Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes

Valentina Pirro; Kenneth D. Roth; Yanzhu Lin; Jill A. Willency; Paul L. Milligan; Jonathan M. Wilson; Giacomo Ruotolo; Axel Haupt; Christopher B. Newgard; Kevin L. Duffin

Disclosures

J Clin Endocrinol Metab. 2022;107(2):363-378. 

In This Article

Abstract and Introduction

Abstract

Context: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss.

Objective: Assess plasma metabolome changes mediated by tirzepatide.

Design: Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed.

Setting: Post hoc analysis.

Participants: 259 subjects with T2D.

Intervention(s): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo.

Main Outcome Measure(s): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction.

Results: At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species.

Conclusions: Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.

Introduction

Type 2 diabetes (T2D) is a global pandemic, predicted to affect more than 500 million individuals by 2030.[1] The disease develops as a result of metabolic dysregulation in multiple organ systems, including impaired insulin signaling in skeletal muscle and adipose tissue; altered hepatic utilization of glucose, lipids, and amino acids; and loss of normal control of insulin and glucagon (GCR) secretion from the pancreatic islet β and α cells, respectively.

New therapies for T2D that target receptors for GCR, GCR-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) have evolved rapidly in recent years.[2–4] This has included steady improvements in efficacy of monotherapies with GLP-1 receptor (R) agonists, currently the standard of care for diabetes, for example, through the development of multiple analogs with enhanced stability and/or delivery as time-release formulations to allow once-weekly or once-monthly injections of these treatments.[5–7]

More recent efforts have focused on the development of dual agonists that combine GLP-1R and GIPR agonism[8] to enhance efficacy of incretin-based therapies. Although not fully understood, the benefits of GIPR engagement are linked to improved adipose tissue health, whole-body energy metabolism, and reduced appetite.[9,10]

Tirzepatide is a dual GIPR and GLP-1R agonist with equal affinity for the GIPR as native GIP, but a 5-fold weaker affinity for the GLP-1R compared to native GLP-1.[11,12] Tirzepatide has been shown to achieve greater weight loss and improvement in glycemic control among patients with T2D compared to the selective GLP-1R agonist dulaglutide or placebo.[13] This includes a superior effect of tirzepatide on biomarkers associated with improved insulin sensitivity compared to dulaglutide. Tirzepatide increased adiponectin levels,[14] lowered levels of serum alanine aminotransferase,[15] and reduced lipoprotein biomarkers such as apolipoprotein C-III, apolipoprotein B, and large triglyceride-rich lipoprotein particles, as well as small low-density lipoprotein particles.[16] Multiple linear regression analysis revealed only 13% and 21% of the improvement in insulin resistance (IR) [measured as homeostatic model assessment (HOMA) 2-IR] could be attributed to tirzepatide-induced weight loss at higher administered doses of 10 and 15 mg,[14] suggesting possible body weight–independent effects of tirzepatide on biochemical pathways related to insulin action. Recent hyperinsulinemic-euglycemic clamp studies in Glp-1r−/− mice provided evidence that GIPR agonism accounts for the weight-independent insulin sensitizing action of tirzepatide.[17]

Concurrent with the advances in the development of incretin-based therapies for T2D, a surge has occurred in efforts to apply comprehensive metabolic profiling or metabolomics for prediction of T2D risk and to gain insights into mechanisms that contribute to the multiorgan metabolic dysregulation driving T2D pathogenesis.[18] From these efforts, several individual metabolites or clusters of related metabolites have emerged that associate with obesity, insulin resistance, risk for future T2D, and intervention outcomes. These include (1) the branched-chain amino acids (BCAA) and related analytes; the cluster is comprised of the 3 BCAA (leucine, valine, and isoleucine), products of BCAA catabolism such as branched-chain ketoacids (BCKA), glutamic acid, 3-hydroxyisobutyric acid (3-HIB), and C3 and C5 acylcarnitines and often includes the aromatic amino acids phenylalanine and tyrosine, possibly due to their shared and competitive use of the same large neutral amino acid carrier used for transport of the BCAA;[18–21] (2) a set of triglycerides (TAGs) with short, highly saturated acyl chains are predictive of T2D in multiple human cohorts, whereas triglycerides with longer chain and polyunsaturated side chains are associated with protection from T2D;[22] and (3) 2 metabolites, identified by untargeted metabolomics, generated by methionine/threonine metabolism, 2-hydroxybutyric acid (2-HB) and 2-ketobutyric acid (2-KB), associated with impaired fasting glucose and impaired glucose tolerance. The association with glycemic variables was found in distinct European cohorts. 2-HB levels are also associated with insulin sensitivity measured by hyperinsulinemic/euglycemic clamp and are predictive for incident increases in fasting glucose, impaired glucose tolerance, and T2D.[23,24] Interestingly 2-HB and 2-KB are readily interconverted by the activity of lactate dehydrogenase, and 2-KB acts as a substrate for 2 α-ketoacid dehydrogenase complexes, pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase (BCKDH), the latter suggesting a possible biochemical/enzymatic relationship between the BCAA-related metabolite cluster and 2-HB/2-KB.

In the current study, we performed a comprehensive survey of the biochemical impact of tirzepatide compared to dulaglutide and placebo in T2D participants. This study was conducted post hoc on the Phase 2b tirzepatide study, the results of which were published in 2018.[13] Our analysis combined 3 mass spectrometry–based assay platforms to measure 193 polar small-molecule metabolites and 665 lipid features. The assay platforms chosen not only provided coverage of the previously referenced glycemiarelated metabolites, including the BCAA-related, TAG, and 2-HB/2-KB clusters, but also allowed us to expand beyond these known biomarkers to conduct a broader and unbiased investigation. Remarkably, we find tirzepatide has specific and selective effects on all 3 sets of metabolites known to be associated with T2D risk and metabolic dysregulation, in all cases changing the profiles in a direction associated with metabolic health.

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