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Statin use is associated with insulin resistance in participants of the Canadian Multicentre Osteoporosis Study
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" In summary, in the Kingston CaMos cohort, statin users had higher indices of insulin resistance. Users of hydrophilic statins had greater HOMA levels; however the majority of the participants were taking the high-potency statin rosuvastatin. Statins, widely prescribed drugs to lower cholesterol, may have unintended consequences related to glucose homeostasis that could be relevant in healthy aging. In those individuals with risk factors for diabetes, consideration for choosing non-lipophilic statins and avoidance of rosuvasatin and lipophilic statins may provide the intended cardiovascular protection without the increased incidence of insulin resistance.
Participants had a median age of 71....In this cohort of community-dwelling participants, users of lipophilic and hydrophilic statins had higher levels of insulin resistance compared to non-statin users with and without propensity score adjustment. Insulin resistance was greater in hydrophilic statin users compared to lipophilic statin users. Although previous studies have implicated lipophilicity as a risk factor for this pleiotropic effect of statins, 73% of the hydrophilic statins in use in this study were rosuvastatin, a high potency statin that has been shown in one other study to have the highest risk for the development of diabetes (12). With respect to calcification, statin users had higher AAC but this was no longer significant after propensity score adjustment.....
Statins, widely prescribed drugs to lower cholesterol, may have unintended consequences related to glucose homeostasis that could be relevant in healthy aging........Taken together, in previous studies high potency and lipophilic statins appear to increase the risk of developing type 2 diabetes and in our study were associated with increasing insulin resistance. The data suggest that it might be prudent to monitor the glycemic status in those at greatest risk for diabetes and consider lower risk statins in those with risk factors. Further consideration for other pharmacological and non-pharmacological options might also be considered.
Although not a disease, insulin resistance appears to be associated with the development of cardiovascular disease based on a meta-analysis of published data from 20 studies (32). The development of impaired fasting glucose resulted in progressively higher risk of developing myocardial infarction, cardiovascular disease and mortality in a large observational study of Korean patients (33). Over time, insulin resistance can lead to type 2 diabetes as the pancreas fails to keep up with the body's increasing demands for insulin. These metabolic abnormalities pre-date the development of diabetes by more than 10 years (34). Although many risk factors for insulin resistance have been identified, obesity remains the most important. "
"There is emerging data to suggest that by inhibiting the production of intermediates of cholesterol biosynthesis, statins also inhibit the mevalonate pathway and impede the production of vitamin K2 in peripheral tissues," Rachel M. Holden, MD, a nephrologist and associate professor in the department of medicine at Queen's University in Kingston, Ontario, Canada, and colleagues wrote in the study background. "There is growing evidence to suggest that vitamin K2 plays a key role in glucose homeostasis as well as vascular calcification. On this background, we hypothesized that statin use would be associated with both insulin resistance and vascular calcification in community-dwelling participants of a large longitudinal study of osteoporosis."
https://www.healio.com/news/endocrinology/20200605/statin-use-may-lead-to-unintended-consequence-of-insulin-resistance?utm_source=selligent&utm_medium=email&utm_campaign=news&m_bt=5557793003224M
By inhibiting HMG-CoA reductase, there are statin-associated downstream effects on the production of other products of the cholesterol biosynthetic pathway including coenzyme 10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate and dolichol. Depletion of these substrates may lead to a downstream reduction of intracellular signalling. Coenzyme Q10 supplementation has been shown to improve glucose homeostasis in various patient populations. In an eight week trial of simvastatin treated patients, Coenzyme Q10 did not change muscle GLUT4 content, insulin sensitivity or secretory capacity. However, hepatic insulin sensitivity appeared to improve (42). Geranylgeranyl pyrophosphate is a key intermediate in the conversion of dietary vitamin K1 to MK-4. Whilst vitamin K1 is the predominant vitamin K form measured in blood, liver, bone and heart, MK-4 (one form of vitamin K2) is the form primarily measured in the pancreas. The function of MK-4 in the pancreas is not clear, however, it might act as a potent amplifier of the incretin effect (20). Novel data support a role of statins in modifying vitamin K status. Harshman et al. recently demonstrated for the first time in vivo that statins reduce endogenous production of MK-4 in mouse kidney by approximately 40% (43). There is emerging data in support of a role for vitamin K in glucose homeostasis (19, 44). In patients with diabetes, vitamin K2 supplementation improved insulin sensitivity (44). However, in healthy people, vitamin K supplementation had no effect on glycemic indices. The uncarboxylated form of osteocalcin (ucOC), a bone derived vitamin K dependent protein that functions as a hormone, has also been implicated in regulating insulin secretion and sensitivity in mice possibly via GPRC6A, a receptor for ucOC (45). Taken together, emerging evidence suggests a role for vitamin K in energy metabolism that may be modified by a statin-induced decrease in MK-4 production in the pancreas.
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Statin use is associated with insulin resistance in participants of the Canadian Multicentre Osteoporosis Study
Journal of the Endocrine Society 15 May 2020 - Karen J. Rees-Milton1 PhD, Patrick Norman2 MSc, Corinne Babiolakis1, Maggie Hulbert1 BSc, Mandy E Turner3 BSc, Claudie Berger4 MSc, Tassos P. Anastassiades1,3, PhD, MD, Wilma M Hopman2,5 MA, Michael A. Adams3 PhD, Wendy L. Powley6 MSc and Rachel M. Holden1,3 MD
1 Department of Medicine, Queen's University, Kingston, ON
2 Kingston General Health Research Institute, Kingston, ON
3 Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON
4 Research Institute of the McGill University Health Centre, Montreal, QC
5 Department of Public Health Sciences, Queen's University, Kingston, ON
6 School of Computing, Queen's University, Kingston, ON
Abstract
Context
Statins have been linked to the development of diabetes and atherosclerotic plaque calcification in patients with cardiac disease.
Objective
To determine the association between statin use and statin characteristics and insulin resistance and abdominal aortic calcification (AAC) in participants of the Canadian Multicentre Osteoporosis Study (CaMos).
Design
Observational study
Setting
General community
Participants
Non-diabetic participants of the Kingston CaMos site
Intervention
Insulin resistance and AAC in statin users and non-statin users were compared with and without the inclusion of a propensity score (PS) to be on a statin. The covariates of hypertension, sex, BMI, smoking, kidney stones and age that were included in the PS were selected based on clinical judgment confirmed by statistical analysis of a difference between statin users and non-statin users.
Main Outcome Measures
Insulin resistance measured by the homeostasis model assessment (HOMA-IR) and AAC assessed on lateral spine radiographs using Framingham methodology.
Results
Using a general linear model, statin use was associated with higher levels of HOMA after stratified PS adjustment [β=1.52, (1.18-1.95), p<0.01]. Hydrophilic statin users (n=9) and lipophilic statins users (n=30) had higher HOMA compared to non-statin users (n=125) ([β=2.29, (1.43-3.68), p<0.001] and [β=1.36, (1.04-1.78), p<0.05]) respectively] in general linear models after stratified PS adjustment. Statin use was associated with AAC without stratifying by PS in the Wilcoxon test, but was no longer significant when stratified by PS.
Conclusions
Statins, widely prescribed drugs to lower cholesterol, may have unintended consequences related to glucose homeostasis that could be relevant in healthy aging.
Introduction
Hypercholesterolemia is a major cardiovascular risk factor and an important therapeutic target. Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitors, are a first line therapy to lower cholesterol levels and thus are widely prescribed drugs. Analysis of the drug dispensing patterns of a Seniors Pharmacare Program in Canada showed a dramatic increase in statin prescription, from 5% to 20%, between the years 2000 and 2013 (1).
Statins have been shown to consistently reduce cardiovascular events in the general population and are thus amongst the first-line therapies for patients at high risk for cardiovascular disease. Statins reduce atherosclerosis by decreasing low-density lipoprotein (LDL) cholesterol and by improving endothelial function (2, 3). However, statins may also have less desirable pleiotropic actions including a reduction in insulin secretion and worsening of insulin resistance (4-6). Some, but not all, large trials of primary prevention have reported an increased incidence of diabetes with statins (7, 8). From a pooled analysis of randomized trials, factors associated with the development of diabetes in statin users included elevated triglycerides, elevated body mass index and a history of hypertension (9). However, these studies continued to demonstrate a reduction in cardiovascular endpoints despite the increased incidence of diabetes thus no change in clinical practice has occurred.
Several factors are proposed to contribute to the pleiotropic effects of statins. First, the pleiotropic actions of statins may differ based on the lipophilicity versus the hydrophilicity of the particular statin drug (10, 11) suggesting that certain statins may decrease cardiovascular risk without increasing the risk of diabetes. Pravastatin and rosuvastatin are hydrophilic statins whereas atorvastatin, fluvastatin, lovastatin and simvastatin are lipophilic. Hydrophilic statins require carrier-mediated uptake while lipophilic statins may diffuse passively through the hepatocellular membrane thus lipophilic statins tend to have been implicated in the development of insulin resistance. The second factor contributing to pleiotropic effects of statins is potency. Rosuvastatin is transported with greater affinity than lipophilic statins, despite being a hydrophilic drug, and is the most potent statin drug to reduce LDL-cholesterol levels. Potency is a second consideration when comparing pleiotropic effects of different statins. In one meta-analysis, rosuvastatin carried the highest risk for the development of type 2 diabetes (12).
Statin drugs have not consistently shown a similar level of cardiovascular benefit in patients with low kidney function and an increased risk of stroke was observed to be associated with statins in one large, well-conducted randomized controlled trial (13). Evidence from one study of patients with reduced kidney function demonstrated that statin drug use was associated with greater severity of coronary artery calcification (CAC) at baseline and greater progression of calcification over 1.5 years (14). A critical tissue-based inhibitor of vascular calcification is matrix Gla protein (MGP), one of several vitamin K dependent proteins in the body (15, 16). There is emerging data to suggest that by inhibiting the production of intermediates of cholesterol biosynthesis, statins also inhibit the mevalonate pathway and impede the production of vitamin K2 in peripheral tissues (17, 18). There is growing evidence to suggest that vitamin K2 plays a key role in glucose homeostasis (19-22) as well as vascular calcification (23-27). On this background, we hypothesized that statin use would be associated with both insulin resistance and vascular calcification in community dwelling participants of a large longitudinal study of osteoporosis.
Our primary objective was firstly to evaluate the association between statin use and insulin resistance assessed by the homeostasis model assessment (HOMA-IR) in non-diabetic participants at year 10 from the Kingston center of the population-based observational Canadian Multicenter Osteoporosis Study (CaMos) (28) and secondly to evaluate the association between statin use and abdominal aortic calcification (AAC) assessed by the Framingham method in participants at year 10 of the CaMos study. Our secondary objective was to explore the impact of the hydrophilicity versus lipophilicity of the specific statin drug on the outcomes.
Results
Differences between statin users and non-statin users in HOMA-IR, AAC and covariates predicted to influence statin use
Table 1 demonstrates demographic and clinical variables at year 10 of follow-up in the Kingston site cohort overall (n=609) as well as stratified by statin users (n=152) versus non-users (n=457). Participants had a median age of 71, the majority (74%) were female, 33% percent had diabetes, more than half had smoked at some point and 44% had a history of hypertension. Compared to non-statin users, statin users were significantly older with greater BMI and were more likely to be male, have hypertension, have diabetes, and have a history of smoking and kidney stones. Statin users had significantly higher HOMA-IR levels (Table 1, Figure 2) (2.6 [1.9-4.4] vs 1.7 [1-2.9], p<0.001). The AAC score was also significantly higher in statin users.
Adjustment for propensity to be on a statin when comparing HOMA and AAC in statin users and non-statin users
Statin users were compared to non-statin users with and without the inclusion of a PS to be on a statin included in the statistical analysis. Variables included in the PS included age, sex, hypertension, BMI, smoking, and kidney stones. HOMA-IR and AAC were higher in statin users with and without the PS included in the statistical analysis (Table 2). HOMA-IR was significantly higher in statin users in the general linear model with log transformed HOMA unadjusted for the PS (exp(β) = 1.64 (1.29, 2.08), p<0.001) and with adjustment for the PS (exp(β) =1.52, (1.18, 1.95, p<0.01). Statin use was associated with higher AAC without the stratifying by PS in the Wilcoxon test, but was no longer significant when stratified by PS.
Influence of statin type on HOMA, AAC and covariates predicted to influence statin use
We examined participant characteristics, demographics, HOMA-IR and AAC based on the hydrophilicity/lipophilicity of the particular statin drug. As demonstrated in Table 3, users of hydrophilic statins were slightly older with lower BMI but were more likely to be male, have hypertension or have kidney stones. HOMA-IR was significantly higher in hydrophilic statin users compared to lipophilic statin users (exp(β)=1.79, (1.15, 2.79), p<0.05). Compared to non-statin users, HOMA was higher in those on hydrophilic statins with (exp(β)=2.29, (1.43-3.68), p<0.001) and without (exp(β)=2.60, (1.63-4.14), p<0.001) PS stratification, as well as in those on lipophilic statins with (exp(β)=1.36, (1.04-1.78), p<0.05) and without (exp(β)=1.45, (1.12-1.88), p<0.01) PS stratification(Table 4). We examined rosuvastatin users separately due to the inherent potency of this particular statin. Compared to lipophilic statin users, HOMA was higher in rosuvastatin users with (exp(β)=2.42, (1.45-4.03), p<0.001) and without (exp(β)=2.80, (1.7-4.61), p<0.001) PS stratification.
Discussion
In this cohort of community-dwelling participants, users of lipophilic and hydrophilic statins had higher levels of insulin resistance compared to non-statin users with and without propensity score adjustment. Insulin resistance was greater in hydrophilic statin users compared to lipophilic statin users. Although previous studies have implicated lipophilicity as a risk factor for this pleiotropic effect of statins, 73% of the hydrophilic statins in use in this study were rosuvastatin, a high potency statin that has been shown in one other study to have the highest risk for the development of diabetes (12). With respect to calcification, statin users had higher AAC but this was no longer significant after propensity score adjustment.
Although not a disease, insulin resistance appears to be associated with the development of cardiovascular disease based on a meta-analysis of published data from 20 studies (32). The development of impaired fasting glucose resulted in progressively higher risk of developing myocardial infarction, cardiovascular disease and mortality in a large observational study of Korean patients (33). Over time, insulin resistance can lead to type 2 diabetes as the pancreas fails to keep up with the body's increasing demands for insulin. These metabolic abnormalities pre-date the development of diabetes by more than 10 years (34). Although many risk factors for insulin resistance have been identified, obesity remains the most important.
With regards to statins, the balance between the benefits of cardiovascular risk reduction versus the cardiovascular risk associated with the development of insulin resistance is not known. Previous studies have implicated statins in the development of diabetes. In a meta-analysis of 17 randomized controlled trials, twelve trials involved studies of secondary prevention whilst the remaining trials studied patients with baseline risk factors (12). Treatment with rosuvastatin had the highest incidence of new-onset diabetes mellitus (DM) (25% increase) whilst pravastatin was deemed 'safest'. The risk for developing DM was not influenced by the different abilities of statins to reduce cholesterol. In the JUPITER trial, a trial of primary prevention, there was a 27% increase in relative risk for physician reported DM in rosuvasatin-treated patients compared to placebo (7). However, despite this apparent risk for diabetes, rosuvastatin significantly reduced the incidence of major cardiovascular events. The Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials determined that the overall diabetogenic impact of atorvastatin treatment was modest. However, it was accentuated dramatically by BMI increase and levels of fasting plasma glucose and triglycerides. This trial was conducted in patients with coronary artery disease (35). Taken together, in previous studies high potency and lipophilic statins appear to increase the risk of developing type 2 diabetes and in our study were associated with increasing insulin resistance. The data suggest that it might be prudent to monitor the glycemic status in those at greatest risk for diabetes and consider lower risk statins in those with risk factors. Further consideration for other pharmacological and non-pharmacological options might also be considered.
Several mechanisms have been proposed to explain the association between statins and new-onset diabetes as reviewed by Brault et al (36). Statins may impact on calcium channels in pancreatic β-cells where an increase in intracellular calcium concentration stimulates insulin secretion. In vitro work suggests that statins block calcium channels suggesting that this is a direct, rather than an indirect, impact of statin drugs. Reduced translocation of glucose transporter 4 has also been implicated suggesting that statins may decrease glucose uptake and increase insulin resistance in adipose tissue, muscle and liver. The impact of statins on adipocyte maturation and differentiation has been evaluated primarily in vitro and in pre-clinical models. An eight-day incubation of 3T3-L1 cells with various statins showed a concentration-dependent inhibition of adipocyte differentiation that may be mediated by inhibition of the transcription factor PPAR-γ (37, 38). As pre-adipocytes do not secrete insulin-sensitizing hormone, the accumulation of undifferentiated adipocytes could contribute to insulin resistance. Pre-clinical studies have also demonstrated that statins have a selective effect on the secretion of adiponectin, an insulin sensitizing adipokine (39). However, studies in vivo have demonstrated both an increase in subcutaneous adipose tissue in obese rats as well as a reduction in adiposity suggesting that the relationship between statin therapy and changes in adiposity is uncertain and requires further study (40, 41)."
By inhibiting HMG-CoA reductase, there are statin-associated downstream effects on the production of other products of the cholesterol biosynthetic pathway including coenzyme 10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate and dolichol. Depletion of these substrates may lead to a downstream reduction of intracellular signalling. Coenzyme Q10 supplementation has been shown to improve glucose homeostasis in various patient populations. In an eight week trial of simvastatin treated patients, Coenzyme Q10 did not change muscle GLUT4 content, insulin sensitivity or secretory capacity. However, hepatic insulin sensitivity appeared to improve (42). Geranylgeranyl pyrophosphate is a key intermediate in the conversion of dietary vitamin K1 to MK-4. Whilst vitamin K1 is the predominant vitamin K form measured in blood, liver, bone and heart, MK-4 (one form of vitamin K2) is the form primarily measured in the pancreas. The function of MK-4 in the pancreas is not clear, however, it might act as a potent amplifier of the incretin effect (20). Novel data support a role of statins in modifying vitamin K status. Harshman et al. recently demonstrated for the first time in vivo that statins reduce endogenous production of MK-4 in mouse kidney by approximately 40% (43). There is emerging data in support of a role for vitamin K in glucose homeostasis (19, 44). In patients with diabetes, vitamin K2 supplementation improved insulin sensitivity (44). However, in healthy people, vitamin K supplementation had no effect on glycemic indices. The uncarboxylated form of osteocalcin (ucOC), a bone derived vitamin K dependent protein that functions as a hormone, has also been implicated in regulating insulin secretion and sensitivity in mice possibly via GPRC6A, a receptor for ucOC (45). Taken together, emerging evidence suggests a role for vitamin K in energy metabolism that may be modified by a statin-induced decrease in MK-4 production in the pancreas.
In this study of community-dwelling people, we did not find an association between statin use and AAC after PS adjustment. Previous studies examining the impact of statins on calcification have evaluated patients with established atherosclerotic disease. In a post-hoc patient-level analysis of eight prospective randomized trials that employed serial coronary intravascular ultrasound, serial changes in coronary percent atheroma volume and calcium were measured in patients with established coronary artery disease (46). Independent of their plaque-regressive effects, statins promoted coronary artery atheroma calcification suggesting a potential role for statins in stabilizing plaque. Our method of calcification measurement does not distinguish between medial and intimal calcification. One study pooled data from two clinical trials involving atorvastatin and a placebo, and examined CAC scores assessed by computed tomography at baseline, two years and at four to six years. After two years of follow-up, a similar increase in CAC score was noted between placebo and low dose atorvastatin. However, at the later time point, atorvastatin use was associated with greater progression of CAC compared to placebo. However, this change did not appear to be clinically significant as the increase in CAC did not translate into more clinical events. Whether an absence of clinical impact would also apply to patients with a propensity to calcify, such as those with reduced kidney function, is not known. The potential tipping point between a beneficial effect of statins on plaque calcification and stabilization versus the impact on progressive arterial medial calcification and vessel stiffening on outcomes including tissue perfusion and cardiomyopathy is unknown.
The percentage of total Kingston CaMos participants taking statins closely mirrors the percentage of seniors taking statins at the same time period in a Canadian Seniors Pharmacare Program (1) . The sex difference in statin use likely reflects the greater proportion of men that would be classified as high cardiovascular disease risk using American College of Cardiology and the American Heart Association and Canadian Cardiovascular Society guidelines. This higher percentage of male compared to female statin users was also seen in the Canadian Health Measures Survey 2007-2011 (47).
There are limitations to our study. The CaMos cohort was a random sample of community living individuals. However, the sampling framework was developed to give greater representation to older women, given the focus on osteoporosis. This may restrict generalizability to other groups. Secondly, the study is cross-sectional; long-term studies would be necessary to resolve the temporal relationship between statin use and the development and progression of insulin resistance. Although we used PS matching in an attempt to eliminate confounding by indication, there is still room for bias based on unobserved or inaccurately measured confounders. Finally, we do not have cholesterol levels or statin doses in these participants. However, a meta-analysis that included 17 randomized controlled trials concluded that the risk for developing DM was not influenced by the degree to which the statin reduced cholesterol (12) . The small sample size in our study limited the analysis of statin type (hydrophilic versus lipophilic) on calcification severity and progression.
In summary, in the Kingston CaMos cohort, statin users had higher indices of insulin resistance. Users of hydrophilic statins had greater HOMA levels; however the majority of the participants were taking the high-potency statin rosuvastatin. Statins, widely prescribed drugs to lower cholesterol, may have unintended consequences related to glucose homeostasis that could be relevant in healthy aging. In those individuals with risk factors for diabetes, consideration for choosing non-lipophilic statins and avoidance of rosuvasatin and lipophilic statins may provide the intended cardiovascular protection without the increased incidence of insulin resistance.
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