The Ozempic injection, one of three FDA-approved semaglutide products, is approved to lower blood sugar levels in adults with type 2 diabetes mellitus (T2DM) and known heart disease. Clinical research findings on the safety of Ozempic (semaglutide) indicate that semaglutide induces primarily mild and transient gastrointestinal (GI) disturbances and increases the risk of cholelithiasis. Researchers suggest further research to assess the long-term risk of pancreatic cancer, thyroid cancer, and diabetic retinopathy (DRP).
What Is Ozempic?
Ozempic is an injection of semaglutide (0.5mg, 1mg, 2mg), a glucagon-like peptide-1 receptor agonist (GLP-1RA) that mimics the GLP-1 hormone released in the GI tract when eating. GLP-1 prompts the body to produce insulin, consequently reducing blood glucose, and also affects parts of the brain that reduce appetite and signal satiety. According to Ozempic drugmaker Novo Nordisk, it also reduces the risk of major cardiovascular events, e.g., heart attack, stroke, or death in adults with T2DM.
Semaglutide, but not Ozempic:
- In September 2019, the FDA approved semaglutide oral tablets (Rybelsus) to improve control of blood sugar in adults with T2DM, along with diet and exercise.
- In June 2021, the FDA approved Wegovy (2.4 mg injections once weekly) for chronic weight management.
The Evidence on the Safety of Ozempic
The FDA indicates that the most common adverse reactions of Ozempic (reported in 5% or more patients treated with Ozempic) include nausea, vomiting, diarrhea, abdominal pain, and constipation; and provides warnings and precautions on serious side effects of thyroid tumors and cancer, pancreatitis, hypoglycemia, acute kidney injury, hypersensitivity reactions, acute gallbladder disease, and DRP complications.
In July 2023, Reuters reported that the European Medicines Agency (EMA) began investigations into Ozempic and weight-loss treatment Saxenda in response to Iceland’s health regulatory agency reporting three cases of patients thinking about suicide or self-harm (two patients on Ozempic and one on Saxenda).
In a global trial on the safety and efficacy of semaglutide across 12 countries, patients were randomly allocated to injecting semaglutide 2.4 mg, semaglutide 1.0 mg, or visually matching placebo once a week for 68 weeks. Researchers found that adverse events were more frequent with semaglutide 2.4 mg (87.6% of patients) and 1.0 mg (81.8%) than with placebo (76.9%). GI adverse events (primarily mild to moderate) were reported in 63.5% of patients with semaglutide 2.4 mg, 57.5% with semaglutide 1.0 mg, and 34.3% with placebo.
The Potential Impact of Ozempic on the Body
There are some negative implications of Ozempic, particularly its correlation with various health factors, including, thyroid cancer, pancreatitis, and pancreatic cancer, hypoglycemia risks, acute kidney injury occurrences, gallbladder events, gastrointestinal disturbances, and cardiovascular effects.
1. Thyroid Cancer
Ozempic has an FDA warning for thyroid C-cell tumors. However, it is not unique among the GLP-1RA. Regulatory authorities have required additional pharmacovigilance to monitor the U.S. annual incidence of medullary thyroid carcinoma (MTC) for at least 15 years (results expected 2035 – 2037).
2. Pancreatitis and Pancreatic Cancer
Based on the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) Phase 3a trials, Smits & Raalte (2021) suggest that the data does not indicate a link between GLP-1RA and pancreatitis and pancreatic cancer incidence. However, they question whether the follow-up duration was long enough for pancreatic cancer to develop.
3. Hypoglycemia
Findings from the SUSTAIN trials and real-world data following patients for six months after starting semaglutide therapy suggest that the risk of hypoglycemia is low with subcutaneous and oral semaglutide. However, the risk increases when combined with sulfonylurea or insulin therapy.
4. Acute Kidney Injury
Only one of the SUSTAIN trials, SUSTAIN 6, reported acute kidney failure, where its occurrence was similar for semaglutide and placebo. A post-hoc analysis of SUSTAIN 6 suggests that semaglutide was associated with fewer events of nephropathy.
5. Gallbladder
In the SUSTAIN program, 1.4% of patients treated with semaglutide developed a gallbladder event (mainly cholelithiasis), compared with 1.9% in the placebo group.
6. Gastrointestinal (GI)
In phase 3 trials, subcutaneous semaglutide was associated with GI disturbances, e.g., nausea, vomiting, and diarrhea. Compared with placebo, subcutaneous semaglutide for 30 weeks induced
- nausea in 11.4 – 20% of semaglutide-treated patients (placebo 3.3 – 8%)
- vomiting in 4 – 11.5% (placebo 2 – 3%)
- diarrhea in 4.5 – 11.3% (placebo 1.5 – 6%)
7. Cardiovascular
All GLP-1RAs increase heart rate. SUSTAIN 6 found a placebo-corrected heart rate increase of 2.75 beats per minute (bpm) for semaglutide 0.5 mg and 3.2 bpm for semaglutide 1.0 mg. The increase detected was not associated with adverse cardiac events.
8. Diabetic Retinopathy (DRP)
In the SUSTAIN-6 trial, more DRP complications were reported for semaglutide compared to placebo.
Ongoing Clinical Trials for Ozempic
A large ongoing trial on the long-term effects of semaglutide on diabetic eye disease (expected completion in 2027) is assessing the long-term impact of semaglutide on DRP in patients with T2DM. A study by Sass et al. (2023) investigates the long-term effects of add-on treatment of semaglutide 1.0 mg injection each week vs. placebo once a week on the metabolic status in pre-diabetic and diabetic patients diagnosed with and receiving treatment for a schizophrenia spectrum disorder.
Protective Effects
While Ozempic is not without its limitations, clinical research is showing positive potential for people suffering from diabetes, and obesity, and it has even shown protective effects in kidney health and respiratory wellness.
Kidney
A review by Popoviciu et al. (2023) found that semaglutide provides kidney protective effects. Separately, an analysis of patients receiving subcutaneous semaglutide 1.0 mg, 2.4 mg, or placebo, subcutaneous semaglutide (both 1.0 mg and 2.4 mg) improved the urine albumin-to-creatinine ratio (UACR) in adults with overweight/obesity and T2DM.
Respiratory Illness
Yu et al. (2023) studied the association between GLP-1 RAs and the risk of 12 respiratory diseases in patients with T2DM, obesity, or overweight. They found that semaglutide reduced the risk of respiratory diseases by 18%.
Conclusion
Clinical research on Ozempic is still being conducted to ensure the long-term safety of this drug. While current findings hold promise, a range of considerations still exist for its extended usage.
The extensive phase 3 registration trial for subcutaneous semaglutide, SUSTAIN, provides valuable safety and efficacy data. Along with ongoing trials studying the long-term effects of semaglutide, researchers can assess the long-term safety of Ozempic and other drugs like it, such as Wegovy and Mounjaro.
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