Unveiling the Therapeutic Potential of the Second-Generation Incretin Analogs Semaglutide and Tirzepatide in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

Abstract

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells, resulting in the lifelong need for exogenous insulin. Over the last few years, overweight and obesity have recently emerged as growing health issues also afflicting patients with T1D. In this context, the term "double diabetes" has been coined to indicate patients with T1D who have a family history of type 2 diabetes mellitus (T2D) and/or patients with T1D who are affected by insulin resistance and/or overweight/obesity and/or metabolic syndrome. At the same time, the use of second-generation incretin analogs semaglutide and tirzepatide has substantially increased on a global scale over the last few years, given the remarkable clinical benefits of these drugs (in terms of glucose control and weight loss) in patients with T2D and/or overweight/obesity. Although the glucagon-like peptide-1 (GLP-1) receptor agonists and the novel dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 receptor agonist tirzepatide are currently not approved for the treatment of T1D, a growing body of evidence over the last few years has shown that these medications may serve as valid add-on treatments to insulin with substantial efficacy in improving glucose control, promoting weight loss, preserving residual beta-cell function and providing other beneficial metabolic effects in patients with T1D, double diabetes and latent autoimmune diabetes in adults (LADA). This manuscript aims to comprehensively review the currently available literature (mostly consisting of real-world studies) regarding the safety and therapeutic use (for different purposes) of semaglutide and tirzepatide in patients with T1D (at different stages of the disease), double diabetes and LADA.

Keywords: C-peptide; GIP; GLP-1; LADA; T1D; autoimmune diabetes; beta-cell function; double diabetes; obesity; overweight; semaglutide; tirzepatide; type 1 diabetes.

Figure 1

Potential and established benefits of the novel incretin analogs semaglutide and tirzepatide in patients with T1D (at different stages of the disease), LADA and double diabetes associated with overweight/obesity. Abbreviations: AID, automated insulin delivery; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; IR, insulin resistance; LADA, latent autoimmune diabetes in adults; MetS, metabolic syndrome; OB, obesity; OW, overweight; RA, receptor agonist; T1D, type 1 diabetes; TAR, time above range; TDD, total daily dose; TIR, time in range.

Figure 2

Vicious cycle of weight gain, insulin resistance and increased exogenous insulin requirements in patients with T1D. In patients with T1D, this perpetuating cycle leads to double diabetes, which is characterized by the coexistence of clinical features of both T1D and T2D in the same subject. Iatrogenic peripheral hyperinsulinemia during intensive exogenous insulin therapy promotes insulin resistance and weight gain. In turn, excess weight gain promotes insulin resistance, which leads to higher exogenous insulin requirements. Moreover, insulin resistance and excess weight gain due to intensive exogenous insulin therapy can increase cardiovascular risk factors (e.g., hypertension, dyslipidemia). *Iatrogenic peripheral hyperinsulinemia during intensive exogenous insulin therapy is related to subcutaneously administered exogenous insulin, which bypasses first-pass hepatic insulin extraction. Abbreviations: CV, cardiovascular; T1D, type 1 diabetes; T2D, type 2 diabetes.

Figure 3

Potential synergistic benefits of second-generation incretin analogs (semaglutide and tirzepatide) and advanced technological devices used for diabetes management in patients with T1D, double diabetes and LADA. Second-generation incretin analogs semaglutide and tirzepatide may be valid allies of the current advanced technological devices employed for the management of autoimmune diabetes (particularly AID systems) by preventing or reducing excess body weight, increasing the time spent in recommended target blood glucose range, reducing time spent in hyperglycemia, and decreasing glycemic variability, insulin resistance and insulin requirements, thus enhancing the glycemic and metabolic benefits of diabetes technological devices/AID systems. On the other hand, the currently available advanced technological devices used for the management of autoimmune diabetes (particularly AID systems), which can predict impending episodes of hypoglycemia or hyperglycemia and promptly and dynamically adjust insulin delivery, may help prevent the most dreaded adverse effects of incretin analogs in patients with autoimmune diabetes (especially hypoglycemia, DKA and euDKA). Abbreviations: AID, automated insulin delivery; CGM, continuous glucose monitoring; CKM, continuous ketone monitoring; DKA, diabetic ketoacidosis; euDKA, euglycemic diabetic ketoacidosis; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; RA, receptor agonist; TAR, time above range; TIR, time in range; T1D, type 1 diabetes.