Comparing the Benefits and Side Effects of Ozempic (Semaglutide)

Michael Greger M.D. FACLM · January 20, 2025 · Volume Ozempic

4.3/5 - (58 votes)

Obesity can be so devastating to our health that the downsides of any effective drug would have to be significant to outweigh its weight-loss benefits.

Discuss

Transcript

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Even the drug manufacturers of Ozempic and similar weight-loss drugs cop to the long list of potentially serious side effects. The absolute risks, though, for serious issues like pancreatitis, thyroid cancer, bowel obstruction were all about one percent or less per year of using GLP-1-type drugs. Of course, when millions of people are on these drugs, even relatively rare side effects will occur in a large number of people, but you know what else can have serious side effects? Obesity.

In fact, one potential side effect of GLP-1 drugs is that they could be too effective, risking excessive weight loss––suppressing the appetite so much, for example, that after taking her first dose, this patient decided to start a new diet composed of: water and diet soda. Or an eat-once-a-week plan. Any discussion of risks versus benefits has to take any benefits of the weight loss itself into account.

Excess body fat is a major risk factor for metabolic diseases involving nearly every organ of our body, such as type 2 diabetes, heart disease, stroke, dementia, liver disease, sleep apnea, osteoarthritis, infertility, several cancers including breast cancer and colon cancer—even psychiatric disorders. Consider the overall health outcomes of those undergoing bariatric surgery, which is not exactly a benign procedure.

In the United States, for instance, hundreds of thousands go under the knife to lose weight. Roux-en-Y gastric bypass is one of the most popular techniques, and is thought to be the “gold standard” method given its safety record, with a mortality rate < 0.5 percent.

Wait, they’re bragging about not killing more than one in 200 people in the operating room?

The surgery is a major rearrangement of your digestive tract, but it can induce a long-term weight loss of about 25 percent, which is similar to some of the best results of the new GLP-1 drugs. So, if you only care about living longer, might the benefits of weight loss outweigh the risks of dying on the operating table? Based on a meta-analysis of millions of patients, only about one in 1,250 people appear to be killed directly by the surgery, and since the ones who don’t lose their lives tend to lose so much weight that bariatric surgery has been associated with a six-year longer lifespan. So, on average, choosing to go under the knife may significantly extend your life—even after taking into account the risk of the operation killing you.

But, of course, there’s also a risk of complications. Approximately one in four bariatric surgery patients experience adverse effects in the five years following surgery, and, for one in 50, it’s so bad they have to go back onto the operating table for further surgery. That’s one advantage of the drug approach. If you experience some serious side effect, it may go away when you stop taking the drug, whereas if you’ve already had your stomach cut out, or your intestines rearranged, there may be less that can be done about it.

Here’s a list of the pros and cons. Researchers looked at the impact of bariatric surgery on more than five dozen health outcomes, and although people who underwent surgery may be more likely to kill themselves, break bones, and suffer acid reflux, they also appear to get less diabetes, high blood pressure, and high cholesterol, and less cancer and cardiovascular disease.

Here’s how it breaks down. Just looking at the statistically significant associations, we can see that those who had bariatric surgery have a lower risk of dying from all causes put together, as well as dying specifically from diabetes, cancer, and cardiovascular disease. But they are at an increased risk of taking their own lives. In terms of metabolic outcomes, lower risks of getting diabetes, high blood pressure, and high cholesterol, lower risks of continuing to have diabetes, high blood pressure, and high cholesterol, and a lower risk of diabetic complications. In terms of getting cancer, there’s a lower risk of developing different types of cancer, and getting any kind of cancer at all, a lower risk of all the cardiovascular diseases the researchers looked at, and most of the digestive diseases, except for reflux with sleeve gastrectomy, and higher or lower risk of kidney stones depending on procedure, but it generally seems to be kidney protective. For women’s health, after bariatric surgery, they had less urinary incontinence and polycystic ovary syndrome, and fewer problems during pregnancy, though the outcomes for infants are mixed, with more preterm birth and death. And finally, less anxiety and depression, though more self-harm, and a lower risk of being hospitalized and dying from COVID.

So, generally, the benefits far outweigh the risks, but really, that says less about the benefits of surgery, and more about the risks of excess body fat. With the GLP-1 drugs, we see largely similar improvements in things like blood sugar control, blood pressure, and cholesterol, and maybe even similar clinical outcomes, like with the risk of dying. If that were the case, then for most people with obesity, like with the bariatric surgery, the benefits of these new drugs would be expected to far exceed the risks.

Yes, there are still issues with the cost of these potentially life-long medications, and lack of knowledge of their long-term side effects, and this, of course, assumes you’re taking the actual drug. Shortage of these pills has led patients to compounding pharmacies that offer versions of the drugs that have not been approved by the U.S. Food and Drug Administration, which in the past has led to serious safety issues, like an epidemic of fungal meningitis caused by moldy bottles of drugs from compounding pharmacies. Seven hundred fifty-one patients were ultimately affected, and more than 60 patients died.

But at least compounding pharmacies have some kind of regulation. Nowadays, people can get injected with God-knows-what at so-called medical spas that may not be under any form of regulation. People don’t seem to be paying much attention to these FDA warnings. As an article in Rolling Stone put it, “The FDA warned Ozempic users, but…they don’t give a f—”….

Yes, these drugs can improve risk factors, but the risk/benefit balance really depends on these clinical disease outcomes. Do people really live longer on these drugs, have less heart attacks?

“Thinner is better” is the conventional wisdom when it comes to minimizing the risk of cardiovascular events like heart attacks and strokes, but there have been cases where weight-loss medications actually led to increased cardiovascular risk, despite significant reductions in body fat. So, we can’t just assume drug-induced weight loss will help. Now, if it’s true that GLP-1 drugs, like Ozempic, reduce cardiovascular events, which are some of our leading causes of death, then that benefit alone would significantly overwhelm the risk of almost any amount of thyroid cancer these drugs may cause. Let’s look at the data.

Some major trials have found that among high-risk individuals with diabetes, risk of cardiovascular events was significantly lower among those randomized to Ozempic, compared to placebo injections, but other trials did not. Interesting how the lack of benefit was spun by saying—hey, it’s not inferior to placebo. But that was the main concern—that Ozempic, like some other weight-loss drugs, would actually increase cardiovascular disease; so, it was considered a relief that it had no effect.

Enough evidence of benefit accrued, though, that Ozempic and another GLP-1 drug were approved for cardiovascular protection among individuals with type 2 diabetes. Remember, these were originally prescribed as diabetes drugs; so, maybe users reduced their cardiovascular risk just by lowering their blood sugars rather than by lowering their weight.

What we want to know is this: what is the effect of Ozempic on cardiovascular outcomes in obesity for people without diabetes? And, in patients who have preexisting cardiovascular disease and are overweight or obese, but do not have diabetes, those randomized to weight-loss doses of Ozempic had an overall lower rate of either having a cardiovascular event like a heart attack or stroke, or dying from it, compared to placebo.

That’s exciting, but we have to highlight another caveat. The researchers just looked at those with preexisting cardiovascular disease. That is an important limitation of these findings. The effects of these weight-loss drugs on the prevention of cardiovascular events in those without diagnosed atherosclerotic disease have not yet been determined.

Still, a lot of overweight people have a history of heart attack, stroke, or peripheral vascular disease. So, how big is the effect? Over a period of a few years, 8 percent of people with cardiovascular disease suffered another event on the placebo, but only 6.5 percent suffered a subsequent event on the drug. Going from 8 to 6.5 is a 20 percent drop. You can see it clearly if you zoom in. Unfortunately, many news stories focused on that 20 percent relative risk reduction, rather than on the absolute risk reduction of 1.5 percent. Yes, 8 to 6.5 is a 20 percent drop, but, at the same time, you’re really only reducing your absolute risk by 1.5 percent. In other words, you have to treat 67 people with the drug for a few years to prevent one heart attack or stroke or cardiovascular death. That may not sound like much on an individual scale. I mean, what are the odds you’re going to be that 1 in 67th person? But on a population scale, it’s huge. In fact, it’s right up there with cholesterol-lowering statin drugs, which have an absolute risk reduction in the same 1.5 percent ballpark. So, indeed, in March 2024, the Food and Drug Administration approved high-dose Ozempic for use beyond just weight loss but also for reducing cardiovascular risk in those with prior cardiovascular disease.

So, how do the benefits and harms stack up? In the summer of 2024, the first quantitative benefit-harm balance analysis was published. The researchers concluded that for those achieving a 10 percent weight loss, there’s more than a 90 percent chance the benefits outweigh the harms, though the opposite was found for only a 5 percent weight loss. Here’s how they broke it down. If 1,000 people go on these GLP-1 drugs, 375 would be expected to lose at least 10 percent of their body weight, with all the ancillary benefits that would bring. On the other side of the equation, 41 people would suffer from abdominal pain, 57 from hair loss, 8 from gallstones, 118 from constipation, 100 from diarrhea, 22 from dizziness, 84 from an upset stomach, 46 from excessive burping, 39 from fatigue, 51 from excessive farting, 13 from headaches, 17 from low blood sugars, 4 from reactions at the injection site, 221 from nausea, 4 from pancreatitis, 43 from upper abdominal pain, and 110 from vomiting.

Now, of course, the net beneﬁt-versus-harm calculation would be highly dependent on different people’s willingness to accept different harms. Like, a bald guy isn’t going to be concerned about hair loss, for example. And this also doesn’t take into account the fact that the benefits peter out—weight loss stalls after a year, but the harms may continue. So, once you’ve already plateaued and stop losing weight, do you keep taking it, even though you get no further weight-loss benefit, but the potential for harm continues to accumulate?

We really don’t know about the long-term harms or benefits, because some of these drugs and dosing schedules are so new––especially now that the American Academy of Pediatrics has suggested offering these drugs for teens and tweens as young as age 12. These drugs work by acting on the brain, so who knows what effect this could have on childhood development and beyond, if they end up taking them for the rest of their lives.

In the end, this story is familiar. A new class of antidiabetic agents is rushed to market, and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates, but it’s vigorously denied or discounted. The manufacturers are expected—quite unrealistically—to monitor the safety of their own products. We should be thankful that those responsible for aircraft safety do not operate on the same assumption. Although we now do have evidence of at least near-term benefit over a few years, we cannot assume long-term safety until it has been demonstrated.

Please consider volunteering to help out on the site.

Sources

Acknowledgements

Motion graphics by Avo Media

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Even the drug manufacturers of Ozempic and similar weight-loss drugs cop to the long list of potentially serious side effects. The absolute risks, though, for serious issues like pancreatitis, thyroid cancer, bowel obstruction were all about one percent or less per year of using GLP-1-type drugs. Of course, when millions of people are on these drugs, even relatively rare side effects will occur in a large number of people, but you know what else can have serious side effects? Obesity.

In fact, one potential side effect of GLP-1 drugs is that they could be too effective, risking excessive weight loss––suppressing the appetite so much, for example, that after taking her first dose, this patient decided to start a new diet composed of: water and diet soda. Or an eat-once-a-week plan. Any discussion of risks versus benefits has to take any benefits of the weight loss itself into account.

Excess body fat is a major risk factor for metabolic diseases involving nearly every organ of our body, such as type 2 diabetes, heart disease, stroke, dementia, liver disease, sleep apnea, osteoarthritis, infertility, several cancers including breast cancer and colon cancer—even psychiatric disorders. Consider the overall health outcomes of those undergoing bariatric surgery, which is not exactly a benign procedure.

In the United States, for instance, hundreds of thousands go under the knife to lose weight. Roux-en-Y gastric bypass is one of the most popular techniques, and is thought to be the “gold standard” method given its safety record, with a mortality rate < 0.5 percent.

Wait, they’re bragging about not killing more than one in 200 people in the operating room?

The surgery is a major rearrangement of your digestive tract, but it can induce a long-term weight loss of about 25 percent, which is similar to some of the best results of the new GLP-1 drugs. So, if you only care about living longer, might the benefits of weight loss outweigh the risks of dying on the operating table? Based on a meta-analysis of millions of patients, only about one in 1,250 people appear to be killed directly by the surgery, and since the ones who don’t lose their lives tend to lose so much weight that bariatric surgery has been associated with a six-year longer lifespan. So, on average, choosing to go under the knife may significantly extend your life—even after taking into account the risk of the operation killing you.

But, of course, there’s also a risk of complications. Approximately one in four bariatric surgery patients experience adverse effects in the five years following surgery, and, for one in 50, it’s so bad they have to go back onto the operating table for further surgery. That’s one advantage of the drug approach. If you experience some serious side effect, it may go away when you stop taking the drug, whereas if you’ve already had your stomach cut out, or your intestines rearranged, there may be less that can be done about it.

Here’s a list of the pros and cons. Researchers looked at the impact of bariatric surgery on more than five dozen health outcomes, and although people who underwent surgery may be more likely to kill themselves, break bones, and suffer acid reflux, they also appear to get less diabetes, high blood pressure, and high cholesterol, and less cancer and cardiovascular disease.

Here’s how it breaks down. Just looking at the statistically significant associations, we can see that those who had bariatric surgery have a lower risk of dying from all causes put together, as well as dying specifically from diabetes, cancer, and cardiovascular disease. But they are at an increased risk of taking their own lives. In terms of metabolic outcomes, lower risks of getting diabetes, high blood pressure, and high cholesterol, lower risks of continuing to have diabetes, high blood pressure, and high cholesterol, and a lower risk of diabetic complications. In terms of getting cancer, there’s a lower risk of developing different types of cancer, and getting any kind of cancer at all, a lower risk of all the cardiovascular diseases the researchers looked at, and most of the digestive diseases, except for reflux with sleeve gastrectomy, and higher or lower risk of kidney stones depending on procedure, but it generally seems to be kidney protective. For women’s health, after bariatric surgery, they had less urinary incontinence and polycystic ovary syndrome, and fewer problems during pregnancy, though the outcomes for infants are mixed, with more preterm birth and death. And finally, less anxiety and depression, though more self-harm, and a lower risk of being hospitalized and dying from COVID.

So, generally, the benefits far outweigh the risks, but really, that says less about the benefits of surgery, and more about the risks of excess body fat. With the GLP-1 drugs, we see largely similar improvements in things like blood sugar control, blood pressure, and cholesterol, and maybe even similar clinical outcomes, like with the risk of dying. If that were the case, then for most people with obesity, like with the bariatric surgery, the benefits of these new drugs would be expected to far exceed the risks.

Yes, there are still issues with the cost of these potentially life-long medications, and lack of knowledge of their long-term side effects, and this, of course, assumes you’re taking the actual drug. Shortage of these pills has led patients to compounding pharmacies that offer versions of the drugs that have not been approved by the U.S. Food and Drug Administration, which in the past has led to serious safety issues, like an epidemic of fungal meningitis caused by moldy bottles of drugs from compounding pharmacies. Seven hundred fifty-one patients were ultimately affected, and more than 60 patients died.

But at least compounding pharmacies have some kind of regulation. Nowadays, people can get injected with God-knows-what at so-called medical spas that may not be under any form of regulation. People don’t seem to be paying much attention to these FDA warnings. As an article in Rolling Stone put it, “The FDA warned Ozempic users, but…they don’t give a f—”….

Yes, these drugs can improve risk factors, but the risk/benefit balance really depends on these clinical disease outcomes. Do people really live longer on these drugs, have less heart attacks?

“Thinner is better” is the conventional wisdom when it comes to minimizing the risk of cardiovascular events like heart attacks and strokes, but there have been cases where weight-loss medications actually led to increased cardiovascular risk, despite significant reductions in body fat. So, we can’t just assume drug-induced weight loss will help. Now, if it’s true that GLP-1 drugs, like Ozempic, reduce cardiovascular events, which are some of our leading causes of death, then that benefit alone would significantly overwhelm the risk of almost any amount of thyroid cancer these drugs may cause. Let’s look at the data.

Some major trials have found that among high-risk individuals with diabetes, risk of cardiovascular events was significantly lower among those randomized to Ozempic, compared to placebo injections, but other trials did not. Interesting how the lack of benefit was spun by saying—hey, it’s not inferior to placebo. But that was the main concern—that Ozempic, like some other weight-loss drugs, would actually increase cardiovascular disease; so, it was considered a relief that it had no effect.

Enough evidence of benefit accrued, though, that Ozempic and another GLP-1 drug were approved for cardiovascular protection among individuals with type 2 diabetes. Remember, these were originally prescribed as diabetes drugs; so, maybe users reduced their cardiovascular risk just by lowering their blood sugars rather than by lowering their weight.

What we want to know is this: what is the effect of Ozempic on cardiovascular outcomes in obesity for people without diabetes? And, in patients who have preexisting cardiovascular disease and are overweight or obese, but do not have diabetes, those randomized to weight-loss doses of Ozempic had an overall lower rate of either having a cardiovascular event like a heart attack or stroke, or dying from it, compared to placebo.

That’s exciting, but we have to highlight another caveat. The researchers just looked at those with preexisting cardiovascular disease. That is an important limitation of these findings. The effects of these weight-loss drugs on the prevention of cardiovascular events in those without diagnosed atherosclerotic disease have not yet been determined.

Still, a lot of overweight people have a history of heart attack, stroke, or peripheral vascular disease. So, how big is the effect? Over a period of a few years, 8 percent of people with cardiovascular disease suffered another event on the placebo, but only 6.5 percent suffered a subsequent event on the drug. Going from 8 to 6.5 is a 20 percent drop. You can see it clearly if you zoom in. Unfortunately, many news stories focused on that 20 percent relative risk reduction, rather than on the absolute risk reduction of 1.5 percent. Yes, 8 to 6.5 is a 20 percent drop, but, at the same time, you’re really only reducing your absolute risk by 1.5 percent. In other words, you have to treat 67 people with the drug for a few years to prevent one heart attack or stroke or cardiovascular death. That may not sound like much on an individual scale. I mean, what are the odds you’re going to be that 1 in 67th person? But on a population scale, it’s huge. In fact, it’s right up there with cholesterol-lowering statin drugs, which have an absolute risk reduction in the same 1.5 percent ballpark. So, indeed, in March 2024, the Food and Drug Administration approved high-dose Ozempic for use beyond just weight loss but also for reducing cardiovascular risk in those with prior cardiovascular disease.

So, how do the benefits and harms stack up? In the summer of 2024, the first quantitative benefit-harm balance analysis was published. The researchers concluded that for those achieving a 10 percent weight loss, there’s more than a 90 percent chance the benefits outweigh the harms, though the opposite was found for only a 5 percent weight loss. Here’s how they broke it down. If 1,000 people go on these GLP-1 drugs, 375 would be expected to lose at least 10 percent of their body weight, with all the ancillary benefits that would bring. On the other side of the equation, 41 people would suffer from abdominal pain, 57 from hair loss, 8 from gallstones, 118 from constipation, 100 from diarrhea, 22 from dizziness, 84 from an upset stomach, 46 from excessive burping, 39 from fatigue, 51 from excessive farting, 13 from headaches, 17 from low blood sugars, 4 from reactions at the injection site, 221 from nausea, 4 from pancreatitis, 43 from upper abdominal pain, and 110 from vomiting.

Now, of course, the net beneﬁt-versus-harm calculation would be highly dependent on different people’s willingness to accept different harms. Like, a bald guy isn’t going to be concerned about hair loss, for example. And this also doesn’t take into account the fact that the benefits peter out—weight loss stalls after a year, but the harms may continue. So, once you’ve already plateaued and stop losing weight, do you keep taking it, even though you get no further weight-loss benefit, but the potential for harm continues to accumulate?

We really don’t know about the long-term harms or benefits, because some of these drugs and dosing schedules are so new––especially now that the American Academy of Pediatrics has suggested offering these drugs for teens and tweens as young as age 12. These drugs work by acting on the brain, so who knows what effect this could have on childhood development and beyond, if they end up taking them for the rest of their lives.

In the end, this story is familiar. A new class of antidiabetic agents is rushed to market, and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates, but it’s vigorously denied or discounted. The manufacturers are expected—quite unrealistically—to monitor the safety of their own products. We should be thankful that those responsible for aircraft safety do not operate on the same assumption. Although we now do have evidence of at least near-term benefit over a few years, we cannot assume long-term safety until it has been demonstrated.

Please consider volunteering to help out on the site.

Motion graphics by Avo Media

Doctor's Note

This is the fifth video in my series on Ozempic. If you missed the previous ones, check out:

Stay tuned for the rest of the series, including:

Don’t want to wait? Get my new book, OZEMPIC: Risks, Benefits, and Natural Alternatives to GLP-1 Weight-Loss Drugs, available as an ebook, audiobook, and softcover (currently on sale for 20% off)

If you haven't yet, you can subscribe to our free newsletter. With your subscription, you'll also get notifications for just-released blogs and videos. Check out our information page about our translated resources.

Pin It on Pinterest

Share This