Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: A rapid review of randomized controlled trials and meta-analysis

Abstract

Tirzepatide, a dual agonist of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide 1 (GLP-1) receptors, improved glucose control and reduced body weight in different therapeutic approaches. Herein, we overviewed the role of GIP and GLP-1 in the pathophysiology of type 2 diabetes and systematically reviewed the efficacy and safety of injectable incretin-based therapy added to basal insulin in light of the results of the SURPASS-5 trial. We identified eleven randomized clinical trials. GLP-1 receptor agonists (GLP-1RAs) or Tirzepatide added to basal insulin than rigorously titrated basal insulin significantly ameliorates glucose control (Δ HbA_1c = -1%, 95% CI -1.25; -0.74, I² 94%; Δ FPG = -14.6 mg/dL, 95% CI -21.6-; -7.6, I² 90%; chance to achieve HbA_{1c <}7% = RR 2.62, 95% CI 2.10; 3.26, I² 89%), reduces body weight (Δ = -3.95 kg, 95% CI -5.1, -2.79, I² 96%) without increasing the risk of hypoglycemia (RR = 1.01, 95% CI 0.86; 1.18, I² 7.7%). Tirzepatide provides an impressive weight loss exceeding that observed with GLP-1RAs. Injectable incretin-based therapy plus basal insulin remains a potent and safe therapeutic approach in uncontrolled type 2 diabetes patients previously treated with basal insulin alone. Tirzepatide is expected to ameliorate the management of "diabesity" in this usually difficult-to-treat cluster of patients.

Keywords: GIP, GLP-1; basal insulin; body weight; hypoglycemia; obesity; tirzepatide; type 2 diabetes.

Figure 1

Tirzepatide primary structure. TZP is a 39-peptide containing different native and not-native incretins fragments, including GIP, GIP, GLP-1, and Extendin-4 (and glucagon, not shared). Alpha aminobutyric acid is placed in positions 2 and 13 and provides TZP an intrinsic resistance to DPP-IV attack and more structural stability, respectively. A 20-carbon fatty acid, namely eicosanedioic acid, is linked to Glu. A 2xAdo unit is attached to the lysine residue in position 20 and allows TZP to be bound to albumin, consequently increasing its half-life to five days. It is currently debated whether the acylation may also increase receptor bounding stability, hypothetically affecting the pharmacological potency of TZP.

Figure 2

The PRISMA flow diagram of included studies.

Figure 3

Quantification of the risk of bias of included studies (A, B).

Figure 4

Forest plots of meta-analysis for change in HbA_1c (A), chance of achieving optimal glucose control as HbA_1c <7% (B), and change in fasting plasma glucose (C) from baseline to the last available follow-up (intention-to-treat analyses). Forest plot of meta-analysis for change in body weight (D) from baseline to the last available follow-up (intention-to-treat analysis). Forest plot of meta-analysis for change in the mean daily dose of basal insulin (E) from baseline to the last available follow-up (intention-to-treat analysis).