Cumulative Duration Of Use Research Articles

Association of RAAS inhibitors on osteoporosis and fracture risk in the hypertensive population–A prospective population-based cohort study in Lanzhou, China

BackgroundRenin-angiotensin-aldosterone system (RAAS) inhibitors appear to benefit bone tissue in antihypertensive treatment. However, the association between RAAS inhibitors and bone metabolism was inconsistent.Methods and study designBased on the study of Risk Evaluation of Cancers in Chinese Diabetic Individuals(REACTION) conducted in 2011, We followed 6,252 Lanzhou residents aged 40–75 years from 2014 to 2016. Finally, 1,625 hypertension cases with complete data were included in the analysis. The study subjects were divided into four groups according to the type of antihypertensive drugs. We employed logistic or multivariate Cox proportional hazards regression to estimate the association between different antihypertensive drug use and osteoporosis, the risk of fracture, and the change in bone mineral density (BMD) level. The association of osteoporosis or the fracture risk by cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated.ResultsThe cross-sectional study showed that there was no significant association between baseline antihypertensive drugs (angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)) use and osteoporosis and fracture. During a mean follow-up of 3.4 years in the longitudinal study, there were 478 new osteoporosis cases and 76 fractures. Compared with patients without antihypertensive drug use, the hazard ratios (HRs) [95% confidence interval (CI)] for the risk of osteoporosis were 1.005(0.651,1.552) and 1.077(0.793,1.462) in ACEI or ARB use (p > 0.05). ACEI or ARB use was also not significantly associated with fracture risk (HR 1.102(0.326,3.726), 0.735(0.251,2.148), p > 0.05). Further analysis showed that the use of ACEI (HR 1.078(0.146,7.950)) or ARB (HR 1.169(0.347,3.939)) was not significantly associated with the improvement of osteoporosis (p > 0.05). In addition, the duration of RAAS inhibitors used showed no apparent correlation with the risk of osteoporosis (≤ 3 years: HR 0.872 (0.516, 1.474), > 3 years: HR 1.151 (0.574, 2.308)), nor with the improvement of osteoporosis and the risk of fracture. Meanwhile, the association mentioned above did not change compared to different RAAS inhibitors.ConclusionsThe use of RAAS inhibitors, including ACEIs and ARBs, was not significantly associated with osteoporosis, risk of fracture, or BMD change.

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2.

It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers. Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression. Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively). Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Exposure to Valsartan Products Containing Nitrosamine Impurities in the United States, Canada, and Denmark.

Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the United States, Canada, and Denmark. We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry. Patients, 18 years and older between May 2012 and December 2020 with a valsartan dispensing were identified in each database. Patients were followed from the date of valsartan dispensing until discontinuation. We defined four valsartan exposure categories based on nitrosamine impurity status; recalled generic products with confirmed NDMA/NDEA levels (recalled-tested); recalled generic products that were not tested (recalled); non-recalled generic and non-recalled branded products. In Denmark, the recalled-tested category was not included due to absence of testing data. The proportion and duration of use of valsartan episodes stratified by nitrosamine-impurity status was calculated. We identified 3.3 and 2.8 million (United States) and 51.3 and 229 thousand (Canada) recalled-tested and recalled valsartan exposures. In Denmark, where valsartan exposure was generally low, there were 10 747 recalled exposures. Immediately after the recall notices were issued, there was increased rates of switching to a non-valsartan ARB. The mean duration of use of the recalled-tested products was 167 (±223.1) and 146 (±255.8) days in the United States and Canada respectively. For the recalled products, mean cumulative duration of use was 178 (±249.6), 269 (±397.3) and 166 (±251.0) days in the United States, Canada, and Denmark, respectively. In this cohort study, despite widespread use of recalled generic valsartan between 2012 and 2018, the duration of use was relatively short and probably did not pose an elevated risk of nitrosamine-induced cancer. However, since products with nitrosamine impurity could have been on the market over a 6-year period, patients exposed to these products for longer durations could have a potentially different risk of cancer.

Abstract PS10-01: Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2

Abstract BACKGROUND: Current use of hormonal contraception is associated with a 20-30% relative increase in the risk of breast cancer (BC) for women in the general population compared with never using. Longer duration of use is associated with higher risk, and the risk remains elevated above that of never users for at least 5 years after cessation. Most published data are for various formulations of the combined oral contraceptive pill, but associations are similar for progestogen-only contraceptives, including intrauterine devices. For women in the general population who use hormonal contraceptives in their 20s and 30s, when baseline BC risk for most women is low, these increased relative risks translate into only small increases in absolute risk. It is unclear whether use of hormonal contraceptives increases BC risk for women carrying a germline BRCA1 or BRCA2 pathogenic variant (PV). These women are at markedly higher risk of early-onset BC, so even slightly increased relative risks could translate to important increases in their absolute risk of BC. This study assessed the association between use of any hormonal contraception and BC risk for BRCA1 and BRCA2 PV carriers using individual participant data from four prospective cohorts. METHODS: Data from females born after 1920 with a PV in BRCA1 or BRCA2 and no history of cancer or bilateral mastectomy at cohort entry were analyzed. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BC (invasive disease or ductal carcinoma in situ) associated with use of hormonal contraceptives for at least 1 year, with age as the timescale, entry at cohort enrolment, and censoring at the earlier of bilateral mastectomy, death, diagnosis of another cancer or last follow-up. Analyses were adjusted for study, birth cohort, first-degree family history of BC, parity, premenopausal bilateral oophorectomy and menopausal status. Current use of hormonal contraceptives was defined as use within the previous year, to account for cessation of use due to BC symptoms or clinical investigation. RESULTS: Of 3,882 BRCA1 and 1,509 BRCA2 PV carriers, 53% and 71%, respectively had ever used hormonal contraceptives (for at least one year). The median cumulative duration of hormonal contraceptive use was 4.8 and 5.7 years, respectively. Overall, 488 BRCA1 and 191 BRCA2 PV carriers developed incident BC during a median of 5.9 and 5.6 years of follow-up, respectively. For BRCA1 PV carriers, use of hormonal contraceptives for at least 1 year was associated with increased BC risk (HR [95% CI]: 1.29 [1.04-1.60] p=0.019). BC risk increased with longer cumulative duration of hormonal contraceptive use (HR [95% CI]: 1.13 [0.88-1.45] p=0.35, 1.48 [1.11-1.96] p=0.007 and 1.56 [1.13-2.17] p=0.007 for 1-5, 6-10 and &amp;gt;10 years of use, respectively), with an estimated proportional increase in risk of 3% (1%-5%, p=0.002) for each additional year of use. For BRCA2 PV carriers, there was no evidence that current or past use, or cumulative duration of use, were associated with increased risk of BC, but confidence intervals on the HRs were wide. CONCLUSION: Hormonal contraceptive use is associated with an increased risk of BC for women carrying PVs in BRCA1 and risk increases with cumulative duration of use. Hormonal contraceptives are an important healthcare option for women; they provide excellent contraceptive efficacy and reduce risks of ovarian and endometrial cancer. Decisions about use of hormonal contraceptives in women at increased risk for BC due to BRCA1 PVs need to carefully weigh the risks and benefits; while shorter-term use may result in only small increases, prolonged cumulative use may result in larger increases in absolute BC risk that may not be acceptable to some women. Citation Format: Kelly-Anne Phillips, Joanne Kotsopoulos, Susan Domchek, James Chamberlain, Julie Bassett, Amber Aeilts, Irene Andrulis, Saundra Buys, Wanda Cui, Mary Daly, Andrea Eisen, William Foulkes, Michael Friedlander, Jacek Gronwald, John Hopper, Esther John, Beth Karlan, Raymond Kim, Jan Lubiński, Kelly Metcalfe, Katherine Nathanson, Christian F. Singer, Heather Symecko, Nadine Tung, Steven Narod, Mary Beth Terry, Roger Milne. Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-01.

Long-Term Safety of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease, a Multinational Observational Database Cohort Study.

This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

Glucagon like peptide-1 receptor agonists and the risk of skin cancer among patients with type 2 diabetes: Population-based cohort study.

The objective of this study was to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. Using the United Kingdom Clinical Practice Research Datalink (2007-2019), we assembled two new-user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP-1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP-1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. Compared with sulfonylureas, GLP-1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person-years, respectively; HR 0.96, 95% CI 0.53-1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person-years, respectively; HR 1.03, 95% CI 0.80-1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. In this population-based cohort study, GLP-1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas.

Dipeptidyl peptidase-4 inhibitors and the risk of skin cancer among patients with type 2 diabetes: a UK population-based cohort study

IntroductionThe dipeptidyl peptidase-4 (DPP-4) enzyme significantly influences carcinogenic pathways in the skin. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma...

1386-P: Dipeptidyl Peptidase-4 Inhibitors and the Risk of Skin Cancer among Patients with Type 2 Diabetes—Population-Based Cohort Study

Introduction: The dipeptidyl peptidase-4 (DPP-4) enzyme influences carcinogenic pathways in the skin, although its exact role remains uncertain. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas. Research Design and Methods: Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96,739 DPP-4 inhibitor users and 209,341 sulfonylurea users, and 96,411 DPP-4 inhibitor users and 208,626 sulfonylurea users for nonmelanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, separately. Results: Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs. 65.3 per 100,000 person-years, respectively; HR 0.77, 95% CI 0.61-0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84-1.54; 2.1-5 years HR 0.44, 95% CI 0.29-0.66; &amp;gt;5 years HR 0.33, 95% CI 0.14-0.74). In contrast, these drugs were not associated with the incidence of nonmelanoma skin cancer, compared with sulfonylureas (448.1 vs. 426.1 per 100,000 person-years, respectively; HR 1.06, 95% CI 0.98-1.15). Conclusions: In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not nonmelanoma skin cancer, compared with sulfonylureas. Disclosure R.Pradhan: None. L.Azoulay: Advisory Panel; Pfizer Inc., Consultant; Pfizer Inc., Speaker's Bureau; Roche Diagnostics. R.W.Platt: Advisory Panel; Pfizer Inc., Consultant; Boehringer Ingelheim (Canada) Ltd., Biogen, Merck &amp; Co., Inc., Nant Pharma, Other Relationship; Boehringer Ingelheim Inc. O.Yu: Consultant; Novo Nordisk. Funding Canadian Institutes of Health Research (FDN143328)

Dihydropyridine Calcium Channel Blockers and Risk of Pancreatic Cancer: A Population-Based Cohort Study.

Background Recent studies have reported that dihydropyridine calcium channel blockers (dCCBs) may increase the risk of pancreatic cancer, but these studies had methodological limitations. We thus aimed to determine whether dCCBs are associated with an increased risk of pancreatic cancer compared with thiazide diuretics, a clinically relevant comparator. Methods and Results We conducted a new user, active comparator, population-based cohort study using the UK Clinical Practice Research Datalink. We identified new users of dCCBs and new users of thiazide diuretics between 1990 and 2018, with follow-up until 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs for pancreatic cancer, comparing dCCBs with thiazide diuretics. Models were weighted using standardized morbidity ratio weights based on calendar time-specific propensity scores. We also conducted secondary analyses by cumulative duration of use, time since initiation, and individual drugs and assessed for the presence of effect modification by age, sex, smoking status, body mass index, history of chronic pancreatitis, and diabetes. The cohort included 344 480 initiators of dCCBs and 357 968 initiators of thiazide diuretics, generating 3 360 745 person-years of follow-up. After a median follow-up of 4.5 years, the weighted incidence rate per 100 000 person-years was 37.2 (95% CI, 34.1-40.4) for dCCBs and 39.4 (95% CI, 36.1-42.9) for thiazide diuretics. Overall, dCCBs were not associated with an increased risk of pancreatic cancer (weighted HR, 0.93; 95% CI, 0.80-1.09). Similar results were observed in secondary analyses. Conclusions In this large, population-based cohort study, dCCBs were not associated with an increased risk of pancreatic cancer compared with thiazide diuretics. These findings provide reassurance regarding the long-term pancreatic cancer safety of these drugs.

GLP-1 Receptor Agonists and the Risk of Thyroid Cancer.

To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer. A nested case-control analysis was performed with use of the French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index. A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1-3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04-3.05). In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1-3 years of treatment.

Cardiovascular medications and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada

ObjectivesResearch examining survival among people with ovarian cancer following use of statins or β-blockers has been conflicting. Many studies to date have suffered from immortal time bias and/or had limited power. To address these limitations, we used time-dependent analyses to study the association between statin or β-blocker use among all people diagnosed with an epithelial ovarian cancer in British Columbia, Canada between 1997 and 2015. MethodsPopulation-based administrative data were linked for 4207 people with ovarian cancer. Statin or β-blocker use was examined using time-dependent variables for any use, cumulative duration of use and by user-group according to whether use was initiated before or after their ovarian cancer diagnosis. Cox proportional hazards models were run to estimate the association between statin or β-blocker use and survival. ResultsAny postdiagnosis use of statins was associated with better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.76, 95% CI 0.64, 0.89) and among women with serous cancers (aHR = 0.80, 95%CI 0.67–0.96). This was primarily driven by new use post-diagnosis (aHR = 0.67, 95%CI, 0.51-0.89), but there was a trend towards better survival among those who continued use from before diagnosis (aHR 0.83, 95%CI, 0.68-1.00). There was no statistically significant association between β-blocker use and survival. ConclusionPostdiagnosis statin use was associated with improved survival among people with ovarian cancer. Given the consistency of this finding in the literature, we recommend a randomized clinical trial of statin use in people with ovarian cancer.

Association between the use of hormonal contraceptives and risk of cholecystectomy in women of reproductive age.

Previous studies have indicated an increased risk of gallbladder disease with hormonal contraceptives although with discordant results. The potential increased risk of gallbladder disease with hormonal contraceptives is concerning given that women are at increased risk of this disease. Thus, the aim of this study was to examine risk of surgery-confirmed gallbladder disease (cholecystectomy) with oral contraceptives, intrauterine devices, and injectable hormonal contraceptives. We conducted a retrospective cohort study. Females aged 15-45 who initiated hormonal contraceptive use were identified in the United States IQVIA Ambulatory electronic medical record database between 2008 and 2018. Cox proportional hazards models were used to estimate adjusted hazards ratios and 95% confidence intervals for cholecystectomy with eight formulations of contraceptives compared with levonorgestrel and ethinyl estradiol combined oral contraceptive. Sensitivity analysis was conducted by lagging exposure by 90days and by excluding patients with history of gallbladder disease. Secondary analyses were conducted by cumulative duration of use. We identified 1,425,821 females who initiated the use of hormonal contraceptives and generated 4417 cholecystectomy events. Overall, the use of medroxyprogesterone acetate (HR: 1.22, 95% CI: 1.07-1.40) and at least 1year of levonorgestrel intrauterine device use (HR: 1.74: 95% CI: 1.19-2.54) were associated with increased risk of cholecystectomy when compared with levonorgestrel and ethinyl estradiol combined oral contraceptive. However, we did not observe an increased risk with other hormonal contraceptives. Consistent results were observed across sensitivity analyses. In this large population-based study, there was an increased risk of cholecystectomy with medroxyprogesterone acetate and intrauterine device but not other hormonal contraceptives. Additional large observational studies are required to corroborate these findings.

Duration, recency, and type of hormonal contraceptive use and antimüllerian hormone levels

To assess whether the duration, recency, or type of hormonal contraceptive used is associated with antimüllerian hormone (AMH) levels, given that the existing literature regarding the association between hormonal contraceptive use and AMH levels is inconsistent. Cross-sectional study. Baseline data from the Study of the Environment, Lifestyle and Fibroids Study, a 5-year longitudinal study of African American women. The patients were 1,643 African American women aged 23-35 years at the time of blood drawing (2010-2012). None. Serum AMH level was measured by an ultrasensitive enzyme-linked immunosorbent assay. Linear regression models were used to estimate percent differences in mean AMH levels and 95% confidence intervals (CIs) according to use of hormonal contraceptives, with adjustment for potential confounders. In multivariable-adjusted analyses, current users of hormonal contraceptives had 25.2% lower mean AMH levels than non-users of hormonal contraceptives (95% CI: -35.3%, -13.6%). There was little difference in AMH levels between former users and non-users of hormonal contraceptives (-4.4%; 95% CI: -16.3%, 9.0%). AMH levels were not appreciably associated with cumulative duration of use among former users or time since last use among non-current users. Current users of combined oral contraceptives (-24.0%; 95% CI: -36.6%, -8.9%), vaginal ring (-64.8%; 95% CI: -75.4%, -49.6%), and depot medroxyprogesterone acetate (-26.7%; 95% CI: -41.0%, -8.9%) had lower mean AMH levels than non-users. The present data suggest that AMH levels are significantly lower among current users of most forms of hormonal contraceptives, but that the suppressive effect of hormonal contraceptives on AMH levels is reversible.

Association of Aspirin, Metformin, and Statin Use with Gastric Cancer Incidence and Mortality: A Nationwide Cohort Study

Anticancer effects of aspirin, metformin, and statins against gastric cancer, one of the most common cancers in the world, have been reported. This retrospective cohort study aimed to investigate independent associations of aspirin, metformin, and statin use with gastric cancer incidence and mortality after adjustment for concomitant use of other drugs, using pooled cohort data extracted from the Korean National Health Insurance claim database. Follow-up started on January 1, 2004 and ended at the date of gastric cancer diagnosis, death, or December 31, 2013. Exposures to drugs were defined as cumulative duration of use for aspirin and cumulative defined daily dose for metformin and statin, and were entered as time-dependent variables in Cox analysis models to avoid immortal time bias. Use of aspirin for longer than 182.5 and 547.5 days during 2-year interval was associated with reduced risks of gastric cancer incidence and mortality, respectively. Patients with diabetes were at higher risk of gastric cancer incidence and mortality than nondiabetic people, regardless of metformin treatment. However, metformin use among patients with diabetes was associated with a reduction in gastric cancer mortality in a dose-response manner. Statin use was also associated with a reduction of gastric cancer mortality in the general population, but not with gastric cancer incidence. In conclusion, long-term use of aspirin was independently associated with reduced incidence and mortality of gastric cancer in the general population, but metformin or statin use was only associated with a reduction of gastric cancer mortality in patients with diabetes and in the general population, respectively. PREVENTION RELEVANCE: Long-term use of aspirin was independently associated with reduced incidence and mortality of gastric cancer in the general population. Metformin or statin use, however, was only associated with a reduction of gastric cancer mortality in diabetic patients and in the general population in a dose-response manner, respectively.

Use of Hydrochlorothiazide and Risk of Melanoma and Nonmelanoma Skin Cancer.

There are concerns that hydrochlorothiazide may increase the risk of incident nonmelanoma (cutaneous squamous cell carcinoma [cSCC], basal cell carcinoma [BCC]) and melanoma skin cancer, with regulatory agencies and societies calling for additional studies. We conducted a propensity score-matched population-based cohort study using the United Kingdom Clinical Practice Research Datalink. A total of 20,513 new users of hydrochlorothiazide were propensity score matched, in a 1:1 ratio, to new users of other thiazide diuretics between January 1, 1988 and March 31, 2018, with follow-up until March 31, 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cSCC, BCC, and melanoma, comparing use of hydrochlorothiazide with use of other thiazide diuretics overall, by cumulative duration of use, and cumulative dose. After an 8.6-year median follow-up, hydrochlorothiazide was associated with an increased risk of cSCC (HR 1.50, 95% CI 1.06-2.11). HRs increased with cumulative duration of use, with evidence of an association after 5-10years (HR 2.10, 95% CI 1.20-3.67) and highest after > 10years (HR 3.70, 95% CI 1.77-7.73). Similarly, HRs increased with cumulative dose, with higher estimates for ≥ 100,000mg (HR 4.96, 95% CI 2.51-9.81). In contrast, hydrochlorothiazide was not associated with an increased risk of BCC (HR 1.01, 95% CI 0.91-1.13) or melanoma (HR 0.82, 95% CI 0.63-1.08), with no evidence of duration- or dose-response relationships. Use of hydrochlorothiazide was associated with an increased risk of cSCC and with evidence of a duration- and dose-response relationship. In contrast, no association was observed for BCC or melanoma.

The Associations of Aspirin, Statins, and Metformin With Lung Cancer Risk and Related Mortality: A Time-Dependent Analysis of Population-Based Nationally Representative Data

The aim of this study was to investigate the associations of aspirin, metformin, and statins with lung cancer risk and mortality using population-based nationwide cohort data. This study included a total of 732,199 participants who underwent a national health check-up from 2002 to 2003. Lung cancer incidence and mortality were identified using a registered lung cancer diagnosis code (International Classification of Diseases, 10th revision, code C34) and the Korean National Death Registry. The study participants were followed up from January 1, 2004 to December 31, 2013. Medication exposure was defined by the cumulative duration of use and cumulative defined daily dose per 2-year interval. To avoid immortal-time bias, drug exposure was inserted as a time-dependent variable in Cox analysis, which evaluated the associations of these medications with lung cancer. Metformin use had a protective association with lung cancer incidence (p's for trend 0.008) and mortality (p's for trend < 0.001) in a dose-response fashion, and these associations were prominent among participants with a metformin cumulative defined daily dose of 547.5 and above compared with patients without diabetes. Lung cancer mortality was dose-dependently reduced with the use of aspirin (p's for trends 0.046) and statin (p's for trends < 0.001). The combined use of aspirin, statins, and metformin exhibited more prominent protective associations with lung cancer risk and mortality. The use of aspirin, metformin, and statins had independent protective associations with lung cancer mortality, and metformin had an inverse association with lung cancer risk. Further studies are necessary to develop clinically applicable anticancer strategies using these drugs for the reduction of lung cancer and related mortality.

Risk of fracture in patients with non-valvular atrial fibrillation initiating direct oral anticoagulants vs. vitamin K antagonists.

To determine the risk of fracture associated with direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF), accounting for cumulative duration of use. Using Quebec administrative healthcare databases, we formed a cohort of all patients aged 40 years or older newly diagnosed with NVAF, who filled a first prescription for DOACs or VKAs between 2011 and 2014. Exposure was modelled as a time-varying variable whereby patients were considered unexposed up to 180 days of cumulative duration of use (to account for a biologically meaningful exposure) and exposed thereafter. The final cohort included 10306 new users of DOACs and 15357 new users of VKAs. After propensity score-based fine stratification and weighting, use of DOACs for 180 days or greater was associated with a 35% decreased risk of fracture [crude incidence rates 7.5 vs. 15.3 per 1000 person-years; adjusted hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.46-0.91] compared to VKA duration ≥180 days. Direct oral anticoagulants use was also associated with a lower risk of hip fracture (HR 0.51, 95% CI 0.31-0.86) compared with VKAs. There was no difference in the rate of fracture for shorter duration of use (HR 1.10; 95% CI 0.79-1.53). The risk was not modified by age, sex, chronic kidney disease, osteoporosis, history of fracture or falls. Prolonged use of DOACs is associated with a lower risk of fracture compared with VKAs. These findings support the first-line recommendation for DOACs in patients with NVAF.

Statin use and lung cancer risk in chronic obstructive pulmonary disease patients: a population-based cohort study

BackgroundPatients living with chronic obstructive pulmonary disease (COPD) are at an increased risk of lung cancer. A common comorbidity of COPD is cardiovascular disease; as such, COPD patients often receive statins. This study sought to understand the association between statin exposure and lung cancer risk in a population-based cohort of COPD patients.MethodsWe identified a population-based cohort of COPD patients based on having filled at least three prescriptions for an anticholinergic or short-acting beta-agonist (SABA). We used an array of methods of defining medication exposure including three conventional methods (ever statin exposure, cumulative duration of use, and cumulative dose) and two novel methods (recency-weighted cumulative duration of use and recency-weighted cumulative dose). To assess residual confounding, a negative control exposure was used to test the validity of our results. All exposure variables were time-dependent.ResultsThe population-based cohort of COPD had 39,879 patients with mean age of 70.6 (SD: 11.2) years and, of which, 53.5% were female. There were 12,469 patients who received at least one statin prescription. Results from the reference case multivariable analysis indicated a reduced risk from statin exposure (HR: 0.85 (95% CI: 0.73–1.00) in COPD patients, but this result not statistically significant. Using the two recency-weighted modelling approaches, statin exposure was associated with a statistically significant reduction in lung cancer risk (recency-weighted cumulative dose, HR: 0.85 (95% CI: 0.77–0.93) and recency-weighted cumulative duration of use, HR: 0.97 (95% CI: 0.96–0.99). Multivariable analysis incorporating the negative control exposure was not statistically significant (HR: 0.89 (95% CI: 0.75–1.10).ConclusionsThe results of this population-based analysis indicate that statin use in COPD patients may reduce the risk of lung cancer. While the effect was not statistically significantly across all exposure definitions, the overall results support the hypothesis that COPD patients might benefit from statin therapy.

Incretin-based drugs and risk of lung cancer among individuals with type 2 diabetes.

To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships. In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Similar Breast Cancer Risk in Women Older Than 65 Years Initiating Glargine, Detemir, and NPH Insulins.

To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes. This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time. Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88-1.06) or detemir (HR 0.98; 95% CI 0.92-1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users. Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.