Ozempic (semaglutide) is well-studied for its short-term side effects like nausea and diarrhea, but the long-term picture is more complex. The longest continuous trial data available spans about four years, which means some effects are well-documented while others are still being tracked. Here’s what the evidence shows so far across the body systems most affected by extended use.
Gastrointestinal Problems Beyond Nausea
The nausea, vomiting, and diarrhea that most people experience when starting Ozempic usually fade within weeks. But more serious gastrointestinal complications can develop with longer use. A large study of roughly 16 million U.S. insurance records, conducted by researchers at the University of British Columbia, found that people using semaglutide or liraglutide for weight loss had 3.67 times the risk of gastroparesis (stomach paralysis) compared to people on a different weight-loss medication. They also had 4.22 times the risk of bowel obstruction, a condition where food can’t pass through the intestines and sometimes requires surgery.
These are still relatively uncommon events in absolute terms, but the elevated risk is significant enough to watch for. Persistent vomiting, severe bloating, cramping, and feeling full long after eating are the warning signs of both conditions.
Muscle and Lean Body Mass Loss
When you lose a large amount of weight on Ozempic, not all of it comes from fat. In the STEP 1 trial, participants lost about 9.7% of their total lean mass (which includes muscle) over the course of treatment. That’s a meaningful amount, though the proportion of lean mass relative to total body weight actually increased by about 3 percentage points, since fat was lost at a faster rate. Separate research found that fat loss outpaced lean mass loss by roughly threefold.
Still, losing nearly 10% of your lean mass matters, especially for older adults. Muscle loss can affect strength, balance, metabolism, and long-term mobility. This is why many clinicians now recommend resistance training alongside Ozempic to preserve as much muscle as possible during weight loss.
Gallstones and Biliary Disease
Rapid weight loss from any cause increases the risk of gallstones, and Ozempic is no exception. A systematic review of 76 randomized controlled trials found that GLP-1 drugs like semaglutide were associated with a 37% higher overall risk of gallbladder and biliary diseases. The risk was even more pronounced at higher doses (56% increase) and with longer treatment duration (40% increase). Weight-loss trials showed a more than twofold increase in gallbladder-related events compared to diabetes trials, likely because the weight loss is more dramatic in obesity treatment.
Gallstones can cause sudden, intense pain in the upper right abdomen, particularly after eating fatty foods. In some cases, they lead to gallbladder inflammation or infection requiring surgical removal.
Bone Density and Fracture Risk
This is one of the less-discussed long-term concerns. Semaglutide has been shown to reduce bone mineral density by about 2.1% in the lumbar spine, 2.6% in the hip, and 1.5% in the shin bone. These losses mirror what’s typically seen with calorie restriction and significant weight loss, rather than being a unique drug effect.
The practical consequences showed up in the SELECT cardiovascular outcomes trial. Among women taking semaglutide, 1.0% experienced hip or pelvic fractures compared to just 0.2% on placebo. The gap was even wider in participants over 75: fracture rates were 2.4% with semaglutide versus 0.6% with placebo. For younger, otherwise healthy people, these bone density changes are likely minor. For postmenopausal women and older adults already at risk for osteoporosis, they deserve attention.
Thyroid Cancer Concerns
Ozempic carries a boxed warning about thyroid tumors because semaglutide caused thyroid C-cell tumors in rodents. The question is whether this translates to humans, and so far the evidence is reassuring but not fully settled. A systematic review of 10 randomized trials involving over 14,500 participants found thyroid cancer in less than 1% of semaglutide-treated patients, with no statistically significant increase over placebo groups. The European Medicines Agency concluded in 2023 that there is no evidence of a causal link between GLP-1 drugs and thyroid cancer.
However, one large observational study did find a 58% higher risk of all thyroid cancers and a 78% higher risk of medullary thyroid cancer specifically among people who used GLP-1 drugs for one to three years. The discrepancy between trial data and real-world data hasn’t been fully resolved. People with a personal or family history of medullary thyroid cancer are still advised not to use Ozempic.
Pancreatitis Risk
Early concerns about GLP-1 drugs triggering pancreatitis have largely been eased by long-term trial data. The major cardiovascular outcome trials, including SUSTAIN-6 and others, found no significant difference in confirmed acute pancreatitis between semaglutide and placebo groups. In the REWIND trial, cases occurred at a rate of less than 0.1% per year. While pancreatitis remains listed as a possible side effect, the actual risk appears low based on multi-year follow-up.
Kidney Effects
For kidney health, the long-term news is actually positive. The FLOW trial, which specifically studied semaglutide in people with type 2 diabetes and chronic kidney disease, found that semaglutide reduced the risk of major kidney events by 24% compared to placebo. Kidney function declined more slowly in the semaglutide group by a meaningful margin, and cardiovascular death risk dropped by 29%. Serious adverse events were also less common in the semaglutide group than in the placebo group. This is one area where extended use appears to be protective rather than harmful.
Eye Health in People With Diabetes
People with diabetes who start Ozempic can experience a temporary worsening of diabetic retinopathy, particularly in the first 16 weeks. This isn’t unique to semaglutide. It’s a well-established phenomenon that occurs whenever blood sugar drops rapidly, and semaglutide lowers blood sugar faster than many alternatives. In trials, patients on semaglutide saw their blood sugar marker drop by 1.9% to 2.5% in just 16 weeks, roughly double the reduction seen with placebo.
Whether this early worsening leads to lasting damage or resolves over time is still being studied. Novo Nordisk launched a dedicated five-year eye trial called FOCUS to answer this question, with results expected around 2026. If you have existing diabetic eye disease, more frequent eye exams during the first year of treatment are worth discussing with your care team.
Mental Health and Suicidal Thoughts
Reports of suicidal thoughts in people taking GLP-1 drugs drew significant attention in 2023 and prompted a formal FDA investigation. The agency completed a comprehensive review and concluded there is no increased risk of suicidal ideation or behavior associated with these medications. The review also found no elevated rates of anxiety, depression, irritability, or psychosis. Based on these findings, the FDA took the unusual step of requesting that manufacturers remove suicidal behavior warnings from GLP-1 drug labels entirely.
How Long the Evidence Actually Extends
The longest continuous semaglutide data comes from the SELECT trial, where weight loss continued over about 65 weeks and was then sustained for up to four years, with participants maintaining an average 10.2% reduction in body weight at 208 weeks. Four years is substantial for a drug trial, but it’s short compared to how long many people will realistically use this medication. Some of the risks described above, particularly bone density loss, thyroid concerns, and gallbladder disease, could compound over decades of use in ways that current data simply can’t capture yet.