GLP-1 agonists were approved by the FDA for weight loss in late 2014. It’s a newer class of drugs better known for its ability to improve blood-sugar control. These medications  were actually designed to treat type II diabetes, but some have also been FDA approved to treat weight loss. The GLP-1 agonists we work with are called Wegovy (Semaglutide) & Zepbound (Tirzepatide). The newest one is called Retatrutide.

Benefits of GLP-1 Agonists

• Helps induce weight loss
• Helps slow food leaving your stomach
• Helps prevent your liver from making too much sugar
• Helps the pancreas produce more insulin when your blood sugar levels are high
• Helps control blood glucose
• Can reduce hyperglycemia, especially after meals
• Can reduce fasting insulin and fasting glucose
• Can reduce hemoglobin A1c
• Can decrease appetite and caloric intake, while inhibiting weight gain
• Has been shown to lower triglyceride levels and oxidative stress from high LDL
• Helps decrease leptin and increase leptin sensitivity
• Can increase the conversion of white fat to brown fat

The addition of GLP-1 agonists to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for the development of type 2 diabetes and cardiovascular disease.

The addition of GLP-1 agonists to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for the development of type 2 diabetes and cardiovascular disease.

SEMAGLUTIDE, TIRZEPATIDE & RETATRUTIDE

These three medications fall into the GLP-1 agonist class of drugs (Glucagon-like Peptide). When this receptor is activated, it slows down how fast the stomach empties. Slower stomach emptying signals the brain to eat less, helping to manage weight. Drugs targeting this receptor were first made to treat type 2 diabetes, but they've been found to help with weight loss and reduce the risk of certain heart problems. Scientists are also looking into whether they could be used to treat depression, alcoholism, and other conditions. When this receptor is activated, it slows down how fast the stomach empties. Slower stomach emptying signals the brain to eat less, helping to manage weight.

Semaglutide, Tirzepatide and Retatrutide all activate this receptor.

Two of the three medications activate an addition GIP receptor (Gastric Inhibitor Peptide). This receptor, also known as the glucose dependent insulinotropic polypeptide receptor, is found in the brain and throughout the digestive system. It seems to be important for controlling hunger and telling the brain when the stomach is full.  Tirzepatide and Retatrutide both activate this receptor in addition to the GLP-1.  

When eating carbs or sugar our body recognizes these nutrients and it releases the GLP-1 and GIP hormones that then stimulate our pancreas to release insulin. The appetite center in the brain also recognizes this and turns on the "sense of fullness" sensation so we stop eating.

Only one medication, Retatrutide activates GCG (Glucagon Receptor). It is the one to activate all three receptors; GLP-1, GIP and GCG. This GCG receptor is mostly found in the liver and kidneys. Changes in this receptor are linked to some types of type 2 diabetes. When Retatrutide attaches to this receptor, it boosts the production of glucagon, a hormone that helps break down stored energy like fat and sugar. This increases the body's basic metabolism, even when sleeping, which leads to overall weight loss and specifically burns fat.

These three medications cause changes to various hormones involved in regulating appetite and body weight: insulin, glucagon, and leptin.

Leptin

Leptin is a hormone that is produced by your body's fat cells. It is supposed to tell your brain that — when you have enough fat stored — you don't need to eat and can burn calories at a normal rate. Leptin's main role is the long-term regulation of energy, including the number of calories you eat and expend, as well as how much fat you store in your body. People who have a lot of excess weight also have high levels of leptin.

Our brains should know that we have plenty of energy stored. Sometimes our leptin signaling doesn’t work and we develop leptin resistance. This is when we have an abundance of leptin, but the brain doesn't see or recognize it. When your brain doesn't receive the leptin signal, it mistakenly thinks that your body is starving even though it has plenty of energy stored. This condition is now believed to be one of the main biological contributors to obesity.

Leptin can determine if you lose weight and how much. GLP-1 agonists like can help lower leptin resistance. It does this by helping to change the biochemistry of the body and at the same time decrease the rise in leptin resistance once you start losing weight. This helps to naturally reduce your appetite, increase your metabolism and increase fat-burning capacity. Correcting this allows for weight loss to occur and more importantly helps you keep off the weight that you have lost. 

Insulin

GLP’s also help reduce insulin resistance. Insulin resistance is when cells in your body start resisting or ignoring the signal that insulin is trying to send out—which is to help glucose enter our cells from the bloodstream. Insulin is also a very important hormone involved in weight loss. High insulin levels make it almost impossible for your body to burn fat.

Insulin blocks an enzyme called hormone-sensitive lipase (HSL). This hormone is responsible for the mobilization of fatty acids from fat cell stores. If levels of insulin are high, it blocks this enzyme. Studies show that HSL is decreased in patients with type 2 diabetes mellitus, and this may be a consequence of elevated insulin levels. Excess insulin also has the added problem of promoting fat storage. 

​GLP’s help sensitize the body to insulin levels and helps to lower blood glucose levels. It also helps reduce fasting insulin and glucose levels. Once insulin levels are stabilized to normal levels this may also improve other hormone imbalances (testosterone for example) which will naturally result in weight loss and a reduction in symptoms associated with those imbalances.

Glucagon

Glucagon helps increase blood sugar levels while insulin lowers blood sugar levels. They are opposites. For hormone-sensitive lipase (fat burning enzyme) to be activated, insulin and glucagon (from glycogen stores) need to be at relatively low levels. High glucagon can also interfere with normal glucose control which in turn can alter how your body burns energy. ​

GLP-1 agonists help reduce glucagon levels while simultaneously reducing insulin resistance. Both of these changes promote more normal blood glucose levels and help promote proper liver metabolism of glucose and help adipose tissue burn fat. ​Glucagon is just as important in the regulation of glucose levels in the body. Treating both insulin and glucagon leads to normal glucose levels and weight loss.

GLP’s can help naturally improve your metabolism over time, probably through its effects on leptin levels. Leptin feeds back to your hypothalamus and helps set your body set point - the number of calories your body burns which in terms alters your appetite.

Remember, our body is constantly trying to match the number of calories you burn to the number of calories that you consume. 

DOSING: 

Zepbound (Tirzepatide) is dosed at 5-15mg per week

Wegovy (Semaglutide) is dosed at 0.5-2.4mg per week

Retatrutide is dosed at 1.2-12mg per week.

What's important is when to increase your dose, how often you increase the dose, and when to dose the medication. The benefits listed above are only achieved at a certain minimum dose and this dose is different for each person. 

We will work with you to reach the correct dose.

SIDE EFFECTS OF GLP-1 AGONISTS

In clinical trials, the most common side effects observed in patients treated with these medications were nausea, low blood sugar, diarrhea, constipation, vomiting, headache, decreased appetite, upset stomach, fatigue, dizziness, and abdominal pain.

In addition, some patients who took these medications reported other side effects including pancreatitis, gallbladder disease, and renal impairment. You should stop taking it if you notice an increase in your resting heart rate that continues over time.

HOW TRANSFORMYOU CAN HELP

Transformyou offers consultations for anyone looking into their medical weight loss options. In the consultations, we work together to develop a medical weight loss plan that is safe and effective for you. Schedule your consultation today!

All patients always work directly with one of our physicians to ensure patient safety and confidentiality.

References

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Harris, “Triple-Hormone Combination Retatrutide Induces 24% Body Weight Loss,” JAMA, vol. 330, no. 4, p. 306, Jul. 2023, doi: 10.1001/jama.2023.12055.

Urva et al., “The novel GIP, GLP- 1 and glucagon receptor agonist retatrutide delays gastric emptying,” Diabetes Obes. Metab., vol. 25, no. 9, pp. 2784–2788, Sep. 2023, doi: 10.1111/dom.15167.

Winkler, J. T. Kis, K. A. Kiss, and L. Schandl, “A GLP1-receptoragonistáktól a glükagonreceptoragonizmussal kiegészített hármashormonreceptor-aktiválásig.:hármashormonreceptor-aktiválásig.: Új távlatok a 2-es típusú diabetes és az elhízás kezelésében,” Orv. Hetil., vol. 164, no. 42, pp. 1656–1664, Oct. 2023, doi: 10.1556/650.2023.32894.

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GLP-1 agonists: Diabetes drugs and weight loss