Molecular targets of statins and their potential side effects: Not all the glitter is gold

Abstract

Statins are a class of drugs widely used worldwide to manage hypercholesterolemia and the prevention of secondary heart attacks. Currently, available statins vary in terms of their pharmacokinetic and pharmacodynamic profiles. Although the primary target of statins is the inhibition of HMG-CoA reductase (HMGR), the rate-limiting enzyme in cholesterol biosynthesis, statins exhibit many pleiotropic effects downstream of the mevalonate pathway. These pleiotropic effects include the ability to reduce myocardial fibrosis, pathologic cardiac disease states, hypertension, promote bone differentiation, anti-inflammatory, and antitumor effects through multiple mechanisms. Although these pleiotropic effects of statins may be a cause for enthusiasm, there are many adverse effects that, for the most part, are unappreciated and need to be highlighted. These adverse effects include myopathy, new-onset type 2 diabetes, renal and hepatic dysfunction. Although these adverse effects may be relatively uncommon, considering the number of people worldwide who use statins daily, the actual number of people affected becomes quite large. Also, co-administration of statins with several other medications, herbal agents, and foods, which interact through common enzymatic pathways, can have untoward clinical consequences. In this review, we address these concerns.

Keywords: Diabetes; Drug interactions; Myopathy; Pleiotropy; Statins.

Figure 1.

Chemical structures of statin medications. Statins exist in an equilibrium between their inactive lactone forms and their active dihydroxy-heptanoic acid forms, with equilibrium favoring the active form. Lovastatin, simvastatin, and mevastatin are administered in the lactone form, whereas all other statins are administered in their active acid form. The open acid form represents its pharmacophore and competitively inhibits HMGR. The R group determines lipophilicity, hepatic/myocyte selectivity. Type 1 statins have a decalin ring (naphthalene) structure. Type 2 statins have central ring structures larger than the decalin ring, along with common fluorophenyl and methyl ethyl groups replacing the butyryl group of type 1 statins. The structure of HMG-CoA is shown in the inset.

Figure 2.

The cholesterol synthesis pathway. Cholesterol synthesis begins with two molecules of acetyl-CoA, which are converted to one molecule of acetoacetyl-CoA by the enzyme thiolase. Acetoacetyl-CoA and another molecule of acetyl-CoA are used to synthesize HMG-CoA by the enzyme HMG-CoA synthase. The rate-limiting enzyme of the pathway is HMGR. HMGR activity is stimulated or activated by several endogenous molecules, including insulin, AMP, and glucagon. Statins competitively inhibit HMGR, resulting in decreased concentrations of all downstream products. Protein prenylation is mediated by intermediate products of the cholesterol synthesis pathway, FPP and GGPP. Decreased protein prenylation decreases the activity of downstream signaling pathways such as ROCK and NADPH oxidases, accounting for many of the pleiotropic effects of statins.

Figure 3.

Pleiotropic effects of statins. Statins’ impact extends beyond cholesterol reduction. Inhibition of FPP and GGPP mediated protein prenylation can be the root of many pleiotropic effects. Inhibition of the Rho/ROCK pathway is responsible for many of these effects. Statin use is associated with increased induction of eNOS, increased bioavailability of NO, decreased induction of NADPH oxidase, reduced incidence of thrombogenesis, cardioprotective effects arising from decreased cardiomyocyte apoptosis, and cardiac fibrosis, and anticancer effects. Statins can induce ferroptosis by decreasing CoQ10 levels. Anti-inflammatory mechanisms of statins include inhibition of the NLRP3 inflammasome, induction of PPA receptor-α and PPA receptor-γ, inhibition of mast cell degranulation, and inhibition of chemokine and integrin expression. Statins also have potential implications in osteogenesis, inducing the differentiation of osteoblasts while simultaneously inhibiting osteoclast activation. Statins also have antifungal properties secondary to FPP inhibition.

Figure 4.

Adverse effects of statins. The two most common adverse effects associated with statins are myopathy and new-onset type 2 diabetes; the mechanisms of this pathology are described above. Myopathy is primarily due to reduced coQ10 production following statin treatment. Reduced levels of coQ10 can decrease mitochondrial respiration, leading to less ATP production in skeletal muscle cells. In a similar mechanism, lactone statins have also been shown to inhibit complex III of the electron transport chain by offsite binding to the Q₀ site. Myopathy can also be triggered by destabilized activation of RYR1, leading to excess calcium release in a pathology similar to malignant hyperthermia. PI3K/Akt inhibition by statins leads to activation of the FOXO protein, which can then increase the nuclear expression of ubiquitin ligases and PDK, both of which can lead to muscle atrophy. There are multiple mechanisms of statin-induced diabetes. Insulin release from pancreatic ß-cells may be impaired by statin-mediated downregulation of GLUT-2 transporter. Inhibition of L-type calcium channels in pancreatic ß-cells (due to cholesterol depletion-associated membrane alteration) can lead to impaired insulin release from the pancreas. Several mechanisms may also lead to insulin resistance. Inhibition of prenylation of RhoA and Rab4 GTPases can lead to inhibition of IRS-1 phosphorylation and thus inhibition of downstream insulin signaling pathways. Downregulation of caveolin-1 expression can lead to decreased GLUT4 translocation to cellular membranes.