Virtual system development has become increasingly important in many industrial domains. It is considered to reduce development time, to lower computing costs, and to shorten time-to-market. Co-simulation is a particularly promising approach for modular and interoperable virtual system development. The Functional Mock-up Interface (FMI) represents an industry software standard for model exchange, co-simulation and tool integration. In practice the integration and coupling of heterogeneous systems still require enormous effort. The novel Distributed Co-Simulation Protocol (DCP), which is under the process of standardization, represents a solution to this problem. It can be used for efficient simulation configuration, data exchange and control. The DCP is designed as a tool and platform independent specification. As soon as any real-time systems are placed in the testing loop, the entire simulation scenario is also subject to safety considerations. Primary goals are to avoid any harm to the operating engineers and prevent damage to deployed equipment and its surroundings. In this paper we describe a lightweight and efficient methodology for safe integration of real-time systems into simulation environments using the DCP. We show how single mechanisms defined in the DCP specification document can be used to ensure safe and reliable operation of real-time systems connected to simulation environments in a systematic way. Our methodology is subject to application in many fields, especially in the automotive domain, where hardware-in-the-loop approaches for test of advanced vehicle functions can benefit from our approach.