Role of Statins in New-onset Diabetes Mellitus: The Underlying Cause, Mechanisms Involved, and Strategies to Combat

Statins have transformed the treatment of cardiovascular diseases through primary and secondary prevention of events. Despite the success of statin's inefficient management of cardiovascular conditions, certain clinical trials, reviews, and meta-analysis point out that statins have the propensity to induce diabetes. The risk further increases with intensive statin therapy or in with patients with diabetes. A proper mechanism for the induction of the diabetic condition has not yet been determined. The involvement of statin with beta cells in insulin secretion and peripheral cells in insulin resistance has been widely studied and established. The present review provides an update on recent understanding of statin-induced diabetes. This covers the origin of statins, their development, possible mechanisms that explain the adverse effects in glucose homeostasis, and probable targets to remedy the condition.

Intensive versus non-intensive statin pretreatment before percutaneous coronary intervention in Chinese patients: a meta-analysis of randomized controlled trials

Background: The results of intensive statin pretreatment before percutaneous coronary intervention (PCI) is inconsistent between Chinese and Western populations and there are no corresponding meta-analyses involving hard clinical end-points in the available published literature. The aim of this study was to evaluate the efficacy and safety of high-dose statin loading before PCI in Chinese patients through a meta-analysis. Method: Relevant studies were identified by searching the electronic databases of PubMed, Embase, and Cochrane’s Library to December 2019. The outcomes included an assessment of major adverse cardiovascular event (MACE), non-fatal myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), myalgia/myasthenia and abnormal alanine aminotransferase (ALT) in all enrolled patients. Results: 12 studies involving 3,183 individuals were included．The results showed statistically significant different in the incidence of MACE (RR=0.49, 95% CI: 0.30-0.80, P=0.004, I2=63%) and non-fatal MI (RR=0.54, 95% CI: 0.33-0.88, P= 0.01, I2=62%) on comparing the intensive statin and non-intensive statin treatment groups. Subgroup analysis further suggested the benefits of different treatments were inconsistent. Compared with preoperative intensive statin therapy, the incidence of MACE and non-fatal MI were significantly elevated in patients receiving placebo or no statin treatment before surgery (RR=0.47, 95% CI: 0.34-0.65, P<0.00001, I2=0%; RR=0.49, 95% CI: 0.35-0.70, P<0.0001, I2=0%). However, the incidence of MACE and non-fatal MI were not statistically significant when comparing preoperative high-intensity statin therapy with moderate-intensity statin therapy (RR=0.96, 95% CI: 0.44-2.08, P=0.91, I2=11%; RR=1.10, 95% CI: 0.86-1.39, P=0.44). The study also demonstrated that the Asian population could tolerate high-intensity atorvastatin during the perioperative period. Conclusion: Compared with placebo or no statin pretreatment, Chinese patients receiving intensive statin therapy before PCI displayed reduced incidence of MACE and non-fatal MI. However, there was no significant benefit between high-intensity and moderate-intensity statin treatment. Further, the Chinese population tolerated well preoperative intensive statin pretretment.

Abstract WP337: Age and Race Disparities in Statin Prescribing Persist Following Discharge for Stroke or Transient Ischemic Attack

Introduction: Prescribing of high intensity statins (atorvastatin 40-80mg/d, rosuvastatin 20-40mg/d) following acute stroke and anti-coagulants in the subgroup with atrial fibrillation (AF) result in reduced risk for a second stroke. Recent data suggests that high intensity statins are less often prescribed for older patients and real-world data are limited for direct-acting oral anti-coagulants (DOAC). The present study examines discharge prescribing patterns for these medications by age and race from a prospective trial in 41 hospitals in North Carolina. Methods: Data are from the Comprehensive Post-Acute Stroke Services Study, a cluster-randomized trial of transitional care for adult stroke or TIA patients discharged directly home after hospital discharge. Analyses included 3787 patients [mean age 66 yrs., 47% female; 30% non-white] linked to the Get-with-the-Guidelines (GWTG) database. Prescribing of intensive statin therapy as well as rivaroxaban or apixaban vs. warfarin in those with a history of AF was abstracted, and was compared by age (< 65 vs. ≥ 65yr.), race (white vs. non-white) and gender. Odds ratios were obtained from logistic mixed models with a random intercept for hospital. Results: Among 3096 patients prescribed statin therapy at discharge, 61% were prescribed intensive statin therapy. Patients who were ≥ 65yr. had significantly lower odds of intensive statin therapy prescription than younger patients (OR=0.54, 95% CI 0.45-0.65); results were similar across all sex-race subgroups. Among 366 patients with a history of AF who were prescribed an anti-coagulant at discharge, 72% were prescribed rivaroxaban or apixaban. Among 254 patients ≥ 65yr., 26 of 39 non-white patients (67%) vs. 156 of 215 white patients (73%) were prescribed rivaroxaban or apixaban [p=0.29]. Conclusion: Intensive statin therapy following mild stroke or TIA is significantly less common in older patients compared with those under age 65. Among patients ≥65yr. with a history of AF and acute stroke, there was minimal difference by race in rivaroxaban or apixaban prescribing. Prescription fills/refills and adherence should be further explored in these patients.

Intensive Statin Therapy Compromises the Adiponectin-AdipoR Pathway in the Human Monocyte-Macrophage Lineage

Background and Purpose— Statins are widely used for cardiovascular disease prevention through cholesterol-lowering and anti-inflammatory effects. Adiponectin, an anti-inflammatory adipokine, acts via two receptors, AdipoR1 and AdipoR2, to exert atheroprotective effects on the vasculature. We investigated whether statins can modulate the adiponectin-AdipoR pathway in the human monocyte-macrophage lineage. Methods— Monocytes were isolated from the whole blood of patients with severe carotid atherosclerosis (cross-sectional study) or from patients with cardiovascular risk factors (longitudinal study) and assessed for AdipoR1 and AdipoR2 gene expression using quantitative real-time polymerase chain reaction. In vitro, THP-1 (Tamm-Horsfall protein 1) macrophages were treated with increasing atorvastatin or rosuvastatin doses for 24- or 72-hours to determine the effect of statins on AdipoR expression and activity. Macrophage cytokine secretion (IL [interleukin]-1β, IL-10, IL-6, and TNF [tumor necrosis factor]-α) was assessed by electrochemiluminescence. Results— AdipoR1 and AdipoR2 mRNA expression on circulating monocytes from patients with carotid atherosclerosis, was significantly lower by 1.36- and 1.17-fold, respectively, in statin users versus statin-naïve patients. Specifically, patients on high doses of atorvastatin (40–80 mg) or rosuvastatin (20–40 mg) had significantly lower AdipoR gene expression versus statin-naïve patients. Similarly, in the longitudinal in vivo study, longer atorvastatin/rosuvastatin treatment (≥5 months) in patients with cardiovascular risk factors resulted in lower AdipoR gene expression on circulating monocytes versus prestatin levels. In vitro, higher statin doses and longer exposure resulted in a greater decrease in AdipoR mRNA expression and greater macrophage secretion of pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α. High statin doses also reduced adiponectin’s capacity to suppress intracellular cholesteryl ester levels in oxLDL (oxidized LDL)-loaded macrophages, with rosuvastatin exhibiting higher potency than atorvastatin. Conclusions— Our in vivo and in vitro studies identified a novel pleiotropic property of statins in modulating the adiponectin-AdipoR pathway in the human monocyte-macrophage lineage, where intensive statin therapy compromised the expression and function of adiponectin and its receptors.

P4615Dyslipidemia as a predictor of no-reflow after primary PCI in STEMI pts

According to current guidelines all pts with ACS should be treated by intensive statin therapy, independently of baseline cholesterol level. However, the significance of baseline lipid profile for the results of treatment in STEMI pts has been insufficiently studied. The aim of the study was to evaluate baseline lipids level in STEMI patients with different degrees of tissue blood flow recovery after primary PCI. Methods 110 pts with STEMI admitted within 24 hrs (4.5±1.2 h) from symptoms onset and treated by primary PCI were included. Patients were treated according to current guidelines, and intensive statin therapy was initiated before any intervention. Blood lipids were tested at admission. Myocardial Blush Grade (MBG) was used for angiographic assessment of myocardial reperfusion. Dyslipidemia was assessed by total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) / HDL-C ratios. Results Good restoration of microvascular perfusion (MBG3) was found in 44 (40%) pts, MBG2 was achieved in 32 (29%) pts, while poor microvascular flow was seen 34 (31%) pts (MBG1 in 17 (15,5%) pts and MBG0 in 17 (15,5%) pts). Pts with MBG0 tended to have higher TC and triglycerides (TG) levels and lower HDL-C levels at baseline. TC/ HDL-C and LDL-C/HDL-C ratios that usually used to predict ischemic heart disease risk were also significantly higher in pts with no-reflow phenomenon (MBG0) (table 1) Table 1 MBG 0 MBG 1 MBG 2 MBG 3 p N=17 (15.5%) N=17 (15.5%) N=32 (29%) N=44 (40%) TC, mmol/l 6.42±0.23 5.9±0.21 6.1±0.25 6.1±0.26 nd LDL-C, mmol/l 4.22±0.21 3.89±0.18 3.95±0.22 3.97±0.2 nd HDL-C, mmol/l 1.24±0.03 1.34±0.02 1.36±0.021 1.39±0.022 nd TG, mmol/l 2.53±0.12 1.8±0.11 1.9±0.11 1.9±0.1 nd nonHDL-C, mmol/l 4.84±0.18 4.69±0.17 4.55±0.19 4.59±0.18 nd LDL-C/HDL-C 3.45±0.17 2.98±0.18 3.02±0.16 2.76±0.15 0.016 TC/HDL-C 5.23±0.21 4.59±0.2 4.71±0.18 4.29±0.19 0.011 Conclusion TC/HDL-C and LDL-C/HDL-C ratios can be used to predict the development of no-reflow after pPCI in STEMI pts.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.