Semaglutide is emerging as a wonder drug for management of various metabolic diseases.
Originally approved for type 2 diabetes, this glucagon like peptide-1 (GLP-1) receptor agonist is now showing promise for treating obesity, non-alcoholic steatohepatitis (NASH), and neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Let’s explore the therapeutic potential of semaglutide and how it acts as a quintessential GLP-1 receptor agonist.
Key Facts:
- Semaglutide is a GLP-1 receptor agonist approved for type 2 diabetes and obesity.
- It reduces appetite and calories leading to weight loss. Phase 3 trials showed up to 16% body weight reduction.
- Semaglutide improves insulin sensitivity in liver and brain, providing hepatoprotective and neuroprotective effects.
- It is being studied for potential treatment of non-alcoholic steatohepatitis (NASH) and neurodegenerative diseases.
- Well tolerated with mild GI side effects. Can be used in elderly, renal/hepatic impairment, and cardiovascular disease.
Source: Pharm Res. 2022
Semaglutide: A GLP-1 Agonist with Therapeutic Versatility
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that was originally developed and approved for treatment of type 2 diabetes.
However, research over the past decade has uncovered additional therapeutic benefits of semaglutide beyond blood glucose control.
The drug is now showing promise for treating obesity, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.
In this article, we will explore the mechanisms of action, clinical evidence, and safety profile of semaglutide.
Semaglutide acts as a quintessential GLP-1 receptor agonist with versatile therapeutic utility through improving insulin sensitivity and providing organ-protective effects.
Semaglutide’s Mechanism of Action
To understand the pleiotropic benefits of semaglutide, we must first look at its mechanism of action.
Semaglutide is a GLP-1 receptor agonist – meaning it activates the GLP-1 receptor similarly to the endogenous hormone GLP-1.
The GLP-1 receptor is expressed in various tissues including the pancreas, GI tract, liver, heart, kidneys, and central nervous system.
Activation of GLP-1 receptors has several beneficial metabolic effects:
- Increases glucose-dependent insulin secretion from pancreatic beta cells
- Suppresses glucagon secretion
- Slows gastric emptying and induces satiety
- Improves insulin sensitivity in liver, muscle, adipose tissue
- Provides cardioprotective and neuroprotective effects
Semaglutide vs Native GLP-1
Unlike native GLP-1 which has a half-life of only 1-2 minutes, semaglutide has been chemically modified to be more resistant to degradation by the enzyme DPP-4.
This results in a prolonged half-life of ~1 week, allowing once weekly dosing.
With 94% structural similarity to native GLP-1, semaglutide provides potent and sustained GLP-1 receptor activation for treatment of type 2 diabetes.
But researchers now believe this pharmacological GLP-1 receptor agonism also underlies the additional therapeutic benefits of semaglutide.
Treating Obesity: Semaglutide for Weight Loss
One of the first expanded indications for semaglutide was chronic weight management.
Activation of GLP-1 receptors in the GI tract and hypothalamus reduces appetite and calorie intake leading to weight loss.
Several large phase 3 trials collectively called STEP (Semaglutide Treatment Effect in People with obesity) explored the weight loss efficacy of subcutaneous semaglutide.
These 68-week trials compared once weekly semaglutide 2.4 mg injections to placebo or other anti-obesity agents like liraglutide.
Results showed semaglutide treatment reduced body weight from baseline by a remarkable 14-16% compared to only 2-6% with placebo or liraglutide.
Gastrointestinal side effects like nausea and vomiting were the most common adverse events.
Based on this data, the FDA approved once weekly semaglutide 2.4 mg injection (brand name Wegovy) for chronic weight management in 2021.
The drug offers a new pharmacological option for treating obesity.
Treating “Diabesity” (Diabetes & Obesity)
Since obesity and type 2 diabetes often occur together, semaglutide provides dual benefit for “diabesity” patients by improving glycemic control and promoting weight loss.
For example, the SUSTAIN trials studied semaglutide in overweight/obese patients with inadequately controlled T2D on other agents.
After 30-56 weeks, semaglutide resulted in significantly greater reductions in HbA1c and body weight compared to other antidiabetic medications like sitagliptin, exenatide ER, and insulin glargine.
Semaglutide is the first GLP-1 receptor agonist that can treat both type 2 diabetes and obesity with a single once weekly injection.
This makes it an attractive option for managing diabesity.
Hepatoprotective Effects in NASH (Liver Benefits)
Non-alcoholic steatohepatitis (NASH) is characterized by fat accumulation and inflammation in the liver. It is closely linked to obesity, insulin resistance, and type 2 diabetes.
While GLP-1 receptor expression in human hepatocytes is still unclear, animal and clinical studies show GLP-1 receptor agonists can reduce hepatic steatosis and improve NASH biomarkers.
In a phase 2 trial, 32 weeks of semaglutide lowered liver fat content and improved NASH histology scores compared to placebo in patients with NASH.
Ongoing phase 3 trials are further assessing semaglutide’s efficacy for treating NASH.
The benefits are thought to be mediated by improving hepatic insulin sensitivity, reducing inflammation and oxidative stress, and enhancing autophagy.
If trials remain positive, semaglutide could become one of the first pharmacological treatments for NASH.
Neuroprotective Effects in Alzheimer’s and Parkinson’s Diseases
There is growing evidence that insulin resistance in the brain contributes to neurodegeneration in Alzheimer’s and Parkinson’s diseases.
By activating central GLP-1 receptors, semaglutide may provide neuroprotective effects.
Preclinical studies showed semaglutide protected against neuronal damage in cellular and animal models of Alzheimer’s and Parkinson’s diseases.
Two large phase 3 trials called EVOKE are now underway studying oral semaglutide for Alzheimer’s dementia.
The exact neuroprotective mechanisms are unknown but likely involve reducing inflammation, oxidative stress, and apoptosis.
Enhanced insulin signaling and synaptic plasticity may also play a role.
While additional clinical data is needed, semaglutide represents a promising drug repurposing opportunity for treating neurodegenerative conditions.
Safety and Tolerability of Semaglutide
As an FDA approved agent, semaglutide has an established safety profile.
The most common adverse effects are mild gastrointestinal problems like nausea, vomiting, and diarrhea, especially when initiating treatment.
These are usually transient, dissipating within 4-8 weeks.
A few precautions exist:
- Semaglutide is not recommended in type 1 diabetes, diabetic ketoacidosis, or congestive heart failure
- Caution if history of diabetic retinopathy due to slightly increased risk
- Avoid in patients with medullary thyroid carcinoma or multiple endocrine neoplasia type 2
- Dose adjustments needed if used with other hypoglycemic medications
Otherwise, semaglutide is generally well tolerated. Importantly, it can be used in adults of all ages including the elderly.
No dosage adjustment is needed in patients with renal impairment or mild-moderate hepatic impairment.
The excellent safety profile allows semaglutide to be used for extended periods as needed for chronic conditions like obesity, NASH, and neurodegenerative disorders.
Conclusion: Semaglutide Has Many Potential Medical Uses
In summary, semaglutide is emerging as a versatile therapeutic agent with benefits beyond diabetes.
As a GLP-1 receptor agonist, it improves insulin sensitivity and provides organ-protective effects in the liver, heart, and brain.
Clinical data support the use of semaglutide for managing type 2 diabetes, obesity, and potentially NASH and neurodegeneration.
Ongoing trials will clarify if semaglutide is effective for treating Alzheimer’s, Parkinson’s and other chronic diseases.
With its once weekly dosing and favorable safety profile, semaglutide acts as a quintessential GLP-1 receptor agonist with broad therapeutic potential.
It represents an exciting drug repurposing opportunity that may continue to unveil new clinical applications in the coming decade.
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