Glucagon Like Peptide 1 (GLP-1) Receptor Agonist - Semaglutide


GLP-1 - is produced from the proglucagon gene in L cells of the small intestine. It binds to a specific GLP-1 receptor, which is expressed in various tissues, including pancreatic beta cells, pancreatic ducts, gastric mucosa, kidney, lung, heart, skin, immune cells, and the hypothalamus. GLP-1 exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets. It has also been shown to slow gastric emptying, and inhibits inappropriate post-meal glucagon release, leading to a reduction in food intake. In patients with type 2 diabetes, there is an impaired insulin response to GLP-1, possibly related to a reduction in postprandial GLP-1 secretion or to other mechanisms.

Although GLP-1 has been shown to promote beta-cell replication and mass in animal models of prediabetes and diabetes, these findings have not been replicated in humans. GLP-1 exhibits a short half-life of one to two minutes due to N-terminal degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Synthetic GLP-1 receptor agonists are variably resistant to degradation by the enzyme DPP-4, and therefore have a longer half-life, facilitating clinical use. Longer-acting GLP-1 receptor agonists can be administered once daily or once weekly. Like native GLP-1, all synthetic GLP-1 receptor agonists bind to the GLP-1 receptor and stimulate glucose-dependent insulin release from the pancreatic islets as their primary effect.

Semaglutide is a selective glucagon-like peptide-1 (GLP-1) receptor agonist that increases glucose-dependent insulin secretion. GLP-1 also inhibits glucagon release and gastric emptying. It is a long-acting GLP-1 and is administered by SubQ injection once weekly.

❖ Incretin-based therapies (IBTs) - reduce post-meal blood sugar
❖ Glucose-lowering effects are achieved without any increase in hypoglycemia (according to studies), however, use caution as clinically we have seen some cases.
❖ Reduction in body weight
❖ Lipid reduction
❖ Blood pressure reduction
❖ Reduction in inflammatory markers
❖ Decrease in oxidative stress
❖ Decrease in endothelial dysfunction, and subclinical atherosclerosis
❖ Appetite suppression
❖ Enhance β-cell proliferation, have anti-apoptotic effects, inducing insulin biosynthesis
❖ Enhance glucose-dependent insulin secretion
❖ Suppress inappropriately elevated glucagon levels, both in fasting and postprandial states
❖ Promotes insulin secretion from pancreatic β-cells while decreasing glucagon secretion in the pancreatic α-cells
❖ Promotes satiety in the brain
❖ Demonstrates neuroprotective and neurotrophic actions
❖ Is in phase 3 trials for non-alcoholic liver disease (Semaglutide)
❖ Demonstrated Improved cognition in some preclinical studies and are under investigation in clinical studies for the treatment of Alzheimer’s disease (Semaglutide)
❖ Modifies the behavior of animals w/ alcohol, nicotine, and cocaine dependence (Semaglutide)

Adverse effects:
❖ Nausea (most common)
❖ Constipation (more common)
❖ Vomiting, Diarrhea, flatulence (gas)
❖ Fatigue, dizziness
❖ Headache, vision changes (diabetic retinopathy)
❖ GERD/ belching/ indigestion
❖ Bloating/ abdominal distention
❖ Hypoglycemia in patients w/ Type 2 Diabetes (caution w/ all patients)
❖ Gastroenteritis

Serious side effects (Ozempic’s website):
❖ Pancreatitis
❖ Vision changes
❖ Hypoglycemia- do not take insulin or sulfonylurea medications
❖ Kidney failure/ kidney problems (encourage good hydration)
❖ Gallbladder problems
❖ Serious allergic Rxn’s

❖ PMH or FHx MTC (medullary thyroid cancer)
❖ PMH MEN 2 (multiple endocrine neoplasia type 2)
❖ Allergy to Semaglutide

Other considerations:
❖ PMH- pancreatic dz, kidney dz, diabetic retinopathy
❖ Pregnancy/breastfeeding- it is not known if Semaglutide will harm unborn babies or if it passes into breast milk. The recommendation is to stop Semaglutide 2 months before plans to become pregnant (Ozempic’s website).

Clinical pearls:
❖ Re: hypoglycemia; studies indicate that GLP-1’s do not cause hypoglycemia unless being used alongside insulin or sulfonylurea medications; also that it is safe to use concomitantly w/ Metformin. My postulation is that most of our patient population is non-diabetic and therefore their blood glucose levels may be considerably lower than a type 2 diabetic’s (which is likely the population that the studies were performed on; they have higher fasting glucose levels to work with). We have had some patients experience hypoglycemia. If any of our non-diabetic patients are on Metformin for weight loss or longevity, we require that they discontinue it prior to initiating Semaglutide or Tirzepatide as we have seen exacerbation of signs of low blood sugar- feeling fatigued, dizzy, lack of energy. When starting Semaglutide or Tirzepatide we instruct our patients to:
➢ Administer in the daytime hours (we don’t want them to be asleep if their blood sugar drops)
➢ Have a meal with carbohydrates within 30-60’ of the injection
➢ Eat healthy carbohydrates every day (NO LOW-CARB DIETS)
➢ Caution w/ intermittent fasting (we use clinical judgment from patient to patient)
➢ Follow our dosing protocols which are different from Ozempic, Wegovvy, & Mounjaro. We have a more gradual, customized approach
➢ Ask the patient’s the right questions during their follow-up visits
❖ Concerns of pancreatitis:
➢ We do baseline pancreatic enzyme testing (Amylase/Lipase). Be aware that they increase fairly easily w/ alcohol use. Best to ask the patient’s to not drink any alcohol 48-72 hours prior to lab testing, and encourage hydration.
➢ We have seen pancreas enzymes increase w/ the use of Semaglutide / Tirzepatide- usually not associated w/ any symptoms.
➢ For symptomatic patients ie. abdominal pain, vomiting, diarrhea, fever, and irregular stool we:
■ Instruct them to discontinue the GLP-1 / GIP until further notice, and encourage hydration if they can tolerate
■ call them back to the office (if it sounds urgent we would send them to the ER- has not happened)
■ order labs with pancreas enzymes
■ perform a physical exam (attention to the abdominal quadrants)
■ Determine the next best steps
❖ Patient’s who struggle to get the most optimal results
➢ Check on their alcohol habits; daily drinkers (2-3 glasses wine/evening) have struggled
➢ Sedentary patients unwilling to exercise
➢ Patients w/ gut inflammation (constipation, bloating, distended, poor diets)
For the best results they need to have a healthy gut; address the microbiome
● Enforce that they use a prebiotic (more important than a probiotic) every day; not just stop after 2 weeks
● If you suspect prior to start, also recommend Prolon for 5 days (fasting-mimicking diet- great to do while they are waiting for their medication to arrive; as we don’t think it is safe for them to do together-> hypoglycemia concerns
● Hx of GERD: Alka Seltzer Gold- AM/ PM (amazing longevity hack)
● Hx Barrett’s Esophagus: Alka Seltzer Gold and Oral BPC 157 (very successful protection; heals ulcers, prevents new damage)
Semaglutide Dosage:
Advitam dosing (see separate dosing schedule):
➢ Our pharmacy compounds Semaglutide w/ BPC 157 & Vit B6
➢ One of our other pharmacies compounds Semaglutide w/ L-Carnitine
➢ The vials come in different strengths and volumes
➢ Depending on the H&P, labs, body composition analysis, medications, and goals of the patient, there are different options
■ Some will use a microdose. Splitting the lowest dose into ½ and administering BIW
■ For the typical patient, titrate:
● Inject 0.25mg SubQ q 7d x 4 wks
● Inject 0.5mg SubQ q7d x 4 wks (at 7 week f/u determine if needs to increase or hold here)
● Inject 1.0mg SubQ q7d x 4 wks (you may want to increase as indicated or stay at 1.0mg if pt trending appropriately- at next 7-week f/u determine if needs to increase or hold here)
● Follow that pattern; the additional adjustments we typically make are:
● Inject 1.25mg SubQ q 7d
● Inject 1.5mg SubQ q 7d
● Inject 2.0mg SubQ q 7d
■ Depending on the Strength compounded in the vial (which varies from pharmacy to pharmacy and sometimes within different strengths from the same pharmacy) will determine the volume to be administered in units. For example:
● Pharmacy A: 10 units equals 0.25mg
● Pharmacy B: 12 units equals 0.25mg
■ Don’t worry we have worked hard in trying to make it easy for you and we will teach you how to make adjustments if necessary.
❖ Typical dosing when using Ozempic:
➢ Inject 0.25mg SubQ q 7d, after 4 weeks increase to;
➢ Inject 0.5mg SubQ q 7d, determine if increase is needed;
➢ Inject 1.0mg SubQ q 7d, determine if increase is needed;
➢ Inject 2.0mg SubQ q 7d (Can increase up to 2.4mg q 7d)