People have been looking for a quick and easy way to lose weight for a good long while, probably for as long as an anorectic physique has been considered attractive. And what easier way could there be than taking a pill? No need to change your diet. No need to exercise (ineffective anyway, I know). Just pop that pill and be done with it!
The first truly effective weight loss pill was perhaps dinitrophenol, which came on the market in the early 1930’s. It had a pretty ingenious mechanism of action, which requires some explaining. In the normal state of things, most of the energy we consume through food is transferred to a molecule called ATP (adenosine triphosphate). ATP in turn functions kind of like a battery, powering most of the things that happen in our bodies.
Most ATP is produced in the mitochondria by a giant (on the molecular scale) enzyme called ATP synthase, that sits on the mitochondrial membrane and looks (and functions) a bit like a wind turbine. ATP synthase is driven by an osmotic gradient, caused by a difference in the number of protons on each side of the mitochondrial membrane. As protons move along the gradient, they cross the mitochondrial membrane, passing through ATP synthase, and ATP is generated.
Dinitrophenol allows protons to bypass ATP synthase, and move across the membrane without transferring energy to ATP. Since energy can’t be destroyed, it is instead released as heat. So the drug basically works by making your metabolism less efficient. More of the energy that you consume ends up being given off as heat rather than being used to power reactions in your body. It’s a bit like replacing a modern low energy light bulb with the old incandescent type.
For a few years, dinitrophenol was very popular. But it ran in to one big problem. It was a bit too easy for people to overdose on it. Occasionally people would take too much of the drug, causing their body temperatures to spike to dangerously high levels, and this would cause them to spontaneously combust. Ok, that’s a bit of an exaggeration, but they died. So the drug stopped being used in the late 1930’s.
After dinitrophenol fell out of use, amphetamines became popular as a weight loss drug for a couple of decades. Among the many effects amphetamines have on the nervous system, they suppress appetite, which makes them pretty effective at helping people to lose weight. But their addictiveness eventually caused them to be classed as narcotics, and so they were also largely taken off the market. People who wanted to lose weight by popping a pill were back at square one.
At present, there is only one drug approved for use as a treatment of obesity, and that is orlistat, a drug that came on the market around the turn of the new millennium. Orlistat inhibits pancreatic enzymes involved in breaking down fats to a form that allows them to be absorbed in to the body. This causes the fats to stay in the intestine, and then pass out with the stool.
Unfortunately, orlistat is pretty useless, at best causing 2 to 3 kilograms of weight loss after a full year of use. And the side effects, which consist of fatty, oily stools and increased farting, aren’t nice. Additionally, people taking orlistat frequently become deficient in the fat soluble vitamins (A, D, E, and K).
Now, amphetamines aren’t the only drugs that over the years have been noticed to have weight loss as a common side effect. Levothyroxine, used to treat hypothyroidism, induces weight loss by speeding up metabolism. Unfortunately the risks associated with its use mean that it can’t be used as a weight loss pill.
Then there’s the GLP-1 analogues. GLP-1 is a hormone that is released when we eat food. It has been found to increase insulin levels and decrease glucagon levels, both of which cause blood sugar to drop. For this reason, GLP-1 was at one time heavily researched as a treatment for type 2 diabetes, and a number of GLP-1 analogues (synthetic drugs that have a physiological effect similar to GLP-1) were developed and marketed for this purpose.
The fist GLP-1 analogue to come on the market was exenatide, which was approved for use in type 2 diabetes in 2005. Unfortunately for pharmaceutical companies, it still isn’t clear whether these drugs actually make people with type 2 diabetes live longer, so they have remained a second-line agent, after older (and cheaper) generic drugs like metformin and sulfonylurea. Fortunately for pharmaceutical companies, the GLP-1 analogues were found to have one beneficial side effect that isn’t seen with either metformin or sulfonylurea – they cause people to lose weight.
Naturally, this has led to the suggestion that they could be used as weight loss drugs in people who are obese but who don’t have diabetes. Which leads us to a study that was recently published in the New England Journal of Medicine.
This was a double-blind randomized controlled trial carried out at over a hundred different sites in 16 different countries. 1,961 participants were recruited and randomized to either a GLP-1 analogue called semaglutide or placebo. The study was funded by Novo Nordisk, which holds the patent on semaglutide.
In order to be included in the study, participants had to be over 18 years old and they had to either have a BMI (Body Mass Index) over 30 (the cut-off for obesity), or over 27 and also have some weight related co-morbidity (e.g. high blood pressure, high cholesterol levels, sleep apnea, or heart disease). People with diabetes were excluded, since earlier studies have already shown that GLP-1 analogues are effective at reducing weight in people with type 2 diabetes. People who had previously suffered from pancreatitis (inflammation of the pancreas) were also excluded, since GLP-1 analogues have previously been shown to increase the risk of pancreatitis. The study also excluded people who had recently been taking some other form of weight loss drug, or who had had weight loss surgery.
Participants received a once-weekly injection of either semaglutide or placebo. All participants also received traditional weight loss councelling once every four weeks, in which they were recommended to follow a low calorie/low fat diet and take regular exercise. They were followed for 68 weeks. The reason 68 weeks was chosen as the length of the study was because there was a 16 week run-in period, during which the dose of semaglutide was gradually titrated up, followed by 52 weeks with the full dose (or a lower dose if a participant was not able to tolerate the full dose).
What can we say so far? This was a well done, high quality study, with lots of participants, which provides a high level of statistical power. Usually studies aim for a power of 80%, which means they have an 80% chance of finding a real difference if one exists. This study had a power of 99%! They recruited participants at lots of different sites in several different countries, which minimizes the risk that some condition specific to one setting will confound the results. The intervention received by the two groups was identical, with the one exception of getting either semaglutide or a placebo. And the participants were followed for over a year.
The average age of the participants was 46 years. The average BMI at the start of the trial was 38, and the average weight was 105 kilograms (231 pounds).
Ok, let’s get to the results. And let’s start with the good news.
At the end of the study, participants in the semaglutide arm had lost 14,9% of their body weight. In the placebo arm, participants had lost 2,4% of their body weight. That means an average weight loss of 15,3 kilograms (34 pounds) in the treatment group, and 2,6 kilograms (5,7 pounds) in the placebo group. The absolute difference in weight loss between the two groups was a 12,4%. That is a big, impressive difference. On average, participants in the treatment arm lost 13 kilograms (28 pounds) more than people in the placebo arm.
Overall, 69% of participants in the semaglutide group lost at least 10% of their body weight, compared with only 12% of participants in the placebo group. Participants in the semaglutide group also saw a much bigger reduction in their waist circumference, losing 13,5 cm, as compared with only 4,1 cm in the placebo group.
Now let’s get to the bad news.
74% of participants in the study were female, and 75% were white. That means the overall results mainly apply to white females. Unfortunately, Novo Nordisk don’t provide a breakdown of the results by either gender or by ethnicity, so it’s impossible to tell whether the benefits seen here apply equally across genders and ethnicities, or whether the benefit is only seen in white females. It’s odd that they don’t provide this information, and the suspicious little devil sitting on my shoulder is whispering in to my ear that that probably means semaglutide only works for white women.
And now, let’s get to the really bad news.
9,8% of participants in the semaglutide arm suffered a serious adverse event, as compared with 6,4% in the placebo gorup. That gives an absolute difference of 3,4%, which would mean that roughly one in thirty people taking the drug for a year can expect to suffer a serious adverse event as a result of taking it. Not good. So, what were these serious adverse events?
Unfortunately Novo Nordisk again aren’t kind enough to provide us with a clear breakdown of what the serious adverse events were, although they say that they mainly consisted of gastrointestinal disorders and hepatobiliary disorders (disorders to do with the liver and gall bladder).
In order to be classified as “serious”, an adverse event generally has to either result in death or at least be potentially life-threatening, or result in hospitalization, or result in permanent disability. In the study, one person died in the treatment group and one person died in the placebo group, so we know that at least the semaglutide wasn’t killing people. Most likely the drug was resulting in an increase in hospitalizations, for example due to gall stones (a hepatobiliary disorder) or dehydration due to vomiting (a gastrointestinal disorder).
It’s unfortunate that Novo Nordisk don’t provide more detail on what the serious adverse events were when there is such a clear signal of harm. Nor do they tell us how many people were hospitalized over the course of the study in each treatment arm. I listened to a half hour interview with one of the lead researchers in charge of this study, and funnily enough he never once mentioned that there was a significant increase in serious adverse events in the treatment group. In fact, he said explicitly that the drug was largely side-effect free, with the exception of some mild nausea that usually resolved within a few weeks of beginning treatment. For those who like relative risk numbers (pharmaceutical companies certainly do if they make their drugs look good), the relative risk of a serious adverse event increased by 53% in the group receiving semaglutide!
So we can conclude that treatment with semaglutide results in some type of gastrointestinal or hepatobiliary illness that is serious enough to at the very least require a trip to the hospital in one person in thirty per year of treatment. If we look at adverse events more generally (not just serious ones), we see that treatment with semaglutide resulted in a significant increase in nausea (44% vs 17%), diarrhea (32% vs 16%), vomiting (25% vs 7%), and constipation (23% vs 10%).
Hmm, suddenly semaglutide isn’t looking quite so good. 7% of participants in the semaglutide group chose to discontinue treatment due to adverse events, as compared with 3% in the placebo group.
Ok, so what can we conclude from all this?
Firstly, semaglutide does appear to be highly effective at helping people to lose weight (at least if those people are white women). As mentioned earlier, the only currently approved weight loss drug on the market is orlistat, which results in 2-3 kilograms of weight loss over the couse of a year. Semaglutide appears to blow orlistat out of the water, resulting in four to five times the amount of weight loss.
Secondly, this study confirms yet again how utterly useless traditional advice, to follow a low fat/low calorie diet and exercise more, is at helping people to lose weight. The placebo group lost less than three kilograms, in spite of being motivated enough to take part in a study and receiving coaching on a regular basis.
Thirdly, semaglutide has a significant side effect profile, resulting in a one in thirty chance of suffering a serious adverse event over the course of a year of treatment, and causing milder gastrointestinal side effects, like nausea, vomiting, and diarrhea, in a large proportion of those taking the drug.
Personally, I’m not a fan of medicalizing lifestyle issues, and using drugs to accomplish what could be accomplished with a change of diet. As I wrote about recently, a ketogenic diet is effective at inducing weight loss (far more so than a low fat/low calorie diet), and it is safe, and should in my opinion be the first line intervention for people who want to lose weight.
For those who don’t achieve sufficient weight loss with a ketogenic diet, or who aren’t willing to try it for whatever reason, semaglutide (or another GLP-1 analogue) could be an option, certainly before taking the more drastic step of doing bariatric surgery. However, patients should be informed about the significant side effect profile of the drug.
Unfortunately, some people have vested interests in becoming fans of medicalising lifestyle issues. The researcher who talked of the treatment being largely side-effect free despite the findings of serious adverse reactions was irresponsible. If people discover after the event that they have been exposed to risk without being informed (especially if there are safer alternatives) their trust in the medical profession could be undermined. Justifiably so.
Just to add, the above post by ‘Roland’ is mine. Thought I’d mention as there is another Roland commenting some of Sebastian’s blog posts, and I wouldn’t wish my namesake to get the impression I was posing as him!
I have PCOS and am hypothyroid. I take Metformin and Levothyroxin and recently my endocrinologist put me on Trulicity because she is not happy with my blood sugar level. Weight loss has always been difficult for me but since starting with the weekly injection of Truicity I have lost 20 kilos over the course of about 12 months. When I do a blood stick, my sugar is acceptable as well.
I try to limit simple carbs, have never been afraid of fats, and am moderately active at age 73. I walk and garden daily and ride a horse twice a week. While a strict Keto diet was not for me, I do eat a modified version that includes a lot of fruit, oranges, apples, grapes, and berries like strawberries, raspberries, and blueberries. I love nuts and even have two macadamia nut trees in the garden along with assorted citrus, raspberry and blueberry bushes, table grape vines, kiwi vines, asparagus plants, and rhubarb. This diet seems to agree with me and fresh produce from the garden is wonderful.
The Trulicity also agrees with me and I have suffered no side effects taking it. If weight loss is a side effect there is that but I am not complaining!
Hi Sebastian,
I appreciate junk food with lots of pizza, beer, ice cream and bread. A ketogenic diet seems not suited for my taste buds and it feels like lowering my quality of life a lot to adhere to it.
I want to loose weight, would you not recommend me to try semaglutide?
I didn’t realize such a large proportion of the world’s population was called Roland until I started this blog!
I know, crazy right?
The original question was really from my sambo who doesn’t want to change her not so healthy lifestyle. I think the question was a bit unfair, since it’s a personal decision how she wants to live her life, but still.
Anyway, having a background in mathematics and natural sciences but not much insight into the field of medicine I do find your blog interesting and inspiring. Keep up your good work and keep me noticed if you will have a meeting somewhere in Gothenburg!
Thank you.
I wish you would do an article on how to GAIN weight!
In my youth I did fall for the anorexic look is beautiful scam and was put on amphetamines.
I’m 76 now and seem to be ‘old age anorexic’. It honestly is difficult to prepare and eat food.
I’m getting Fortisip free on our NHS but that tastes disgusting and it’s difficult to force it down.
Your ketatonic diet DOES work, I know, for those that are overweight. I wish there was something for the underweight.
I’m vegetarian now because I’m horrified by modern ‘factory farming’.
Our stupid Lock Downs here in U.K. have made life even more difficult. But I am able to get genuine Free Range eggs. I’ve even ‘gone off’ eating them!
So it must be something to do with ME.
As a non-professional, so not dispensing medical advice but it seems to me that you need to eat meat. How about you try Kosher meat? Also, you surely can make delicious protein shakes, add nut butter and some fruit for flavor?
Thanks for this summary.
Surely the very loss of weight in itself brings on all kinds of effects which may multiply with more weight loss.
Obviously losing the first 3 or more Kg has a huge psychological effect. That has certainly been my experience when losing weight in the past, an initial kick-start is a huge help. And of course losing weight makes exercise easier which also re-doubles motivation.
So the control group is not quite the right comparison. Perhaps a better trial would require a 2nd control group who were given semaglutide for 16 weeks + 3 months to start them off and then switched to a placebo.
The other question then is side effects. Are they caused by the semaglutide vs placebo treatments or are they caused by the rapid vs slow weight loss experience. Losses of 10%+ of bodyweight surely has an effect to the system.
Fasting seems to be a way to loose weight that actually works. But it is a lifestyle change.
I started with 20-24 hour fasting once a week a year ago, trying to turn the upwards going weight trend. And it worked like a charm. Went from 86kg and leveled out at 77-78 kg in 6 months, hitting the middle of the normal BMI. That kind of fasting actually reduces food intake by some 10-15% over the week. And, is much easier to keep up than continuously starving yourself.
The corporate giants make us fat and ill with cheap addictive food and then the corporate giants offer to make us thin and well with their drugs and other interventions.
They get rich at both ends of the deal.
Hi,
I recently completed a 30 day course of Semaglutide tablets as part of a calorie restricted regime. I didn’t complete the course, (nausea, primarily) but did lose 24lbs over a 31 day period.
Dr. Rushworth, When you discussed the history of diet pills, I thought you would address Fen-Phen, which was popular in the 1990s before it was tied to heart problems. When my 59-year-old overweight mother died of a heart attack in that time period, some relatives suspected she had been using it. It wouldn’t have been unthinkable that she looked for pill to solve her weight problem.
Thanks for the tip, it’s another good example of a weight loss drug that was approved and then taken off the market after a few years because it was found to cause dangerous side effects.
I was prescribed semaglutide weekly injections for T2 diabetes. I stopped taking it due constant nausea and for vomiting dark brown coffee-grain like liquid after the weekly injections. I was told this was a serious side effect.
Dr. Rushworth, Any thoughts on Contrave (combination of Bupropion and Naltrexone)? It’s advertised as a weight loss pill. I took Bupropion for depression for about 18 months without knowing that weight loss was a side effect. After about 6 months I noticed that I had lost about 10lbs, and was somewhat surprised (pleasantly) as it wasn’t a conscious effort. It then occurred to me that it simply took away my desire to snack continuously and I was satisfied with one serving of food at meals. I discontinued it due to the annoying side effect of tinnitus. I’m a new subscriber to your blog and enjoying your posts!
Weight loss is a common side effect of bupropion. I haven’t looked in to contrave specifically.
Firstly, I love your blog. I arrived here via Malcolm Kendrick and have found your posts really thought provoking. Thank you for taking the time to do them.
I am fascinated by weightloss and almost more importantly by retention of the weightloss. I am a middle aged woman and have struggled not to be overweight all my life, until the last few years. I realise my story is just anecdotal but it does cover more than just my own experience, as it seems to me that many women obsess constantly over weightloss.
Personally, I think that all diets work. I have tried a great deal of them and I always lose weight. A critical factor is actually sticking to the diet, which is the first stumbling block for very many people. They manage from Monday to Friday and then they go out on Friday night and blow it and then they think they’ve ruined it, so they eat everything they shouldn’t over the weekend, return to their diet on Monday filled with a sense of remorse and failure and then they wonder why it doesn’t work and go and tell their GP that they’ve tried so hard but they’re just not losing weight.
Secondly, and by far the bigger problem in my opinion is keeping the weight off. Like I say, I have successfully lost weight on so many diets – but that in itself suggests that diets don’t work for long-term sustained weightloss – as why would I have done so many of them? Why is there a very financially successful diet industry? Why are there so many diets? Why are scientists trying to invent more diet pills? Why are doctors actually chopping out bits of stomachs in hospital for no other reason than those people eat too much?
Until we address the reasons why people overeat and become overweight, we will continue to watch people fail to lose weight and / or keep the lost weight off.
As for myself, a few years ago I had some counselling for an entirely unrelated issue and once that was successfully dealt with, much to my amazement my relationship with food changed completely and instead of eating for comfort or eating to help me cope with stress (even though I didn’t know I was doing this!), I stopped and ate because food was a fuel that my body needed. Slowly but consistently I lost weight by simply eating less and doing more exercise because instead of seeing it as a punishment for overeating I saw it as something to be enjoyed in itself and I am now 20kg lighter than I used to be and have remained so for quite some time.
I did notice a UK TV programme recently that did try to address why people were not successful losing weight and they looked at gut bacteria, comfort eating and poor food choices. So, hopefully the tide might be slowly turning on this.
There is a very simple and effective way to loose weight:
1. Purchase an artificially sweetened drink mix such as Tang(R).
2. Purchase a product consisting of psyllium husks such as Metamucil(R).
In a drinking glass add a squirt of the flavoring agent and no more than 1/2 teaspoon of psyllium, and mix with 150ml(5oz) water.
Drink one glass of this mix first thing in the morning, and 1/2 hour before lunch and dinner.
That’s it. Do this forever.
Much easier Robert, and no disgusting artificial flavouring of Tang or similar.
Psyllium Husk capsules. Available from Amazon UK, if you live UK.
I got them to bulk my stools, thinking it might help avoid constipation. But I noticed they did seem to fill my stomach for a while so it struck me they would help anyone wanting to lose weight by eating less.
Thank you for your articles Dr Rushworth. Love what you do, please continue 🙂
Studies have suggested that pea protein (250mg/kg), EPA/DHA (1-2g), bile acid, Berberine (500mg BID), chewing food, high dose glutamine (30g/day), quercetin, fiber/resistant starch, olive leaf extract, MUFA’s can all increase GLP-1. I wonder if incorporating these suggestion with a keto diet could produce better results than the keto diet alone?
Do you have any clues?
People lose weight on Keto because they eat less and feel satiated by the protein. They won’t lose weight on Keto if they are eating more than whatever their calorie deficit is to lose weight (Butter coffee, etc) It’s easier to eat mainly protein (filling + satiating) and always be in a calorie deficit until you reach your goal weight. There is no reason to add additional fat to your diet. Walk for an hour a day.
This has been shown to be incorrect. People lose weight switching from a high carb to a low carb diet without any decrease in total calorie intake. The idea that it’s all about calories in vs calories out and how satiating different foods are is simplistic and wrong, and ignores the metabolic and hormonal changes associated with high vs low carbohydrate diets.
Hi Dr Rushworth,
My doctor has prescribed Phentermine for weight loss. I’m not a big fan of pills but Keto hasn’t helped. I’m desperate to lose 10kg but exercise and healthy eating is just not working. I keep staying in a certain range.
Could you let me know if this product Phentermine / Dorumine is dangerous? I’m actually feeling worried taking it after seeing all of the negative comments online. I would only be taking 7mg a day