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

Abstract

Background: Skeletal 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 γ agonist, on muscle-related outcomes in adults. Methods: We 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. Results: Fourteen 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-α (TNF-α) levels (−30%; P = 0.02; n = 29), with mixed effects on serum TNF-α 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]), PGC1α and PGC1β 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. Conclusions: Pioglitazone therapy increases skeletal muscle insulin sensitivity and can decrease intramuscular inflammation.