GLP-1s & Medications

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.

Comparing the effectiveness of weight loss drugs

A recent analysis has compared the effectiveness of the 5 weight-loss drugs that have been approved by the USA’s FDA. These drugs are: orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide. The drugs were compared against a placebo, and not against each other. The authors of this study conducted a systematic review with a meta-analysis that included 28 randomised clinical trials, which related to 29,018 patients. They also looked at the incidence of adverse events whilst patients were on these drugs.

Each drug was associated with achieving at least 5% weight-loss at 52 weeks, with phentermine-topiramate and liraglutide having the highest odds of achieving 5% weight loss. The authors highlighted that more work is necessary to discover the long-term effects of pharmacotherapy for obesity, as concerns over their safety still exist amongst clinicians. The authors go on to explain how there are no recommendations for clinicians when it comes to choosing individual drugs for patients and with differences in safety, efficacy and response to therapy, the ideal approach to weight-loss should be highly individualised, identifying appropriate candidates for pharmacotherapy, behavioural interventions and surgery.

Does nanoparticle drug delivery offer hope to obese patients?

Researchers at MIT and Brigham and Women’s Hospital have developed nanoparticles to deliver anti-obesity drugs. In a study using a mouse model, researchers were able to effectively deliver drugs which converted white adipose tissue into brown adipose tissue – thereby helping to burn off the fat. The drugs also increased vasculature to these areas, allowing for more drugs to be subsequently delivered to the correct areas, helping to avoid unwanted side effects in other parts of the body.

The researchers are particularly encouraged to know that they can deliver the drug to particular areas and have an overall positive effect. After treating the mice intravenously, it was noted that those on a high-fat diet lost approximately 10% of their body weight, with cholesterol and triglyceride levels also dropping. Furthermore, the treatment did not cause any side effects to the mice. Further research involves looking into an easier delivery approach of the nanoparticles, such as delivering them by mouth – something that has proven difficult in the past. Overall, the authors are reassured by their results and are looking forward to taking the research further.

Fatty liver disease reversed by pill in mice

In the search for a pill to combat obesity and its associated co-morbidities, researchers have found a bile acid that is capable of preventing and treating fatty liver disease in mice. In a recent study obese and diabetic mice were fed glycine-beta muricholic acid (Gly-MCA) pills. Even with a high fat diet these mice were less fat and had less insulin resistance than the control group who weren’t given Gly-MCA.

Gly-MCA is a bile acid that can inhibit the farnesoid X receptor (FXR) which maintains metabolism by sensing and regulating bile acids, fats and glucose in the body. The receptor itself plays a complex role in the pathogenesis of metabolic dysfunction in the body and that may be why Gly-MCA had such a large effect on the obesity of the mice. Usually, bacteria break down the bile acids that inhibit FXR, however these researchers found a bacteria resistant acid, Gly-MCA, that also inhibits FXR, allowing them to conduct the study. The drug itself can be consumed in pill form for humans and provides a possible avenue for the treatment of obesity, as well as fatty liver disease. However until now there has been little research into its usage, particularly with regard to toxicity. In the mice, there were no signs of systemic, hepatic or intestinal toxicity, but more work remains to be done in order to fully explore the effects of this drug in animal models and humans.

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Antibiotics encourage obesity

Continued use of antibiotics in children can lead to obesity, changes in bone growth and altered gut bacteria, according to a new study in Nature Communications. The team stated that, in the USA, 262 million courses of antibiotics were prescribed to outpatients, that’s 842 per 1000 people a year, with use at its highest in children under 10. Estimates suggest children may have had 10 courses by this age. Antibiotics are well known to impact on microbial function, but little study has been done into how they affect host health during critical developmental stages.

The researchers mimicked childhood antibiotic use by using mice as their models. They found that early life pulsed antibiotic treatment (PAT) leads to short term increases in mouse weight and bone growth, whilst also leading to long-term changes in composition of gut bacteria. These changes included altering the species of the bacteria present and therefore the metabolic functions as well. Furthermore, they found that the bacteria in the antibiotic treated mice took much longer to adapt to new diets than those without antibiotics. The team remain cautious regarding the implication for humans though.

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Liraglutide, a new drug for weight management

Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon like peptide-1 analogue that is used in pill form to treat diabetes, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. There has been concurrent reductions in glycaemic variables and multiple cardiometabolic risk factors, as well as improvements in health-related quality of life.

The 56-week study was a double-blind trial involving 3731 patients with a BMI above 30 that did not have type 2 diabetes. Patients were randomly assigned in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients). Both groups received counselling on lifestyle modification.

63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight, and 33.1% and 10.6%, respectively, lost more than 10% of their body weight. This illustrates the effectiveness in losing weight from this recently marketed drug, which has been approved by the European Medicines Agency but is yet to be licensed in the UK, where still the only available drug is orlistat.

Study link