GLP-1RAs & Medications

Antibiotic consumption and childhood obesity

A growing base of evidence suggests antibiotic use results in microbial disturbances in the gut. These disturbances in the microbiome may contribute to weight gain. In comparisons between individuals, it has been shown that those with obesity have a lower diversity of microbes in their gut. This research is supported by studies in animal models. In infancy, a baby’s microbiome is rapidly developing. It is thus suggested by some researchers that any antibiotic exposure in infancy may impede the establishment of the healthy gut microbiome and have lifelong metabolic consequences.

In a systematic review and meta-analysis, Miller and colleagues showed that the antibiotic use in infancy is indeed related to overweight and obesity in childhood. There were notable differences however by gender with boys appearing to be more affected by antibiotic use than girls.

The authors looked at multiple drugs finding that macrolides were most strongly related to increased obesity risk while narrow-spectrum drugs were not significantly associated. These researchers suggest in the fight against childhood obesity we need to examine antibiotic prescriptions and use across populations.

Efficacy and safety of semaglutide for weight loss in patients with obesity

In this paper, published in The Lancet, the authors sought to assess efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide, in comparison with a similar drug liraglutide, and placebo. The study was done in 8 countries, involving 71 clinical sites, with the primary endpoint being weight loss at week 52.

GLP-1 analogues mimic the function of human GLP-1, which regulates insulin secretion and glucagon secretion. These processes are linked with appetite, satiety and energy intake. This study found that these drugs, which were initially licensed for diabetes treatment, resulted in weight reductions which were significantly greater than the placebo group at 52 weeks. This weight loss is primarily due to the individuals consuming less energy, because of a combination of appetite suppression and enhanced satiety. Semaglutide was found to be the most effective, with weight loss of 11-14%, compared to Liraglutide’s 7-8%. In terms of side-effects, the most common complaint was of nausea. This was found to be dose dependent, so higher doses made side-effects more likely. Overall however, semaglutide was well tolerated, with no unanticipated safety or tolerability outcomes. Semaglutide has been shown to have a good benefit-risk profile which further supports its use as a weight management drug in its own right, instead of just being licensed for diabetes. Phase-3 studies are ongoing.

Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients

In some patients, weight-loss guidelines recommend the use of pharmacological agents as adjuncts to lifestyle modification. Although not many are licensed, they have been shown to be effective for long-term weight management. One of the serious downsides of these drugs is the side-effects. Depending on their sight of action, they have been known to precipitate severe complications in the cardiovascular or neuropsychiatric systems, leading to their removal by regulatory agencies over safety concerns.  

Lorcaserin is a selective serotonin 2c receptor agonist that modulates appetite. It has proven efficacy for weight management in overweight or obese patients. This paper published in the New England Journal of Medicine sought to determine the cardiovascular risk associated with its use as an obesity treatment. From the study of 12,000 patients, it found no increased risk of cardiovascular complications. It also found that alongside significant weight loss there were also reductions in triglyceride levels and in dysglycaemia.  In addition, it was found that there was an improvement in heart rate and blood pressure, which is in contrast to most other weight loss agents. Overall, this drug is an effective adjunct to lifestyle interventions in patients with obesity and cardiovascular disease, and doesn’t increase the risk of cardiovascular events.

How Physiological Changes Associated with Obesity Affect Drug Metabolism

Obesity is known to have a significant impact on many organ systems that are crucial in drug metabolism. As the prevalence of obesity continues to rise, clinicians are being challenged with the problem of dosing in the extreme overweight population. This review article discusses the different physiological changes associated with obesity and how they affect absorption, distribution, drug metabolism and clearance in morbidly obese patients.

The changes that occur in the organs of the body do not correlate linearly with BMI, but also includes factors such as time and individual body composition. For example, in the kidney of an obese patient, renal clearance is initially enhanced by a compensatory hyperfiltration and hyper-perfusion, though, eventually, this declines as a result of a constantly elevated intra-glomerular pressure which leads to chronic kidney disease. Likewise, cardiac output is increased in obese patients in order to provide oxygen and nutrients to the excess tissue. This should mean that that blood flow to the liver increases, however due to non-alcoholic fatty liver disease resulting in steatosis, together with sinusoidal narrowing, blood flow may actually decrease over time.

Obesity also has an effect on the gastric emptying and gut permeability, meaning that drugs are absorbed at different rates to normal. Drug penetration into tissue is also affected, meaning that a higher dose may be needed in order to reach effective concentrations. For example, with antibiotics to treat a local infection, obese patients may require a much higher dose, which can then introduce issues of drug toxicity.

What is clear from these few examples is that with a growing number of obese patients, there needs to be a quantitative system in place that can derive drug dosing recommendations for obese patients. Currently there is a lack of understanding of how obesity affects the pharmacokinetics and pharmacodynamics of drugs, which leads to improper and potentially dangerous dosing of obese patients.

To learn more about obesity, its prevention, and its treatment please look at CCH’s Postgraduate Academic Courses in Obesity Care, and CPD Short Courses in topics such as childhood obesity and behaviour change, designed to up-skill health professionals in this vitally important, and often overlooked, area of care.

Efficacy, Safety, and Mechanisms Of Herbal Medicines Used In The Treatment Of Obesity: A Protocol For Systematic Review

There is a huge amount of conflicting evidence over the potential efficacy of herbal remedies for the treatment of obesity. Although several systematic reviews have been conducted, the market is saturated with poorly evidenced claims, and a huge number of different remedies. This study sets out a protocol for a comprehensive systematic review into herbal remedies and their efficacy at treating obesity.

Herbal medicines can cause weight loss through 5 different mechanisms, namely appetite control, stimulation of thermogenesis, inhibition of fat absorption as well as decreasing lipogenesis.

Efficacy has been evaluated before, however, the authors feel a new systematic review, focussing on clinical trials data is needed. This systematic review will be seen as an update, with all new data plus any new research on active components and methods of action.

Herbal remedies are defined as raw or refined products derived from plants or parts of plants, in this case used for the treatment of obesity. The primary outcomes expected will be an improvement in BMI, waist circumference, waist-hip ratio, body fat and appetite. Secondary outcomes will focus more on the metabolic features of obesity, meaning improvements to cholesterol, low-density lipoprotein, high-density lipoprotein, blood pressure, triglycerides and blood sugar.

The increasing number of randomised controlled clinical trials means that a new and updated review of the mechanisms of action and efficacy of these treatments is needed. They have the potential to become a cheap new therapy in the treatment of obesity or if proven otherwise, then this systematic review will put to rest the debate over their efficacy.

Future Pharmacotherapy for Obesity: New Anti-Obesity Drugs on the Horizon

This review published in Current obesity reports looks at how our increased understanding of energy regulation and neurohormonal pathways in energy homeostasis (the body’s mechanism for controlling caloric intake and energy expenditure) are being utilised to find pharmacological solutions to obesity. The review looks at centrally acting agents, gut hormones & incretin targets and other novel targets which include anti-obesity vaccines.

Centrally acting agents are drugs which work by altering brain neuronal circuits, by simulating or blocking the effects of other brain neurotransmitters, leading to changes in metabolism and behavior. This paper discusses four of these drugs, which can increase resting energy expenditure- leading to weight-loss- and can also change feelings of hunger/satiety, which then leads to decreased food intake.

Gut hormones and incretin targets are drugs that utilise the complex neurohormonal system of the gut and pancreas to alter feelings of hunger and fullness, with some also improving glucose control. The seven drugs discussed are at varying stages of clinical trials, some only being tested in animals while others are in phase-II. The promise in the phase-II trials is high though, meaning that this new class of anti-obesity drug could soon enter clinical practice.

Five other novel targets were also discussed. Firstly, a drug that reduces production of new fatty acids by the liver and converts stored fats into useful energy; leading to increased energy expenditure. Second, an enzyme inhibitor which leads to reduced absorption of fats in the gut; meaning fewer calories are extracted from food.  Third, a triple monoamine reuptake inhibitor of neurotransmitters in the brain, which has proven effective and entered phase-II trials, despite some safety concerns. Fourth is a growth hormone that turns white fat into brown fat; this leads to increased energy expenditure. Alongside this it also provides added benefits such as anti-inflammatory properties. The final drugs discussed are anti-obesity vaccines; these involve targeting molecules that lead to obesity (e.g. ghrelin) or a vaccine to an adenovirus that has been shown to cause significant obesity in mice and may also do so in humans.

New combination of drugs cause enhanced weight loss

Researchers at the University of Pennsylvania have found that a unique combination of weight loss drugs can have a dramatic effect on laboratory animals. The researchers studied the effect of two different drug classes that affect the hormones amylin and glucagon-like peptide-1 (GLP-1). They found that cycling between the two drug regimens over the course of a month achieved a greater degree of weight loss than normal regimens. These include a continuous combined therapy or using just one of the drugs.

Unlike many other trials that examine new drugs, this research involves drugs that are already approved by many different organisations, including the FDA. This means that the types of regimens being suggested could be in use in the very near future. Currently, the authors are finalising their work to show how the two hormonal systems interact with each other to achieve this greater weight loss.

Keeping an eye out for medications that can cause weight gain

In a study published in Gastroenterology researchers have urged physicians to be mindful of drugs that can increase weight gain in patients that are already obese. This must be done by evaluating the potential side effects of medications that are prescribed to this group of patients and familiarising themselves with the alternatives that may limit weight gain. Medications such as steroids or contraceptive pills are commonly given to obese patients; however, these drugs may sometimes exacerbate the weight problems of the individuals.

The researchers want to highlight that each practitioner has a goal in mind, for example, a cardiologist may want to lower blood pressure, however the drug that they prescribe may in turn affect weight. Therefore, physicians must make themselves aware of the interactions between drugs and the potential alternatives that they may be able to use. In addition to this, there are some drugs that can minimise the bad effects of others; however this becomes difficult as patients get prescribed more and more medications. In summary, the researchers are hoping that their study will help physicians pay more attention to the overall side effects that medication has on individual patients.

Cancer-fighting drugs help weight loss

Researchers from the Mayo clinic have found that two common anti-cancer drugs have caused significant weight loss in mice. This effect was seen even though the mice continued consuming a high-fat diet. Originally, this research was conducted to address obesity’s impact on cancer treatment, however the shift of focus occurred once the weight loss was observed. The two drugs, methotrexate and cyclophosphamide were dosed to a level that reversed obesity, but without detectable toxicity. They also tested the drugs in mice without cancer and observed the same results.

The researchers were especially surprised by the ease in which they were able to reverse obesity, when compared to current strategies. They also controlled for other factors that may have influenced the outcome, such as ensuring that the mice were moving the same amount and consuming the same number of calories. The multiple effects of methotrexate and cyclophosphamide all came together to produce this outcome by depleting fat cell precursors. The researchers hypothesised that treatment with these drugs can lead to the liver burning off fat rather than keeping it in storage, however more research must be carried out to explore the full mechanisms of the drugs.

Narcolepsy drugs could help food addicts

Narcolepsy is a sleep disorder that causes people to fall asleep at inappropriate times, and now a recent study has found that a drug that is used in the condition may help food addicts lose weight. Recent evidence has shown that obesity is not just caused by a behavioural disorder, but many overweight people are physically addicted to foods rich in fat and sugar. When we consume good tasting food the reward centres in our brain release a chemical called dopamine which is involved in pleasure pathways. Some obese people are deficient in a certain type of dopamine, meaning that they have to eat more in order to release higher amounts of the chemical.

Scientists from the University of Warwick and Imperial College London have found that a drug called Modafinil, which is used in narcolepsy, may help reduce impulsivity and therefore food addiction. They have published their findings in Personality and Individual Differences. Food addicts are known to act impulsively, especially when it comes to choices about their diet. By giving these people more control, they may be able to manage their weight. Many food addicts know that they need to lose weight however, their desire for more food is overwhelming and this can commonly lead to psychological issues. The authors of this study hope that more research will be undertaken in order to better understand the potential uses of Modafinil in food addiction.

New drug treatment for rare genetic disease

A new drug has been shown to be effective in the treatment of a rare genetic disease that leads to obesity. In a paper published in NEJM, Setmelanotide was shown to induce weight loss and reduce appetite in patients with Pro-opiomelanocortin (POMC) deficiency. This extremely rare disorder, which leads to early-onset obesity and a high appetite, is caused by a defect in the MCR4 gene, and is thought to only affect 100-500 people worldwide.

Although only 2 patients were included in this trial, due to the disorders rarity, the researchers were excited by their response to setmelanotide as it highlights the importance of the MCR4 gene in weight regulation. The lead author, Dr Peter Kühnen, explains that if the continued use of the drug carries on being effective, then it could be administered in the treatment of other genetic disorders associated with obesity.

Obesity in China still a growing problem

A large study has found that 1 in 3 people are overweight and 1 in 7 are obese in the Jilin Province in Northeast China. Over recent years, China has been experiencing an increase in the rates of obesity within its population. The researchers of this paper wanted to examine a densely populated part of China in order to uncover influential factors that may be addressed in future health policy to protect people from obesity. The study included nearly 21,000 randomly selected adults in 2012.

They found many contributing factors, with the major one being the adoption of the ‘Western lifestyle’ across such a large population. The study also showed that regular intake of meat and alcohol, having been married and getting less than 7 hours sleep a night were all associated with a higher risk of developing obesity. The researchers were particularly worried about the rate at which obesity was growing and the subsequent increase in chronic diseases that will occur. They are hoping to increase awareness of this problem so that more effort is put into slowing these rates and preventing the development of obesity within China.