Review of Interventions for the Frailty Syndrome and the Role of Metformin as a Potential Pharmacologic Agent for Frailty Prevention

Abstract

Purpose: Frailty is a syndrome of vulnerability and physical decline with aging that increases risk for disability, hospitalizations, and death. To date, interventions for frailty have primarily focused on exercise and/or nutritional interventions, many of which show improvement in frailty-related characteristics, such as gait speed and lower extremity strength and function. The goal of this article was to review prior research studies investigating interventions for frailty and review the literature with regard to the role of insulin resistance and inflammation in the development of frailty. Also included is a discussion of potential therapeutic interventions for frailty.

Methods: A literature search was conducted by using PubMed and the search terms frailty, interventions, and older adults. This review focused on larger studies (N ≥ 100 participants) that examined the effect of specific interventions on frailty as a primary outcome or on measures that are closely related to frailty, such as gait speed, muscle strength, and/or sarcopenia.

Findings: The results of prior studies of exercise interventions for the frailty syndrome as the primary outcome are mixed, with some but not all showing benefit. However, many exercise interventions have demonstrated improvement in components of frailty, such as strength, gait speed, and physical activity. The evidence shows that regular physical activity is beneficial for frail older adults or those at high risk of frailty and that the adverse effects related to exercise are minimal compared with the potential gains. However, questions remain as to the optimal type and duration of exercise and whether results of clinical trials are easily and feasibly implemented in a clinical setting in individuals whose motivation for exercise may be low. There is now increasing interest in pharmacologic agents that could potentially be useful in the prevention or treatment of frailty, in part based on advances in basic biology of aging research demonstrating that pharmacological agents extend lifespan in rodents. Several studies now show that obesity, insulin resistance, inflammation, and diabetes are associated with and predict frailty. Because metformin targets insulin resistance and inflammation, it is a plausible pharmacologic agent to prevent frailty. A clinical trial is underway to examine metformin's usefulness in frailty prevention.

Implications: Although the benefits of exercise are known, adherence to these regimens may be difficult for individual older adults due to lack of motivation, access, or limitations due to chronic medical conditions. Studies are currently underway to examine novel agents for the prevention of frailty in older adults.

Keywords: diabetes; frailty; inflammation; insulin resistance; metformin; older adults.