Statins in T2D – friend or foe?

12th March 2022, Dr Chee L Khoo

Nox family
friend or foe?

When you look at the management of patients with type 2 diabetes (T2D), almost all the patients are on a statin for both primary and secondary prevention of cardiovascular complications. I suspect that those that are not already on a statin should be on as some doctors are not aware of the tightened lipid targets in the management of patients with T2D. Over the last few years, observational studies, clinical trials and meta-analysis have indicated that statins are associated with an increased risk of developing new onset diabetes. We now have a report indicating that statins may be associated a significant progression of T2D. What are the mechanisms of that?

Mechanism of action of statins

Statins have a HMG-CoA-like portion which binds on reversibly and competitively to HMG-CoA reductase which is the rate limiting enzyme in the cholesterol biosynthesis pathway. As a result, the mevalonate pathway is inhibited with a reduction in downstream products including cholesterol (see Figure 1). This decrease in intracellular cholesterol content leads to up-regulation of the LDL receptor (LDLR) in the liver and peripheral tissues, resulting in decreased blood LDL cholesterol (LDL-C). LDLR is the primary route by which LDL-C is removed from circulation and its synthesis has been shown to be inversely correlated to the amount of cholesterol synthesised by a cell.

Different statins, different solubility, different adverse effects

Statins are classified according to their hydrophobicity into hydrophilic statins (pravastatin and

rosuvastatin) and lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin

and simvastatin). See Table 1.

Hydrophilic statins target the liver more efficiently because their uptake is carrier-mediated, while lipophilic statins passively diffuse through the hepatocellular membrane and similarly are also able to diffuse in extrahepatic tissues, thus showing reduced hepatoselectivity. Their diffuse influence on extrahepatic tissues may explain the higher incidence of adverse effects observed with lipophilic statins. The notable exception to this is rosuvastatin, which is a hydrophilic statin but has a similar activity profile to lipophilic statins.

Benefits of statins

Statins are the gold standard treatment for the prevention and management of cardiovascular disease and their use in T2D patients is recommended by international and Australian guidelines. In addition to the reduction of cholesterol levels and dyslipidaemia improvement by reducing lipoprotein levels in plasma, the pleiotropic effects of statins reduce high sensitive C-reactive protein and other pro-inflammatory markers [34], improve endothelial function and reduce oxidative stress [35], which together contribute to a significant CVD reduction in T2D patients.

Numerous clinical trials have convincingly demonstrated the benefits of statins in reducing cardiovascular events in patients with T2D (1-4).

How do statins increase T2D risk?

Amidst all the fancies during the 80’s shortly after statins became widely prescribed for reduction of cardiovascular risk reduction observational studies showed an increased T2D risk upon statin administration in several populations. Despite the considerable variability among these studies and the statin administered, hazard ratios (HR) were statistically significant ranging from 1.19 to 1.57, after follow-up durations of 3–6 years [5-7]. Observational studies carried out in Canada, Taiwan and Ireland examining the association between statin administration and T2D development, showed 10–22%, 15% and 20% increases in the risk of T2D associated with statin therapy, respectively [8-10].

The METSIM study (2015) examined the effects of statins on the risk of T2D and deterioration in 8749 non-diabetic Finnish men over a 6-year period and found that statin therapy was associated with a 46% increased risk of T2D along with worsening of hyperglycaemia. In addition, the study found statin use to be associated with a 24% reduction in insulin sensitivity and a 12% decrease in beta-cell count compared to individuals not taking statin therapy. Notably, treatment with both simvastatin and atorvastatin was associated with reductions in insulin sensitivity and secretion in a dose-dependent manner [11].

Similar findings were reported in the JUPITER, SEARCH and The Cholesterol Treatment Trialists’ Collaborators meta-analysis (CTT) implicating different statins (12-14). Overall, meta-analysis studies found a clear association between diabetes and statins across multiple statins, indicating that the diabetogenic property of statins is a class effect. As listed above, clinical trials, meta-analyses and observational studies highlight that patients who received statin treatment had a 10–12% increase in T2D risk . However, the risk is even higher in patients receiving high-intensity statin therapy and among patients with pre-existing risk factors for diabetes.

Development of T2D during statin treatment is more frequent among individuals with pre-existing risk factors, including increased adiposity, predisposing dietary patterns, sedentary lifestyle, psychosocial factors and previous medical history as well as age and gender.

Mechanism of harm?

The actual mechanism which statin induces T2D is not fully understood but it is thought that chronic inhibition of the mevalonate pathway affects many other biosynthetic pathways:

Insulin resistance

When insulin binds to its insulin receptor, a series of downstream events is triggered which sees migration of GLUT-4 to the plasma membrane which facilitates transport of glucose into the cells in adipose tissues, cardiomyocytes and muscles. It also triggers glycogen synthesis within those cells.

Statins have been shown to interfere with many of those intracellular events including migration of GLUT-4 to the plasma membrane. HMG-CoA reductase inhibition by statins leads to free fatty acid accumulation in skeletal muscles. FFA accumulation also has been shown to impair some of the intracellular events.

Beta-cell function

Simvastatin Impairs beta cell function by inhibiting mitochondrial K-ATP channels and Ca2+ channels which are responsible for insulin secretion (75). GLUT-2 receptors is the predominant receptor responsible for glucose uptake which triggers insulin secretion. Pravastatin and atorvastatin inhibit GLUT-2 expression. However, rosuvastatin and pitavastatin showed a slight increase in GLUT-2 expression.

Liver effects

It has been shown that statins stimulate hepatic endogenous gluconeogenesis by activating phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), the

major rate-limiting gluconeogenic enzymes in human liver cells.  Excess free fatty acid accumulation in the liver also contributes towards increase in hepatic insulin resistance.

Gene expression

MicroRNAs (miRs) are small (22 nucleotide) noncoding regulatory RNAs, which act as post-transcriptional regulators of gene expression [123,124]. miRs usually silence gene expression through mRNA degradation or sequestration of the target mRNA from translation machinery [125]. It has been shown that miRs are involved in many biological processes including insulin expression, skeletal muscle adaptation to elevated glucose, insulin sensitivity and glucose stimulated insulin secretion.

Statin therapy has been found to affect the expression of several miRs, which play a central role

in the regulation of lipid and glucose metabolism and that are associated with development

of T2D. For example, it has been demonstrated that simvastatin and atorvastatin induce expression of miR-33a in the liver, thus suggesting a link between reduced insulin secretion and, ultimately, the development of statin-induced T2D.

Not all statins are the same

As indicated in previous sections, lipophilic statins (atorvastatin, simvastatin, lovastatin, fluvastatin and pitavastatin) may be more diabetogenic than hydrophilic statins (pravastatin and rosuvastatin) as they can more readily penetrate extrahepatic cell membranes such as beta-cells, adipocytes and skeletal muscle cells. Conversely, hydrophilic statins (e.g., pravastatin) are more hepatocyte specific and less likely to enter beta-cells or adipocytes]. Indeed, a high hepato-selectivity translates into minimal interference with cholesterol metabolism in tissues other than the liver and consequently to a lesser diabetogenicity. Several studies have shown that the detrimental effects of statins are dose and potency dependent and primarily related to their lipophilicity. See Table 1.

In summary, there are a number of mechanisms by which statin may worsen hyperglycaemia in our patients with T2D or are at high risk of developing T2D. There are effects on beta cell function, insulin resistance and microRNA.

This serves to remind us that in patients with dyslipidaemia whom we are treating with statins, their cholesterol levels are not the only thing we need to treat and monitor. As good clinicians, these patients need work done on lifestyle, in particular, diet and exercises.

Despite the increase and potentially worsening of T2D, it is important to emphasise that the benefits of statin administration in reducing myocardial infarction, stroke and cardiovascular deaths in high CVD risk patients are enough to warrant statin treatment, although T2D prevention and screening is important to take into consideration. It is all a balancing act.

References:

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  2. Neil, H.A.; DeMicco, D.A.; Luo, D.; Betteridge, D.J.; Colhoun, H.M.; Durrington, P.N.; Livingstone, S.J.; Fuller, J.H.; Hitman, G.A.; Investigators, C.S. Analysis of e_cacy and safety in patients aged 65–75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS). Diabetes Care 2006, 29, 2378–2384.
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