Large impact of antidiabetic drug treatment and hospitalizations on economic burden of diabetes mellitus in The Netherlands during 2000 to 2004.

OBJECTIVE: To estimate the burden of diabetes mellitus (DM) and its complications in The Netherlands. METHODS: The PHARMO Record Linkage System comprised among others linked drug dispensing, hospital and clinical laboratory data from approximately 2.5 million individuals in The Netherlands. Patients with DM (type 1 and type 2) were included in the study cohort from 2000 to 2004 if they used antidiabetic drugs or had HbA1c >or= 6.5 mmol/L or had a hospitalization for DM or a diabetic complication in the measurement year or in the preceding year. Controls, defined as subjects without a diagnosis of DM and/or subjects not prescribed glucose-lowering medication, were 1:1 matched to patients with diabetes, on birth year, zip code, and gender. Complications (hospitalizations and dispensings for cardiovascular disease/eye problems/amputations) were classified into stages. Complications attributed to DM were estimated as complication stages 1 and 2 among patients minus those among controls. Drug costs were extrapolated to The Netherlands by direct standardization. RESULTS: Among the total population in The Netherlands, the prevalence of DM increased from 2.8% in 2000 to 4.0% in 2004. Severe cardiovascular complications attributed to DM increased from 18,000 to 39,000 patients. Per DM patient the cost of direct treatment attributed to DM increased from Euro 974 in 2000 to Euro 1283 in 2004. Per 100 members of the total population, this increase was from Euro 2764 in 2000 to Euro 5140 in 2004. Most of these costs (65% in 2004) were because of hospitalizations. CONCLUSION: Drug treatment, hospitalizations, and cost attributed to diabetes mellitus have almost doubled between 2000 and 2004, but so did the "background" costs in the general population, perhaps because of preventive efforts.

Effect of non-persistent use of oral glucose-lowering drugs on HbA1c goal attainment.

OBJECTIVES: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA(1c) goal attainment (<7%) in daily practice. METHODS: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999-2004 were identified. Patients with a baseline HbA(1c) > or =7% and at least one HbA(1c) measurement in the period of 6-12 months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA(1c) measurement within 6-12 months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA(1c) <7% were defined as having attained goal. RESULTS: The study cohort included 2023 patients with a mean baseline HbA(1c) of 8.9 +/- 1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA(1c) measurement within 6-12 months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%CI 0.74-0.91), compared to persistent OGLD users. CONCLUSION: Non-persistent use of OGLD leads to a 20% decreased probability of HbA(1c) goal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12 000 new and 10 000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled.

Determinants of non-compliance with bisphosphonates in women with postmenopausal osteoporosis.

OBJECTIVE: To identify determinants of non-compliance with bisphosphonates in women with postmenopausal osteoporosis. By considering the year of the introduction of weekly bisphosphonates important additional information is obtained. METHODS: New female users of daily or weekly alendronate or risedronate between 1999 and 2004, aged >or= 45 years were identified from PHARMO RLS, including drug-dispensing and hospitalisation data of > 2 million residents of the Netherlands. One-year compliance with bisphosphonates was measured using the Medication Possession Ratio (MPR). To identify determinants of non-compliance, non-compliant women (MPR < 50%) were compared to compliant women (MPR >or= 80%). The effect of patient age, prescriber, initial dosing regimen, gastrointestinal adverse events, co-medication and fractures on non-compliance was investigated. RESULTS: The study cohort included 8822 new users of bisphosphonates, of whom 5079 (58%) were compliant and 2720 (31%) were non-compliant after 1 year. Only 1023 women (11%) had a MPR between >or= 50% and < 80%. Daily dosing at start, increased number of co-medications and new use of intestinal agents in the year after starting bisphosphonates were independently associated with an increased odds of non-compliance. In contrast, higher age, first prescription from a specialist, osteoporosis related hospitalisation and use of NSAIDs in the year preceding bisphosphonate therapy decreased the odds of non-compliance. CONCLUSION: This study revealed several determinants of non-compliance with bisphosphonates, the best controllable being the type of initial bisphosphonate, with daily dosing leading to more non-compliance than weekly dosing. However, compliance for both regimens is suboptimal, pointing to an unmet medical need.

Extent of uncontrolled disease and associated medical costs in severe asthma--a PHARMO study.

OBJECTIVE: Asthma is a major public health problem with considerable economic impact. The highest costs being observed in patients with severe asthma. Furthermore, despite the use of recommended therapies, asthma control can still be poor. Therefore, the objective of this study was to assess the extent of uncontrolled disease and associated medical costs in severe asthma. METHODS: The PHARMO Record Linkage System includes among others drug dispensing and hospitalizations for > or = 2 million subjects in The Netherlands. Severe asthma patients used long-acting beta-agonists and inhaled corticosteroids for over 200 days and short-acting beta-agonists for at least 100 days in 2004. Severe uncontrolled asthma was defined as a hospitalization for asthma or use of multiple short courses of oral corticosteroids assessed in 2004. Reimbursed costs of asthma drugs and hospitalizations were calculated during this year. A matched nested-case control study was performed to identify treatment-related risk factors for uncontrolled disease. Information on clinical diagnosis of (severity of) asthma was not available. RESULTS: About 17% of patients with severe asthma aged 12-49 years (N = 1158) showed lack of control. Excess drug costs for severe uncontrolled asthma with hospitalization mounted up to 700 Euro per patient per year and 300 Euro per patient per year for patients without hospitalization. Including hospital admission costs, excess costs mounted up to over 10,000 Euro per patient per year. Lack of control did not seem to be caused by under-treatment. CONCLUSION: Poor control of severe asthma leads to disproportionately increased direct costs compared to severe controlled asthma, especially when hospital admission is required.

Treatment with inhaled corticosteroids in asthma is too often discontinued.

PURPOSE: To study persistence with inhaled corticosteroids (ICS) and its determinants in asthma-patients. METHODS: From the PHARMO database, asthma-patients (age < 35 years) with a first dispensing for ICS in 1999-2002 and > or = 2 dispensings in the first year were included. Persistence during the first year was defined as the number of days from start to time of first failure to continue renewal of the initial ICS. Potential determinants of persistence were assessed at ICS-start and 1 year before. RESULTS: The study-cohort included 5563 new users of single ICS and 297 of fixed-combined ICS. Less than 10% of patients using single ICS and 15% of patients using fixed-combined ICS were persistent at 1 year. Similar persistence-rates were observed when stratified for age (children/adolescents: 0-18 years and adults: 19-34 years). Increased persistence with single ICS was observed with the type of ICS (budesonide), prescriber (specialist), prior use of long-acting beta-agonists, previous hospitalization for asthma, metered-dose inhaler, low starting-dose and once-daily dosing regimen at start. Persistence with fixed combined ICS-treatment increased with younger age and was decreased in patients having high starting-dose of ICS and prior use of antibiotics. CONCLUSION: New users of both single and fixed combined ICS have alarming low persistence rates with ICS-treatment in the first year of follow-up. Persistence was mainly related to patient factors, such as severity of disease, and to treatment-related factors, such as once-daily dosing frequency.

Incidence of cardiovascular events in breast cancer patients receiving chemotherapy in clinical practice.

PURPOSE: To assess the incidence of cardiovascular events among breast cancer patients after chemotherapy. METHODS: Women > or =18 years with a breast tumour who received chemotherapy in 1992-2003 were selected from the PHARMO RLS. Chemotherapy with anthracyclines, a combination of anthracyclines and taxanes or second line treatment with trastuzumab was classified as cardiotoxic. Cardiovascular events were determined based on drug use and hospital admissions. Incidence rates of cardiovascular events and hazard ratios (HR) for the cardiotoxic versus non-cardiotoxic chemotherapy group were assessed during the first year and total follow-up. RESULTS: Of 648 patients with breast cancer included in the study cohort, 353 (54%) received cardiotoxic chemotherapy. At baseline, patients who received cardiotoxic chemotherapy compared with patients receiving non-cardiotoxic chemotherapy, received less anticoagulants/haemostatics (5 vs. 11%; p = 0.012) and had been less often hospitalised for cardiovascular disease (1 vs. 5%; p = 0.007) 2 years before the cohort entry date. After 1-year follow-up, the incidence rate of cardiovascular events was 69/1000 person years (py) for patients with cardiotoxic chemotherapy and 98/1000 py for patients with non-cardiotoxic chemotherapy, which did not differ significantly (HR 0.74 95% confidence interval (CI): 0.39, 1.41). After total follow-up, this was 81/1000 py for patients with cardiotoxic and 92/1000 py for patients with non-cardiotoxic chemotherapy (HR 0.81, 95%CI: 0.54, 1.20). CONCLUSIONS: This study showed similar cardiovascular incidence rates during follow-up for breast cancer patients treated with cardiotoxic and non-cardiotoxic chemotherapy. Specialists seemed to take pre-existing cardiovascular diseases into account when treating the breast cancer patient.

Large-scale stopping and switching treatment with COX-2 inhibitors after the rofecoxib withdrawal.

PURPOSE: To compare treatment changes after the rofecoxib withdrawal with changes occurring normally and to re-assess 12 months afterwards. METHODS: The PHARMO database comprised medication and hospital discharge records of over 3 million inhabitants in the Netherlands. The Study cohort included chronic coxib users with a coxib prescription on 30th September 2004; the Reference cohort others with a coxib prescription on 1st June 2004. Initial treatment changes were based on first new prescription since cohort entry. Twelve-month changes were studied within the Study cohort only. RESULTS: The Study cohort (n = 6974) and Reference cohort (n = 5393) had similar demographics, stratified on type of coxib. In the Study cohort, 3341 (48%) initially stopped coxibs, of whom 1121 (16%) stopped all analgesic, versus 13 and 5% in the Reference cohort (p < 0.001). Among 'other coxib' users 32% stopped coxibs, and 15% stopped all analgesics, versus 14% and 4%, p < 0.001 in the Reference cohort. Among those who stopped coxibs, 34% switched to non-selective non-steroidal anti-inflammatory drug (nsNSAID) without PPI, 21% to nsNSAID with PPI, and 45% stopped NSAID treatment (Reference cohort: 35, 20, and 44%, respectively). These rates for 'other coxib users' were: switching to nsNSAID without PPI 23% (Study Cohort) versus 35% (Reference Cohort), 13 versus 28%, and 64 versus 37% respectively (p < 0.001). Twelve months later, stopping NSAID increased to 43%, stopping all analgesics to 32%. Rheumatologists continued coxibs more frequently than other caregivers (87, 65, 54%, respectively). CONCLUSIONS: The rofecoxib withdrawal resulted in a large proportion of patients who discontinued analgesic treatment altogether regardless of original coxib therapy.

Medicinal cannabis in oncology.

In The Netherlands, since September 2003, a legal medicinal cannabis product, constituting the whole range of cannabinoids, is available for clinical research, drug development strategies, and on prescription for patients. To date, this policy, initiated by the Dutch Government, has not yet led to the desired outcome; the amount of initiated clinical research is less than expected and only a minority of patients resorts to the legal product. This review aims to discuss the background for the introduction of legal medicinal cannabis in The Netherlands, the past years of Dutch clinical experience in oncology practice, possible reasons underlying the current outcome, and future perspectives.

Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents.

OBJECTIVE: In 2003 and 2004, U.S. and European regulators issued public health warnings about a possible association between antidepressants and suicidal thinking and behavior. The authors assessed whether these warnings discouraged use of antidepressants in children and adolescents and whether they led to increases in suicide rates as a result of untreated depression. METHOD: The authors examined U.S. and Dutch data on prescription rates for selective serotonin reuptake inhibitors (SSRIs) from 2003 to 2005 in children and adolescents (patients up to age 19), as well as suicide rates for children and adolescents, using available data (through 2004 in the United States and through 2005 in the Netherlands). They used Poisson regression analyses to determine the overall association between antidepressant prescription rates and suicide rates, adjusted for sex and age, during the periods preceding and immediately following the public health warnings. RESULTS: SSRI prescriptions for youths decreased by approximately 22% in both the United States and the Netherlands after the warnings were issued. In the Netherlands, the youth suicide rate increased by 49% between 2003 and 2005 and shows a significant inverse association with SSRI prescriptions. In the United States, youth suicide rates increased by 14% between 2003 and 2004, which is the largest year-to-year change in suicide rates in this population since the Centers for Disease Control and Prevention began systematically collecting suicide data in 1979. CONCLUSIONS: In both the United States and the Netherlands, SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory agencies issued warnings about a possible suicide risk with antidepressant use in pediatric patients, and these decreases were associated with increases in suicide rates in children and adolescents.

Enhanced persistence with tiotropium compared with other respiratory drugs in COPD.

BACKGROUND: Tiotropium is a once-daily inhaled anticholinergic maintenance treatment with demonstrated effectiveness in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To compare persistence of tiotropium-use with other inhaled respiratory drugs in COPD in current clinical practice. METHODS: The PHARMO database includes, among others, drug-dispensing and hospital discharge records for 2> or = million subjects in the Netherlands. All probable COPD-patients were identified by new respiratory drug use (age >54 years) or COPD-hospitalisations. New users of tiotropium, ipratropium, long-acting beta-agonists (LABAs), or fixed combination of LABA and inhaled corticosteroids (LABA+ICS), in 1998-2003, were included in the study. Persistence was assessed quarterly during the first year of follow-up. Patients with a proportion of days covered (PDC) > or =80% were considered persistent. Persistence was analysed using generalised estimating equations model. RESULTS: About 37% of new users of tiotropium continued treatment for 1 year, compared with 14% for ipratropium, 13% for LABA, and 17% for LABA+ICS. Multivariate analyses showed that tiotropium-users were 2-3 times more persistent with their therapy than patients using ipratropium (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.8-2.3), LABA (RR: 2.9; 95% CI: 2.4-3.6), or LABA+ICS (RR: 2.4; 95% CI: 2.1-2.8), respectively. Sub-analyses in patients with a prior hospitalisation for COPD showed that 1-year persistence rates were increased for all treatments (varying from 33% for patients using LABA+ICS to 61% for patients using tiotropium), while persistence with tiotropium was again 2-3 times higher compared with other treatments. CONCLUSION: Persistence with tiotropium was higher compared to other inhaled respiratory drugs in COPD in clinical practice.

Higher persistence with valsartan compared with enalapril in daily practice.

OBJECTIVE: To compare persistence with valsartan and enalapril in daily practice. METHODS: The PHARMO Record Linkage System includes various data registries including drug dispensing and hospitalizations for > or =2 million subjects in the Netherlands. Patients newly treated with valsartan or enalapril in the period of 1999-2002 were selected. Persistence was calculated by summing up the number of days of continuous treatment. Patients who remained on therapy with valsartan or enalapril for 12 or 24 months were defined as persistent at 1 or 2 years, respectively. RESULTS: 3364 patients received valsartan and 9103 patients received enalapril. About 62% of patients treated with valsartan and 55% of patients treated with enalapril remained on therapy at 12 months after the initial dispensing, while 48% of patients treated with valsartan and 43% of patients treated with enalapril were persistent at 24 months. Patients treated with valsartan were about 20% more likely to stay on treatment than patients treated with enalapril (1 year RR(adj): 1.23, 95% CI: 1.16-1.32; 2 years RR(adj): 1.16, 95% CI: 1.11-1.23). CONCLUSIONS: Real-life persistence is higher with valsartan than with enalapril. The results of this and other studies on persistence in daily practice should be taken into account when deciding upon drug treatment for hypertension.

Determinants of persistence with bisphosphonates: a study in women with postmenopausal osteoporosis.

BACKGROUND: Although bisphosphonates are useful in the management of osteoporosis, patients often discontinue treatment. OBJECTIVES: The aims of this study were to investigate persistence with bisphosphonates, and to assess whether the dose interval influenced persistence, among women with postmenopausal osteoporosis. METHODS: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of > 1 million subjects in defined areas in The Netherlands. Women who were new users of alendronate (daily or weekly), etidronate (daily), or risedronate (daily) during the period from January 2000 through September 2003 were eligible for inclusion in the study if they were aged > or = 55 years or had been hospitalized for a menopausal disorder. One-year rates of persistence with treatment (defined as the percentage of patients who used the drug for > or = 365 days without failure to continue renewals) were determined by using episodes of bisphosphonate treatment. The association between persistence and dose intervals, type of bisphosphonate, and other determinants (including age, occurrence of gastrointestinal adverse events as measured by use of concomitant medications [eg, antacids, proton pump inhibitors, histamine2 (H2)-receptor antagonists, misoprostol, laxatives, antidiarrheals, bowel motility enhancers] and fractures) was assessed. To study whether persistence with bisphosphonates was associated with the former use of other antiosteoporosis medication or the presence of drug-induced osteoporosis, the use of hormone replacement therapy, raloxifene, and systemic corticosteroids in the 6 months before the index date were included as determinants. RESULTS: The study sample included 2124 women who were new users of bisphosphonates. The mean (SD) age of the study population was 71.6 (8.7) years. After 1 year, 51.9% of weekly alendronate users and 30.1% to 42.2% of daily bisphosphonate users were persistent. In the multivariate analysis (which included age, concomitant medication, and fractures), patients using alendronate weekly were significantly more likely to persist than those using alendronate daily (relative risk [RR], 1.56 [95% CI, 1.32-1.85]). The likelihood of persistence was similar among those who used the daily regimens of risedronate, etidronate, and alendronate. The occurrence of gastrointestinal adverse events was associated with decreased persistence with bisphosphonates (H2)-receptor antagonists: RR, 0.71 [95% CI, 0.53-0.94]; bowel motility enhancers: RR, 0.78 [95% CI, 0.65-0.94]). CONCLUSIONS: In this study, dose interval and the occurrence of gastrointestinal adverse events were independent determinants of persistence with bisphosphonate therapy. Although the likelihood of persistence with bisphosphonate use was significantly higher among those who used a less frequently administered regimen, persistence rates were still suboptimal.

Differences in antihypertensive drug persistence associated with drug class and gender: a PHARMO study.

OBJECTIVE: The objective of the study is to investigate factors related to treatment persistence among users of antihypertensive (AHT) drugs in daily practice. METHODS: Data for this study were obtained from the PHARMO database including pharmacy records and hospitalizations in the Netherlands (n=950,000). Patients who newly received AHT therapy (n=17,113) between 1997 and 2001 were selected. Of these patients, random samples of 500 patients per drug class were drawn. One-year persistence was defined as (1) the percentage of patients using AHTs at least 270 days and receiving AHT in 3 months after the 1-year follow-up period, and (2) Catalan method (Kaplan-Meier curves). Gender specific persistence rates per drug class were adjusted for significant factors including age, use of antidiabetics and lipid lowering drugs, and prior cardiovascular hospitalizations (OR and 95%CI). RESULTS: Persistence was highest in users of angiotensin II receptor blockers (ARBs) (62.0%), progressively lower in users of angiotensin converting enzyme inhibitors (ACE-inhibitors, 59.7%), betablockers (35.0%), calcium channel blockers (34.7%), and diuretics (33.0%), resulting in the highest OR of 3.4 [95%CI: 2.6-4.5] for ARBs compared to diuretics. The persistence of AHT use in women was substantially lower (40.1% vs. 50.2%, OR 0.7 [95%CI: 0.6-0.8]) and differences between drug classes were larger than in men. CONCLUSIONS: These results demonstrate marked differences in persistence between AHT classes, with the highest persistence for ARBs and lowest for diuretics. Women were less persistent with their AHT compared to men. This low persistence leads to suboptimal treatment with a potential for substantial clinical consequences. Especially in women, more attention paid to AHT persistence patterns could improve their cardiovascular outcome.

Antipsychotic drugs may worsen metabolic control in type 2 diabetes mellitus.

BACKGROUND: Several studies have indicated that type 2 diabetes mellitus is more common among schizophrenic patients than in the general population. In this study, we investigated whether the use of antipsychotic drugs in patients with diabetes leads to worsening of glycemic control. METHOD: In this cohort study, patients with newly diagnosed type 2 diabetes were selected from the PHARMO Record Linkage System, which comprises pharmacy records for all 320000 residents of 6 Dutch cities. In total, we identified 2585 patients with incident cases of type 2 diabetes who began treatment with oral hypoglycemic agents between 1991 and 1997 and had a medication history of at least 2 years after diagnosis of diabetes. A change in treatment from oral hypoglycemic agents alone to insulin therapy (with or without continuation of oral hypoglycemic agents) was considered a proxy for deterioration of beta-cell function. We compared the incidence of initiation of insulin therapy between users and nonusers of antipsychotic drugs by performing a Cox proportional hazards model analysis. RESULTS: We found an increased risk for initiation of insulin therapy at 2 years after diagnosis of diabetes in users of antipsychotics compared with nonusers; the relative hazard (hazard ratio) was 2.0 (95% CI = 1.2 to 3.3), which did not change after adjustment for potential confounders. The risk decreased in the years after diagnosis of diabetes. CONCLUSION: It seems that use of antipsychotics by patients with type 2 diabetes mellitus is associated with initiation of insulin therapy (i.e., "secondary failure"), especially in the first 2 years of the disease.

Antihypertensive drug therapy and the risk of lower extremity amputations in pharmacologically treated type 2 diabetes patients.

PURPOSE: The objective of this study was to determine the association between different antihypertensive drug therapies and lower extremity amputations (LEAs) in type 2 diabetes patients. METHODS: Data were obtained from the PHARMO Record Linkage System comprising pharmacy records and data on hospitalisations for all 450,000 residents of eight Dutch cities. In a nested case-control study among 12,140 type 2 diabetes patients who used antihypertensive drugs, 26 cases with a first LEA and 94 controls without a LEA matched on age, sex and calendar time were identified. Logistic regression was used to estimate the relative risk of LEA and to adjust for potential confounding factors. RESULTS: Among type 2 diabetes patients who used antihypertensive drugs, subjects who used thiazide diuretics, alone or in combination, had a higher risk of LEA compared to subjects who used Angiotensin Converting Enzyme (ACE) inhibitor monotherapy (crude odds ratio (OR): 6.11 [95% confidence interval (CI): 1.32-28.27]). The use of thiazide diuretics was also associated with an increased risk of LEA when compared to the use of any non-thiazide antihypertensive drug (adjusted OR: 7.04 [1.10-45.30]). The increased risk of LEA associated with the use of thiazides compared to the use of non-thiazides depended on the duration of use (adjusted OR(< or = 365 days), 4.82 [0.61-38.34] and adjusted OR(>365 days), 26.16 [1.02-674.02], p-trend = 0.01). CONCLUSIONS: Treatment with thiazide diuretics compared to treatment with other antihypertensive drugs was associated with excess amputations in type 2 diabetes patients. Due to several limitations of this study, our findings do not preclude the use of thiazides in type 2 diabetes mellitus patients as yet.

Increased suicide attempt rate among patients interrupting use of atypical antipsychotics.

PURPOSE: The aim of the study is to investigate whether patients at risk to commit suicide could be identified based on their drug refill patterns. METHODS: Data for this study were obtained from the PHARMO system comprising drug-dispensing data linked to hospital discharge records. All patients aged 15-45 years, suspected to suffer from schizophrenia and exclusive users of olanzapine or risperidone were selected. The use of antipsychotics was converted into treatment episodes of uninterrupted use. Therapy non-compliance was defined as a drug holiday of at least 30 days. The follow-up started with a treatment episode of at least 90 days. Relative risks for suicide attempts and 95% confidence limits due to drug holidays were estimated using Poisson regression analyses. RESULTS: Of 603 patients, 33% interrupted treatment for at least 30 days. An increased suicide attempt rate was observed when comparing uninterrupted and interrupted drug use (20.0/1000 person years vs 72.1/1000 person years, respectively). A four-fold increased risk for attempting suicide among patients with drug holidays was found (RR adjusted for age and gender 4.2, 95% CI: 1.7-10.1) compared to patients without drug holidays. CONCLUSIONS: Patients who do not refill atypical antipsychotics in time can be identified in the pharmacy and are most likely those with an increased risk to commit suicide.

Refill compliance in type 2 diabetes mellitus: a predictor of switching to insulin therapy?

OBJECTIVE: To assess whether switching to insulin therapy in patients with type 2 diabetes mellitus is associated with medication refill compliance of oral hypoglycemic agents. RESEARCH DESIGN AND METHODS: The PHARMO Record Linkage System was used as data source for this study. Patients with newly treated type 2 diabetes mellitus were defined as subjects in whom oral hypoglycemic therapy was initiated between 1991 and 1998. We performed a matched case-control study in this cohort. Cases were patients who switched to insulin therapy. Date of switching in the case was defined as the index date. Controls were subjects still on oral therapy on the index date, matched on duration of diabetes and calendar time. We measured the medication refill compliance in the year starting 18 months before the index date and calculated various compliance indices. RESULTS: In total, 411 cases and 411 matched controls were identified. Cases suffered more often from more severe comorbidity and used a higher number of oral hypoglycemic agents and concomitant non-diabetic drugs. The overall compliance rate did not differ significantly between cases and controls, the adjusted odds ratio (OR) was 1.3 (CI 95% 0.6-2.8). After performing multivariate logistic regression modeling, age at onset of diabetes, gender, comedication, combination therapy, and daily dosage frequency, were independently related to switching. CONCLUSIONS: We were unable to confirm the hypothesis that noncompliance with treatment is more prevalent in patients with secondary failure. Other variables, like comorbidity and disease-related factors seem to play a more important role in switching to insulin therapy.

Cardiovascular risk factors and diseases precede oral hypoglycaemic therapy in patients with type 2 diabetes mellitus.

Although patients with type 2 diabetes mellitus and cardiovascular disease share common risk factors, the link between these diseases remains largely unexplained. In this case-control study, the earlier use of cardiovascular drugs (before the diagnosis of diabetes) was investigated among cases with type 2 diabetes mellitus and controls without diabetes. Using the PHARMO database, we identified 4,864 patients who were prescribed oral hypoglycaemic agent (OHA) therapy between 1985-1998 in the Netherlands. For each case, two controls matched on age, sex and pharmacy were randomly selected. Controls had not received insulins or OHA therapy. There were 2,656 (55.0%) cases compared with 2,727 (28.1%) controls who used cardiovascular drugs at the start of OHA therapy. Cases had a 3.5-fold increased risk of cardiovascular drug use (OR(95% CI) = 3.5 [3.2-3.8]) compared to controls. Differences in cardiovascular drug use were noted as early as 7 years before the start of OHA therapy, distinguishing cases from controls. Our finding that patients with type 2 diabetes mellitus were more likely to receive treatment for cardiovascular disease several years before they start diabetes therapy supports the hypothesis of a common underlying mechanism of these two disorders and stresses the importance of the pre-diabetic state.