Huabing Zhang

Discontinuation of Statins in Routine Care Settings: A Cohort Study

BACKGROUND Systematic data on discontinuation of statins in routine practice of medicine are limited. OBJECTIVE To investigate the reasons for statin discontinuation and the role of statin-related events (clinical events or symptoms believed to have been caused by statins) in routine care settings. DESIGN A retrospective cohort study. SETTING Practices affiliated with Brigham and Womens Hospital and Massachusetts General Hospital in Boston. PATIENTS Adults who received a statin prescription between 1 January 2000 and 31 December 2008. MEASUREMENTS Information on reasons for statin discontinuations was obtained from a combination of structured electronic medical record entries and analysis of electronic provider notes by validated software. RESULTS Statins were discontinued at least temporarily for 57 292 of 107 835 patients. Statin-related events were documented for 18 778 (17.4%) patients. Of these, 11 124 had statins discontinued at least temporarily; 6579 were rechallenged with a statin over the subsequent 12 months. Most patients who were rechallenged (92.2%) were still taking a statin 12 months after the statin-related event. Among the 2721 patients who were rechallenged with the same statin to which they had a statin-related event, 1295 were receiving the same statin 12 months later, and 996 of them were receiving the same or a higher dose. LIMITATIONS Statin discontinuations and statin-related events were assessed in practices affiliated with 2 academic medical centers. Utilization of secondary data could have led to missing or misinterpreted data. Natural-language-processing tools used to compensate for the low (30%) proportion of reasons for statin discontinuation documented in structured electronic medical record fields are not perfectly accurate. CONCLUSION Statin-related events are commonly reported and often lead to statin discontinuation. However, most patients who are rechallenged can tolerate statins long-term. This suggests that many of the statin-related events may have other causes, are tolerable, or may be specific to individual statins rather than the entire drug class. PRIMARY FUNDING SOURCE National Library of Medicine, Diabetes Action Research and Education Foundation, and Chinese National Key Program of Clinical Science.

Discontinuation of Statins in Routine Care Settings

Hypercholesterolemia is one of the most common chronic conditions and is strongly associated with cardiovascular disease, including cardiovascular mortality (1-3). Hydroxy methylglutaryl coenzyme A reductase inhibitors (a.k.a. statins) decrease mortality in patients with hypercholesterolemia (4-10) and are the most commonly used medications for treating hypercholesterolemia in the U.S (11). Despite their well documented benefits, statins are commonly discontinued (12-15). Statin discontinuation has been linked to increased risk of cardiovascular events and death in patients with coronary artery disease (16-19). Nevertheless the reasons why statins are stopped are only starting to be explored (20-22). Adverse reactions to statins feature prominently in these reports. At the same time, in randomized, placebo controlled clinical trials statins are associated with only a slight increase in adverse reactions and no increase in discontinuation of treatment as compared to placebo, with a total incidence of adverse reactions around 5-10% (9, 23, 24). It is not known whether this difference is real or reflects misattribution of the patients’ symptoms. In particular, it is not clear whether these symptoms are reproducible when rechallenged with a different or even the same statin. Consequently it is possible that statins may be discontinued inappropriately or unnecessarily, representing a major barrier to this potentially lifesaving therapy (13). This lack of information reflects the challenges of studying epidemiology of reported adverse reactions to statins in routine care settings. Prominent among them is the fact that these adverse reactions are frequently documented only in narrative documents (25). To address this gap in knowledge, we used a validated natural language processing software (25) in an electronic medical record system (EMR) to analyze statin discontinuation in a large cohort of patients with a particular focus on statin-related clinical events that may be interpreted as adverse reactions by patients or their clinicians.

Acarbose Reduces Blood Glucose by Activating miR-10a-5p and miR-664 in Diabetic Rats

MicroRNAs (miRNAs) are non-coding RNA molecules involved in the post-transcriptional regulation of a large number of genes, including those involved in glucose metabolism. Acarbose is an α-glucosidase inhibitor that improves glycemic control by decreasing the intestinal absorption of glucose, thereby decreasing the elevation of postprandial blood glucose. However, acarbose is poorly absorbed into the blood stream from the gut. Therefore, the exact mechanisms by which acarbose affects glucose metabolism are unclear. This study investigated the effect of acarbose on glucose metabolism in diabetic rats and tested the hypothesis that acarbose acts directly through miRNA-regulated expression in the intestinal epithelium. Rats were divided into four groups: a control group, a diabetic group (DM), a low dose of acarbose group (AcarL) and a high dose of acarbose group (AcarH). Ileum samples were analyzed using miRCURY LNA™ microRNA Array, qPCR and immunohistochemistry. We found that 8-week treatment with acarbose significantly decreased fasting blood glucose. Oral glucose tolerance tests (OGTT) showed that blood glucose was significantly reduced in the AcarL and AcarH groups at 30 min, 60 min and 120 min after oral glucose administration. We found that miR-151*, miR-10a-5p, miR-205, miR-17-5p, miR-145 and miR-664 were up-regulated in the AcarH group, while miR-541 and miR-135b were down-regulated. Through target gene analysis, real time PCR and immunohistochemistry verification, we found that these miRNAs suppressed the expression of proinflammatory cytokines [IL6 (interleukin 6) and TNF (tumor necrosis factor)] and mitogen activated protein kinase 1 (MAPK1). Our data suggest that acarbose can improve blood glucose in diabetic rats through the MAPK pathway and can down-regulate proinflammatory factors by activating miR-10a-5p and miR-664 in the ileum.

Drivers of the Sex Disparity in Statin Therapy in Patients with Coronary Artery Disease: A Cohort Study

Background Women are less likely to be prescribed statins than men. Existing reports explain only a fraction of this difference. We conducted a study to identify factors that account for sex differences in statin therapy among patients with coronary artery disease (CAD). Methods and Results We retrospectively studied 24,338 patients with CAD who were followed for at least a year between 2000 and 2011 at two academic medical centers. Women (9,006 / 37% of study patients) were less likely to either have initiated statin therapy (81.9% women vs. 87.7% men) or to have persistent statin therapy at the end of follow-up (67.0% women vs. 71.4% men). Women were older (72.9 vs. 68.4 years), less likely to have ever smoked (49.8% vs. 65.6%), less likely to have been evaluated by a cardiologist (57.5% vs. 64.5%) and more likely to have reported an adverse reaction to a statin (27.1% vs. 21.7%) (p < 0.0001 for all). In multivariable analysis, patients with history of smoking (OR 1.094; p 0.017), younger age (OR 1.013 / year), cardiologist evaluation (OR 1.337) and no reported adverse reactions to statins (OR 1.410) were more likely (p < 0.0001 for all) to have persistent statin therapy. Together, these four factors accounted for 90.4% of the sex disparity in persistent statin therapy. Conclusions Several specific factors appear to underlie divergent statin therapy in women vs. men. Identifying such drivers may facilitate programmatic interventions and stimulate further research to overcome sex differences in applying proven interventions for cardiovascular risk reduction.

miR-375 and miR-30d in the Effect of Chromium-Containing Chinese Medicine Moderating Glucose Metabolism

In China, TianMai Xiaoke tablet (TM) is used to treat type 2 diabetes. However, the exact mechanism of TM is not clear. This study is to investigate the effect of TM on glucose metabolism in diabetic rats and to identify whether TM takes a direct action through microRNAs on islet. Rats were divided into control group, diabetic group, low dose of TM group (TML), and high dose of TM group (TMH). Pancreas samples were analyzed using microRNA array and Q-PCR. Eight-week treatment with TM significantly decreased fasting blood glucose. The blood glucose was significantly reduced in TM-treated groups before and after oral glucose administration. Fasting insulin and HOMA-IR were suppressed in TM-treated groups. miR-448, let-7b, miR-540, miR-296, miR-880, miR-200a, miR-500, miR-10b, miR-336, miR-30d, miR-208, let-7e, miR-142-5p, miR-874, miR-375, miR-879, miR-501, and miR-188 were upregulated, while miR-301b, miR-134, and miR-652 were downregulated in TMH group. Through target gene analysis and real-time PCR verification, we found that these miRNAs, especially miR-375 and miR-30d, can stimulate insulin secretion in islet. Our data suggest that TM can improve blood glucose in diabetic rats which involved increasing the expression of miR-375 and miR-30d to activate insulin synthesis in islet.

Reasons for Discontinuation of Lipid-Lowering Medications in Patients with Chronic Kidney Disease

Background/Aims: Many patients with chronic kidney disease (CKD) do not receive lipid-lowering therapy despite their high cardiovascular risk. The reasons for this are unknown. Methods: We have conducted a retrospective cohort study of discontinuation of lipid-lowering drugs in patients with CKD stage 3 and higher treated in practices affiliated with two academic medical centers between 2000 and 2010. Information on medication discontinuation and its reasons was obtained from electronic medical records, including natural language processing of electronic notes using previously validated software. Results: Out of 14,034 patients in the study cohort, 10,072 (71.8%) stopped their lipid-lowering drugs at least once, and 2,444 (17.4%) stopped them for at least 1 month. Patients who had a comorbidity associated with higher cardiovascular risk were less likely to stop lipid-lowering drugs. Insurance request was the most common explicitly documented reason for discontinuation, and adverse reactions were the most common reason for long-term discontinuation. In a multivariable analysis, patients were more likely to stop a lipid-lowering drug because of an insurance request if they had government insurance and they were also more likely to stop a lipid-lowering drug because of adverse reactions if they had a history of multiple adverse reactions to other medications. There was no significant relationship between CKD stage and the reason for discontinuation of lipid-lowering drugs. Conclusions: Patients with CKD frequently stop lipid-lowering drugs. Insurance requests and adverse reactions are common reasons for the discontinuation. Further research is needed to ensure appropriate lipid-lowering therapy for these individuals at high cardiovascular risk. i 2014 S. Karger AG, Basel

Positive Association Between Type 2 Diabetes Risk Alleles Near CDKAL1 and Reduced Birthweight in Chinese Han Individuals

Background: Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population. Methods: Twelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed. Results: Birthweight was inversely associated with CDKAL1-rs10946398 (&bgr; = −41 g [95% confidence interval [CI]: −80, −3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (&bgr; = −36 g [95% CI: −72, −0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085). Conclusions: This study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.

Mis)interpreting studies on the adverse effects of statins.

Our study “Discontinuation of statins in routine care settings”1 has been cited in recent discussions in The BMJ on statin intolerance.2 3 4 Some of these reports misinterpreted our study. Our study sought to investigate the “real world” experience of patients who developed symptoms that they, or their healthcare providers, thought might have been caused by statins. Using natural language …

Preliminary screening of mutations in the glucokinase gene of Chinese patients with gestational diabetes

Mutations in the glucokinase gene (GCK) are a pathogenetic cause of maturity‐onset diabetes of the young. Studies have found that female patients with GCK maturity‐onset diabetes of the young often present with gestational diabetes during pregnancy. Our aim was to preliminarily assess the prevalence of mutations in the glucokinase gene in Chinese women with gestational diabetes.

Ambulatory Medication Reconciliation and Frequency of Hospitalizations and Emergency Department Visits in Patients With Diabetes

OBJECTIVE To investigate the association between ambulatory medication reconciliation and health care utilization in patients with diabetes. RESEARCH DESIGN AND METHODS In this retrospective cohort analysis, we studied adults taking at least one diabetes medication treated in primary care practices affiliated with two academic medical centers between 2000 and 2014. We assessed the relationship between the fraction of outpatient diabetes medications reconciled over a 6-month period and the composite primary outcome of combined frequency of emergency department (ED) visits and hospitalizations over the subsequent 6 months. RESULTS Among 261,765 reconciliation assessment periods contributed by 31,689 patients, 176,274 (67.3%), 27,775 (10.6%), and 57,716 (22.1%) had all, some, or none of the diabetes medications reconciled, respectively. Patients with all, some, or no diabetes medications reconciled had 0.354, 0.377, and 0.384 primary outcome events per 6 months, respectively (P < 0.0001). In a multivariable analysis adjusted for demographics and comorbidities, having some or all versus no diabetes medications reconciled was associated with a lower risk of the primary outcome (rate ratio 0.94 [95% CI 0.90–0.98; P = 0.0046] vs. 0.92 [0.89–0.95; P < 0.0001], respectively). Introduction of feedback to individual providers was associated with a significant increase in the odds of all diabetes medications being reconciled (2.634 [2.524–2.749]; P < 0.0001). CONCLUSIONS A higher fraction of reconciled outpatient diabetes medications was associated with a lower frequency of ED visits and hospitalizations. Individual performance feedback could help to achieve more comprehensive medication reconciliation.