Metformin in Elderly Patients With Type 2 Diabetes and Muscle Strength, Muscle Mass, and Physical Function: Positive or Negative Correlation?

Overview

With the accelerating aging process in China, sarcopenia has drawn increasing attention. Sarcopenia is an age-related geriatric syndrome characterized by reductions in muscle mass, muscle strength, and/or physical function. Sarcopenia has a high prevalence, often insidious onset, and broad impacts on physiological functions. According to the 2019 report from the Asian Working Group for Sarcopenia (AWGS), sarcopenia prevalence among elderly Asians ranged from 5.5% to 25.7%, with males exhibiting higher rates (5.1% to 21.0%) than females (4.1% to 16.3%). Particularly among patients with diabetes, sarcopenia incidence was significantly elevated, with a prevalence of 14.8% reported in Chinese diabetic populations. Sarcopenia exerts numerous adverse effects. Sarcopenia is strongly associated with adverse cardiovascular events and increased mortality. Sarcopenia is linked to cancer and significantly elevates the risk of various postoperative complications in patients with gastrointestinal malignancies, including dysphagia, cognitive impairment, fractures, falls, hospitalization, and all-cause mortality. Sarcopenia and diabetes frequently coexist within the same individual, leading to multiple adverse outcomes. Sarcopenia results in declining in function flexibility and responsiveness in diabetic patients, causing gait alterations and impaired balance, limiting daily activities, and is closely linked to risks of falls, fractures, depression, frailty, and mortality. Thus, it is critically important to treat sarcopenia alongside diabetes and avoid detrimental effects of hypoglycemic drugs on muscle. Metformin lowers blood glucose by increasing muscle glucose uptake, inhibiting hepatic glucose output and gluconeogenesis, and promoting glucose excretion into the intestinal lumen; it also reduces the risk of diabetic cardiovascular disease, diabetic retinopathy, nephropathy, and neuropathy. There remains controversy in current studies regarding metformin's impact on sarcopenia. Some studies indicate that metformin may have potential beneficial effects on grip strength, skeletal muscle mass, and gait speed. Nordklint AK reported that after 18 months of metformin intervention in patients with type 2 diabetes, bone mineral content and density were improved. Qaisar R conducted a 16-week metformin trial on older men, finding improvements in grip strength and gait speed with statistical significance (P \< 0.05). Klimova AV found that a 6-month metformin intervention improved physical function in patients. Lyu Q's murine study demonstrated that 5 months of metformin treatment conferred benefits and recovery effects on the gastrocnemius muscle in sarcopenia models. Conversely, some studies indicate no impact of metformin on muscle mass, grip strength, or gait speed. Qaisar R reported no improvement in body composition or gait speed after 4 months of metformin use. Laksmi PW found no significant difference in grip strength between groups after a 16-week metformin intervention. Koshizaka M reported that after 24 weeks of intervention with ipragliflozin or metformin in patients with type 2 diabetes, metformin had no significant effect on muscle mass. Previous studies have also elucidated mechanisms underlying metformin's effects on muscle. According to Kang MJ, metformin induced myostatin expression in skeletal muscle cells via the Adenosine5'-monophosphate-activated protein kinase (AMPK)-FoxO3a-HDAC6 pathway, thereby impairing muscle function. Other studies found that metformin reduced expression of mTORC1-related genes in muscles of elderly individuals with impaired glucose tolerance, potentially leading to decreased muscle protein synthesis or increased autophagy. Therefore, this study enrolled elderly patients with type 2 diabetes and employed a cross-sectional design with propensity score matching to elucidate the association between metformin and muscle strength, muscle mass, and physical function, providing evidence for rational clinical use of hypoglycemic drugs.