisiana, Mississippi, and West Virginia have the highest rate of sugar-sweetened beverage consumption. When looking at other factors that cause an increase in sugar consumption, the highest prevalence was seen in adults ages 18-24 years old, in men, in non-Hispanic African Americans, in unemployed adults, and in people with less than a high school education. The intake of these high sugar-content beverages was also found to be an effective biomarker for inflammation and insulin resistance that can then lead to cardiovascular disease and diabetes. Public health actions that should be taken to reduce the intake of these sugary beverages include education and awareness initiatives, increasing the access to healthier food options, food service guidelines being more readily accessible, and the promotion of drinking water in schools and in the general population. In addition, health care providers can screen patients’ sugar content and provide counseling on how to reduce their intake and give resources to help support them in this change.

MMWR Morb Mortal Wkly Rep.2016;65(Early Release):169-174

I chose this article because obesity and diabetes are two extremely common illnesses facing the American population. Food and beverages that contain high levels of additives, including sugar, are a major source of these problems. As this survey has shown, this problem affects a high percentage of our population and this will only increase if we do not take action. Making healthier options, such as fruit, vegetables, and water more available to the public, especially is the Northeastern and Southern regions of the country, will help reduce the prevalence we are seeing. Pharmacists counsel patients everyday on the numerous medications that are available for these conditions associated with high sugar intake, but we should also be counseling the patient on life-style changes. What good is the medication if the person does not change the behavior that is the core of the problem? I believe we need to shift our focus from purely talking about the side effects of these types of medications to informing the public that these medications are actually side effects of their high-sugar intake, and although the medications are helpful, they should not be seen as the solution. As health care providers, we need to start motivating people to change their dietary behaviors to prevent these conditions from occurring, and to prevent people from taking additional and unnecessary medications.

 

 

 

Pharmacotherapy Options for Obesity

A recent article published in The Annals of Pharmacotherapy did a comparison of the available pharmacotherapy options for patients struggling with obesity. Specifically, Nuffer and colleagues looked at phase 3 clinical trial data from 4 new drug therapies that have been approved for the weight management and obesity. Because obesity is closely related to a wide variety and large number of health problems and disease states, it is important to look into potential pharmacotherapies that could be helpful and effective. The drugs studied in this trial are lorcaserin, naltrexone/bupropion SR, phentermine/topiramate ER, and liraglutide. According to the research in this article, the phase 3 clinical trial data shows that each of these four medications contribute to long-term weight loss. Additionally, each of the four drugs can also lead to GI-related adverse events, such as nausea, vomiting, and constipation. One important note about all of the medications is that they are all pregnant category X drugs.

The authors conclude by explaining that the introduction of these 4 medications approved for the management of obesity advance a physician’s ability to effectively help their patients. These authors examined the data from each of these medications but there have not been any direct comparisons performed between them to tease out which would be the most effective. All of the medications show promise at achieving long-term weight loss. The suggestion offered by the authors is that because there is not a single drug that stands out as being better than the others, physicians need to decide on medications in a patient-specific manner. Other factors such as lifestyle, other disease states, and other medications could impact the decision of which medication to use.

Overall the article was meant to summarize the benefits and problems associated with 4 medications recently approved for weight management and obesity. As noted by the authors, the lack of a direct comparison between the medications means that there is not yet an objective means of determining which of the drugs if any would be safer or more effective. Obesity is a serious problem that is affecting people around the globe and is directly associated with many negative outcomes. As of yet, there is not a truly good means of maintaining long-term weight loss so I am looking forward to following these medications to see if we can finally provide patients with the help they need to lose weight.

Nuffer W, Trujillo JM, Megyeri J. A Comparison of New Pharmacological Agents for the Treatment of Obesity. Ann Pharmacother. 2016 Feb 17.

http://aop.sagepub.com.pitt.idm.oclc.org/content/early/2016/02/16/1060028016634351.full

Fish Intake in Pregnancy and Child Growth

Fish are commonly exposed to persistent organic pollutants, which may have endocrine-disrupting properties that contribute to obesity development. Fish intake of pregnant mothers has been shown to increase fetal growth, but this study set out to see if increased fish consumption affects child obesity as well.

Over 26,000 woman through the span on 15 years were studied through childbirth and followed up with every two years until the child was 6 years old. The results were that woman who consumed fish more than 3 times/ week gave birth to children with higher BMIs compared to those children whose mothers consumed fish less than 3 times/ week. The high fish intake mothers had children who had increased risk of rapid infant growth as well as increased risk for obesity at 4 years and 6 years old.

FDA advice on fish consumption in woman who are pregnant, breast feeding, or thinking about becoming pregnant changed in June of 2104 to match the data found in this trial. FDA now recommends for pregnant woman to consume more fish due to its cognitive benefits for their offspring, but to consume no more than 3 meals of fish/ week.

As pharmacists, we deal with a variety of factors that impact our patients health. Fish oil supplements as well as diet is something that we need to consider when counseling maternal populations.

Link to Article

Stratakis N, Roumeliotaki T, Oken E, Barros H, et al. Fish intake in pregnancy and child growth. JAMA Pediatr. 2015. doi:10.1001

Drug Dosing and Pharmacokinetics in Children With Obesity

A sixth of children in the United States are affected by obesity. When a person is obese, their body composition and physiology is altered, which results in a change in effects associated with drug dosing and pharmacokinetics. Thus, the effect of  drug disposition on obesity can possibly lead to therapeutic failure or toxic side effects. Although this fact is well known, there is little information known about the effect of childhood obesity of drug pharmacokinetics. Currently, there is no comprehensive, evidence based understanding of the effect of childhood obesity of drug pharmacokinetics. Thus, researchers conducted a systematic review to find studies in the last 40 years that provided evidence of the effect of obesity on drug disposition in children. They searched literature databases to find if any studies contained data on drug clearance, volume of distribution, or drug concentration in obese children.

Researchers were able to discover 20 studies in the last 40 years that met the inclusion criteria and contained pharmacokinetic data for 21 drugs. Out of these studies, 11 out of 17 drugs had clinically significant pharmacokinetic alterations observed in children with obesity. In addition, for 5 out of 13 drugs studies showed that pharmacokinetic alterations resulted in substantial differences in exposure between children with and without obesity. Overall, studies indicated important obesity-related changes in drug pharmacokinetics. However, there were many limitations associated with these studies. For example, the majority of studies included small numbers of children. Furthermore, many drugs that were studies are not commonly prescribed drugs. There was no data for several important drug classes where obesity-related toxic overdosing or subtherapeutic underdosing may have been previously observed in adults, such as in acute care, cardiovascular, and anesthesia.

After reviewing these articles, researchers concluded that the relative information available about the drug pharmacokinetics of children who are obese is concerning, because it is so limited. To account for physiological and pharmacologic factors, some physicians adjust weight-based dosing using various metrics of body size, such as ideal body weight. However, this dosing strategy is largely based on theory or extrapolated data from studies in adults. Some analyses have identified that these dosing strategies may give false predictions of clearance and other pharmacokinetic values. To address this issue, researchers are currently collaborating with the National Institute of Child Health and Human Development in a systematic review of acute care and commonly used drugs to develop a pharmacokinetic database for obese children. As a result, data generated from this review will be utilized to make appropriate dosing recommendations for obese children. For future studies about pharmacokinetics in obese children, researchers hope to focus on including drugs if different therapeutic drug classes, based on drug use, medical need, and expected pharmacokinetic alterations in obesity (based on adult studies).

After reviewing this article, I was surprised to find that there were very few studies published about the pharmacokinetic factors of drugs in obese children. Since there are many children who are obese in the United States, I believe it is important to discover the pharmacokinetic parameters of drugs in obese children. With more information available, pharmacists and physicians will be able to better treat these children. Did you find this article surprising? Why or why not? Do you have any thoughts on why there have not been many studies published about childhood obesity and drug pharmacokinetics?

 

Harskamp-van Ginkel MW, Hill KD, Becker KC, et al. Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review. JAMA Pediatr. 2015;169(7):678-685.

 

The Obesity Epidemic- Understanding the Disease and the Treatment

Childhood obesity has been a hot topic in recent years. From Michelle Obama’s program to reconstruct school lunches to the many childhood fitness centers opening up, the health of our future has been on everyone’s mind. The prevalence of childhood obesity has risen from 4% to 6% from 1999-2004 to during 2011-2012 as stated in the article. Our children’s chances for more serious diseased states in their later years is increasing with every incidence of severe childhood obesity.

In this editorial, there is good evidence showing that obesity can be considered a disease that is initiated by interactions of genetics and the environment. Around 90% of children with severe obesity will become obese adults. The disease may start off as a lifestyle problem, but it can rapidly lead to energy-balance imbalances. In a way, the body sets a new body-weight set point and continues to try to maintain that.

It’s most important to note that none of the medications that have recently been approved and studied in adults to lower body weight have been studied in children. These drugs such as phentermine, lorcaserin, liraglutide have no evidence backing their use in the younger obese population. This puts a damper on the treatment of childhood obesity and the prevention of what disease states await these children. Bariatric surgery has been used on some adolescents as a means of sustained weight loss. But, the risks and benefits have yet to be closely analyzed in this population. There are social benefits to the patient but longitudinal studies of these patients still has to be done to establish if there are any long term risks. The main point of the article is that obesity is difficult to manage and prevention is one of the best and only ways that we can safely target our adolescent and child population against this disease. Lifestyle interventions should be closely instituted in children and followed through during their learning ages to best equip them to make the healthiest and safest decisions in their lives.

Knowing that lifestyle is one of the biggest preceptors to childhood obesity, should the parents of obese children be instructed to take parental guidance classes to help themselves and their children make healthier lifestyle changes?

 

 

Citation:

N Engl J Med. 2016; 374:177-179

http://www.nejm.org/doi/full/10.1056/NEJMe1514957

 

 

 

Weight Gain in Children

In the longitudinal study, researchers were determined to track and identify possible causes of adolescent weight gain in hopes of finding an area of effective intervention. The study included 652 children aged 4, 6 and 8 with follow-ups every two years as well as regular community health checkpoints. The body mass index and body fat phenotypes were measured for each of the children at the beginning and throughout the study. Of the beginning 652, nine percent were overweight and just .2 percent were obese. Additionally, genetic risks for obesity were measured using a genetic risk score for 32 single-nucleotide polymorphisms. The results of the study indicated that children with a higher genetic risk for obesity gained weight and fat mass much faster than those without. The study was looking more specifically at the appetite traits of individuals with and without the genetic risk for obesity in order to eventually use this as a means of treating and preventing obesity, especially in the younger populations. The study revealed that those children with a higher genetic risk for obesity had higher levels of obesogenic appetite traits meaning that their decision making and portion control were poor in comparison to a healthy individual.

Identifying this specific problem with weight gain in the adolescent population is significant in making a future change in the developments and obesity patterns of children. Knowing what area to target for intervention can help lead to a more successful treatment plan. The results of the study ultimately lead to the idea that education is a large part of the treatment plan. Teaching families including parents and the children at risk, how to eat healthy can avoid the significant weight gain associated with the genetic risk that may be unavoidable. As my future role in the field of medicine, I can make an impact with direct patient care and counseling to aide in the education process of treating and changing the appetite traits of children with a genetic risk for obesity.

JAMA Pediatrics. 2016;170(2)