Mechanisms of statin‐induced new‐onset diabetes

Abstract

Statins, with their lipid‐lowering properties, are a first‐line therapy for the prevention of cardiovascular diseases. Recent evidence, however, suggests that statins can increase the risk of new‐onset diabetes (NOD). The molecular mechanisms of statin‐induced NOD are not precisely known, although some pathophysiologic mechanisms have been suggested. Specific to the beta cell, these mechanisms include alterations in insulin secretion, changes in ion channels, modulation of signaling pathways, and inflammation/oxidative stress. Outwith the beta cell, other suggested mechanisms involve adipocytes, including alterations in adipocyte differentiation and modulation of leptin and adiponectin, and genetic and epigenetic mechanisms, including alterations in microRNA. The evidence supporting these and other mechanisms will be discussed. Greater understanding of the underlying mechanisms linking the onset of diabetes to statin therapy is essential and clinically relevant, as it may enable novel preventative or therapeutic approaches to be instituted and guide the production of a new generation of statins lacking this side effect.

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

“…Among experimental studies, multiple works have indicated that statins diminish pancreatic β-cell function via Ca 2+ signaling pathways impairment [19,20], compromise insulin signaling and down-regulate the insulin-responsive glucose transporter 4 (GLUT-4) [21,22]. In addition, it has also been described that statins impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs [23].…”

Fixed‐dose combination of amlodipine and atorvastatin improves clinical outcomes in patients with concomitant hypertension and dyslipidemia

“…In a previous collaborative meta‐analysis assessing randomized statin trials, statin use was associated with a 9% increased risk of developing NODM, 30 which was positively correlated with the strength of the statin 31 ; however, the risk was reportedly low in absolute terms and when compared with the reduction in coronary events. Furthermore, the underlying mechanisms of statin‐induced NODM are not precisely known, and several possibilities have been proposed 32 . Notably, the beneficial effects of statins on CVD outweigh its risk of NODM development, with no neutralizing factor for such a risk documented in the literature.…”

Statins are associated with new onset type 2 diabetes mellitus (T2DM) in Medicare patients ≥65 years

“…The HMG‐CoA inhibitors (statins) are one of the most commonly prescribed drugs worldwide to reduce cholesterol and prevent or manage coronary heart disease . In a meta‐analysis of 13 randomised trials, the use of statins was associated with a 12% increase in the risk of T2DM onset, with the risk being the highest in older populations ≥65 years .…”

“…Possible mechanisms involve more than 15 pathways through which statins may plausibly affect risk of new onset T2DM . Statins up regulate low density lipoprotein receptor gene (LDLP) via sterol regulatory element‐binding protein 2 (SREBP2).…”

“…Several risk factors are associated with T2DM onset such as: family history of T2DM; age; obesity; physical inactivity; prior history of gestational diabetes; impaired glucose tolerance; dipocytokines; inflammatory factors and hepatocyte factors; race/ethnicity; alcohol consumption; tobacco smoking; diet; high blood pressure; appendectomy and hypothyroidism . In addition to the above factors, medications such statins or 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) inhibitors have also been linked with onset of T2DM …”