Semaglutide, known by brand names like Ozempic and Wegovy, has gained widespread attention, initially approved in 2017 as a treatment for type 2 diabetes (Ozempic), for its weight-loss benefits, which led to the approval of Wegovy. While its effectiveness in weight management is well-publicized, semaglutide offers a spectrum of advantages that extend beyond just shedding pounds. This article explores the multifaceted benefits of semaglutide, drawing on clinical trials and expert opinions to provide a comprehensive overview.
Understanding Semaglutide
Semaglutide belongs to a class of drugs called GLP-1 receptor agonists. These drugs mimic the effects of a natural hormone called glucagon-like peptide-1 (GLP-1). Semaglutide stimulates the pancreas to produce insulin and reduces the hunger hormone ghrelin, which can decrease your appetite and slow down the rate of stomach emptying. As a result, semaglutide helps lower blood sugar levels and promotes weight loss.
Glycemic Control in Type 2 Diabetes
Semaglutide was initially approved in 2017 as a new treatment option for type 2 diabetes. Clinical trials found that semaglutide lowered the diabetes management marker hemoglobin A1C, on average, by up to 2 percentage points. People taking semaglutide also were more likely to achieve an A1C treatment goal of less than 7% compared with using other medicines. These initial studies also showed evidence of weight loss and cardiovascular risk reduction.
Mechanism of Action in Glycemic Control
Semaglutide, a GLP-1 receptor agonist, has emerged as a promising therapeutic for T2DM management. Its pharmacological profile is characterized by high affinity and specificity for the GLP-1 receptor, coupled with a prolonged half-life of about one week due to albumin binding.
At the molecular level, semaglutide's mechanism of action involves the GLP-1 receptor (GLP-1R), a G-protein coupled receptor. Upon binding to GLP-1R, semaglutide leads to increased intracellular cyclic adenosine monophosphate (cAMP) levels, activating protein kinase A (PKA). PKA is involved in the synthesis and secretion of insulin but inhibits the release of glucagon. Increased levels of cAMP can also activate the Rap1 via EPAC (Exchange Protein directly Activated by cAMP), which is involved in regulation of insulin secretion.
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In pancreatic β-cells, this signaling cascade also enhances glucose-dependent insulin secretion and sensitivity of peripheral tissues to insulin.
Formulations and Dosage
Semaglutide is available in two formulations: oral and subcutaneous.
Oral Semaglutide: Therapy should start at 3 mg once daily for a month before doses are increased to 7 mg once daily. If necessary, after a month of maintenance, dosage can be increased to 14 mg once daily. This formulation should be taken on an empty stomach, with a 30-minute wait before eating or taking other medications to optimize absorption, as food and increased fluid intake can affect bioavailability. The absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) is used to improve its minimal bioavailability, which ranges from 0.4% to 1%. Peak concentration is reached approximately 1-hour post-dose, with steady-state achieved after 4-5 weeks. Recent clinical trials, like OASIS 1, have shown that overweight or obesity adults without T2DM should take oral semaglutide 50 mg once per day best weight loss results.
Subcutaneous Semaglutide: Therapy should start at 0.25 mg once weekly and after 4 weeks, dosage can be increased to 0.5 mg once weekly. If necessary, dosage can be increased to 1 mg once weekly after another 4 weeks. This route offers a high bioavailability of 89%, with peak concentrations reached within 1-3 days and steady-state occurring after 4-5 weeks. The subcutaneous administration is flexible regarding meal timing, with injection sites rotated weekly among the abdomen, thigh, and upper arm.
Both formulations share an elimination half-life of about one week, remaining in circulation for around five weeks post-last dose, with clearance rates of 0.05 L/h for subcutaneous and 0.04 L/h for oral in healthy individuals. Elimination occurs primarily through the urine and feces.
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Comparative Efficacy
Subcutaneous semaglutide, administered once weekly, has shown a 1.5-1.8% reduction in HbA1c levels over 30-56 weeks in various SUSTAIN trials. In contrast, oral semaglutide, taken once daily, demonstrated HbA1c reductions ranging from 1.0-1.4% in the PIONEER trials, achieving a 1.4% reduction after 26 weeks in PIONEER 1. Although effective, this was slightly less potent compared to subcutaneous semaglutide. Nevertheless, oral semaglutide achieved similar efficacy to liraglutide and better outcomes than sitagliptin or empagliflozin.
Cardiovascular Benefits
Studies have found that semaglutide reduces the risk of major cardiovascular events, including heart attack and stroke, in adults with overweight or obesity who have known cardiovascular disease, both with and without diabetes. A large clinical trial in people with diabetes found semaglutide can reduce the risk of major cardiovascular events or death by 26% compared with placebo. Semaglutide also has been studied in individuals with certain types of obesity-related heart failure, both with and without diabetes. Studies suggest that semaglutide may help improve heart failure-related symptoms, such as tiredness, shortness of breath and swelling.
In November 2023, results from the ‘Semaglutide and cardiovascular outcomes in obesity without diabetes’ (SELECT) trial, funded by Novo Nordisk, revealed that non-diabetic, overweight adults taking semaglutide for more than three years had a 20% lower risk of heart attack, stroke or death resulting from cardiovascular disease. An accompanying conference abstract and poster, presented at the 31st European Congress on Obesity in May 2024, also indicated that patients may derive cardiovascular benefit from semaglutide regardless of weight loss.
Cardioprotective Mechanisms
Semaglutide, a GLP-1 receptor agonist, has demonstrated superior cardioprotection for people with T2DM compared to other treatments. Clinical trials like SUSTAIN and PIONEER found that it reduced major adverse cardiovascular events (MACE) by approximately 26%, outperforming other diabetes drugs. Its benefits extend beyond glycemic control, including weight reduction and anti-inflammatory effects, which collectively lower cardiovascular risks.
Additionally, in patients with Heart Failure With Preserved Ejection Fraction (HFpEF) and obesity, semaglutide produced large improvements in HFpEF related symptoms. HFpEF is when the ventricles of the heart are unable to fill or eject blood as they should. Thus, patients suffer from dyspnea, fatigue, congestion and heart failure (HF).
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Using mouse models, Withaar et al. came the same conclusion, finding that semaglutide treatment significantly reduced messenger RNA levels of cardiac stretch marker and inflammatory markers like interleukin-6, which is consistent with functional improvements. Semaglutide treatment is also found to decrease myocardial diastolic stiffness and improve actin-myosin and muscle contraction pathways.
Semaglutide therapy also reduced incidence of any stroke when compared to a placebo through significant reductions in risk of small-vessel occlusion in a post hoc analysis of the SUSTAIN 6 and PIONEER 6 trials. In addition, Avgerinos et al., conducted a meta-analysis and concluded that semaglutide therapy was associated with a 39% decrease In the risk of ischemic stroke. Semaglutide therapy also seems to decrease incidence of stroke comparative to other therapies, specifically a dipeptidyl peptidase-4 inhibitor. Maskery et al. conducted a systematic review confirming previous studies findings that semaglutide therapy is associated with decreased incidences of stroke. The study also concluded semaglutide therapy was associated with reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow.
SELECT Trial: Weight Loss and Anthropometric Outcomes
In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes.
In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (−10.2%), waist circumference (−7.7 cm) and waist-to-height ratio (−6.9%) versus placebo (−1.5%, −1.3 cm and −1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events.
Kidney Health
Semaglutide also may protect the kidneys from damage caused by high blood sugar levels, which can lead to chronic kidney disease and kidney failure. Results from the SELECT trial also indicated that a dose of 2.4mg of semaglutide has potential to combat kidney function decline among individuals with cardiovascular disease who are overweight or have obesity, but without diabetes. Adverse kidney-related events were experienced by 22% fewer people on semaglutide, while its ability to prevent the onset of macroalbuminuria was highlighted as a pivotal factor in reducing the likelihood of kidney-related complications. The results also indicated semaglutide’s potential to protect kidney function in individuals with a pre-existing kidney impairment, and reduction in urinary albumin-to-creatinine ratio (UACR).
Results from the Novo Nordisk-funded ‘FLOW’ trial, published in May 2024, also suggested that semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with T2DM and chronic kidney disease (CKD), with the risk of a primary-outcome event 24% lower in the semaglutide group than placebo.
Impact on CKD Progression
The FLOW clinical trial investigated whether semaglutide can slow the progression of CKD in people with T2DM. Participants were randomly assigned to receive either subcutaneous semaglutide or a placebo, administered weekly. Among 3533 randomized participants, the semaglutide group had demonstrated benefits for kidney-specific outcomes, cardiovascular death, and other secondary outcomes, including a slower decline in kidney function.
Potential in Alzheimer’s Disease Treatment
Semaglutide therapy has also garnered attention for its potential therapeutic effects for Alzheimer’s Disease. Alzheimer’s Disease is a neurodegenerative disease characterized by dementia and cognitive impairment in language, comprehension, memory and more. Specifically, semaglutide therapy has been associated with associated with decreased amyloid-beta plaque deposition and neuroinflammation. It’s effects on the central and peripheral nervous system are thought to mediate these effects, party through ability to cross the blood-brain barrier.
While the specific mechanism of action is unknown, it is thought that since neurons rely on consistent regulation of glucose transporters to prevent neurodegeneration, a pathway that semaglutide therapy directly modulate, it is able to exhibit pleiotropic effects. Pooled data from three randomized controlled trails and a nationwide registry-based cohort have consistent findings. Nørgaard et al. found that rates of dementia were lower in patients undergoing G1PR agonists compared to a placebo in both the randomized control trail patient data and nationwide cohort data. There is a need for more studies to explore the idea of repurposing semaglutide therapy for Alzheimer’s Disease treatment.
Use in Polycystic Ovary Syndrome (PCOS)
PCOS is a major cause of infertility in women of reproductive age, with oral contraceptives being commonly used for treatment. However, these drugs only target a few symptoms and may have severe adverse effects. Repurposing existing drugs could be a feasible option to improve PCOS outcomes with less adverse events.
The use of GLP-1R agonists in women with PCOS could provide weight loss effects, as well as improve hyperinsulinism, hyperandrogenism, normalize total testosterone, insulin resistance markers, and total cholesterol. A total of 176 participants from four RCTs were included in a systematic review study, where GLP1-R agonist use was associated with a significant reduction in waist circumference, BMI, serum triglycerides, and total testosterone levels compared to placebo. However, no significant differences were found in total cholesterol and insulin resistance marker levels. Another study also showed that semaglutide effectively reduces body weight in obese PCOS patients who did not respond to lifestyle changes. After three months of treatment, most patients lost weight, with 80% achieving a weight loss of at least 5%, and improvements in insulin resistance and fasting blood glucose were observed, with minimal side effects. Those who continued treatment for six months experienced further weight loss and normalization of menstrual cycles.
Adverse Effects and Considerations
Semaglutide may cause some mild to moderate side effects, which often decrease over time, such as nausea, vomiting, diarrhea, constipation and abdominal pain. If using semaglutide with certain other medications for diabetes, low blood sugar also may result. In clinical trials, approximately 20% of people discontinued the medication due to side effects. Semaglutide is not recommended for people with type 1 diabetes, diabetic ketoacidosis, or a history of pancreatitis or a certain type of thyroid cancer.
Currently, there are two potential barriers to starting or continuing semaglutide: cost and availability. The average retail cost of a 28-day supply of semaglutide is over $1,000. Your cost will vary depending on your insurance coverage, dosage and the specific brand prescribed. Discounts, coupons and assistance programs may be available.
Long-Term Effectiveness and Lifestyle Integration
Despite the promising results, experts have suggested these findings could be limited by the difficulty of separating the benefits of weight loss from semaglutide specifically. When considering the benefits of semaglutide on cardiovascular outcomes, Bryan Williams, chief scientific and medical officer for the British Heart Foundation, says: “A lot has been made of the potential benefit ‘beyond weight loss’ but my view is that in reality, this is all likely to be due to the reversal of the abnormal and damaging biology of obesity by reversing the weight gain.”
However, semaglutide is not a permanent solution here. A study abstract presented at the American Society for Metabolic and Bariatric Surgery 2024 Annual Scientific Meeting on 11 June 2024 showed that weight loss from bariatric surgery was maintained at approximately 25% for up to ten years, while patients who stopped GLP-1s regained 50% of the weight lost within one year.
O’Neil adds that while GLP-1s can be “a really good kick-start” for patients needing to change their relationship with food, there is more to a healthy life than medication - particularly given potential tolerance issues and complications such as pancreatic inflammation.