The first high fidelity gyrokinetic simulations of the energy losses in the transport barriers of large tokamaks in pursuit of fusion gain are presented. These simulations calculate the turbulent energy losses with an extensive treatment of relevant physical effects—fully kinetic, non-linear, electromagnetic—inclusive of all major plasma species, and in equilibria with relevant shape and local bootstrap current for fusion-relevant cases. We find that large plasmas with a small normalized gyroradius lie in an unexpected regime of enhanced losses that can prevent the projected energy gain. Our simulations are qualitatively consistent with recent experiments on JET with an ITER-like wall. Interestingly and very importantly, the simulations predict parameter regimes of reduced transport that are quite fusion-favorable.