[Prevalence and drug treatment of people with type 2 diabetes mellitus and a very high risk of cardiovascular disease]. / Diabetes type 2 én een hoog risico op hart- en vaatziekten.

OBJECTIVE: Dutch diabetes guidelines have been updated to incorporate specific therapies with cardiovascular and kidney outcomes benefit in type 2 diabetes patients (T2D) at very high risk for cardiorenal complications. This is part of a comprehensive approach to reduce the risk of diabetes-related complications, including management of glycemia, blood pressure, and lipids. The current study examines the prevalence of T2D at very high cardiorenal risk and the deployment of evidence-based approaches to lower this risk. DESIGN: Cross-sectional, observational study. METHOD: A representative population) with T2D in primary care (N= 64,224) was selected from the PHARMO Data Network. A very high risk of CVD was defined as: 1) established CVD, 2) CKD with (very) high cardiovascular risk and 3) heart failure. Drug treatment was determined according to prescriptions in 2019. RESULTS: 25,901 subjects with T2D had a very high risk of CVD (mean age 73.3 years; 42% female). Established CVD, CKD with (very) high cardiovascular risk, and heart failure were observed in 82%, 26% and 22% of patients, respectively. Low-dose salicylates, lipid-lowering and blood pressure-lowering medication were used by 39%, 70% and 69%, respectively. Glucose-lowering medication use included metformin (53%), sulfonylurea-derivatives (24%), and insulin (19%). 2% of the population used a SGLT2 inhibitor or GLP1-receptor agonist. CONCLUSION: 40% of people with DM2 have a very high risk of CVD. Although our findings reflect the recommendations of the previous treatment guideline for DM2, they also show that the new guideline has significant implications for the treatment of a large proportion of people with DM2.

Evaluating the real-life effect of MP-AzeFlu on asthma outcomes in patients with allergic rhinitis and asthma in UK primary care.

BACKGROUND: MP-AzeFlu (Dymista®; spray of azelastine/fluticasone propionate) is the most effective allergic rhinitis (AR) treatment available. Its effect on asthma outcomes in patients with AR and asthma is unknown. METHODS: This pre-post historical cohort study, using the Optimum Patient Care Research Database, included patients aged ≥12 years, from UK general practice with active asthma (defined as a recorded diagnosis, with ≥1 prescription for reliever or controller inhaler) in the year before or at the initiation date. The primary study outcome was change in number of acute respiratory events (i.e. exacerbation or antibiotic course for a respiratory event) between baseline and outcome years. The effect size of MP-AzeFlu was quantified as the difference in % of patients that improved and worsened. RESULTS: Of the 1,188 patients with AR and asthma included, many had a record of irreversible obstruction (67%), and uncontrolled asthma (70.4%), despite high mean daily doses of reliever/controller therapy and acute oral corticosteroid use, in the year pre-MP-AzeFlu initiation. MP-AzeFlu initiation was associated with fewer acute respiratory events (effect size (e) = 5.8%, p = 0.0129) and a reduction in daily use of short-acting ß2-agonists, with fewer patients requiring >2 SABA puffs/week (e = 7.7% p < 0.0001). More patients had well-controlled asthma 1-year post-MP-AzeFlu initiation (e = 4.1%; p = 0.0037), despite a reduction in inhaled corticosteroids (e = 4.8%; p = 0.0078). CONCLUSIONS: This study provides the first direct evidence of the beneficial effect of MP-AzeFlu on asthma outcomes in co-morbid patients in primary care in the United Kingdom. TRIAL REGISTRATION: EUPAS30940. Registered August 13, 2019.

Distribution, Temporal Stability and Appropriateness of Therapy of Patients With COPD in the UK in Relation to GOLD 2019.

BACKGROUND: The 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report made recommendations for the assessment, initial and subsequent treatment chronic obstructive pulmonary disease (COPD) based on biomarkers, including blood eosinophil counts. METHODS: We evaluated the distribution of UK COPD patients initiating maintenance therapy and established patients by GOLD group, the prevalence of comorbidities and appropriateness of therapy using electronic patient records from the Optimum Patient Care Research Database (OPCRD). Changes in effective GOLD group, therapy and exacerbation rates over the next 2 years were analysed. FINDINGS: 11,409 established COPD patients and 699 starting therapy were studied. 44·3%, 25·7%, 13·8% & 16·2% of established COPD patients and 45·2%, 28·5%, 15·7% & 10·6% initiating therapy were in GOLD groups A, B, C & D respectively.The overall proportion in each GOLD group was similar after 2 years but there was substantial movement of patients between groups. Diabetes and cardiovascular disease were the most common comorbidities in all groups in both cohorts.LAMA monotherapy was the commonest initial therapy in all GOLD groups. In both cohorts there was over-treatment with escalation, de-escalation or switching in nearly 50% during follow-up.In both cohorts, exacerbation rates were highest in group D and appeared higher in over-treated patients. INTERPRETATION: Most patients are not at risk of exacerbations and co-morbidities are common. Many patients change effective GOLD group and therapy over time. Prescribing is not in accordance with guideline recommendations and many patients still appear over treated.

Animal exposure over the life-course and risk of multiple sclerosis: A case-control study within two cohorts of US women.

BACKGROUND: Whether animal exposure and specifically the timing of such exposure alters multiple sclerosis (MS) risk is unclear. We examined whether animal exposure was associated with MS risk, and whether risk differed by the participants' age. METHODS: We conducted a case-control study within the Nurses' Health Study ((NHS)/NHSII cohorts). Overall, 151 women with MS and 235 controls, matched by age and study cohort, completed an animal exposure history questionnaire. Animal exposure pre-MS onset was assessed as 'any' exposure, then by the participants age, and animal family. Conditional logistic regression was used to estimate relative MS risks, adjusted (adj.RR) for potential confounders. RESULTS: 'Any' animal exposure was reported by 136 (90.1%) MS cases compared to 200 (85.1%) matched controls, with dog exposure being the most common [120 (79.5%) cases vs. 170 (72.3%) controls]. There was no association between 'any' animal exposure and MS risk (adj.RR:1.52;95%CI:0.76-3.04). However, both 'any' animal and specifically dog exposure at ages 10-14 years were associated with an increased MS risk (adj.RR:1.67;95%CI:1.05-2.66 and 1.76;95%CI:1.12-2.78, respectively). CONCLUSION: Animal exposure, and specifically dog exposure, in early adolescence was associated with an increased risk of MS. Further work is needed to confirm this finding.

Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink.

We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged ≥40 years with at least one prescription of statins (1995-2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non-users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88-1.27) or past statin users (HRadj,1.18;99%CI:0.88-1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01-1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings.

Pattern of risks of systemic lupus erythematosus among statin users: a population-based cohort study.

OBJECTIVES: To examine the association between the use of statins and the risk of systemic lupus erythematosus (SLE) with focus on describing the patterns of risks over time. SETTING: A population-based cohort study using the UK Clinical Practice Research Datalink. PARTICIPANTS: All patients aged 40 years or older who had at least one prescription of statins during the period 1995-2009 were selected and matched by age, sex, practice and date of first prescription to non-users. The follow-up period of statin users was divided into periods of current, recent and past exposure, with patients moving among these three exposure categories over time. Current statin users were also stratified into ≤1 year or >1 year of use. MAIN OUTCOME MEASURES: Time-dependent Cox models were used to calculate HRs of SLE, adjusted for disease history and previous drug exposure. RESULTS: We included 1 039 694 patients, of whom 519 847 were statin users. Current statin users did not have an increased risk of developing SLE among patients aged ≥40 years (HRadjusted 0.75, 95% CI 0.53 to 1.07). Current statin users who continued the therapy for >1 year had a 38% lower risk of developing SLE (HRadjusted 0.62, 95% CI 0.42 to 0.93). When more specific definitions for SLE were used, this latter finding, however, was not observed. CONCLUSIONS: Our findings showed no effect of statins on the risk of developing SLE among patients aged ≥40 years. Further research is needed to study the long-term effects of statins on SLE.

Evaluating the safety of ß-interferons in MS: A series of nested case-control studies.

OBJECTIVE: To examine the association between interferon-ß (IFN-ß) and potential adverse events using population-based health administrative data in British Columbia, Canada. METHODS: Patients with relapsing-remitting multiple sclerosis (RRMS) who were registered at a British Columbia Multiple Sclerosis Clinic (1995-2004) were eligible for inclusion and were followed up until death, absence from British Columbia, exposure to a non-IFN-ß disease-modifying drug, or December 31, 2008. Incidence rates were estimated for each potential adverse event (selected a priori and defined with ICD-9/10 diagnosis codes from physician and hospital claims). A nested case-control study was conducted to assess the odds of previous IFN-ß exposure for each potential adverse event with at least 30 cases. Cases were matched by age (±5 years), sex, and year of cohort entry, with up to 20 randomly selected (by incidence density sampling) controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated with conditional logistic regression adjusted for age at cohort entry. RESULTS: Of the 2,485 eligible patients, 77.9% were women, and 1,031 were treated with IFN-ß during follow-up. From the incidence analyses, 27 of the 47 potential adverse events had at least 30 cases. Patients with incident stroke (ORadj 1.83, 95% CI 1.16-2.89), migraine (ORadj 1.55, 95% CI 1.18-2.04), depression (ORadj 1.33, 95% CI 1.13-1.56), and hematologic abnormalities (ORadj 1.32, 95% CI 1.01-1.72) were more likely to have previous exposure to IFN-ß than controls. CONCLUSIONS: Among patients with RRMS, IFN-ß was associated with a 1.8- and 1.6-fold increase in the risk of stroke and migraine and 1.3-fold increases in depression and hematologic abnormalities.

Statin use and markers of immunity in the Doetinchem cohort study.

It has been suggested that statins can both stimulate and suppress the immune system, and thereby, may influence autoimmune diseases. Therefore, we studied effects of statins on innate and adaptive immunity, and self-tolerance by measuring serological levels of C-reactive protein (CRP), neopterin, immunoglobulin E (IgE) antibodies and the presence of autoantibodies (antinuclear antibodies (ANA) and IgM rheumatoid factor (RF)) in the general population. We conducted a nested case-control study within the population-based Doetinchem cohort. Data from health questionnaires, serological measurements and information on medication from linkage to pharmacy-dispensing records were available. We selected 332 statin users (cases) and 331 non-users (controls), matched by age, sex, date of serum collection, history of cardiovascular diseases, diabetes mellitus type II and stroke. Multivariate regression analyses were performed to estimate effect of statins on the immune system. The median level of CRP in statin users (1.28 mg/L, interquartile range (IQR): 0.59-2.79) was lower than in non-users (1.62 mg/L, IQR: 0.79-3.35), which after adjustment was estimated to be a 28% lower level. We observed an inverse association between duration of statin use and CRP levels. Elevated levels of IgE (>100 IU/mL) were more prevalent in statin users compared to non-users. A trend towards increased levels of IgE antibodies in statin users was observed, whereas no associations were found between statin use and levels of neopterin or the presence of autoantibodies. In this general population sub-sample, we observed an anti-inflammatory effect of statin use and a trend towards an increase of IgE levels, an surrogate marker for Th (helper) 2 responses without a decrease in neopterin levels, a surrogate marker for Th1 response and/or self-tolerance. We postulate that the observed decreased inflammatory response during statin therapy may be important but is insufficient to induce loss of self-tolerance.

Suboptimal prescribing of proton-pump inhibitors in low-dose aspirin users: a cohort study in primary care.

OBJECTIVE: Determine the adherence to recommendations of concomitant proton-pump inhibitor (PPI) treatment in regular low-dose of aspirin (LDASA) users, taking factors associated with the probability of receiving a PPI into account. DESIGN: Cohort study. SETTING: Data were obtained from 120 Dutch primary care centres participating in the Netherlands Information Network of Primary Care (LINH). PARTICIPANTS: Patients 18 years and older who were regularly prescribed LDASA (30-325 mg) in 2008-2010 were included. MAIN OUTCOME MEASURES: Regular medication use was defined as receiving each consecutive prescription within 6 months after the previous one. Based on national guidelines, we categorised LDASA users into low and high gastrointestinal (GI) risk. A multilevel multivariable logistic regression analysis was applied to identify patient characteristics that influenced on the probability of regular PPI prescriptions. RESULTS: We identified 12 343 patients who started LDASA treatment, of whom 3213 (26%) were at increased risk of GI complications. In this group, concomitant regular use of PPI was 46%, 36% did not receive PPI prescriptions and 18% obtained prescriptions irregularly (p<0.0001). The chance to obtain regularly PPI prescriptions versus no PPI was significantly influenced by, among others, previous GI complications (OR 13.9 (95% CI 11.8 to 16.4)), use of non-steroidal anti-inflammatory drugs (OR 5.2 (4.3 to 6.3)), glucocorticosteroids (6.1 (4.6 to 8.0)), selective serotonin reuptake inhibitors (9.1 (6.7 to 12.2)), drugs for functional GI disorders (2.4 (1.9 to 3.0)) and increased age. CONCLUSIONS: Primary care physicians do not fully adhere to the current recommendations to prescribe PPIs regularly to LDASA users with an increased GI risk. More than 50% of the patients with an increased GI risk are not treated sufficiently with a concomitant PPI, increasing the risk of GI side effects. This finding underlines the necessity to consider merging recommendations into one common, standard and frequently used recommendation by primary care physicians.

Statin-associated polymyalgia rheumatica. An analysis using WHO global individual case safety database: a case/non-case approach.

OBJECTIVE: To assess whether there is an association between statin use and the occurrence of polymyalgia rheumatic (PMR) in the spontaneous reporting database of the World Health Organisation (WHO). METHODS: We conducted a case/non-case study based on individual case safety reports (ICSR) in the WHO global ICSR database (VigiBase). Case reports containing the adverse event term polymyalgia rheumatica (WHOART or MedDRA Preferred Term) were defined as cases. Non-cases were all case reports containing other adverse event terms. Each case was matched to five non-cases by age, gender, and time of reporting. Case reports regarding a statin as suspected or concomitant drug were identified using the Anatomical Therapeutic Chemical (ATC) classification. Multivariate logistic regression was used to calculate reporting odds ratios (RORs) with 95% confidence intervals (CI). RESULTS: We identified 327 reports of PMR as cases and 1635 reports of other ADRs as non-cases. Among cases, statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were significantly associated with reports of PMR (ROR 14.21; 95% CI 9.89-20.85). CONCLUSION: The results of this study lends support to previous anecdotal case reports in the literature suggesting that the use of a statin may be associated with the occurrence of PMR. Further studies are needed to study the strength of the association in more detail and to elucidate the underlying mechanism.

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and the risk of developing rheumatoid arthritis in antihypertensive drug users.

PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective in the treatment of cardiovascular disease. Next to effects on hypertension and cardiac function, these drugs have anti-inflammatory and immunomodulating properties which may either facilitate or protect against the development of autoimmunity, potentially resulting in autoimmune diseases. Therefore, we determined in the current study the association between ACE inhibitor and ARB use and incident rheumatoid arthritis (RA). METHODS: A matched case-control study was conducted among patients treated with antihypertensive drugs using the Netherlands Information Network of General Practice (LINH) database in 2001-2006. Cases were patients with a first-time diagnosis of RA. Each case was matched to five controls for age, sex, and index date, which was selected 1 year before the first diagnosis of RA. ACE inhibitor and ARB exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI). RESULTS: Our study included 211 cases and 667 matched controls. After controlling for potential confounders, ever use of ACE inhibitors or ARBs was not associated with incident RA (adjusted ORs [95%CI], 0.99 [0.55-1.79] and 1.02 [0.67-1.56], respectively). The adjusted ORs (95%CI) for current and past use of ACE inhibitors were 1.18 (0.75-1.85) and 0.61 (0.28-1.35). For current and past use of ARBs, these adjusted ORs (95%CI) were 1.40 (0.80-2.45) and 0.29 (0.05-1.67), respectively. No duration and dose-effect relationship was observed. CONCLUSIONS: ACE inhibitor or ARB use is not associated with incident RA.

Statins accelerate the onset of collagen type II-induced arthritis in mice.

INTRODUCTION: Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding. METHODS: The mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured. RESULTS: Statin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNγ production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine. CONCLUSION: These data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity.

Association between statin use and lupus-like syndrome using spontaneous reports.

OBJECTIVES: Several case reports of lupus-like syndrome suggest that statins could have triggered the development of this rare autoimmune disease. However, data on the association between statin use and lupus-like syndrome are scarce. We assessed whether there was an association between statin use and the occurrence of lupus-like syndrome. METHODS: A case/noncase study based on individual case safety reports listed in the World Health Organization global individual case safety reports database (VigiBase) was conducted. According to World Health Organization adverse reaction terminology, cases were defined as reports of lupus-like syndrome. Each case was matched with 5 noncases by age, gender, and time of reporting. Use of statins was classified according to the Anatomical Therapeutic Chemical classification code system. Covariates, ie, use of corticosteroids, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, proton pump inhibitors, and cardiovascular drugs, were determined. Multivariate logistic regression was used to calculate the reporting odds ratios with 95% confidence intervals. RESULTS: We identified 3362 reports of lupus-like syndrome as cases and 27,092 reports of other adverse drug reactions as noncases. Statins were more frequently reported as suspected drug in cases (3.2%) than in noncases (1.5%). After adjustment for several covariates, statins were associated with the reporting of lupus-like syndrome (reporting odds ratios 2.01; 95% confidence intervals 1.61-2.51). CONCLUSIONS: We found an association between reporting of statins and lupus-like syndrome. Further studies are needed to confirm this finding in more detail and establish causality.

Alcohol consumption and blood lipids in elderly coronary patients.

Alcohol may have a beneficial effect on coronary heart disease (CHD) that could be mediated by elevation of high-density lipoprotein cholesterol (HDLC). Data on alcohol consumption and blood lipids in coronary patients are scarce. We studied whether total ethanol intake and consumption of specific types of beverages are associated with blood lipids in older subjects with CHD. Blood lipids were measured in 1052 myocardial infarction patients aged 60 to 80 years (78% male). Intake of alcoholic beverages, total ethanol, and macronutrients was assessed by food frequency questionnaire. Seventy percent of the subjects used lipid-lowering medication. Total cholesterol was on average 5.14 mmol/L, and HDLC was on average 1.28 mmol/L. Among men, total ethanol intake was positively associated with HDLC (difference of 0.094 mmol/L for > or =15 g/d vs 0 g/d, P = .024), whereas the association with HDLC among women was not significant (difference of 0.060 mmol/L for > or =5 g/d vs 0 g/d, P = .560) after adjustment for dietary, lifestyle, and CHD risk factors. Liquor consumption was weakly positively associated with HDLC in men (P = .045). Beer consumption in men and wine consumption in women were also positively associated with HDLC, but were not significant in the fully adjusted model. In conclusion, moderate alcohol consumption may elevate HDLC in treated post-myocardial infarction patients. This may be due to ethanol and not to other beneficial substances in alcoholic beverages. Based on this finding, further research needs to be done to examine the effects of the residual substances from different types of alcoholic beverages on HDLC.