SEMAGLUTIDE (WEGOVY®)

• ACRONYMS AND DEFINITIONS

• A1C - Hemoglobin A1C
• ADA - American Diabetes Association
• CAD - Coronary artery disease
• CrCl - Creatinine clearance
• CVD - Cardiovascular disease
• DM - Diabetes mellitus
• FBS - Fasting blood sugar
• GFR - Glomerular filtration rate
• GI - Gastrointestinal
• GLP-1 - Glucagon-like peptide-1
• OSA - Obstructive sleep apnea
• PAD - Peripheral artery disease
• RCT - Randomized controlled trial
• SBP - Systolic blood pressure
• Thyroid C-cell tumor = Thyroid medullary tumor

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• DRUGS IN CLASS

• GLP-1 analogs
• Semaglutide (Wegovy®) is a GLP-1 analog, a drug class used to treat type 2 diabetes. Patients receiving GLP-1 analogs sometimes saw significant weight loss, and this created interest in using them as an obesity treatment. Another GLP-1 analog, liraglutide (Saxenda®), was FDA-approved for weight loss in 2014.
• Semaglutide is available in three different medications: Wegovy®, Ozempic®, and Rybelsus®. Ozempic® (injection) and Rybelsus® (tablet) are FDA-approved to treat type 2 diabetes, and Wegovy® is approved for weight loss.
• GLP-1 analogs
• Saxenda® (liraglutide)

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• MECHANISM OF ACTION

• GLP-1 analogs
• GLP-1 stands for "glucagon-like peptide-1." GLP-1 is a hormone secreted into the bloodstream by special cells in the intestine in response to food consumption. In the pancreas, GLP-1 stimulates insulin release and suppresses glucagon secretion. GLP-1 receptors are also found in parts of the brain that regulate appetite and food intake, and this is where its hunger-suppressing effects are believed to occur. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1 and makes it inactive.
• GLP-1 analogs have a similar structure to endogenous GLP-1, and they mimic its actions in the pancreas and brain. They have also been modified so that DPP-4 cannot metabolize them.
• GLP-1 therapies illustration

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• FDA-APPROVED INDICATIONS

• Weight loss (adults)
• As an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with either of the following:
• BMI ≥ 30 (obesity)
• BMI ≥ 27 (overweight) in the presence of at least one weight-related comorbid condition (e.g. hypertension, type 2 diabetes mellitus, or dyslipidemia)
• See BMI calculator for adults


• Weight loss (children ≥ 12 years old)
• As an adjunct to a reduced-calorie diet and increased physical activity in pediatric patients aged 12 years and older with an initial BMI at the 95th percentile or greater for age and sex. See BMI calculator for children.

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• WEIGHT LOSS

• Overview
• The effects of Wegovy on weight loss were studied in the four trials detailed below. In the first two trials, Wegovy was compared to placebo in adults without diabetes. In the third trial, it was compared to the diabetes formulation of semaglutide (Ozempic®) and placebo in adults with diabetes. In the fourth trial, Wegovy went head-to-head with Saxenda, another GLP-1 agonist approved for weight loss.

• STUDY
  STEP 3 Trial - Semaglutide vs Placebo for Weight Loss in Overweight Adults Without DM, JAMA (2021) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=611 | length = 68 weeks) in overweight or obese adults (average weight 233 lbs | average BMI 38) without diabetes
• Treatment: Semaglutide 2.4 mg sub-q once weekly vs Placebo. All patients received diet counseling and behavioral therapy.
• Primary outcome: Percentage change in body weight and the proportion of participants who lost at least 5% of baseline weight by week 68
• Results:
• Primary outcome (% weight loss): Semaglutide - 16%, Placebo - 5.7% (p<0.001)
• Primary outcome (≥ 5% weight loss): Semaglutide - 86.6%, Placebo - 47.6% (p<0.001)
• Average weight loss: Semaglutide - 37 lbs (16.8 kg) , Placebo - 13.6 lbs (6.2 kg) (p<0.001)
• Adverse gastrointestinal events: Semaglutide - 83%, Placebo - 63%
• Adverse events leading to drug discontinuation: Semaglutide - 5.9%, Placebo - 2.9%
• Findings: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.

• STUDY
  STEP 2 Trial - Semaglutide 2.4 mg vs Semaglutide 1 mg vs Placebo for Weight Loss in Overweight Diabetics, Lancet (2021) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=1210 | length = 68 weeks) in overweight diabetics with BMI ≥ 27 (average weight 220 lbs | average BMI 35.7) and an A1C of 7 - 10% (average 8.1%)
• Treatment: Semaglutide 2.4 mg sub-q once weekly vs Semaglutide 1 mg sub-q once weekly vs Placebo
• Primary outcome: Percentage change in body weight from baseline to week 68 and loss of at least 5% of baseline weight at week 68 for semaglutide 2.4 mg vs placebo
• Results:
• Primary outcome (% weight loss): Semaglutide 2.4 mg - 9.64%, Semaglutide 1 mg - 6.99%, Placebo - 3.42% (Semaglutide 2.4 vs placebo, p<0.0001)
• Primary outcome (≥ 5% weight loss): Semaglutide 2.4 mg - 68.8%, Semaglutide 1 mg - 57.1%, Placebo - 28.5% (Semaglutide 2.4 vs placebo, p<0.0001)
• Average weight loss: Semaglutide 2.4 mg - 21.3 lbs (9.7 kg), Semaglutide 1 mg - 15.2 lbs (6.9 kg), Placebo - 7.7 lbs (2.2 kg)
• Decrease in A1C: Semaglutide 2.4 mg - 1.6%, Semaglutide 1 mg - 1.5%, Placebo - 0.4%
• Adverse gastrointestinal events: Semaglutide 2.4 mg - 63.5%, Semaglutide 1 mg - 57.5%, Placebo - 34.3%
• Adverse events leading to drug discontinuation: Semaglutide 2.4 mg - 6.2%, Semaglutide 1 mg - 5%, Placebo - 3.5%
• Findings: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in body weight compared with placebo.

• Summary
• Wegovy achieved impressive weight loss in the trials detailed above, and it was decisively more effective than Saxenda in the STEP 8 trial.
• In the STEP 2 trial that only included overweight diabetics, Wegovy was more effective than semaglutide 1 mg (Ozempic) for weight loss, but the difference was not as impressive (9.6% vs 7%). A1C reduction was also similar (1.6% vs 1.5%). Overweight diabetics who want to take Wegovy may find Ozempic easier to obtain and will likely see similar results with it.
• In another Wegovy trial (STEP 4), overweight patients were treated with Wegovy for 20 weeks (average weight loss 10.6% at 20 weeks) and then randomized to continue Wegovy or switch to placebo for 48 weeks. That trial found that patients who continued Wegovy lost an additional 7.9%, whereas patients who switched to placebo gained back 6.9%. [PMID 33755728]
• Gastrointestinal adverse events were common in all the trials, but they did not lead to a large number of discontinuations

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• WEIGHT LOSS IN ADOLESCENTS

• Overview
• The STEP TEENS study detailed below evaluated the effects of Wegovy on weight loss in obese adolescents aged 12 - 17 years.

• Summary
• Semaglutide caused impressive weight loss in the STEP TEENS study, and its effects appear to be greater than other drugs approved for adolescent obesity (see Qsymia and Saxenda). As expected, gastrointestinal side effects were common, and 4% of semaglutide-treated patients experienced cholelithiasis, a known adverse effect of rapid weight loss. In 2022, Wegovy received FDA approval to treat adolescent obesity based on the STEP TEENS study.

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• SIDE EFFECTS

• Gastrointestinal (GI) side effects
• Gastrointestinal complaints are the most common type of side effect seen with Wegovy. The table below gives the incidence of GI side effects from Wegovy trials. To minimize the risk, Wegovy should be started at low doses and titrated gradually.

• Reference [1]

Side effect	Wegovy (N=1261)	Placebo (N=2116)
Nausea	44%	16%
Diarrhea	30%	16%
Vomiting	24%	6%
Constipation	24%	11%
Abdominal pain	20%	10%
Dyspepsia	9%	3%
Abdominal distension	7%	5%
Belching	7%	< 1%
Flatulence	6%	4%

• Hypoglycemia
• Wegovy by itself does not pose a significant risk of hypoglycemia. When it is taken with diabetes medications, particularly insulin and insulin secretagogues, the risk of hypoglycemia is increased.
• In the STEP 1 Study that only enrolled nondiabetics, Wegovy did not increase the risk of hypoglycemia. In trials involving diabetics, the incidence of hypoglycemia was 6.2% in Wegovy-treated patients and 2.5% in placebo-treated patients.
• Patients who are taking concomitant diabetes medications should monitor their blood sugars closely and be prepared to treat hypoglycemia (see hypoglycemia for more)

• Injection site reactions
• Injection site reactions including pruritus, erythema, inflammation, induration, and irritation may occur. In studies, reactions were reported in 1.4% of Wegovy-treated patients and 1.0% of placebo-treated patients.

• Hypersensitivity reactions
• Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with semaglutide
• Avoid use in patients with a history of reactions to semaglutide and use caution in patients with a history of reactions to other GLP-1 analogs

• Semaglutide antibodies
• Semaglutide has the potential to induce an immune response. The immune response can lead to the production of antibodies against semaglutide, and in some cases, the antibodies cross-react with endogenous GLP-1.
• In trials, 2.9% of Wegovy-treated patients developed anti-semaglutide antibodies, and of these patients, 56% had antibodies that cross-reacted with endogenous GLP-1. The effects of anti-semaglutide antibodies on efficacy and hypersensitivity reactions are unknown.

• Pancreatitis
• Acute pancreatitis has been reported in patients receiving GLP-1 analogs, including semaglutide. In trials, acute pancreatitis occurred in 4 Wegovy-treated patients (0.2 cases per 100 patient-years) and 1 placebo-treated patient (< 0.1 cases per 100 patient-years). If symptoms of pancreatitis occur (e.g. abdominal pain, nausea, vomiting), discontinue Wegovy and initiate appropriate care. Wegovy has not been studied in patients with a history of pancreatitis.

• Decreased kidney function
• There have been case reports of decreased kidney function in patients receiving semaglutide. In a majority of the cases, symptoms of nausea, vomiting, and/or diarrhea were present. These symptoms are common side effects of semaglutide, and they can lead to dehydration and worsening kidney function.
• Caution should be used when prescribing semaglutide to patients with renal impairment. Monitor renal function in patients who are experiencing significant gastrointestinal reactions.

• Hypotension and syncope
• Gastrointestinal side effects from Wegovy can lead to dehydration and lower blood pressure in some patients. In trials, hypotensive events were reported in 1.3% of Wegovy-treated patients and 0.4% of placebo-treated patients, and syncope in 0.8% and 0.2%, respectively. Patients taking antihypertensives are at greater risk. Monitor blood pressure closely in susceptible patients.

• Gallbladder disease
• In adult trials, cholelithiasis was more common in Wegovy-treated patients than placebo-treated patients (1.6% vs 0.7%), as was cholecystitis (0.6% vs 0.2%). In adolescent trials, Wegovy-treated patients were also more likely to experience cholelithiasis (3.8% vs 0%) and cholecystitis (0.8% vs 0%). Substantial or rapid weight loss can increase the risk of cholelithiasis; however, even after accounting for the degree of weight loss, Wegovy-treated patients still had a higher incidence of acute gallbladder disease.
• Patients who report symptoms of gallbladder disease (e.g. abdominal pain, nausea, vomiting) should have a prompt workup

• Thyroid cancer
• In toxicology studies, a dose-dependent and treatment-duration-dependent increase in the incidence of malignant and benign thyroid medullary tumors (C-cell tumors) was observed in rats and mice receiving clinically relevant doses of GLP-1 analogs. This prompted the FDA to place a boxed warning about medullary thyroid cancer on some GLP-1 analogs, including semaglutide. It is unknown if GLP-1 analogs increase the risk of tumors in humans as the incidence of these events is too low to establish causality.
• Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, a condition that increases the risk for medullary thyroid cancer. Patients should be aware of the potential risk and report any thyroid symptoms if they occur. Medullary thyroid cancer usually causes elevations in calcitonin levels above 50 ng/L.

• Diabetic retinopathy
• In adult trials with type 2 diabetics, diabetic retinopathy was reported in 4% of Wegovy-treated patients and 2.7% of placebo-treated patients. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with diabetic retinopathy at baseline may be at greater risk for worsening and should be monitored appropriately. The long-term effects of semaglutide therapy on diabetic retinopathy have not been studied.

• Pancreatic enzyme elevations
• In trials, patients treated with Wegovy had an average increase from baseline in amylase of 16% and lipase of 39%. No increase was observed in placebo-treated patients. The significance of these effects is unknown.

• Heart rate increase
• In adult trials, Wegovy-treated patients had an average increase in heart rate of 1 - 4 bpm compared to placebo. Maximum increases of 10 - 19 bpm from baseline at any visit were observed in more Wegovy-treated patients than placebo-treated patients (41% vs 34%), as were increases of ≥ 20 bpm (26% vs 16%). In adolescent trials, changes in heart rate of 20 bpm or more were more common in Wegovy-treated patients than placebo-treated patients (54% vs 39%).
• Monitor heart rates in Wegovy-treated patients and discontinue therapy if sustained increases occur

• Suicide behavior and ideation
• Suicidal behavior and ideation have been reported in clinical trials with other weight management products. Monitor patients for depression, suicidal thoughts, or other unusual changes in mood. Avoid use in patients with a history of suicidal behavior, and discontinue therapy in patients who develop suicidal ideation.

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• CONTRAINDICATIONS

• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in Wegovy

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• PRECAUTIONS

• Kidney disease
• No dose adjustment is necessary for any degree of renal impairment

• Liver disease
• No dose adjustment is necessary for any degree of hepatic impairment

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• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.

• Semaglutide (Wegovy®)
• Insulin and insulin secretagogues - when combined with insulin or insulin secretagogues (e.g. sulfonylureas, meglitinides), semaglutide increases the risk of hypoglycemia. Monitor blood sugars closely and adjust medications as needed.
• Drugs affected by decreased gastric emptying - see gastric emptying below
• Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of GLP-1 analogs
• Examples include:
• Anticholinergic medications
• Opiate pain medications (hydrocodone, morphine, etc.)

• Drugs affected by gastric emptying
• Medications are partially digested in the stomach before being emptied into the small intestine, where most drugs are absorbed. GLP-1 analogs slow the process of gastric emptying, and this may alter the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
• Antibiotics
• Antibiotics require rapid absorption to achieve their desired therapeutic effect
• Drugs with a narrow therapeutic index
• Drugs with narrow therapeutic index may have their steady-state altered by delayed gastric emptying
• Examples of drugs with a narrow therapeutic index:
• Carbamazepine (Tegretol®)
• Cyclosporine (Neoral®)
• Digoxin
• Levothyroxine (Synthroid®)
• Lithium
• Phenytoin (Dilantin®)
• Tacrolimus (Prograf®)
• Theophylline (Theo-24®)
• Warfarin (Coumadin®) [2]

• Metabolism and clearance
• Semaglutide is metabolized by proteolytic cleavage and beta-oxidation. The remnants of these processes are eliminated via the urine and feces.

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• DOSING

• Dosage forms (single-dose pen-injector)
• 0.25 mg/0.5 ml
• 0.5 mg/0.5 ml
• 1 mg/0.5 ml
• 1.7 mg/0.75 ml
• 2.4 mg/0.75 ml
• Comes in carton with 4 pens
• Store in refrigerator. May be kept at room temperature for up to 28 days.
• No generic. Cost > $150/month.

• Dosing (adults and children ≥ 12 years)
• The recommended titration schedule for Wegovy is provided in the table below
• Wegovy is given once weekly, on the same day each week, at any time of day, with or without meals
• Administer subcutaneously in the abdomen, thigh, or upper arm
• Missed doses: If one dose is missed and the next scheduled dose is more than 48 hours away, administer Wegovy as soon as possible. If one dose is missed and the next scheduled dose is less than 48 hours away, do not administer the dose. Resume dosing on the regularly scheduled day of the week. If more than 2 consecutive doses are missed, resume dosing as scheduled or, if needed, reinitiate Wegovy and follow the dose escalation schedule, which may reduce the occurrence of gastrointestinal symptoms associated with reinitiation of treatment.

Weeks	Weekly Dose
1 through 4	0.25 mg
5 through 8	0.5 mg
9 through 12	1 mg
13 through 16	1.7 mg
Week 17 and onward	2.4 mg

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• LONG-TERM SAFETY

• The first GLP-1 analog (exenatide) was FDA-approved in 2005. When used appropriately, GLP-1 analogs appear to be safe.

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• BIBLIOGRAPHY

• 1 - Wegovy PI
• 2 - North Carolina Pharmacy Practice Act. Article 4A. 90-85.28(b1).