Can pioglitazone be used for optimization of nutrition in critical illness? A systematic review

BackgroundSkeletal muscle wasting is a determinant of physical disability in survivors of critical illness. Intramuscular bioenergetic failure, altered substrate metabolim, and inflammation are likely underpinning mechanisms. We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on muscle-related outcomes in adults. MethodsWe included randomized controlled trials in which pioglitazone was administered (no dose/dosage restrictions) and muscle-related outcomes were reported. We searched MEDLINE, CENTRAL, EMBASE, CINAHL, and trial registries. Risk of bias was assessed using RoB 2. Primary outcomes were physical function and symptoms, muscle mass and function, or body composition and muscular compositional change. Secondary outcomes included muscle insulin sensitivity, mitochondrial effects, and intramuscular inflammation. ResultsFourteen studies over 19 publications (n = 474 patients) were included. Lean body mass was unaffected in three studies (n = 126) and increased by 1.8-1.92 kg in two studies (P = 0.02 and 0.003, respectively; n = 48). Pioglitazone was associated with increased peripheral insulin sensitivity (+23%-72%, standardized mean difference of 0.97 from trial start point to end point [95% CI, 0.36-1.58; n = 213]). Treatment reduced intramuscular tumor necrosis factor-alpha (TNF-alpha) levels (-30%; P = 0.02; n = 29), with mixed effects on serum TNF-alpha and intramyocellular lipid concentrations. Treatment increased intramuscular markers of adenosine triphosphate (ATP) biosynthesis (ATP5A [+33%, P <= 0.05], ETFA [+60%, P <= 0.05], and CX6B1 [+ 33%, P = 0.01] [n = 24]), PGC1 alpha and PGC1 beta messenger RNA expression (P < 0.05; n = 26), and AMPK phosphorylation (+38%, P < 0.05; n = 26). These data have low-quality evidence profiles owing to risk of bias. ConclusionsPioglitazone therapy increases skeletal muscle insulin sensitivity and can decrease intramuscular inflammation.