A Major Shift in Obesity Medicine?
Have you heard the recent news about Ozempic or semaglutide? Is it a new game-changer drug in obesity medicine? Maybe?
There was a flurry of news articles all about it last month. (I don’t claim to be a breaking news reporter.) Anywho, you have probably heard of Ozempic or, as the commercial goes, “Oh, Oh, Oh, Ozempic!” Catchy, I know!
Ozempic is a medication that is currently available in Canada and the US for diabetes management. However, the hot news around it concerned the recent studies completed that showed some impressive results regarding weight loss. Obviously, this is kinda sort of a big deal in my practice, and I have gotten a few questions. So hopefully, I can piece together some answers for you here.
What is Ozempic?
Ozempic belongs to a class of medications called GLP-1 receptor agonists (GLP-1 RAs). GLP-1 is a hormone naturally produced in our bodies and is what we call a satiety hormone. As a receptor agonist, these drugs bind to the same receptors that the natural GLP-1 hormone binds to in our bodies and elicits the same biological response. In fact, GLP-1 RAs are identical to the human GLP-1 hormone with the exception of a few modifications to prevent them from being broken down as quickly as the natural human hormone, therefore, having a longer-lasting effect.
One of the first GLP-1 RAs to come to market several years ago was Victoza – some of you may have heard of this drug and its use for diabetes. The generic name of Victoza is liraglutide. Victoza, or the prodigy child, was not only shown to help blood sugars, but it also had some benefit on the heart and, and you guessed it, led to weight-loss.
Now, given the current obesity epidemic, Novo Nordisk, the maker of Victoza, was like, “Heyyy, we got something here. I wonder what would happen if we increased the dose of Victoza to say 3mg a day?” And from there, Saxenda was born or, more correctly, Victoza grew up and changed their name.
Victoza and Saxenda both contain liraglutide – Saxenda is just titrated up to 3mg/day vs. 1.8mg/day in Victoza. Since Victoza’s creation, a number of other GLP-1 RAs have come to market for the management of diabetes, and they all have shown some weight management benefits.
Now, like any good progressive and innovative company that wants to keep its shareholders happy, Novo Nordisk didn’t stop at Saxenda. (Side Note: from here on out, I’ll be referring to Novo Nordisk as simply Novo – my computer wants to keep replacing the ‘s’ in Nordisk with a ‘c.’ I’m not entirely sure what that is all about, but I should try to keep some shred of professionalism)
Novo continued with research & development to produce Ozempic. Comparing treatments, Victoza/Saxenda is a once-daily injection while Ozempic is a once-weekly injection.
Currently, Ozempic has one indication: treating Type 2 Diabetes at a max dose of 1mg per week. However, the studies demonstrating weight-loss benefit in Obesity (STEP Trials) have used a dose of 2.4mg once weekly. The STEP trials created the news flurry!
Novo has now applied to the FDA and Health Canada for Ozempic to receive the indication for Obesity at a dose of 2.4mg per week. I suspect, like Victoza/Saxenda, Novo will likely rename Ozempic and come up with an equally catchy jingle that will be forever burned into the deep recesses of your brain and spontaneously pop into your mind at the most inappropriate times. Can’t wait!
I should also note there is an oral formulation of Ozempic called Rybelsus. It is a once-daily tablet. I won’t cover it today, but rest assured, I have plans to share my opinion!
So what does GLP-1 even do?
I am so glad you asked!
As I said, GLP-1 is a hormone that is naturally produced by the body. Specifically, it gets released into the blood from what are called the L-cells in the intestinal tract in response to food coming into the stomach. (Side Note: Don’t ask me why they are called L-cells, I am assuming they look like cute little ‘L’s under a microscope, but I suspect there is a more sciency reason for the name.)
GLP-1 has a few functions in the body. First, it goes to the pancreas and tells the pancreas to get ready to release insulin as there are nutrients inbound. Next, it goes to the liver and tells the liver to stop creating/dumping new sugar into the bloodstream, again because new sugar is coming into the system. These two mechanisms are largely how GLP-1 RAs help to manage blood sugars and diabetes.
Quick point: when blood sugars are within normal ranges, these GLP-1 mechanisms lie dormant; therefore, the chance of experiencing hypoglycemia (too low blood sugar) when taking GLP-1 RAs, whether you have diabetes or not, is very minimal. So, it is safe for people who don’t have diabetes! However, like any medication, there are always potential risks. Similar to being murdered by a cat, the risk is never completely zero.
Let’s continue with the GLP-1 process. After talking to the liver, GLP-1 goes to the stomach next and slows down gastric emptying, or how quickly food moves from your stomach to the small intestine. Food will sit in your stomach longer, which helps to tell you that you are full and that it would be wise to stop eating. Now, this is what causes a lot of the side effects concerning GLP-1 RAs.
A vast majority of the side effects reported in the trials are GI in nature – nausea, heartburn, upset stomach, constipation, diarrhea, and vomiting. Especially if you eat large portions or eat too quickly, you are going to have an awful time. Many people believe this is how it helps you lose weight: if you feel nauseated all the time, yes, you won’t feel like eating. However, these effects are short-lived and what we would call transient. Your body just needs to get used to the medication, and the side effects will resolve. That is why we increase the dose of these drugs slowly to improve tolerance. Many people will say the drug is losing its effectiveness as they get used to these side effects and notice their hunger and ability to eat larger portions return. This is a sign we need to make some dietary changes.
Now the final area that GLP-1 acts in is within the mesolimbic or reward area of the brain. It decreases our want and drive for food. This is the GLP-1 RAs’ main benefit in supporting weight management. If you have a lower drive/reward feedback for food, you will engage in less food-seeking and overeating behaviours, which for many can lead to weight loss. Neat!
So, how effective is Ozempic?
In one of the most recent STEP trials, Wilding et al. demonstrated some pretty profound results in terms of weight-loss. It is not often I give a *positive hmm* with a slight head nod in agreement. Usually, I offer a snort of derision, a skeptical eye, and a giggle at some of the conclusions the authors draw in their discussions. But, this earned an approving nod.
Anyways, in this randomized controlled trial, Wilding and friends found that Ozempic at a dose of 2.4mg/week led to a weight-loss of 14.9% from baseline or ~33lbs on average over 68 weeks. To give you some perspective, other obesity medications have shown ~4-11% weight-loss from baseline.
Furthermore, 32% of participants lost greater than or equal to 20% of their baseline body weight. In practice, a weight-loss of 5-10% is substantial. A loss of more than 20% is huge! It’s comparable to the amount of weight that can be lost post-bariatric surgery. Ultimately, part of our goal is to find medications that can produce similar results to bariatric surgery. The less we have to cut people, the better.
Of course, these studies are all done in conjunction with lifestyle interventions such as a 500kcal/day deficit, increasing physical activity and ongoing supportive counselling. Lifestyle is and will always be foundational in managing any chronic disease. #sorrynotsorry.
Overall, the trial by Wilding and friends was relatively well done. There were no glaring shortcomings. Their placebo group received only the lifestyle interventions as well as some placebo injections and had decent weight-loss results, too. This indicated that lifestyle interventions were adequate and beneficial, just not as effective as those interventions combined with Ozempic. The difference in weight-loss between the groups was 12.4%.
Of course, the Ozempic group did experience more adverse effects, primarily GI in nature. In practice, nearly every patient I have worked with that has taken Ozempic has experienced some form of side effects, whether that is nausea, heartburn, constipation, or vomiting. However, I have also never seen a drug be so effective in managing blood sugars and weight.
So that is Ozempic. In reality, it is just the start of a new wave of Obesity medications that will start appearing on the market. There are a ton of agents in the pipeline that I suspect will demonstrate equivalent or even better results than Ozempic.
Between the advancements in these medications, 3D printing, immunotherapies, and in the COVID vaccine, I believe we are entering a new age of medicine that will transform healthcare as we know it! Again, #sorrynotsorry but lifestyle and behaviours modification will still be the cornerstone! Until next time!
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Feb 10. doi: 10.1056/NEJMoa2032183. Epub ahead of print. PMID: 33567185.