1. Introduction
Statins are a guideline-directed, first line therapy for prevention of primary and secondary cardiovascular disease (CVD), which is the leading cause of mortality worldwide [
1,
2]. Although the principal mechanism of the action of statins is inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme-A (HMG-CoA) reductase, statins have been implicated in several other beneficial pleiotropic effects including improving endothelial function, stabilization of atherosclerotic plaques and anti-inflammatory activities [
3]. Despite the safety and relative tolerability of statins, observational studies [
4,
5,
6,
7,
8], clinical trials [
9,
10] and meta-analyses [
11,
12,
13,
14,
15,
16] have found that statins can increase the risk of new-onset type 2 diabetes mellitus (T2DM). These studies implicated statins in negatively impacting insulin sensitivity, decreasing secretion by pancreatic β-cells and increasing insulin resistance [
11,
17,
18]. While the lipid-lowering mechanism of statins is relatively well understood, the mechanisms underlying statin-induced T2DM development seem to be multifactorial and remain unclear. 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].
This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. Here, we will describe the existing data from clinical studies as well as experimental results that shed some light on the mechanisms of this association.
2. Primary Action of Statins: Cholesterol Biosynthetic Pathway
Statins are reversible and competitive inhibitors of HMG-CoA reductase, which is the rate-determining enzyme in the cholesterol biosynthetic pathway [
24]. The HMG-like portion of statins, which is a modified 3,5-dihydroxyglutaric acid moiety, is structurally similar to HMG-CoA and causes the inhibition of HMG-CoA reduction reactions [
25]. Through this mechanism, the mevalonate pathway is inhibited along with a consequent decrease in downstream products and cholesterol synthesis (
Figure 1A). In addition, this statin-mediated 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) [
26]. 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 synthesized by a cell [
27]. Through the action of statins, the cellular cholesterol concentration decreases, stimulating production of more LDLR and promoting LDL-C removal from the bloodstream, ultimately reducing CVD risk [
27].
Statins are classified according to their hydrophobicity into hydrophilic statins (pravastatin and rosuvastatin) and lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin and simvastatin) [
28,
29]. The solubility and pharmacological properties of statins are determined by the substituents on the ring attached to the active moiety [
29]. Hydrophilicity originates from polar substituents added to the active site while the addition of nonpolar substituents leads to lipophilicity [
25,
29] (
Figure 1B). Although the target of both types of statins is HMG-CoA reductase, the inhibitory mechanisms are distinct. 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 [
29,
30]. 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 [
31].
3. Beneficial Effects of Statins on Diabetic Complication and/or Inflammation in T2DM
There are many factors that contribute to the development of atherosclerotic cardiovascular disease, the main mortality cause in T2DM patients. These include dyslipidemia, increased oxidative stress, enhanced protein glycation or chronic inflammatory state all of them worsen in T2DM [
32]. Statins are the gold standard treatment for the prevention and management of cardiovascular disease and their use in T2DM patients is recommended by The American Diabetes Association 2019 guidelines [
33]. In addition to the reduction of cholesterol levels and dyslipidemia 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 T2DM patients.
Several clinical trials have pointed out the beneficial effects of statins in diabetic patients [
36]. The collaborative atorvastatin diabetes study (CARDS) showed nearly 40% reduction in relative risk of cardiovascular events in diabetic patients aged 45–70 years old with high cholesterol levels and treated with atorvastatin during 4 years [
37]. A meta-analysis of 14 randomized trials including more than 18,000 patients confirmed the beneficial effects of statins in diabetic patients showing a 21% reduction in major vascular events per mmol/L LDL-C reduction [
38]. Further studies, confirmed the benefits of statin treatment in diabetic patients independently of LDL-C baseline [
39].
Unfortunately, in some cases, statin treatment leads to adverse effects such as the decreased insulin sensitivity shown by atorvastatin, simvastatin and rosuvastatin [
40]. For atorvastatin and simvastatin, one proposed explanation is that the higher diffusion rate of lipophilic statins to the intracellular space can interfere with cellular processes, leading to decreased intracellular insulin secretion in response to glucose [
41]. For rosuvastatin, despite its hydrophilicity, the higher affinity and efficient transport of rosuvastatin into cells, which can underlie it effects on insulin sensitivity [
29].
4. Statin Therapy and Risk of Developing T2DM: Observational Studies, Clinical Trials and Meta-Analysis
Statins, discovered in the early 70s and commercially available in the mid-80s, have well-characterized benefits in terms of lowering LDL-C and cardiovascular risk reduction. However, 20 years after becoming commonly prescribed, findings from observational studies showed an increased T2DM 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 [
4,
6,
7]. Observational studies carried out in Canada, Taiwan and Ireland examining the association between statin administration and T2DM development, showed 10–22%, 15% and 20% increases in the risk of T2DM associated with statin therapy, respectively [
42,
43,
44]. Later on, the effects of statin treatment on the risk of T2DM and hyperglycemia deterioration were assessed in the metabolic syndrome in men (METSIM) study cohort, which found that statin therapy was associated with a 46% increased risk of T2DM along with worsening of hyperglycemia [
45]. In addition, the study found statin use to be associated with a 24% reduction in insulin sensitivity and a 12% decrease in β-cell count compared to individuals not taking statin therapy [
45]. Notably, treatment with both simvastatin and atorvastatin was associated with reductions in insulin sensitivity and secretion in a dose-dependent manner [
5].
Collectively, statin randomized control trials (RCT) were designed and, large, long-term, double blind, placebo-controlled studies were conducted to evaluate the effects of statins in a variety of clinical situations. Although most statin RCTs, including the largest statin RCT trial, were designed primarily to evaluate efficacy in a variety of clinical situations, several RCTs also evaluated the relationship between stain treatment and T2DM development. Among them, the justification for the use of statin in prevention: an intervention trial evaluating rosuvastatin (JUPITER), study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) and Cholesterol Treatment Trialists trials were un-confounded regarding the intervention and aimed to recruit at least 1000 participants with treatment duration of at least 2 years.
The justification for the use of statin in prevention: an intervention trial evaluating rosuvastatin (JUPITER) trial showed a small but significant increase in diabetes incidence rates in patients who received statin treatment when compared to placebo over a median of 1.9 years (absolute increase of 0.6%; relative increase of 24%;
p = 0.01) [
46]. Subsequent meta-analyses of the available randomized controlled trials showed that standard statin dose regimens were associated with a proportional increase of about 10% in reported T2DM. According to the results of the JUPITER trial, treatment with high statin concentrations resulted in a further increase by 10% [
16,
47]. In addition, a post-hoc analysis of the JUPITER trial showed that participants with one or more major diabetes risk factor were at higher risk of developing T2DM than were those without a major risk factor. Of note, however, benefits of statin therapy exceeded the diabetes hazard even in participants at high risk of developing diabetes [
10]. In patients who had risk factors for diabetes (e.g., elevated body-mass index or HbA1c, or impaired fasting glucose), the excess of T2DM diagnoses appeared soon after the start of statin therapy, and did not appear to get larger as treatment continued [
10,
48,
49].
Another RCT carried out by the study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) collaborative group found that the simvastatin treatment was associated with a dose-dependent increased risk of diabetes, with diabetes found in 11.6% participants who received 80 mg simvastatin compared to 10.9% in participants receiving 20 mg simvastatin [
50]. Collectively, the findings of multiple RCTs indicate that statin therapy may lead to the development of diabetes [
51]. Although results from individual RCTs have shown substantial variability in the association between statin therapy and incident diabetes, they generated a large amount of data that could be more powerfully analyzed in meta-analysis. For the most relevant insights, meta-analyses that compile data from several RCTs represent a powerful tool for understanding the impacts of statin therapy.
Consistent with the aforementioned RCTs, The Cholesterol Treatment Trialists’ Collaborators meta-analysis (CTT) showed that LDL-C reduction is associated with a 21% reduction in the incidence of any major vascular event in both patients with or without diabetes [
38]. In the study, randomized trials were eligible for inclusion if: (i) the main effect of at least one of the trial interventions was to modify lipid levels; (ii) the trial was unconfounded with respect to this intervention (i.e., no other differences in modification of risk factors between the relevant treatment groups were intended) and (iii) the trial aimed to recruit 1000 or more participants with treatment duration of at least 2 years [
38]. The study assessed possible variation in the proportional effects of allocation to a statin in different circumstances only for major vascular events. Trial participants were considered to have diabetes if they had a recorded history of diabetes at randomization, and subdivision of diabetes subtypes was done according to the definitions used in the individual trials [
38]. The study showed that statins are directly correlated with an increased risk of developing T2DM. Interestingly, multiple meta-analyses have found that the risk of statin-associated T2DM is higher in participants taking higher doses when compared to patients taking lower doses [
15,
16,
47]. Accordingly, the data obtained indicated an excess risk ranging from 9% to 13%, with the highest risk of T2DM seen in patients taking high-intensity statin therapy [
13,
15,
16,
43,
47,
52]. Specifically, a recent meta-analysis showed that atorvastatin 80 mg is associated with the highest risk of T2DM, followed by rosuvastatin and simvastatin 80 mg, indicating that statins have varying effects on the risk of T2DM [
53]. 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. Most importantly, despite the increase of T2DM, it is important to emphasize 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 T2DM prevention and screening is important to take into consideration.
As listed above, clinical trials, meta-analyses and observational studies highlight that patients who received statin treatment had a 10–12% increase in T2DM risk [
17]. However, the risk is even higher in patients receiving high-intensity statin therapy and among patients with pre-existing risk factors for diabetes. Recent studies indicate a clear correlation between statin type and treatment intensity with T2DM development. Specifically, pravastatin 40 mg/day treatment has been associated the lowest risk of T2DM, while rosuvastatin 20 mg/day and atorvastatin 80 mg/day treatment are associated with increased risks of T2DM. Between rosuvastatin and atorvastatin, rosuvastatin has been associated with the higher risk of T2DM [
14].
However, even if statin type and treatment intensity clearly correlate with T2DM development, individual’s risk factors should not be overlooked. Development of T2DM 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 [
54], as well as age and gender [
55]. In fact, for patients with none to 1 risk factor, the incidence of T2DM is similar between those receiving high dose and moderate dose of statins (3.22% and 3.35%, respectively). Conversely, for patients with 2–4 risk factors the incidence is 14.3% in the high dose group and 11.9% in the moderate dose group [
17].
6. Differences in Diabetogenic Effects between Hydrophilic and Lipophilic Statins
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 β-cells, adipocytes and skeletal muscle cells. Conversely, hydrophilic statins (e.g., pravastatin) are more hepatocyte specific and less likely to enter β-cells or adipocytes [
29]. Indeed, a high hepato-selectivity translates into minimal interference with cholesterol metabolism in tissues other than the liver and consequently to a lesser diabetogenicity [
29,
30,
56]. Several studies have shown that the detrimental effects of statins are dose and potency dependent and primarily related to their lipophilicity [
5,
14,
41,
47,
166].
While lipophilic statins have negative effects on pancreatic β-cell function, for hydrophilic statins such as pravastatin, neutral or improving effects have been observed [
40,
41,
167]. As mentioned in
Section 4, it has been reported that statins can inhibit glucose-induced cytosolic Ca
2+ signaling and insulin secretion by blocking L-type Ca
2+ channels in β-cells. These inhibitory potencies may be particularly evident for the lipophilic rather than the hydrophilic statins [
41,
166,
168]. Indeed, unlike hydrophilic statins, the lipophilic ones have a strong affinity for the cell membrane, and therefore have easier access to the intracellular space [
168]. In this context, statins may inhibit the endogenous metabolic pathways described in
Section 5.1 that are associated with glucose-stimulated insulin secretion, including endogenous cholesterol synthesis [
73,
166] and Ca
2+-dependent insulin responses to glucose [
168]. It has been shown that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affects insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models [
169].
As described in
Section 5.2.1,
Section 5.2.2 and
Section 5.2.3, GLUT-4 mediates insulin-stimulated glucose uptake [
86] in a process that requires fusion of the transporter with the plasma membranes facilitated by IRS-1 and several kinases [
86,
170,
171]. The small GTP-binding proteins are also key players in this process [
22,
86] and they require isoprenylation by mevalonate products for their association with the cell membranes. The statin-mediated inhibition of the synthesis of the above products increases insulin resistance in parallel with the mevalonate synthesis inhibitory capacity [
21,
172]. Furthermore, several other processes involved in the GLUT-4 signaling pathway may be inhibited by statins. These include IRS-1, insulin receptor β subunit, and Akt phosphorylation [
22,
166]. It has been suggested that these effects are relevant only for lipophilic statins (e.g., atorvastatin and simvastatin), but not for hydrophilic statins (e.g., pravastatin) [
22,
166]. The capacity of the former to enter adipocytes through passive diffusion can help explain this difference.
7. Conclusions
Taken together, the studies described in this review, ranging from clinical studies to in vivo and in vitro experimental results, confirm and reinforce the diabetogenic effect of statins. Although a number of questions remain unanswered, the available evidence supports that statins do increase the chances of T2DM with some statins being more strongly related (e.g., simvastatin, rosuvastatin and atorvastatin) than others (e.g., pravastatin). Intense research is currently going on to elucidate the mechanisms of statin induced T2DM at the molecular level. In light of the evidence from multiple observational studies, it is important to emphasize that there is still a favorable risk–benefit ratio for statin therapy, due to the large reduction in cardiovascular risk, despite the adverse effect of T2DM development. Overall, the risk of incident diabetes mellitus with statin therapy is present but largely outweighed by the actual cardiovascular benefits [
16]. Thus, statins should be continued in patients in whom these drugs are prescribed due to high or very high CVD risk, despite the risk of T2DM development until they achieve the target LDL-C levels. Before initiation of statin therapy the risk of diabetes should be assessed [
8,
16,
173]. Statin-treated patients at high risk of developing diabetes should be monitored for changes in blood glucose and HbA1c levels, and preventive lifestyle modification should be introduced. If diabetes develops, it should be managed according to the guidelines [
16]. Patients should be educated regarding the risk of incident diabetes mellitus with statins as with other risk–benefit of all therapies [
174]. Lifestyle modification should be encouraged to lower cardiovascular risk and that for developing T2DN [
175] and national guidelines should be used to manage diabetes mellitus [
176,
177].
Several mechanisms through which statin treatment causes β-cell dysfunction and insulin resistance in peripheral tissues have been identified. Specifically, these the diabetogenic effects are related both to the dose and statin class. In addition, miRs are glucose homeostasis regulators through the specific modulation of insulin signaling components. Growing evidence indicates that statin modulation of miRs expression may also be another mechanism through which statins increase the risk of T2DM. A multifactorial combination of these effects is what most likely contributes to the diabetogenic effects of statins described here. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management. Ultimately, since the risk of statin-induced T2DM is still being characterized, and the efficacy of statins in preventing CVD is very well documented, statins remain a first line treatment for prevention of CVD.