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Review
. 2020 Jul 2;21(13):4725.
doi: 10.3390/ijms21134725.

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

Unai Galicia-Garcia  1 , Shifa Jebari  2   3 , Asier Larrea-Sebal  1   2 , Kepa B Uribe  4 , Haziq Siddiqi  5 , Helena Ostolaza  1   2 , Asier Benito-Vicente  1   2 , César Martín  1   2
Affiliations
Review

Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

Unai Galicia-Garcia et al. Int J Mol Sci. .

Abstract

Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins' impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.

Keywords: clinical trial; insulin resistance; microRNA; statin; type 2 diabetes mellitus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Statin-induced inhibition of the mevalonate pathway and structure of statins. (A) Inhibition of HMG-CoA reductase significantly blocks the production of mevalonate, a necessary precursor for cholesterol synthesis. Mevalonate is the building block for a variety of other compounds. (B) Structural formulas of statins and HMG-CoA. The HMG-like moiety (in red) is conserved in all statins. The polar substituents responsible of pravastatin and rosuvastatin are colored in green.
Figure 2
Figure 2
Principal mechanisms for T2DM development induced by statins.
Figure 3
Figure 3
Intracellular actions of statins in β-cells. Red lines indicate the mechanisms affected by statins.
Figure 4
Figure 4
Intracellular actions of statins in adipocytes. Red lines indicate the mechanisms affected by statins.
Figure 5
Figure 5
Intracellular actions of statins in muscle cells. White lines indicate the mechanisms affected by statins.
Figure 6
Figure 6
Intracellular actions of statins in hepatocytes. White lines indicate the mechanisms affected by statins.
See this image and copyright information in PMC

References

    1. Baigent C., Keech A., Kearney P.M., Blackwell L., Buck G., Pollicino C., Kirby A., Sourjina T., Peto R., Collins R., et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278. doi: 10.1016/S0140-6736(05)67394-1. - DOI - PubMed
    1. Colhoun H.M., Betteridge D.J., Durrington P.N., Hitman G.A., Neil H.A.W., Livingstone S.J., Thomason M.J., Mackness M.I., Charlton-Menys V., Fuller J.H. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–696. doi: 10.1016/S0140-6736(04)16895-5. - DOI - PubMed
    1. Mihos C.G., Pineda A.M., Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties. Pharm. Res. 2014;88:12–19. doi: 10.1016/j.phrs.2014.02.009. - DOI - PubMed
    1. Casula M., Mozzanica F., Scotti L., Tragni E., Pirillo A., Corrao G., Catapano A.L. Statin use and risk of new-onset diabetes: A meta-analysis of observational studies. Nutr. Metab. Cardiovasc. Dis. 2017;27:396–406. doi: 10.1016/j.numecd.2017.03.001. - DOI - PubMed
    1. Cederberg H., Stancakova A., Yaluri N., Modi S., Kuusisto J., Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: A 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58:1109–1117. doi: 10.1007/s00125-015-3528-5. - DOI - PubMed

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