GLP-1RA and Tirzepatide Discontinuation Leads to Weight Regain, Worsened Cardiometabolic Risk

Glucagon-like peptide 1 receptor (GLP1R) agonists and tirzepatide are foundational in managing type 2 diabetes mellitus (T2DM) and obesity due to their potent glycaemia-lowering, weight-lowering, and cardiorenal benefits. Despite these advantages, real-world persistence on these medications is frequently suboptimal, with many patients discontinuing therapy, often within the first year. This leads to a critical gap in understanding the specific reasons for discontinuation and, more importantly, the subsequent cardiometabolic consequences, which this review aims to address.

This review synthesizes recent real-world data concerning the discontinuation of GLP-1RAs and tirzepatide. It systematically examines common reasons cited for stopping therapy, including gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear of rare adverse effects. The authors then analyze available evidence related to the potential cardiometabolic consequences following treatment cessation. The review also discusses the long-term implications for T2DM care, weight management, and ultimately, cardiorenal disease prevention in patients with these conditions.

Discontinuation of GLP-1RAs or tirzepatide commonly leads to significant adverse cardiometabolic outcomes. Weight regain is a frequent consequence, often accompanied by the deterioration of multiple cardiometabolic risk factors. The review highlights that repeated cycles of initiation, interruption, and re-initiation of these drugs can induce fluctuations in body weight and HbA1c levels, both of which are established risk factors for cardiovascular and microvascular events. When treatment is discontinued, weight regain and the deterioration of multiple cardiometabolic risk factors are common. These phenomena, coupled with the re-development of overweight or obesity and poor glycaemic control, are likely to increase the long-term risk of complications. Furthermore, the review notes that the lack of anti-atherosclerotic and plaque-stabilizing effects of incretin-based medications might contribute to elevated cardiovascular risk, particularly acutely following their discontinuation.