Once-Weekly Semaglutide in Adults with Overweight or Obesity, 2021, Wilding et al

[Andy]

I've been asked to post this.

Abstract

BACKGROUND
Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

METHODS
In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

RESULTS
The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

CONCLUSIONS
In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935. opens in new tab).

Paywall, https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

Article, https://www.nytimes.com/2021/02/10/health/obesity-weight-loss-drug-semaglutide.html

 

[arewenearlythereyet]

Generally, insurers have refused to pay for the weight-loss drugs on the market. Semaglutide is likely to be expensive. The lower dose used to treat diabetes carries an average retail price of nearly $1,000 a month. (Insurers usually pay for diabetes drugs, Dr. Kushner noted.)

Dr. Caroline Apovian, co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital and a member of Novo Nordisk’s advisory board, said the effectiveness of semaglutide was “phenomenal” and that the trial results may lead insurers to cover it.

Semaglutide is a synthetic version of a naturally occurring hormone that acts on appetite centers in the brain and in the gut, producing feelings of satiety. A high-dose regimen of the drug has not been studied long enough to know if it has serious long-term consequences.

And it is expected that patients would have to take it for a lifetime to prevent the weight loss from coming back.

sounds impressive but I guess this will not become available on the NHS as a treatment for the masses whilst the belief that patients should have more will power still resides.

Far easier to make up pretend solutions and churn out misleading food industry-bashing papers out of Queen Mary’s to deflect attention away from the real issues (poverty etc)

perhaps Boris’ s new app will make us all better?

 

[Hutan]

The trial does look good from the abstract. Double-blind; an intention-to-treat analysis; a substantial loss of weight, way more than that achieved by the control; recording of harm. It looks like it's a trial funded by the manufacturer, so you'd want to see some independent validation. The treatment has an obvious basis for working:

Semaglutide is a synthetic version of a naturally occurring hormone that acts on appetite centers in the brain and in the gut, producing feelings of satiety. A high-dose regimen of the drug has not been studied long enough to know if it has serious long-term consequences.

And it is expected that patients would have to take it for a lifetime to prevent the weight loss from coming back.

Yeah, it does look very expensive, although I expect it could become cheaper over time. Bulk production of a hormone surely doesn't need to cost thousands for a monthly dose.

The semaglutide study confirms what scientists already know, Dr. Kushner said: Willpower is not enough. In the new trial, participants who received the placebo and diet and exercise counseling were unable to see any significant difference in their weight.

This alone was quite interesting. Participants were injecting themselves with a placebo - that should be a really powerful placebo. And yet that, even with counselling on diet and exercise, was not enough to make much of a difference in weight. So, the placebo effect wasn't looking very effective. And neither were the usual approaches of encouraging people to eat better and be more active.

 

[Wonko]

Of course the reported main side effects, nausea and diarrhea, don't affect appetite or weight at all.

 

[Jonathan Edwards]

The trial does look good from the abstract. Double-blind; an intention-to-treat analysis; a substantial loss of weight, way more than that achieved by the control; recording of harm. It looks like it's a trial funded by the manufacturer, so you'd want to see some independent validation.

It certainly looks to satisfy a number of quality criteria and the result looks clinically relevant.
There remains a problem, however, relating to the effectiveness of blinding. Blinding matters here because although weight loss is objective in the sense that you cannot influence the result of the measurement it is subjective in that it may come about because of the psychological or subjective context of the trial which may not hold outside a trial.

If the drug makes people nauseous, or even just lack appetite, then there is a fairly high chance that subjects will figure out whether or not they are on the drug or just saline, especially if they have a chance to chat in the waiting room.

We then have two very different psychological contexts. One is a group people keen enough to lose weight to go in a trial and put up with nausea for months feeling that they have a real chance of getting somewhere by carrying on, not eating much. The other is a group of people keen enough to lose weight to go in a trial who realise that they are on the dummy and will have to work just as hard as they ever did to lose weight by not eating much. It would be no great surprise if the first lost weight and the second did not.

What that seems to imply is that all this trial is showing at best is that if you take something that makes you feel sick and stick at it long enough because you have some special motivation to do so like being in a trial you may lose weight. That would not be very surprising. It raises the question as to whether there is a cheaper and perhaps safer way to make yourself feel nauseous. The problem is that if the psychological context of being in a trial plays a major part then the effect is not going to carry over into routine practice.

Unfortunately, I doubt that anyone will have access to the drug in order to do an independent validation. That does not happen in pharmaceuticals in general. If the drug is already licensed then they could buy it but that would be expensive.

 

[arewenearlythereyet]

Yeah, it does look very expensive, although I expect it could become cheaper over time. Bulk production of a hormone surely doesn't need to cost thousands for a monthly dose.

I don’t see why they would make it cheaper though. It’s not about the cost of production but about what price they can get away with/what the market will tolerate. I suspect this will be positioned as a cheaper alternative to surgery and the price will reflect that.

it doesn’t preclude someone else inventing an alternative though. My main concerns aren’t the short term side effects, but the unknown long-term effects of taking a hormone therapy, particularly in an area that in science terms is relatively new.

Hormone therapy has plenty of pitfalls.

having said all that, the results and trial structure do look good, and a non-invasive alternative still should be much more cost effective.

 

[Hutan]

It's hard to tell from an abstract and an article, but the side effects don't sound too terrible for most. Possibly they weren't even noticeable for many?

Here someone 'not involved in the trial' says the side effects were 'really marginal'.

Dr. Clifford Rosen of Maine Medical Center Research Institute, who was not involved in the trial, said, “I think it has a huge potential for weight loss.” Gastrointestinal symptoms among the participants were “really marginal — nothing like with weight loss drugs in the past,” added Dr. Rosen, an editor at the New England Journal of Medicine and a co-author of an editorial accompanying the study.

And the person written about in the article claims to have not guessed that she was on the drug until she could tell that the weight was coming off:

Qiana Mosely, who lives in Chicago, spent years trying to lose weight with diets and drugs, but to no avail. Then Ms. Mosely joined the semaglutide trial and lost 40 pounds, about 15 percent of her weight. Ms. Mosely didn’t know until recently whether she was getting the drug or the placebo. Even though she was trying to eat well and exercise, her weight “was dropping too fast,” she said. “It had to be the meds.”

She says she didn't have side effects:

She experienced no side effects, she said. But when the trial ended and she no longer received the drug, the weight started coming back. “I was so sad,” she said. She is eager to resume taking the drug once it’s available.

It raises the question as to whether there is a cheaper and perhaps safer way to make yourself feel nauseous.

If the abstract and the article are fair representations, then I don't think the weight loss can be attributed to lots of people feeling nauseous for a lot of the time.

 

[arewenearlythereyet]

I agree blinding does appear to be an issue, even small amounts of nausea etc will swing the results due to the power of suggestion.

however it is also not clear how many people in the control group would have suffered side effects just from eating less compared to their normal eating regime and this may have put them off persisting with the reduced calories?

I guess this is difficult to account for in a trial design though, unless you design it in such a controlled way that it becomes unrealistic and with other biases introduced (e.g. forced choice of offering/preferences). There is a lot of food/diet-based behavioural conditioning to get past by the time we are adults.

 

[Hutan]

I don’t see why they would make it cheaper though.

If making it cheaper opens up a vast weight loss market, then it might make sense to do so.

it doesn’t preclude someone else inventing an alternative though.

Yeah, that was my vague thought, if the drug is based on a naturally occurring hormone, then maybe all relevant options can't all be tied up with patents. And maybe it's possible for modified bacteria to produce it cheaply.

Anyway. It's just that I was asked to look at the abstract, and I was surprised by how good it looked. I guess we will see if it actually is eventually.

 

[arewenearlythereyet]

If making it cheaper opens up a vast weight loss market, then it might make sense to do so.

Yeah, that was my vague thought, if the drug is based on a naturally occurring hormone, then maybe all relevant options can't all be tied up with patents. And maybe it's possible for modified bacteria to produce it cheaply.

Anyway. It's just that I was asked to look at the abstract, and I was surprised by how good it looked. I guess we will see if it actually is eventually.

Yes I think this could be possible. To access the domestic market though it would need to come down quite a bit (bearing in mind the obesity crisis is heavily skewed to the poorest in society). Not sure but €30-100 per month feels more realistic than €1000. So ...it’s a maths game. I think 40% of USA are obese so there ain’t no shortage of punters. It has to be balanced against the saving in food bill perhaps?

Main unknown is still how long a patient can be on the treatment. I suspect we don’t really know enough and after a while the brain may adjust to its new normal in any case ...we do have a satiating hormone already and consumers are able to override this now so why not the artificial one over time as well?

 

[Hutan]

Unfortunately, I doubt that anyone will have access to the drug in order to do an independent validation. That does not happen in pharmaceuticals in general. If the drug is already licensed then they could buy it but that would be expensive.

That seems to be quite a structural problem. I think we've talked before about the idea of governments giving selected universities funds to replicate studies. That way, everyone has better information, universities have money and students learn to do really good research (as opposed to research that produces the 'right' answers).

It would seem logical for drug companies (and, for that matter, proponents of therapies) to pay for independent testing institutions to conduct final tests before approval is given. There aren't that many places where marking your own test is seen as an acceptable approach. Odd that it's ok when people's health and lives are at stake.

I think 40% of USA are obese so there ain’t no shortage of punters. It has to be balanced against the saving in food bill perhaps?

Yes, and governments (and even insurers) might be willing to pay part of the cost for something that reduces the burden of diabetes and cardiovascular disease.

Main unknown is still how long a patient can be on the treatment.

Yep, I think that is the biggest question. 68 weeks was a decent start though. I wonder if weight loss plateaued during that time.

 

[Jonathan Edwards]

If the abstract and the article are fair representations, then I don't think the weight loss can be attributed to lots of people feeling nauseous for a lot of the time.

The abstract and article are not going to be 'fair representations' I am afraid but I agree that things may be more subtle.
The side effects need not be too bad, just noticeable now and again. I wouldn't put a lot of faith in testimonials about not knowing if you were on the drug. Very likely subjects will have wanted to 'help' the researchers in their comments just as in CBT trials. No doubt we do not get to hear from the person who realised they were on it on day 1.

I think it highly likely that the drug does work in a trial context but I think there are big questions about how useful it would be in routine care.

 

[Jonathan Edwards]

It would seem logical for drug companies (and, for that matter, proponents of therapies) to pay for independent testing institutions to conduct final tests before approval is given. There aren't that many places where marking your own test is seen as an acceptable approach. Odd that it's ok when people's health and lives are at stake.

But 'independent testing institutions' seem to throw up people like the inventors of the Risk of Bias Tool2 that conveniently plays down risk of bias. Paying people to be independent tends not to work.

The current situation is barmy. When rituximab for RA went to NICE all the evidence was submitted by Roche. I was not asked to be involved in any way despite having done the proof of concept work and being independent, having received little or nothing from Roche to do studies. The initial submission was turned down because Roche had not submitted certain things. It was of no interest to NICE whether or not the drug worked - only whether Roche could prove it to them. Presumably the assumption was that the benefit from the use of the drug was just to Roche.

 

[Midnattsol]

Putting someone on a reduced calorie diet for over a year does sound like a recipe for becoming fed up with the "treatment". Especially if weight loss is slow, I would not be surprised if motivation to continue the lifestyle change dropped (follow-up every four weeks is pretty good in a clinical setting though, in the two hospitals I've interned at in Norway follow up in the obesity clinic is once every three to four months).

Even if the diet was followed to the letter, weight loss in the beginning might not be very rapid if the estimated energy requirements are off (and they very well might be, they don't say how the estimates were done. Based on different formulas my basal metabolic rate can vary with >200kcal, then you add in the even more subjective physical activity modulator. They did after all plan to increase physical activity in the participants, was this new level of physical activity used to calculate how much energy the participants required?). The group that got the GLP-1 might have found it easier to eat less than the diet plan > more rapid weight loss > more motivation to continue what they were doing > still keeping with the program for a longer amount of time.

Losing 15kg in a year is not bad, but it's not something that can't be done without drugs. The problem is generally not to lose the weight, but to keep it off. And this trial does not tell us that the drug helps with that.

 

[Sisyphus]

If ya really wanna lose weight and u have our disease, get accustomed to feeling slightly hungry alla time. Not gnawing, consuming hunger, just a feeling of being a little short of satisfied. It has to be all day, every day. It’s a hard habit to establish, and harder to keep long enough to make it stick.

imho, once one establishes that reset diet changes and calorie tracking will work for us. Without it, they probably won’t.

 

[Milo]

Losing 15kg in a year is not bad, but it's not something that can't be done without drugs. The problem is generally not to lose the weight, but to keep it off. And this trial does not tell us that the drug helps with that.

I have lost about 50 lbs (22.5 kg) over 18 months, so it can be done, but you need to be motivated and committed. It is terribly hard to maintain, and in my case i did not. I was on a 1200 calories diet.

I have struggled with my weight all of my life, but it was easier to control when i was active.
I would welcome this drug if it was covered, just to give me a little bit of a push in the right direction .

 

[Mithriel]

I get hunger as a symptom which is as unrelenting as a pain. It is obviously part of my PEM and like other things happens with no rhyme nor reason. I know from experience that eating does not relieve it so it is something to endure. Sometimes I crack and have a bit of dry toast which doesn't much help but feels better for a short while. It is a horrible thing.

The experience of hunger is not considered enough. Like every other part of our biology it can go wrong.

Taking a drug occasionally seems a better option than bariatric surgery which has horrendous side effects because of problems with mineral absorption.

 

[Sid]

I know a guy who took part in a clinical trial of this drug for diabetes several years ago, years before this trial for obesity was published. He has battled weight for years and remarked that he was surprised to discover that it was the first thing in his life that got rid of his constant hunger. As a result he lost weight.

My understanding is that the nausea side effect can't explain the large and clinically meaningful difference between the drug and placebo because for many people the nausea is mild and occurs only initially. The cost, however, is extreme at present and the necessity for self-injections is also a problem.

What's also interesting is how this trial yet again shows that diet and exercise have next to 0 effectiveness in obesity yet the entirety of our public health policy in dealing with the obesity epidemic is predicated on the notion that people can just diet and exercise their way out of it.

 

[Jonathan Edwards]

What's also interesting is how this trial yet again shows that diet and exercise have next to 0 effectiveness in obesity

Diet and exercise are actually totally effective overweight and obesity, as was documented by people like Hugh de Wardener on Japanese prisoners of war - when they also worked out the minimum daily requirements of vitamins. The problem is sticking to the diet and exercise.

I don't think the nausea effect needs to be even as much as to be noticeable - presumably the way this drug works is to block appetite (it is said to help you feel full after food) and feeling full is pretty much tending to nausea. If it does that in a more cost-effective manner than other things fine but I am sceptical. There does not seem to be a suggestion that it increases metabolic rate so it isn't as if it increases using up the calories taken in. It just makes people diet.

 

[Sid]

Diet and exercise are actually totally effective overweight and obesity, as was documented by people like Hugh de Wardener on Japanese prisoners of war - when they also worked out the minimum daily requirements of vitamins. The problem is sticking to the diet and exercise.

I don't think the nausea effect needs to be even as much as to be noticeable - presumably the way this drug works is to block appetite (it is said to help you feel full after food) and feeling full is pretty much tending to nausea. If it does that in a more cost-effective manner than other things fine but I am sceptical. There does not seem to be a suggestion that it increases metabolic rate so it isn't as if it increases using up the calories taken in. It just makes people diet.

Obviously if you are locked up in a concentration camp and are taking in fewer calories than you need you will lose weight. This trivial observation has nothing to do with free-living individuals in the uncontrolled environment of the real world where decades of research shows that people in these sorts of trials lose about 4 lbs in a year, on average, doing diet and exercise. A drop in the bucket. This is because most people cannot voluntarily endure chronic hunger. And why should they? People who are naturally normal weight don't have to subject themselves to a 1200 calorie per day diet (a semi-starvation diet for an adult male) to maintain their normal weight. The job of obesity research should be to figure out why overweight people feel hungry all the time instead of moralising.