Repurposing Drugs for Diabetes Mellitus as Potential Pharmacological Treatments for Sarcopenia – A Narrative Review

Abstract

Sarcopenia, the age-related loss of muscle strength and mass or quality, is a common condition with major adverse consequences. Although the pathophysiology is incompletely understood, there are common mechanisms between sarcopenia and the phenomenon of accelerated ageing seen in diabetes mellitus. Drugs currently used to treat type 2 diabetes mellitus may have mechanisms of action that are relevant to the prevention and treatment of sarcopenia, for those with type 2 diabetes and those without diabetes. This review summarises shared pathophysiology between sarcopenia and diabetes mellitus, including the effects of advanced glycation end products, mitochondrial dysfunction, chronic inflammation and changes to the insulin signalling pathway. Cellular and animal models have generated intriguing, albeit mixed, evidence that supports possible beneficial effects on skeletal muscle function for some classes of drugs used to treat diabetes, including metformin and SGLT2 inhibitors. Most human observational and intervention evidence for the effects of these drugs has been derived from populations with type 2 diabetes mellitus, and there is a need for intervention studies for older people with, and at risk of, sarcopenia to further investigate the balance of benefit and risk in these target populations. Not all diabetes treatments will be safe to use in those without diabetes because of variable side effects across classes. However, some agents [including glucagon-like peptide (GLP)-1 receptor agonists and SGLT2 inhibitors] have already demonstrated benefits in populations without diabetes, and it is these agents, along with metformin, that hold out the most promise for further investigation in sarcopenia.Extended author information available on the last page of the article Key PointsType 2 diabetes mellitus and sarcopenia share multiple pathophysiological mechanisms.Preclinical, observational and interventional data suggest that some drugs used to treat diabetes may have beneficial effects on sarcopenia even in patients without diabetes. Clinical trials of these agents have not focussed on enrolling people with sarcopenia, and such trials are needed to evaluate whether diabetes drugs could improve or prevent sarcopenia in patients with or without diabetes.

Sarcopenia and Diabetes: A Detrimental Liaison of Advancing Age

“…Moreover, metformin activates the forkhead box O3a or FoxO3a, via AMPK, a key transcription factor of myostatin, a potent inhibitor of myofibrillar synthesis and skeletal muscle growth [ 115 ]. Observational data suggest that metformin may have a protective effect against sarcopenia [ 116 , 117 , 118 ]. However, the level of evidence is slight and possibly affected by confounding factors, such as exercise, diets, or nutraceuticals ( Table 2 ).…”

Drug‐related sarcopenia as a secondary sarcopenia

“…Basic studies, including animal studies, have reported that glucagon‐like peptide‐1 (GLP‐1) receptor agonists promote insulin secretion, increase insulin sensitivity, inhibit myostatin expression, suppress muscle protein degradation, and decrease inflammation and reactive oxygen species (ROS) production 19,20 . These pharmacological effects suggest that GLP‐1 receptor agonists may have protective effects on skeletal muscle, i.e., they may have inhibitory effects on sarcopenia.…”

“…While some clinical studies support these findings, others report that GLP‐1 receptor agonists decrease skeletal muscle mass and impair muscle performance (Table 3). 19,23,24 It is unclear whether the negative effects of these drugs on skeletal muscle are secondary effects mediated by decreased appetite or direct effects on skeletal muscle. Thus, the definitive clinical effects of GLP‐1 receptor agonists on skeletal muscle remain unclear.…”

“…Other glucose‐lowering drugs such as biguanides, thiazolidinediones, dipeptidyl peptidase‐4 inhibitors, and insulin may be protective with respect to sarcopenia (Table 3). 19,20,22 The effects of alpha‐glucosidase inhibitors on sarcopenia are unknown, as there are no reports of their effects on skeletal muscle. However, given their mechanism of action (inhibition of alpha‐glucosidase, a digestive enzyme secreted from the small intestine), a direct effect on skeletal muscle is unlikely.…”

“…Among those, there are drugs that also affect skeletal muscle metabolism and may be associated with a risk of developing sarcopenia (Table 3). 19,20 Most studies on the effects of diabetes medications on skeletal muscle are based on observational studies, and even in intervention studies, muscle assessment is a secondary endpoint, not a primary endpoint, and studies that comprehensively assess skeletal muscle, including muscle mass, strength, and physical function are very limited. Therefore, the definitive effects of some drugs on skeletal muscle are still unclear.…”