Older Age, Polypharmacy, and Low Systolic Blood Pressure Are Associated With More Hypotension-Related Adverse Events in Patients With Type 2 Diabetes Treated With Antihypertensives

Background and Aims: Low systolic blood pressure (SBP) levels while being treated with antihypertensives may cause hypotension-related adverse events (hrAEs), especially in the elderly, women, and frail patients. We aimed to assess the association between the occurrence of hrAEs and low SBP levels, age, sex, and polypharmacy among patients with type 2 diabetes (T2D) treated with antihypertensives.Methods: In this cohort study, we used the Groningen Initiative to ANalyse Type 2 diabetes Treatment (GIANTT) database which includes patients managed for T2D in primary care from the north of the Netherlands. Patients treated with ≥1 antihypertensive drug and ≥1 SBP measurement between 2012 and 2014 were included. The outcome was the presence of an hrAE, i.e. postural hypotension, dizziness, weakness/tiredness, and syncope in 90 days before or after the lowest recorded SBP level. Age (≥70 vs. <70 years), sex (women vs. men), polypharmacy (5–9 drugs or ≥10 drugs vs. <5 drugs), and SBP level (<130 or ≥130 mmHg) were included as determinants. Logistic regression analyses were conducted for age, sex and polypharmacy, including the SBP level and their interaction, adjusted for confounders. Odds ratios (OR) with 95% confidence intervals (CI) are presented.Results: We included 21,119 patients, 49% of which were ≥70 years old, 52% were women, 57% had polypharmacy, 61% had an SBP level <130 mmHg and 5.4% experienced an hrAE. Patients with an SBP level <130 mmHg had a significantly higher occurrence of hrAEs than patients with a higher SBP level (6.2 vs. 4.0%; ORs 1.41, 95%CI 1.14–1.75, 1.43, 95%CI 1.17–1.76 and 1.33, 95%CI 1.06–1.67 by age, sex, and polypharmacy, respectively). Older patients (OR 1.29, 95%CI 1.02–1.64) and patients with polypharmacy (OR 5–9 drugs 1.27, 95%CI 1.00–1.62; OR ≥10 drugs 2.37, 95% CI 1.67–3.37) were more likely to experience an hrAE. The association with sex and the interactions between the determinants and SBP level were not significant.Conclusion: Low SBP levels in patients with T2D treated with antihypertensives is associated with an increase in hrAEs. Older patients and those with polypharmacy are particularly at risk of hrAEs. Age, sex, and polypharmacy did not modify the risk of hrAEs associated with a low SBP level

Changes in blood pressure thresholds for initiating antihypertensive medication in patients with diabetes: a repeated cross-sectional study focusing on the impact of age and frailty

Objective To assess trends in systolic blood pressure (SBP) thresholds at initiation of antihypertensive treatment in patients with type 2 diabetes and the impact of age and frailty on these trends.Study design and setting A repeated cross-sectional cohort study (2007–2014) using the Groningen Initiative to Analyse Type 2 diabetes Treatment database was conducted. The influence of calendar year, age or frailty and the interaction between year and age or frailty on SBP thresholds were assessed using multilevel regression analyses adjusted for potential confounders.Results We included 4819 patients. The mean SBP at treatment initiation was 157 mm Hg in 2007, rising to 158 mm Hg in 2009 and decreasing to 151 mm Hg in 2014. This quadratic trend was significant (p<0.001). Older patients initiated treatment at higher SBP, but similar decreasing trends after 2009 were observed in all age groups. There were no significant differences in SBP thresholds between patients with different frailty groups. The association between year and SBP threshold was not influenced by age or frailty.Conclusion After an initial rise, the observed SBP thresholds decreased over time and were not influenced by age or frailty. This is in contrast with changed guideline recommendations towards more personalised treatment during the study period and illustrates that changing prescribing practice may take considerable time. Patient-specific algorithms and tools focusing on when and when not to initiate treatment could be helpful to support personalised diabetes care

Construct and concurrent validity of a patient-reported adverse drug event questionnaire:a cross-sectional study

Background: Direct patient-reported information about adverse drug events (ADEs) is important since it adds to healthcare professional-reported information about the safety of drugs. Previously, we developed an instrument to assess patient-reported ADEs in research settings. The aim of this study is to assess the construct and concurrent validity of the questionnaire. Methods: Patients on at least an oral glucose-lowering drug completed the ADE questionnaire, the World Health Organization Quality of Life-BREF, and the Treatment Satisfaction Questionnaire for Medication (TSQM). The ADE questionnaire assesses ADEs for any drug that the patient uses. Construct validity was assessed by testing whether patients reporting an ADE had a lower general quality of life and physical health than those not reporting an ADE, using Mann-Whitney U-tests and t-tests (significance level Results: We included 135 patients (mean age 64 years, 35% women). Patients who reported an ADE (N = 37) had a lower general quality of life and physical health than those not reporting an ADE (P Conclusions: The construct validity of the patient-reported ADE questionnaire was sufficient for reporting any versus no ADE, but the concurrent validity was only partly demonstrated. Therefore, the questionnaire needs to be adapted before it can be used

The Role of Patients' Age on Their Preferences for Choosing Additional Blood Pressure-Lowering Drugs:A Discrete Choice Experiment in Patients with Diabetes

ObjectivesTo 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 MethodsPatients 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 (aged) using Pearson chi(2)-tests. Multinomial logit models were used to assess and compare the importance attached to the characteristics.ResultsOf 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).ConclusionsAged 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.</p

Drug Safety Issues Covered by Lay Media:A Cohort Study of Direct Healthcare Provider Communications Sent between 2001 and 2015 in The Netherlands

Background: Some drug safety issues communicated through direct healthcare professional communications (DHPCs) receive substantial media coverage, while others do not. Objectives: The objective of this study was to assess the extent of coverage of drug safety issues that have been communicated through DHPCs in newspapers and social media. A secondary aim was to explore which determinants may be associated with media coverage. Methods: Newspaper articles covering drug safety issues communicated through 387 DHPCs published between 2001 and 2015 were retrieved from LexisNexis Academic™. Social media postings were retrieved from Coosto™ for drugs included in 220 DHPCs published between 2010 and 2015. Coverage of DHPCs by newspapers and social media was assessed during the 2-month and 14-day time periods following issuance of the DHPC, respectively. Multivariate logistic regression was used to assess potential DHPC- and drug-related determinants of media coverage. Results: 41 (10.6%) DHPC safety issues were covered in newspaper articles. Newspaper coverage was associated with drugs without a specialist indication [adjusted odds ratio 5.32; 95% confidence interval (2.64–10.73)]. Negative associations were seen for time since market approval [3–5 years 0.30; (0.11–0.82), 6–11 years 0.18; (0.06–0.58)] and year of the DHPC [0.88; (0.81–0.96)]. In the social media, 180 (81.8%) drugs mentioned in 220 DHPCs were covered. Social media coverage was associated with drugs without a specialist indication [6.92; (1.56–30.64)], and for DHPCs communicating clinical safety issues [5.46; (2.03–14.66)]. Conclusions: Newspapers covered a small proportion of DHPC safety issues only. Most drugs mentioned in DHPCs were covered in social media. Coverage in both media were higher for drugs without a specialist indication

Potential Overtreatment and Undertreatment of Diabetes in Different Patient Age Groups in Primary Care After the Introduction of Performance Measures

OBJECTIVETo assess whether after the introduction of diabetes performance measures decreases in undertreatment correspond with increases in overtreatment for blood pressure (BP) and glycemic control in different patient age groups.RESEARCH DESIGN AND METHODSWe conducted a cohort study using data from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database. General practices were included when data were available from 1 year before to at least 1 year after the introduction of diabetes performance measures. Included patients had a confirmed diagnosis of type 2 diabetes. Potential overtreatment was defined as prescribing maximum treatment or a treatment intensification to patients with a sustained low-risk factor level. Potential undertreatment was defined as a lack of treatment intensification in patients with a sustained high-risk factor level. Percentages of over- and undertreated patients at baseline were compared with those in subsequent years, and stratified analyses were performed for different patient age groups.RESULTSFor BP, undertreatment significantly decreased from 61 to 57% in the first year after the introduction of performance measures. In patients >75 years of age, undertreatment decreased from 65 to approximate to 61%. Overtreatment was relatively stable (approximate to 16%). For glycemic control, undertreatment significantly increased from 49 to 53%, and overtreatment remained relatively stable (approximate to 7%).CONCLUSIONSThe improvement of BP undertreatment after introduction of the performance measures did not correspond with an increase in overtreatment. The performance measures appeared to have little impact on improving glucose-regulating treatment. The trends did not differ among patient age groups

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

Prediction of the Effects of Empagliflozin on Cardiovascular and Kidney Outcomes Based on Short-Term Changes in Multiple Risk Markers

Aims: The EMPA-REG OUTCOME trial demonstrated that the sodium-glucose cotransporter-2 inhibitor (SGLT2) empagliflozin reduces the risk of cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. We previously developed the parameter response efficacy (PRE) score, which translates drug effects on multiple short-term risk markers into a predicted long-term treatment effect on clinical outcomes. The main objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of empagliflozin in reducing the risk of CV and kidney outcomes. Methods: Short-term (baseline to 6-months) changes in glycated hemoglobin (HbA1c), systolic blood pressure (SBP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, uric acid, and potassium were determined among 7020 patients with type 2 diabetes and established CV disease in the EMPA-REG OUTCOME trial. The beta-coefficients, derived from a Cox proportional hazards model in a pooled database consisting of 6355 patients with type 2 diabetes, were applied to the short-term risk markers in the EMPA-REG OUTCOME trial to predict the empagliflozin-induced impact on CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, or CV death) and kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) outcomes. Results: Empagliflozin compared to placebo reduced HbA1c (0.6%), SBP (4.2 mmHg), UACR (13.0%), body weight (2.1 kg), uric acid (20.4 μmol/L), and increased hemoglobin (6.6 g/L), LDL-cholesterol (0.1 mmol/L) and HDL-cholesterol (0.04 mmol/L) (all p<0.01). Integrating these effects in the PRE score resulted in a predicted relative risk reduction (RRR) for the CV outcome of 6.4% (95% CI 1.4–11.7), which was less than the observed 14.7% (95% CI 1.3–26.4%) RRR. For the kidney outcome, the PRE score predicted a RRR of 33.4% (95% CI 26.2–39.8); the observed RRR was 46.9% (95% CI 26.8–61.5). In a subgroup of 2,811 patients with UACR ≥30 mg/g at baseline, the PRE score predicted RRR was 40.8% (95% CI 31.2–49.1) vs. the observed RRR of 40.8% (95% CI 12.4–60.0) for the kidney outcome. Conclusions: Integrating multiple short-term risk marker changes in the PRE score underestimated the effect of empagliflozin on CV and kidney outcomes, suggesting that the currently used risk markers do not fully capture the effect of empagliflozin. In patients with increased albuminuria, the PRE score adequately predicted the effect of empagliflozin on kidney outcomes

Factors Influencing Preferences and Responses Towards Drug Safety Communications:A Conjoint Experiment Among Hospital-Based Healthcare Professionals in the Netherlands

Introduction Healthcare professionals (HCPs) are informed about new drug safety issues through Direct Healthcare Professional Communications (DHPCs). The influence of DHPC content on the impact of the communication is unclear. Objectives The aim of this study was to assess the effect of content elements 'frequency of the safety issue', 'seriousness of the safety issue', 'need to take action', 'life span of drug involved' and 'type of evidence supporting the safety issue' on hospital-based HCPs' preferences and responses towards DHPCs. Methods A survey study including a conjoint experiment was performed among hospital-based HCPs in the Netherlands. Hypothetical DHPCs varying on the five content elements were constructed. Each respondent received eight out of 16 hypothetical DHPCs and was asked about (1) importance to be informed (fixed-point scale), (2) preferred communication timing (multiple options) and (3) their stated actions (multiple options). Associations were tested using generalized linear mixed models. Results In total, 178 HCPs participated. DHPCs concerning more frequent or serious safety issues, or requiring action, were associated with a higher perceived importance to be informed and a preference for immediate communication. Periodic communication was preferred for DPHCs concerning less frequent or serious safety issues. The most commonly stated action was to discuss the DHPC with colleagues. Monitoring was common when this was recommended. High frequency and seriousness were associated with more prescribing-related actions. Conclusion Frequency and seriousness of the safety issue and the recommended action are likely to influence the impact of DHPCs. The timing of communication could be tailored depending on the content, where less urgent safety issues might be communicated periodically

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