is the Increased Resistance to a Drug s Effects Accompanying Continued Use

Highlights

Statin therapy decreases the risk of atherosclerotic cardiovascular disease but increases the risk of type 2 diabetes.
It is unclear whether the increased type 2 diabetes risk is caused by increased insulin resistance or decreased insulin secretion.
We conducted an open-label clinical trial of atorvastatin 40 mg daily in 75 adults without known atherosclerotic cardiovascular disease or type 2 diabetes.
High-intensity atorvastatin for 10 weeks increased insulin resistance and insulin secretion, measured by the insulin suppression test and the graded-glucose infusion test, respectively.
Investigations are needed into the cellular mechanisms of increased insulin resistance and the trajectory of insulin secretion with long-term statin therapy.

Introduction

See accompanying editorial on page 2798

Statin treatment dramatically decreases the risk of atherosclerotic cardiovascular disease (ASCVD) by decreasing plasma levels of atherogenic lipoproteins.^1–4 Statins are among the most prescribed medications in the world, and statin treatment is indicated for nearly half of the United States adult population either for primary or secondary prevention.⁵ Statins are generally well tolerated but clinical trial data suggest that statin therapy is associated with an ≈10% overall increased risk of incident type 2 diabetes (T2D)^6–10 over 5 years. This risk is increased in those with prediabetes and insulin resistance.^11,12

The mechanisms for statin-related T2D are unclear. There is evidence that statins may adversely impact both insulin resistance and secretion. In that context, studies have shown that treatment with statins is associated with increase in fasting insulin^13–15 as well as increase in insulin resistance as assessed by measures obtained during the oral glucose tolerance test (OGTT).^9,16 For example, Cederberg et al⁹ showed in a large prospective study (N=8749 men) that participants treated with statins (N=2142) had a 46% increase in incident T2D, associated with a 24% increase in insulin resistance and a 12% decrease in insulin secretion. These conclusions were based on surrogate estimates of insulin resistance and secretion which are only modestly correlated with direct measures of insulin action and secretion.^17–19 On the contrary, in small studies of 18 to 20 individuals that quantified insulin resistance by direct methods, insulin resistance did not significantly increase after treatment with pravastatin, simvastatin, or rosuvastatin.^20–23 Furthermore, the effect of statin therapy on insulin secretion has not been evaluated with direct methods. Finally, different statins may also differently affect glucose and insulin metabolism^10,21–23 and direct assessments of the effect of atorvastatin (recommended as first line by current guidelines⁴) on insulin resistance and secretion are less available. Therefore, there is insufficient understanding of the effects that statins have on insulin resistance and insulin secretion, which limits our ability to identify the underlying mechanisms for this unwanted side effect and devise means to ameliorate it.

To investigate the mechanism of statin-related T2D, we conducted an open-label clinical trial to determine whether treatment with atorvastatin increases whole body insulin resistance and decreases insulin secretion as quantified by sensitive and reproducible direct methods.

Materials and Methods

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request, and summary statistics are available at ClinicalTrials.gov.

Study Design

This was an open-label, single group, prospective study to evaluate the effect of high-dose atorvastatin therapy on insulin resistance and insulin secretion rate. Each participant served as his or her own control. The study was performed between 2015 and 2019 at the Stanford Clinical and Translational Research Unit. The study was approved by Stanford University's Institutional Review Board, and all participants gave written informed consent.

Study Participants

We recruited volunteers from the San Francisco Bay Area without T2D who were eligible for statin therapy for primary prevention of ASCVD. We excluded individuals with statin intolerance; marked kidney, liver, or heart disease; anemia or active malignancy (Figure 1). Detailed inclusion and exclusion criteria are presented in Appendix in the Data Supplement. Our goal was to ensure recruitment across a broad range of insulin resistance. We and others have shown that high plasma triglyceride concentrations are associated with increased insulin resistance as assessed by gold-standard measures.^24,25 Therefore, we targeted advertisements to enrich for individuals with high triglyceride levels (≥150 mg/dL) as a surrogate for increased insulin resistance. Individuals who were receiving statin therapy were included if they were able to undergo a 4-week statin washout with approval of their treating physician. The decision to include persons previously treated with statins was encouraged by the results of the study of Ahmadizar et al¹⁵ showing that risk of incident diabetes is higher in current but not past users of statins. Of the 71 subjects whose data was analyzed, 44 (62%) were statin naive and 27 (38%) were receiving statin therapy at enrollment (statin exposed).

**Figure 1.** **Study participant flow.** GGIT indicates graded-glucose infusion test; IST, insulin suppression test; and OGTT, oral glucose tolerance test.

Study Visits

Participants gave written informed consent and were screened for the study on visit 1. Those who qualified underwent an OGTT on visit 2. Within 2 weeks, they were scheduled for the baseline graded-glucose infusion test (GGIT) and insulin suppression test (IST) which were generally performed about a week apart from one another. On the day of their last baseline test, a lipid panel with calculated LDL-C (low-density lipoprotein cholesterol) was performed and this was considered their baseline lipid panel.

Once participants completed the last baseline test (IST or GGIT) they were started on atorvastatin 40 mg daily (week zero). Study participants were asked to make no changes to their diet, weight, or physical activity during the study.

While on atorvastatin, study participants were seen every 2 weeks from week zero to week 10 (Table I in the Data Supplement). The OGTT was repeated at week 8, the GGIT at week 9 and the IST at week 10 while participants remained on atorvastatin. The lipid panel completed on the day of the final test was considered their statin-treated lipid panel. Body mass index and blood pressure were assessed using standard techniques (Appendix in the Data Supplement).

Oral Glucose Tolerance Test

Following a 12-hour fast, participants had a 75 g OGTT (Appendix in the Data Supplement). Blood was collected at baseline and 30, 60, 90, 120 minutes following an oral glucose load. Prediabetes (abnormal glucose tolerance [AGT]) was defined as presence of having fasting glucose ≥100 mg/dL, 2-hour OGTT glucose ≥140 mg/dL, or both.

Graded-Glucose Infusion Test

Insulin secretion was quantified during the GGIT as previously reported²⁶ after an overnight fast (Appendix in the Data Supplement). The GGIT measures insulin secretion rate by deconvolution of peripheral C-peptide concentrations in response to increases in intravenous glucose.²⁷ The primary metric of insulin secretion during the GGIT is the insulin secretion rate area under the curve (ISR_AUC), where a higher ISR_AUC indicates greater insulin secretion rate than a lower ISR_AUC. Hereafter, for ease of use, we refer to ISR_AUC (in pmol/min×4 h) as insulin secretion except in the statistical analysis section.

Insulin Suppression Test

Insulin resistance was quantified by a modified version of the IST²⁸ after an overnight fast (Appendix in the Data Supplement). The IST measures peripheral insulin-stimulated glucose uptake, which primarily occurs in skeletal muscle. The primary metric of insulin resistance during the IST is the steady-state plasma glucose (SSPG) concentration, where a higher SSPG concentration indicates greater insulin resistance than a lower SSPG concentration. Insulin resistance measured by the IST highly correlates with that measured by the euglycemic hyperinsulinemic clamp.²⁹ Hereafter, for ease of use, we refer to SSPG concentration (in mg/dL) as insulin resistance except in the statistical analysis section.

Laboratory Measurements

Insulin, glucose, and C-peptide measurements were performed at the Core Laboratory for Clinical Studies at Washington University School of Medicine. Lipids were measured at the Stanford Health Care Clinical Laboratory (Appendix in the Data Supplement).

Outcomes

The co-primary outcomes were changes in insulin resistance during the IST and insulin secretion during the GGIT. Secondary outcomes included glucose and insulin concentrations measured fasting and during the OGTT. A prespecified subgroup analysis compared results between insulin sensitive versus insulin resistant participants. Additional analyses were performed by glucose tolerance status and by the diagnosis of the metabolic syndrome.³⁰

Statistical Analysis

Based on our prior work,³¹ we calculated that with 60 subjects, we would be able to detect an 8% change in insulin resistance (SSPG concentration) and an 8% change in insulin secretion (ISR_AUC) after atorvastatin therapy with 80% power and 2-side significance level of 5% using a paired sample t test. Thus, we estimated needing to enroll 75 subjects with an anticipated dropout rate of 20%.

Summary statistics are reported as median (interquartile range) or number (percent) of participants unless otherwise specified. Shapiro-Wilk tests were used to assess normality of data, and variables that were not normally distributed were log-transformed, including: C-peptide, Homeostasis Model Assessment of Insulin Resistance, hs-CRP (high sensitivity C-reactive protein), insulin, ISR_AUC, SSPG, steady-state plasma insulin, and triglycerides. Percent changes in variables were calculated by the formula: ([end-of-study value]−[baseline value]/baseline value)×100. Paired sample t tests were used to compare baseline and end-of-study means. One sample t tests were employed to evaluate whether percent changes in variables were significantly different from zero (no change). Pearson correlation coefficients were calculated to determine the strength of association between variables of interest. Prespecified subgroup analyses were performed by stratifying for insulin resistant versus insulin sensitive subjects. Baseline SSPG concentration median (138 mg/dL) was used to define subjects as being insulin resistant (SSPG >138 mg/dL) or insulin sensitive (SSPG ≤138 mg/dL). As insulin resistance is a continuous trait, the median SSPG cut point (138 mg/dL) was informed by a prospective study of apparently healthy individuals, those with similar SSPG concentration (≥143 mg/dL) developed more cardiovascular disease (hypertension, coronary heart disease, stroke, or peripheral vascular disease) than those with SSPG below that cut point.³² Subgroup means were compared by independent samples t tests and proportions by χ² tests or Fisher exact tests. Statistical analyses were performed by using statistical software IBM SPSS version 26.0.

Results

Participants

Of the 132 volunteers who were screened, 115 qualified for the study and 75 participants completed baseline studies and began statin therapy (Figure 1). For the primary outcomes of insulin resistance and insulin secretion, complete data were available for 70 and 64 participants, respectively. This included 18 participants with a baseline triglyceride concentration ≥150 mg/dL (enriched for insulin resistance). The median length of time between the first and last IST was 77 days (interquartile range [IQR], 70–84).

The median age of the study participants was 61 years; 37% were women; and 65% were non-Hispanic White (Table II in the Data Supplement). At baseline, the overall study group was overweight (median body mass index, 27.8 kg/m²) with elevations in total and LDL-cholesterol concentrations (237 and 156 mg/dL, respectively; Table IV in the Data Supplement). There were 45 (63.4%) participants with AGT and 26 (36.6%) with normal glucose tolerance (NGT; Table VIII in the Data Supplement). Participant with AGT had higher body mass index, were more insulin resistant and had higher insulin secretion than those with NGT. There were 29 (40.8%) participants with the metabolic syndrome and 42 (59.2%) without the metabolic syndrome (Table IX in the Data Supplement). Participants with the metabolic syndrome were more insulin resistant and had higher insulin secretion than those without the metabolic syndrome. Correlations between baseline variables are shown in Table III in the Data Supplement and are consistent with prior findings. Baseline fasting insulin strongly correlated with baseline insulin resistance (r=0.74; P<0.001) and insulin secretion (r=0.80; P<0.001).

Effect of Atorvastatin on Body Weight and Concentrations of Lipids, Glucose, and Insulin

Statin therapy reduced total cholesterol by 37%, LDL-C by 53%, and triglycerides by 28% (Table IV in the Data Supplement). There was no change in body weight.

Effect of Atorvastatin on Insulin Resistance

Statin treatment significantly increased insulin resistance, a co-primary outcome. Across the entire study population, the median insulin resistance (ie, SSPG) increased from 130 to 139 mg/dL (P=0.01) while the median percent increase in insulin resistance was 8% (IQR, −10% to 32%; Table; Figure 2A, Figure I in the Data Supplement). Steady-state plasma insulin decreased by 5%, but there was no significant correlation between the change in steady-state plasma insulin and the change in insulin resistance (data not shown).

****Table.** Effect of Atorvastatin on Primary and Secondary Outcomes of Insulin Resistance and Insulin Secretion (N=71)***
Variable	Baseline	End-of-study	P value†
Primary outcomes
Insulin suppression test
Insulin resistance (by SSPG, mg/dL)	130 (85–193)	139 (93–211)	0.01
SSPI, mU/L	64.7 (54.6–75.4)	61.3 (55.7–71.4)	0.02
Graded-glucose infusion test
Insulin secretion (by ISR_AUC, pmol/min×4 h)	1824 (1385–2549)	1942 (1480–2755)	<0.001
Glucose_AUC, mmol/L×4 h	31.2 (28.0–34.5)	31.8 (28.4–34.7)	0.10
Insulin_AUC, pmol/L×4 h	652 (430–1108)	712 (458–1263)	0.001
C-peptide_AUC, nmol/L×4 h	6.5 (4.9–8.3)	6.5 (5.3–8.9)	<0.001
Secondary outcomes
Fasting glucose, mg/dL	99 (92–108)	100 (94–107)	0.10
Fasting insulin, mU/L	10.1 (7.3–14.8)	10.6 (7.6–15.1)	0.01
HOMA-IR	2.44 (1.71–3.73)	2.68 (1.81–4.07)	0.01
OGTT Glucose_AUC, mg/dL×2 h	295 (241–336)	299 (254–339)	0.03
OGTT Insulin_AUC, mU/L×2 h	127 (74–217)	133 (88–218)	0.27

**Figure 2.** **Effect of atorvastatin treatment on insulin resistance and insulin secretion.** In A, waterfall plot depicts percent change in insulin resistance, measured by steady-state plasma glucose (SSPG), during the insulin suppression test (N=70). The mean (95% CI) percent change in SSPG concentration was 15 (6–23) mg/dL. One sample t test was used to compare mean percent change in SSPG to zero (no change). In B, baseline and end-of-study insulin secretion rate (ISR) mean (SEM) values are plotted against the incremental increase in plasma glucose during the graded-glucose infusion test (N=64). Baseline and end-of-study ISR area under the curve (ISR_AUC) means were compared by paired sample t test after log-transformation of ISR_AUC values.

There was no significant relationship between the change in LDL-C and the change in insulin resistance (Pearson correlation, −0.06, P=0.65). In addition, the small changes in weight that did occur were not significantly associated with changes in insulin resistance (Pearson correlation, 0.08, P=0.50). There was no difference in effect of statin treatment on insulin resistance in those who were statin naive versus those who were statin exposed (median percent change, 7%; IQR, −10% to 36% versus 11%; IQR −10 to 26%, respectively; P=0.81).

In terms of secondary outcomes, there was a small but significant increase in glucose_AUC during the OGTT (0.05%; IQR, −0.1% to 0.2%). Fasting insulin levels were increased by 7% (IQR, −4% to 27%) and Homeostasis Model Assessment of Insulin Resistance by 11% (IQR, −4% to 23%) after statin treatment (Table).

Effect of Atorvastatin on Insulin Secretion

During the GGIT, glucose_AUC was similar but insulin_AUC and C-peptide_AUC significantly increased following statin treatment (Table). Thus, the dose-response relationship between glucose and rate of insulin secretion was shifted higher by statin treatment, resulting in a significant increase in insulin secretion (ie, ISR_AUC; (P<0.001), a co-primary outcome (Figure 2B). The median percent increase in insulin secretion was 9% (IQR, −2% to 19%; Figure II in the Data Supplement). There was no significant relationship between the change in LDL-C and the change in insulin secretion (Pearson correlation, 0.12; P=0.35). There was no difference in effect of statin treatment on insulin secretion in those who were statin naive versus statin exposed at the time of enrollment (median percent increase, 11%; IQR, 1% to 29% versus 8%; IQR, −4% to 16%, respectively; P=0.28).

Effect of Atorvastatin on the Relationship Between Insulin Resistance and Insulin Secretion

At baseline, there was a positive (r=0.68; P<0.001) relationship between insulin resistance and insulin secretion, confirming that insulin secretion increases linearly with increase in insulin resistance (Figure III in the Data Supplement). To explore this interaction, we plotted the percent change in insulin secretion against the percent change in insulin resistance for each participant where full data were available (N=63; Figure 3). There was an enrichment of participants in the upper right quadrant (N=29, 46%), indicating an increase in insulin resistance accompanied by an increase in insulin secretion. However, there remained a fraction of the study participants (N=9, 14%) who experienced an increase in insulin resistance and a decrease in insulin secretion.

**Figure 3.** **Relationship between change in insulin resistance and change in insulin secretion after atorvastatin treatment.** The 4-quadrant scatterplot shows data on 63 individuals who underwent both the insulin suppression test and the graded-glucose infusion test. Number of subjects in each quadrant is shown. Percent change was calculated by using the formula: ([end-of-study value]−[baseline value]/baseline value)×100. ISR_AUC indicates insulin secretion rate area under the curve; and SSPG, steady-state plasma glucose.

Effect of Atorvastatin in Insulin Resistant Versus Insulin Sensitive Participants

Compared with insulin sensitive participants, those with insulin resistance at baseline (as defined in the statistical section) were heavier, were more likely to have dyslipidemia with higher median triglyceride (122 versus 90 mg/dL) and lower HDL-cholesterol (46 versus 61 mg/dL) levels, and had higher median fasting glucose (103 versus 97 mg/dL) and insulin concentrations (14.8 versus 7.9 mU/L). Among the insulin sensitive and insulin resistant participants, there were no difference in the distribution of individuals who were statin naïve versus statin exposed (P=0.74; Tables V, VI, and VII in the Data Supplement).

Statins were equally effective in lowering LDL-C in insulin resistant versus insulin sensitive participants and changes in weight, glucose, and insulin were also similar between the 2 groups (Tables VI and VII in the Data Supplement).

Insulin resistance increased in both insulin sensitive and insulin resistant participants (baseline values of 86 and 194 mg/dL which increased to 93 and 208 mg/dL, respectively) though only the difference in insulin sensitive participants was significant (Table VII and Figure IV in the Data Supplement). The median percent change in insulin resistance was a 16% increase (IQR, −3% to 50%) in insulin sensitive participants versus a 1% increase in insulin resistant participants (IQR, −21% to 14%; Figure V in the Data Supplement). The changes in insulin resistance also paralleled changes in fasting insulin in both the insulin sensitive and insulin resistant participants (Table VII in the Data Supplement). To further examine the effect of baseline insulin resistance on statin-related increases in insulin resistance, a regression analysis was performed to determine if baseline insulin resistance predicted changes in insulin resistance after atorvastatin treatment. The results showed that baseline insulin resistance was a significant predictor of percent change in insulin resistance where lower baseline insulin resistance was associated with greater increase in insulin resistance (standardized coefficient, −0.39, P <0.001). For example, an individual with a baseline insulin resistance (ie, SSPG) of 100 mg/dL would have a 23% increase in insulin resistance after atorvastatin therapy, whereas a person with baseline insulin resistance of 200 mg/dL would have a 3% increase in insulin resistance.

There was little difference in the change in insulin secretion between insulin sensitive and insulin resistant participants. The median percent change in insulin secretion was 11% in insulin sensitive participants (IQR, −3% to 23%) versus 9% in insulin resistant participants (IQR, −2% to 18%; Table VII in the Data Supplement).

Effect of Atorvastatin on Insulin Resistance and Insulin Secretion by Glucose Tolerance Status

Insulin resistance did not significantly increase in persons with AGT, but it did increase in those with NGT. The median percent change in insulin resistance was 5% in participants with AGT (IQR, −11% to 17%; P=0.07) versus 13% in participants with NGT (IQR, −1% to 53%; P=0.004). Insulin secretion significantly increased both in individuals with AGT and in those with NGT. The median percent change in insulin secretion was 11% in participants with AGT (IQR, −4% to 19%; P<0.001) versus 9% in participants with NGT (IQR, −0.0002% to 23%; P=0.01).

Effect of Atorvastatin on Insulin Resistance and Insulin Secretion by the Diagnosis of the Metabolic Syndrome

Insulin resistance did not significantly increase in persons with the metabolic syndrome, whereas it did increase in those without the metabolic syndrome. The median percent change in insulin resistance was 4%, in participants with the metabolic syndrome (IQR, −11% to 16%; P=0.21) versus 11% in participants without the metabolic syndrome (IQR, −7% to 41%; P=0.004). Insulin secretion significantly increased both in persons with the metabolic syndrome and in those without the metabolic syndrome. The median percent change in insulin secretion was 8% in participants with the metabolic syndrome (IQR, −3% to 16%; P=0.01) versus 11% in participants without the metabolic syndrome (IQR, −1% to 24%; P<0.001).

Other Subgroup Exploratory Analyses

Atorvastatin treatment was associated with similar increases in insulin resistance and insulin secretion in subgroup analyses stratified by sex, race/ethnicity, age, body mass index, triglycerides, glucose tolerance, and the metabolic syndrome (Figure 4).

**Figure 4.** **Changes in insulin resistance and insulin secretion in subgroups after atorvastatin treatment.** Forest plots depict changes in insulin resistance (A) and insulin secretion (B) in the whole group and in subgroups based on baseline characteristics: insulin resistance status, sex, race/ethnicity, age, body mass index (BMI), triglycerides (TG), glucose tolerance, and diagnosis of the metabolic syndrome (MetSyn). Data are means and 95% CIs. Within each subgroup, means were compared by independent samples t tests. Only the differences in insulin resistance (A) between insulin sensitive and insulin resistant subgroups were significantly different (P=0.002). AGT indicates abnormal glucose tolerance; ISR_AUC, insulin secretion rate area under the curve; NGT, normal glucose tolerance; NHW, non-Hispanic White; and SSPG, steady-state plasma glucose.

Discussion

Statin therapy, a cornerstone of ASCVD prevention also increases the risk of developing T2D.^{6–9,11,12,33,34} Individuals with T2D generally have defects in both insulin action and secretion as hyperglycemia only ensues when the insulin secretory response is inadequate. However, prior studies have not been able to determine whether statins increase the risk of T2D primarily by increasing insulin resistance or by decreasing insulin secretion.^35,36 Our results show that treatment with high-dose atorvastatin for 10 weeks increases insulin resistance and insulin secretion.

The modest increase we observed in insulin resistance (median 8% increase in SSPG) is likely the primary abnormality associated with statin treatment. Increase in insulin secretion is likely secondary and compensates for increase in insulin resistance and maintains glucose homeostasis in the short term.³⁷ Increases in insulin resistance have been reported in prior studies using surrogate estimates of insulin resistance. These studies showed that statin therapy was associated with increases in fasting insulin^13–15 as well as increases in insulin resistance assessed by OGTT-based measures.^9,16 However, differences in insulin resistance were not seen in several prior smaller studies using gold-standard methods in nondiabetic individuals^20–23,38 treated with statins for 8 to 12 weeks. All of these trials enrolled 20 or fewer individuals and only 2 used what would be considered high-intensity statin therapy (ie, rosuvastatin 40 mg daily).^22,23 In contrast, in a study of 32 patients with type IIA and IIB dyslipidemia, treatment with pravastatin 10 to 20 mg per day for 3 months led to relatively small but significant increases in insulin resistance as measured by the IST.²⁴

We did not observe obvious differences by sex, age or race/ethnicity. However, we saw proportionately greater increases in insulin resistance in those who were more insulin sensitive at baseline. This may represent a ceiling effect for some insulin resistant participants. In that vein, we have observed that those with marked insulin resistance at baseline may not get substantially more insulin resistant even with modest weight gain.³⁹

The mechanism of increase in insulin resistance associated with statin therapy is unclear. Some literature suggests that long-term statin use could cause weight gain and thereby increase insulin resistance.⁴⁰ However, we detected an increase in insulin resistance without an increase in weight gain. Recent genetic observations have corroborated a potentially negative role of increased intracellular cholesterol for T2D and insulin resistance. Individuals with naturally occurring mutations that inhibit HMGCR have low plasma LDL-C levels, but increased intracellular cholesterol levels and a greater risk of T2D⁴¹ while individuals with mutations in the LDLR (low-density lipoprotein receptor) have extreme elevations in plasma LDL-C levels but a decreased prevalence of T2D proportional to the severity of the LDLR mutation.⁴² Other proposed mechanisms for how statins may increase insulin resistance include deregulation of intracellular or membrane bound cholesterol levels⁴³; suppression of intracellular levels of isoprenoids⁴⁴; perturbation of insulin signaling pathways^45–47; accumulation of free fatty acids⁴⁸; and mitochondrial dysfunction^49,50; all of which have been associated with increased insulin resistance.^51–56 Additional human studies are needed to determine if these or other mechanisms explain our results.

In addition to an increase in insulin resistance, we also show that short-term statin treatment increases insulin secretion, a well-known compensatory response to increases in insulin resistance.³⁷ Prior studies examining the effect of statin therapy on insulin secretion used surrogate measures and reported disparate results. In a prospective, randomized, double-blind, placebo-controlled study of 28 women with polycystic ovarian syndrome, treatment with atorvastatin 20 mg per day for 6 months increased insulin secretion measured by the insulinogenic index.¹⁶ In contrast, in a prospective study of 8749 men without diabetes, treatment with atorvastatin or simvastatin was associated with decreases in insulin secretion measured by OGTT-derived disposition index after a follow up of 5.9 years.⁹ In contrast to the prior studies that employed surrogate estimates of insulin secretion, we quantified insulin secretion using a direct method to evaluate the effect of atorvastatin treatment on insulin secretion.

The short duration of our study did not allow us to determine the trajectory of insulin secretion with long-term statin therapy. Nevertheless, our results provide some insights into the potential course of beta cell function over time. As seen in Figure 3, insulin secretion increased with increase in insulin resistance in the majority of participants (upper right quadrant). This pattern indicates that the increase in insulin secretion was driven by change in insulin resistance to maintain glucose homeostasis. In other participants (lower right quadrant), insulin secretion decreased despite increase in insulin resistance. This pattern may indicate an inability to compensate for increase in insulin resistance and might be a harbinger of statin-related T2D. Lastly, in some participants (upper left quadrant), insulin secretion increased despite a decrease or no change in insulin resistance. This pattern may represent an independent effect of statins to increase insulin secretion.

The cellular mechanisms that could explain the increased insulin secretion are not completely understood though some evidence suggests that exposure of pancreatic beta cells to increased LDL-C levels may disrupt glucose homeostasis. First, incubating human and mouse pancreatic beta cells and islets with LDL-C decreases glucose-stimulated insulin secretion and increases cell death.^57–59 Second, statin treatment of mouse pancreatic islets in vitro reduced intracellular cholesterol levels and enhanced insulin secretion.⁶⁰ Finally, in vivo studies in high-fat fed mice suggests that atorvastatin treatment preserves beta cell function, increases proliferation, and reduces ER stress and apoptosis.⁶¹ We cannot exclude the possibility that long-term statin treatment could adversely affect insulin secretion and note that lifelong deletion of Hmgcr in mouse beta cells causes a decrease in beta cell mass and insulin secretion.⁶²

Persons with greater severity of the metabolic syndrome are at higher risk for developing incident T2D due to statin use.^33,34 In that regard, individuals with the metabolic syndrome have features such as greater insulin resistance and higher fasting glucose that increase their risk of T2D. Consistent with that, in our study, participants with the metabolic syndrome were more insulin resistant than those without the metabolic syndrome (Table IX in the Data Supplement). In addition, participants with more elements of the metabolic syndrome had greater insulin resistance and higher insulin secretion than those with fewer elements of the metabolic syndrome (Table X in the Data Supplement). However, after statin therapy, insulin resistance did not increase in participants with the metabolic syndrome but insulin secretion did increase (Figure 4). Due to the short duration of our study, we could not determine the trajectories of insulin resistance and insulin secretion with statin use as a function of the severity of the metabolic syndrome. With long-term statin therapy, T2D likely occur in those individuals with the metabolic syndrome who develop additional increases in insulin resistance (due to statins, weight gain, or physical inactivity) and are unable to maintain increase in insulin secretion to compensate for insulin resistance.

Adverse effects such as T2D are associated with a lack of acceptance and underutilization of statins.^63,64 Our study should not be interpreted as an argument against the use of statins. In primary prevention, modeling suggests that treatment of 10 000 patients with an underlying ASCVD risk of 5% to 10% over 5 years with atorvastatin 40 mg daily for 5 years would be expected to cause an excess of about 100 new cases of T2D.³ Among the subset of 100 patients with incident (excess) statin-related T2D, even if statin-related T2D doubles the risk of an ASCVD resulting in an excess of 5 to 10 ASCVD events, this small number of excess events pales in comparison to the estimated 500 major ASCVD events that would be prevented.³ Furthermore, clinical trial data suggests that statin-related T2D may not markedly increase risk.³³

The risk of statin-related T2D varies considerably depending on the population. In large statin trials both insulin resistance and prediabetes are independent risk factors for statin-related T2D and when they co-exist the risk of incident T2D over 7 years is 20%^11,12 versus 3% when neither insulin resistance nor prediabetes is present. However, those at risk for statin-related T2D also have higher ASCVD risk. Therefore, the net clinical benefit of statins remains substantial even if those benefits are nominally blunted by statin-related, incident T2D. An analysis of the primary prevention JUPITER trial limited to the 486 participants (out of 17 603) who developed T2D during a median follow-up of 1.9 years (N=270 on rosuvastatin 20 mg daily, N=216 on placebo), showed that the cardiovascular risk reduction associated with rosuvastatin (hazard ratio, 0.63 versus placebo) was consistent with that observed for the entire trial (hazard ratio, 0.56 versus placebo) and that rosuvastatin accelerated the diagnosis of T2D by only about 5.4 weeks (84.3 versus 89.7 weeks).⁸ Given the unambiguous effects of statins in reducing the risk of ASCVD, it is imperative to emphasize healthy diet and lifestyle choices such as physical activity and maintenance of a healthy body weight to offset statin-related insulin resistance and T2D.

Limitations of our study include a single-center trial design with a single dose of atorvastatin without a placebo control group. However, we demonstrate adherence with statin treatment with resultant decreases in LDL-C accompanied by significant changes in insulin resistance and insulin secretion. Participants in our study were without diabetes and ASCVD and may not have been representative of the general population of patients taking statins. We are not able to determine the primary tissue responsible for the increase in insulin resistance. As the IST quantifies insulin-mediated glucose uptake primarily at skeletal muscle, it is likely that the increase in insulin resistance by atorvastatin occurs in skeletal muscle. In general, muscle insulin resistance parallels adipose tissue insulin resistance. We have shown that insulin-mediated glucose uptake, highly correlates with insulin-mediated suppression of lipolysis.⁶⁵ Our study was also short term and longer trials are needed to assess for potential decreases in insulin secretion or further increases in insulin resistance.

Strengths of our study include that we investigated the mechanism of statin-related T2D by using gold-standard methods for accurately measuring both insulin resistance and insulin secretion in a relatively large number of participants (N=71). The study subjects were treated with a commonly used high-intensity statin (atorvastatin 40 mg daily). Furthermore, baseline insulin resistance of our study participants varied several-fold.

In summary, we found that short-term treatment with high-intensity atorvastatin therapy results in increases in insulin resistance accompanied by increases in insulin secretion. Over time, the risk of new-onset T2D associated with statin therapy may increase in those individuals who become more insulin resistant but are unable to maintain compensatory increase in insulin secretion. All individuals on statin therapy should be encouraged to mitigate risk of diabetes through healthy lifestyle incorporating a nutrition and exercise plan. Finally, although our study provides insights into a potential mechanism of statin-related T2D, investigations are needed into the cellular mechanisms of increased insulin resistance and the trajectory of insulin secretion with long-term statin therapy.

Article Information

Acknowledgments

We thank all the individuals in the trial for their participation as well as the staff of the Stanford Clinical and Translational Research Unit for their assistance. We thank David Maron, Fatima Rodriguez, and David Waters for helpful comments. Gerald Reaven, MD, died on February 12, 2018.

Sources of Funding

The Doris Duke Charitable Foundation, grant No. 2016097 provided major funding for this trial. Dr Knowles is supported by the National Institutes of Health (NIH) through grants: P30DK116074 (to the Stanford Diabetes Research Center), R01 DK116750, R01 DK120565, R01 DK106236; and by the American Diabetes Association (grant No. 1-19-JDF-108). Dr Kim is supported by the Bose Family Foundation and P30DK116074. The Washington University at St. Louis Diabetes Research Center central lab is supported by NIH grant P30 DK020579. Dr Snyder was supported by the Metabolic Health Center through Lucille Packard Children's Hospital, the Stanford Precision Health and Integrated Diagnostics Initiative and the NIH R01 AT01023203. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR003142. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Supplemental Materials

Expanded Materials and Methods

Data Supplement Tables I–X

Data Supplement Figures I–V

References ^1–3

Nonstandard Abbreviations and Acronyms

ASCVD	atherosclerotic cardiovascular disease
GGIT	graded-glucose infusion test
hs-CRP	high sensitivity C-reactive protein
IQR	interquartile range
ISRAUC	insulin secretion rate area under the curve
IST	insulin suppression test
LDL-C	low-density lipoprotein cholesterol
NGT	normal glucose tolerance
OGTT	oral glucose tolerance test
SSPG	steady-state plasma glucose
T2D	type 2 diabetes

Footnotes

References

1. Baigent C, Blackwell L, Emberson Jet al. . Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670–81. doi: 10.1016/S0140-6736(10)61350-5CrossrefMedlineGoogle Scholar
2. Taylor F, Huffman MD, Macedo AFet al. . Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev . 2013: CD004816. doi: 10.1002/14651858.CD004816.pub5CrossrefGoogle Scholar
3. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, et al. . Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet . 2016; 388:2532–2561. doi: 10.1016/S0140-6736(16)31357-5CrossrefMedlineGoogle Scholar
4. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, et al. . 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol . 2019; 73:3168–3209. doi: 10.1016/j.jacc.2018.11.002CrossrefMedlineGoogle Scholar
5. Pencina MJ, Navar-Boggan AM, D'Agostino RB, Williams K, Neely B, Sniderman AD, Peterson ED. Application of new cholesterol guidelines to a population-based sample. N Engl J Med . 2014; 370:1422–1431. doi: 10.1056/NEJMoa1315665CrossrefMedlineGoogle Scholar
6. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, et al. . Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet . 2010; 375:735–742. doi: 10.1016/S0140-6736(09)61965-6CrossrefMedlineGoogle Scholar
7. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, et al. . Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA . 2011; 305:2556–2564. doi: 10.1001/jama.2011.860CrossrefMedlineGoogle Scholar
8. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet . 2012; 380:565–571. doi: 10.1016/S0140-6736(12)61190-8CrossrefMedlineGoogle Scholar
9. Cederberg H, Stančáková 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/s00125-015-3528-5CrossrefMedlineGoogle Scholar
10. Olotu BS, Shepherd MD, Novak S, Lawson KA, Wilson JP, Richards KM, Rasu RS. Use of statins and the risk of incident diabetes: a retrospective cohort study. Am J Cardiovasc Drugs . 2016; 16:377–390. doi: 10.1007/s40256-016-0176-1CrossrefMedlineGoogle Scholar
11. Kohli P, Waters DD, Nemr R, Arsenault BJ, Messig M, DeMicco DA, Laskey R, Kastelein JJP. Risk of new-onset diabetes and cardiovascular risk reduction from high-dose statin therapy in pre-diabetics and non-pre-diabetics: an analysis from TNT and IDEAL. J Am Coll Cardiol . 2015; 65:402–404. doi: 10.1016/j.jacc.2014.10.053CrossrefMedlineGoogle Scholar
12. Kohli P, Knowles JW, Sarraju A, Waters DD, Reaven G. Metabolic markers to predict incident diabetes mellitus in statin-treated patients (from the treating to new targets and the stroke prevention by aggressive reduction in cholesterol levels trials). Am J Cardiol . 2016; 118:1275–1281. doi: 10.1016/j.amjcard.2016.07.054CrossrefMedlineGoogle Scholar
13. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol . 2010; 55:1209–1216. doi: 10.1016/j.jacc.2009.10.053CrossrefMedlineGoogle Scholar
14. Thongtang N, Ai M, Otokozawa S, Himbergen TV, Asztalos BF, Nakajima K, Stein E, Jones PH, Schaefer EJ. Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation. Am J Cardiol . 2011; 107:387–392. doi: 10.1016/j.amjcard.2010.09.031CrossrefMedlineGoogle Scholar
15. Ahmadizar F, Ochoa-Rosales C, Glisic M, Franco OH, Muka T, Stricker BH. Associations of statin use with glycaemic traits and incident type 2 diabetes. Br J Clin Pharmacol . 2019; 85:993–1002. doi: 10.1111/bcp.13898CrossrefMedlineGoogle Scholar
16. Puurunen J, Piltonen T, Puukka K, Ruokonen A, Savolainen MJ, Bloigu R, Morin-Papunen L, Tapanainen JS. Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab . 2013; 98:4798–4807. doi: 10.1210/jc.2013-2674CrossrefMedlineGoogle Scholar
17. Reaven GM. HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not? Diab Vasc Dis Res . 2009; 6:133–138. doi: 10.1177/1479164109336038CrossrefMedlineGoogle Scholar
18. Ingelsson E, Langenberg C, Hivert MF, Prokopenko I, Lyssenko V, Dupuis J, Mägi R, Sharp S, Jackson AU, Assimes TL, et al. ; MAGIC investigators. Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes . 2010; 59:1266–1275. doi: 10.2337/db09-1568CrossrefMedlineGoogle Scholar
19. Pisprasert V, Ingram KH, Lopez-Davila MF, Munoz AJ, Garvey WT. Limitations in the use of indices using glucose and insulin levels to predict insulin sensitivity: impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans. Diabetes Care . 2013; 36:845–853. doi: 10.2337/dc12-0840CrossrefMedlineGoogle Scholar
20. Galvan AQ, Natali A, Baldi S, Frascerra S, Sampietro T, Galetta F, Seghieri G, Ferrannini E. Effect of a reduced-fat diet with or without pravastatin on glucose tolerance and insulin sensitivity in patients with primary hypercholesterolemia. J Cardiovasc Pharmacol . 1996; 28:595–602. doi: 10.1097/00005344-199610000-00019CrossrefMedlineGoogle Scholar
21. Altunbaş H, Balci MK, Karayalçin U. No effect of simvastatin treatment on insulin sensitivity in patients with primary hypercholesterolemia. Endocr Res . 2003; 29:265–275. doi: 10.1081/erc-120025034CrossrefMedlineGoogle Scholar
22. ter Avest E, Abbink EJ, de Graaf J, Tack CJ, Stalenhoef AF. Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia. Eur J Clin Invest . 2005; 35:558–564. doi: 10.1111/j.1365-2362.2005.01549.xCrossrefMedlineGoogle Scholar
23. Lamendola C, Abbasi F, Chu JW, Hutchinson H, Cain V, Leary E, McLaughlin T, Stein E, Reaven G. Comparative effects of rosuvastatin and gemfibrozil on glucose, insulin, and lipid metabolism in insulin-resistant, nondiabetic patients with combined dyslipidemia. Am J Cardiol . 2005; 95:189–193. doi: 10.1016/j.amjcard.2004.09.005CrossrefMedlineGoogle Scholar
24. Sheu WH, Shieh SM, Fuh MM, Shen DD, Jeng CY, Chen YD, Reaven GM. Insulin resistance, glucose intolerance, and hyperinsulinemia. Hypertriglyceridemia versus hypercholesterolemia. Arterioscler Thromb . 1993; 13:367–370. doi: 10.1161/01.atv.13.3.367LinkGoogle Scholar
25. Armato J, Ruby R, Reaven G. Plasma triglyceride determination can identify increased risk of statin-induced type 2 diabetes: a hypothesis. Atherosclerosis . 2015; 239:401–404. doi: 10.1016/j.atherosclerosis.2015.02.010CrossrefMedlineGoogle Scholar
26. Kim SH, Abbasi F, Chu JW, McLaughlin TL, Lamendola C, Polonsky KS, Reaven GM. Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals. Diabetes . 2005; 54:2447–2452. doi: 10.2337/diabetes.54.8.2447CrossrefMedlineGoogle Scholar
27. Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes . 1992; 41:368–377. doi: 10.2337/diab.41.3.368CrossrefMedlineGoogle Scholar
28. Pei D, Jones CN, Bhargava R, Chen YD, Reaven GM. Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test. Diabetologia . 1994; 37:843–845. doi: 10.1007/BF00404344CrossrefMedlineGoogle Scholar
29. Knowles JW, Assimes TL, Tsao PS, Natali A, Mari A, Quertermous T, Reaven GM, Abbasi F. Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism . 2013; 62:548–553. doi: 10.1016/j.metabol.2012.10.002CrossrefMedlineGoogle Scholar
30. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation . 2009; 120:1640–1645. doi: 10.1161/CIRCULATIONAHA.109.192644LinkGoogle Scholar
31. Kim SH, Liu A, Ariel D, Abbasi F, Lamendola C, Grove K, Tomasso V, Reaven G. Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study. Diabetologia . 2014; 57:455–462. doi: 10.1007/s00125-013-3134-3CrossrefMedlineGoogle Scholar
32. Yip J, Facchini FS, Reaven GM. Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J Clin Endocrinol Metab . 1998; 83:2773–2776. doi: 10.1210/jcem.83.8.5005CrossrefMedlineGoogle Scholar
33. Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, Kastelein JJ, Colhoun H, Barter P. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol . 2011; 57:1535–1545. doi: 10.1016/j.jacc.2010.10.047CrossrefMedlineGoogle Scholar
34. Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, Breazna A, Pedersen TR. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol . 2013; 61:148–152. doi: 10.1016/j.jacc.2012.09.042CrossrefMedlineGoogle Scholar
35. Betteridge DJ, Carmena R. The diabetogenic action of statins - mechanisms and clinical implications. Nat Rev Endocrinol . 2016; 12:99–110. doi: 10.1038/nrendo.2015.194CrossrefMedlineGoogle Scholar
36. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res . 2019; 124:328–350. doi: 10.1161/CIRCRESAHA.118.312782LinkGoogle Scholar
37. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes . 1988; 37:1595–1607. doi: 10.2337/diab.37.12.1595CrossrefMedlineGoogle Scholar
38. Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract . 2010; 87:98–107. doi: 10.1016/j.diabres.2009.10.008CrossrefMedlineGoogle Scholar
39. McLaughlin T, Craig C, Liu LF, Perelman D, Allister C, Spielman D, Cushman SW. Adipose cell size and regional fat deposition as predictors of metabolic response to overfeeding in insulin-resistant and insulin-sensitive humans. Diabetes . 2016; 65:1245–1254. doi: 10.2337/db15-1213CrossrefMedlineGoogle Scholar
40. Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, Sofat R, Stender S, Johnson PC, Scott RA, et al. ; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium. HMG-coenzyme a reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet . 2015; 385:351–361. doi: 10.1016/S0140-6736(14)61183-1CrossrefMedlineGoogle Scholar
41. Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, et al. . Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med . 2016; 375:2144–2153. doi: 10.1056/NEJMoa1604304CrossrefMedlineGoogle Scholar
42. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA . 2015; 313:1029–1036. doi: 10.1001/jama.2015.1206CrossrefMedlineGoogle Scholar
43. Parpal S, Karlsson M, Thorn H, Strålfors P. Cholesterol depletion disrupts caveolae and insulin receptor signaling for metabolic control via insulin receptor substrate-1, but not for mitogen-activated protein kinase control. J Biol Chem . 2001; 276:9670–9678. doi: 10.1074/jbc.M007454200CrossrefMedlineGoogle Scholar
44. Chamberlain LH. Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes. FEBS Lett . 2001; 507:357–361. doi: 10.1016/s0014-5793(01)03007-1CrossrefMedlineGoogle Scholar
45. Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia . 2006; 49:1881–1892. doi: 10.1007/s00125-006-0269-5CrossrefMedlineGoogle Scholar
46. Takaguri A, Satoh K, Itagaki M, Tokumitsu Y, Ichihara K. Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes. J Pharmacol Sci . 2008; 107:80–89. doi: 10.1254/jphs.fp0072403CrossrefMedlineGoogle Scholar
47. Li W, Liang X, Zeng Z, Yu K, Zhan S, Su Q, Yan Y, Mansai H, Qiao W, Yang Q, et al. . Simvastatin inhibits glucose uptake activity and GLUT4 translocation through suppression of the IR/IRS-1/Akt signaling in C2C12 myotubes. Biomed Pharmacother . 2016; 83:194–200. doi: 10.1016/j.biopha.2016.06.029CrossrefMedlineGoogle Scholar
48. Kain V, Kapadia B, Misra P, Saxena U. Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism. Sci Rep . 2015; 5:13823. doi: 10.1038/srep13823CrossrefMedlineGoogle Scholar
49. Mullen PJ, Zahno A, Lindinger P, Maseneni S, Felser A, Krähenbühl S, Brecht K. Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt. Biochim Biophys Acta . 2011; 1813:2079–2087. doi: 10.1016/j.bbamcr.2011.07.019CrossrefMedlineGoogle Scholar
50. Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol . 2013; 61:44–53. doi: 10.1016/j.jacc.2012.09.036CrossrefMedlineGoogle Scholar
51. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med . 2004; 350:664–671. doi: 10.1056/NEJMoa031314CrossrefMedlineGoogle Scholar
52. Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes . 2005; 54:1392–1399. doi: 10.2337/diabetes.54.5.1392CrossrefMedlineGoogle Scholar
53. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes . 2006; 55 Suppl 2:S9–S15. doi: 10.2337/db06-S002CrossrefMedlineGoogle Scholar
54. Patti ME, Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev . 2010; 31:364–395. doi: 10.1210/er.2009-0027CrossrefMedlineGoogle Scholar
55. Kleiner S, Mepani RJ, Laznik D, Ye L, Jurczak MJ, Jornayvaz FR, Estall JL, Chatterjee Bhowmick D, Shulman GI, Spiegelman BM. Development of insulin resistance in mice lacking PGC-1α in adipose tissues. Proc Natl Acad Sci USA . 2012; 109:9635–9640. doi: 10.1073/pnas.1207287109CrossrefMedlineGoogle Scholar
56. Johnson Andrew MF, Olefsky Jerrold M. The origins and drivers of insulin resistance. Cell . 2013; 152:673–684. doi: 10.1016/j.cell.2013.01.041CrossrefMedlineGoogle Scholar
57. Cnop M, Hannaert JC, Grupping AY, Pipeleers DG. Low density lipoprotein can cause death of islet beta-cells by its cellular uptake and oxidative modification. Endocrinology . 2002; 143:3449–3453. doi: 10.1210/en.2002-220273CrossrefMedlineGoogle Scholar
58. Roehrich ME, Mooser V, Lenain V, Herz J, Nimpf J, Azhar S, Bideau M, Capponi A, Nicod P, Haefliger JA, et al. . Insulin-secreting beta-cell dysfunction induced by human lipoproteins. J Biol Chem . 2003; 278:18368–18375. doi: 10.1074/jbc.M300102200CrossrefMedlineGoogle Scholar
59. Rütti S, Ehses JA, Sibler RA, Prazak R, Rohrer L, Georgopoulos S, Meier DT, Niclauss N, Berney T, Donath MY, et al. . Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells. Endocrinology . 2009; 150:4521–4530. doi: 10.1210/en.2009-0252CrossrefMedlineGoogle Scholar
60. Wijesekara N, Zhang LH, Kang MH, Abraham T, Bhattacharjee A, Warnock GL, Verchere CB, Hayden MR. miR-33a modulates ABCA1 expression, cholesterol accumulation, and insulin secretion in pancreatic islets. Diabetes . 2012; 61:653–658. doi: 10.2337/db11-0944CrossrefMedlineGoogle Scholar
61. Chen ZY, Liu SN, Li CN, Sun SJ, Liu Q, Lei L, Gao LH, Shen ZF. Atorvastatin helps preserve pancreatic β cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress. Lipids Health Dis . 2014; 13:98. doi: 10.1186/1476-511X-13-98CrossrefMedlineGoogle Scholar
62. Takei S, Nagashima S, Takei A, Yamamuro D, Wakabayashi T, Murakami A, Isoda M, Yamazaki H, Ebihara C, Takahashi M, et al. . β-Cell-Specific Deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase causes overt diabetes due to reduction of β-Cell mass and impaired insulin secretion. Diabetes . 2020; 69:2352–2363. doi: 10.2337/db19-0996CrossrefMedlineGoogle Scholar
63. Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J . 2016; 37:908–916. doi: 10.1093/eurheartj/ehv641CrossrefMedlineGoogle Scholar
64. Fung V, Graetz I, Reed M, Jaffe MG. Patient-reported adherence to statin therapy, barriers to adherence, and perceptions of cardiovascular risk. PLoS One . 2018; 13:e0191817. doi: 10.1371/journal.pone.0191817CrossrefMedlineGoogle Scholar
65. Abbasi F, McLaughlin T, Lamendola C, Reaven GM. The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers. J Clin Endocrinol Metab . 2000; 85:1251–1254. doi: 10.1210/jcem.85.3.6450MedlineGoogle Scholar

millarnerty1951.blogspot.com

Source: https://www.ahajournals.org/doi/10.1161/ATVBAHA.121.316159