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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

ABSTRACT: Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of ABCG1 through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at ABCG1 and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, n = 2741), with validation in the Women's Health Initiative Study (WHI, n = 2020). The causal effect of statin use on the risk of type 2 diabetes was examined using a two-step Mendelian randomization approach. Next, based on transcriptome analysis, we determined the links between the medication-associated epigenetic status of ABCG1 and biological pathways on the pathogenesis of type 2 diabetes. Our results showed that DNA methylation levels at cg06500161 of ABCG1 were positively associated with the use of statin, type 2 diabetes and related traits (fasting glucose and insulin) in FHS and WHI. Two-step Mendelian randomization suggested a causal effect of statin use on type 2 diabetes and related traits through epigenetic mechanisms, specifically, DNA methylation at cg06500161. Our results highlighted that gene expression of ABCG1, ABCA1 and ACSL3, involved in both cholesterol metabolism and glycemic pathways, was inversely associated with statin use, CpG methylation, and diabetic signatures. We concluded that DNA methylation site cg06500161 at ABCG1 is a mediator of the association between statins and risk of type 2 diabetes.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7308584 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

Liu Yuwei Y Shen Yu Y Guo Tao T Parnell Laurence D LD Westerman Kenneth E KE Smith Caren E CE Ordovas Jose M JM Lai Chao-Qiang CQ

Frontiers in genetics 20200616

Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of ABCG1 through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at ABCG1 and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, n = 27 ...[more]

PMID: 32612641

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Project description:To test associations between statin use and cognitive impairment in adults with childhood-onset type 1 diabetes (T1D).In 2010-13, n = 108 middle-aged participants from ongoing observational Pittsburgh Epidemiology of Diabetes Complications Study underwent neurocognitive assessment (mean age and T1D duration of 49 and 41 years, respectively). All were diagnosed with childhood-onset (i.e., prior to age 18) T1D between 1950 and 1980 and were seen within one year of diagnosis at Children's Hospital of Pittsburgh. Self-reported statin use (yes/no and if yes, name of statin) was collected biennially from parent study baseline (1986-1988) to time of neurocognitive testing. Logistic regression models tested associations between statin use groups and cognitive impairment (defined as having two or more cognitive test scores 1.5SD or worse than published norms) while linear regression models tested associations between statin use groups and cognitive domain z-scores (domains: Verbal IQ, memory, executive function, psychomotor speed, and visuo-construction). All models controlled for education and age. To address confounding by indication, models were repeated using a propensity score for statin use.Of the 108 participants, 51 reported never using statins. Median duration of statin use among the 57 ever users was 6 years. These 57 ever statin users were split to create two groups (≤ or > median years of statin use): 1-6 years (n = 25), and 7-12 years (n = 32). Compared with never users, using statins 1-6 years tripled the odds of cognitive impairment (OR = 3.16; 95%CI: 0.93-10.72; P = 0.06) and using statins 7-12 years almost quintupled the odds of cognitive impairment (OR = 4.84; 95%CI: 1.63-14.44; P = 0.005). Compared with never users, using statins 1-6 or 7-12 years was related to worse performance in the memory domain (β = -0.52; P = 0.003, and -0.39; P = 0.014, respectively). Adjusting for coronary artery disease, low density lipoprotein cholesterol, and Apo E4 status did not substantially alter results, and none of these covariates were significantly related to cognitive outcomes (all P > 0.05). Propensity score analyses support that associations between poor cognitive outcomes and statin use were not due merely to confounding by indication.Statin use was associated with cognitive impairment, particularly affecting memory, in these middle-aged adults with childhood-onset T1D, whom at this age, should not yet manifest age-related memory deficits.

Project description:BACKGROUND:We evaluated the effect of statin use on new-onset type 2 diabetes among individuals without atherosclerotic cardiovascular disease (ASCVD) using nationally representative South Korean claims data (2002-2013, N?=?1,016,820). METHODS:A total of 13,698 patients (statin users 5273, non-statin users 5273) aged 40-74 years, newly diagnosed with dyslipidemia but without any history of diabetes or ASCVD, were selected in 2005. We followed up the final sample until 2013 and evaluated the cumulative incidence of type 2 diabetes. We used extended Cox regression models to estimate the time-varying adjusted hazard ratios of statin use on new-onset type 2 diabetes. We performed further analyses based on the cumulative defined daily dose of statin received per year to evaluate the degree of risk compared to non-statin users. RESULTS:Over the mean follow-up period of 7.1 years, 3034 patients developed type 2 diabetes; the number of statin users exceeded that of non-users, demonstrating that statin use significantly increased the risk of new-onset type 2 diabetes. The risk of new-onset type 2 diabetes differed among statin users according to cDDD per year (adjusted HR?=?1.31 [95% CI 1.18-1.46] for less than 30 cDDD per year; 1.58 [1.43-1.75] for 30-120 cDDD per year; 1.83 [1.62-2.08] for 120-180 cDDD per year; and 2.83 [2.51-3.19] for more than 180 cDDD per year). The diabetogenic effect of pitavastatin was not statistically significant, but the risk was the largest for atorvastatin. Long-term exposure (??5 years) to statins was associated with a statistically significant increase in the risk of new onset type 2 diabetes in all statin subtypes explored, with the highest magnitude for simvastatin (HR?=?1.916, 95% CI 1.647-2.228) followed by atorvastatin (HR?=?1.830, 95% CI 1.487-2.252). CONCLUSIONS:Statin use was significantly associated with an increased risk of new-onset type 2 diabetes. We also found a dose-response relationship in terms of statin use duration and dose maintenance. Periodic screening and monitoring for incident type 2 diabetes may be warranted in long-term statin users.

Project description:BackgroundEven though statins have been proven to be effective in both primary and secondary prevention of cardiovascular disease among diabetic patients, a suboptimal use of the latter has been detected in real clinical practice, especially among older adults.ObjectiveThis study aimed to evaluate the patterns and predictors of statin use among elderly patients with type 2 diabetes mellitus (T2DM) in Lebanon.MethodsThis is a cross-sectional study that extended between April 2021 and February 2022. Our study involved elderly T2DM outpatients, aged 65-80 years, who presented to 40 community pharmacies for prescription filling. Diabetes status was ascertained via dispensed medication information, and patients were classified based on the American Diabetes Association preset risk scores for cardiovascular diseases in diabetics: low, moderate, or high risk. The questionnaire included patients' demographics, clinical information, and status of statin use.ResultsA total of 420 diabetic geriatric patients were observed in this study; their mean age was 70 years (± 7), and there was a predominance of males, 270 (64.3%). Almost all patients were classified as being at high risk, 396 (94.3%), while the rest were at moderate risk; thus, all were recommended to receive statins; however, statin prescription was only reported among 197 (46.9%), with atorvastatin and rosuvastatin being the most used: 102 (51.8%) and 62 (31.5%), respectively. Of patients prescribed statins, 60 (14.3%) were taking them for primary prevention and 137 (32.6%) for secondary prevention. Patients having a higher Charlson Comorbidity Index score had lesser odds of being prescribed statins (odds ratio [OR] 0.15, 95% confidence interval [CI] 0.02-0.8, p = 0.028); however, those presenting with a history of dyslipidemia and coronary artery disease had higher odds of statin prescription (OR 10.5, 95% CI 4.2-26.1, p < 0.001, and OR 5.0, 95% CI 2.4-10.5, p < 0.001, respectively).ConclusionDespite patients' eligibility to receive statins, statin undertreatment was evident among elderly outpatients with T2DM in Lebanon, which was modulated by several predictors.

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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at <i>ABCG1</i>.

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