An oral combination therapy or oral composition that protects orally administered exogenous leptin from the environment of the gastrointestinal tract, allowing delivery of the exogenous leptin to the bloodstream. The oral combination therapy includes (a) leptin or a leptin functional derivative (b) a stomach acid-neutralizing agent such as a buffer and (c) a pancreatic protease inhibitor that protects the exogenous leptin from degradation by pancreatic enzymes and (d) a bile acid or a bile acid analog that facilitates absorption of the exogenous leptin. The oral combination therapy or oral composition may also include at least one agent that stimulates endogenous leptin secretion as well as at least one agent capable of promoting, enhancing or improving adherence to treatment such as a sweetener or a satiety triggering agent. The oral combination therapy or oral composition can be a single composition in liquid or solid form, or can be administered simultaneously or sequentially so that the components mix in the stomach cavity of the patient. Methods and uses relating to the above oral combination therapy or oral composition to treat or prevent diseases of conditions that are associated with or can be ameliorated by leptin (e.g., obesity, weight gain, diabetes) are also included.
