Non-surgical weight loss in a capsule - watch this space!
16 May 2023
I love seeing articles like this that describe what may be coming over the horizon for obesity management. Anti-Obesity Medications (AOMs) have been becoming more mainstream which is likely to make them more accessible and affordable. This is an interesting one though, because it isn't actually a medication - it acts locally on the GI tract. The obvious advantage of this is that there are fewer side effects. It's main mechanism of action is to absorb gut contents which then decreases the absorption of calories and sugar from a meal. The weight loss stats appear to be impressive too.
We are using more AOMs in the treatment of obesity in the pre-op stage and even as an adjunct in the post-op stage. Saxenda is being used by some - it is expensive and has a significant side effect profile that makes it intolerable to some. Ozempic, Saxenda's cousin, has recently been approved by Medsafe for use in New Zealand - so look out for that becoming available too. Exciting times! With any of these medications, it is a case of trying it for yourself for 6 weeks and seeing how it works for you. Please contact us if you need more information or advice regarding AOMs. We look forward to making contact.
Results from the LIGHT-UP clinical trial for adults with overweight or obesity who have prediabetes or type 2 diabetes and were treated with either GS200 or placebo, revealed that approximately six out of ten adults treated with GS200 achieved clinically meaningful response to treatment (achieving at least 5% body weight loss), losing on average 11% of their body weight (~23lbs) and an average reduction of 5.5 inches off their waist circumference. The findings were presented at the European Congress on Obesity 2022.
GS200 is a non-systemic, superabsorbent hydrogel in development for the treatment of obesity and for glycemic control. It is made by utilizing the same proprietary hydrogel platform technology Gelesis developed for its previously FDA cleared product, GS100 (Plenity). Like GS100, GS200 is made from naturally derived cross-linked modified cellulose, however with a higher molecular weight.
GS200 was designed to hydrate faster and create a higher elastic response in the GI tract compared with GS100. Its properties were optimised in preclinical studies based on its effect on the gut barrier and microbiome, as well as reduced insulin resistance and weight loss. Like GS100, GS200 is a three-dimensional matrix of cellulose, capable of absorbing a much larger volume of water in the stomach and small intestines.
Orally administered in capsules with water before meals, GS200 particles rapidly absorb water in the stomach and homogenously mix with ingested food. This creates thousands of small individual gel pieces with composition (cellulose and water) and elasticity (firmness) similar to solid ingested raw vegetables, without any caloric value. Once it arrives in the large intestine, the hydrogel is partially broken down by naturally occurring enzymes, and loses its three-dimensional structure along with most of its absorption capacity.
The released water is reabsorbed in the large intestine, and the remaining cellulosic material is expelled naturally. GS200 is considered a medical device because it achieves its primary intended purpose through mechanical modes of action consistent with mechanobiology constructs, and it is not absorbed through the gastrointestinal tract. GS200 received a Non-Significant Risk (NSR) determination by the FDA for the LIGHT-UP study.
Participants in LIGHT-UP were also instructed to follow a modestly reduced calorie diet along with moderate-intensity physical activity. In the GS200 group there was clear and early separation between responders and non-responders to treatment, and response to therapy could be predicted as early as 6 weeks of treatment.
“There is a very large population of adults with prediabetes and diabetes who have a greater need for weight loss due to higher medical risks and a greater difficulty losing weight,” said Dr Frank L Greenway, Medical Director and Professor at the Pennington Biomedical Research Center of the Louisiana State University and one of the study’s lead investigators. “The compelling weight loss data that favours diabetes and prediabetes is unique among weight loss treatments. Its convenient oral administration, and very favourable tolerability make it a potentially important tool to aid clinicians and patients achieve clinically meaningful weight loss.”
The multicentre, double-blind, randomized, placebo-controlled study enrolled 254 subjects and was designed to assess the change in body weight in adults with overweight or obesity, who have prediabetes or diabetes, after six months of treatment with a new oral superabsorbent hydrogel (GS200) or placebo. The study met both of its primary endpoints: the proportion of participants who achieved at least 5% body weight loss and the change in body weight after six months of therapy.
A highly binary effect was observed with the GS200 treatment group, with a clear separation between responders and non-responders as early as after 6 weeks of treatment. Among the adults who completed the study protocol requirements (PP population), 64% of GS200-treated adults were Responders vs. 41% in the placebo group (p=0.001). In the analysis which also included data from the participants who didn’t fully complete the study (ITT-MI), 55% of GS200-treated adults were Responders vs. 34% in the placebo group (p=0.0004). The average body weight loss of the Responders was 11% (approximately 23 pounds) and their waist circumference was reduced by 5.5 inches on average.
Importantly, Gelesis treated individuals had 2.8 higher odds compared with placebo to become Responders (p=0.0004), achieving the first primary endpoint of the study.
With respect to average total weight loss, the complete GS200 treatment group (including both Responders and Non-Responders) demonstrated superiority over placebo after 6 months of treatment (body weight loss of 7.1% vs. 4.6%, P=0.0029 in the PP population or 6.9% vs. 4.3%, P=0.0011 in the ITT population), thereby achieving the second primary endpoint.
GS200 demonstrated a highly favorable safety and tolerability profile as the overall incidence of adverse events (AEs) in adults treated with GSP200 was similar to the incidence of AEs in the placebo group.
Approximately 1 out of 3 GS200-treated adults were “super responders,” losing at least 10% of their body weight and on average losing 13% (~30lbs) or 7 inches off their waist circumference.
“There is a real need for tolerable, effective, and affordable therapeutics to aid in weight loss for patients with prediabetes and type 2 diabetes. Approximately 130 million Americans have prediabetes or type 2 diabetes and approximately 80% struggle with excess weight. Importantly, these individuals also have a high risk of heart disease and other serious chronic conditions, related to overweight and obesity, making this one of the biggest public health issues facing our society,” said Harry L. Leider, MD, MBA, FACPE, Chief Medical Officer of Gelesis. “These data show that GS200 produces clinically meaningful weight loss for the majority of patients and that it’s possible to identify these responders early in treatment. Given the highly attractive safety and tolerability profile, GS200 has the potential to become an exciting new therapy, especially among those in the lower spectrum of excess weight who also have prediabetes or type 2 diabetes.”
Brain networks can play a role in weight loss success.
7 April 2023
Whilst we know that our body weight and BMI is determined by many factors, it is the role of the brain that is very difficult to measure and see. This study uses functional scans of the brain to measure activity in different parts of the brain. The scans are repeated after food based stimuli are given to see how they affect the brain activity. The change in the functional activities of the brain are compared with weight loss outcomes after a "behaviour-based intervention" was given. The weight loss outcomes were directly correlated with the degree of activity in these specific brain networks, seeming to suggest that brain activity is dictating how well a patient is able to lose weight with a treatment. Whilst it doesn't give us any solution in the pursuit of optimising weight loss outcomes, it does open up avenues for further research and targeted therapy trials that may ultimately give results. Each contribution to research in this area helps with getting closer to answers that may result in more effective treatments for obesity - and we can all be happy with that.
Happy Easter and kind regards,
Wake Forest University School of Medicine researchers discovered that two specific brain networks can greatly impact how successful a person is at losing weight. According to the study’s principal investigator, Dr Jonathan Burdette, professor of radiology at Wake Forest University School of Medicine, these findings may eventually aid in the development of tailored behavior-based treatments that target specific brain circuitry to aid in weight loss. The outcomes featured in the paper, ‘Longitudinal relationship of baseline functional brain networks with intentional weight loss in older adults’, published in Obesity.
“These findings show that the brain network properties of people who were less successful at weight loss were different from folks who were more successful,” explained Burdette. “Some people have a stronger unconscious sensory motor bias to pursue food, while others appear to have less. In a society of food abundance with food cues everywhere, this information can help explain why some people have such difficulty in taking off excess weight and maintaining it.”
The goal of the Empowered with Movement to Prevent Obesity and Weight Regain (EMPOWER) study was to determine whether the degree of weight loss after six months of a behaviour-based intervention was related to connectivity within two functional networks (FNs), FN1 and FN2, in a group of older adults with obesity. Functional brain networks are areas of the brain that are working together in sync. FN1 and FN2 were first identified by Burdette and his team in 2018 as being involved in successful weight loss.
In total, 71 participants enrolled in a randomised weight-loss clinical trial were scanned at the beginning of the trial with functional magnetic resonance imaging to determine if FN1 and FN2 would be predictive of weight loss and if so how. Participants were scanned during a resting state and then again after receiving a food-cue task. At the end of the six-month trial, the data were then analysed to compare the relationships between the baseline networks and the change in the participants’ weight.
Burdette’s team found that during the resting state the relationship of brain function in FN1, which involves sensory and motor skills, was significantly associated with six-month weight loss. During the food-cue state, six-month weight loss was significantly associated with FN2, which includes self-regulation and the ability to focus attention.
Two distinct brain network biases are related to the degree of success with weight loss: within the resting state, there is a sensory motor motivational bias to pursue food, whereas when processing food cues, there is a deficit in the executive control and attention network.
This is the first study to link key concepts that have been identified as important in understanding obesity and overeating to success with behavioural weight loss among older adults with obesity.
“Our findings provide further insight into complex functional circuits in the brain so we now have a mechanistic understanding of why people aren’t losing weight,” he added. “In theory, if you know more about urges and control, we will be able to tailor therapies to an individual as opposed to treating everyone the same.”
Why all patients with obesity don't develop Type 2 diabetes
7 March 2023
This is some exciting new research into the origins of Type 2 Diabetes and why some patients are affected and some remain obese without developing Type 2 diabetes. Who would have thought the gut microbiome has something to do with it? Sadly, the population of gut microbiota is in the order of 10 trillion organisms in a single person, so identifying one or two responsible microbes maybe just the tip of the iceberg. However, any information that can be gained about the hows and whys of type 2 diabetes is landmark information and will potentially be likely to change the landscape of treatment in the future. It won't be in the near future though based on how technical this disease is. My advice is to avoid diabetes in the first instance or 'treat' it with bariatric surgery - the only known 'cure' for type 2 diabetes (in certain situations).
If you do have any questions about this then send me an email. Love to hear from you.
Researchers at Oregon State University (OSU) have invented a new analytical method that sheds light on an enduring mystery regarding type 2 diabetes: Why some patients with obesity develop the disease and others don’t.
Drs Andrey Morgun and Natalia Shulzhenko of OSU and Giorgio Trinchieri of the National Cancer Institute developed a novel analytical technique, multi-organ network analysis, to explore the mechanisms behind early-stage systemic insulin resistance. The scientists sought to learn which organs, biological pathways and genes are playing roles. Reporting their findings in the paper, ‘Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages’, in the Journal of Experimental Medicine, they show that a particular type of gut microbe leads to white adipose tissue containing macrophage cells - large cells that are part of the immune system -associated with insulin resistance.
"Our experiments and analysis predict that a high-fat/high-sugar diet primarily acts in white adipose tissue by driving microbiota-related damage to the energy synthesis process, leading to systemic insulin resistance," said Morgun, associate professor of pharmaceutical sciences in the OSU College of Pharmacy. "Treatments that modify a patient's microbiota in ways that target insulin resistance in adipose tissue macrophage cells could be a new therapeutic strategy for type 2 diabetes."
The human gut microbiome features more than 10 trillion microbial cells from about 1,000 different bacterial species.
Morgun and Shulzhenko, an associate professor in OSU's Carlson College of Veterinary Medicine, in earlier research developed a computational method, transkingdom network analysis, that predicts specific types of bacteria controlling the expression of mammalian genes connected to specific medical conditions such as diabetes.
"Type 2 diabetes is a global pandemic, and the number of diagnoses is expected to keep increasing over the next ten years," said Shulzhenko. "The so-called 'western diet' - high in saturated fats and refined sugars - is one of the primary factors. But gut bacteria have an important role to play in mediating the effects of diet."
In the new study, the scientists relied on both transkingdom network analysis and multi-organ network analysis. They also conducted experiments in mice, looking at the intestine, liver, muscle and white adipose tissue, and examined the molecular signature - which genes were being expressed - of white adipose tissue macrophages in obese human patients.
"Diabetes induced by the western diet is characterised by microbiota-dependent mitochondrial damage," added Morgun. "Adipose tissue has a predominant role in systemic insulin resistance, and we characterised the gene expression program and the key master regulator of adipose tissue macrophage that are associated with insulin resistance. We discovered that the Oscillibacter microbe, enriched by a western diet, causes an increase of the insulin-resistant adipose tissue macrophage."
The researchers add, however, that Oscillibacter is unlikely to be the only microbial regulator for expression of the key gene they identified - Mmp12 - and that the Mmp12 pathway, while clearly instrumental, is probably not the only important pathway, depending on which gut microbes are present.
"We previously showed that Romboutsia ilealis worsens glucose tolerance by inhibiting insulin levels, which may be relevant to more advanced stages of type 2 diabetes," Shulzhenko concluded.
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