Revisiting Statin Associated Muscle Symptoms through the Lens of Sports Medicine and Muscle Biology – Can Exercise even Increase Statin Tolerance?

The privotal role of regular physical exercise in cardiovascular prevention is a basic fact of (sports) medicine and part of common knowledge. A complementary cornerstone are statins, highly effective lipid lowering drugs with proven effectiveness in preventing cardiovascular disease (5, 16). 

Almost 40 years after the market approval of lovastatin (Mevacor®), statins are still among the most prescribed class of drugs worldwide (9). While statins have a positive overall safety profile, patient adherence and clinical utility are challenged by a characteristic side effect: Statin-associated muscle symptoms (SAMS) (5, 18). Despite decades of research into mechanisms (5) and management (6) of SAMS, a substantial proportion of patients discontinue therapy due to muscle pain, weakness, or reduced exercise tolerance (2, 18). The determinants of statin tolerance are not yet fully understood. However, several lines of evidence point towards an interaction between statins and physical exercise. This supposition originated from the clinical observation that SAMS are more pronounced in regular exercisers (3) and statins are rarely tolerated in athletes (17). Moreover, adverse effects of statins on load tolerance (8, 14), performance capacity (13), and training adaptation (12) have been reported. This imperfect compatibility between two cornerstones of cardiovascular prevention is clearly a concern. However, the proportion of patients in which it actually limits adherence and achievement of therapeutic goals remains unclear. This uncertainty is due in part to the generally higher prevalence of SAMS in observational studies compared to muscle symptoms reported as adverse events in clinical trials (10, 18). But, even if the proportion of patients in which the interaction between statins and exercise becomes clinically relevant was small, the absolute number would still be considerable (18).

From the perspective of sports medicine and exercise physiology, it is striking that differences between statins in their tendency to induce SAMS are well studied (10, 18) while “physical exercise” has long been considered rather globally. This is particularly surprising in light of the marked differences in muscle strain imposed by various training modalities as well as in the ensuing signalling, restorative, and adaptive processes. In fact, recent insights into the molecular mechanisms of SAMS (7) and its interaction with physical exercise (6, 7) point to a critical role of muscle strain and thereby of exercise mode. Specifically, statins induce the expression of glucocorticoid-induced leucine zipper (GILZ), a regulatory protein that also mediates the well-known muscle related side effects of glucocorticoids (7). The implicated antimyogenic signalling pathways impede the anabolic, restorative processes which are of particular importance after exercise with high muscle strain. 

This consideration has spurred follow-up research into the exercise induced regulation of GILZ expression. The two studies published so far consistently found a suppression of GILZ expression after exercise with high muscle strain (e.g., resistance exercise) but not after exercise with low muscle strain (e.g., moderate intensity endurance exercise) (6, 15). Again, this regulation of an antimyogenic pathway makes sense in light of the exercise induced recovery needs. Consequently, it seems plausible to suspect the opposite regulation of GILZ to be part of the mechanism behind the interaction of statins and exercise (6, 15). Put bluntly, statins seem to reduce the recovery and adaptive capacity of skeletal muscle. Or the other way round, exercise with high muscle strain may overwhelm the reduced loading capacity of patients under statin medication. Emerging evidence, suggesting that moderate intensity endurance type exercise is well tolerated in statin users, supports this scenario (1). However, prospective studies specifically designed to challenge it remain to be concluded. Should these studies lend further support, adaptations of training recommendations for statin users, favouring exercise modes with low muscle strain, may enable a decisive step forward in cardiovascular prevention (while limiting the excessive healthcare cost associated with novel lipid lowering drugs). 

As a bonus, there is another twist to the above scenario: Endurance type exercise with low muscle strain (e.g., moderate intensity cycling) does not only accommodate a side effect of statin medication but may even increase statin tolerance due to its beneficial effects on mitochondrial function (see figure 6 in (15)). Note that, here too, prospective experimental verification and evidence of clinical relevance are pending. 

Finally, beyond potential clinical benefits, the workup of SAMS provides as case in point for the importance of a differentiated view on physical exercise in the context of prevention and therapy (which is self-evident in the context of sports performance). This illustrates the crucial contribution of exercise physiology and sports medicine as experts for the “pharmacology of exercise as a medication”.