Case-control study

The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study.

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Abstract

Objective To determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in people with type 2 diabetes.

Design Retrospective cohort study using a nested case-control analysis.

Setting Over 600 general practices in the United Kingdom contributing to the general practice research database.

Participants The cohort consisted of people with type 2 diabetes who were newly treated with oral hypoglycaemic agents between 1 January 1988 and 31 December 2009. All incident cases of bladder cancer occurring during follow-up were identified and matched to up to 20 controls on year of birth, year of cohort entry, sex, and duration of follow-up. Exposure was defined as ever use of pioglitazone, along with measures of duration and cumulative dosage.

Main outcome measure Risk of incident bladder cancer associated with use of pioglitazone.

Results The cohort included 115 727 new users of oral hypoglycaemic agents, with 470 patients diagnosed as having bladder cancer during follow-up (rate 89.4 per 100 000 person years). The 376 cases of bladder cancer that were diagnosed beyond one year of follow-up were matched to 6699 controls. Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83, 95% confidence interval 1.10 to 3.05). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99, 1.14 to 3.45) and in those with a cumulative dosage greater than 28 000 mg (2.54, 1.05 to 6.14).

Conclusion The use of pioglitazone is associated with an increased risk of incident bladder cancer among people with type 2 diabetes.

Source: BMJ

 

The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study.

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Abstract

Objective To determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in people with type 2 diabetes.

Design Retrospective cohort study using a nested case-control analysis.

Setting Over 600 general practices in the United Kingdom contributing to the general practice research database.

Participants The cohort consisted of people with type 2 diabetes who were newly treated with oral hypoglycaemic agents between 1 January 1988 and 31 December 2009. All incident cases of bladder cancer occurring during follow-up were identified and matched to up to 20 controls on year of birth, year of cohort entry, sex, and duration of follow-up. Exposure was defined as ever use of pioglitazone, along with measures of duration and cumulative dosage.

Main outcome measure Risk of incident bladder cancer associated with use of pioglitazone.

Results The cohort included 115 727 new users of oral hypoglycaemic agents, with 470 patients diagnosed as having bladder cancer during follow-up (rate 89.4 per 100 000 person years). The 376 cases of bladder cancer that were diagnosed beyond one year of follow-up were matched to 6699 controls. Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83, 95% confidence interval 1.10 to 3.05). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99, 1.14 to 3.45) and in those with a cumulative dosage greater than 28 000 mg (2.54, 1.05 to 6.14).

Conclusion The use of pioglitazone is associated with an increased risk of incident bladder cancer among people with type 2 diabetes.

Discussion

The use of pioglitazone in patients newly treated with oral hypoglycaemic agents is associated with a significant increased risk of bladder cancer. This effect was not observed with rosiglitazone, confirming a drug specific effect. Furthermore, a dose-response relation was observed for cumulative duration of use, with the highest risk observed in participants who used pioglitazone for more than 24 months. A similar dose-response relation was observed in patients who received a high cumulative dosage of pioglitazone. These findings remained consistent in several sensitivity analyses.

Comparison with previous studies

To our knowledge, few observational studies have examined the association between pioglitazone use and the risk of bladder cancer.3 4 5 11 12 The first study did not find an overall increase in risk (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5), although a modest increased risk was observed after two years of use (1.4, 1.03 to 2.0).4 The second study found that pioglitazone was associated with a modest increased risk of bladder cancer overall (hazard ratio 1.22, 95% confidence interval 1.05 to 1.43), which was driven by an increased risk after two years of use (1.34, 1.04 to 1.79).5 In the third study, ever use of pioglitazone was not associated with an increased risk of bladder cancer overall (odds ratio 0.95, 95% confidence interval 0.70 to 1.29), although an increased risk could not be excluded with more than three years of use (1.56, 0.51 to 4.47). In the fourth study, ever use of pioglitazone was not statistically associated with an increased risk of bladder cancer, but the study was possibly underpowered owing to the few cases of bladder cancer included in the analysis (n=165).12 By combining both new and prevalent users of antidiabetic drugs, these previous studies may have underestimated the association between pioglitazone and bladder cancer.26Specifically, patients receiving pioglitazone who developed bladder cancer before entry to the cohort were, according to the inclusion criteria, selected out of the previous studies. Thus these designs may have missed several cases of bladder cancer that developed among pioglitazone users, a limitation further exacerbated by the fact that this therapy seems to increase the risk over a relatively short duration of use—that is, after two years. Furthermore, the magnitude of the association observed in our study (twofold increased risk after 24 months of use) is consistent with the nearly threefold increased risk observed in the PROactive trial after an average three year follow-up (14 cases in the pioglitazone group versus 5 in the placebo group).7

Possible biological mechanisms

Thiazolidinedione peroxisome proliferator activated receptor gamma (PPARγ) ligands have complex biological effects,27 28 but no obvious a priori mechanism links these agents to bladder cancer. In fact, growth inhibitory actions attributed to on-target effects of PPAR ligands have been reported in tissue culture systems, and these results do not predict increased risk of carcinogenesis.29 30 31 However, bladder tumours have been reported in laboratory animals exposed to compounds with PPARγ activity, although these models are of uncertain relevance to human carcinogenesis, as considerable species specificity has been noted, with pioglitazone induced bladder cancer being documented in rats but not in mice.32 One line of research implicates chronic bladder irritation as a result of crystal formation, rather than PPAR related signalling, in the observed urothelial carcinogenesis.33 It is of interest that muraglitazar, another PPAR agonist that has been experimentally associated with bladder cancer in rats,34 is also associated with urolithiasis. However, additional research is needed to elucidate the mechanisms by which a subset of pioglitazone PPAR agonists may increase the risk of bladder cancer, and specifically to determine if risk is indeed correlated with increased urinary crystals in humans, and if so to determine the basis of the crystal formation.

What is already known on this topic

  • The association between use of the thiazolidinedione antidiabetic agent pioglitazone and bladder cancer is controversial
  • The few population based studies on this subject produced conflicting results
  • Additional studies are needed to confirm or refute this association
  • Overall, the use of pioglitazone, and not the thiazolidinedione rosiglitazone, was associated with an increased risk of bladder cancer
  • This risk increased with duration of use and cumulative dosage and was highest among those using the drug for more than 24 months and those receiving cumulative dosages greater than 28 000 mg

What this study adds

 

Sourc: BMJ

Exposure to pesticides or solvents and risk of Parkinson disease.

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ABSTRACT

Objective: To investigate the risk of Parkinson disease (PD) associated with exposure to pesticides and solvents using meta-analyses of data from cohort and case-control studies.

Methods: Prospective cohort and case-control studies providing risk and precision estimates relating PD to exposure to pesticides or solvents or to proxies of exposure were considered eligible. The heterogeneity in risk estimates associated with objective study quality was also investigated.

Results: A total of 104 studies/3,087 citations fulfilled inclusion criteria for meta-analysis. In prospective studies, study quality was not a source of heterogeneity. PD was associated with farming and the association with pesticides was highly significant in the studies in which PD diagnosis was self-reported. In case-control studies, study quality appeared to be a source of heterogeneity in risk estimates for some exposures. Higher study quality was frequently associated with a reduction in heterogeneity. In high-quality case-control studies, PD risk was increased by exposure to any-type pesticides, herbicides, and solvents. Exposure to paraquat or maneb/mancozeb was associated with about a 2-fold increase in risk. In high-quality case-control studies including an appreciable number of cases (>200), heterogeneity remained significantly high (>40%) only for insecticides, organochlorines, organophosphates, and farming; also, the risk associated with rural living was found to be significant.

Conclusions: The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. Further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. The studies should also focus on specific chemical agents.

DISCUSSION

Exposure to pesticides and solvents appears to be a risk factor for PD. Our evidence also supports the involvement of specific compounds, such as paraquat, maneb/mancozeb family, as well as proxies of exposure. However, it could be argued that the evidence collected is still limited, or at least inconclusive, because there was no definitive agreement between cohort and case-control studies.

Indeed, most of the evidence found relied on data from case-control studies. To investigate an etiologic relationship, the use of cohort studies is preferable. However, the incidence of PD is low and usually occurs in the elderly; large populations, a large number of cases, and a long follow-up are required to achieve adequate statistical power. Accordingly, most neuroepidemiologists resort to case-control studies, which are practical and, despite their retrospective nature, have the advantage of more detailed exposure assessment.

We have also partly explained the sources of heterogeneity in individual study results. In prospective studies, differences in estimates of exposure to pesticides appeared to depend on the method of ascertainment of PD. This factor is less likely to have been a source of bias in case-control studies because, although different sets of well-accepted diagnostic criteria were used, in most cases secondary causes of PD were excluded in patients recruited at movement disorders clinics. However, we did not assess the effect of this feature and we recognize that this is a possible limitation of our study. Heterogeneity in case-control studies appeared to be due mainly to study quality and size. With respect to study quality, our results are consistent with previous suggestions.e86 However, the issue of sample size analysis was addressed by only a few authors.e25,e60,e66,e80 To detect an OR of 2 and an exposure frequency of 20% we calculated that at least 200 case-control pairs would be needed.

A meta-analysis investigating several sources of heterogeneity in risk estimates has recently shown that study design (case-control vs prospective), source of controls (community vs non-community controls), type of exposure (occupational vs non-occupational/others type), adjustment for potential confounders, or geographical area do not appear to be important determinants. Accordingly, no consistent explanation of heterogeneity has been provided. The only factor that appeared to contribute was the method used for exposure assessment, as the use of job title–based exposure matrix resulted in a higher risk than assignment based on self-reported exposure.17 Unfortunately, this method could not be applied with sufficient accuracy to specific working occupations.

Despite our methodologic approach to quantitative synthesis, notable heterogeneity, probably affecting the evidence of an increased risk associated with exposure, was still present for insecticides, organochlorines, organophosphates, and farming. There are some possible explanations for this observation. With respect to farming, we observed that exposure was assessed either by open questions or by specific industry coding systems. Moreover, the choice of controls may introduce bias. Few studies have considered the effect of geography (area/region of residence; the additional criteria for “comparability” in our quality assessment process) in study design or adjustment of analyses. Regional controls may be preferable for the evaluation of direct exposure but both these and neighboring areas may affect the assessment of risk associated with this proxy measure of exposure. Insecticides are a heterogeneous class of compounds to which most organochlorines and organophosphates belong. Indeed, among organochlorines the most frequently used insecticide is DDT and the risk associated with this compound was found to be nonsignificant. In some cases, frequency of exposure is low and there may be difficulties in recalling specific product names. Given the advanced age of patients with PD, impairment of cognitive function is possible. Although poor cognition has been considered as an exclusion criterion during recruitment in some studies, only one research group adjusted for this covariate.e63,e68 Exposure to insecticides also appears to be closely correlated with exposure to herbicides.16

Finally, there may be residual confounders that we were not able to address. In some cases, data derived from proxy respondents were pooled with those reported by cases,29,e10,e44,e51,e79,e84 probably introducing misclassification bias.e6,e8

Confounding also could be secondary to the use of protective equipment and compliance with suggested, or even recommended, preventive practices. Only one study addressed this issue.26 Prevalent exposure was heterogeneous among the populations investigated and was likely to be higher in certain working categories. Inclusion bias should be taken into consideration, because in some studies selection of cases or controls was performed by linking to professional and insurance databases26,e7,e15,e38,e39,e45,e63,e68,e77,e79,e84 or in geographical areas characterized by extensive use of pesticides. A few studies investigated the role of genetic susceptibility. Although mechanisms of action at the molecular level are largely unknown, there is a growing body of evidence progressively substantiating the hypothesis of a gene–environment interaction.14 Finally, positive exposure was defined according to different levels (e.g., number of chemicals or times of usage over a period), types (particularly for toxin application), or durations.

The present study highlights unresolved issues with implications for health policies. From a preventive perspective, we observed that the route of exposure (e.g., inhaled or transcutaneous) and the method of toxin application (e.g., spraying or mixing) has never been investigated. Risk appears to increase as the duration of exposure increases. Since several compounds are likely to be used by the same people, different routes of exposure may act synergistically in increasing the risk. Unfortunately, it was not possible to investigate the issue of a dose–response relationship and to provide a cutoff for exposure.

The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. However, further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. Although some compounds have been withdrawn from the market in industrialized countries, they are still in use in developing parts of the world. According to our review of the sources of funding, interest in this issue should come also from chemicals manufacturers. This should be emphasized because an interest in the adverse effects of specific compounds appears justified.

Source: http://www.neurology.org

 

Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study.

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Abstract

Objective To determine the association between concentration of prostate specific antigen (PSA) at age 40-55 and subsequent risk of prostate cancer metastasis and mortality in an unscreened population to evaluate when to start screening for prostate cancer and whether rescreening could be risk stratified.

Design Case-control study with 1:3 matching nested within a highly representative population based cohort study.

Setting Malmö Preventive Project, Sweden.

Participants 21 277 Swedish men aged 27-52 (74% of the eligible population) who provided blood at baseline in 1974-84, and 4922 men invited to provide a second sample six years later. Rates of PSA testing remained extremely low during median follow-up of 27 years.

Main outcome measures Metastasis or death from prostate cancer ascertained by review of case notes.

Results Risk of death from prostate cancer was associated with baseline PSA: 44% (95% confidence interval 34% to 53%) of deaths occurred in men with a PSA concentration in the highest 10th of the distribution of concentrations at age 45-49 (≥1.6 µg/L), with a similar proportion for the highest 10th at age 51-55 (≥2.4 µg/L: 44%, 32% to 56%). Although a 25-30 year risk of prostate cancer metastasis could not be ruled out by concentrations below the median at age 45-49 (0.68 µg/L) or 51-55 (0.85 µg/L), the 15 year risk remained low at 0.09% (0.03% to 0.23%) at age 45-49 and 0.28% (0.11% to 0.66%) at age 51-55, suggesting that longer intervals between screening would be appropriate in this group.

Conclusion Measurement of PSA concentration in early midlife can identify a small group of men at increased risk of prostate cancer metastasis several decades later. Careful surveillance is warranted in these men. Given existing data on the risk of death by PSA concentration at age 60, these results suggest that three lifetime PSA tests (mid to late 40s, early 50s, and 60) are probably sufficient for at least half of men.

Discussion

Overview of findings

PSA concentration can be used to predict of long term risk of metastasis or death from prostate cancer. It can identify a small group of men at greatly increased risk compared with a much larger group highly unlikely to develop prostate cancer morbidity if rescreening is delayed for seven or eight years. As PSA screening was extremely rare in this cohort, our findings can be used to design screening programmes by determining the age at which men should start to undergo screening and the interval between screenings. Men at low risk of death from prostate cancer without screening have little to gain from being screened but still risk overdiagnosis and overtreatment; men likely to die from prostate cancer without screening could avoid cancer specific mortality if they choose to be screened.

In an earlier paper, we showed that PSA concentration at age 60 had a strong association with the risk of death from prostate cancer by age 85 (AUC 0.90),7 with extremely low risk (≤0.2%) in men with PSA concentration below the median (≤1.0 µg/L). Taken together with our current data, this suggests a simple algorithm for prostate screening. All men with a reasonable life expectancy could be invited for PSA screening in their mid to late 40s. Men with a PSA concentration <1.0 µg/L would be advised to return for screening in their early 50s and then again at age 60, whereas men with PSA ≥1.0 µg/L would return for more frequent screening, with literature suggesting repeat tests every two or four years.19 The choice of 1.0 µg/L as a tentative threshold might vary according to preference. At age 60, men with PSA at median or lower—that is, ≤1.0 µg/L (or possibly below the highest quarter, ≤2.0 µg/L, depending on preference)—would then be exempted from further screening; men with a higher concentration would continue to undergo screening until around 70.1 Particular focus should be placed on men in the highest 10% of PSA concentrations at age 45-55, who will contribute close to half of all deaths from prostate cancer occurring before the age of 70-75. Some of these men will have concentrations above current thresholds for consideration of biopsy—such as 3 µg/L—and should be referred to a urologist. The remaining men could be told that, although they will probably not die from prostate cancer (with a mean risk of metastasis within 25 years close to 10%), they are at much higher risk than average and that it is especially important that they return for regular, frequent, and possibly more elaborate screening. It is also worth considering whether management of these men should become proactive, with reminder letters and attempts to follow-up non-compliers by telephone. Most importantly, the proposed PSA concentration of 1.0 µg/L to discriminate a low from a higher risk group is not suggested to serve as an indication for biopsy but rather be used to determine the frequency and intensity of subsequent monitoring.

What is known on this topic

  • Prostate specific antigen screening is widely used for the early detection of prostate cancer but remains highly controversial.
  • Focusing on the men at highest risk of prostate cancer metastasis and death could improve the ratio between benefits and harms of screening.
  • It is difficult to justify initiating PSA screening at 40 for men with no other significant risk factor
  • Men with PSA in highest 10th at age 45-49 contribute nearly half of prostate cancer deaths over the next 25-30 years
  • At least half of all men can be identified as being at low risk, and probably need no more than three PSA tests lifetime (mid to late 40s, early 50s, and 60)

What this study adds

Source: BMJ

 

 

 

 

 

 

Use of caffeinated substances and risk of crashes in long distance drivers of commercial vehicles.

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caffeinecrystalsObjective To determine whether there is an association between use of substances that contain caffeine and the risk of crash in long distance commercial vehicle drivers.

Design Case-control study.

Setting New South Wales (NSW) and Western Australia (WA), Australia.

Participants 530 long distance drivers of commercial vehicles who were recently involved in a crash attended by police (cases) and 517 control drivers who had not had a crash while driving a commercial vehicle in the past 12 months.

Main outcome measure The likelihood of a crash associated with the use of substances containing caffeine after adjustment for factors including age, health disorders, sleep patterns, and symptoms of sleep disorders as well as exposures such as kilometres driven, hours slept, breaks taken, and night driving schedules.

Results Forty three percent of drivers reported consuming substances containing caffeine, such as tea, coffee, caffeine tablets, or energy drinks for the express purpose of staying awake. Only 3% reported using illegal stimulants such as amphetamine (“speed”); 3,4 methylenedioxymethamphetamine (ecstasy); and cocaine. After adjustment for potential confounders, drivers who consumed caffeinated substances for this purpose had a 63% reduced likelihood of crashing (odds ratio 0.37, 95% confidence interval 0.27 to 0.50) compared with drivers who did not take caffeinated substances.

Conclusions Caffeinated substances are associated with a reduced risk of crashing for long distance commercial motor vehicle drivers. While comprehensive mandated strategies for fatigue management remain a priority, the use of caffeinated substances could be a useful adjunct strategy in the maintenance of alertness while driving.

 

Source:BMJ

 

Breast Irradiation and Increased Risk for Ischemic Heart Disease: New Data Emerge.

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A case-control study in the New England Journal of Medicine provides new information on the link between breast irradiation and increased risk for ischemic heart disease.

Using national registries, researchers in Sweden and Denmark studied nearly 2200 women who underwent radiotherapy for breast cancer between 1958 and 2001; roughly 1000 who subsequently had a major coronary event were matched with 1200 controls.

The rate of coronary events increased with the mean estimated dose of radiation to the heart. The risk increase was observed within 5 years after treatment and lasted for at least 20 years. The absolute risk for coronary events was particularly high for women who had preexisting cardiac risk factors.

In Journal Watch Oncology and Hematology, William Gradishar concludes: “Efforts to provide women with the option of breast conservation should not be abandoned, but for select women with very significant cardiac risk factors … a mastectomy might be a better option.”

Source: NEJM 

 

Meta-Analysis: Progestin-Only Pills, IUDs Don’t Increase VTE Events.

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Progestin-only pills and intrauterine devices do not increase the risk for venous thromboembolic events, according to a meta-analysis in BMJ. However, an association between injectable progestin and VTE could not be ruled out.

The meta-analysis included three retrospective cohort studies and five case-control studies comparing progestin-only contraception use with no hormone use. Overall, progestin-only methods were not associated with VTE risk — a finding that held true in subanalyses of progestin-only pills and IUDs. Use of injectable progestin was associated with a doubling of risk, although only two studies evaluated this formulation.

The authors call for more research into the potential increase in risk with injectable progestin. “In the interim,” they conclude, “we suggest consideration of non-injectable forms of progestin-only contraception for highest risk women.”

Source: BMJ

ACE Inhibitor Use Lowers Risks for Pneumonia.

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A meta-analysis showed that angiotensin-converting–enzyme inhibitors, but not angiotensin-receptor blockers, lowered risk.

Many patients (as many as one third) who take angiotensin-converting–enzyme (ACE) inhibitors develop coughs. However, an enhanced cough reflex might lower risk for pneumonia. In this meta-analysis of 37 studies (18 randomized trials, 11 cohort studies, and 8 case-control studies), investigators evaluated the association between use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and risk for pneumonia.

Overall, use of ACE inhibitors was associated with a significant 34% lower risk for pneumonia compared with no use of ACE inhibitors and a significant 30% lower risk for pneumonia compared with ARB use. Subgroup analyses of patients with stroke or heart failure yielded similar results. Finally, use of ACE inhibitors compared with no use was associated with a significant 27% lower risk for pneumonia-related death.

Comment: In this study, ACE inhibitor use was associated with attenuation of risks for pneumonia and pneumonia-related death. The authors suggest that “patients taking ACE inhibitors who develop cough should, providing that cough is tolerable, persist with treatment.” Although this suggestion is reasonable (especially because ACE inhibitors confer considerable cardiovascular benefit), many patients with ACE inhibitor–related cough find this side effect too annoying or disruptive to continue taking the drug.

Source: Journal Watch General Medicine