Our aim was to assess whether long-term adherence to a Mediterranean diet (MedDiet) and leisure-time physical activity (LTPA) were associated with a lower initiation of cardiovascular drug use. We studied the association between cumulative average of MedDiet adherence and LTPA and the risk of cardiovascular drug initiation in older adults at high cardiovascular risk (PREvención con DIeta MEDiterránea trial participants) non-medicated at baseline: glucose-lowering drugs (n = 4437), antihypertensives (n = 2145), statins (n = 3977), fibrates (n = 6391), antiplatelets (n = 5760), vitamin K antagonists (n = 6877), antianginal drugs (n = 6837), and cardiac glycosides (n = 6954). One-point increases in MedDiet adherence were linearly associated with a decreased initiation of glucose-lowering (HR: 0.76 [0.71–0.80]), antihypertensive (HR: 0.79 [0.75–0.82]), statin (HR: 0.82 [0.78–0.85]), fibrate (HR: 0.78 [0.68–0.89]), antiplatelet (HR: 0.79 [0.75–0.83]), vitamin K antagonist (HR: 0.83 [0.74; 0.93]), antianginal (HR: 0.84 [0.74–0.96]), and cardiac glycoside therapy (HR: 0.69 [0.56–0.84]). LTPA was non-linearly related to a delayed initiation of glucose-lowering, antihypertensive, statin, fibrate, antiplatelet, antianginal, and cardiac glycoside therapy (minimum risk: 180–360 metabolic equivalents of task-min/day). Both combined were synergistically associated with a decreased onset of glucose-lowering drugs (p-interaction = 0.04), antihypertensive drugs (p-interaction p-interaction = 0.04), and cardiac glycosides (p-interaction = 0.01). Summarizing, sustained adherence to a MedDiet and LTPA were associated with lower risk of initiating cardiovascular-related medications.
