Use of 5-alpha reductase inhibitors and risk of gastrointestinal cancers in men with benign prostatic hyperplasia: A population-based cohort study.

Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.

Sodium-glucose cotransporter-2 inhibitors and the risk of lung cancer among patients with type 2 diabetes.

We sought to determine whether the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of incident lung cancers among patients with type 2 diabetes. We assembled a new-user, active comparator cohort of SGLT-2 inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor users using the United Kingdom Clinical Practice Research Datalink. We fit Cox proportional hazards models with propensity score fine stratification weighting to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident lung cancer. Crude incidence rates were 0.94 per 1000 person-years among 69 675 SGLT-2 inhibitor users followed for a median of 2.4 years and 1.45 per 1000 person-years among 151 495 DPP-4 inhibitor users followed for a median of 3.7 years. No reduced short-term risk of lung cancer was observed among SGLT-2 inhibitor users after weighting (HR 0.96, 95% CI 0.77-1.21). Further research with a longer follow-up period may be warranted.

Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

Thiazide Diuretics and Risk of Colorectal Cancer: A Population-Based Cohort Study.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

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

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

INTRODUCTION: The 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 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 non-melanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs of melanoma and non-melanoma 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 to 0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84 to 1.54; 2.1-5 years HR 0.44, 95% CI 0.29 to 0.66; >5 years HR 0.33, 95% CI 0.14 to 0.74). In contrast, these drugs were not associated with the incidence of non-melanoma skin cancer, compared with sulfonylureas (448.1 vs 426.1 per 100 000 person-years, respectively; HR 1.06, 95% CI 0.98 to 1.15). CONCLUSIONS: In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not non-melanoma skin cancer, compared with sulfonylureas.

The Cardiovascular Safety of Five-Alpha-Reductase Inhibitors Among Men with Benign Prostatic Hyperplasia: A Population-Based Cohort Study.

BACKGROUND: Five-alpha reductase inhibitors (5αRIs) are used to treat benign prostatic hyperplasia (BPH). However, the cardiovascular effects of 5αRIs remain poorly understood. The study objective was to compare the rate of hospitalization for heart failure among men with BPH prescribed 5αRIs to that of men with BPH not prescribed BPH medications. METHODS: Using the Clinical Practice Research Datalink linked with hospitalization and vital statistics data, we conducted a population-based cohort study among patients newly diagnosed with BPH. We defined exposure as the current use of 5αRIs, current use of alpha-blockers, and no current use of BPH medications in a time-varying approach. The primary endpoint was hospitalization for heart failure, and secondary endpoints were myocardial infarction, stroke, and cardiovascular death. We used time-dependent Cox-proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Our cohort included 94,440 men with incident BPH. A total of 3893 hospitalizations for heart failure occurred over 527,660 person-years of follow-up (incidence rate 7.38; 95% CI, 7.15-7.61, per 1000 person-years). Compared with no current use of BPH medications, current use of 5αRIs was not associated with an increased risk of hospitalization for heart failure (HR 0.94; 95% CI, 0.86-1.03), myocardial infarction (HR 0.92; 95% CI, 0.81-1.05), stroke (HR 0.94; 95% CI, 0.85-1.05), or cardiovascular death (HR 0.89; 95% CI, 0.80-0.99). CONCLUSIONS: The use of 5αRIs was not associated with an increased risk of hospitalization for heart failure, myocardial infarction, stroke, or cardiovascular death compared with non-use.

The application of lag times in cancer pharmacoepidemiology: a narrative review.

PURPOSE: With the increasing utilization of medications worldwide, coupled with the increasing availability of long-term data, there is a growing opportunity and need for robust studies evaluating drug-cancer associations. One methodology of importance in such studies is the application of lag times. METHODS: In this narrative review, we discuss the main reasons for using lag times. RESULTS: Namely, we discuss the typically long latency period of cancer concerning both tumor promoter and initiator effects and outline why cancer latency is a key consideration when choosing a lag time. We also discuss how the use of lag times can help reduce protopathic and detection bias. Finally, we present practical advice for implementing lag periods. CONCLUSIONS: In general, we recommend that researchers consider the information that generated the hypothesis as well as clinical and biological knowledge to inform lag period selection. In addition, given that latency periods are usually unknown, we also advocate that researchers examine multiple lag periods in sensitivity analyses as well as duration analyses and flexible modeling approaches.

Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study.

BACKGROUND: The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial. OBJECTIVE: To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors and calcium channel blockers. METHODS: Two new-user, active comparator cohorts were assembled using 6 Canadian databases. Site-specific hazard ratios (HRs) with 95% CIs were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis. RESULTS: HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with angiotensin-converting enzyme inhibitors or calcium channel blockers, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with angiotensin-converting enzyme inhibitors, but a 32% increased risk with calcium channel blockers (crude incidence rates: 64.2 vs 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1627 patients), with increased risks with longer durations and cumulative doses. LIMITATIONS: Residual confounding due to the observational design. CONCLUSIONS: Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ.

5α-Reductase Inhibitors and Risk of Kidney and Bladder Cancers in Men with Benign Prostatic Hyperplasia: A Population-Based Cohort Study.

BACKGROUND: Preclinical evidence suggests that 5α-reductase inhibitors (5ARi), commonly used to treat benign prostatic hyperplasia (BPH), are associated with reduced incidence of certain urologic cancers, yet epidemiologic studies are conflicting. This study aimed to determine whether 5ARi's are associated with a reduced risk of kidney and bladder cancers. METHODS: We conducted a new-user active-comparator cohort study in the United Kingdom Clinical Practice Research Datalink. From a base cohort of patients with incident BPH, new users of 5ARi's and α-blockers were identified. Patients were followed up until a first ever diagnosis of kidney or bladder cancer, death from any cause, end of registration, or December 31, 2017. Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI) for incident kidney and bladder cancer. RESULTS: There were 5,414 and 37,681 new users of 5ARi's and α-blockers, respectively. During a mean follow-up of 6.3 years, we found no association between the use of 5ARi's and kidney (adjusted HR, 1.26; 95% CI, 0.74-2.12; n = 23) or bladder (adjusted HR, 0.89; 95% CI, 0.64-1.23; n = 57) cancer risk compared with α-blockers. Similar results were observed across sensitivity analyses. CONCLUSIONS: In this study, we found no association between the use of 5ARi's and kidney or bladder cancer incidence in men with BPH when compared with α-blocker use. IMPACT: The findings of this study indicate that 5ARi's are unlikely to reduce kidney or bladder cancer risk.

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.

Sodium-Glucose Cotransporter 2 Inhibitors and the Short-term Risk of Bladder Cancer: An International Multisite Cohort Study.

OBJECTIVE: To determine whether sodium-glucose cotransporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide 1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase 4 (DPP-4) inhibitors, are associated with an increased risk of early bladder cancer events. RESEARCH DESIGN AND METHODS: We conducted a multisite, population-based, new-user, active comparator cohort study using the U.K. Clinical Practice Research Datalink, Medicare fee-for-service, Optum's de-identifed Clinformatics Data Mart Database (CDM), and MarketScan Health databases from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating 1) SGLT2 inhibitors or GLP-1RAs and 2) SGLT2 inhibitors or DPP-4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% CIs of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models. RESULTS: SGLT2 inhibitor (n = 453,560) and GLP-1RA (n = 375,997) users had a median follow-up ranging from 1.5 to 2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer compared with GLP-1RAs (HR 0.90, 95% CI 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n = 853,186), SGLT2 inhibitors (n = 347,059) were not associated with an increased risk of bladder cancer (HR 0.99, 95% CI 0.91-1.09) over a median follow-up ranging from 1.6 to 2.6 years. Results were consistent across sensitivity analyses. CONCLUSIONS: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer compared with GLP-1RAs or DPP-4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence.

Incretin-Based Drugs and the Risk of Acute Liver Injury Among Patients With Type 2 Diabetes.

OBJECTIVE: To determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors. RESEARCH DESIGN AND METHODS: We used the U.K. Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active-comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9,470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% CIs of acute liver injury. RESULTS: Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR 1.53, 95% CI 1.02-2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR 1.11, 95% CI 0.57-2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR 3.22, 95% CI 1.67-6.21) and GLP-1 RAs (HR 3.23, 95% CI 1.44-7.25). CONCLUSIONS: In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users.

Menopausal Hormone Therapy Formulation and Breast Cancer Risk.

OBJECTIVE: To evaluate whether the increased risk of breast cancer is dependent on the formulation of menopausal hormone therapy (HT) used. METHODS: We performed a population-based case-control study of women aged 50 years or older using data from the U.K. Clinical Practice Research Datalink. Women with incident cases of breast cancer were age-matched (1:10) with a control group of women with comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following menopausal HT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of menopausal HT formulation on breast cancer risk. RESULTS: Between 1995 and 2014, 43,183 cases of breast cancer were identified and matched to 431,830 women in a control group. In adjusted analyses, compared with women who never used menopausal HT, its use was associated with an increased risk of breast cancer (odds ratio [OR] 1.12, 95% CI 1.09-1.15). Compared with never users, estrogens were not associated with breast cancer (bioidentical estrogens: OR 1.04, 95% CI 1.00-1.09; animal-derived estrogens: OR 1.01, 95% CI 0.96-1.06; both: OR 0.96, 95% CI 0.89-1.03). Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: OR 0.99, 95% CI 0.55-1.79; synthetic progestin: OR 1.28, 95% CI 1.22-1.35; both OR 1.31, 0.30-5.73). CONCLUSION: Although menopausal HT use appears to be associated with an overall increased risk of breast cancer, this risk appears predominantly mediated through formulations containing synthetic progestins. When prescribing menopausal HT, micronized progesterone may be the safer progestogen to be used.

Rationale, Strengths, and Limitations of Real-World Evidence in Oncology: A Canadian Review and Perspective.

Randomized controlled trials (RCTs) continue to be the basis for essential evidence regarding the efficacy of interventions such as cancer therapies. Limitations associated with RCT designs, including selective study populations, strict treatment regimens, and being time-limited, mean they do not provide complete information about an intervention's safety or the applicability of the trial's results to a wider range of patients seen in real-world clinical practice. For example, recent data from Alberta showed that almost 40% of patients in the province's cancer registry would be trial-ineligible per common exclusion criteria. Real-world evidence (RWE) offers an opportunity to complement the RCT evidence base with this kind of information about safety and about use in wider patient populations. It is also increasingly recognized for being able to provide information about an intervention's effectiveness and is considered by regulators as an important component of the evidence base in drug approvals. Here, we examine the limitations of RCTs in oncology research, review the different types of RWE available in this area, and discuss the strengths and limitations of RWE for complementing RCT oncology data.

Aromatase inhibitors and the incidence of Parkinson disease: A population-based cohort study.

BACKGROUND: Current guidelines recommend the treatment of hormone receptor-positive breast cancer with aromatase inhibitors (AIs) and tamoxifen in the adjuvant setting. Some observational studies have raised concerns that tamoxifen may be associated with an increased risk of Parkinson disease (PD). However, no studies have directly compared the risk of PD between AIs and tamoxifen in women diagnosed with breast cancer. METHODS: Using the UK Clinical Practice Research Datalink, the authors assembled a cohort of women newly diagnosed with breast cancer and newly treated with either AIs or tamoxifen between January 1, 1995, and December 31, 2017. Patients were followed 1 year after treatment initiation (ie, a 1-year lag) until an incident diagnosis of PD or were censored at death from any cause, the date of transfer out of the practice, or the end of the study period (December 31, 2018). Cox proportional hazards models with inverse probability of treatment weights were used to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for PD comparing AIs with tamoxifen and accounting for more than 30 confounders. RESULTS: In all, 30,140 women with nonmetastatic breast cancer were identified: 13,838 initiated AIs, and 16,302 initiated tamoxifen. Compared with tamoxifen, AIs were not associated with an increased risk of PD (HR, 0.94; 95% CI, 0.60-1.47). Consistent results were observed across all secondary and sensitivity analyses. CONCLUSIONS: In this large observational study, the use of AIs, in comparison with tamoxifen, was not associated with an increased risk of PD in women diagnosed with nonmetastatic breast cancer in a real-world setting. LAY SUMMARY: Previous studies have indicated that tamoxifen may increase the risk of Parkinson disease in the treatment of breast cancer. However, no studies have directly compared the risk of Parkinson disease between aromatase inhibitors and tamoxifen. This study included 30,140 women diagnosed with breast cancer and treated with aromatase inhibitors or tamoxifen. Overall, compared with tamoxifen, aromatase inhibitors were not associated with an increased risk of Parkinson disease in women diagnosed with breast cancer. This study provides an important addition to the comparative safety profile of aromatase inhibitors and tamoxifen in the treatment of breast cancer.

Incretin-Based Drugs and the Incidence of Prostate Cancer Among Patients With Type 2 Diabetes.

BACKGROUND: There is some evidence that glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have chemopreventive effects on prostate cancer cells but real-world evidence for this possible effect is lacking. Thus, the objective of this study was to estimate whether use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, is associated with a decreased risk of prostate cancer among patients with type 2 diabetes. METHODS: We assembled two new-user, active-comparator cohorts using the UK Clinical Practice Research Datalink (2007 to 2019). The first cohort included 5,063 initiators of GLP-1 receptor agonists and 112,955 of sulfonylureas. The second cohort included 53,529 initiators of DPP-4 inhibitors and 114,417 of sulfonylureas. We fit Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer. We weighted the models using propensity score fine stratification, which considered over 50 potential confounders. RESULTS: GLP-1 receptor agonists were associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 156.4 vs. 232.0 per 100,000 person-years, respectively; HR = 0.65; 95% CI = 0.43, 0.99). DPP-4 inhibitors were also associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 316.2 vs. 350.5 events per 100,000 person-years, respectively; HR = 0.90; 95% CI = 0.81, 1.00). CONCLUSIONS: The results of this study are consistent with the hypothesis that the use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, may decrease the risk of prostate cancer when compared with the use of sulfonylureas.

Long-Term patterns of cancer incidence among patients with and without type 2 diabetes in the United Kingdom.

AIMS: Studies using contemporary cohorts are needed to assess the association between type 2 diabetes and cancer. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we matched patients with type 2 diabetes between 1988 and 2019 to patients without type 2 diabetes. Poisson regression models were fit to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for cancer. In secondary analyses, we determined whether the strength of the association varied with calendar time and whether patients with type 2 diabetes had a higher incidence of being diagnosed with multiple cancers during the follow-up period. RESULTS: 890,214 patients with type 2 diabetes were matched to an equal number of patients without type 2 diabetes. Patients with type 2 diabetes had a higher cancer incidence than patients without type 2 diabetes (IRR 1.19, 95% CI 1.18-1.21). The IRR was higher 2010 onwards (IRR: 1.25, 95% CI: 1.23-1.28) compared with the association in previous years. Overall, patients with type 2 diabetes had a 5% higher incidence of being diagnosed with multiple cancers (IRR: 1.05, 95% CI: 1.04-1.07). CONCLUSIONS: The results of this large population-based study indicate that type 2 diabetes is associated with an increased risk of several cancers.