Revisiting insulin resistance in human cancer cachexia - a systematic review and meta-analysis

BackgroundApproximately half of all patients with cancer experience unintentional weight loss called cancer cachexia (CAC), which reduces overall survival and impairs quality of life. Metabolic dysfunction is frequently observed in patients with cancer, likely due to insulin resistance. Due to its anabolic effects, insulin resistance could be implicated in the progression of CAC. However, comprehensive clinical data in human populations remain limited, and the potential association between insulin resistance and CAC has yet to be clearly established. Covering this knowledge gap will guide our search for treatable targets to alleviate patients in the future. MethodsTo address this knowledge gap, we performed a systematic review and meta-analysis, including comprehensive searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). By including studies reporting both fasting levels of insulin and glucose in patients with cancer and CAC according to the internationally accepted CAC definition, we calculated HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) index for each study and thereby estimated the level of insulin resistance (defined as HOMA-IR above 2.0) in patients with CAC. A subgroup analysis was conducted from studies reporting a HOMA-IR index both from a group of patients with CAC and a group of patients without CAC (non-CAC). ResultsThe mean HOMA-IR of all studies was 1.84 (95%CI: 1.77-1.91). Seventeen studies, with a total of 197 patients with CAC, conducted from 1982 to 2007, fulfilled the inclusion criteria. Age ranged from 52 to 68 years. Five studies reported a HOMA-IR above 2.0, indicative of insulin resistance. Twelve studies found HOMA-IR below 2.0. No differences between disease- or patient characteristics between the studies reporting HOMA-IR values above 2.0 vs. those below 2.0 were identified. Five of the 17 studies also reported HOMA-IR from a group of patients with cancer without CAC, allowing for a separate meta-analysis. In 37 patients with CAC and 49 patients without CAC we documented a mean difference of -0.42 (95%CI: -2.24-1.40) in favor of a lower HOMA-IR in patients with CAC compared to without CAC. Heterogeneity between studies was significant with I2 ={square}94% (P{square}<{square}0.05). ConclusionsThis systematic review indicates that insulin resistance in patients with cancer and cachexia does not manifest to the same extent as in cancer populations without cachexia. These findings challenge the prevailing understanding of insulin resistance as a driver of cancer cachexia and underscore the need for further longitudinal research in this area.