Oral Semaglutide, available by the brand name of Rybelsus, and Injectable Semaglutide, available by the brand name of Ozempic are two available formulations manufactured by Novo Nordisk.

Semaglutide is a GLP-1 agonist that is 94% identical to the natural human GLP-1. It is used in the treatment of patients with Diabetes Mellitus Type 2 who do not achieve their target glycemic control with diet, exercise, and first-line therapy.

It may be used in combination with other antidiabetic medicines like metformin, sulfonylureas, SGLT2 inhibitors, and insulin.

It should not be used as a first-line of therapy in diabetic patients. Furthermore, it should be avoided in patients at risk of pancreatitis, Diabetic Ketoacidosis, and Diabetes Mellitus Type 1.

Injectable Semaglutide has got FDA approval about 2 years back, while the oral Semaglutide (Rybelsus) has recently got FDA approval.

Both the Oral and injectable Semaglutide have similar efficacy in terms of glycemic control and weight loss.

Rybelsus is taken orally once daily while the injectable Semaglutide (Ozempic injection) is administered subcutaneously once a week.

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Semaglutide (Rybelsus and Ozempic) for Weight Loss: Update!

A recent study titled: "Once-Weekly Semaglutide in Adults with Overweight or Obesity" has been published in NEJM [Ref].

The study evaluated the role of once-weekly semaglutide at a dose of 2.4 mg in obese and overweight individuals.

Participants in the intervention group had a greater improvement in their cardiometabolic risk profile compared to those in the placebo group.

Overall weight reduction at week 68 in patients treated with semaglutide 2.4 mg once weekly was as follows:

• 5% or more weight loss: 1047 participants equivalent to 86.4% vs. 182 or 31.5% in the placebo,
• 10% or more weight loss: 838 participants or 69.1% vs. 69 or 12.0% in the placebo, and
• 15% or more weight loss: 612 participants or 50.5% vs. 28 participants or 4.9% in the placebo arm.

P values for all the three comparisons of odds: <0.001

FDA recently approved high-dose injectable Semaglutide for the treatment of Obesity and overweight.

Semaglutide 2.4 mg administered subcutaneously once a week resulted in weight loss ranging from 9% to 16% in individuals with or without diabetes. It is marketed by Novo Nordisk by the brand name of Wegovy.

Recommended for You: Wegovy Comparison with other Weight Loss Drugs

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Semaglutide safety in diabetic patients with cardiovascular diseases:

The SUSTAIN-6 trial evaluated the cardiovascular safety of Semaglutide in more than 2700 diabetic patients with established cardiovascular disease in 83% of the patients.

Compared to placebo, there was a significant reduction (26%) in the rates of MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and nephropathy.

However, the rates of retinopathy-related complications were significantly higher including blindness, vitreous hemorrhage, and conditions requiring photocoagulation or the administration of intravitreal agents) [Ref].

Semaglutide does not increase the risk of QTc prolongation.

Semaglutide effects on Diabetic Retinopathy:

The SUSTAIN-6 trial found a significant increase in the incidences of diabetic retinopathy-related complications including blindness.

However, the SUSTAIN 1-5 and the Japanese trials did not significantly worsen diabetic retinopathy-related complications [Ref].

A rapid reduction in blood glucose as evidenced by a drop in the glycated hemoglobin levels and the use of Semaglutide in patients with pre-existing diabetic retinopathy were the important factors that resulted in an increase in the retinopathy complications.

The effect of Semaglutide on diabetic retinopathy is similar to bariatric surgery, intensified insulin, and pregnancy.

All these conditions have been associated with worsening diabetic retinopathy as a result of better glycemic control.

Ozempic Retinopathy

The emerging role of Semaglutide in NASH and Fatty liver (NAFLD):

Fatty liver and NASH (non-alcoholic steatohepatitis) is a common cause of liver failure in the west.

NAFLD and NASH are closely linked to insulin resistance, obesity, and diabetes.

It is characterized by fat deposition and inflammation resulting in hepatocyte damage ultimately resulting in fibrosis, cirrhosis, and hepatocellular carcinoma.

Semaglutide once-weekly subcutaneous injection was found to reduce ALT levels in 46% of the patients.

Likewise, high-sensitive CRP (hsCRP) was also significantly reduced compared to placebo [Ref].

Liraglutide, like Semaglutide, has also been found effective in the treatment of NAFLD and NASH.

Semaglutide Vs Dulaglutide Vs Liraglutide: Glycemic control & weight loss

The SUSTAIN 7 trial compared once-weekly Dulaglutide and Once weekly Semaglutide.

Once Weekly Semaglutide was found to be superior at both low and high doses compared to dulaglutide in terms of glycemic control and weight loss.

Semaglutide was equally safe and well-tolerated as liraglutide [Ref]. Compared to Liraglutide once daily, once-weekly Semaglutide resulted in comparable weight loss and safety profile [Ref].

Another study compared once-daily liraglutide with once-daily oral Semaglutide.

Once-daily oral Semaglutide had comparable efficacy in terms of glycemic control but superior efficacy in terms of weight loss.

A weight loss of 4.4 kgs was observed with once-daily Semaglutide compared to a weight loss of 3.3 kgs with liraglutide [Ref]. Once-weekly Semaglutide was also found to be superior to Exenatide 2 mg in improving glycemic control [Ref].

Injectable and Oral Semaglutide Vs Liraglutide:

	Semaglutide	Liraglutide
Brands	Ozempic injection Rybelsus Oral tablets	Victoza Saxenda
Mode of administration	Subcutaneous and oral	subcutaneous
Dosage duration	The oral tablet is taken once daily Subcutaneous is administered weekly	Administered daily
Efficacy	More effective	Less effective compared to Semaglutide
Glycemic control	Both the injectable and oral Semaglutide have similar efficacy as liraglutide	Similar glycemic efficacy
Weight loss	Oral Semaglutide is superior to liraglutide in terms of weight loss.	Liraglutide is inferior to oral semaglutide but has similar efficacy as subQ semaglutide.
Cost of the maximum dose per month in the US	Ozempic: $1235.9 Rybelsus: $927	Saxenda: $399.12 Victoza: $491.6

Ozempic (Injectable Semaglutide) Dose in Adults

Ozempic (Injectable Semaglutide) Dose in the treatment of Diabetes mellitus Type 2:

• Semaglutide 0.25 mg SubQ once a week for four weeks.
• The dose is then increased to 0.5 mg once a week for at least four weeks.
• The dose may be further increased to the maximum recommended dose of 1 mg once a week if required and tolerated.

Note:

• Semaglutide in a dose of 0.25 mg is not usually effective for glycemic control.
• It is only intended for the initiation of the treatment.
• If the day of administration is rescheduled, at least 48 hours gap should be maintained between the doses.

• Missed doses:

  • A missed dose should be administered as soon as possible and within five days.
  • If more than five days elapse, the dose should be skipped.
  • The dose should be resumed on the regularly scheduled days.

Rybelsus (Oral Semaglutide) Dosage in Diabetes Mellitus Type 2:

• It is initially given as 3 mg orally once a day.
• The dose may be increased after 30 days to 7 mg once a day if required.
• Patients who do not achieve their target glycemic control may increase the dose further to the maximum dose of 14 mg after 30 days.

How to switch from SubQ  to Oral Semaglutide and Vice Versa:

Patients on oral Semaglutide 14 mg may be switched to 0.5 mg SubQ administered weekly that is initiated one day after the last oral dose.

Patients on injectable 0.5 mg Once-weekly Semaglutide may be switched to 7 mg or 14 mg oral Semaglutide approximately one week after the last dose of Injectable Semaglutide. 

Use in children:

It is not recommended for use in children

Pregnancy Risk Category: C

• Patients with diabetes should plan their pregnancy.
• Semaglutide should not be used during a planned pregnancy.
• An increased chance of adverse maternal and fetal outcomes is associated with uncontrolled diabetes during pregnancy. These include preeclampsia and diabetic ketoacidosis.
• Before and during pregnancy, blood sugars should be within the target range.
• Pregnancy is a time when insulin and metformin are the most preferred antidiabetic medications.

Use while breastfeeding

• It is unknown if the drug is excreted into breastmilk.
• It is important to weigh the benefits and risks of drug use during lactation.

Dose in kidney disease:

Adjustment in the dose is not necessary in patients with kidney disease. 

Dose in Liver disease:

Adjustment in the dose is not necessary in patients with liver disease. 

Injectable and Oral Semaglutide Side Effects (Common):

• Endocrine & Metabolic:

  • Increased Amylase

• Gastrointestinal:

  • Increased Serum Lipase
  • Nausea

Less Common Side Effects of Semaglutide Include:

• Endocrine & Metabolic:

  • Hypoglycemia

• Gastrointestinal:

  • Diarrhea
  • Vomiting
  • Abdominal Pain
  • Constipation
  • Dyspepsia
  • Eructation
  • Flatulence
  • Gastroesophageal Reflux Disease
  • Cholelithiasis

• Immunologic:

  • Antibody Development

Rare Side effects of Semaglutide:

• Cardiovascular:

  • Increased Heart Rate

Injectable & Oral Semaglutide Contraindication:

• Allergy reactions to any component of the drug or the drug itself
  • Patients who have a family or personal history of medullary cancer should consult a doctor immediately.
  • Multiple endocrine neuroplasia type 2 (MEN2) patients
  • Pregnancy
  • Breastfeeding

Warnings and Precautions:

• Formation of antibodies:

  • Semaglutide may be able to cause antibodies in 1% of patients.
  • These antibodies could cross-react to native GLP-1.

• Gallbladder disease

  • GLP-1 agonist is a common treatment for gallbladder disease and bile duct diseases.
  • Gallbladder stones can cause complications that could require hospitalization or surgery.

• Hypersensitivity reactions

  • Angioedema or anaphylactic reactions can be serious allergic reactions.
  • After a severe hypersensitivity reaction, treatment may have to be stopped.
  • Patients who have had anaphylaxis, angioedema or angioedema from a GLP-1 Agonist in the past should be cautious about taking this drug. There is a possibility of cross-sensitivity.

• Pancreatitis

  • Semaglutide can cause acute and chronic pancreatitis.
  • Pancreatitis symptoms should be reported by patients.
  • The treatment should be stopped immediately and not resumed until an alternative cause is identified.
  • Patients who have had pancreatitis in the past should be cautious about taking this drug.

• Effects on the renal system:

  • There have been cases of acute renal failure, exacerbations or underlying chronic acute and chronic renal failure. This medication may sometimes require hospitalization and hemodialysis.
  • It should be used with caution for patients at high risk of kidney failure, such as those suffering from nausea, dehydration, vomiting, or other symptoms.
  • When increasing doses or initiating therapy, it is important to monitor your renal function.

• Thyroid tumors: [US Boxed Warning]

  • GLP-1 agonists, including Semaglutide, have been linked to an increase in medullary gland carcinoma.
  • Patients who take it for a longer time and at higher doses are at greater risk of developing thyroid C-cell cancers.
  • Thyroid tumors should be checked for signs such as shortness of breath and hoarseness, difficulty swallowing, or a mass in one's neck.
  • Patients with MEN 2 (multiple endocrine neoplasia), or a history of medullary cancer should not take semaglutide or other GLP-1 agonists.
  • Patients with thyroid swelling should be examined and measured for calcitonin.
  • It is not clear what the role of thyroid ultrasound or regular calcitonin monitoring is.

• Bariatric surgery

  • Dehydration
    • As acute renal failure is more likely, patients should be closely monitored following surgery. Dehydration should also be avoided.
    • Post-surgical nausea, gastrointestinal upset, and other symptoms may occur. This may lead to volume loss.
  • Excessive glucagon-like peptide-1:
    • Endogenous GLP-1 concentrations are significantly increased by gastric bypass and sleeve gastrectomy.
    • Acute pancreatitis should be closely monitored.
    • GLP-1 exogenous administration can reduce or not be necessary in some cases.
    • Notable is also the fact that gastric band ligation doesn't affect endogenous GLP-1 levels.

• Diabetic Retinopathy:

  • This is linked to an increased risk for diabetic retinopathy.
  • It is important to screen patients for retinopathy before they reach adulthood.
  • Retinopathy patients who have had a history of it should be cautious.

• Gastroparesis

  • It can delay gastric emptying and could impair the absorption of medication.
  • You should use it with caution.

Monitor:

• The plasma glucose levels
• HbA1C levels (every 3 months if target HbA1C not met, and every 6 months if target hbA1C achieved).
• Monitor renal function
• Clinical characteristics of Pancreatitis
• Triglyceride levels
• Gallbladder disease clinical features

How to administer the Injectable and Oral Semaglutide?

It can be taken as an injectable or oral medicine.

SubQ (injectable formulation):

• SubQ is administered in the abdomen, thigh or upper arm every week, with or without meals, at any time during the week.
• It is necessary to allow at least 48 hours between the scheduled day and another day if the day is being switched.
• Rotating the site of injection (like insulin) is a good idea.
• It should not mixed with any other products or be administered near other injections.
• Before administering the solution, it should be crystal clear and not cloudy.

How to use the Oral Semaglutide, (Rybelsus).

You should take it with a full stomach, preferably in the morning. Concomitant medications should be taken within a minimum of 30 minutes. You should push the tablet out of the blister. It should not be broken. You should not chew, crush, or split the tablet. You should take it with a glass water. 

Semaglutide Mechanism of Action (MOA):

• Semaglutide activates the endogenous Incretin receptors by activating them.
• It increases insulin secretion through a glucose-dependent mechanism (both first and second phases of insulin), decrease inappropriate secretion of glucagon, and delays gastric emptying.

Protein-bound: It is primarily bound to albumin and metabolized by proteolytic cleavage.

It has been a bioavailability of 89% and a half-life of approximately one week.

The maximum plasma concentration is reached in approximately 1 to 3 days after one dose.

The steady-state concentration can be reached after 4 to 5 weeks with the injectable formulation.

After one hour, the Oral drug reaches its maximum serum concentration. In 4 to 5 weeks, the steady-state serum concentration can be achieved.

Half-life of the drug is approximately one week. The drug remains in the blood for approximately five weeks after the last dose. 

It is excreted in the urine and feces.

Semaglutide Brand Names (International):

Injectable Semaglutide:

• Ozempic (0.25 mg, 0.5 mg, and 1 mg)

Oral Semaglutide tablets

• Rybelsus:
  • 3 mg, 7 mg, 14 mg

Price of Injectable Semaglutide:

• Solution Pen-injector (Ozempic (0.25 or 0.5 mg/dose)

  • 2 mg/1.5 mL (per mL): $617.95

• Solution Pen-injector (Ozempic (1 mg/dose)

  • 2 mg/1.5 mL (per mL): $308.97

Price of Oral Semaglutide (Rybelsus):

3 mg (per each): $30.90 7 mg (per each): $30.90 14 mg (per each): $30.90.

Semaglutide brand names in Pakistan:

Ozempic (Injection Semaglutide) has been recently marketed by Novo Nordisk in Pakistan.

It is available as one injectable pen device that contains four doses of 0.5 mg Ozempic.

It will cost PKR 21020 per month ( four doses).