Why I made the Podcast....
GLP1 drugs are not entirely new. Slightly different versions have been used for diabetes since 2005. What is different is the dosage and the time those dosages last in the human body when prescribed for weight loss. It is a significantly higher dose that lasts a significantly longer time than what was available in the past.
So when I hear people say "Oh...we've been using these drugs for decades".........I don't agree.
Ozempic and Wegovy contain the identical GLP1 drug called semaglutide. The difference is Wegovy, which is prescribed specifically for weight loss, comes in a much higher dosage weekly injection.
I'd been digging for over a year into the clinical trials that Novo Nordisk - the Danish drug Manufacturer had published, with the hope that no customer would bother to read, let alone question and found this dosage issue among many others while I was researching weight loss drugs and reading clinical trials. Everything in medicine usually starts with clinical trials. They are generally thought to be the "proof" that a drug is safe to use.
It used to be that Government bodies conducted clinical trials but that is just not the case anymore. The reason is expense - they can cost billions of dollars. It's been shown by researchers that the pharmaceutical company-sponsored studies are four times more likely to return results favourable to the sponsor aka drug company, than are studies with other sponsors . Plus changes in more recent years have also increased the number of standard new drug applications approved the very first time around by the FDA from 38% in 2005 to 61% in 2018. A huge increase.
Keep in mind that Novo Nordisk design these expensive clinical trials very carefully, they conduct them and they audit them. To me that level of control over a drug they actively want to be a billion dollar blockbuster feels biased or a conflict of interest at the very minimum, with researchers agreeing. It's like me doing my taxes and then saying that I've calculated that I owe 1 dollar and then I audit myself and I confirm that this is correct. It's laughable but that's what can happen.
The diabetes clinical trials (Ozempic) Novo Nordisk held were called SUSTAIN (The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) with the first SUSTAIN Stage 3 trial starting in 2014. The weight loss (Wegovy) trials were called STEP (Semaglutide Treatment Effect in People with Obesity) with Stage 3 trials often starting in 2018 with their results published in 2021, with many of them published online. Stage 3 is generally considered to be one of the largest and most important stages when developing a drug for market. Billions of dollars’ worth of clinical trials available for anyone to read.
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So I did. I read them all.
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I knew that semaglutide was initially developed to help with diabetes and the once a week Ozempic injection, approved by the FDA in Dec 2017 ,was a game changer for diabetics who often struggled to lose weight. This unusual side effect of weight loss, led to the same GLP1 drug, Semaglutide, being used for Wegovy.
I wonder if this development into a purpose built weight loss drug would have happened at all at Novo Nordisk, unless the CEO Lars Sorensen, who was leading the company for 34 years, hadn't departed abruptly after the share price took a deep dive. Lars Sorensen was a marathon running, cross country ski going Dane who stated in 2005 that Novo Nordisk had no business in weight loss drugs. Lars believed a radical restructuring of society was needed to combat obesity. Plus he claimed that didn't want to taint a good diabetes drug like Ozempic.
His exit and the promotion into the top job by an economically minded Dane "who according to a Time article is "very, very comfortable in taking huge risks" called Lars Jorgensen sealed the deal. The new Lars, first call of business in 2017 was to kick start the multi million dollar weight loss (Wegovy) clinical trials. In 2023 the economically focused CEO earned US9.9 million in salary, with shares making up nearly half of this payment.
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I had been looking at the difference in adverse events (side effects) with various dosages of the GLP1 - semaglutide and I would have thought that because of the huge number of side effects seen in the Ozempic clinical trials, plus the evidence that diabetics required approximately 15% more semaglutide than non-diabetics, that Novo Nordisk would use less semaglutide for weight loss. However I was wrong. It was more - way more.
The standard dosage prescribed for diabetes (Ozempic) is generally 0.5mg or 1.0mg. In the Ozempic leaflet it says to increase the dose to 0.5mg after 4 weeks of 0.25mg dosage. This 0.5mg dose for diabetics is nearly one fifth the recommended 2.4mg dosage that is often suggested for weight loss maintenance with Wegovy.
I guess people will pay anything to lose weight because Wegovy is always more expensive than Ozempic, no matter what country you buy it in - despite it being the identical drug. Plus as many scientists note - we don't know the effect of using this higher dosage of the GLP1 drug over considerable years as Wegovy was only approved by the FDA in 2021.
Novo Nordisk seemed to have completely forgotten the scientifically proven fact in all of their clinical trials that many of the unpleasant side effects of semaglutide magnify as the dosage is increased - particularly gastrointestinal side effects. In fact Novo were encouraged by the FDA in 2017 meeting notes to explore the risk of gastric emptying plus the FDA suggested to use various dosages in the stage 3 Wegovy trials which didn't seem to happen.
It is very difficult for me to find solid evidence of these suggested gastric trials being completed because many of the trials held on gastic effects seem to have no results posted. It was common to see in the published STEP (Wegovy) clinical trials testing a 2.4mg dose, adverse events (aka side effects) affecting approx. 85-95% of participants, whereas in the SUSTAIN 1 (Ozempic) clinical trial testing 0.5mg and 1mg doses, adverse events were often between 36-41% - which is less than half.
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Clinical trials are required to be published within 12 months of completion. A Novo Nordisk dose finding trial for Ozempic, from 2008 that was completed in 2009 was inexplicitly held back from publication for nearly 10 years stated that:
"The incidence of gastrointestinal side effects observed with the 1.6mg dose of semaglutide were not considered acceptable. Therefore 1.6 mg was not taken forward into phase 3 trials for diabetics."
When scientists tested the 1.6mg weekly dose - which was escalated over two weeks. The result was 93.6% of people suffered from side effects plus 11% of people dropped out of the trial because of gastrointestinal issues that were too severe to continue. Admittedly the escalation of dosage is slightly different to what we have now - we now escalate over four weeks.
I wondered why would Novo Nordisk seemingly ignore this finding when working out a dose for Wegovy - and why would they look to be burying this trial? Is it because they didn't want anyone to know that when working on Ozempic they had ditched the 1.6mg dosages because of the enormous amount of side effects it caused, but then changed their minds when they were working on Wegovy? I started digging.
I could see that two of the senior scientists who had done work with Novo Nordisk on the development of the GLP1 semaglutide had submitted an Independent Editorial in October 2017. It was published in the Annals of Translational Medicine back in December 2017 (the same month that Ozempic was approved) titled: "Semaglutide seems to be more effective the other GLP-1Ras".
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This article said the following bombshell statement:
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" The unusual efficacy of semaglutide, not the least with respect to loss of appetite, has inspired the company to develop semaglutide further for obesity without diabetes. It has been suggested that higher doses of GLP-RAs are needed for the weight loss effects, but the use of higher doses of semaglutide was not supported by the phase 2 studies"
This opinion came from two scientists who are both leaders in their field. This is not a statement made by two slacker hippies high on weed wearing lab coats. These guys are respected and pretty famous in their fields. I couldn't think of any other reason for them both to say this statement - except that it was true.
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I went onto the clinicaltrials.gov website and searched for aforementioned Phase 2 trials that Novo Nordisk had held on semaglutide and literally found nothing. Even when I went back to the Phase 1 trials, there were 43 trials listed but no results posted. It is considered good clinical practice and ethically transparent for pharmacy companies to publish both results and trials - within 18 months of completion. This lack of transparency is concerning and it made me wonder what they were hiding.
Another statement from a 2019 review of GLP1 from 25 leading scientists from around the world kind of summed it all up:
"Higher doses of GLP-1R agonists can achieve clinically relevant weight loss, and greater increases in dose levels, in theory, can drive more weight-lowering efficacy. However, adverse gastrointestinal effects generally preclude the use of higher doses."
This was published two years before Wegovy was approved by the FDA in 2021 at nearly 2.5 times the dosage of Ozempic.
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These statement made me search back to the initial dose finding study for Wegovy completed on 12 April 2017. It was a 52 week trial - so I estimated it must have started around April 2016. A dose finding study is one that works out the safest dosage to move forward with when developing a new drug - and it is critically important.
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What I saw blew my mind.
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Instead of using a weekly injection, which is how both Ozempic and Wegovy are required to be administered. This dose finding study for Wegovy used a low daily injection on the 65% of woman participating in the trial, with the maximum daily dosage being a 0.4mg injection.
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I don't know how Novo Nordisk got away with giving these low daily dosages for a dose finding trial because no-one on the planet is injecting Wegovy daily. It is directed to be a weekly injection of 1.7mg or 2.4mg. I equated it to trying to eat a whole cheesecake in one sitting or cutting it into 7 pieces and eating one tasty piece a day. It's a very different experience.
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The European Medicines Agency (EMA) which is like the European FDA assessment of Wegovy's dose finding study questioned this daily injection choice for the trial, with Novo Nordisk giving the excuse that they thought that fluctuating plasma concentrations might increase gastric side effects. This response gave a big heads up about what Novo Nordisk were actually worried about - Gastric side effects.
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I would guess that Novo Nordisk knew there were possibly going to be an unacceptable amount of gastric side effects (adverse events) if they had conducted the trial with the larger weekly dosages, such as what had already happened in the Ozempic trials with the 1.6mg dose - admittedly the titration rate was slightly different. It didn't take long to confirm these suspicion.
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I happened to stumble across a clinical trial from 2015. It had no results posted on the clinicaltrials.gov website and on the usually flawless Novo Nordisk (find a clinical trial) website it had spelling mistakes in the title - calling semaglutide - tosemaglutide which made this trial nearly impossible to find. It is like calling Gucci - Pucci.
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I only opened it because I wondered what the hell tosemaglutide was.
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In short the trial, paid for and conducted by Novo Nordisk in Germany had tested over 17 weeks and found that giving a once daily dose of semaglutide resulted in less adverse events with less severity of events and less Gastrointestinal events compared to giving a weekly dose. The trial was completed in April 2016. I could see that the initiation date on this trial was 23 Sept 2015 and the official Wegovy dose finding study that was submitted to the FDA, was conveniently initiated on 1st October 2015. Literally one week later.
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I believe that this is why Novo Nordisk wanted to do daily dosing for Wegovy's official dosage trial. It was because they already knew what would happen. Daily dosing should show fewer side effects and possibly enable Novo Nordisk to obtain a higher dosage approval from the FDA.... if the FDA accepted the daily dosing schedule.
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This higher dosage could lead to faster weight loss and the ability to claim higher weight loss in advertising but could also possibly cause far more side effects when given.
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Contrary to Wegovy's daily dose finding trial, Ozempic's 2009 dose finding study, had injected weekly.
The end result for Wegovy was that Novo Nordisk used this daily injection method and an equation (based on using population pharmacokinetic (PK) modelling) to tell Government regulators such as the FDA that a dose of 2.4mg should be ok for Wegovy. These equations do have their problems and have estimated incorrectly in the past when calculating dosage.
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I reached out to the FDA who told me that according to a tiny footnote in their Wegovy Drug Evaluation report that "The Division did not object to the applicant’s proposal for the phase 3 dose regimen at the time of the end-of- phase 2 meeting, although because the 2.4 mg weekly dosage was not evaluated in a phase 2 dose-ranging trial, the company was reminded that there was some risk in dose selection". No shit.
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The FDA then encouraged me to reach out to my health professional if I had further questions which is problematic because my doctor did not approve Wegovy to be used by millions of people at higher dosages - the FDA did.
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Despite all of this dodgy behaviour, Wegovy achieved approval in multiple countries at the higher 2.4mg dosage by Government Regulators such as the FDA who are primarily funded by Big Pharma through fees and payments.
Snuck within the FDA Assessment Reports on semaglutide it does say "Semaglutide doses of 0.5 mg and 1 mg provide adequate systemic exposure over a body weight range of 40-198 kg". That's because the effect of GLP1 dosage is commonly agreed to be weight related, but is confoundingly not prescribed like that. According to this weight related scale the heaviest woman on earth (291.6kg or 643lbs) could be taking less than1.5mg of semaglutide.
Novo Nordisk clearly state on their website that” The 0.25 mg, 0.5 mg, and 1 mg once-weekly dosages of Wegovy are initiation and escalation dosages and are not approved as maintenance dosages. They want you to hit that 2.4mg dosage.
​​I was really concerned when I read that teenagers are now being prescribed Wegovy at a dosage of 2.4mg and that Novo Nordisk had only conducted one single clinical trial on adolescents and no dosage trial for that age group. This seemed to be enough for the FDA to say OK start prescribing.
I believe Novo Nordisk asked for an exemption from conducting more clinical trials on adolescents. This is despite just over 800 side effects suffered from around 70% of the 201 kids participating in that trial. That's averages to just under 6 side effects each, for kids that all weighed far less than me.
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In an early 1996 study gender was identified as one of the major independent covariate for GLP-1 responses, with higher values of all parameters - such as increased weight loss and increased side effect found in females. In fact woman reported to the FDA, nearly double the amount of side effects. Unsurprisingly age is also a covariate.
The big issue seems to be surrounding Gastric Emptying. There is already a class action lawsuit against Novo Nordisk in the Eastern District of Pennsylvania. It’s about whether Novo Nordisk adequately warned plaintiffs or their prescribing physicians about the alleged dangers of Ozempic and Wegovy, and whether defendants made false, misleading, or incomplete representations regarding the safety of products - in particular the risk of gastroparesis and other gastrointestinal injuries. Novo Nordisk deny these allegations. ​
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It is not known exactly why woman react differently to GLP1 drugs but it is guessed that it has to do with hormones and the fact that woman commonly are a lighter body weight than men, yet often are instructed to take the same dosage. I find this very concerning considering that in the USA 79% of the users of GLP1's are woman. If I throw in the medical fact that woman also naturally have slower gastric emptying than men (about 15%) it becomes even more concerning.
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To top it off I found that Novo Nordisk had held and completed several clinical trials, years ago - mostly in Europe, studying the Gastric emptying effects of GLP1 drugs, yet the results of these trials on clinicaltrials.com were nowhere to be found. Considering gastric side effects are a hot topic with GLP1 drugs and the FDA had advised Novo Nordisk to further study these effects, I found this lack of transparency interesting, to put it mildly.
This result made me curious so I did a search at clinicaltrials.gov website to see how many clinical trials Novo Nordisk had completed, but not yet reported any results from between Jan 2010- Jan 2020, for any drug they were trialing. The numbers were pretty confronting. There were 557 trials completed and 356 of them had no results posted. I wondered if Novo Nordisk were inefficient or lazy or something worse.
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I noticed in the semaglutide clinical dosage trials for (Wegovy) obesity that they used far more woman (64.8%) than men (35.2%) and the opposite was true in the (Ozempic) diabetes trial with men (69.2%) and woman (30.8%). Plus the body weight of the individuals was often 25 kilos heavier in the Wegovy trial.
These choices no doubt helped boost the speed of weight loss found along with the large reduction in calories, exercise and counselling that all of the Novo Nordisk STEP/Wegovy trials included. These tactics might help a drug company claim that they are the fastest at weight loss and attract the publicity, increase in stock price and sales that often come along with sensational weight loss claims, but it does feel kind of rigged, particularly when the STEP 3 trial fed participants a 1000-1200 liquid calorie diet for the first 8 weeks.
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In the UK the National Institute for Health Care and Excellence (NICE) said in 2024 that "there is no evidence of effectiveness of semaglutide if used as a single stand-alone treatment". In other words you need to incorporate diet and exercise, in order to lose weight. I totally believe this to be true.
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Now don't get me wrong, despite all of this I believe that these new GLP1 drugs can be amazing. I just don't think we have been given the opportunity to use them in any kind of a personalised and flexible manner, plus we don't know nearly enough about these drugs short and long term.
We are using them in far higher dosages than diabetics, with a patented injection device which is attached to a patented needle that Novo Nordisk own. We can't change the dosage because Wegovy injection devices are fixed and our time poor doctors, more often than not, follow the prescribing recommendations from Novo Nordisk. We're told to double our dosages multiple times and that the lowest dose is initiation only. It says this in bold letters on the information sheets and online for Wegovy.
If there is anything that stands out on social media posts about Wegovy and Ozempic - it is that everyone reacts differently to semaglutide. It is literally screaming out for flexibility in dosage.
I reached out to a senior scientist in Denmark who worked on developing semaglutide, he told me it is
"a general experience that some people stay for long on a certain, even low dose to avoid side effects. It is now generally accepted that this is a reasonable approach that may have good results in terms of weight loss”.
Maybe someone should tell Novo Nordisk that.
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I felt I was onto something significant when documents I had requested to look at through Freedom of Information kept getting delayed because the provider (Novo Nordisk) wanted to redact so much information and my Government Drug Regulation Body (Therapeutic Goods Australia) wasn't agreeing.
There are side effects that scientists have yet to fully understand - like why can our heart rate increase when we take GLP1 drugs. The SUSTAIN 6 clinical trial which is a trial specifically studying cardiovascular effects on diabetics, reported an increase of 2.8 beats per minute for 0.5mg dose and an increase of 3.2 beats for the 1.0mg dose.
For Wegovy the heart rate increase while resting is even higher at 5 beats per minute for 2.4mg as seen in the STEP 4 clinical trial for weight loss. A heart rate increase has been shown in many Novo Nordisk trials for GLP1's despite the fact that semaglutide has been approved to help with heart related issues in those that have pre-existing cardiovascular disease such as those overweight (but not diabetic) that had previously suffered a heart attack or stroke.
I wonder about the rest of us that don't have a pre-existing heart condition.
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We also don't understand why our bodies possibly want us to drink less water (up to 36% less) when taking these drugs and why we excrete more sodium - possibly affecting our electrolyte balance as shown in a 2006 study. We don't fully understand the function of what is happening in our brains with GLP1 and how it affects other organs in our bodies such as lungs, pancreas, kidneys and heart. Like with any new drug, we have a lot to learn.
In the USA there is no stopping notice, like there is in other countries such as the UK and Australia. A stop notice tells you to stop using a medicine if you haven't lost a certain percentage of weight in a certain period of time because you're unnecessarily exposing yourself to risks and side effects by taking the drug.
Drug companies are often opposed to agreeing to stop notices because it's good for business to have someone take a drug for life. Plus, people in the USA are also paying a very high price to use these medications - more than 10 times what they're paying in Australia.
It's hard to trust someone when they buy everyone around you. Professionals I should trust like doctors, oncologists, journalists and nurses had attended seminars and eaten fancy food all paid for by Novo Nordisk. When it comes to prescribing these medicines, doctors are statically much more likely to get out their prescription pads and start writing if they had attended these seminars.
There are thousands of health professionals attending seminars worldwide with millions of dollars being spent by Novo Nordisk. $25.8 mil in the USA, another 7.8 million British Pounds (over US$10 million) in the UK where Novo Nordisk "accidentally" misplaced the payments to hundreds of health care professionals. This plus other infringements resulted in Novo Nordisk recently being kicked out of the British Pharmaceutical Society for 2 years. It was shocking and unprecedented behaviour for a Big Pharma manufacturer to act so dishonestly.
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In September 2017 the US Department of Justice Announced that Novo Nordisk Inc. will pay $58.65 million to resolve allegations that the company failed to comply with the FDA-mandated Risk Evaluation and Mitigation Strategy for its GLP1 medication Victoza. The included a payment of $12.15 million for alleged violations of the Federal Food, Drug, and Cosmetic Act from 2010 to 2012 and a payment of $46.5 million for alleged violations of the False Claims Act from 2010 to 2014. Victoza is an early GLP1 FYI.
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In 2009 Novo Nordisk agreed to pay US$9 million in connection with a kickback scheme that operated within the United Nations Oil for Food scheme. In 2011 Novo Nordisk paid US$25m for off label promotion of one of its drugs and again in 2022 Novo Nordisk paid US$6.3 million to resolve False Claim Act Allegations. Since 2000 Novo Nordisk has paid out US$129,887,792 for 15 offences. Many of these were settlements, often with no admission of liability.
I could see in Novo Nordisk's annual report of 2023 that they had put aside 3,786 million Danish Krone (over US$533 million) for legal matters for the next year.
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I think they might need it.
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At the end of my research I had some pretty challenging questions on my mind:
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Why did Novo Nordisk choose to use significantly more woman than men in clinical trials for Wegovy, yet use significantly more men than woman in the trials for Ozempic?
Is it because gender and body weight are known to effect results and therefore trial outcomes?
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Why did Novo Nordisk up the dosage of the GLP1 semaglutide for weight loss when scientists had said it would only make people suffer more debilitating side effects?
Is it because they want to say they are the fastest at weight loss and therefore increase their sales and stock
price, no matter the cost?
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Why only offer a single dose, patented pen that offers no flexibility in dosage?
Is it because it limits us to only use higher dosages and consume more of the drug?
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Why conduct critical dosage trials using daily injections when that is not how these drugs are administered?
Is this about manipulating trials to obtain a particular result?
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Why pay thousands of health professionals worldwide?
Is this about buying votes?
I believe all of these questions come down to one simple motive - Greed. It is extremely profitable to claim to sell a drug that helps people lose weight quickly. Novo Nordisk's stock price has increased from approx $46 in 2018 to approx $120 in 2024 (+260%) making them the most lucrative company in Europe with most of its revenue coming from North America.
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I came across a very recent article in which Novo Nordisk were testing lowering the semaglutide amount in their next generation weight loss drug called Cagrisema. Phase 3 tests reduced semaglutide testing down from 2.4mg to 1mg and 1.7mg dosages for the weekly injection. It's certainly a smarter financial decision to reduce a dosage when a drug is in the testing phase and isn't being prescribed to millions of people. I can't imagine the lawsuits that Novo Nordisk would be facing if they turned around and said ...mmmm now....about Wegovy.
I contacted Danish scientists who worked on semaglutides to increase my understanding about these drug as I don't work in the medical field. In an effort to find out how much 'truth' lies in what I learned I also reached out to Novo Nordisk multiple times, with no response for months now. I'm certain that there is still much I don't know, but I do feel that I am far more informed than what I was.
I also realise that everyone is unique and what works for some might not work for others. Coincidentally a large survey of Danish users of Wegovy found many were not using it as directed by Novo Nordisk, instead were using a significantly lower dose. Clearly the Danes know something we don't.
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I had no idea when I started looking into these GLP1 drugs just how many rabbit holes I would need to go down in order to get to anything that remotely resembled the truth. I believe that it's only with time, perspective and data that we come to fully understand a drug. We need enough time for people to use and provide the data and an impartial perspective that isn't motivated by dollars and that will take years.
After all of my research, I believe that for me - if used in an individualised and flexible dosage for my gender and weight, and combined with healthy eating and moderate exercise that GLP1 drugs can be life changing. I feel the very significant risks are worth the health benefits when suffering from the life shortening medical complications that come along with obesity. However, when used by people who only need to drop a few pounds I believe they are absolutely not worth the risks.
Plus, there is the very obvious elephant in the room that we are barely even talking about. Our Food Supply. I agree with the previous CEO of Novo Nordisk - we do need a radical restructuring - in regard to our foods. We need to change the source of the problem and not try to put a giant expensive band aid across the entire picture.
When I lived in the USA, I remembered the surprise and amusement that I felt when advertisements for drugs would come on the TV. It is something that isn't allowed in Australia - no prescription drug advertising. Novo Nordisk spent over $471million in ad spends in 2023 with the Ozempic ad running alongside the song ...oh oh oh...it's magic, and Wegovy TV ads assuring us that ...We have a power.
I finally found something that I could totally agree upon with Novo Nordisk.
I do have a power.
As long as my doctor agrees, I can choose to use these drugs with more flexibility for significantly healthier and cheaper weight loss.