Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist drug used for the treatment of type 2 diabetes and obesity. It was developed by the Danish pharmaceutical company Novo Nordisk and approved by the FDA in 2017 under the brand name Semaglutide as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

What is Semaglutide?

Semaglutide is a GLP-1 analogue that mimics the effects of the natural hormone GLP-1. GLP-1 is released after eating and functions to lower blood sugar levels by stimulating insulin release and suppressing glucagon secretion. It also increases a feeling of fullness, thereby reducing appetite. Semaglutide exerts similar effects by activating GLP-1 receptors in the pancreas, stomach, and brain. It has a significantly longer circulating half-life of approximately one week compared to native GLP-1, allowing for once-weekly subcutaneous administration.

Mechanism of Action

The primary mechanisms through which Semaglutide regulates blood sugar and promotes weight loss include:

- Stimulating the release of insulin from pancreatic beta cells in a glucose-dependent manner. This helps lower blood sugar levels after meals.

- Inhibiting the release of glucagon from pancreatic alpha cells. Glucagon promotes the release of glucose from the liver, so suppressing it aids glycemic control.

- Slowing gastric emptying. This helps spread out the release of glucose into the bloodstream after eating.

- Activating brain centres that reduce appetite and increase feelings of fullness. Semaglutide effectively curbs unnecessary snacking and overeating.

Effects on Blood Sugar Control

Numerous clinical trials have demonstrated Semaglutide potent blood sugar lowering abilities in type 2 diabetes:

- In SUSTAIN trials, patients treated with Semaglutide saw their A1C levels drop by 1-1.5% on average compared to placebo after 30-68 weeks of therapy.

- Treatment led to greater reductions in fasting and post-prandial glucose when compared to other diabetes medications like sitagliptin, exenatide, and insulin glargine.

- 74-93% of patients achieved an A1C of less than 7% with Semaglutide versus 37-67% with comparators, meeting the widely accepted glycemic target for diabetes care.

Weight Loss Effects

Semaglutide has generated excitement for its highly effective weight management capabilities:

- In SUSTAIN clinical trials, patients lost an average of 15 lbs. over 68 weeks with the 0.5 mg dose and 27 lbs. with the 1 mg dose compared to 2.8 lbs. with placebo.

- The drug achieved weight loss of over 10% of initial body weight in 33-58% of individuals versus 12-17% for comparators.

- Reductions in waist circumference, blood pressure, and triglyceride levels accompanied the weight loss.

- Mechanistically, Semaglutide promotes weight loss by curbing appetite and food cravings through action in the hypothalamus.

Approval for Obesity

Based on data from the STEP trials showing sustained weight loss of up to 20%, in June 2021 the FDA approved Semaglutide 2.4 mg once weekly under the brand name Wegovy for chronic weight management in adults with obesity or who are overweight with at least one weight-related condition like high blood pressure or diabetes.

Side Effects and Safety

The most commonly reported side effects with Semaglutide in clinical trials were:

- Nausea (experienced by 25-30% of patients but usually mild to moderate and transient).

- Diarrhea (in 10-18% of cases but also typically mild).

- Constipation and vomiting occurred in less than 10% of individuals.

- There were no significant safety concerns or risks identified after treatment in over 6000 patient-years of follow-up.

- Pancreatitis and gallbladder problems theoretically could occur but actual verified cases were very rare in trials.

- Caution is warranted in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Dosage and Administration

Semaglutide is available as pre-filled disposable pens for subcutaneous injections:

- For type 2 diabetes, the recommended dose of Semaglutide is 0.25 mg or 0.5 mg once weekly based on individual response.

- For obesity, Wegovy is administered at a higher dose of 2.4 mg once weekly which has been shown to maximize weight loss potential.

- Dosing is started at 0.25 mg for 4 weeks and then titrated up gradually every 4 weeks to the target dose based on tolerability.

- It can be taken with or without meals and injected into the thigh, abdomen, or upper arm region. The site should be rotated to prevent lipodystrophy.

- No dosage adjustments are typically required based on age, gender or kidney or liver impairment.

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