Semaglutide, Weight Loss

Semaglutide for Weight Loss

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is approved by the US Food and Drug Administration (FDA) as 3 separate brand name medications—Ozempic®, Wegovy®, and Rybelsus®. Each brand name comes with its own associated indications, preparations, and dosages to consider. Due to the increased complexity involved, special attention is necessary for every FDA-approved indication and current off-label use.

FDA-Approved Indication

Ozempic® injection: This brand is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. This injection also provides an additional indication of reducing the risk of major adverse cardiovascular events, such as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, in patients with and without T2DM and established cardiovascular disease.

Wegovy® injection: In a recent development, semaglutide received FDA approval as an adjunct under the brand name Wegovy® for promoting weight loss in individuals dealing with obesity and overweight. Wegovy® injection is used in combination with a reduced-calorie diet and increased physical activity for long-term weight management in adults with obesity., defined by an initial body mass index (BMI) of 30 kg/m² or higher. This injection is also approved for those who are overweight, with a BMI of 27 kg/m² or higher, in the presence of at least a weight-related comorbid condition such as hypertension, T2DM, or dyslipidemia. The FDA has also approved its use for pediatric patients aged 12 and older with an initial BMI at or above the 95th percentile for their age and sex.

T2DM and reduction of major cardiovascular events: The SUSTAIN clinical trials have exhibited favorable outcomes in reducing hemoglobin A1C (HbA1c) in patients with T2DM through the weekly subcutaneous semaglutide brand name Ozempic®. These trials compared semaglutide injection to placebo (SUSTAIN 1), sitagliptin (SUSTAIN 2), exenatide extended-release (SUSTAIN 3), daily insulin glargine with metformin and/or a sulfonylurea (SUSTAIN 4), and basal insulin with or without metformin (SUSTAIN 5).[1][2][3][4][5] Each trial demonstrated statistically significant reductions in HbA1c with semaglutide.

Upon further examination of signals indicating cardiovascular benefits identified in the first 5 SUSTAIN trials, the SUSTAIN 6 trial examined the effects of semaglutide (Ozempic®) versus placebo over 2 years on a composite outcome comprising cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. [6] The estimated hazard ratio for the time-to-first event of the composite outcome was 0.74 (95% CI; 0.58-0.95), indicating the superiority of semaglutide (Ozempic®) over placebo.

Following the positive findings from the SUSTAIN clinical trial program, the FDA approved weekly subcutaneous semaglutide (Ozempic®) as an adjunct to diet and exercise for managing T2DM in adults. In addition, Ozempic® is approved for reducing the risk of major cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, in adults with T2DM and established cardiovascular disease.

The PIONEER clinical trials program has demonstrated the effectiveness of oral semaglutide (Rybelsus®) in managing T2DM compared to placebo (PIONEER 1), empagliflozin (PIONEER 2), sitagliptin with or without metformin and/or a sulfonylurea (PIONEER 3 and PIONEER 7), liraglutide (PIONEER 4), and basal insulin with or without metformin (PIONEER 8).[7][8][9][10][11][12][13] The PIONEER 6 trial examined the benefits of oral semaglutide (Rybelsus®) on the risk of major cardiovascular events similar to the aforementioned SUSTAIN 6 trial. In this trial, noninferiority with placebo was demonstrated in the composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.[14]

Based on the favorable results observed in the T2DM trials, the FDA has approved oral semaglutide (Rybelsus®) as an adjunct to diet and exercise for managing T2DM. This marks the first approval of an oral GLP-1 receptor agonist for T2DM management. Unlike injectable semaglutide (Ozempic®), oral semaglutide (Rybelsus®) does not decrease major cardiovascular events.

Chronic weight management: The Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial program meticulously investigated the effects of weekly subcutaneous Semaglutide under the brand name Wegovy®on weight loss in adult patients with obesity (BMI ≥30 kg/m2) or in patients who are overweight (BMI ≥27 kg/m2) with comorbidities.[15][16][17][18][19] Following the positive outcomes observed in the 4 STEP trials (STEPs 1, 2, 3, and 4), the FDA has approved the use of 2.4 mg weekly subcutaneous semaglutide for chronic weight management in adult patients with obesity and in patients who are overweight with at least 1 weight-related condition, such as hypertension, T2DM, or dyslipidemia.

The recommended approach for weight management includes the integration of semaglutide with a balanced diet and regular exercise. Another active comparator trial, the STEP 8 trial, compared subcutaneous weekly semaglutide (Wegovy®) to subcutaneous daily liraglutide, revealing semaglutide's superiority in the primary outcome of mean percentage change in body weight.[20]

The STEP TEENS trial examined the efficacy and safety of semaglutide (Wegovy®) compared to placebo in adolescents aged 12 to less than 18 with obesity. This trial revealed that subcutaneous semaglutide (Wegovy®) at a dosage of 2.4 mg weekly, along with lifestyle interventions, provided superior reductions in BMI in adolescents than placebo and lifestyle interventions.[21]

Off-Label Uses

The FDA has approved using semaglutide for weight loss, marketed under the brand name Wegovy®. The recommended standard maintenance dosage for weight management is 2.4 mg, administered through weekly subcutaneous self-injections. With growing interest in semaglutide for weight control, healthcare professionals are responding to the demand by occasionally prescribing alternative brands of semaglutide, such as Ozempic® and Rybelsus®, for off-label use (using a drug approved by the FDA for a different purpose). Differences in insurance coverage between Wegovy® versus Ozempic® and Rybelsus® may also fuel this off-label use.

The FDA issued a postmarket drug safety alert regarding the prevalence of compounded and counterfeit preparations of semaglutide. The increasing popularity of semaglutide for weight loss is a driving force behind compounded and counterfeit preparations. The healthcare team should advise patients that they "should only obtain drugs containing semaglutide with a prescription from a licensed health care provider, and obtain medicines only from state-licensed pharmacies or outsourcing facilities registered with FDA."

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Mechanism of Action

Semaglutide operates as a GLP-1 receptor agonist, sharing a remarkable 94% structural homology with human GLP.[22]. The mechanisms through which semaglutide delivers its benefits in lowering blood glucose levels and promoting weight loss involve the activation of GLP-1 receptors primarily located in the gastrointestinal tract, pancreas, and brain.

Upon activation of the GLP-1 receptor, semaglutide enhances glucose-dependent insulin secretion, providing a physiological response to elevated blood glucose levels after a meal.[23] Simultaneously, it slows gastric emptying, increases pancreatic β-cell proliferation, and reduces glucagon release, contributing to an overall reduction in appetite.[23][24]

Furthermore, semaglutide's interaction with GLP-1 receptors in the hypothalamus may mitigate sensations of hunger, alleviate food cravings, and enhance the feelings of satiety.[25][26] These multifaceted actions contribute to the comprehensive metabolic effects of semaglutide in managing blood glucose levels and facilitating weight loss.

Semaglutide is also considered a "long-acting" GLP-1 receptor agonist, alongside extended-release exenatide and dulaglutide.[27] The extended half-life of semaglutide may be attributed to 2 structural modifications—one modification promotes albumin binding, leading to prolonged renal clearance, whereas the other shields it from metabolic degradation by the dipeptidyl peptidase-4 (DPP-4) enzyme.[27]

Pharmacokinetics

Absorption: Subcutaneous semaglutide has high bioavailability (89%), with peak concentration achieved within 1 to 3 days of initiation.[28] Achieving steady-state exposure typically occurs after 4 to 5 weeks of weekly administration, demonstrating a proportional increase with escalating doses up to 2.4 mg.

Due to the high homology to human GLP-1 peptide, oral semaglutide possesses properties inherent to peptide-like compounds. These include high molecular weight, susceptibility to enzymatic degradation, hydrophilicity, and low permeability, resulting in minimal bioavailability of approximately 0.01%.[29][30][31][32][31] To address this limitation, an absorption enhancer called sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) is incorporated, enhancing the transcellular absorption of oral semaglutide across the gastric mucosa.[29] The commercially available oral semaglutide exhibits an improved, although still minimal, bioavailability range of 0.4% to 1%.[33] Gastric fluid composition, influenced by food and increased water volumes, significantly affects oral semaglutide absorption.[29][34]

After oral administration, the maximum concentration of semaglutide is typically reached within 1 hour post-dose. Steady-state exposure is typically achieved after 4 to 5 weeks of daily administration.[35]

Distribution: Following subcutaneous administration, the mean apparent volume of distribution for semaglutide is approximately 12.5 L.[36] In healthy subjects, the volume of distribution is approximately 8 L following oral administration.[35]

Metabolism: Semaglutide undergoes metabolism through the proteolytic cleavage of the peptide backbone, followed by sequential β-oxidation of the fatty acid sidechain.[37]

Elimination: Both oral and subcutaneous semaglutide have an elimination half-life of approximately 1 week, remaining in circulation for about 5 weeks after the last dose. The clearance of subcutaneous semaglutide in individuals with T2DM or obesity or those who are overweight is approximately 0.05 L/h. In comparison, the clearance of oral semaglutide in healthy subjects is approximately 0.04 L/h.[35][36] Semaglutide is primarily eliminated in the urine (3% as an unchanged drug) and feces.[35][38]

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Administration

The injection formulations should be administered subcutaneously into the abdomen, thigh, or upper arm. Patients should be advised to rotate injection sites within the same body region (eg, upper arm) to avoid injecting in the same spot each week. Although insulin and semaglutide injections may be administered in the same body region, patients should be cautioned against using the same injection site. Mixing semaglutide injection and insulin directly is not recommended, and it is essential to follow dose escalation instructions diligently to reduce the risk of gastrointestinal adverse events.

Available Dosage Forms

The available dosage forms for semaglutide include subcutaneous injections, such as Ozempic® and Wegovy®, and oral tablets, such as Rybelsus®.

Available Strengths

Available strengths of Ozempic® as prefilled multidose injection pens include 2 mg/3 mL (3 mL), 4 mg/3 mL (3 mL), and 8 mg/3 mL (3 mL).

Available strengths for Wegovy® as prefilled single-dose injection pens include 0.25 mg/0.5 mL (0.5 mL), 0.5 mg/0.5 mL (0.5 mL), 1 mg/0.5 mL (0.5 mL), 1.7 mg/0.75 mL (0.75 mL) and 2.4 mg/0.75 mL (0.75 mL).

Available strengths for Rybelsus® as oral tablets include 3 mg, 7 mg, and 14 mg.

Adult Dosage

Subcutaneous semaglutide for T2DM or reduction of cardiovascular mortality Ozempic®

Semaglutide naive: For semaglutide-naive patients, the recommended dosing regimen starts with 0.25 mg weekly for 4 weeks, followed by a dose escalation to 0.5 mg weekly.
- The 0.5-mg weekly dosage can be escalated to 1 mg weekly if glycemic control is inadequate after 4 weeks on the 0.5 mg/week dosage. Furthermore, the 1-mg weekly dosage can be further escalated to 2 mg weekly, which may occur after 4 weeks to achieve glycemic goals. The maximum recommended dosage is 2 mg weekly.

Converting from oral semaglutide Rybelsus® 14 mg PO daily: When converting from oral semaglutide Rybelsus® 14 mg taken PO daily, the recommended approach is to initiate a dosage of 0.5 mg subcutaneously once weekly starting the day after the final oral dose.

Converting from oral semaglutide Rybelsus® 7 mg PO daily: When transitioning from oral semaglutide Rybelsus® 7 mg taken PO daily, as there is no equivalent oral dose provided in the FDA package insert, one may consider initiating a weekly subcutaneous dose of 0.5 mg beginning the day following the final oral administration.

Special considerations for subcutaneous semaglutide Ozempic®

If a dose of weekly subcutaneous semaglutide is missed, it should be administered promptly within 5 days, and then the regular schedule should be resumed. If more than 5 days have passed, the missed dose can be skipped, and administration can be resumed at the next scheduled weekly dose.

When changing the weekly subcutaneous semaglutide administration day, ensuring a minimum of 48 hours between 2 consecutive doses is essential.

Blood glucose should be closely monitored when converting to or from oral semaglutide.

Oral semaglutide for T2DM Rybelsus®

Semaglutide-naive: For individuals who are semaglutide-naive, the recommended starting dose is 3 mg daily for 30 days, followed by an increase to 7 mg daily. After 30 days on the 7 mg dose, patients may consider escalating to 14 mg daily to achieve their glycemic goals.

Converting from semaglutide injection Ozempic® 0.5 mg weekly: When transitioning from semaglutide injection Ozempic® 0.5 mg weekly, one may consider switching to either 7 mg or 14 mg taken PO daily for up to 7 days after the last injection. No equivalent dose exists for the 1 mg subcutaneous weekly dosing of Ozempic®.

Special considerations for oral semaglutide Rybelsus®

If a dose of oral semaglutide is missed, the individual should skip the missed dose and resume with the next scheduled dose.

To ensure optimal absorption of oral semaglutide, it should be administered at least 30 minutes before the first consumption of food, beverages, or other medications of the day. The medication should be ingested with no more than 4 ounces (120 mL) of water. The lower initial dose for both weekly subcutaneous semaglutide and daily oral semaglutide aims to mitigate gastrointestinal symptoms.

When individuals convert to or from oral semaglutide, monitoring their blood glucose levels closely is crucial.

Subcutaneous semaglutide for chronic weight management Wegovy®

For chronic weight management with subcutaneous semaglutide (Wegovy®), it is necessary to follow the following steps:

Wegovy® dosage should be administered 0.25 mg weekly for the first 4 weeks.

Wegovy® dosage should be increased to 0.5 mg weekly for weeks 5 through 8.

Wegovy® dosage should be further increased to 1 mg weekly for weeks 9 through 12.

Wegovy® dosage should be further progressed to 1.7 mg weekly for weeks 13 through 16.

Finally, Wegovy® should be maintained at a dosage of 2.4 mg weekly thereafter.

Special considerations for subcutaneous semaglutide (Wegovy®)

If patients experience difficulty with a dosage increase, healthcare providers should consider postponing the increase for an additional 4 weeks.

If the 2.4 mg weekly dosage is not well tolerated, healthcare providers may consider reducing the dose to 1.7 mg weekly for a maximum of 4 weeks. After this period, the dosage should be increased to 2.4 mg weekly. If the patient continues to experience intolerance, discontinuing semaglutide (Wegovy®) should be considered.

If a dose is missed and the next scheduled dose is more than 2 days away (48 hours), it should be administered as soon as possible. However, if a dose is missed and the next scheduled dose is less than 2 days away (48 hours), it should not be administered. In such cases, the patient should resume dosing on the regularly scheduled day of the week.

If 2 or more consecutive doses are missed, the patient should resume dosing as scheduled. If necessary, they may reinitiate and follow the dose escalation schedule, which may help reduce the occurrence of gastrointestinal symptoms associated with restarting treatment.

Specific Patient Populations

Hepatic impairment: No dosage adjustment is needed for subcutaneous or oral semaglutide in patients with hepatic impairment.[39][40]

Renal impairment: No dosage adjustment is necessary for subcutaneous or oral semaglutide in mild-to-severe impairment.[37][41] Caution should be exercised when initiating or escalating doses.

The manufacturer advises against adjusting the dosage of subcutaneous and oral Semaglutide for patients undergoing three or more weekly hemodialysis sessions. However, due to limited clinical evidence, caution is advised. Furthermore, the manufacturer recommends against adjusting the subcutaneous and oral semaglutide dosage for patients undergoing peritoneal dialysis. Again, caution is advised due to limited clinical evidence.

Pregnancy considerations: Current clinical trial data and pharmacovigilance reports on semaglutide use in pregnant women are insufficient to ascertain its association with significant congenital defects, miscarriage, or adverse outcomes for both the mother and the fetus. However, findings from animal reproduction studies indicate potential risks to the fetus with semaglutide exposure during pregnancy. In addition, the weight loss effects of semaglutide are not deemed beneficial for pregnant individuals and may pose a risk of harm to the fetus. As a result, the manufacturer recommends against the use of semaglutide during pregnancy due to the potential fetal risks.

For the management of diabetes mellitus or weight loss, discontinuation of semaglutide is advised for a minimum of 2 months before attempting to conceive. According to the 2021 guidelines from the American College of Obstetricians and Gynecologists (ACOG), weight loss medications are not recommended at conception.[42]

Breastfeeding considerations: Insufficient data exist regarding semaglutide or its metabolites in human milk and the potential effects on breastfed infants and milk production. Semaglutide was identified in milk at levels 3 to 12 times lower than in maternal plasma in lactating rats. Although information on the impact of semaglutide in human milk is unavailable, it may be present in human milk if present in animal milk. The decision to use injectable semaglutide while breastfeeding should carefully consider the potential risk of infant exposure versus the benefits of breastfeeding.

Regarding the oral formulation containing SNAC, it is unclear whether SNAC is excreted in breast milk. Due to this uncertainty, oral semaglutide is not recommended during breastfeeding, as the unknown risk of SNAC accumulation in infants is a concern.

Pediatric patients: The safety and efficacy of subcutaneous semaglutide (Ozempic®) and oral semaglutide (Rybelsus®) have not been established in individuals aged 18 or younger. However, Wegovy®, specifically indicated for weight loss, is approved for use in pediatric patients aged 12 and older with a BMI corresponding to ≥95th percentile standardized for age and sex. This approval is based on a 68-week, double-blind, placebo-controlled clinical trial (STEP TEENS) involving 201 pediatric patients aged 12 and older with a BMI corresponding to ≥95th percentile for age and sex.[21]

The approved dosage for chronic weight management in the pediatric and adolescent age groups of ≥12 and ≤18 is similar to the adult dosing outlined earlier, with the following exceptions:

If patients do not tolerate the 2.4 mg weekly, the maintenance dosage may be reduced to 1.7 mg indefinitely.

If the 1.7 mg weekly dose is not tolerated, semaglutide should be discontinued.

Notably, cholelithiasis, cholecystitis, hypotension, rash, and urticaria were more prevalent in this younger age group than in adults treated with Wegovy®. Meticulous attention to the dose escalation strategy may help mitigate the incidence of adverse events.

Older patients: No overall differences in safety and efficacy have been observed in patients aged 65 and older.

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Adverse Effects

Adverse Drug Reactions

Adverse drug reactions caused by semaglutide are listed below.

Hypoglycemia: GLP-1 agonists lower blood glucose and may cause hypoglycemia. The risk of hypoglycemia significantly increases with escalating doses and when semaglutide is administered with other anti-hyperglycemic medications such as sulfonylureas, metformin, or insulin.

Gastrointestinal: The adverse effects most frequently reported and most associated with discontinuation of semaglutide include nausea, vomiting, abdominal pain, constipation, and diarrhea.[43] Nearly one-fifth of all patients in clinical trials with Ozempic® and Rybelsus® experienced nausea, which is the most prevalent adverse effect, whereas 44% of patients treated with Wegovy® reported the same adverse effects. In addition, decreased appetite, dysgeusia, and dyspepsia have been documented. Although the precise mechanism behind these effects is not entirely elucidated, it may stem from delayed gastric emptying or the activation of brain centers implicated in appetite regulation, satiety, and nausea.[44] Higher doses and dose escalations are associated with the risk of these adverse effects.

Renal: Semaglutide can result in acute kidney injury. Patients who experienced nausea, vomiting, diarrhea, or dehydration during the treatment were at the highest risk of acute kidney injury, with volume depletion being the suspected link. Discontinuation or dose reduction of semaglutide is recommended rather than relying solely on symptomatic treatment of volume depletion.

Gallbladder disorders: Semaglutide has been associated with gallbladder and biliary tract issues, including cholelithiasis and cholecystitis.[45] The exact mechanism behind this adverse effect is not entirely understood. Animal studies and in vitro data suggest that GLP-1 enhances cholangiocyte proliferation and functional activity, which could contribute to gallbladder diseases.[46] Some authors have proposed that semaglutide can potentially suppress cholecystokinin secretion, reduce gallbladder emptying, and prolong gallbladder refilling, or a combination of these factors contributing to gallbladder disease.[47]

Anaphylaxis and angioedema: GLP-1 receptor agonists (GLP-1 RAs) can induce severe type 1 hypersensitivity reactions, such as anaphylaxis and angioedema.[48][49] A possibility of cross-reactivity among different GLP-1 receptor agonists exists. Therefore, caution is advised when prescribing semaglutide to patients with a history of anaphylaxis or angioedema in response to other GLP-1 receptor agonists, pending further studies.

Pancreatitis: Although cases of acute pancreatitis have been associated with semaglutide use, findings from the SUSTAIN 6 trial indicate a similar incidence rate of pancreatitis with semaglutide compared to the placebo group.[6]The causal relationship between semaglutide and acute pancreatitis has not been definitively established. GLP-1 receptor agonists directly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells. Researchers suggest that this stimulation may lead to the overgrowth of cells covering smaller ducts, causing hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic inflammation.[50]

Diabetic retinopathy: Semaglutide use may potentially elevate the risk of diabetic retinopathy, particularly in patients with retinopathy at baseline. The exact relationship between semaglutide and the development or exacerbation of diabetic retinopathy remains incompletely understood. However, it may be associated with rapid improvements in glucose control, as identified in other studies.[51]

Risk of thyroid C-cell tumors: During the initial phases of drug development, animal studies involving semaglutide revealed the development of thyroid C-cell tumors. However, the potential association between semaglutide and thyroid cancers in humans remains unclear. Individuals with a personal or family history of medullary thyroid carcinoma (MTC) or those diagnosed with multiple endocrine neoplasia type 2 (MEN 2) syndrome may face an elevated risk. The manufacturer acknowledges reported cases of MTC associated with liraglutide, which is another GLP-1 receptor agonist.

Additional adverse reactions: Other reported adverse reactions associated with semaglutide include fatigue, headache, rash, alopecia, vitreous hemorrhage in patients with diabetic retinopathy, anxiety, dizziness, discomfort at the injection site, and erythema at the injection site.

Drug-Drug Interactions

Semaglutide causes a delay in gastric emptying, which may lead to delayed absorption of concurrently administered oral medications. However, clinical pharmacology trials with subcutaneously administered semaglutide have demonstrated no significant impact on the absorption of orally administered medications. Nonetheless, cautious monitoring of the effects of oral medications is recommended when used concurrently with semaglutide, especially those with a narrow therapeutic window.

When semaglutide is used alongside other blood-glucose-lowering agents, there is a notable risk of hypoglycemia.

Semaglutide should not be used with other GLP-1 receptor agonists or tirzepatide, as they are contraindicated.

When semaglutide is administered alongside insulins or insulin secretagogues, such as sulfonylureas, it is recommended to consider reducing the dosage of these medications to mitigate the risk of hypoglycemia.

Medications that have the potential to augment the hypoglycemic effects of semaglutide include beta-blockers, monoamine oxidase inhibitors, androgens, quinolones, salicylates, selective serotonin reuptake inhibitors, and other antidiabetic medications.

Medications that may diminish the therapeutic effects of semaglutide include furosemide, thiazide diuretics, and ritodrine.

Semaglutide may increase the serum concentrations of levothyroxine.

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Contraindications

Box Warning

Semaglutide has been shown to induce dose-dependent and treatment-duration–dependent thyroid C-cell tumors in rodents. However, it remains uncertain whether semaglutide poses a similar risk of cancer in humans. This aspect may become more apparent as more data on this medication become available over the next few years. Given this potential risk, semaglutide is contraindicated in patients with a personal or family history of MTC or MEN 2 syndrome. Patients prescribed semaglutide should receive counseling regarding the potential risk of thyroid cancers.

Precautions

Suicidal behavior has been reported with other medications prescribed for weight management. Therefore, it is advisable to avoid the use of Semaglutide in individuals with a history of suicidal attempts or current suicidal ideation. Patients with suicidal ideations should seek immediate assistance.

Semaglutide can potentially slow gastric emptying and impede the absorption of other medications.

The multiple-dose injection pen (Ozempic®) should not be shared among individuals to mitigate the risk of infection transmitting infections.

Semaglutide is contraindicated in patients with type 1 diabetes.

As the effectiveness of semaglutide in combination with other weight loss medications is not established, concurrent use of this drug with other weight loss medications should be avoided.

Patients with a history of bariatric surgery face an increased risk of gastrointestinal complications when using semaglutide. Therefore, regular monitoring for such complications is recommended.

If the medication is discontinued after attaining weight loss, a risk of rebound weight gain exists. This was demonstrated in an extension of the STEP 1 trial, where participants, after discontinuing weekly subcutaneous semaglutide 2.4 mg and lifestyle interventions for 1 year, experienced a regain of approximately two-thirds of their initial weight loss.[52]

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Monitoring

Before initiating and periodically during treatment with either oral or subcutaneously administered semaglutide, patients should receive counseling regarding potential adverse effects or complications. They should also be instructed to report any concerns to their healthcare providers promptly.

Monitoring for complications should be conducted collaboratively by the patient and their clinician, focusing on the following aspects:

Vigilance for hypoglycemia is essential, especially when semaglutide is used with other glucose-lowering agents.

Due to a heightened risk of gastrointestinal adverse effects such as nausea, vomiting, diarrhea, and constipation, close monitoring of patients for these adverse reactions is essential, with meticulous adherence to dose escalation.

Dehydration resulting from gastrointestinal adverse effects poses a potential risk of renal failure. Therefore, monitoring renal function is paramount, especially in individuals experiencing gastrointestinal adverse effects.

Healthcare providers should assess the risk of gallbladder or ductal disease and pancreatitis in patients using semaglutide who exhibit characteristic signs or symptoms.

A potential risk of diabetic retinopathy complications underscores the importance of monitoring for any changes in vision and providing exceptional care to patients with baseline retinopathy.

Although the risk of thyroid tumors in humans remains unclear, patients and healthcare providers should remain vigilant for the development of any signs, such as a neck lump, hoarseness, dyspnea, or dysphagia while on semaglutide.

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Toxicity

Signs and Symptoms of Overdose

Overdose with oral or subcutaneous semaglutide can cause severe nausea, vomiting, and hypoglycemia.

Oral semaglutide is often co-administered with SNAC to increase gastric absorbability. Animal studies have indicated that higher SNAC exposure can result in lethargy, abnormal respiration, ataxia, and reduced activity.

Management of Overdose

In case of an overdose with oral or subcutaneous semaglutide, management involves implementing suitable supportive measures according to observed signs and symptoms. Consultation with poison control or a toxicologist is recommended. Due to the long half-life of semaglutide, an extended period of observation and treatment may be necessary.

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Enhancing Healthcare Team Outcomes

The collaborative efforts of the healthcare team, including the physician or advanced practice clinician, pharmacist, dietitian, and nurse, are essential for achieving optimal outcomes in managing T2DM, reducing cardiovascular death, or facilitating weight loss with semaglutide treatment. Effective communication and collaboration among team members are fundamental for reaching treatment goals. As the comprehensive benefits of semaglutide are intricately linked to lifestyle modifications, dietitians are crucial in providing tailored recommendations for glucose-lowering, cardiovascular protection, and weight loss.

The gradual dose escalation of semaglutide and the potential for increased adverse effects at higher doses emphasize the importance of proactive counseling by the healthcare team, including the patient's pharmacist. Close monitoring of the patient ensures adherence to the appropriate dose and facilitates early detection of adverse effects. Pharmacists and nurses, in particular, play crucial roles in promptly reporting any observed adverse effects to the physician, who can then consider necessary interventions such as dosage adjustments or discontinuation of the drug based on the severity of the adverse effects. Pharmacists can also identify potential drug-drug interactions and collaborate with the treating physician. This collective approach, involving each team member's expertise, enhances patient outcomes in semaglutide treatment.

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Review Questions

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References

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Ahrén B, Masmiquel L, Kumar H, Sargin M, Karsbøl JD, Jacobsen SH, Chow F. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017 May;5(5):341-354. [PubMed]

Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care. 2018 Feb;41(2):258-266.[PubMed]

Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, Rowe E, DeVries JH. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017 May;5(5):355-366. [PubMed]

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Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzík M., PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1724-1732. [PubMed]

Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SØ, Lingvay I, Søndergaard AL, Treppendahl MB, Montanya E., PIONEER 2 Investigators. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019 Dec;42(12):2272-2281. [PubMed]

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