GLP-1R Actions on Muscle and the Skeleton

Obesity and type 2 diabetes remain at epidemic proportions in our country particularly in vulnerable populations such as elderly, and minority patients. Over the last 20 years, the use of incretin-based agents (Glucagon-like Peptide 1 Receptor Agonist (GLP-1 RA) and Glucose dependent insulinotrophic polypeptide (GIP) to treat these disorders has offered unprecedented advances based on significant weight loss and reduction in major cardiovascular endpoints. Whilst weight loss provides a vital aspect for addressing obesity and type 2 diabetes, there are concerns associated with the quality of weight reduction.

The impact of losing weight on the musculoskeletal system has garnered recent attention in the lay press. Reported high-impact studies have reported excessive loss of skeletal muscle using GLP-1 RAs. The data regarding combined therapies (GLP-1 RA and GIP) suggested smaller loses. This preliminary data is based on using a surrogate marker (fat-free mass) determined by dual energy x-ray absorptiometry (DXA).

Recent reviews evaluating the impact that incretin-based agents have on fat-free-mass were found to be inconclusive based on high variability and multiple confounding factors. Assessing the impact that these agents have on the musculoskeletal system is now an important endeavor. (Aim 1-2) Diet-induced weight loss is also associated with bone loss, although little attention has focused on this potentially problematic outcome. In the CALERIE study, modest caloric restriction (15%) over two years led to weight loss and a 2% reduction in hip bone mineral density (BMD) among normal weight individuals. The mechanisms of weight loss-induced bone loss are unclear, although a drop in fat-free mass (which is composed of skeletal muscle, organs, water and connective tissues) principally muscle, such as occurs with the GLP1RAs, may predispose to injury, disability and bone loss. Another possibility is a mechanical form of skeletal adaptation to lower lean mass, through myokine mediated bone remodeling. However, significant trabecular bone loss in a non-weight bearing skeletal site occurs in mice as the investigators have shown in the mandible, from a 30% CR diet (Liu, personal communication). As such gravitational unloading due to weight loss is not solely responsible for deleterious skeletal changes. Despite the dramatic weight and lean mass loss from the GLP1 RAs, few clinical trials have focused on loss of muscle mass and fewer on any skeletal changes. In those that did, the results suggest equipoise for skeletal changes. There are no data on the skeletal effects from tirzepatide which can drive up to 25% weight loss. (Aim 1c) Also, it is unknown whether the addition of dietary modifications and resistance-based exercises impacts skeletal adaptation, muscle mass and bone loss. (Aim 2) Furthermore, there are inconsistent data in non-Hispanic Blacks with the GLP1 RAs because trial participation in under-represented populations has been poor. Hence, there is a major knowledge gap in our understanding the impact that a mixed GIP and GLP1RA, tirzepatide affects muscle and bone mass, particularly among underserved populations.

The wide-spread usage of GLP-1 related agents has not required formal recommendations regarding the use of exercises, specifically resistance-based exercises, or dietary protein optimization to address the potential for loss of fat-free mass or bone mineral density that has been suggested in studies evaluating body composition and bone density in subjects using these compounds. While the data for using such lifestyle interventions with diet and bariatric surgery have confirmed benefits in reducing loss of fat-free mass, the investigators know of only 1 published report using GLP-1 agents and exercise: Lundgren et al. found that in subjects using additional resistance-based exercise had a more favorable impact on sparing fat-free mass.

Additional gaps in our understanding remain despite the growing use and popularity of these agents. Additionally, patients with obesity and type 2 diabetes tend to develop ectopic fat within muscle (myosteatosis) that is not measured as part of fat free mass by DXA. It is posited that the major depot for acute loss of skeletal muscle from rapid weight loss may be from this portion of poor-quality lipid-rich tissue quelling major concerns. (Aim 2b) Aim 3, an explorative outcome, the investigators will determine if tirzepatide causes bone loss by measuring bone formation (P1NP) and bone resorption markers (NTx), if imbalanced skeletal remodeling is related to the change in total lean mass, muscle mass through reduced myokine (i.e., irisin) release, skeletal adaptation to weight change or another endocrine mechanism. Using a team science approach, the investigators will combine the expertise in metabolism and body composition of the PBRC group with skeletal expertise from MaineHealth to provide key insights into musculoskeletal effects from tirzepatide, a relatively new but often sought after drug for weight loss and type 2 diabetes. This supplement could also shed light on newer mechanisms of weight loss-induced bone loss and set the stage for a larger clinical trial.