Detecting drug interactions from adverse-event reports: interaction between paroxetine and pravastatin increases blood glucose levels.
ABSTRACT: The lipid-lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS) for side-effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins.
Project description:AIM: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms. METHODS: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion. RESULTS: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine. CONCLUSION: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.
Project description:<h4>Objective</h4>To determine random capillary blood glucose (RCBG) cut points that discriminate diabetic and pre-diabetic subjects from normal individuals.<h4>Research design and methods</h4>RCBG was performed in 1,333 individuals randomly chosen from 63,305 individuals who had participated in an opportunistic screening program. An oral glucose tolerance test was also performed by venous plasma glucose on an autoanalyzer. RCBG cut points that discriminate diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) were determined using receiver operating characteristic curves.<h4>Results</h4>Using 2-h plasma glucose >or=200 mg/dl (11.1 mmol/l) criterion, the RCBG cut point of 140 mg/dl (7.7 mmol/l) gave the highest sensitivity and specificity. For 2-h plasma glucose >or=200 mg/dl (11.1 mmol/l) and fasting plasma glucose (FPG) >or=126 mg/dl (7.0 mmol/l) criteria, either 2-h plasma glucose >or=200 mg/dl (11.1 mmol/l) or FPG >or=126 mg/dl (7.0 mmol/l) criterion, and the FPG >or=126 mg/dl (7.0 mmol/l) criterion, RCBG cut point was 143 mg/dl (7.9 mmol/l). RCBG cut points for IGT, IFG according to World Health Organization criterion, and IFG according to American Diabetes Association criterion were 119 mg/dl (6.6 mmol/l), 118 mg/dl (6.6 mmol/l), and 113 mg/dl (6.3 mmol/l), respectively.<h4>Conclusions</h4>Asian Indians with RCBG >110 mg/dl at screening can be recommended to undergo definitive testing.
Project description:The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reduced cardiovascular outcomes. We evaluated diabetes mellitus incidence in this randomized trial that compared intensive blood pressure strategy (systolic blood pressure <120 mm Hg) versus standard strategy (<140 mm Hg). Participants were ?50 years of age, with systolic 130 to 180 mm Hg and increased cardiovascular risk. Participants were excluded if they had diabetes mellitus, polycystic kidney disease, proteinuria >1 g/d, heart failure, dementia, or stroke. Postrandomization exclusions included participants missing blood glucose or ?126 mg/dL (6.99 mmol/L) or on hypoglycemics. The outcome was incident diabetes mellitus: fasting blood glucose ?126 mg/dL (6.99 mmol/L), diabetes mellitus self-report, or new use of hypoglycemics. The secondary outcome was impaired fasting glucose (100-125 mg/dL [5.55-6.94 mmol/L]) among those with normoglycemia (<100 mg/dL [5.55 mmol/L]). There were 9361 participants randomized and 981 excluded, yielding 4187 and 4193 participants assigned to intensive and standard strategies. There were 299 incident diabetes mellitus events (2.3% per year) for intensive and 251 events (1.9% per year) for standard, rates of 22.6 (20.2-25.3) versus 19.0 (16.8-21.5) events per 1000 person-years of treatment, respectively (adjusted hazard ratio, 1.19 [95% CI, 0.95-1.49]). Impaired fasting glucose rates were 26.4 (24.9-28.0) and 22.5 (21.1-24.1) per 100 person-years for intensive and standard strategies (adjusted hazard ratio, 1.17 [1.06-1.30]). Intensive treatment strategy was not associated with increased diabetes mellitus but was associated with more impaired fasting glucose. The risks and benefits of intensive blood pressure targets should be factored into individualized patient treatment goals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.
Project description:BACKGROUND:The objective of this study was to identify the minimum basal insulin infusion rates and bolus insulin doses that would result in clinically relevant changes in blood glucose levels in the most insulin sensitive subjects with type 1 diabetes. METHODS:The UVA/PADOVA Type 1 Diabetes Simulator in silico population of children, adolescents, and adults was administered a basal insulin infusion rate to maintain blood glucose concentrations at 120 mg/dL (6.7 mmol/L). Two scenarios were modeled independently after 1 hour of simulated time: (1) basal insulin infusion rates in increments of 0.01 U/h were administered and (2) bolus doses in increments of 0.01 U were injected. Subjects were observed for 4 hours to determine insulin delivery required to change blood glucose by 12.5 mg/dL (0.7 mmol/L) and 25 mg/dL (1.4 mmol/L) in only 5% of the in silico population. RESULTS:The basal insulin infusion rates required to change blood glucose by 12.5 mg/dL and 25 mg/dL in 5% of children, adolescents, and adults were 0.03, 0.11, and 0.10 U/h and 0.06, 0.21, and 0.19 U/h, respectively. The bolus insulin doses required to change blood glucose by the target amounts in the respective populations were 0.10, 0.28, and 0.30 U and 0.19, 0.55, and 0.60 U. CONCLUSIONS:In silico modeling suggests that only a very small percentage of individuals with type 1 diabetes, corresponding to children with high insulin sensitivity and low body weight, will exhibit a clinically relevant change in blood glucose with very low basal insulin rate changes or bolus doses.
Project description:In Sweden, FreeStyle Libre a flash glucose monitoring system came onto the market in 2014 as a complement to self-monitoring of blood glucose. The aim of this study was to evaluate the accuracy and treatment experience of the FreeStyle Libre system.Fifty-eight adults with type 1 diabetes used FreeStyle Libre for 10-14 days and measured capillary blood glucose levels with the HemoCue blood glucose measurement system at least six times a day simultaneously.For the entire study period, the mean absolute relative difference (MARD) was 13.2% (95% confidence interval [CI] 12.0%-14.4%). MARD was 13.6% (95% CI 12.1%-15.4%) during week 1 and 12.7% (95% CI 11.5%-13.9%) during week 2. The mean absolute difference (MAD) for the whole study period was 19.8?mg/dL (1.1?mmol/L) (95% CI 17.8-21.8?mg/dL), including 20.5?mg/dL (1.14?mmol/L) during week 1 and 19.0?mg/dL (1.05?mmol/L) during week 2. The overall correlation coefficient was 0.96. For glucose values <72, 72-180, and >180?mg/dL (<4, 4-10, and >10?mmol/L), the MARD was 20.3% (95% CI 17.7%-23.1%), 14.7% (95% CI 13.4%-16%), and 9.6% (95% CI 8.5%-10.8%), respectively, and respective MAD values were 12.3, 17.8, and 23.6?mg/dL (0.69, 0.99, and 1.31?mmol/L). Using the 10-item visual analog scale, patients rated their experience with FreeStyle Libre as generally positive, with mean values ranging from 8.22 to 9.8.FreeStyle Libre had a similar overall MARD as continuous blood glucose monitoring systems in earlier studies when studied in similar at-home conditions. The overall patient satisfaction was high.
Project description:INTRODUCTION:Closed-loop systems titrate insulin based on sensor glucose levels, providing novel means to reduce the risk of hypoglycaemia while improving glycaemic control. We will assess effectiveness of 6-month day-and-night closed-loop insulin delivery compared with usual care (conventional or sensor-augmented pump therapy) in children and adolescents with type 1 diabetes. METHODS AND ANALYSIS:The trial adopts an open-label, multicentre, multinational (UK and USA), randomised, single-period, parallel design. Participants (n=130) are children and adolescents (aged ?6?and <19 years) with type 1 diabetes for at least 1?year, and insulin pump use for at least 3 months with suboptimal glycaemic control (glycated haemoglobin ?58?mmol/mol (7.5%) and ?86?mmol/mol (10%)). After a 2-3?week run-in period, participants will be randomised to 6-month use of hybrid closed-loop insulin delivery, or to usual care. Analyses will be conducted on an intention-to-treat basis. The primary outcome is glycated haemoglobin at 6 months. Other key endpoints include time in the target glucose range (3.9-10?mmol/L, 70-180?mg/dL), mean sensor glucose and time spent above and below target. Secondary outcomes include SD and coefficient of variation of sensor glucose levels, time with sensor glucose levels <3.5?mmol/L (63?mg/dL) and <3.0?mmol/L (54?mg/dL), area under the curve of glucose <3.5?mmol/L (63?mg/dL), time with glucose levels >16.7?mmol/L (300?mg/dL), area under the curve of glucose >10.0?mmol/L (180?mg/dL), total, basal and bolus insulin dose, body mass index z-score and blood pressure. Cognitive, emotional and behavioural characteristics of participants and caregivers and their responses to the closed-loop and clinical trial will be assessed. An incremental cost-effectiveness ratio for closed-loop will be estimated. ETHICS AND DISSEMINATION:Cambridge South Research Ethics Committee and Jaeb Center for Health Research Institutional Review Office approved the study. The findings will be disseminated by peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER:NCT02925299; Pre-results.
Project description:OBJECTIVE:According to recent guidelines, individuals with type 1 diabetes should spend <4.0% of time per day with glucose levels <3.9 mmol/L (<70 mg/dL) and <1.0% per day with glucose levels <3.0 mmol/L (<54 mg/dL). RESEARCH DESIGN AND METHODS:In the GOLD randomized crossover trial, 161 individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) were randomized to continuous glucose monitoring (CGM) or conventional therapy with self-monitoring of blood glucose (SMBG) and evaluated over 16 months. We estimated the association between time spent in hypoglycemia and various mean glucose and HbA1c levels. RESULTS:Time spent in hypoglycemia (<3.9 mmol/L and <3.0 mmol/L) increased significantly with lower mean HbA1c and mean glucose levels during both CGM and conventional therapy. During CGM, 24 (57.1%) individuals with HbA1c <7.5% (<58 mmol/mol) had <1.0% time spent in hypoglycemia <3.0 mmol/L and 23 (54.8%) had <4.0% time spent in hypoglycemia <3.9 mmol/L. During CGM, mean time spent in hypoglycemia for individuals with mean HbA1c 7.0% (52 mmol/mol) was estimated to be 5.4% for <3.9 mmol/L and 1.5% for <3.0 mmol/L. The corresponding values during SMBG were 9.2% and 3.5%, respectively. Individuals with mean glucose levels of 8 mmol/L spent 4.9% units more time with glucose levels <3.9 mmol/L and 2.8% units more time <3.0 mmol/L during SMBG compared with CGM. CONCLUSIONS:Reaching current targets for time in hypoglycemia while at the same time reaching HbA1c targets is challenging for patients with type 1 diabetes treated with MDI both with CGM and SMBG monitoring. However, CGM is associated with considerably less time in hypoglycemia than SMBG at a broad range of HbA1c levels and is crucial for patients with MDI treatment if they are to have a chance to approach hypoglycemia targets.
Project description:The aim of this study was to compare the accuracy of 5 blood glucose monitoring systems (BGMSs; CONTOUR(®)PLUS [CP], Accu-Chek(®) Active [ACA], Accu-Chek(®) Performa [ACP], FreeStyle Freedom™ [FF], OneTouch(®) SelectSimple™ [OTSS]).Study staff tested fingerstick samples from 106 subjects aged ≥18 years using the 5 BGMSs. Some samples were modified to achieve blood glucose concentrations throughout the measuring range. The primary endpoint was comparison of the mean absolute relative difference (MARD) from the reference value (Yellow Springs Instruments [YSI]) across the overall tested glucose range. Other endpoints were MARD in the low (≤80 mg/dL [≤4.4 mmol/L]), middle (81-180 mg/dL [4.5-10.0 mmol/L]), and high (>180 mg/dL [>10.0 mmol/L]) glucose ranges, and MARD for unmodified samples in the overall glucose range.CONTOUR(®)PLUS had a statistically significantly lower MARD than all BGMSs across the overall tested range (27-460 mg/dL [1.5-25.5 mmol/L]) and in the high glucose range. In the low glucose range, CP had a lower MARD than all BGMSs, which was statistically significant except for ACP. For unmodified samples across the overall tested range, CP had a lower MARD than all BGMSs and was statistically significantly lower except for ACA.CONTOUR(®)PLUS had the lowest mean difference from the reference values (by MARD) when compared with other BGMSs across multiple glucose ranges with modified and unmodified samples.Bayer HealthCare LLC, Diabetes Care.ClinicalTrials.gov Identifier NCT01714232.
Project description:Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 ?-cells by 59% and 79% (p<0.01) at glucose concentration of 5.5 mmol/l and 16.7 mmol/l, respectively, compared to control, whereas pravastatin did not impair insulin secretion. Simvastatin induced decrease in insulin secretion occurred through multiple targets. In addition to its established effects on ATP-sensitive potassium channels (p = 0.004) and voltage-gated calcium channels (p = 0.004), simvastatin suppressed insulin secretion stimulated by muscarinic M3 or GPR40 receptor agonists (Tak875 by 33%, p = 0.002; GW9508 by 77%, p = 0.01) at glucose level of 5.5 mmol/l, and inhibited calcium release from the endoplasmic reticulum. Impaired insulin secretion caused by simvastatin treatment were efficiently restored by GPR119 or GLP-1 receptor stimulation and by direct activation of cAMP-dependent signaling pathways with forskolin. The effects of simvastatin treatment on insulin secretion were not affected by the presence of hyperglycemia. Our observation of the opposite effects of simvastatin and pravastatin on glucose-stimulated insulin secretion is in agreement with previous reports showing that simvastatin, but not pravastatin, was associated with increased risk of incident diabetes.
Project description:OBJECTIVE:The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes. RESEARCH DESIGN AND METHODS:β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95-125 mg/dL (5.3-6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c 5.8-7.0% (40-53 mmol/mol), and BMI 25-40 kg/m(2). Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30-40 kg/m(2), HbA1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m(2), 10-19 years of age, and diabetes <6 months. RESULTS:Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points. CONCLUSIONS:RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.