Rikje Ruiter

Lower Risk of Cancer in Patients on Metformin in Comparison With Those on Sulfonylurea Derivatives Results from a large population-based follow-up study

OBJECTIVE Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives. RESEARCH DESIGN AND METHODS Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. RESULTS Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88–0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives. CONCLUSIONS In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.

Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer

Increasing evidence suggests that diabetes mellitus (DM) is associated with increased cancer incidence and mortality. Several mechanisms involved in diabetes, such as promotion of cell proliferation and decreased apoptosis, may foster carcinogenesis. This study investigated the association between DM and cancer incidence and cancer‐specific mortality in patients with breast and colorectal carcinoma.

A Genome‐Wide Association Study for Venous Thromboembolism: The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen

AIMS Variant alleles of the CYP2C19 gene were recently associated with survival in breast cancer patients on tamoxifen therapy. CYP2C19 is one of the enzymes involved in the metabolism of tamoxifen into active metabolites. We investigated the hypothesis that CYP2C19*2 and *3 variants, known for their lack of enzyme activity, are associated with an increased breast cancer mortality rate in patients using tamoxifen. MATERIALS & METHODS In the prospective population based Rotterdam study, the association between CYP2C19*2 carriers and breast cancer mortality was studied among 80 incident users of tamoxifen. Survival was analyzed with life tables and Cox regression analysis, with drug exposure as a time-dependent variable. Adjustments were made for calendar time, average tamoxifen dose, age, the indication for tamoxifen, CYP2D6 genotype and concomitant use of CYP2C19 inhibitors or inducers. RESULTS In patients on tamoxifen, CYP2C19*2 carriers were associated with a significantly longer breast cancer survival rate than patients with the wild-type (hazard ratio 0.26, 95%CI: 0.08-0.87). CONCLUSION This study suggests that CYP2C19 genotype may possibly be a predictive factor for survival in breast cancer patients using tamoxifen.

Adverse drug reaction-related hospitalizations in persons aged 55 years and over: a population-based study in the Netherlands.

AbstractBackground: Elderly individuals appear to be particularly at risk of developing adverse drug reactions (ADRs) because of higher rates of polypharmacy, age-related pharmacokinetic changes, pharmacodynamic variations and substantial co-morbidity levels. Thus, the increasing contribution of elderly individuals to the total population means ADR-related hospitalizations are expected to become more frequent. However, a recent study conducted in the Netherlands found that ADR-related hospitalizations had stabilized during the years 1997–2007. Nonetheless, this study did not take into account the number of medicines used. Objectives: Therefore, the objectives of this study were to describe the association between age and sex, and the risk of an adverse drug reaction (ADR)-related hospitalization in persons aged 55 years and over in the Netherlands and to correlate these ADR-related hospitalizations with the number of dispensed medicines over the same period. Methods: Data on hospital admissions were obtained from the Dutch nationwide registry of hospital discharges. Data from Statistics Netherlands were used to obtain population demographics. Data on dispensed medicinal products were obtained from the Dutch Foundation for Pharmaceutical Statistics. Analyses were performed by calculating relative risks (RRs). Results: Those aged ≥75 years were at a more than 4-fold increased risk of being hospitalized in comparison with those aged 55–64 years (RR 4.15; 95% CI 4.12, 4.18). In addition, female sex was associated with an increased risk of an ADR-related hospitalization (RR 1.05; 95% CI 1.03, 1.08) in comparison with males. When taking into account the number of dispensings, elderly ≥75 years of age were at an increased risk of being hospitalized for an ADR due to anticoagulants (RR 2.20; 95% CI 2.12, 2.28), antidiabetic agents (RR 3.53; 95% CI 3.39, 3.66), salicylates (RR 1.70; 95% 1.54, 1.86) and antirheumatics (RR 2.19; 95% CI 2.06, 2.33). Conclusion: In our study, we showed that elderly aged ≥75 years were at increased risk of an ADR-related hospitalization. Given that the number of elderly and very old will continue to grow, it is of pivotal importance to further endorse drug safety in this vulnerable patient group.

Prescribing of Rosiglitazone and Pioglitazone Following Safety Signals Analysis of Trends in Dispensing Patterns in the Netherlands from 1998 to 2008

I read with interest the article by Ruiter et al. [1]. I must say that I found it odd that the results of this study differ from those of other studies in European regions in terms of the use of glitazones [2]. Other European studies have found that rosiglitazone was still used more than pioglitazone in early 2008, despite cardiovascular safety warnings, while this study results were shown differently. In figure 2 of the study by Ruiter et al. [1], a sharp drop in the data series in mid 2007 caught my attention. At that point, a strong diminution in the use of all glitazones can be seen, especially for rosiglitazone, which falls more than 50 %. Before that point, rosiglitazone was being used more than pioglitazone; afterwards, it was the opposite. That led me to suspect that, on that date, an intervention other than the safety warning may have occurred, perhaps some kind of administrative measure regarding the prescription of glitazones. For example, Carracedo-Martı́nez et al. [3] found that no decrease in the use of piroxicam was observed after a health safety warning; however, the month after mandatory prior authorization for piroxicam was introduced (6 months after the safety warning), its use declined sharply (more than 95 %). According to prior authorization rules, the medicine would not be reimbursed for a certain patient if it was not authorized by a health authority, which would only authorize treatment with such medicine if certain prerequisites were met. Indeed, after searching, I found that, in the Netherlands, from 1 July 2007, a measure similar to prior authorization was implemented regarding the prescription of glitazones, and health insurers would be more stringent [4]. The use of glitazones by patients with diabetes who do not meet certain conditions according to health insurance regulations would no longer be reimbursed [4]. Ruiter et al. [1] make no mention of this change in the administrative status of glitazone prescriptions that took place in July 2007. It is neither included in the study design nor mentioned in the discussion. In particular, some safety warnings that were released near July 2007 have proved statistically significant in the study. Ruiter et al. [1] conclude that, in their study, it was difficult to disentangle the effect of Direct Healthcare Professional Communications and European Medicines Agency press releases from the effect of reports published in the literature. I believe that not only that, but also changes in the administrative status of medicines (for instance, if a medicine goes from normal prescription to prescription requiring prior authorization, or if health insurance for a particular medicine changes) should also be taken into account. The fact that, according to figure 2, the strongest diminution by far in the use of glitazones takes place just after such a change in their administrative status in July 2007 [4] is very suggestive.

Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: the Rotterdam Study.

Some studies suggest a favorable role of antioxidants on breast cancer risk but this is still inconclusive. The aim of this study was to assess whether overall dietary antioxidant capacity, as assessed by dietary ferric reducing antioxidant potential (FRAP), and individual dietary antioxidant intake were associated with breast cancer risk. Data was used from women participating in the Rotterdam Study, a prospective cohort study among subjects aged 55 years and older (N = 3,209). FRAP scores and antioxidant intake (i.e., vitamin A, C, E, selenium, flavonoids and carotenoids) was assessed at baseline by a food frequency questionnaire. Incident cases of breast cancer were confirmed through medical reports. During a median follow‐up of 17 years, 199 cases with breast cancer were identified. High dietary FRAP score was associated with a lower risk of breast cancer [hazard ratio (HR): 0.68; 95% confidence intervals (CI): 0.49, 0.96]. No overall association between individual antioxidant intake and breast cancer risk was found. However, low intake of alpha carotene and beta carotene was associated with a higher risk of breast cancer among smokers (HR: 2.48; 95% CI: 1.21, 5.12 and HR: 2.31; 95% CI: 1.12, 4.76 for alpha and beta carotene, respectively) and low intake of flavonoids was associated with breast cancer risk in women over the age of 70 (HR: 1.80; 95% CI: 1.09, 2.99). These results suggest that high overall dietary antioxidant capacity is associated with a lower risk of breast cancer. Individual effects of dietary carotenoids and dietary flavonoids may be restricted to subgroups such as smokers and elderly.

Prescribing of Rosiglitazone and Pioglitazone Following Safety Signals

AbstractBackground: Relevant safety signals in the EU are regularly communicated in so-called ‘Direct Healthcare Professional Communications’ (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. Objective: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. Methods: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998–2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. Results: for rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. Conclusions: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Adverse drug reaction-related hospitalizations in persons aged 55 years and over

AbstractBackground: Elderly individuals appear to be particularly at risk of developing adverse drug reactions (ADRs) because of higher rates of polypharmacy, age-related pharmacokinetic changes, pharmacodynamic variations and substantial co-morbidity levels. Thus, the increasing contribution of elderly individuals to the total population means ADR-related hospitalizations are expected to become more frequent. However, a recent study conducted in the Netherlands found that ADR-related hospitalizations had stabilized during the years 1997–2007. Nonetheless, this study did not take into account the number of medicines used. Objectives: Therefore, the objectives of this study were to describe the association between age and sex, and the risk of an adverse drug reaction (ADR)-related hospitalization in persons aged 55 years and over in the Netherlands and to correlate these ADR-related hospitalizations with the number of dispensed medicines over the same period. Methods: Data on hospital admissions were obtained from the Dutch nationwide registry of hospital discharges. Data from Statistics Netherlands were used to obtain population demographics. Data on dispensed medicinal products were obtained from the Dutch Foundation for Pharmaceutical Statistics. Analyses were performed by calculating relative risks (RRs). Results: Those aged ≥75 years were at a more than 4-fold increased risk of being hospitalized in comparison with those aged 55–64 years (RR 4.15; 95% CI 4.12, 4.18). In addition, female sex was associated with an increased risk of an ADR-related hospitalization (RR 1.05; 95% CI 1.03, 1.08) in comparison with males. When taking into account the number of dispensings, elderly ≥75 years of age were at an increased risk of being hospitalized for an ADR due to anticoagulants (RR 2.20; 95% CI 2.12, 2.28), antidiabetic agents (RR 3.53; 95% CI 3.39, 3.66), salicylates (RR 1.70; 95% 1.54, 1.86) and antirheumatics (RR 2.19; 95% CI 2.06, 2.33). Conclusion: In our study, we showed that elderly aged ≥75 years were at increased risk of an ADR-related hospitalization. Given that the number of elderly and very old will continue to grow, it is of pivotal importance to further endorse drug safety in this vulnerable patient group.

The ACE insertion/deletion polymorphism and its association with metabolic syndrome

The angiotensin-1-converting enzyme (ACE) gene has been suggested to be involved in the development of metabolic syndrome (MetS). However, results have been inconsistent. In this study, a meta-analysis was performed to investigate the association between ACE insertion/deletion (I/D) polymorphism and MetS. Published literature from PubMed, EMBASE, and ISI Web of Science databases was searched for eligible publications. All studies assessing the association between ACE I/D polymorphism and MetS were included. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Ten studies (1939 cases/2845 controls) for ACE I/D polymorphism were included in this meta-analysis. Most of the studies were performed in whites. The ACE I/D polymorphism was associated with an increased OR of MetS under a dominant model (DD + ID vs II: OR = 1.39; 95% CI, 1.22-1.60; P < .001). Using this model, similar results were found among studies using different ethnic populations, studies using different MetS definitions, and studies with more than 100 cases. This meta-analysis indicated that the D allele of the ACE gene, known to be related to higher levels of angiotensinogen, is associated with an increased OR of MetS. However, given the limited sample size, this association warrants further investigation.