Time-related Biases Research Articles

Highlights of This Issue

Metformin is widely used in the management of type 2 diabetes mellitus. Epidemiologic studies have reported strong inverse associations between metformin use and risk of several cancers, including colorectal (CRC). Concern that time-related biases, such as immortal time bias, were influencing reported associations led Bradley and colleagues to re-examine metformin and CRC risk using methods to minimize these biases. Specifically, the authors accounted for time-varying exposure to metformin and other diabetes medications and adjusted for diabetes duration. Despite applying more rigorous methods, the authors observed an inverse association between long-term metformin use and CRC risk that appeared to be restricted to men.Hepatocellular carcinoma (HCC) incidence is rising in regions where established HCC risk factors are not predominant. The rise is likely due to factors such as obesity and unhealthy lifestyle exposures. This study, by Assi and colleagues, presents an analytical framework to explore exposure-specific metabolic signatures and assess their mediating role in the association between various lifestyle behaviors and HCC risk using detailed metabolomic and lifestyle data from a large prospective cohort. Metabolic profiles of obesity, smoking, and alcohol intake mediated HCC carcinogenesis. These findings contribute to further understanding of HCC etiology, thus strengthening public health advice for cancer prevention by modifying unhealthy lifestyle behaviors.Using novel questionnaire, biomarker, and vital records data, this study by Boen and colleagues examines how diverse measures of social support relate to mortality risk among individuals with cancer as well as the mediating role of inflammation as a biological mechanism. Findings revealed that cancer patients reporting less social support satisfaction had higher mortality risk than those reporting greater satisfaction, partly due to the elevated risk of inflammation associated with low satisfaction. The study offers new insights for intervention efforts aimed at promoting meaningful social connections as a means for improving cancer survival.Endometrial cancer incidence has been increasing among black women. Despite established roles of estrogens and progestins in endometrial cancer etiology, few studies have investigated the influence of exogenous hormone use among black women. Similar to prior findings, the Black Women's Health Study found that oral contraceptive use was associated with reduced endometrial cancer risk; estrogen-only menopausal hormone use was associated with increased risk. Also consistent with previous studies, the protective effects of oral contraceptive use were weaker among obese women. The results of this study by Sponholzt and colleagues suggest that the high obesity prevalence among black women may contribute to their increasing endometrial cancer incidence by mitigating the beneficial effects of oral contraceptive use.

A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus.

Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. ©2018 AACRSee related commentary by Jackson and García-Albéniz, p. 520.

Hospital costs associated with psychiatric comorbidities: a retrospective study

BackgroundPsychiatric comorbidities are relevant for the diagnostic and therapeutic regimes in somatic hospital care. The main aim of this study was to analyse the association between psychiatric comorbidities and hospital costs per inpatient episode. A further aim was to discuss and address the methodological challenges in the estimation of these outcomes based on retrospective data.MethodsThe study included 338,162 inpatient episodes consecutively discharged between 2011 and 2014 at a German university hospital. We used detailed resource use data to calculate day-specific hospital costs. We adjusted analyses for sex, age, somatic comorbidities and main diagnoses. We addressed potential time-related bias in retrospective diagnosis data with sensitivity analyses.ResultsPsychiatric comorbidities were associated with an increase in hospital costs per episode of 40% and an increase of reimbursement per episode of 28%, representing marginal effects of 1344 € and 1004 €, respectively. After controlling for length of stay, sensitivity analyses provided a lower bound increase in daily costs and reimbursement of 207 € and 151 €, respectively.ConclusionIf differences in hospital costs between patient groups are not adequately accounted for in DRG-systems, perverse incentives are created that can reduce the efficiency of care. Therefore, we suggest intensifying the inclusion of psychiatric comorbidities in the German DRG system. Future research should investigate the appropriate inclusion of psychiatric comorbidities in other health care systems’ payment schemes.

Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias?

Two recent observational studies reported a remarkably lower rate of all-cause death associated with sodium-glucose cotransporter 2 inhibitor (-SGLT2i) use in all patients with type 2 diabetes and not only those at increased cardiovascular risk. The >50% lower mortality rates reported in these studies are much greater than those found in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) randomized trials. We show that these observational studies are affected by time-related biases, including immortal time bias and time-lag bias, which tend to exaggerate the benefits observed with a drug. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study, based on 166,033 users of SGLT2i and 1,226,221 users of other glucose-lowering drugs (oGLD) identified from health care databases of six countries, was affected by immortal time bias. Indeed, the immortal time between the first oGLD prescription and the first SGLT2i prescription was omitted from the analysis, which resulted in increasing the rate of death in the oGLD group and thus producing the appearance of a lower risk of death with SGLT2i use. The Swedish study compared 10,879 SGLT2i/dipeptidyl peptidase 4 inhibitor (DPP-4i) users with 10,879 matched insulin users. Such comparisons involving second-line therapies with a third-line therapy can introduce time-lag bias, as the patients may not be at the same stage of diabetes. This bias is compounded by the fact that the users of insulin had already started their insulin before cohort entry, unlike the new users of SGLT2i. Finally, the study also introduces immortal time bias with respect to the effects of SGLT2i relative to DPP-4i. In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time-lag biases. It thus remains uncertain whether the benefit seen with empagliflozin in the EMPA-REG OUTCOME trial applies to all SGLT2i and to all patients with type 2 diabetes, not only those at increased cardiovascular risk. While observational studies can provide crucial real-world evidence for the effects of medications, they need to be carefully conducted to avoid such major time-related biases.

Recovery from DSM-IV post-traumatic stress disorder in the WHO World Mental Health surveys.

Research on post-traumatic stress disorder (PTSD) course finds a substantial proportion of cases remit within 6 months, a majority within 2 years, and a substantial minority persists for many years. Results are inconsistent about pre-trauma predictors. The WHO World Mental Health surveys assessed lifetime DSM-IV PTSD presence-course after one randomly-selected trauma, allowing retrospective estimates of PTSD duration. Prior traumas, childhood adversities (CAs), and other lifetime DSM-IV mental disorders were examined as predictors using discrete-time person-month survival analysis among the 1575 respondents with lifetime PTSD. 20%, 27%, and 50% of cases recovered within 3, 6, and 24 months and 77% within 10 years (the longest duration allowing stable estimates). Time-related recall bias was found largely for recoveries after 24 months. Recovery was weakly related to most trauma types other than very low [odds-ratio (OR) 0.2-0.3] early-recovery (within 24 months) associated with purposefully injuring/torturing/killing and witnessing atrocities and very low later-recovery (25+ months) associated with being kidnapped. The significant ORs for prior traumas, CAs, and mental disorders were generally inconsistent between early- and later-recovery models. Cross-validated versions of final models nonetheless discriminated significantly between the 50% of respondents with highest and lowest predicted probabilities of both early-recovery (66-55% v. 43%) and later-recovery (75-68% v. 39%). We found PTSD recovery trajectories similar to those in previous studies. The weak associations of pre-trauma factors with recovery, also consistent with previous studies, presumably are due to stronger influences of post-trauma factors.

Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer—Response

We appreciate the letter of Alam and colleagues, who underscore the point we made in our discussion section when we noted that time-related biases, such as immortal time bias, can threaten pharmacoepidemiologic studies of metformin as a potential chemotherapeutic agent ([1][1]). Vivid illustrations

Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients.

Metformin has garnered more interest as a chemo-preventive agent given the increased liver cancer risk in diabetic patients. This work was undertaken to better understand the effect of metformin use on liver cancer risk in diabetic patients.A comprehensive literature search was performed in PubMed, Embase, BIOSIS Previews, Web of Science, and Cochrane Library through July 30, 2016. Meta-analyses were performed using Stata version 12.0, with odds ratio (ORs) and 95% confidence intervals (CIs) as effect measures.Twenty-three studies were included. Meta-analysis of 19 studies involving 550,882 diabetic subjects suggested that metformin use reduced the ratio of liver cancer by 48% (OR = 0.52; 95% CI, 0.40–0.68) compared with nonusers. The protective effect was validated in all the exploratory subgroup analyses, except that pooled result of post hoc analyses of 2 randomized controlled trials found no significant difference between subjects with metformin and those without, with OR being 0.84 (95% CI, 0.10–6.83). After adjusting for hepatitis B/C virus infection, cirrhosis, obesity, behavioral factors, and time-related bias, the association was stable, pooled OR ranged from 0.42 to 0.75.A protective effect for liver cancer was found in diabetic metformin users. However, more randomized clinical evidence is still needed to verify the results.

Optimal specifications for beam calibration checks in radiotherapy calculated with gauge repeatability and reproducibility, and sensitivity and specificity studies

Introduction. Several medical physicists have moved to a statistical process control-oriented approach to learn more about the intrinsic performance of radiotherapy equipment. Our aim is to report how gauge repeatability and reproducibility (R&R) and sensitivity and specificity studies can provide optimal specifications for radiotherapy-beam calibration checks. Methods. A team of three medical physicists performed gauge R&R studies on 6 megavolt (MV) photon, and 4, 9, and 15-megaelectron volt electron-beams. The operator order was randomized to reduce time-related biases. Checks were performed accurately using ionization chambers with a water phantom. These gauge R&R studies allowed us to determine the proportion of variation due to the repeatability, operator, and beam-to-beam components associated with repeated beam-calibration checking. We then calculated the conditional probabilities of misclassifying the check results as a false accept (β = 1–sensitivity) and a false reject (δ = 1–specificity) by changing the beam calibration specifications. Using this information we plotted the receiver operating characteristic curves in order to identify the sensitivity and specificity settings that maximize detection. Results. The main component of variation was due to the operator; the repeatability component was less than 30%. The intrinsic variation component for 6 MV photon-beams was approximately 20%, whereas it was over 34% for electron-beams. The optimal specification bands expressed as a percentage of the mean were ±0.7% for 6 MV photons and ±0.9% for electron-beams. Optimal sensitivity was over 50%, whereas specificity was not less than 0.995. The very low δ indicates that the system is unlikely to reject a correct beam calibration. However, the high β shows that should we require high levels of precision and therefore adopt such optimized specifications, the probability of accepting a drifted beam calibration would be fairly high. Therefore, the combination of ‘medical physicist, water phantom, and ionization chamber’ is an excellent tool for correctly adjusting beam calibrations to their specifications; moreover, this procedure could also be further improved in order to detect drifts in beam calibrations if the specifications required were to tighten in the future. Conclusion. Calculating the optimal specifications is feasible and leads to a very high detection specificity, but with low sensitivity. The operator-associated variation component contributed the most to the overall variation in check results. The beam calibration procedure might need to be adapted if the demand for precision in radiotherapy increases.

Statin use and breast cancer survival: a nationwide cohort study in Scotland.

BackgroundPreclinical evidence suggests that statins could delay cancer progression. Previous epidemiological findings have been inconsistent and some have been limited by small sample sizes, as well as certain time-related biases. This study aimed to investigate whether breast cancer patients who were exposed to statins had reduced breast cancer-specific mortality.MethodsWe conducted a retrospective cohort study of 15,140 newly diagnosed invasive breast cancer patients diagnosed from 2009 to 2012 within the Scottish Cancer Registry. Dispensed medication usage was obtained from linkages to the Scottish Prescribing Information System and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Using time-dependent Cox regression models, hazard ratios (HR) and 95 % confidence intervals (CI) were calculated for the association between post-diagnostic exposure to statins (including simvastatin) and breast cancer-specific mortality. Adjustments were made for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of aspirin.ResultsA total of 1,190 breast cancer-specific deaths occurred up to January 2015. Overall, after adjustment for potential confounders, there was no evidence of an association between statin use and breast cancer-specific death (adjusted HR 0.93, 95 % CI 0.77, 1.12). No significant associations were observed in dose–response analyses or in analysis of all-cause mortality. For simvastatin use specifically, a weak non-significant reduction in breast cancer-specific mortality was observed compared to non-users (adjusted HR 0.89, 95 % CI 0.73, 1.08). Statin use before diagnosis was weakly associated with a reduction in breast cancer-specific mortality (adjusted HR 0.85, 95 % CI 0.74, 0.98).ConclusionOverall, we found little evidence of a protective association between post-diagnostic statin use and cancer-specific mortality in a large nation-wide cohort of breast cancer patients. These findings will help inform the decision whether to conduct randomised controlled trials of statins as an adjuvant treatment in breast cancer.

Common medications and prostate cancer mortality: a review.

Most prostate cancer patients also have comorbidities that are treated with both prescription and nonprescription medications; furthermore, many use dietary supplements. We assess their association with prognosis after prostate cancer diagnosis, and we discuss methodological challenges and clinical implications. We reviewed high-quality observational studies investigating the association of commonly used medications and supplements with prostate cancer-specific mortality. There is preliminary evidence that statins and metformin use may be associated with lower risk of cancer-specific mortality after prostate cancer diagnosis; conversely, high calcium and multivitamin supplementation may be associated with increased risk. Evidence is inconclusive for nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (aspirin), insulin, antihypertensives such as angiotensin-converting enzyme inhibitors and beta-blockers, digoxin, and warfarin. Common limitations of the internal validity of studies examined include unmeasured confounding and confounding by indication, competing risks, and time-related biases such as immortal time bias. The majority of studies focused on Caucasian men with specific comorbidities, while heterogeneity among patients and tumors was mostly not assessed. Commonly prescribed medications and over-the-counter supplements may influence prognosis among prostate cancer patients. Further well-designed pharmacoepidemiologic studies and randomized controlled trials of selected medications in appropriate patient groups are necessary before these drugs can bear new indications for prostate cancer treatment. We discuss considerations when deciding about use of these drugs in clinical practice at the present time.

Invited Commentary: Influenza, Influenza Immunization, and Pregnancy-It's About Time.

Immunization of pregnant women against influenza has the potential to reduce adverse fetal outcomes by reducing prenatal exposure to influenza illness. However, as touched on by Fell et al. (Am J Epidemiol. 2016;184(3):163-175) and Vazquez-Benitez et al. (Am J Epidemiol. 2016;184(3):176-186) in this issue of the Journal, observational studies in which the causal effect of maternal influenza illness and influenza immunization on fetal health are evaluated are prone to bias because of the complex temporal nature of influenza illness seasonality, influenza immunization schedules, and gestation itself. Immortal time bias is introduced by an "anytime-in-pregnancy" exposure definition because the shortened pregnancy duration associated with many adverse fetal outcomes limits the opportunity to become exposed, whereas including follow-up time during which pregnancies are no longer at risk of an adverse outcome (e.g., gestational time after 37 weeks in studies of preterm birth) can lead to overestimation of any true benefits of immunization (or harms from influenza illness). We present a framework to avoid time-related biases in the study of influenza illness and immunization in pregnancy and advise that investigations of fetal benefit from maternal influenza immunization should only be undertaken when information is available on the calendar time of influenza virus circulation and the gestational age at which maternal influenza immunization occurred.

Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies.

Observational studies examining the association between long-acting insulin analogs and cancer incidence have produced inconsistent results. We conducted a systematic review of these studies, focusing on their methodological strengths and weaknesses. We systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). We included cohort and case-control studies published in English on insulin glargine and detemir and any cancer incidence among patients with type 1 or 2 diabetes. The methodological assessment involved the inclusion of prevalent users, inclusion of lag periods, time-related biases, and duration of follow-up between insulin initiation and cancer incidence. A total of 16 cohort and 3 case-control studies met our inclusion criteria. All studies evaluated insulin glargine, and four studies also examined insulin detemir. Follow-up ranged from 0.9 to 7.0 years. Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (<5 years) follow-up. The observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk.

Does Metformin Reduce Cancer Risks? Methodologic Considerations.

The substantial burden of cancer and diabetes and the association between the two conditions has been a motivation for researchers to look for targeted strategies that can simultaneously affect both diseases and reduce their overlapping burden. In the absence of randomized clinical trials, researchers have taken advantage of the availability and richness of administrative databases and electronic medical records to investigate the effects of drugs on cancer risk among diabetic individuals. The majority of these studies suggest that metformin could potentially reduce cancer risk. However, the validity of this purported reduction in cancer risk is limited by several methodological flaws either in the study design or in the analysis. Whether metformin use decreases cancer risk relies heavily on the availability of valid data sources with complete information on confounders, accurate assessment of drug use, appropriate study design, and robust analytical techniques. The majority of the observational studies assessing the association between metformin and cancer risk suffer from methodological shortcomings and efforts to address these issues have been incomplete. Future investigations on the association between metformin and cancer risk should clearly address the methodological issues due to confounding by indication, prevalent user bias, and time-related biases. Although the proposed strategies do not guarantee a bias-free estimate for the association between metformin and cancer, they will reduce synthesis of and reporting of erroneous results.

Abstract A23: Cancer outcomes in the diabetes prevention program outcomes study

Abstract Numerous observational studies have reported decreased cancer incidence and cancer-related mortality in patients with diabetes receiving standard doses of metformin. A recent meta-analysis of these studies suggested a 31% reduction in overall cancer incidence, summary relative risk (0.69; 95% confidence interval, 0.52-0.90), in subjects taking metformin as compared with other antidiabetic drugs. Separate meta-analyses of studies that adjusted for BMI or time-related bias suggested an attenuation of this signal, but still showed a significant reduction in cancer incidence. However, studies published to date are limited by the observational nature of the data and the randomized controlled trials that have been used to examine metformin's potential as an anti-cancer agent in patients with diabetes have had insufficient follow-up for cancer endpoints. These data also do not address the cancer risk in non-diabetic populations, in which the cancer preventive potential of metformin is unknown. The Diabetes Prevention Program (DPP) was a national multi-center, randomized, placebo-controlled clinical trial, which enrolled 3234 participants between 1996 and 1999, designed to investigate whether intensive lifestyle modification or treatment with metformin (850mg twice a day) delayed or prevented the onset of type 2 diabetes in a high risk population. The DPP and its follow up study, the Diabetes Prevention Program Outcomes Study (DPPOS), provide a unique opportunity to examine the role of metformin and lifestyle intervention in reducing cancer incidence in an overweight adult population with impaired glucose regulation, before the onset of diabetes. The National Cancer Institute Division of Cancer Prevention, in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the DPPOS investigators, proposed a study to examine the hypothesis that metformin and/or lifestyle intervention can modify total cancer incidence and/or obesity-related cancer incidence (breast, colorectal, endometrium, pancreas, lower esophagus, gall-bladder, and kidney) in DPP/DPPOS participants. The DPPOS protocol and consent were modified to allow collection of data to support the inclusion of cancer incidence as an endpoint of interest in the study. Participants complete a cancer risk questionnaire that includes family history of cancer, cancer screening activities, and use of aspirin and NSAIDs including dose and frequency. The participants who previously reported a cancer diagnosis, through the SAE reporting process and/or an annual questionnaire, or during a subsequent follow-up visit, are asked to provide physician information to obtain medical records for case adjudication. This protocol will allow for the examination of the effect of metformin and lifestyle intervention on cancer incidence in an initially pre-diabetic population potentially through a median of 20 years of follow-up. Data from this study will compare incidence of total and obesity-related cancers between the original treatment groups; assess cancer (total and obesity-related) incidence by metformin exposure across all treatment groups, using a “met-years” variable, and explore subgroups to investigate effect modification by sex, age group, race/ethnicity, diabetes status, or weight loss at 1 year or mean weight loss since study baseline. Citation Format: Brandy M. Heckman-Stoddard, Jill P. Crandall, Sharon L. Edelstein, Richard F. Hamman, Philip C. Prorok, Anne Ryan, Dana Dabelea, Helen P. Hazuda, Edward Horton, Mary A. Hoskin, Susan Jeffries, William C. Knowler, Kieren J. Mather, Susana M. Shapiro, Farzana L. Walcott, Leslie G. Ford. Cancer outcomes in the diabetes prevention program outcomes study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A23.

Metformin use and survival after colorectal cancer: A population‐based cohort study

Preclinical evidence suggests that metformin could delay cancer progression. Previous epidemiological studies however have been limited by small sample sizes and certain time-related biases. This study aimed to investigate whether colorectal cancer patients with type 2 diabetes who were exposed to metformin had reduced cancer-specific mortality. We conducted a retrospective cohort study of 1,197 colorectal cancer patients newly diagnosed from 1998 to 2009 (identified from English cancer registries) with type 2 diabetes (based upon Clinical Practice Research Datalink, CPRD, prescription and diagnosis records). In this cohort 382 colorectal cancer-specific deaths occurred up to 2012 from the Office of National Statistics (ONS) mortality data. Metformin use was identified from CPRD prescription records. Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% CIs were calculated for the association between post-diagnostic exposure to metformin and colorectal cancer-specific mortality. Overall, there was no evidence of an association between metformin use and cancer-specific death before or after adjustment for potential confounders (adjusted HR 1.06, 95% CI 0.80, 1.40). In addition, after adjustment for confounders, there was also no evidence of associations between other diabetic medications and cancer-specific mortality including sulfonylureas (HR 1.14, 95% CI 0.86, 1.51), insulin use (HR 1.35, 95% CI 0.95, 1.93) or other anti-diabetic medications including thiazolidinediones (HR 0.73, 95% CI 0.46, 1.14). Similar associations were observed by duration of use and for all-cause mortality. This population-based study, the largest to date, does not support a protective association between metformin and survival in colorectal cancer patients.

No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK.

In observational studies, a lower cancer risk was reported for patients with diabetes using metformin. However, many of these studies had shortcomings like time-related biases. We aimed to compare the incidence rate of any cancer and some selected cancer sites in metformin, sulfonylurea, and insulin users and to reduce some major biases common in observational studies. In a retrospective database study, we used patient data from general practices throughout Germany and the UK. Eighty thousand two hundred and sixty-three patients aged 30-89 years at diagnosis of diabetes were observed for a mean follow-up of 4.8 years after the first antidiabetes medication. In Cox regression models adjusted for age, sex, country, metabolic factors, diabetes duration, medication, and comorbidity, patients who started using metformin were compared with those who started using sulfonylurea (or insulin) (intention-to-treat type analysis), and, additionally, patients with metformin monotherapy were compared with those with sulfonylurea (or insulin) monotherapy. The initial 12 months of follow-up after the first antidiabetes prescription were excluded. Four thousand seven hundred seventy-nine (6.0%) incident cases of cancer were identified. Throughout all analyses, hazard ratios were close to the null for comparisons of metformin use with sulfonylurea and insulin use. For example, in intention-to-treat analyses comparing metformin with sulfonylurea use, hazard ratios were 1.05 (95%CI: 0.99-1.12) for any cancer, 1.05 (0.85-1.30) for colorectal, 1.04 (0.82-1.31) for lung, 1.03 (0.81-1.30) for breast, and 0.89 (0.73-1.08) for prostate cancer. This study provides evidence that metformin has no protective effect on the incidence of cancer in persons with diabetes.

The impact of time-window bias on the assessment of the long-term effect of medication adherence: the case of secondary prevention after myocardial infarction

ObjectivesTime-window bias was described in case–control studies and led to a biased estimate of drug effect. No studies have measured the impact of this bias on the assessment of the...

Assessing the Effect of Treatment Duration on the Association between Anti-Diabetic Medication and Cancer Risk

Most studies that have evaluated the association between anti-diabetic medication and cancer risk have suffered from methodological drawbacks. To avoid time-related biases, we evaluated the effect of treatment duration on the cancer risk among naive users of anti-diabetic medication as compared to non-users. In addition, we addressed the influence of common risk factors such as smoking and BMI. The study population comprised 23,394 participants of FINRISK surveys. Data on cancer and anti-diabetic medication were linked with the study cohorts. We applied Lexis tabulation to the data and analyzed split records by using Poisson regression. Changes in cancer incidence in relation to treatment duration were examined by modeling the rate ratio (RR). After a median follow-up of 9 years, 53 cancer cases among users of anti-diabetic medication and 1,028 among non-users were diagnosed. No significant difference in cancer risk between users and non-users was observed after adjustment. The RR for all medication regardless of its duration was 1.01 [95% CI 0.75–1.33], and 1.37 [0.94–1.94] for period of 1–4 years. The results were similar for metformin, sulfonylurea, and insulin. This study demonstrates that evaluation of the variation in cancer risk in relation to treatment duration is of particular importance for enhancing the accuracy of conclusions on the link between exposure to anti-diabetic medication and cancer risk.

Time-related Bias in Administrative Health Database Studies of Disease Incidence

Time-related Bias in Administrative Health Database Studies of Disease Incidence

Are sulfonylurea and insulin therapies associated with a larger risk of cancer than metformin therapy? A retrospective database analysis.

Several meta-analyses of observational studies suggested that metformin use reduces cancer risk in type 2 diabetes. However, this result was not confirmed by the few available randomized controlled trials (RCTs), and many observational studies on metformin and cancer were potentially afflicted with time-related bias. We aimed to avoid this bias when comparing cancer incidence in users of sulfonylurea, insulin, and other diabetes medications, respectively, with cancer incidence in metformin users. In a retrospective observational study, we used the German Disease Analyzer database with patient data from general practices throughout Germany. The study sample included 22,556 patients diagnosed with type 2 diabetes. During the median follow-up time of 4.8 years, 1,446 (6.4%) patients developed any cancer. In Cox regression analyses with either monotherapies or first diabetes medications as drug exposure, users of sulfonylurea (or insulin or other antidiabetes medications) were compared with metformin users. In multivariable adjusted models, hazard ratios were 1.09 (95% CI 0.87-1.36) for sulfonylurea monotherapy, 1.14 (95% CI 0.85-1.55) for insulin monotherapy, and 0.94 (95% CI 0.67-1.33) for other diabetes medications compared with metformin monotherapy. Results were similar for comparison of first diabetes medications. In a retrospective database analysis, taking into account potential time-related biases, no reduced cancer risk was found in metformin users. To clarify the association between diabetes medication and cancer risk, further well-designed observational studies and RCTs are needed.