Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has gained significant attention for its effectiveness in weight management and type 2 diabetes mellitus (T2DM) treatment. However, emerging research suggests that its benefits extend far beyond these initial applications, offering potential therapeutic advantages for cardiovascular and kidney health, Alzheimer’s disease, and polycystic ovary syndrome (PCOS).
The Rise of Semaglutide
Semaglutide mimics the functions of the body’s natural incretin hormones, which help lower blood sugar levels after a meal and promote a feeling of fullness. It is available in different doses under the brand names Ozempic for T2DM treatment and Wegovy for weight management. Wegovy is typically prescribed to patients with a BMI of 30 or more, or a BMI of 27 or more with at least one weight-related comorbidity. Studies have shown that approximately half of Wegovy users experience a weight loss of at least 15%.
Concerns and Controversies
Despite its success, semaglutide has become a popular dieting trend, leading to concerns about inappropriate access and potential risks. Victoria Ruszala, a specialist pharmacist, notes that private online prescribing is not fully controlled, resulting in shortages. Philip Newland-Jones, a consultant pharmacist, highlights instances of counterfeit semaglutide being sold online, causing harm, including hospitalizations.
Wes Streeting, the shadow health minister, has expressed concerns about the safety and regulation of semaglutide prescribing. He emphasized the need for closer clinical oversight to prevent misuse.
Cardiovascular Benefits
Recent studies have revealed significant cardiovascular benefits associated with semaglutide, even independent of weight loss.
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The SELECT Trial
The ‘Semaglutide and cardiovascular outcomes in obesity without diabetes’ (SELECT) trial, funded by Novo Nordisk, demonstrated that non-diabetic, overweight adults taking semaglutide for more than three years had a 20% lower risk of heart attack, stroke, or death from cardiovascular disease. Preliminary findings from a University College London-led research team indicated that these cardiovascular benefits were irrespective of starting weight and amount of weight lost.
Newland-Jones commented that the medicine has wider cardiovascular effects that extend beyond weight loss and appetite suppression. Tricia Tan, a consultant in diabetes, endocrinology, and metabolic medicine, highlighted the implications for NICE guidance, suggesting that treatment should continue even in patients who do not achieve significant weight loss.
Implications for Clinical Practice
In March 2024, the US Food and Drug Administration approved Wegovy for treating adults with cardiovascular disease who are also obese or overweight, but without diabetes mellitus. Paul Wright, a consultant cardiovascular pharmacist, anticipates that NICE will follow suit, opening up eligibility to a larger cohort of individuals at high cardiovascular risk.
Ruszala emphasizes the potential anti-inflammatory properties of GLP-1s, driving interdisciplinary collaboration to determine the most significant benefits.
Kidney Health
Research indicates that semaglutide may also play a role in protecting kidney function, particularly in individuals with cardiovascular disease and T2DM.
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The SELECT Trial and Kidney Function
Results from the SELECT trial suggested that a 2.4mg dose of semaglutide has the potential to combat kidney function decline among individuals with cardiovascular disease who are overweight or have obesity, but without diabetes. The trial showed that semaglutide reduced adverse kidney-related events by 22% and prevented the onset of macroalbuminuria, a key factor in reducing kidney-related complications.
The FLOW Trial
The ‘FLOW’ trial, also funded by Novo Nordisk, indicated that semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with T2DM and chronic kidney disease (CKD). Clare Morlidge, a consultant renal pharmacist, noted that semaglutide is another valuable tool for slowing the progression of CKD, which is predicted to be the fifth largest cause of mortality by 2040.
O’Neil suggests the need for larger trials to assess the impact of GLP-1s in conjunction with standard therapies, considering the expense of these medications.
Long-Term Effectiveness and Considerations
While the benefits of semaglutide are promising, experts caution that the findings could be limited by the difficulty of separating the effects of weight loss from the specific actions of semaglutide. Bryan Williams, chief scientific and medical officer for the British Heart Foundation, suggests that the cardiovascular benefits are likely due to the reversal of the abnormal biology of obesity through weight loss.
Sustainability and Resource Allocation
Wright emphasizes that semaglutide is not a permanent solution and that weight regain can attenuate health benefits. He also points out that scarce resources should be prioritized for individuals with poorly controlled diabetes who derive significant benefit from the medication.
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Newland-Jones highlights the need to balance the significant benefits of semaglutide with budgetary constraints. He argues that addressing the obesity crisis requires tackling the social, financial, and environmental factors that drive it, rather than relying solely on medication.
O’Neil adds that GLP-1s can be a good starting point for patients needing to change their relationship with food, but a healthy life requires more than medication.
Dual Receptor Agonists
Semaglutide may be paving the way for dual receptor agonists and combination products, such as tirzepatide. These newer medications may offer enhanced benefits due to their action on multiple receptors.
Semaglutide for Type 2 Diabetes Mellitus
Semaglutide 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.
Mechanism of Action
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). 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. Semaglutide, mimicking GLP-1 signaling, can also activate the PI3K/Akt pathway involved in maintenance and viability of pancreatic β-cells.
In pancreatic β-cells, this signaling cascade enhances glucose-dependent insulin secretion and sensitivity of peripheral tissues to insulin. Semaglutide also has an effect on receptors in the peripheral and central nervous systems, potentially improving symptoms like peripheral neuropathy. The central effects of semaglutide on energy homeostasis are mediated through its action on GLP-1 receptors in the hypothalamus and brainstem, leading to reduced appetite and food intake. Additionally, semaglutide has been shown to delay gastric emptying, further contributing to its weight loss effects.
Formulations and Administration
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.
- 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.
Cardiovascular Protection
Semaglutide has demonstrated superior cardioprotection for people with T2DM compared to other treatments. Clinical trials have found that it reduced major adverse cardiovascular events (MACE) by approximately 26%, outperforming other diabetes drugs.
Semaglutide treatment is also found to decrease myocardial diastolic stiffness and improve actin-myosin and muscle contraction pathways. Additionally, semaglutide therapy seems to decrease incidence of stroke comparative to other therapies.
Impact on HbA1c Levels
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.
Semaglutide and Alzheimer’s Disease
Semaglutide therapy has garnered attention for its potential therapeutic effects for Alzheimer’s Disease. It has been associated with decreased amyloid-beta plaque deposition and neuroinflammation. Its effects on the central and peripheral nervous system are thought to mediate these effects, partly through its ability to cross the blood-brain barrier.
Pooled data from randomized controlled trails and a nationwide registry-based cohort have consistent findings, indicating that rates of dementia were lower in patients undergoing G1PR agonists compared to a placebo.
Semaglutide and Chronic Kidney Disease (CKD)
The FLOW clinical trial investigated whether semaglutide can slow the progression of CKD in people with T2DM. The semaglutide group demonstrated benefits for kidney-specific outcomes, cardiovascular death, and other secondary outcomes, including a slower decline in kidney function.
Semaglutide and Polycystic Ovary Syndrome (PCOS)
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. Studies have shown that GLP1-R agonist use was associated with a significant reduction in waist circumference, BMI, serum triglycerides, and total testosterone levels compared to placebo.
Another study also showed that semaglutide effectively reduces body weight in obese PCOS patients who did not respond to lifestyle changes, with improvements in insulin resistance and fasting blood glucose.
Semaglutide and Cardiovascular Risk Reduction
The SELECT trial demonstrated that weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months in patients with preexisting cardiovascular disease and overweight or obesity but without diabetes.
Potential Adverse Effects and Contraindications
Semaglutide therapy is associated with concerning adverse effects like acute pancreatitis, anesthetic risks like pulmonary aspiration or residual gastric content, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy and diabetic retinopathy. Contraindications of semaglutide include history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy.
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