Statin treatment increases the clinical risk of tendinopathy through matrix metalloproteinase release – a cohort study design combined with an experimental study

Abstract

Recent experimental evidence indicates potential adverse effects of statin treatment on tendons but previous clinical studies are few and inconclusive. The aims of our study were, first, to determine whether statin use in a cohort design is associated with tendinopathy disorders, and second, to experimentally understand the pathogenesis of statin induced tendinopathy. We studied association between statin use and different tendon injuries in two population-based Swedish cohorts by time-dependent Cox regression analysis. Additionally, we tested simvastatin in a 3D cell culture model with human tenocytes. Compared with never-users, current users of statins had a higher incidence of trigger finger with adjusted hazard ratios (aHRs) of 1.50 for men (95% confidence interval [CI] 1.21–1.85) and 1.21 (1.02–1.43) for women. We also found a higher incidence of shoulder tendinopathy in both men (aHR 1.43; 1.24–1.65) and women (aHR 1.41; 0.97–2.05). Former users did not confer a higher risk of tendinopathies. In vitro experiments revealed an increased release of matrix metalloproteinase (MMP)-1 and MMP-13 and a weaker, disrupted matrix after simvastatin exposure. Current statin use seems to increase the risk of trigger finger and shoulder tendinopathy, possibly through increased MMP release, and subsequently, a weakened tendon matrix which will be more prone to injuries.

A Global Phosphorylation Atlas of Proteins Within Pathological Site of Rotator Cuff Tendinopathy

“…In our candidates, there were two statin-treated patients. Eliasson et al (2017Eliasson et al ( , 2019 found that statin could reduce the mechanical properties of tendon constructs and increase the risk of tendinopathy. However, no subgroup analysis was performed between statin-treated and non-treated patients on account of the small amount of each human sample.…”

Chronic hyperglycemia, hypercholesterolemia, and metabolic syndrome are associated with risk of tendon injury

“…An important confounding factor is statin treatment; 5.5% of the cohort had a self‐reported daily intake of statins. These individuals will likely have total cholesterol in the normal range <5 mmol/L, but at the same time the use of statins to treat hyperlipidemia may also result in at least transient changes that are detrimental to tendon structure and function resulting in increased risk of tendon injury 24,28 . In addition, the degree to which elevated total cholesterol contributes to tendon injury may be less predictable among varying patient populations and different injury patterns 24 …”

“…These individuals will likely have total cholesterol in the normal range <5 mmol/L, but at the same time the use of statins to treat hyperlipidemia may also result in at least transient changes that are detrimental to tendon structure and function resulting in increased risk of tendon injury. 24,28 In addition, the degree to which elevated total cholesterol contributes to tendon injury may be less predictable among varying patient populations and different injury patterns. 24 Importantly, the present study found a significant 2-3 fold higher risk of tendon injury in individuals that fulfilled the criteria of having metabolic syndrome.…”

“…27 BMI was calculated as kg/m 2 , and the subjects were classified as running vs. no running (<0 h/week) smokers vs. non-smokers based on self-reporting. Likewise, regular use of painkillers, the treatment with lipid-lowering statins, 28 and medication as treatment for asthma/bronchitis, 29 which may cause tendon damage, were registered based on self-reporting.…”

Inflammatory mechanisms linking obesity and tendinopathy

“…Indeed, there were some early in vitro and in vivo studies on the effects of metformin and glycyrrhizin for the treatment of tendon overuse with encouraging results [ 102 , 126 , 127 ]. However, recent studies have shown that statins use was associated with higher risk of trigger finger and shoulder tendinopathy, possibly through MMP release [ [143] , [144] ], suggesting that the medication used for the management of obesity may also do harm more than good on tendons. However, a systematic review reported the opposite and suggested that statins could decrease the risk of developing rotator cuff disease and the incidence of revision after rotator cuff repair [ 145 ].…”