Semaglutide is the word on people’s lips right now. This injectable medication dramatically reduced weight at 68 weeks in a large double-blind randomized controlled trial published in The New England Journal of Medicine. The STEP 1 trial randomized 1961 obese people without diabetes to a once weekly injection of semaglutide or placebo in a 2:1 ratio (which means twice as many people were in the treatment group).

How dramatic was the weight loss?

Half the people in the treatment group lost 15% or more of their body weight. Only 5% of those in the placebo group lost that much. The primary endpoint was actually two coprimarys of % change in body weight and weight reduction of at least 5%. For the former, there was a 15% reduction in weight in the treatment group versus 2% in the placebo group. For the latter, 86% of people in the treatment group lost 5% or more of their body weight compared to 32% of people in the placebo group. Those who received semaglutide also 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.  I think everyone would agree these benefits are dramatic.

Why 68 weeks?

The medication was titrated up from 0.25mg to 2.4mg over 16 weeks. Then from there you have your classic year-long trial, which is still an arbitrary timeline but reasonable to demonstrate efficacy I think.

What about side effects?

Common side effects of semaglutide were nausea and diarrhea. 5% of people in the treatment group stopped treatment due to gastrointestinal events compared to 1% of people in the placebo group. Safety of this drug has been looked in previous diabetes studies but, in short, there is still a concern about pancreatic/hepatobiliary disorders. It’s probably safe enough but when thinking about treating obese people who are otherwise healthy, one does need to think twice about risk when there may be other ways of losing weight. Not many though.

What did we already know about semaglutide?

Semaglutide increases insulin production and was established for use in type 2 diabetes 5 years ago. More recently it was approved by the FDA for reducing cardiovascular risk in people with type 2 diabetes. It reduced rates of myocardial infarction and stroke but not heart failure (indeed in trials of patients with HFrEF, heart failure events were increased by use of a GLP-1 agonist). Aside from the reduction in myocardial infarction and stroke, semaglutide reduced weight in these trials so a positive STEP 1 result isn’t altogether unsurprising. Having this evidence in people without type 2 diabetes is a huge step forward though.

What does Milton Packer say?

“So, this is a “big” deal.  But the idea has been centerstage for a while.

This drug is a GLP-1 receptor agonist, and it produces impressive weight loss.  The degree of weight loss is greater than was seen in the trials in type 2 diabetes.  The other piece of news is that we know (from large-scale trials) a lot about the safety of these drugs.  As a result, there is a clear regulatory path for the FDA/EMA approval of these drugs for weight loss.”

What does Sanjay Kaul say?

“In order for weight loss interventions to have clinically meaningful benefits, they need to induce a weight loss of >10-15% (which is greater than the FDA standard of >5% for weight-loss interventions) that is sustained long term.

In this trial nearly a third of patients on semaglutide achieved a weight loss of >20% which is comparable to what we see achieved with bariatric surgery (a messy and not a pragmatic therapeutic option). This makes it a highly desirable option.

What is noticeable to me is that the weight loss peaks at around 60 weeks which is longer than what we see with Saxenda (around 44-50 weeks) and Qsymia or Contrave (24-30 weeks).

There were no new adverse events identified and the drug has an acceptable safety profile based on previous trials.

I would have liked to see a more diverse and a higher-risk (T2DM, obstructive sleep apnea) patient population enrolled, but I am sure these must be coming.

The graveyard of obesity therapeutics is littered with many drugs that were initially hailed as ‘magic bullet’ but turned out to be more bullet than magic. With its blockbuster weight loss efficacy and proven safety track record, it appears that semaglutide might finally achieve the elusive goal of being a gamechanger in the war against the obesity epidemic.

I don’t see any headwinds to thwart a smooth pathway for approval.”

I personally disagree that with Sanjay that bariatric surgery is “messy and not pragmatic”. It’s by no means a small undertaking but Roux-en-Y gastric bypass, in particular, is incredibly effective and durable with many a happy patient to testify to how it changed their lives radically for the better. With semaglutide, it’s only effective for reducing weight for as long as it is being administered, and it’s hardly pleasant to keep inflicting oneself with ongoing nausea and diarrhea (although in the trial most people did keep taking the drug anyway but I imagine the impetus to continue would be a bit less in real life).

Future directions

Will weight loss efficacy translate into cardiovascular protection? A separate semaglutide trial, SELECT, is looking at this question. The SELECT trial takes people with obesity and prior cardiovascular disease (but no diabetes) and randomizes them to semaglutide or placebo in a double-blind fashion. The primary endpoint is a composite of cardiovascular death, myocardial infarction or stroke. We await the results eagerly!

The underlying premise in this area is to exploit the body’s own regulatory systems for weight loss and to improve metabolic dysfunction. In this sense, Milton Packer explains that semaglutide is only a “first step”:

“There is an endogenous polypeptide — related to GLP-1 — known as GIP.   The two molecules tend to reinforce each other in the body.  That knowledge led pharmaceutical companies to synthesize molecules that act as dual GLP-1/GIP agonists, i.e., they mimicked the action of BOTH molecules in a single drug.  Interestingly, when you do that, the degree of weight loss is substantially greater than seen with semaglutide in the NEJM paper.

“The weight loss effect is so dramatic that we are launching a long-term clinical trial of a novel dual GLP-1/GIP agonist for the treatment of a very specific form of heart failure that is directly linked to and caused by morbid obesity, i.e., obesity-related HFpEF.  The hope is that the patients’ heart failure will improve dramatically if they lose significant amounts of weight.  (In this form of heart failure, we already know that bariatric surgery leads to very significant resolution of heart failure.)”

What do you think about semaglutide for obesity? Share your thoughts in the comment section.

 

 

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