Research on Effects of Drugs on Body Composition and Function With Imaging in Diabetes

In Canada, older adults are projected to represent nearly one-fourth of the population by 2040, with the number of old older adults (75 and older) growing at an even faster rate. This demographic shift has important implications, including a rising prevalence of aging-related disease. Approximately 1 in 4 Canadians aged 65 or older have type 2 diabetes (DM2).

Aging and DM2 often coexists with obesity, chronic kidney disease (CKD) and/or cardiovascular disease (CVD) as well as cardiovascular-kidney-metabolic (CKM) syndrome. Aging and chronic disease also independently elevate the risk of sarcopenia (age-related progressive loss of muscle mass and strength) and frailty.

Glucagon-like peptide 1 receptor agonists (GLP-1RA like Ozempic) have revolutionized the management of chronic metabolic disease. These agents lower blood glucose, promote weight loss, and protect the heart, brain, and kidneys, making them the cornerstone of therapy for diabetes, kidney, cardiovascular, and CKM syndrome. However, concerns have been raised about the amount of weight loss elicited by these medications, particularly the associated loss of skeletal muscle mass. In some studies, weight loss of greater than 10 kg have been described with GLP-1RA (i.e., semaglutide) or GLP-1RA/GIP (tirzepatide) drugs, with up to 40% of total weight loss from lean body mass reported with semaglutide. Loss of lean body mass (including skeletal muscle mass), could be particularly worrisome to those at high risk for frailty and sarcopenia, both of which are associated with increased morbidity, hospitalizations, reduced quality of life, disability and mortality. There is also evidence that these medications could negatively impact bone quality and fracture risk.

Existing studies on the impact of GLP-1RA and GLP-1RA/GIP on lean body mass have been limited; they primarily measured body composition using dual energy x ray absorptiometry (DXA) which is unable to quantify intramuscular fat, and is less sensitive to body thickness and hydration/pathologic status. DXA also has lower precision/accuracy compared with CT scan and MRI, leading to more variability. Among studies that have used MRI to examine body composition, many were secondary analyses of clinical trials, excluded individuals with body mass index (BMI) ≤25 kg/m2 and/or DM2, had short follow-up, and lacked functional assessments. Evidence indicates that intramuscular fat is more strongly associated with adverse outcomes than muscle quantity, highlighting the importance of exploring the impact of GLP-1RA and GLP-1RA/GIP on both muscle mass and muscle composition. There also remains an opportunity to examine the association between changes in body composition and measures of muscle strength/function, which are highly prognostic of outcomes such as disability, hospitalizations, and mortality. There is also a dearth of evidence regarding the impact of GLP-1RA and GLP-1RA/GIP medications on muscle blood flow, glucose metabolism, or bone blood flow, which may correlate with clinically important patient outcomes like falls and fracture.

The investigators propose a single-arm, open-label, prospective study to explore changes in body composition, muscle mass, composition, and function, in patients with DM2 with and without CKM following initiation of a GLP-1RA (semaglutide or Ozempic is the most commonly prescribed) or GLP-1RA/GIP (tirzepatide or Mounjaro is the most commonly prescribed). The goal is to characterize and quantify early changes in muscle and physical function that could signal harm; This will allow the development clinical prediction tool to guide treatment decisions before initiating semaglutide or tirzepatide, and to design targeted interventions aimed at preserving muscle and bone health in real-world patients with type 2 diabetes prescribed GLP-1RA or GLP-1RA/GIP therapies.