SEMAGLUTIDE (WEGOVY®)

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• GLP-1 analogs
• Semaglutide (Wegovy®) is a GLP-1 analog, a drug class originally developed to treat type 2 diabetes. Patients receiving GLP-1 analogs sometimes saw significant weight loss, creating 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 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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• GLP-1 analogs
• Glucagon-like peptide-1 (GLP-1) is a hormone secreted into the bloodstream by special cells in the intestine in response to food consumption. GLP-1 has the following actions: (1) slows gastric emptying; (2) stimulates insulin release and suppresses glucagon secretion in the pancreas; (3) suppresses appetite in the brain. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1, rendering it inactive.
• GLP-1 analogs have a similar structure to endogenous GLP-1, mimicking its actions in the pancreas, stomach, and brain. They have also been modified so that DPP-4 cannot metabolize them.


• GLP-1 therapies illustration

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• 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) [STEP 1 study]
• Adult BMI calculator


• 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 (pediatric BMI calculator) for age and sex. [STEP TEENS study]


• Secondary prevention of CVD (adults)
• To reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with established cardiovascular disease and either obesity or overweight. [SELECT trial]

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• Overview
• The effects of Wegovy on weight loss were studied in the five trials detailed below. In the first two trials, Wegovy was compared to placebo in adults without diabetes. In the third trial, all patients were given Wegovy for 20 weeks and then randomized to continue it or switch to placebo for 48 additional weeks. In the fourth trial, it was compared to Ozempic and placebo in adults with diabetes, and in the fifth trial, it went head-to-head with Saxenda, another GLP-1 agonist approved for weight loss.

• RCT
  STEP 3 Trial - Wegovy 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: Wegovy 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): Wegovy - 16%, Placebo - 5.7% (p<0.001)
• Primary outcome (≥ 5% weight loss): Wegovy - 86.6%, Placebo - 47.6% (p<0.001)
• Average weight loss: Wegovy - 37 lbs (16.8 kg) , Placebo - 13.6 lbs (6.2 kg) (p<0.001)
• Adverse gastrointestinal events: Wegovy - 83%, Placebo - 63%
• Adverse events leading to drug discontinuation: Wegovy - 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.

• RCT
  STEP 4 study - Continue vs Stop Wegovy after 20 Weeks in Overweight Adults, JAMA (2021) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=902 | length = 68 weeks) in overweight or obese adults (average weight 235 lbs | average BMI 38) without diabetes
• Treatment: All patients received Wegovy for 20 weeks. Those who were receiving Wegovy 2.4 mg at week 20 were randomized to continue Wegovy 2.4 mg or placebo for 48 more weeks.
• Primary outcome: Percent change in body weight from randomization (week 20) to week 68
• Results:
• At week 20, average weight loss was 10.6%
• Primary outcome: Continue Wegovy -7.9%, Placebo +6.9% (p <0.001)
• Findings: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks

• RCT
  STEP 2 Trial - Wegovy 2.4 mg vs Ozempic 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: Wegovy 2.4 mg sub-q once weekly vs Ozempic 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): Wegovy 2.4 mg - 9.64%, Ozempic 1 mg - 6.99%, Placebo - 3.42% (Semaglutide 2.4 vs placebo, p<0.0001)
• Primary outcome (≥ 5% weight loss): Wegovy 2.4 mg - 68.8%, Ozempic 1 mg - 57.1%, Placebo - 28.5% (Semaglutide 2.4 vs placebo, p<0.0001)
• Average weight loss: Wegovy 2.4 mg - 21.3 lbs (9.7 kg), Ozempic 1 mg - 15.2 lbs (6.9 kg), Placebo - 7.7 lbs (2.2 kg)
• Decrease in A1C: Wegovy 2.4 mg - 1.6%, Ozempic 1 mg - 1.5%, Placebo - 0.4%
• Adverse gastrointestinal events: Wegovy 2.4 mg - 63.5%, Ozempic 1 mg - 57.5%, Placebo - 34.3%
• Adverse events leading to drug discontinuation: Wegovy 2.4 mg - 6.2%, Ozempic 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 better than Saxenda in the STEP 8 trial.
• In the STEP 2 trial that only enrolled overweight diabetics, Wegovy caused more weight loss than Ozempic 1 mg, but the difference was not overwhelming (9.6% vs 7%). A1C reductions were also similar between the groups (1.6% vs 1.5%).
• In the STEP 4 trial, patients lost 10.6% of their body weight after 20 weeks of Wegovy, and those who continued it lost an additional 7.9% over 48 weeks. Patients who were switched to placebo gained back 6.9%.
• Gastrointestinal side effects were common in all the trials but did not lead to a large number of discontinuations

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

• Summary
• Wegovy caused impressive weight loss in the STEP TEENS study, and its effects were greater than other drugs approved for adolescent obesity (see Qsymia and Saxenda). As expected, gastrointestinal side effects were common, and 4% of Wegovy-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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• Overview
• HFpEF is a syndrome where patients with an ejection fraction ≥ 45% experience symptoms of heart failure (e.g., dyspnea, fluid retention, fatigue). It is believed to occur secondary to impaired left ventricular relaxation during diastole. HFpEF is notoriously hard to treat, and currently, only two drugs, the SGLT2 inhibitors dapagliflozin and empagliflozin, have received HFpEF indications. The STEP-HFpEF trial detailed below compared semaglutide to placebo in obese patients with HFpEF.

• AHA recommendations
• See HFpEF treatment recommendations

• Summary
• Semaglutide improved HFpEF symptoms in the STEP-HF trial, which is unsurprising given that intentional, significant weight loss improves almost any cardiac outcome. In their discussion, the authors note that the difference in KCCQ-CSS improvement between semaglutide and placebo (8 points) was much greater than that seen in trials with other agents, including SGLT2 inhibitors, Entresto, and spironolactone (typically 0.5 - 2.3 points). SGLT2 inhibitor trials were longer and primarily focused on cardiovascular outcomes (e.g., heart failure hospitalization, cardiovascular death), whereas STEP-HF evaluated symptoms and weight loss.

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• Overview
• The SELECT trial below evaluated the effects of semaglutide on the secondary prevention of cardiovascular disease in nondiabetics

• AHA recommendations
• See coronary artery disease secondary prevention and stroke secondary prevention

• Summary
• The SELECT trial found that semaglutide improved cardiovascular outcomes among patients with established CVD, which is unsurprising given the positive effects weight loss has on a person's health. The absolute risk reductions were small, only 1.5% (6.5% vs 8%) for the composite outcome and 0.9% (4.3% vs 5.2%) for overall mortality, but the enormous size of the trial (N=17,604) caused them to come back significant. The number needed to treat to prevent one composite event is 67, and one death is 111. Semaglutide-treated patients lost an average of 9.4% of their body weight over two years, while 17% discontinued the drug because of side effects.

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• Gastrointestinal (GI) side effects
• Gastrointestinal complaints are the most common side effects of Wegovy. To help prevent these issues, Wegovy is started at a low dose and titrated gradually. Incidences of GI complaints from Wegovy trials are presented in the table below.

• 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 known hypersensitivity to semaglutide and use caution in patients with a history of reactions to other GLP-1 analogs

• Semaglutide antibodies
• Semaglutide can induce an immune response that leads to the production of anti-semaglutide antibodies, and in some cases, these 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 these 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). There is limited data on the use of Wegovy in patients with a history of pancreatitis, and it is unknown if these patients are at increased risk of Wegovy-induced pancreatitis. If symptoms of pancreatitis occur (e.g., abdominal pain, nausea, vomiting), discontinue Wegovy and initiate appropriate care.

• Decreased kidney function
• There have been case reports of decreased kidney function in patients receiving semaglutide. In most cases, patients were experiencing GI side effects of semaglutide (e.g. nausea, vomiting, and/or diarrhea) that can lead to dehydration and worsening kidney function.
• Use caution in patients with renal impairment, and monitor renal function in patients experiencing significant GI reactions

• Hypotension and syncope
• GI side effects from Wegovy can lead to dehydration and low blood pressure. In trials, hypotensive events were reported in 1.3% of Wegovy-treated patients and 0.4% of placebo-treated patients, and syncope occurred 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 type 2 diabetic trials, 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 baseline diabetic retinopathy may be at greater risk for worsening and should be monitored appropriately. The long-term effects of semaglutide 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. On 1/11/2024, the FDA issued a communication stating that after a review of clinical trial data, they have not found an association between GLP drugs and suicidal behavior or thoughts. Their review is ongoing. FDA Safety Communication

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• 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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• 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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• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).

• 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 drug absorption occurs. GLP-1 analogs slow the process of gastric emptying, potentially altering 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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• 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

• Storage
• Keep pens refrigerated. Do not freeze.
• Prior to cap removal, pens may be kept at room temperature for up to 28 days.

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• The first GLP-1 analog (exenatide) was FDA-approved in 2005. When used appropriately, GLP-1 analogs have a good safety record.

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