Prediabetes occurs when blood glucose levels are higher than normal but have not reached the threshold for type 2 diabetes. This condition increases the risk of developing type 2 diabetes, heart disease, and stroke. Prediabetes is often silent, with diagnosis typically occurring through routine blood testing. It is defined by a glycated hemoglobin (A1C) level between 5.7% and 6.4%, or a fasting plasma glucose level between 100 and 125 mg/dL. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is primarily approved for managing type 2 diabetes and chronic weight management in adults with obesity or overweight.
Semaglutide’s Mechanism in Glucose Control
Semaglutide functions by mimicking the action of a natural gut hormone called GLP-1, which is released after eating. The drug activates GLP-1 receptors found in various tissues, including the cells in the pancreas responsible for producing insulin. This activation stimulates the release of insulin, but only when blood sugar levels are elevated, which is a glucose-dependent effect that reduces the risk of low blood sugar (hypoglycemia) compared to some other diabetes medications.
The medication also acts on the pancreas to suppress the secretion of glucagon, a hormone that instructs the liver to release stored glucose into the bloodstream. By lowering glucagon, semaglutide decreases the amount of glucose the liver produces, which contributes to better blood sugar control, especially between meals and overnight. The combined effect of increased insulin release and reduced glucose production helps normalize blood glucose levels, which is the direct goal in managing prediabetes.
Beyond its direct effects on insulin and glucagon, semaglutide slows down the rate at which the stomach empties its contents into the small intestine. This delayed gastric emptying helps to moderate the rise in blood sugar that occurs immediately after a meal, smoothing out post-meal glucose spikes. This action also contributes to a feeling of fullness and reduced appetite, which is a mechanism that supports weight loss and further improves insulin sensitivity.
Clinical Evidence for Preventing Type 2 Diabetes
Clinical trials evaluating semaglutide for weight management have provided strong evidence regarding its effect on prediabetes. A pooled analysis of the Semaglutide Treatment Effect in People with obesity (STEP) trials included individuals with prediabetes treated with once-weekly semaglutide (2.4 mg dose) alongside intensive lifestyle intervention. The results showed that a substantial majority of participants achieved normoglycemia, meaning normal blood glucose levels.
Specifically, across the STEP trials, between 84.1% and 89.8% of participants with baseline prediabetes who received semaglutide achieved normoglycemia after 68 weeks. This compared favorably to the placebo groups, where the rate of normoglycemia achievement ranged from 47.8% to 70.4%. The significant difference highlights the drug’s effectiveness in resolving the prediabetic state.
The SELECT trial, which studied semaglutide in people with overweight or obesity and cardiovascular disease, further supported this benefit. Over 156 weeks, 69.5% of participants treated with semaglutide were normoglycemic compared to 35.8% in the placebo group. Progression to biochemical diabetes (A1C of 6.5% or higher) was also significantly lower in the semaglutide group (1.5%) compared to the placebo group (6.9%). This indicates that semaglutide is highly effective at preventing the onset of type 2 diabetes in high-risk individuals.
Safety Profile and Common Side Effects
The most frequently reported side effects associated with semaglutide are related to the gastrointestinal system. These commonly include nausea, vomiting, diarrhea, constipation, and abdominal pain. These symptoms are often mild to moderate and are most prominent during the initial dose-escalation period.
The slow, gradual dose increase over several weeks helps the body adjust and minimizes the severity of these gastrointestinal effects. For most patients, these digestive issues lessen in frequency and intensity as treatment continues. Dehydration can occur due to persistent vomiting or diarrhea, potentially leading to kidney problems, underscoring the importance of adequate fluid intake.
While rare, there are more serious risks that patients should be aware of, including the potential for pancreatitis, which is inflammation of the pancreas. Symptoms of pancreatitis, such as severe, persistent abdominal pain that may radiate to the back, require immediate medical attention. Semaglutide also carries a warning regarding the risk of thyroid C-cell tumors, based on findings in rodent studies, and is generally not recommended for individuals with a personal or family history of medullary thyroid carcinoma.
Placement in Prediabetes Management
The standard of care for prediabetes management begins with intensive lifestyle modifications, focusing on diet changes and increased physical activity. Programs promoting these changes have demonstrated effectiveness in preventing or delaying the progression to type 2 diabetes. Standard medications such as metformin are often considered for patients at higher risk or whose blood sugar is not adequately controlled by lifestyle changes alone.
Semaglutide is not currently approved by regulatory bodies specifically for prediabetes reversal or prevention of type 2 diabetes. Its use in this population is considered a secondary benefit, stemming from its approvals for treating type 2 diabetes and chronic weight management. The decision to use semaglutide in a person with prediabetes is usually reserved for those with significant co-existing risk factors, such as obesity or established cardiovascular disease.
A healthcare provider may consider semaglutide when lifestyle interventions and first-line medications like metformin have been insufficient, or in high-risk individuals who meet the criteria for the approved weight management dosage. The drug’s effect on weight loss, combined with its direct glucose-lowering mechanisms, positions it as an effective tool in managing the underlying metabolic dysfunction that characterizes prediabetes. While not a first-line treatment, semaglutide represents a strong therapeutic option for individuals with prediabetes who require substantial metabolic intervention.