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Instalab ResearchSemaglutide is part of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) family, which works by stimulating insulin secretion, lowering glucagon, slowing digestion, and reducing appetite. Injecting semaglutide under the skin provides consistent absorption and near-complete bioavailability, making it reliable and predictable.
Oral semaglutide had to be engineered differently. Because peptides are normally broken down in the digestive tract, the oral form uses an absorption enhancer called SNAC to allow some of the drug to reach circulation. Even then, only around 1% of the drug enters the bloodstream compared to near-total absorption with injections. Despite this challenge, clinical studies have shown that oral semaglutide at higher doses still achieves meaningful clinical results.
A sublingual version, which would deliver semaglutide under the tongue and bypass the digestive system, has been proposed. However, no large-scale clinical trials have yet been published on its performance. Without such data, it is impossible to know whether it could match the reliability of injectables.
Injectable semaglutide has been rigorously tested in the large-scale SUSTAIN clinical trials, consistently showing significant reductions in HbA1c in people with type 2 diabetes. These reductions were greater and more consistent than those seen with other GLP-1 receptor agonists such as exenatide or liraglutide. The results have made injectable semaglutide one of the most effective glucose-lowering therapies currently available.
Oral semaglutide has also been tested in multiple phase 3 clinical programs and has also proven to reduce HbA1c meaningfully. At its highest 14 mg dose, oral semaglutide achieved reductions similar to injectable semaglutide in some patient groups. However, the oral route tends to be slightly less consistent in its effect, likely due to variability in absorption. Importantly, the clinical evidence supporting oral semaglutide is strong and statistically significant.
For sublingual semaglutide, there are no large randomized controlled trials demonstrating outcomes in blood sugar control. As a result, injections remain the most dependable method, with oral semaglutide offering a valid alternative when injections are not acceptable to patients.
Perhaps the most striking success of semaglutide has been in weight management. In the STEP clinical program, people with obesity who received once-weekly injectable semaglutide lost an average of around 15% of their body weight over 68 weeks. This level of weight reduction is unmatched by any other approved weight-loss medication and rivals the results of some surgical interventions.
Oral semaglutide also produces weight loss, though the results are less dramatic. Clinical studies report an average of 3 to 5 kilograms of weight reduction at the highest oral doses. This remains clinically meaningful and is especially valuable for patients who prefer a non-injectable option.
At this time, no peer-reviewed clinical trials have examined sublingual semaglutide for weight management. Without reliable data, injections must still be considered the standard for weight loss efficacy.
Injectable semaglutide has also been shown to protect the heart. The SUSTAIN-6 trial and subsequent large-scale studies demonstrated that semaglutide injections reduce the risk of major adverse cardiovascular events, including heart attack and stroke. These findings have made semaglutide one of the most important drugs not only for managing diabetes and obesity but also for reducing cardiovascular risk.
Oral semaglutide has been studied in the PIONEER 6 cardiovascular trial. While it was shown to be safe and not inferior to placebo, it did not demonstrate the same level of cardiovascular protection as the injectable form. Later reviews suggest both forms may reduce cardiovascular risk factors, but injectable semaglutide remains the most strongly supported by statistically significant data.
Sublingual semaglutide has not yet been studied in cardiovascular outcome trials.
Both injectable and oral semaglutide share a similar safety profile. The most common side effects are gastrointestinal, including nausea, vomiting, and diarrhea, which typically occur during the first weeks of treatment. These are dose-related and usually improve over time. Injectable semaglutide has been associated with a slightly higher risk of diabetic retinopathy complications in certain patients, a finding that continues to be monitored. Oral semaglutide appears to trigger gastrointestinal side effects at a similar rate but may bring them on sooner due to its daily dosing schedule.
Recent reviews comparing different forms suggest that injectable semaglutide may carry a slightly higher risk of retinal complications, while oral formulations more often trigger blurred vision. These differences remain under study. For sublingual semaglutide, safety data is not yet available.
For many patients, the biggest difference between semaglutide forms comes down to convenience and personal preference. Injections, while highly effective, can be a barrier for people uncomfortable with needles. Oral semaglutide, taken once daily, has opened new opportunities for patients who otherwise might not have considered semaglutide at all. Surveys show that many patients prefer the idea of a pill, even if injections are relatively simple to administer. A sublingual version, if proven effective, could add even more flexibility, though it is still only theoretical at this point.
The evidence is strong and clear. Injectable semaglutide remains the most powerful and reliable option for controlling blood sugar, promoting weight loss, and protecting the heart. Oral semaglutide is a valuable alternative for patients who prefer a non-injectable option and has been validated by high-quality clinical trials, though its effects are slightly less consistent and less dramatic. Sublingual semaglutide is still experimental and has not yet been studied in large, statistically significant clinical trials. Until that evidence emerges, it cannot be considered equal to injections.