No significant association of type 2 diabetes-related genetic risk scores with glycated haemoglobin levels after initiating metformin or sulphonylurea derivatives

AIM: To explore the added value of diabetes-related genetic risk scores (GRSs) to readily available clinical variables in the prediction of glycated haemoglobin (HbA1c) levels after initiation of glucose-regulating drugs. MATERIALS AND METHODS: We conducted a cohort study in people with type 2 diabetes (T2DM) from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database who initiated metformin (MET) or sulphonylurea derivatives (SUs) and for whom blood samples were genotyped. The primary outcome was HbA1c level at 6 months, adjusted for baseline HbA1c. GRSs were based on single nucleotide polymorphisms linked to insulin sensitivity, β-cell activity, and T2DM risk in general. Associations were analysed using multiple linear regression to assess whether adding the GRSs increased the explained variance in a prediction model that included age, gender, diabetes duration and cardio-metabolic biomarkers. RESULTS: We included 282 patients initiating MET and 89 patients initiating SUs. In the MET prediction model, diabetes duration of >3 months when starting MET was associated with 2.7-mmol/mol higher HbA1c level. For SUs, no significant clinical predictors were identified. Addition of the GRS linked to insulin sensitivity (for MET), β-cell activity (for SUs) and T2DM risk (for both) to the models did not improve the explained variance significantly (22% without vs. 22% with GRS) for the MET and (14% without vs. 14% with GRS) for the SUs model, respectively. CONCLUSION: This study did not indicate a significant effect of GRS related to T2DM in general or to the drugs' mechanism of action for prediction of inter-individual HbA1c variability in the short term after initiation of MET or SU therapy

Sex disparities in treatment patterns after metformin initiation among patients with type 2 diabetes mellitus

PURPOSE: To assess sex differences in treatment patterns after metformin initiation among type 2 diabetes mellitus (T2D) patients.METHODS: A cohort study was conducted using the Groningen Initiative to ANalyze Type 2 diabetes Treatment (GIANTT) primary care database. Patients aged ≥18 years initiating metformin were followed 2-5 years. Markov modeling was conducted to estimate treatment transition rates and calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI) comparing men with women adjusted for age, HbA1c level at initiation, and cardiovascular disease history. Kaplan-Meier analyses and Cox proportional-hazards models were used to determine the time to and likelihood of getting treatment intensification. HbA1c levels at initiation and intensification were compared using Mann-Whitney U tests.RESULTS: In total, 11 508 metformin initiators were included (50.1% women). The most common transition after initiation was a dose increase (probability women 0.52, men 0.59, no significant difference). Women were more likely than men to switch to any other non-insulin hypoglycemic agent after initiation (aHR 1.66; 95% CI 1.31-2.12), after dose increase (aHR 1.48; 95% CI 1.10-1.98) and after dose decrease (aHR 2.64; 95% CI 1.28-5.46). Time to intensification was longer, time to switching was shorter, and HbA1c levels at initiation and intensification were lower for women than men.CONCLUSIONS: Sex disparities were observed in treatment transitions after metformin initiation. Women more often switched treatment than men, which suggest that prescribers acknowledge more tolerance or other problems for metformin in women. Men intensified treatment earlier and at higher HbA1c levels, indicative of a higher need for treatment intensification.</p

Trends in hyperlipidemia and hypertension management in type 2 diabetes patients from 1998–2004: a longitudinal observational study

BACKGROUND: Lack of treatment initiation or intensification might explain why some patients with type 2 diabetes do not reach target goals. The objective is to assess trends in risk factor treatment, and identify determinants for medication adjustments in patients with uncontrolled hypertension and/or hyperlipidemia. METHODS: We conducted a cohort study using data from the Zwolle Outpatient Diabetes project Integrated Available Care (ZODIAC)-study in The Netherlands. Management of hypertension and hyperlipidemia was assessed yearly from 1998-2004 by measuring the percentage of patients receiving a treatment initiation or intensification among all patients with elevated risk factor levels. Generalized estimating equation analyses were performed. RESULTS: During the study period, the percentage of patients with an elevated total cholesterol/high-density lipoproteins ratio (>6) decreased considerably (from 29% to 4%) whereas the percentage of hypertensive patients decreased only slightly (>or= 150/85 mmHg; from 58% to 51%). Initiation of lipid-lowering therapy and intensification of antihypertensive therapy was higher in more recent years. However, still two-third of patients with insufficiently controlled blood pressure in 2003 did not receive an initiation or intensification of antihypertensive treatment in the following year. Treatment changes were mainly determined by elevated levels of the corresponding risk factor. We did not observe increased initiation rates for lipid-lowering therapy in patients with both hypertension and hyperlipidemia. CONCLUSION: Hypertension and hyperlipidemia management in type 2 diabetes patients has improved in the past decade but further improvement is possible. Greater effort is needed to stimulate medication adjustments in patients with insufficiently controlled hypertension and combined risk factors

Medication Adherence Affects Treatment Modifications in Patients With Type 2 Diabetes

Background: Low rates of treatment modification in patients with insufficiently controlled risk factors are common in type 2 diabetes. Although adherence problems are often mentioned in surveys as a reason for not intensifying treatment, observational studies have shown inconclusive results. Objective: To assess how medication adherence affects treatment modifications for hypertension and hyperglycemia in patients with type 2 diabetes. Methods: This was a cohort study of 11,268 primary care patients with type 2 diabetes in the Netherlands. Inclusion criteria were diagnosis before 2007, >= 1 prescription to antihypertensive or glucose-regulating medication in the preceding 6 months, and a systolic blood pressure level >= 140 mm Hg or glycosylated hemoglobin >= 7% in 2007. Patients on maximal treatment were excluded. Treatment modifications as observed from prescriptions were classified as none, dose increase, dose decrease, class switch, class addition, or class discontinuation. Refill adherence was assessed as medication possession ratio or length of last gap between refills. We performed multilevel multinomial regression analysis to test for associations. Results: We included 4980 diabetic patients with elevated blood pressure and 2945 diabetic patients with elevated glycosylated hemoglobin levels. Patients with lower adherence for antihypertensive drugs were more likely to have those medications discontinued (odds ratio [OR] for every 10% lower medication possession ratio =1.22; 95% CI, 1.11-1.33) or the dose decreased (OR = 1.14; CI 1.01-1.28). For glucose-regulating medication, dose increases (OR = 0.92; 95% CI, 0.85-0.98) and medication additions (OR = 0.90; 95% CI, 0.82-0.99) were less likely in patients with lower adherence levels. Conclusions: Low adherence inhibits the intensification of glucose-regulating but not antihypertensive medication in type 2 diabetic patients with insufficiently controlled risk factors in the Netherlands. Adherence problems may lead to diminished or even discontinued antihypertensive treatment. (Clin Ther. 2011;33:121-134) (c) 2011 Elsevier HS Journals, Inc

Sex Differences in Adverse Drug Reactions of Metformin:A Longitudinal Survey Study

Introduction: In general, women more often experience metformin-associated adverse drug reactions (ADRs) than men. Objectives: We aimed to assess whether sex differences in reported ADRs for metformin are observed at different times after initiation, and to explore their concurrence with sex differences in the dose of metformin over time. This may guide future studies in assessing the involved mechanisms of sex differences in metformin-associated ADRs and may guide sex-specific management of ADRs in clinical practice. Methods: This study has a longitudinal design using data about patients initiating metformin collected by the Dutch National Pharmacovigilance Center Lareb through their Intensive Monitoring program. Patients were asked to complete a web-based questionnaire six times after initiation (i.e., at 2 weeks, 6 weeks and at 3, 6, 9, and 12 months). The outcome variables were the proportion of patients reporting any ADR (primary) and the dose of metformin (secondary). Sex differences in the proportions of ADRs and in the dose were tested at each assessment using Pearson Chi-Squared tests and Wilcoxon rank-sum tests, respectively. Using Bonferroni adjustment for multiple testing, a p value &#x003C; 0.01 was considered statistically significant. Results: The number of included patients was 1712 (40.9% women). Women reported an ADR more often than men, which was statistically significant at the assessment at 2 weeks (34% vs 25%, p &#x003C; 0.001), and 6 weeks (37% vs 28%, p = 0.001) after initiation. In general, women were reported to be prescribed a lower dose than men, which became statistically significant at the 9-month assessment (p &#x003C; 0.01). Conclusions: Sex differences in reported ADRs were seen in the first weeks after metformin initiation, whereas statistically significant differences in self-reported prescribed dosing were observed after several months. Patients, in particular women, might benefit from being prescribed lower metformin doses at treatment initiation

Is guideline-adherent prescribing associated with quality of life in patients with type 2 diabetes?

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.</p

Trends in polypharmacy and dispensed drugs among adults in the Netherlands as compared to the United States

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

Long-term exposure to anticholinergic and sedative medications and cognitive and physical function in later life

Background: Anticholinergic and sedative medications are frequently prescribed to older individuals. These medications are associated with short-term cognitive and physical impairment, but less is known about long-term associations. We therefore examined over twenty years whether cumulative exposure to these medications was related to poorer cognitive and physical functioning. Methods: Older adult participants of the Longitudinal Aging Study Amsterdam (LASA) were followed from 1992-2012. On 7 measurement occasions, cumulative exposure to anticholinergic and sedative medications was quantified with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Cognitive functioning was assessed with the Mini Mental State Examination (MMSE), Alphabet Coding Task (ACT, 3 trials), Auditory Verbal Learning Test (AVLT, learning and retention condition), and Raven Colored Progressive Matrices (RCPM, 2 trials). Physical functioning was assessed with the Walking Test (WT), Cardigan Test (CT), Chair Stands Test (CST), Balance Test (BT), and self-reported Functional Independence (FI). Data were analyzed with linear mixed models adjusted for age, education, sex, living with a partner, BMI, depressive symptoms, co-morbidities (cardiovascular disease, diabetes, cancer, COPD, osteoarthritis, CNS diseases), and prescribed medications. Results: Longitudinal associations were found of the DBI with poorer cognitive functioning (less items correct on the 3 ACT trials, AVLT learning condition, and the 2 RCPM trials) and with poorer physical functioning (longer completion time on the CT, CST, and lower self-reported FI). Conclusions: This longitudinal analysis of data collected over 20 years, showed that higher long-term cumulative exposure to anticholinergic and sedative medications was associated with poorer cognitive and physical functioning

Differential Effects of Comorbidity on Antihypertensive and Glucose-Regulating Treatment in Diabetes Mellitus – A Cohort Study

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