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1.  Hydroxychloroquine and Glycemia in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus 
The Journal of rheumatology  2010;37(6):1136-1142.
Objective
To determine the relationship between current hydroxychloroquine (HCQ) use and 2 indicators of glycemic control, fasting glucose and insulin sensitivity, in nondiabetic women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).
Methods
Nondiabetic women with SLE (n = 149) or RA (n = 177) recruited between 2000 and 2005 for a cross-sectional evaluation of cardiovascular risk factors were characterized by HCQ usage status. Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation] were compared among HCQ users and nonusers for disease-specific groups.
Results
More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001; mean dose ~ 400 mg vs ~ 200 mg). For women with SLE or RA, after adjustment for age, waist circumference, disease duration, prednisone dosage, C-reactive protein, menopausal status, nonsteroidal antiinflammatory drugs, and disease-specific indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 vs 89.3 mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05). In women with SLE, HCQ use also was associated with lower logHOMA-IR (0.97 vs 1.12, p = 0.09); in those with RA, no differences in logHOMA-IR were seen. HCQ usage was not associated with fasting insulin levels in either patient group.
Conclusion
HCQ use was associated with lower fasting glucose in women with SLE or RA and also lower logHOMA-IR in the SLE group. The use of HCQ may be beneficial for reducing cardiovascu lar risk by improving glycemic control in these patients.
doi:10.3899/jrheum.090994
PMCID: PMC3457696  PMID: 20436082
HYDROXYCHLOROQUINE; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS; HYPERGLYCEMIA; DIABETES MELLITUS
2.  Hydroxychloroquine in patients with inflammatory and erosive osteoarthritis of the hands (OA TREAT): study protocol for a randomized controlled trial 
Trials  2014;15(1):412.
Background
Osteoarthritis (OA) is a heterogeneous group of conditions with disturbed integrity of articular cartilage and changes in the underlying bone. The pathogenesis of OA is multifactorial and not just a disease of older people. Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic drug (DMARD) typically used for the treatment of various rheumatic and dermatologic diseases. Three studies of HCQ in OA, including one abstract and one letter, are available and use a wide variety of outcome measures in small patient populations. Despite initial evidence for good efficacy of HCQ, there has been no randomized, double-blind, and placebo-controlled trial in a larger patient group. In the European League Against Rheumatism (EULAR), evidence-based recommendations for the management of hand OA, HCQ was not included as a therapeutic option because of the current lack of randomized clinical trials.
Methods/Design
OA TREAT is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial. A total of 510 subjects with inflammatory and erosive hand OA, according to the classification criteria of the American College of Rheumatology (ACR), with recent X-ray will be recruited across outpatient sites, hospitals and universities in Germany. Patients are randomized 1:1 to active treatment (HCQ 200 to 400 mg per day) or placebo for 52 weeks. Both groups receive standard therapy (non-steroidal anti-inflammatory drugs [NSAID], coxibs) for OA treatment, taken steadily two weeks before enrollment and continued further afterwards. If disease activity increases, the dose of NSAID/coxibs can be increased according to the drug recommendation. The co-primary clinical endpoints are the changes in Australian-Canadian OA Index (AUSCAN, German version) dimensions for pain and hand disability at week 52. The co-primary radiographic endpoint is the radiographic progression from baseline to week 52. A multiple endpoint test and analysis of covariance will be used to compare changes between groups. All analyses will be conducted on an intention-to-treat basis.
Discussion
The OA TREAT trial will examine the clinical and radiological efficacy and safety of HCQ as a treatment option for inflammatory and erosive OA over 12 months. OA TREAT focuses on erosive hand OA in contrast to other current studies on symptomatic hand OA, for example, HERO [Trials 14:64, 2013].
Trial registration
ISRCTN46445413, date of registration: 05-10-2011.
doi:10.1186/1745-6215-15-412
PMCID: PMC4219005  PMID: 25348033
Erosive hand osteoarthritis; Hydroxychloroquine; Double-blind; Hand; Placebo-controlled; Randomized
3.  Changes in Glycated Hemoglobin after Initiation of Hydroxychloroquine or Methotrexate in Diabetic Patients with Rheumatologic Diseases 
Arthritis and rheumatism  2010;62(12):3569-3573.
Objective
Prior research demonstrates that hydroxychloroquine (HCQ) lowers glycated hemoglobin (HbA1c) in non-rheumatic diabetic patients. We examined medical records of patients with diabetes mellitus (DM) and concomitant rheumatic illness to measure changes in HbA1c after starting HCQ or methotrexate (MTX).
Methods
We utilized electronic medical records to identify patients initiating either HCQ or MTX, with a diagnosis of DM or HbA1c ≥ 7%, and with at least one HbA1c measurement before and within 12 months after initiation. A structured medical record abstraction examined rheumatologic diagnosis, use of oral glucocorticoids, body mass index, age, gender. Adjusted linear regression models determined changes in HbA1c from pre-drug values to the lowest post-drug values within twelve months.
Results
We identified 45 HCQ users and 37 MTX users who met inclusion criteria. Half in each group carried a rheumatoid arthritis diagnosis. Age, gender, and mean pre-drug HbA1c levels were similar across groups. Mean BMI for HCQ users (35.4 kg/m2) was slightly higher than MTX users (32.2 kg/m2) (p = 0.13). Glucocorticoid use appeared more common in MTX (46%) than HCQ (29%) users (p = 0.17). The mean reduction in HbA1c between pre- and post-HCQ was 0.66% (95% CI 0.26–1.05) versus 0.11% (95% CI −0.18 – 0.40) for MTX. In fully adjusted analyses, the reduction in HbA1c among HCQ users was 0.54% greater than the drop among MTX users (p = 0.041).
Conclusion
HCQ initiation was associated with a significantly greater reduction in HbA1c as compared to MTX initiation among diabetic patients with rheumatic disease.
doi:10.1002/art.27703
PMCID: PMC2992611  PMID: 20722019
4.  Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in Chemoprophylaxis against Malaria Caused by Plasmodium vivax▿  
Hydroxychloroquine (HCQ) is an antimalarial drug used as chemoprophylaxis against malaria caused by Plasmodium vivax in the Republic of Korea Army (ROKA). In this study, we evaluated the pharmacokinetics (PK) of HCQ and its metabolites and the relationship between the PK of HCQ and the effect of treatment of HCQ on vivax malaria in South Koreans. Three PK studies of HCQ were conducted with 91 healthy subjects and patients with vivax malaria. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling approaches. A two-compartment model with first-order absorption best described the data. The clearance and the central and peripheral volumes of distribution were 15.5 liters/h, 733 liters, and 1,630 liters, respectively. We measured the plasma concentrations of HCQ in patients with prophylactic failure of HCQ and compared them with the prediction intervals of the simulated concentrations for HCQ from the final PK model built in this study. In 71% of the patients with prophylactic failure, the plasma concentrations of HCQ were below the lower bounds of the 95% prediction interval, while only 8% of them showed higher levels than the upper bounds of the 95% prediction interval. We report that a significant cause of prophylactic failure among the individuals in ROKA was ascribed to plasma concentrations of HCQ lower than those predicted by the PK model. However, prophylactic failure despite sufficient plasma concentrations of HCQ was confirmed in several individuals, warranting continued surveillance to monitor changes in the HCQ susceptibility of Plasmodium vivax in the Republic of Korea.
doi:10.1128/AAC.00339-08
PMCID: PMC2663072  PMID: 19188392
5.  Effects of low-dose hydroxychloroquine on expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in peri-infarct myocardium in rats 
BACKGROUND:
Low-dose hydroxychloroquine (HCQ) and ataxia-telangiectasia-mutated (ATM) protein kinase have recently been postulated to be beneficial for the prevention of the age-associated metabolic syndrome including hypertension, hypercholesterolemia and glucose intolerance; however, the effects of low-dose HCQ on the expression of ATM downstream phosphorylated Akt (protein kinase B) and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium remain unclear.
OBJECTIVE:
To explore the effects of low-dose HCQ on the expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium in a rat model.
METHODS:
Myocardial infarction (MI) was induced experimentally in a subset of rats, while others underwent sham operation (sham). Three days after operation, surviving Sprague-Dawley male rats were divided into MI+HCQ, MI, sham+HCQ and sham groups. MI+HCQ and sham + HCQ groups were treated with HCQ (3.4 mg/kg); and MI and sham groups were treated with phosphate buffered (ie, physiological) saline (10 mL/kg) by gavage every day for 12 weeks. The expression of phosphorylated Akt and p53 proteins and cardiomyocyte apoptosis in the peri-infarct myocardium was detected by Western blot and terminal deoxynucleotidyl transferase dUTP nick end labelling, respectively.
RESULTS:
Twelve weeks after treatment, the expression of phosphorylated Akt protein was significantly increased (P<0.05). Expression of phosphorylated p53 protein was not significantly different (P>0.05) in the peri-infarct myocardium of the MI+HCQ group from that in the MI group. The cardiomyocyte apoptosis rate in the peri-infarct myocardium was significantly decreased in the MI+HCQ group compared with the MI group (P<0.05).
CONCLUSION:
Low-dose HCQ can significantly increase the expression of phosphorylated Akt protein without significantly impacting expression of phosphorylated p53 protein in the peri-infarct myocardium. Accordingly, it can inhibit cardiomyocyte apoptosis in the peri-infarct myocardium.
PMCID: PMC3718607  PMID: 23940455
Akt (protein kinase B); Cardiomyocyte apoptosis; Hydroxychloroquine (HCQ); Myocardial infarction (MI); P53 (protein 53)
6.  Effect of atorvastatin and hydroxychloroquine combination on blood glucose in alloxan-induced diabetic rats 
Indian Journal of Pharmacology  2009;41(3):125-128.
Objective:
To evaluate the antihyperglycemic activity of atorvastatin and hydroxychloroquine combination in alloxan-induced diabetic rats.
Materials and Methods:
Alloxan induced diabetic Wistar male rats were randomized into six groups of 6 rats each. (Normal rats, diabetic control, atorvastatin (ATV), hydroxychloroquine (HCQ), ATV 5 mg /kg + HCQ 100 mg/kg, and ATV 10 mg/kg + HCQ 200 mg/kg). The rats were treated for 9 days and blood samples were collected at baseline and end of therapy. These samples were analyzed for plasma glucose by autoanalyzer. Changes in body weight, water, food intakes and total protein content were also recorded.
Results:
Atorvastatin and hydroxychloroquine alone and in combination reported significant fall in blood glucose level from baseline. Fall in glucose level was significantly more in high dose combination of atorvastatin and hydroxychloroquine (ATV: 10 mg/kg + HCQ: 200 mg/kg) as compared to other study treatment groups (ATV: 17% Vs HCQ: 7% Vs ATV 5mg/kg + HCQ 100mg /kg: 14% Vs ATV 10mg/kg + HCQ 200mg /kg: 21%; p<0.01). ATV and HCQ individually and in combination also improved the body weight loss. The weight gain was significantly more in combination treated rats as compared to positive control group and greater than those who received atorvastatin and hydroxychloroquine alone. Rats treated with the combination also reported significant decrease in food intake and significant increase in total protein.
Conclusion:
Increased hypoglycemic effect in combination may be due to potentiation or synergism between HCQ and ATV. Further studies are required to demonstrate clinically significant antidiabetic effect.
doi:10.4103/0253-7613.55213
PMCID: PMC2861813  PMID: 20442820
Antihyperglycemic activity; alloxan; atorvastatin; hydroxychloroquine; plasma glucose
7.  Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2007;66(6):821-824.
Background
Poor adherence to treatment is difficult to diagnose accurately. Hydroxychloroquine (HCQ) has a long elimination half‐life and its concentration in whole blood can be measured easily.
Objective
To evaluate the utility of a very low blood HCQ concentration as a marker of poor compliance in patients with systemic lupus erythematosus (SLE).
Methods
HCQ concentrations were determined on a blinded basis in 203 unselected patients with SLE. At the end of the study, the patients were informed of the results and retrospectively interviewed about their adherence to treatment.
Results
14 (7%) patients said that they had stopped taking HCQ (n = 8) or had taken it no more than once or twice a week (n = 6). Their mean (SD) HCQ concentration was 26 (46) ng/ml. range (0–129 ng/ml) By contrast, the other patients had a mean HCQ concentration of 1079 ng/ml range (205–2629 ng/ml). The principal barriers to adherence were related to HCQ treatment characteristics. Adherence subsequently improved in 10 of the 12 patients whose blood HCQ concentrations were remeasured.
Conclusions
Very low whole‐blood HCQ concentrations are an objective marker of prolonged poor compliance in patients with SLE. Regular drug assays might help doctors in detect non‐compliance and serve as a basis for counselling and supporting these patients.
doi:10.1136/ard.2006.067835
PMCID: PMC1954674  PMID: 17324970
8.  Treatment with cyclosporin switching to hydroxychloroquine in patients with rheumatoid arthritis 
Kim, W | Seo, Y | Park, S | Lee, W | Lee, S | Paek, S | Cho, C | Song, H | Kim, H
Annals of the Rheumatic Diseases  2001;60(5):514-517.
OBJECTIVE—To investigate the therapeutic benefit of cyclosporin A (CSA) switching to hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA).
METHODS—Thirty four patients with RA who displayed residual inflammation and disability despite partial responses to prior maximal tolerated doses of methotrexate, were included. All were treated with a staged approach using CSA for 24 weeks to induce clinical improvement, followed by HCQ for 16 weeks to maintain the improvement. Seven ACR core set measures were evaluated every four to eight weeks.
RESULTS—During a 40 week open trial, 27/34 patients completed the study. CSA treatment significantly reduced the tender joints score, swollen joints score, visual analogue pain scale, patient's or doctor's global assessment, patient's self assessed disability, and C reactive protein. Compared with the time of entry into the trial, patients who switched from CSA to HCQ still possessed significantly lower levels of most variables, determined at 28, 32, and 40 weeks. According to the ACR 20% improvement definition, 15/27 (56%) patients had improved at 24 weeks after CSA treatment, and 14/27 (52%) remained improved at 16 weeks after the change to HCQ. Frequent side effects, such as hypertrichosis, gastrointestinal trouble, and hypertension, were noted during CSA treatment, but most of these disappeared after switching to HCQ. The mean levels of blood pressure and serum creatinine were significantly increased during CSA treatment, but returned to normal after changing to HCQ.
CONCLUSIONS—The data suggest that CSA switching to HCQ treatment may be an effective strategy for patients with RA partially responding to methotrexate, particularly those with toxicity due to CSA.


doi:10.1136/ard.60.5.514
PMCID: PMC1753640  PMID: 11302876
9.  Long term effectiveness of antimalarial drugs in rheumatic diseases 
Annals of the Rheumatic Diseases  1998;57(10):582-587.
OBJECTIVE—The purpose of this study was to compare the long term effectiveness between chloroquine (CQ) and hydroxychloroquine (HCQ).
METHODS—Medical charts of all patients seen by eight rheumatologists practising in two tertiary care centres and starting antimalarial treatment between January 1985 and December 1993 were reviewed. Patient characteristics, disease, and treatment information were collected. The main outcome measures were the cause of and the time to the discontinuation of antimalarial drugs resulting from all causes, principally toxicity or inefficacy, or both. Bivariate analysis including t tests and χ2 tests were used to assess differences between means and proportions respectively. Survival curves were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox regression) was used to adjust for potential confounders.
RESULTS—After all medical records were reviewed, 1042 eligible cases were identified. From these, 940 (90%) had usable information and they represent the cohort. Five hundred and fifty eight had rheumatoid arthritis, 178 had systemic lupus erythematosus, 127 had palindromic arthritis, and 77 had other diagnoses. Fifty seven per cent of the patients received CQ and 43% HCQ. The proportion of patients with side effects taking HCQ and CQ was 15% and 28% respectively (p=0.001). Using Cox regression model to adjust for age at the onset of antimalarial treatment, physician differences, sex, disease type, disease duration before treatment, and rank selection, there were no differences in the hazard ratio (HR) for overall discontinuations between CQ and HCQ. While the HR for discontinuations because of toxicity was lower for HCQ (HR= 0.6, 95% CI 0.4, 0.9), the HR for discontinuations because of inefficacy was significantly higher for HCQ (HR= 1.4, 95% CI 1.1, 1.9).
CONCLUSIONS—After adjusting for time and several confounders HCQ was less toxic but less effective than CQ. Only one case of probable/possible retinopathy was found. Therefore, we propose a careful baseline ophthalmological evaluation by an expert and then one or every two years if proper doses are used.

 Keywords: antimalarial drugs; long term effectiveness; efficacy; toxicity; rheumatic diseases
PMCID: PMC1752486  PMID: 9893568
10.  Hydroxychloroquine use in a community-based cohort of patients with systemic lupus erythematosus 
Arthritis care & research  2010;62(3):386-392.
Background
In recent years hydroxychloroquine (HCQ) has emerged as a key therapy in systemic lupus erythematosus (SLE). We determined the rates of HCQ use in a diverse, community-based cohort of patients with SLE and identified predictors of current HCQ use.
Methods
Patients were participants in the University of California San Francisco (UCSF) Lupus Outcomes Study (LOS), an ongoing longitudinal study of patients with confirmed SLE. We examined the prevalence of HCQ use per person-year and compared baseline characteristics of users and non-users, including demographic, socioeconomic, clinical, and health-system use variables. Multiple logistic regression with generalized estimating equations was used to evaluate predictors of HCQ use.
Results
Eight hundred and eighty one patients contributed 3095person-years of data over 4 interview cycles. The prevalence of HCQ use was 55 per 100 person-years and was constant throughout the observation period. In multivariate models, the odds of HCQ use were nearly doubled among patients receiving their SLE care from a rheumatologist compared to those identifying generalists or nephrologists as their primary sources of SLE care. In addition, patients with shorter disease duration were more likely to use HCQ, even after adjusting for age and other covariates.
Conclusions
In this community-based cohort of patients, HCQ use was suboptimal. Physician specialty and disease duration were the strongest predictors of HCQ use. Patients who are not using HCQ, those with longer disease duration, and those who see non-rheumatologists for their SLE care should be targeted for quality improvement.
doi:10.1002/acr.20002
PMCID: PMC2947342  PMID: 20391485
11.  A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti-inflammatory role 
Hydroxychloroquine (HCQ), a commonly used antimalarial drug in rheumatic diseases, has shown favorable metabolic effects on both glucose control and lipid profiles. We describe a case of a young woman with type 1 diabetes whose glycemic control was optimized with the introduction of HCQ as a treatment for her Sjogren syndrome in addition to a subtle yet measurable improvement in her lipid profile. An increasing body of evidence supports the beneficial impacts of HCQ in various ancillary conditions, including diabetes mellitus and dyslipidemia. However, mechanisms of action responsible for these effects remain ill-defined and may include alterations in insulin metabolism and signaling through cellular receptors. These favorable metabolic effects of HCQ and further understanding of underlying mechanisms may provide an additional rational for its use in rheumatic diseases, conditions associated with an elevated cardiovascular risk.
doi:10.1177/2042018814547204
PMCID: PMC4206615  PMID: 25343023
anti-inflammatory; antimalarials; chloroquine; diabetes; dyslipidemia; glycemic control; literature review; rheumatoid arthritis; systemic lupus erythematosus
12.  Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study 
Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
doi:10.1186/ar2045
PMCID: PMC1779436  PMID: 16984661
13.  Moderate diet-induced weight loss is associated with improved insulin sensitivity in middle-aged healthy obese Korean women 
Nutrition Research and Practice  2014;8(4):469-475.
BACKGROUND/OBJECTIVE
The goal of the present study was to investigate the effects of moderate caloric restriction on β-cell function and insulin sensitivity in middle-aged obese Korean women.
SUBJECTS/METHODS
Fifty-seven obese pre-menopausal Korean women participated in a 12-week calorie restriction program. Data on total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and fasting serum levels of glucose, insulin, C-peptide, blood pressure, leptin and anthropometrics were collected. A dietary intake assessment was based on three days of food recording. Additionally, β-cell function [homeostasis model assessment of β-cell (HOMA-β), insulinogenic index (ISI), C-peptide:glucose ratio, and area under curve insulin/glucose (AUCins/glu)] and insulin sensitivity [homeostasis model assessment for insulin resistance (HOMA-IR), Quantitative insulin-sensitivity check index (QUICKI) and Matsuda index (MI)] were recorded.
RESULTS
When calories were reduced by an average of 422 kcal/day for 12 weeks, BMI (-2.7%), body fat mass (-10.2%), and waist circumference (-5%) all decreased significantly (P < 0.05). After calorie restriction, weight, body fat percentage, hip circumference, BP, TC, HDL-C, LDL-C, plasma glucose at fasting, insulin at fasting and 120 min, AUCglu and the insulin area under the curve all decreased significantly (all P < 0.05), while insulin sensitivity (HOMA-IR, QUICKI and Matsuda index) measured by OGTT improved significantly (P < 0.01).
CONCLUSIONS
Moderate weight loss due to caloric restriction with reduction in insulin resistance improves glucose tolerance and insulin sensitivity in middle-aged obese women and thereby may help prevent the development of type 2 diabetes mellitus.
doi:10.4162/nrp.2014.8.4.469
PMCID: PMC4122721  PMID: 25110569
Oderate weight loss; β-cell function and insulin sensitivity
14.  Cellular and urinary microRNA alterations in NZB/W mice with hydroxychloroquine or prednisone treatment 
International immunopharmacology  2013;17(3):10.1016/j.intimp.2013.09.013.
Determining alterations to disease-associated miRNAs induced by specific therapeutics may allow the use of tailored therapy in lupus. We determined miRNA alterations in female NZB/W lupus mice treated with hydroxychloroquine (HCQ) or prednisone (PRED) for 12 weeks beginning at 24 weeks-of-age. B cell, PBMC, and urinary miR-let-7a expression were decreased with HCQ or PRED treatment. HCQ or PRED treatment reduced miR-21 expression in mesangial cells, T cells, pDCs, PBMCs, and the urine. MiR-146a expression was reduced in mesangial cells with HCQ treatment and in pDCs with HCQ or PRED treatment. PRED treatment increased miR-155 expression in mesangial, B, and T cells and PBMCs yet decreased miR-155 expression in pDCs and the urine. In vitro studies confirmed that HCQ or PRED’s anti-inflammatory actions are dependent on their ability to inhibit miRNA expression. Our studies indicate that lupus therapeutics may work, in part, by altering the expression of disease-associated iRNAs.
doi:10.1016/j.intimp.2013.09.013
PMCID: PMC3868221  PMID: 24121037
hydroxychloroquine; microRNAs; NZB/W mice; prednisone; systemic lupus erythematosus
15.  Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus 
Arthritis Research & Therapy  2012;14(3):R155.
Introduction
Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.
Methods
Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry.
Results
After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01).
Conclusions
Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists.
doi:10.1186/ar3895
PMCID: PMC3446541  PMID: 22734582
16.  A Case of Hydroxychloroquine Induced Acute Generalized Exanthematous Pustulosis Confirmed by Accidental Oral Provocation 
Annals of Dermatology  2010;22(1):102-105.
Acute generalized exanthematous pustulosis (AGEP) is a clinical reaction pattern that is principally drug induced and this is characterized by acute, nonfollicular sterile pustules on a background of edematous erythema. Hydroxychloroquine (HCQ) has been widely used to treat rheumatic and dermatologic diseases and HCQ has been reported to be an uncommon cause of AGEP. A 38-year-old woman with a 1-year history of dermatomyositis and polyarthralgia was treated with HCQ due to a lack of response to a previous medication. Three weeks after starting HCQ therapy, the pustular skin lesion developed and then this resolved after the HCQ was withdrawn and steroid treatment was started. A similar pustular eruption developed after HCQ was accidentally readministered.
doi:10.5021/ad.2010.22.1.102
PMCID: PMC2883386  PMID: 20548896
Acute generalized exanthematous pustulosis; Adverse drug reactions; Hydroxychloroquine; Provocation test
17.  Therapeutic Efficacy of Chloroquine in Plasmodium vivax and the pvmdr1 Polymorphisms in the Republic of Korea Under Mass Chemoprophylaxis 
Chemoprophylaxis with hydroxychloroquine (HCQ) and primaquine has been used in the Republic of Korea (ROK) Army since 1997. It may facilitate the development of chloroquine (CQ)-resistant strains of Plasmodium vivax. We investigated the therapeutic efficacy of HCQ and the pvmdr1 gene polymorphisms in P. vivax. From June to September 2006, 102 soldiers with vivax malaria near the demilitarized zone in Gyeonggi-do, ROK, were enrolled in the study. We determined the status of compliance of chemoprophylaxis. In 85 patients, therapeutic efficacy was monitored 28 days after standard HCQ treatment; 66 (64.7%) of 102 malaria patients had taken all chemoprolaxis with HCQ. In all patients enrolled in the therapeutic efficacy monitoring, parasitemia had not been observed since 3 days after standard HCQ treatment. However, the ubiquitous presence of the F1076L mutation of the pvmdr1 was observed. There was no evidence that the F1076L mutation of pvmdr1 could contribute to failure of HCQ treatment.
doi:10.4269/ajtmh.2011.10-0486
PMCID: PMC3062443  PMID: 21460004
18.  Development of polyether urethane intravaginal rings for the sustained delivery of hydroxychloroquine 
Hydroxychloroquine (HCQ) has been shown to demonstrate anti-inflammatory properties and direct anti-HIV activity. In this study, we describe for the first time the fabrication and in vitro evaluation of two types of intravaginal ring (IVR) devices (a surfaced-modified matrix IVR and a reservoir segmental IVR) for achieving sustained delivery (>14 days) of HCQ as a strategy for preventing male-to-female transmission of HIV. Both IVRs were fabricated by hot-melt injection molding. Surface-modified matrix IVRs with polyvinylpyrrolidone or poly(vinyl alcohol) coatings exhibited significantly reduced burst release on the first day (6.45% and 15.72% reduction, respectively). Reservoir IVR segments designed to release lower amounts of HCQ displayed near-zero-order release kinetics with an average release rate of 28.38 μg/mL per day for IVRs loaded with aqueous HCQ and 32.23 μg/mL per day for IVRs loaded with HCQ mixed with a rate-controlling excipient. Stability studies demonstrated that HCQ was stable in coated or noncoated IVRs for 30 days. The IVR segments had no significant effect on cell viability, pro-inflammatory cytokine production, or colony formation of vaginal and ectocervical epithelial cells. Both IVR systems may be suitable for the prevention of HIV transmission and other sexually transmitted infections.
doi:10.2147/DDDT.S71352
PMCID: PMC4199968  PMID: 25336923
intravaginal delivery; matrix system; reservoir system; polymeric drug carrier; drug release; microbicide; HIV/AIDS
19.  A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non-Small Cell Lung Cancer 
Introduction
This investigator-initiated study explores the safety, maximum tolerated dose (MTD), clinical response, and pharmacokinetics (PK) of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small cell lung cancer (NSCLC).
Methods
Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3+3 dose escalation schema.
Results
Twenty-seven patients were treated, 8 with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of patients and 85% had received ≥2 prior therapies. Arm A had no dose-limiting toxicities (DLTs), but the MTD was not reached as this arm closed early to increase overall study accrual. In arm B, 1 patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia, 1 had grade 4 anemia, and 1 developed fatal pneumonitis, all considered unrelated to HCQ. There were no DLTs, therefore the highest tested dose for HCQ with erlotinib 150mg was 1000mg daily. One patient had a partial response (PR) to erlotinib/HCQ, for an overall response rate of 5% (95% CI, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the PK of erlotinib.
Conclusions
HCQ with or without erlotinib was safe and well-tolerated. The recommended phase 2 dose of HCQ was 1000mg when given in combination with erlotinib 150mg.
doi:10.1097/JTO.0b013e318262de4a
PMCID: PMC3791327  PMID: 22878749
20.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
21.  Maternal history of diabetes is associated with increased cardiometabolic risk in Chinese 
Nutrition & Diabetes  2014;4(3):e112-.
Objective:
Positive family history is associated with increased type 2 diabetes (T2D) risk, and reflects both genetic and environmental risks. Several studies have suggested an excess maternal transmission of T2D, although the underlying mechanism is unknown. We aimed to examine the association between maternal diabetes and cardiometabolic risk in the offspring.
Methods:
Parental history of diabetes and clinical data including anthropometric traits, fasting plasma glucose and insulin (FPG, FPI), blood pressure and lipid profile were collected from 2581 unrelated Chinese offspring (2026 adolescents from a population-based school survey and 555 adults from a community-based health screening programme). A subset of subjects (n=834) underwent oral glucose tolerance test to measure the glucose and insulin concentrations at 0, 15, 30, 60 and 120 min for evaluation of the areas under the curve (AUC) of glucose and insulin at 0–120 min, homoeostasis model assessment of insulin resistance (HOMA-IR) and bell-cell function, insulinogenic index, insulin sensitivity index (ISI) and oral disposition index (DI).
Results:
A positive parental history of diabetes was associated with increased risk of obesity (odd ratios (OR) (95% confidence interval (CI))=1.48 (1.10–2.00)), central obesity (OR (95% CI)=1.67 (1.21–2.32)), higher FPI, HOMA-IR, 2-h insulin, AUC of glucose at 0–120 min, triglycerides, reduced ISI and DI. Compared with individuals without parental diabetes, offspring with diabetic mother had significantly increased risk of obesity (OR (95% CI)=1.59 (1.07–2.35)), central obesity (OR (95% CI)=1.88 (1.23–2.88)), higher glucose levels and BP, were more insulin resistant but also had impaired first-phase insulin response and worse lipid profile. However, paternal history of diabetes had no effect on any of the studied traits, except higher body mass index, waist circumference in females and FPG.
Conclusions:
Our findings suggested that maternal history of diabetes conferred increased risk of cardiometabolic abnormalities, and was associated with both insulin resistance and impaired first-phase insulin secretion. Further investigation into the mechanism of transgenerational diabetes is warranted.
doi:10.1038/nutd.2014.9
PMCID: PMC3974036  PMID: 24614663
22.  Insulin resistance as estimated by the homeostatic method at diagnosis of gestational diabetes: estimation of disease severity and therapeutic needs in a population-based study 
Background
Chronic insulin resistance, exacerbated in the course of pregnancy, is an important pathophysiologic mechanism of gestational diabetes mellitus (GDM). We hypothesise that the degree of insulin resistance, assessed at diagnosis of GDM, is a parameter of its pathophysiologic heterogeneity and/or severity. Thus, it offers potential to open new avenues for the personalization of therapy in affected women.
Methods
1254 Polish Caucasian women with GDM were recruited into the study. The following parameters were assessed in the course of the study: body mass index (BMI), parity, weight gain during pregnancy, glycated haemoglobin, glucose level during an oral glucose tolerance test (OGTT), insulin, insulin resistance and insulin secretion. The severity of GDM was assessed based on insulin use and daily insulin dose during gestation. In order to evaluate insulin secretion and insulin resistance the homeostatic method was used (HOMA-B and HOMA-IR, respectively). We compared all the metabolic parameters and methods of treatment of GDM in women subdivided by quartiles of insulin resistance.
Results
The HOMA-IR in the whole population ranged from 0.34 to 20.39. The BMI, fasting insulin, fasting glucose and insulin dose per day increased along with increasing quartiles (HOMA-IR > 1.29). We observed a decrease of HOMA-B in the third quartile (1.92-2.89) compared with the first quartile (0.34-1.29). Insulin treatment was associated with HOMA-IR (<1.29 vs. >2.89), OR: 3.37, fasting glucose (≤6.11 vs. >6.11 mmol/dl), OR: 2.61, age (≤30 vs. >30 y. o.), OR: 1.54, and BMI (<25 vs. ≥25 kg/m2), OR: 1.45. Maximum insulin dose was associated with HOMA-IR, OR: 2.00, after adjustment for family history of diabetes, and 2-h OGTT glucose.
Conclusion
Insulin resistance assessed by the HOMA index at diagnosis is associated with the severity and pathophysiological heterogeneity of GDM. A HOMA-IR >1.29 points to the major role of insulin resistance, indicating the need for a treatment aimed at improving tissue sensitivity to insulin. A HOMA-IR 1.29-2.89 suggests reduced insulin secretion, which is an indication for the introduction of insulin therapy. A HOMA-IR >2.89 indicates insufficient compensation for insulin resistance, which suggests the need for a treatment aimed at improving susceptibility of tissues to insulin combined with insulin therapy.
doi:10.1186/1472-6823-13-21
PMCID: PMC3702418  PMID: 23819910
Gestational Diabetes; Pathophysiology; Gestational Diabetes; Treatment; Gestational Diabetes; Insulin Resistance; Gestational Diabetes; HOMA
23.  Maternal Use of Hydroxychloroquine is Associated with a Reduced Risk of Recurrent Anti-SSA/Ro Associated Cardiac Manifestations of Neonatal Lupus 
Circulation  2012;126(1):76-82.
Background
A recent case control study suggested a benefit of hydroxychloroquine (HCQ) in lowering the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in pregnancies of anti-SSA/Ro positive patients with Systemic Lupus Erythematosus (SLE). A historical cohort assembled from three international databases was used to evaluate whether HCQ reduces the nearly tenfold increase in risk of recurrence of cardiac-NL, independent of maternal health status.
Methods and Results
Two hundred fifty seven pregnancies of anti-SSA/Ro positive mothers (40 exposed and 217 unexposed to HCQ) subsequent to the birth of a child with cardiac-NL were identified from three databases (U.S., England, and France). Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation prior to ten weeks of gestation. The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5% (3/40) compared to 21.2% (46/217) in the unexposed group (p=0.050). While there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 22%. In a multivariable analysis which adjusted for database source, maternal race/ethnicity, and anti-SSB/La status, HCQ use remained significantly associated with a decreased risk of cardiac-NL (Odds Ratio=0.23; 95% CI: 0.06–0.92; p=0.037). Similar results were obtained with propensity score analysis, an alternative approach to adjust for possible confounding by indication.
Conclusions
Based on aggregate data from a multinational effort, in mothers at high risk of having a child with cardiac-NL, the use of HCQ may protect against recurrence of disease in a subsequent pregnancy.
doi:10.1161/CIRCULATIONAHA.111.089268
PMCID: PMC3437628  PMID: 22626746
heart block; antibodies; cardiomyopathy; prevention; hydroxychloroquine
24.  INFLUENCE OF GENDER ON THE RELATIONSHIP BETWEEN INSULIN SENSITIVITY, ADIPOSITY AND PLASMA LIPIDS IN LEAN NON-DIABETIC SUBJECTS 
Metabolism: clinical and experimental  2009;58(11):1602-1608.
Individuals with obesity frequently have an atherogenic lipid profile. It has been proposed that the insulin resistance observed in these individuals is involved in the development of these lipid abnormalities. However, most studies that have examined the relationship between insulin resistance and lipid abnormalities have included subjects who are either obese and/or glucose intolerant, two factors that may affect lipid levels independent of insulin resistance. We have therefore examined the impact of insulin resistance on plasma lipids in a healthy, lean (average BMI < 24), non-diabetic population (n =104). In our subjects we observed a wide range of values for insulin sensitivity index values (ISI) as calculated by the formula of Matsuda and DeFronzo. Lipid values ranged considerably in this population, but incidence of hypertriglyceridemia and hypercholesterolemia were low in the absence of obesity. We first examined the relationship between ISI and total and regional adipose stores as assessed by dual-energy X-ray absorptiometry (DXA). In men, we observed higher values for indices of total and central adipose stores that were significantly associated with decreased insulin sensitivity. In contrast, in women, ISI values were not associated with any variables related to either total or regional adiposity. In men, ISI was also significantly associated with higher triglycerides levels (P < 0.01) when adjusted for age and percent truncal fat. In women however, there was no significant association between ISI and triglycerides (P = 0.14). Instead, in women, the total and truncal fat were independent predictors of several lipid levels. These results both highlight gender differences in the associations between insulin resistance, regional adipose stores and lipids values, and emphasize the importance of adipose stores on the development of an individual’s lipid profile.
doi:10.1016/j.metabol.2009.05.012
PMCID: PMC2763945  PMID: 19604524
25.  Hydroxychloroquine facilitates autophagosome formation but not degradation to suppress the proliferation of cervical cancer SiHa cells 
Oncology Letters  2014;7(4):1057-1062.
Hydroxychloroquine (HCQ), the hydroxylated analog of chloroquine, is an antimalarial lysomotropic agent that inhibits autophagy due to lysosomal acidification, and subsequently blocks the fusion of autophagosomes with lysosomes which leads to the accumulation of autophagosomes that may accelerate tumor cell death. Given these hypothesis the aim of this study was to investigate the effects of HCQ in the inhibition of autophagy and the induction of apoptosis in cervical cancer SiHa cells. Cervical cancer SiHa cells were cultured with Hank’s balanced salt solution (HBSS) as positive control of autophagy or treated with HCQ as part of the experimental groups. LC3 and P62/SQSTM1 were detected by quantitative polymerase chain reaction (qPCR) and western blotting, respectively in order to evaluate initially autophagosome formation and their degradation. Specific green fluorescent protein (GFP)-LC3 was subsequently detected by fluorescence microscopy in order to confirm the formation of autophagosomes. MTT and flow cytometry were adopted respectively to assess the proliferation and apoptosis of the SiHa cells. miRNA-9* was also investigated. The results demonstrated that HCQ increased the expressions of LC3 mRNA and LC3II protein and GFP-LC3 signalling but reduced the expression of p62/STSQM1 in cervical cancer SiHa cells. These results indicated HCQ has the ability to inhibit autophagy as incapable of degrading the autophagosome. However, HCQ may promote SiHa cell apoptosis as the MTT, apoptotic assay and miRNA-9* results revealed. HCQ has the ability to inhibit autophagy by blocking the degradation of autophagosomes and subsequently facilitates the apoptosis of cervical cancer SiHa cells.
doi:10.3892/ol.2014.1879
PMCID: PMC3961458  PMID: 24944668
hydroxychloroquine; cervical cancer; autophagy; apoptosis

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