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Background: Adherence to antihypertensive drugs in patients with diabetes is important. To support adherence, attention should be paid to the dynamic process of implementation, persistence and reinitiation of these drugs. We assessed non-adherence, non-persistence and reinitiation patterns for antihypertensive drugs in patients on oral diabetes drugs and identified pharmacy-based predictors of these processes. Methods: We conducted a cohort study in patients on oral diabetes drugs who initiated antihypertensive drugs between 1995–2015, as registered in the IADB.nl pharmacy database. Non-adherence was defined as a medication possession ratio < 80% and non-persistence as a gap > 180 days. We defined reinitiation as the dispensing of an antihypertensive drug within one year following discontinuation. We provide descriptive statistics for different time periods and applied logistic and Cox regressions to assess associations with sociodemographic and drug-related factors. Results: Of 6,669 initiators, non-adherence rates in persistent patients decreased from 11.0% in the first year to 8.5% and 7.7% in the second and third years, respectively. Non-persistence rates decreased from 18.0% in the first year to 3.7% and 2.9% in the second and third years, respectively. Of the 1,201 patients who discontinued in the first year, 22.0% reinitiated treatment within one year. Non-adherence and non-persistence rates were lower in the more recent time period. Predictors of non-adherence were secondary prevention (OR: 1.45; 95% CI: 1.10–1.93) and diuretics as initial drug class (OR: 1.37; 95% CI: 1.08–1.74). Predictors of non-persistence were female gender (HR: 1.18; 95% CI: 1.05–1.32), older age (HR: 1.33; 95% CI: 1.08–1.63) and diuretics, beta-blocking agents or calcium channel blockers as initial drug class. Longer duration of persistence was a predictor of reinitiation. Conclusions: Adherence to antihypertensive drugs in patients on oral diabetes drugs has improved over time. The first year after initiation is the most crucial with regard to non-adherence and non-persistence, and the risk groups are different for both processes. Early non-persistence is a risk factor for not reinitiating treatment. [ABSTRACT FROM AUTHOR]

Background: Increasingly, genetic analyses are conducted using information from subjects with established disease, who often receive concomitant treatment. We determined when treatment may bias genetic associations with a quantitative trait. Methods: Graph theory and simulated data were used to explore the impact of drug prescriptions on (longitudinal) genetic effect estimates. Analytic derivations of longitudinal genetic effects are presented, accounting for the following scenarios: 1) treatment allocated independently of a genetic variant, 2) treatment that mediates the genetic effect, 3) treatment that modifies the genetic effect. We additionally evaluate treatment modelling strategies on bias, the root mean squared error (RMSE), coverage, and rejection rate. Results: We show that in the absence of treatment by gene effect modification or mediation, genetic effect estimates will be unbiased. In simulated data we found that conditional models accounting for treatment, confounding, and effect modification were generally unbiased with appropriate levels of confidence interval coverage. Ignoring the longitudinal nature of treatment prescription, however (e.g. because of incomplete records in longitudinal data), biased these conditional models to a similar degree (or worse) as simply ignoring treatment. Conclusion: The mere presence of (drug) treatment affecting a GWAS phenotype is insufficient to bias genetic associations with quantitative traits. While treatment may bias associations through effect modification and mediation, this might not occur frequently enough to warrant general concern at the presence of treated subjects in GWAS. Should treatment by gene effect modification or mediation be present however, current GWAS approaches attempting to adjust for treatment insufficiently account for the multivariable and longitudinal nature of treatment trajectories and hence genetic estimates may still be biased. [ABSTRACT FROM AUTHOR]

Background and purpose: Polypharmacy is becoming increasingly common owing to the ageing population, which can pose problems for patients and society. We investigated the trends in polypharmacy and underlying drug groups among adults in the Netherlands from 1999 to 2014 stratified by age, and compared these with findings from the United States (US). Methods: We conducted a repeated cross-sectional study using the Dutch IADB.nl prescription database. All patients aged 20 years and older in the period 1999 to 2014 were included. Polypharmacy was defined as the dispensing of five or more chronic drugs at the pharmacological subgroup level. Chi-square tests were applied to calculate the p-value for trends. Changes in prevalences were compared between the Netherlands and the US. Results: The prevalence of polypharmacy increased from 3.1% to 8.0% (p-value for trend <0.001) over 15 years, and increased in all age groups. The highest rates were observed in patients aged ≥65 years, but the relative increase over time was higher in the younger age groups. Overall, large increases were observed for angiotensin-II inhibitors, statins and proton-pump inhibitors. The relative increase in polypharmacy was larger in the Netherlands than in the US (ratio of polypharmacy prevalence 2.4 versus 1.8). The Netherlands showed larger relative increases for angiotensin-II inhibitors, statins, proton-pump inhibitors, biguanides and smaller relative increases for antidepressants, benzodiazepines and insulins. Conclusions: Polypharmacy more than doubled from 1999 to 2014, and this increase was not limited to the elderly. The relative increase was larger in the Netherlands compared to the US, which was partly due to larger increases in several guideline-recommended preventive drugs. [ABSTRACT FROM AUTHOR]

Background: Guideline-adherent prescribing for treatment of multiple risk factors in type 2 diabetes (T2D) patients is expected to improve clinical outcomes. However, the relationship to Health-Related Quality of Life (HRQoL) is not straightforward since guideline-adherent prescribing can increase medication burden. Objectives: To test whether guideline-adherent prescribing and disease-specific medication burden are associated with HRQoL in patients with T2D. Methods: Cross-sectional study including 1,044 T2D patients from the e-VitaDM/ZODIAC study in 2012 in the Netherlands. Data from the diabetes visit, such as laboratory and physical examinations and prescribed medication, and from two HRQoL questionnaires, the EuroQol 5 Dimensions 3 Levels (EQ5D-3L) and the World Health Organization Well-Being Index (WHO-5) were collected. Twenty indicators assessing prescribing of recommended glucose lowering drugs, statins, antihypertensives and renin-angiotensin-aldosterone system (RAAS)-inhibitors and potentially inappropriate drugs from a validated diabetes indicator set were included. Disease-specific medication burden was assessed using a modified version of the Medication Regimen Complexity Index (MRCI). Associations were tested with regression models, adjusting for age, gender, diabetes duration, comorbidity, body mass index and smoking. Results: The mean MRCI was 7.1, the median EQ5D-3L-score was 0.86 and the mean WHO-5 score was 72. Seven indicators included too few patients and were excluded from the analysis. The remaining thirteen indicators focusing on recommended start, intensification, current and preferred use of glucose lowering drugs, statins, antihypertensives, RAAS inhibitors, and on inappropriate prescribing of glibenclamide and dual RAAS blockade were not significantly associated with HRQoL. Finally, also the MRCI was not associated with HRQoL. Conclusions: We found no evidence for associations between guideline-adherent prescribing or disease-specific medication burden and HRQoL in T2D patients. This gives no rise to refrain from prescribing intensive treatment in T2D patients as recommended, but the interpretation of these results is limited by the cross-sectional study design and the selection of patients included in some indicators. [ABSTRACT FROM AUTHOR]

Background: Accounting for justifiable variance is important for fair comparisons of treatment quality. The variance between general practices in treatment quality of type 2 diabetes (T2DM) patients may be attributed to the underlying patient population and practice characteristics. The objective of this study is to describe the between practice differences in treatment, and identify patient and practice level characteristics that may explain these differences. Methods: The data of 24,607 T2DM patients from 183 general practices in the Netherlands were used. Treatment variance was assessed in a cross-sectional manner for: glucose-lowering drugs/metformin, lipid-lowering drugs/statins, blood pressure-lowering drugs/ACE-inhibitor or ARB. Patient characteristics tested were age, gender, diabetes duration, comorbidity, comedication. Practice characteristics were number of T2DM patients, practice type, diabetes assistant available. Multilevel logistic regression was used to examine the between practice variance in treatment and the effect of characteristics on this variance. Results: Treatment rates varied considerably between practices (IQR 9.5–13.9). The variance at practice level was 7.5% for glucose-lowering drugs, 3.6% for metformin, 3.1% for lipid-lowering drugs, 10.3% for statins, 8.6% for blood pressure-lowering drugs, and 3.9% for ACE-inhibitor/ARB. Patient and practice characteristics explained 19.0%, 7.5%, 20%, 6%, 9.9%, and 13.4% of the variance respectively. Age, multiple chronic drugs, and ≥3 glucose-lowering drugs were the most relevant patient characteristics. Number of T2DM patients per practice was the most relevant practice characteristic. Discussion: Considerable differences exist between practices in treatment rates. Patients’ age was identified as characteristic that may account for justifiable differences in especially lipid-lowering treatment. Other patient or practice characteristics either do not explain or do not justify the differences. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether patients’ willingness to add a blood pressure-lowering drug and the importance they attach to specific treatment characteristics differ among age groups in patients with type 2 diabetes. Materials and Methods: Patients being prescribed at least an oral glucose-lowering and a blood pressure-lowering drug completed a questionnaire including a discrete choice experiment. This experiment contained choice sets with hypothetical blood pressure-lowering drugs and a no additional drug alternative, which differed in their characteristics (i.e. effects and intake moments). Differences in willingness to add a drug were compared between patients <75 years (non-aged) and ≥75 years (aged) using Pearson χ2-tests. Multinomial logit models were used to assess and compare the importance attached to the characteristics. Results: Of the 161 patients who completed the questionnaire, 151 (72%) could be included in the analyses (mean age 68 years; 42% female). Aged patients were less willing to add a drug than non-aged patients (67% versus 84% respectively; P = 0.017). In both age groups, the effect on blood pressure was most important for choosing a drug, followed by the risk of adverse drug events and the risk of death. The effect on limitations due to stroke was only significant in the non-aged group. The effect on blood pressure was slightly more important in the non-aged than the aged group (P = 0.043). Conclusions: Aged patients appear less willing to add a preventive drug than non-aged patients. The importance attached to various treatment characteristics does not seem to differ much among age groups. [ABSTRACT FROM AUTHOR]

Aims: To estimate the efficacy of standard and intensive statin treatment in the secondary prevention of major cardiovascular and cerebrovascular events in diabetes patients. Methods: A systematic search was conducted in Medline over the years 1990 to September 2013. Randomized, double-blind, clinical trials comparing a standard-dose statin with placebo or a standard-dose statin with an intensive-dose statin for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients were selected. Trial and patient characteristics were extracted independently by two researchers. The combined effect on the composite primary endpoint was measured with a fixed-effect model. Potential publication bias was examined with a funnel plot. Results: Five trials were included in the analysis comparing standard-dose statins with placebo with a total of 4 351 participants. Four trials were included for comparing standard-dose with intensive-dose statins, including 4 805 participants. Compared with placebo, standard-dose statin treatment resulted in a significant relative risk (RR) reduction of 15% in the occurrence of any major cardiovascular or cerebrovascular event (RR 0.85, 95% CI 0.79–0.91). Compared with standard-dose statin treatment, intensive-dose statin treatment resulted in an additional 9% relative risk reduction (RR 0.91, 95% CI 0.84–0.98). Conclusion: Treatment with standard-dose statins to prevent cardiovascular or cerebrovascular events in diabetes patients with manifest cardiovascular disease results in an estimated 15% relative risk reduction and intensive-dose statin treatment adds 9%. If proven cost-effective, more intensive statin treatment should be recommended for diabetes patients at high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: Landmark clinical trials have led to optimal treatment recommendations for patients with diabetes. Whether optimal treatment is actually delivered in practice is even more important than the efficacy of the drugs tested in trials. To this end, treatment quality indicators have been developed and tested against intermediate outcomes. No studies have tested whether these treatment quality indicators also predict hard patient outcomes. Methods: A cohort study was conducted using data collected from >10.000 diabetes patients in the Groningen Initiative to Analyze Type 2 Treatment (GIANTT) database and Dutch Hospital Data register. Included quality indicators measured glucose-, lipid-, blood pressure- and albuminuria-lowering treatment status and treatment intensification. Hard patient outcome was the composite of cardiovascular events and all-cause death. Associations were tested using Cox regression adjusting for confounding, reporting hazard ratios (HR) with 95% confidence intervals. Results: Lipid and albuminuria treatment status, but not blood pressure lowering treatment status, were associated with the composite outcome (HR = 0.77, 0.67–0.88; HR = 0.75, 0.59–0.94). Glucose lowering treatment status was associated with the composite outcome only in patients with an elevated HbA1c level (HR = 0.72, 0.56–0.93). Treatment intensification with glucose-lowering but not with lipid-, blood pressure- and albuminuria-lowering drugs was associated with the outcome (HR = 0.73, 0.60–0.89). Conclusion: Treatment quality indicators measuring lipid- and albuminuria-lowering treatment status are valid quality measures, since they predict a lower risk of cardiovascular events and mortality in patients with diabetes. The quality indicators for glucose-lowering treatment should only be used for restricted populations with elevated HbA1c levels. Intriguingly, the tested indicators for blood pressure-lowering treatment did not predict patient outcomes. These results question whether all treatment indicators are valid measures to judge quality of health care and its economics. [ABSTRACT FROM AUTHOR]

Background: Comorbidity is often mentioned as interfering with "optimal" treatment decisions in diabetes care. It is suggested that diabetes-related comorbidity will increase adequate treatment, whereas diabetes-unrelated comorbidity may decrease this process of care. We hypothesized that these effects differ according to expected priority of the conditions. Methods: We evaluated the relationship between comorbidity and treatment intensification in a study of 11,248 type 2 diabetes patients using the GIANTT (Groningen Initiative to Analyse type 2 diabetes Treatment) database. We formed a cohort of patients with a systolic blood pressure ≥140 mmHg (6,820 hypertensive diabetics), and a cohort of patients with an HbA1c ≥7% (3,589 hyperglycemic diabetics) in 2007. We differentiated comorbidity by diabetes-related or unrelated conditions and by priority. High priority conditions include conditions that are life-interfering, incident or requiring new medication treatment. We performed Cox regression analyses to assess association with treatment intensification, defined as dose increase, start, or addition of drugs. Results: In both the hypertensive and hyperglycemic cohort, only patients with incident diabetes-related comorbidity had a higher chance of treatment intensification (HR 4.48, 2.33-8.62 (p<0.001) for hypertensives; HR 2.37, 1.09-5.17 (p = 0.030) for hyperglycemics). Intensification of hypertension treatment was less likely when a new glucose-regulating drug was prescribed (HR 0.24, 0.06-0.97 (p = 0.046)). None of the prevalent or unrelated comorbidity was significantly associated with treatment intensification. Conclusions: Diabetes-related comorbidity induced better risk factor treatment only for incident cases, implying that appropriate care is provided more often when complications occur. Diabetes-unrelated comorbidity did not affect hypertension or hyperglycemia management, even when it was incident or life-interfering. Thus, the observed "undertreatment" in diabetes care cannot be explained by constraints caused by such comorbidity.. [ABSTRACT FROM AUTHOR]

Background: Performance indicators assessing quality of diabetes care often look at single processes, e.g. whether an HbA1c test was conducted. Adequate care, however, consists of consecutive processes which should be taken in time (clinical pathways). We assessed quality of diabetes care by looking at single processes versus clinical pathways. In addition, we evaluated the impact of time period definitions on this quality assessment. Methodology: We conducted a cohort study in 2007-2008 using the GIANTT (Groningen Initiative to Analyse type 2 diabetes Treatment) database. Proportions of patients adequately managed for HbA1c, systolic blood pressure (SBP), LDLcholesterol (LDL-C), and albumin/creatinin ratio (ACR) were calculated for the pathway of (1) risk factor level testing, (2) treatment intensification when indicated, (3) response to treatment evaluation. Strict and wide time periods for each step were defined. Proportions of patients adequately managed regarding the overall pathway and single steps, using strict or wide time periods were compared using odds ratios (OR) with 95% confidence intervals. Findings: Of 11176 patients diagnosed with type 2 diabetes, 9439 with complete follow-up were included. The majority received annual examination of HbA1c (86%) and SBP (86%), whereas this was 67% for LDL-C and 49% for ACR. Adequate management regarding the three-step pathway was observed in 73%, 53%, 46%, 41% of patients for HbA1c, SBP, LDL-C, and ACR respectively. Quality scores reduced significantly due to the second step (OR 0.43, 0.18, 0.44, 0.74), but were not much further reduced by the third step. Timely treatment evaluation occurred in 88% for HbA1c, 87% for SBP, 83% for LDLC, and 76% for ACR. The overall score was not significantly changed by using strict time windows. Conclusion: Quality estimates of glycemic, blood pressure and cholesterol management are substantially reduced when looking at clinical pathways as compared to estimates based on commonly used simple process measures. [ABSTRACT FROM AUTHOR]