What is the increased risk associated with Semaglutide (generic name) in patients with Type 2 Diabetes Mellitus (T2DM), Hypertension (HTN), Depression, and Obesity?

From the Guidelines

Semaglutide increases the risk of several adverse effects in patients with type 2 diabetes, hypertension, depression, and obesity, including gastrointestinal issues, pancreatitis, gallbladder disease, and acute kidney injury, as well as potential worsening of depressive symptoms or increased suicidal ideation, and hypoglycemia, particularly when used with insulin or insulin secretagogues 1. The most common side effects of semaglutide include:

• Gastrointestinal issues such as nausea, vomiting, diarrhea, and constipation
• Increased risk of pancreatitis, gallbladder disease, and acute kidney injury
• Potential risk of thyroid C-cell tumors, though this has primarily been observed in animal studies
• Potential worsening of depressive symptoms or increased suicidal ideation in some individuals, requiring careful monitoring
• Hypotension, especially when combined with other antihypertensive medications
• Hypoglycemia, particularly when used with insulin or insulin secretagogues These risks occur because semaglutide, as a GLP-1 receptor agonist, affects multiple body systems including slowing gastric emptying, influencing pancreatic function, and potentially impacting neural pathways involved in mood regulation 1. It is essential to carefully monitor patients with depression, hypertension, or those taking insulin or insulin secretagogues when prescribing semaglutide, and to consider the potential benefits and risks of treatment in each individual case 1. The American Gastroenterological Association recommends using semaglutide 2.4 mg with lifestyle modifications for the long-term treatment of obesity in adults with a BMI of 30 kg/m² or higher, or a BMI of 27 kg/m² or higher with at least one weight-related condition, due to its glucoregulatory benefits and approval for the treatment of type 2 diabetes 1.

From the FDA Drug Label

The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain The exposure of semaglutide decreases with an increase in body weight. Renal impairment does not impact the pharmacokinetics of semaglutide in a clinically relevant manner. Hepatic impairment does not have any impact on the exposure of semaglutide In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0. 3,1 and 3 mg/kg/day [5-, 17-, and 59-fold the maximum recommended human dose (MRHD) of 1 mg/week, based on AUC] were administered to the males, and 0.1,0. 3 and 1 mg/kg/day (2-, 5-, and 17-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (>2X human exposure).

The increased risk associated with Semaglutide in patients with Type 2 Diabetes Mellitus (T2DM), Hypertension (HTN), Depression, and Obesity includes:

• Thyroid C-cell tumors: There is an increased risk of thyroid C-cell tumors, including adenomas and carcinomas, as observed in animal studies 2.
• No direct information on HTN, Depression: There is no direct information in the provided drug label regarding the increased risk of semaglutide in patients with hypertension or depression.
• Obesity: The exposure of semaglutide decreases with an increase in body weight, but semaglutide doses of 0.5 mg and 1 mg provide adequate systemic exposure over the body weight range of 40-198 kg evaluated in the clinical trials 2.
• Renal and Hepatic impairment: Renal and hepatic impairment do not have a clinically meaningful effect on the pharmacokinetics of semaglutide 2.

From the Research

Increased Risk Associated with Semaglutide

The use of semaglutide in patients with Type 2 Diabetes Mellitus (T2DM), Hypertension (HTN), Depression, and Obesity is associated with several increased risks, including:

• Gastrointestinal side effects, such as nausea, vomiting, and diarrhea 3, 4
• Increased risk of biliary disease, including cholelithiasis 3
• Increased risk of diabetic retinopathy (DR) complications, particularly in patients with pre-existing DR 3, 4
• Increased risk of acute pancreatitis, as reported in a case study 5
• Potential risks of acute kidney injury, gallbladder events, and thyroid cancer, although the evidence is limited and inconclusive 3, 6
• Anesthetic risks, such as pulmonary aspiration or residual gastric content, due to delayed gastric emptying and constipation 6

Specific Risks in Patients with Comorbidities

Patients with certain comorbidities may be at increased risk of adverse events when taking semaglutide, including:

• Patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, who are contraindicated for semaglutide therapy 6
• Patients with obesity, who may experience improvements in body mass index (BMI) and weight, but may also be at increased risk of acute pancreatitis 7, 5
• Patients with type 2 diabetes, who may experience improvements in glycemic control, but may also be at increased risk of diabetic retinopathy complications 3, 4

Real-World Evidence

Real-world data analysis has shown that semaglutide is generally well-tolerated and effective in reducing BMI, body weight, and HbA1c in patients with type 2 diabetes and obesity 7. However, the magnitude of these improvements may be smaller than those observed in clinical trials. Additionally, the risk of newly diagnosed common adverse events is relatively low, approximately 1.0% of patients 7.