Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist developed by the Danish pharmaceutical company Novo Nordisk for the treatment of type 2 diabetes and obesity. It was first approved by the European Commission in 2017 under the brand name Semaglutide as an once-weekly subcutaneous injection for the treatment of type 2 diabetes. In 2021, the FDA approved it under the brand name Wegovy for chronic weight management.
Mechanism of Action
Semaglutide works by mimicking the effects of the natural hormone GLP-1. GLP-1 is released after eating by L cells in the intestines and helps regulate blood sugar levels by several mechanisms. It stimulates the release of insulin from the pancreas, suppresses the release of glucagon, slows gastric emptying which helps you feel full for longer. It also reduces appetite by acting on the central nervous system.
Semaglutide binds to and activates GLP-1 receptors in the pancreas, stomach, brain and other organs. This leads to an increase in the levels of insulin and a decrease in the levels of glucagon released after eating. It also delays gastric emptying and induces a feeling of satiety or fullness thereby reducing appetite and food intake. All these actions together help in controlling blood sugar levels as well as aiding in weight loss.
Efficacy in Type 2 Diabetes
Several phase 3 clinical trials have proven the efficacy and safety of Semaglutide in type 2 diabetes. In the SUSTAIN 1-6 trials, participants were given Semaglutide 0.5 mg or 1 mg injections once-weekly for 30-56 weeks.
The trials showed Semaglutide significantly reduced HbA1c or average blood sugar levels compared to other antidiabetic drugs like sitagliptin, empagliflozin and insulin glargine. It also helped many participants achieve the HbA1c target of less than 7%. Semaglutide use was associated with weight loss of 6-11 kg depending on the dose versus 1-3 kg weight loss with comparators. It also led to significant improvements in systolic blood pressure.
The benefits were seen irrespective of other medications participants were using like metformin, sulfonylureas etc. Semaglutide was generally well tolerated with the most common side effects being nausea, diarrhea and vomiting which were usually mild to moderate in severity. It did not cause any increased risk of hypoglycemia when combined with other antidiabetics, except insulin or insulin secretagogues.
Efficacy in Weight Management
The cardiovascular outcome trial of Semaglutide called PIONEER 6 specifically assessed its efficacy and safety for weight management in obese individuals without diabetes. In this 68 week trial, participants were given Semaglutide 2.4 mg injections once-weekly and were put on a reduced calorie diet and exercise plan.
The trial found participants receiving Semaglutide lost on an average 15.2% of their initial body weight compared to 2.6% in the placebo group. 87.4% of participants in the Semaglutide arm lost at least 5% of their body weight versus 27.9% in the placebo arm. It also significantly improved several cardiovascular and metabolic risk factors associated with obesity like waist circumference, blood pressure, lipids etc.
Semaglutide was generally well tolerated in this trial too with side effects similar to previous T2D trials. However, it did not increase the risk of major adverse cardiovascular events. This proved Semaglutide's potential as the first GLP-1 based therapy approved for chronic weight management.
Dosage and Administration
Semaglutide comes as a pre-filled, disposable 'pen' device containing the drug solution. The recommended starting dose is 0.25 mg given as a subcutaneous injection in the abdomen, thigh or upper arm once weekly. This is increased in gradual steps to the maintenance dose of 1 mg once weekly for type 2 diabetes treatment.
For chronic weight management, the approved maintenance dose of Semaglutide is 2.4 mg once weekly. No dose adjustment is needed based on age, gender or renal impairment. However, caution needs to be exercised in patients with severe renal impairment or end stage renal disease requiring dialysis. Dose reductions or discontinuation may be needed in such patients due to increased risk of adverse events.
Ongoing Research
Several trials are ongoing to further evaluate the efficacy and safety of Semaglutide in different clinical settings:
- PIONEER 8 trial is assessing 2.4 mg Semaglutide once weekly for chronic weight management in adolescents with obesity.
- PIONEER 9 trial is exploring cardio-renal benefits of oral Semaglutide in T2D patients with chronic kidney disease versus placebo.
- PIONEER 4 trial is determining cardiovascular risk reduction efficacy of oral Semaglutide versus placebo in T2D patients with high cardiovascular risk.
- STEP trials are specifically looking at Semaglutide in doses up to 1.7 mg weekly for prevention of type 2 diabetes in prediabetic individuals.
Semaglutide has emerged as a promising new treatment option for type 2 diabetes and obesity based on its unique dual mechanism of improving blood sugar control and aiding significant weight loss. It offers advantages like once weekly dosing with consistent efficacy and safety demonstrated through large phase 3 trials. Wider real-world use may further establish its long-term benefits and cardiovascular risk reduction ability. Though more expensive than older drugs, its superior efficacy could make it a cost-effective option in the long run.
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