BACKGROUND: Enteral nutrition (EN) increases hyperglycemia due to high carbohydrate concentrations while providing insufficient protein. The study tested whether an EN formula with very high-protein- and low-carbohydrate-facilitated glucose control delivered higher protein concentrations within a hypocaloric protocol. METHODS: This was a multicenter, randomized, open-label clinical trial with parallel design in overweight/obese mechanically ventilated critically ill patients prescribed 1.5 g protein/kg ideal body weight/day. Patients received either an experimental very high-protein (37%) and low-carbohydrate (29%) or control high-protein (25%) and conventional-carbohydrate (45%) EN formula. RESULTS: A prespecified interim analysis was performed after enrollment of 105 patients (52 experimental, 53 control). Protein and energy delivery for controls and experimental groups on days 1-5 were 1.2 +/- 0.4 and 1.1 +/- 0.3 g/kg ideal body weight/day (P = .83), and 18.2 +/- 6.0 and 12.5 +/- 3.7 kcals/kg ideal body weight/day (P < .0001), respectively. The combined rate of glucose events outside the range of >110 and =150 mg/dL were not different (P = .54, primary endpoint); thereby the trial was terminated. The mean blood glucose for the control and the experimental groups were 138 (-SD 108, +SD 177) and 126 (-SD 99, +SD 160) mg/dL (P = .004), respectively. Mean rate of glucose events >150 mg/dL decreased (Delta = -13%, P = .015), whereas that of 80-110 mg/dL increased (Delta = 14%, P = .0007). Insulin administration decreased 10.9% (95% CI, -22% to 0.1%; P = .048) in the experimental group relative to the controls. Glycemic events =80 mg/dL and rescue dextrose use were not different (P = .23 and P = .53). CONCLUSIONS: A very high-protein and low-carbohydrate EN formula in a hypocaloric protocol reduces hyperglycemic events and insulin requirements while increasing glycemic events between 80-110 mg/dL.