There have been stories in the media recently about well known people who have been taking a diabetes drug for weight loss. Celebrities include Jeremy Clarkson, Elon Musk, Chelsea Handler, and Remi Barder (Ref 1). The drug is called Semaglutide. It is sold under the brand names Ozempic, Wegovy and Rybelsus. Semaglutide is a prescription drug. It is injected into the stomach weekly.
Semaglutide belongs to the class of drug called “incretin mimetics.” They are used for type 2 diabetes (T2D) as they reduce blood glucose levels. The drugs are called “incretin mimetics” because these drugs mimic the effects of incretins. Incretins are hormones produced and released into the blood by the intestine in response to food. The incretin of key relevance with semaglutide is GLP-1 (Glucagon-Like-Peptide-1). GLP-1 increases the release of insulin from the pancreas, slows absorption of glucose from the gut and reduces the amount of glucose being produced by the liver. All three actions are intended to reduce levels of glucose in the blood stream – hence their use for T2D.
Semaglutide was developed by Novo Nordisk in 2012. The drug was originally intended for T2D. It was approved by the FDA for weight loss in June 2021 (Ref 2).
The more scientific articles about the ‘diet craze’ reference the academic study underpinning the drug (Ref 3). The major trial of Semaglutide was published in the New England Medical Journal in February 2021 (Ref 4). I covered it in a note shortly after that publication (Ref 5).
It was a high quality trial – a double-blinded, randomised controlled trial. That means that neither the participant nor the researchers knew who was in each group. That’s the theory. The reality was that the side effects were so pronounced (and the loss of appetite from the drug) that people probably knew which group they were in. The trial was large (1,961 people) and long (68 weeks) and multi-site (129 sites in 16 countries). Novo Nordisk sponsored the trial, designed the trial and oversaw its conduct.
The average BMI was 38 at the start of the trial. The participants were randomly assigned in a 2:1 ratio to the semaglutide injection (2.4mg once a week) or a placebo injection. Both groups also adopted lifestyle changes (counselling sessions every 4 weeks to help participants adhere to a 500 calorie deficit daily and 150 minutes of physical activity per week).
The results were impressive. I reported in my 2021 Monday note that “they were the best I have seen in any drug vs placebo weight loss trial.” I added “they were almost unbelievable.” The enthusiasm for the drug among celebrities suggests that the results might be believable – even though the trial had company conflicts.
The drug does seem to decrease appetite. Clarkson quipped “You can look at a Sunday roast, with gravy and beef and perfect Yorkshire puddings, and you think: ‘I’ll just have a stick of celery instead‘” (Ref 6). In the same article, Chelsea Handler, who stopped taking the drug, was quoted as saying “”But I like having an appetite. It made me nauseous, and I don’t like to be nauseous.”
This brings us to the observations that I made about side effects when I first looked at the NEMJ study. The adverse events reported in the drug group were primarily gastrointestinal: 44% reported nausea; 32% diarrhoea and 25% reported vomiting. Overall, 74% reported gastrointestinal disorders. These numbers were all significantly higher than those reported in the placebo group. Perhaps semaglutide reduced appetite because eating became so traumatic that it wasn’t worth the effort. Diarrhoea and vomiting would reduce absorption of food and this could have impacted weight loss. (It would also have impaired nutrient absorption). Twice as many people in the drug group withdrew from the trial (compared to the placebo group). Nearly 12 times as many people withdrew from the drug group for gastrointestinal reasons as did in the placebo group.
The patient leaflet cautions that serious outcomes include pancreatitis; hypoglycemia; retinopathy (diabetic eye disease), as well as all the gastrointestinal effects reported in the trial (Ref 7). The retinopathy and eye problems are reported to be common serious side effects (affecting up to 1 in 10 people). Other common side effects include gas, bloating, gallstones, reflux, heartburn and hair loss. Acute pancreatitis is reported as “may affect 1 in 100 people.” Nausea, vomiting, diarrhoea, constipation, stomach pain and feeling weak or tired are reported as very common (may affect more than 1 in 10 people).
The patient leaflet doesn’t mention the most serious issue. This is prominently featured in the FDA approval document (Ref 8). The header of page one of the approval document has this prominent warning about thyroid cancer.
There is another issue with semaglutide, which celebrities taking it may not yet have realised. The drug needs to be taken on an ongoing basis. The weight loss is reversed if the drug is stopped.
A double-blinded, randomised controlled trial studied the effect of switching people from semaglutide to placebo after 20 weeks of all participants taking semaglutide (Ref 9). Those who continued to take semaglutide continued to lose weight. They had an average (mean) body weight loss from week 20 to week 68 of 7.9%. Those who were switched to a placebo gained 6.9% body weight on average.
The lead author for this study reported receiving speaker fees, consulting fees, and honoraria from Novo Nordisk and being a shareholder in Novo Nordisk. Hence, it could be argued that she had an incentive to find that the drug should be continued. The differences of 7.9% loss vs 6.9% gain are so large that I suspect author conflicts are irrelevant. It is fair to conclude that stopping the drug will lead to weight being regained.
One celebrity who does appear to have worked this out is Remi Barder. She found that her binge eating became worse after she stopped taking the weekly injection. Barder reported gaining double the weight back when she stopped.
This brings us to the lessons from our second story. Whatever you are doing to lose/maintain weight must be sustainable. If it isn’t, you may as well stop now, because you’ll regain if you do stop. Dr Michael Mosley’s latest book, The Fast 800 Keto, is based on 800 calories a day, with carbohydrates under 50g per day and protein above 50g (Ref 10). Unless you can keep this up, you are highly likely to regain when you stop (Ref 11). If, for another example, you are trying to live on one meal a day, unless you can keep this up, you are highly likely to regain when you stop.
People are so desperate to lose weight that they do unwise and often dangerous things. Semaglutide strikes me as more unwise and more dangerous than most other options. An up to 1 in 10 chance of retinopathy and eye problems… An approximate 1 in 100 chance of acute pancreatitis… An unknown risk of thyroid cancer… And a virtual guarantee of weight regain – and possibly more – unless weekly stomach injections are continued for life. Elon Musk is one of the brightest people in the world and he’s doing one of the dumbest things to lose weight (Ref 12). That just shows how powerful the desire to be slim is.
p.s. a recent (rodent) study found that this drug increases the risk of intestinal blockage, which can be fatal.
Ref 1: https://www.newsweek.com/celebrities-hollywood-weight-loss-diabetes-drug-ozempic-1774677
Ref 2: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
Ref 4: Wilding et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. NEMJ. February 2021. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2032183
Ref 5: https://www.zoeharcombe.com/2021/03/semaglutide-weight-loss/
Ref 6: https://www.newsweek.com/celebrities-hollywood-weight-loss-diabetes-drug-ozempic-1774677
Ref 7: https://www.medicines.org.uk/emc/files/pil.13803.pdf
Ref 8: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf
Ref 9: Rubino et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. April 2021. https://pubmed.ncbi.nlm.nih.gov/33755728/
Ref 10: https://thefast800.com/how-to-do-the-fast-800-keto/
Ref 11: Franz et al. Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc. 2007. https://pubmed.ncbi.nlm.nih.gov/17904936/
Ref 12: https://twitter.com/elonmusk/status/1576367983051489281
Fasting + Ozempic/Wegovy + no tasty food near me
— Elon Musk (@elonmusk) November 16, 2022