What are the potential side effects and management strategies for a patient with type 2 diabetes or obesity considering Ozempic (semaglutide) therapy, particularly those with a history of pancreatitis, impaired renal function, or thyroid disease?

Ozempic (Semaglutide) Side Effects

Most Common Side Effects

Gastrointestinal symptoms are the predominant side effects of Ozempic, occurring in the majority of patients but typically being dose-dependent, transient, and most pronounced during initial treatment or dose escalation. 1

Gastrointestinal Effects

• Nausea occurs in 18-40% of patients, representing the most frequent adverse effect 1
• Diarrhea affects 12% of patients and is functional in nature, typically improving with continued use or dose adjustment 1, 2
• Vomiting occurs in 8-16% of patients 1
• Constipation, abdominal pain, and esophageal reflux are also common, with reflux resulting from delayed gastric emptying 1, 3
• Slow dose titration starting at 0.25 mg weekly for 4 weeks minimizes these gastrointestinal side effects, which are the primary reason for treatment discontinuation 1, 4

Management Strategies for GI Side Effects

• Reduce meal size and limit alcohol and carbonated drinks to manage nausea and reflux symptoms 1
• Avoid high-fat diets to help with constipation 1
• If more than 2 consecutive doses are missed and the patient previously tolerated the medication well, resume at the same dose; however, if 3 or more consecutive doses are missed, restart the titration schedule 1

Serious Adverse Events

Ozempic carries a 38% higher risk of serious adverse events compared to placebo (95% CI 1.10-1.73), including pancreatitis, gallbladder disease, acute myocardial infarction, and acute kidney injury. 1

Pancreatitis

• Acute pancreatitis has been reported in clinical trials, though causality remains unestablished 1, 3
• Ozempic has not been studied in patients with a history of pancreatitis; consider other antidiabetic therapies in these patients 3, 4
• Monitor for persistent severe abdominal pain, which may indicate pancreatitis 1

Gallbladder Disease

• Increased risk of cholelithiasis (gallstones) and cholecystitis requires monitoring 1, 3
• The mechanism relates to rapid weight loss and altered bile composition 1
• Monitor for gallbladder disease symptoms periodically 1

Renal Complications

• Acute kidney injury and worsening chronic renal failure can occur, particularly from dehydration secondary to severe gastrointestinal effects 1
• Monitor renal function closely when initiating or escalating doses, especially in patients with pre-existing kidney disease 1, 5
• Ensure adequate fluid intake to prevent dehydration-related kidney injury 1
• Initial eGFR decline occurs from baseline to week 12-16, then plateaus; overall eGFR decline is similar to placebo by end of treatment 5

Absolute Contraindications

Ozempic is absolutely contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). 1, 3, 4

Thyroid Cancer Risk

• In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures 3
• It is unknown whether Ozempic causes thyroid C-cell tumors in humans, as human relevance has not been determined 3
• Counsel patients regarding symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness) 3
• Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early detection of MTC 3

Other Contraindications

• Pregnancy and breastfeeding are absolute contraindications 1
• Known hypersensitivity to semaglutide or any product components 3

Special Populations Requiring Caution

Patients with Impaired Renal Function

• Semaglutide can be used with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²), unlike exenatide which is contraindicated 1
• No dose adjustment is required across all stages of CKD 1
• Careful monitoring for gastrointestinal side effects that could lead to dehydration is essential 1
• Semaglutide reduces albuminuria and slows eGFR decline, with greater UACR reductions in patients with pre-existing microalbuminuria or macroalbuminuria 5

Patients with Gastroparesis

• Semaglutide is not recommended in patients with clinically meaningful gastroparesis, as it delays gastric emptying and may worsen symptoms 1
• Patients with severe gastroparesis may experience worsened symptoms due to delayed gastric emptying 1

Patients with Diabetic Retinopathy

• Patients with a history of diabetic retinopathy should be monitored closely for progression due to increased risk of diabetic retinopathy complications 1

Patients on Insulin or Sulfonylureas

• Risk of hypoglycemia increases when semaglutide is used with insulin or insulin secretagogues; dose reduction of these medications is required 1, 3
• When combined with insulin, reduce basal insulin by 20% at initiation to prevent hypoglycemia 1

Cardiovascular Considerations

Despite the 38% higher risk of serious adverse events, semaglutide demonstrates significant cardiovascular benefits in appropriate populations. 1

• In the SUSTAIN-6 trial, major cardiovascular events occurred in 6.6% of semaglutide patients compared with 8.9% of placebo patients (HR 0.74,95% CI 0.58-0.95) 1
• Semaglutide reduces the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 26% in patients with type 2 diabetes and established cardiovascular disease 1
• Monitor for elevated heart rate, which is a common side effect 1

Other Notable Side Effects

• Injection site reactions occur with subcutaneous administration 1
• Insomnia has been reported as a potential side effect 1
• Suicidal ideation has been reported in clinical trials 1
• Severe allergic reactions are possible 1

Drug Interactions and Absorption Issues

• Semaglutide delays gastric emptying, which may affect absorption of concomitantly administered oral medications, particularly those with narrow therapeutic index like warfarin 1
• For oral hormonal contraceptive users, switch to non-oral contraception or add barrier method for 4 weeks after initiation and each dose escalation due to potential reduced efficacy from delayed gastric emptying 1

Monitoring Recommendations

Establish a structured monitoring schedule to detect complications early. 1

• Assess efficacy and safety at least monthly for the first 3 months, then at least quarterly thereafter 1
• Monitor renal function, especially with severe GI symptoms 1
• Check for signs of gallbladder disease periodically 1
• Monitor blood pressure as weight loss may necessitate antihypertensive medication adjustment 1
• Regular monitoring of gastrointestinal symptoms and signs of pancreatitis is advised 1

Critical Pitfalls to Avoid

• Do not prescribe to patients without documenting absence of personal or family history of MTC or MEN 2 2
• Do not measure pancreatic lipase, amylase, or calcitonin levels routinely before initiation, as these are not standard screening tests despite being important for detecting complications 2
• Do not combine with other GLP-1 receptor agonists or DPP-4 inhibitors 1
• Do not use in type 1 diabetes or diabetic ketoacidosis, as it would not be effective 3