Introduction

Novel anti-obesity agents not only focus on reducing the weight of the patients but focus on improving the health of the patients via improvement in metabolic diseases.

Antiobesity drug development is following a path similar to the historic development of antidiabetes, antihypertension, and dyslipidemia drug treatments.It is hoped that through more effective and better tolerated antiobesity agents, better recognition of obesity as a disease, and (over time) diminished bias regarding the treatment of patients with obesity, patients with obesity will soon have a greater number of better options available with indications that will not only improve the weight of the patients, but improve the health of the patients as well.

One of those antiobesity agents that is currently being in use recently with promising results is semaglutide.

Not a single day goes by when as an obesity specialist I am not asked about this miracle drug semaglutide with its remarkable benefits for weight loss in adults with overweight and obesity once a week injection.

Over the past couple of years ever since it has been used as a weight loss medication not only for diabetes, my experience and clinical insight on observation is that it has highly promising results.

What are incretins?

They belong to a group of metabolic hormones(peptides) called incretins incretins that decrease blood glucose levels, by stimulating (help body release) insulin secretion from the pancreatic beta cells when needed.

There are 2 primary incretin hormones secreted from the L-cells in the intestines in response to food intake (ingestion of glucose or nutrients) to stimulate insulin secretion from the pancreas, with some similarities and differences.

1. Glucose - dependant insulinotropic peptide(GIP)
2. Glucagon-like peptide-1 receptor agonist(GLP-1).

In addition to their insulin secreting and sensitizing benefits both GIP and GLP-1 agents play critical roles in various biological processes in different tissues and organs including the pancreas, fat ,bone and the brain.

What is semaglutide?

{GLP- 1 agonist}. Semaglutide

Glucagon-like peptide 1-receptor agonist

GLP-1 has multiple effects, and GLP-1 receptors are found throughout the body including brain, gastrointestinal tract, pancreas, fat cells and other organs

In other words these 2 incretins, not only act on pancreas, but also target the gastrointestinal system, brain(central nervous system), and fat tissue(adipose tissue) thereby not only helping with glucose control but also help with fat loss(weight loss).

Of note there are multiple GLP-1 RA’s for use, all of which are associated with weight loss benefits. However, LIRAGLUTIDE and SEMAGLUTIDE are The only 2 medications approved by FDA for long-term weight loss.

The way these medications work is they mimic a hormone that your own body normally makes called GLP-1, the hormone that OUR GUT (intestines) make to communicate with the pancreas. This is the hormone your GUT uses to tell your pancreas to start getting ready to process the carbohydrates(sugars) that are coming in with food that you are about to eat. Mimicking that hormone these medications help your body do a couple of different things. They help your body produce more insulin when it is needed, pushing out as much insulin as needed depending on your sugar levels.

Another effect that happens is these molecules reduce the amount of glucagon, which is a hormone that increases the sugar levels. So, we are balancing insulin and glucagon.

Let’s discuss more about semaglutide (GLP-1 receptor agonist).This is currently THE SINGLE AND MOST TALKED MEDICATION its role and benefits in weight loss under brand names OZEMPIC, WEGOVY, terzapatide.

From a weight loss and metabolic perspective, semaglutide has numerous actions. Most relevant actions are:

1. It helps regulate appetite and lower glucose
2. Acts at the hypothalamus (BRAIN), regulating appetite by increasing satiety. Helps the brain tell the body ‘’ when you are full’’
3. Acts on the gut to slow gastrointestinal motility and increase satiety. Helps to slow food leaving stomach, reducing blood sugar spikes.
4. Acts on the pancreas to up regulate insulin secretion from pancreatic beta cells. Helps to keep the liver from releasing too much glucose into the blood.

Clinical trials and efficacy of GLP-1 RECETOR AGONISTS

Both liraglutide (branded SAXENDA) (ONCE A DAY SUBCUTANEOUS INJECTION) and semaglutide (Branded Ozempic, Wegovy) (ONCE A WEEK SUBCUTENEOUS INJECTION) share over 90% homology to native GLP—1
Both have been modified to reversibility bind and to serum albumin in the body. This increases their half-life.

Both liraglutide and semaglutide were initially approved as glucose-lowering medications in type 2 diabetes. However, both have been found to be causing significant weight loss in many individuals.

Dedicated trials in individuals with overweight and obesity without type 2 diabetes have confirmed their efficacy for weight loss in nondiabetic populations.

The SCALE TRIAL (double-blind randomized controlled trial) established liraglutide’s efficacy in weight management.

The STEP TRIAL is another double-blind randomized control trial established efficacy of semaglutide in weight management.After 68 weeks patient's lost about 15% of weight. The take away point being significant weight reduction was seen with the use of semaglutide 2.4 mg once weekly. Comparative studies in step 8 trial between semaglutide versus liraglutide showed that semaglutide significantly reduces greater weight in comparison to liraglutide after 68 weeks. Mean weight change for semaglutide at 15.8% versus 6.4% with liraglutide. Treatment difference of 9.4% weight loss.

Continued use of GLP-1 receptor agonist is needed to , maintain weight loss. This was established in the step 4 TRIAL.

HOW IS IT AVAILABLE?

Semaglutide which is once a week injection comes in a easy-to-use devices in a pen form.

WHO SHOULD AVOID USING SEMAGLUTIDE ?

Those who have a history of the following:

1. history of thyroid cancer
2. Pancreatitis
3. Gallbladder problems

WHAT ARE THE COMMON SIDE EFFECTS?

1. Nausea
2. Vomiting
3. Diarrhea
4. Constipation
5. Headache
6. Decreased Appetite
7. Abdominal Pain
8. Depression
9. Hypoglycemia -ONLY if Taken with Insulin or other Oral Diabetic Medications (Sulfonylureas).

Semaglutide used alone does not cause blood sugars to go low.

HOW TO MINIMIZE SIDE EFFECTS?

1. Eat smaller and less fatty meals
2. Eat slowly
3. Stop eating at first sign of fullness
4. Do not lie down after eating

Dose is increased slowly to decrease the side effects. The side effects usually wean off after a few weeks.

OTHER BENEFITS

Like the mechanism of action being multimodal the benefits are also multimodal.

1. In the central nervous system with its positive effect on satiety and appetite
2. in the adipose tissue(fat cells) increase lipolysis(fat breakdown), glucose uptake.
3. stimulate insulin decreased gastric emptying.
4. increase his production of glucose from the liver and decreased fat production in the liver.
5. cardio protective benefits include reducing inflammation, improving left ventricular function, and reducing ischemic injury. All of this affects including the effects on the vascular (blood vessel)wall explains some of the cardiovascular benefits that you see with this class of medication.

Of the 6 medications that have been approved so far for LONG-TERM Weight management as of 2023, most of the agents work in large part by regulating appetite at the level of the central nervous system. Most promising and remarkable benefits of semaglutide compared to other medications is its significant weight loss benefits of 15%-16% when compared to other medications whose maximum benefit extends up only 7%-8%. This is a very exciting aspect of semiglutide in addition to the other health benefits.

For more detailed information on semaglutide see our videos listed below.