Dipeptidyl peptidase-4 inhibitors and mortality risks in patients with prostate cancer receiving androgen deprivation therapy: a population-based cohort study

doi:10.21203/rs.3.rs-2070021/v1

Background

Dipeptidyl peptidase-4 inhibitors (DPP-4I) have demonstrated survival benefit in patients with cancer, but their impact on patients with prostate cancer (PCa), especially with androgen deprivation therapy (ADT), is unclear. This study examined the impact of DPP-4I use on mortality risks in patients with type 2 diabetes (T2D) and PCa receiving ADT.

Methods

Adults with T2D and PCa who received metformin and ADT attending public hospitals in Hong Kong between 1 January 2006 and 31 March 2021 were retrospectively identified. Patients with < 6 months of chemical castration without bilateral orchidectomy, < 6 months of concurrent DPP-4I and ADT use, or missing baseline HbA1c were excluded. DPP-4I users had ≥ 6 months of concurrent DPP-4I and ADT use, while non-users never had DPP-4I use. Included patients were followed-up until 30 September 2021. The endpoints were PCa-specific mortality and all-cause mortality. Inverse probability treatment weighting was used to balance covariates.

Results

In total, 1465 patients (286 DPP-4I users and 1179 non-users; mean age 76.0 ± 7.9 years old) were analyzed. Over a mean follow-up of 4.0 ± 3.0 years, DPP-4I users had lower risks of PCa-specific mortality (weighted hazard ratio (wHR) 0.40 [95% confidence interval (CI) 0.26–0.59], p < 0.001) and all-cause mortality (wHR 0.59 [95% CI 0.48–0.73], p < 0.001). Such associations were independent of diabetic control. Moreover, the association between DPP-4I use and risks of PCa-specific mortality was independent of chemotherapy or androgen receptor signaling inhibitor use.

Conclusions

DPP-4I use is associated with decreased mortality risks in patients with T2D and PCa receiving ADT.

Dipeptidyl peptidase-4 (DPP-4) is a multi-functional protein found in many types of cells, playing a role in chemokine signaling, immunoregulation, and glucose homeostasis [1–3]. In 2006, DPP-4 inhibitors (DPP-4I) were introduced for the treatment of type 2 diabetes (T2D). As they have low hypoglycemia risks and favorable safety profiles, DPP-4I are increasingly replacing sulfonylureas as second-line therapy after metformin failure, and many metformin/DPP-4I combinations are available [4].

DPP-4 may also be involved in cancer biology, functioning as a tumor suppressor or activator depending on the cancer type [3]. It is expressed in various primary tumors and metastases such as mesothelioma, renal cell carcinoma, and colorectal, lung, and prostate cancer (PCa) [5], with higher levels being associated with cancer progression and tumor malignant behavior [1–3, 6]. In colorectal, lung, head, and neck tumors, survival benefit was consistently shown with DPP-4I use [7, 8].

However, there is discrepancy in relation to the impact on survival of DPP-4I use in PCa [9, 10]. Furthermore, the interplay between DPP-4I and the androgen receptor is still in question. One of the mainstays of treatment in advanced and metastatic PCa is androgen deprivation therapy (ADT). Recently, it was shown that androgen receptor activity persists when DPP-4 is downregulated, thus the inhibition of DPP-4 may provide a resistance mechanism to ADT in patients with metastatic PCa [11]. Therefore, it is important to explore if the survival benefit of DPP-4I use is applicable in patients with PCa receiving ADT. In this study, we examined the impact of DPP-4I use on mortality risks in patients with T2D and PCa receiving ADT.

This retrospective cohort study was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee and conducted in accordance with the Declaration of Helsinki and STROBE guideline. Patient consent was waived as deidentified data were used. All data underlying this study is available upon reasonable request to the corresponding author.

Source of data

All data were retrieved from the Clinical Data Analysis and Reporting System (CDARS), a population-based electronic database of all patients attending public healthcare institutions in Hong Kong. All diagnoses are coded by International Classification of Diseases, Ninth Revision (ICD-9) codes. CDARS is linked to the Hong Kong Death Registry, a population-wide governmental registry of all Hong Kong citizens’ death records, from which mortality data may be obtained. Causes of mortality were encoded using ICD-9 or ICD-10, depending on the year of death. This system has been used extensively for research [12–14].

Study design and population

Adult patients (18 years old or above) diagnosed with PCa and T2D, who were receiving ADT in Hong Kong between 1 January 2006 and 31 March 2021 were included. As metformin use has consistently shown survival benefit in men with T2D and PCa [15], we only included patients who received metformin to evaluate the impact of DPP-4I use beyond that possibly provided by metformin. Diagnoses of PCa and T2D were determined by ICD-9 codes (Supplementary Table 1), and that of T2D was further determined by any baseline use of antidiabetic medication or baseline HbA1c level higher than 6.5%. ADT included bilateral orchidectomy, gonadotrophin-releasing hormone agonists, and gonadotrophin-releasing hormone antagonists.

The following patients were excluded: (a) with less than six months of chemical castration without bilateral orchidectomy, (b) with less than six months of concurrent DPP-4I use and ADT, or (c) with missing baseline HbA1c value.

DPP-4I users were defined as patients who had at least six months of concurrent DPP-4I use and ADT. DPP-4I non-users were defined as patients who never had DPP-4I use.

Follow-up and outcomes

All patients were followed-up from the day of ADT initiation (baseline date) until 30 September 2021. The primary outcome was PCa-specific mortality. The secondary outcome was all-cause mortality. The duration between ADT initiation and mortality was recorded. All death causes were indicated by ICD codes (Supplementary Table 2).

Covariates

All patients’ age, other comorbidities at baseline as determined by ICD-9 codes (Supplementary Table 1), type of ADT received, duration of ADT, duration of metformin use, use of other medications, use of other treatments of PCa (radical prostatectomy, radiotherapy, and chemotherapy), and HbA1c level at baseline were recorded. The list of medications used were summarized in Supplementary Table 3.

Subgroup analyses

An a priori subgroup analysis was performed for the use of chemotherapy or androgen receptor signaling inhibitors (abiraterone, enzalutamide), usual treatments for metastatic PCa, to explore whether the associations between DPP-4I use and mortality risks would apply to metastatic PCa. Furthermore, to examine the interactions between DPP-4I’s associations with mortality risks and diabetic control, a priori subgroup analyses were performed for baseline insulin use and baseline HbA1c level (< 7%, ≥ 7%), with corresponding p-values for interaction generated. HbA1c level of 7% was used as the cut-off point because the Hong Kong Reference Framework for Diabetes Care in Primary Care Settings and global guidelines recommend the target HbA1c level of < 7% for most patients with T2D [16, 17].

Sensitivity analysis

To investigate whether DPP-4I use at the time of ADT initiation had any effect on the observed results, a sensitivity analysis was performed where patients who were not using DPP-4I at the time of ADT initiation were excluded from the DPP-4I user group, such that only DPP-4I users who had DPP-4I use at the time of ADT initiation were compared against patients who never used DPP-4I.

Statistical analyses

Continuous variables were expressed as mean ± standard deviation. Inverse probability treatment weighting (IPTW) using the aforementioned covariates was used to balance the treatment groups. The propensity scores were constructed using a generalized boosted model with a maximum of 5,000 regression trees and an iteration stopping point that minimized the absolute standardized mean difference (SMD) of the mean effect size. SMD were calculated for each covariate to examine the balance of covariates between treatment groups, with values ≤ 0.2 being considered to represent good balance.

The proportional hazards assumption was kept as evaluated using Schoenfield residuals. IPTW-univariable Cox regression was used to assess the associations of DPP-4I treatment with the risks of outcomes. Weighted hazard ratios (wHR) with 95% confidence intervals (CI) were used as the summary statistics. Kaplan-Meier curves were used to visualize the cumulative freedom from the outcomes.

All p-values were two-sided, with values less than 0.05 considered statistically significant. All statistical analyses were performed on Stata (version 16.1, StataCorp LLC, USA).

In total, 10,394 patients were eligible for inclusion. After applying the exclusion criteria, 1,465 patients (mean age 76.0±7.9 years old) were included in the final analysis (Figure 1), of whom 286 were DPP-4I users and 1,179 were non-users. Among those who received chemical castration only, the mean duration of treatment was 3.0±2.4 years. Baseline characteristics of included patients were summarized in Table 1, which also demonstrates good balance of all covariates by IPTW (SMD ≤0.2 for all).

Over a mean follow-up duration of 4.0±3.0 years, 355 patients (24.2%) had PCa-specific mortality, and 873 (60.0%) had all-cause mortality. Overall, DPP-4I users had significantly lower risks of PCa-specific mortality (wHR 0.40 [95% CI 0.26, 0.59], p<0.001; Figure 2) and all-cause mortality (wHR 0.59 [95% CI 0.48, 0.73], p<0.001; Figure 3).

Subgroup analyses

Among patients with or without chemotherapy or androgen receptor signaling inhibitor use (n=287 and n=1,178, respectively), DPP-4I users had significantly lower risks of PCa-specific mortality (p-value for interaction=0.629; Table 2), while only DPP-4I users without chemotherapy or androgen receptor signaling inhibitor use had significantly lower risks of all-cause mortality (p-value for interaction=0.164). This may suggest that the survival benefits associated with DPP-4I use are consistent regardless of metastatic disease or not and are exerted in this population through mostly antitumour properties.

Among both insulin users (n=367) and non-users (n=1,098) (Supplementary Table 4), DPP-4I users had significantly lower risks of PCa-specific mortality (p-value for interaction=0.996) and all-cause mortality (p-value for interaction=0.168). Similarly, among both patients with baseline HbA1c level <7% (n=843) and ≥7% (n=622), DPP-4I users had significantly lower risks of PCa-specific mortality (p-value for interaction=0.699) and all-cause mortality (p-value for interaction=0.654), as summarized in Supplementary Table 5. These suggested that baseline diabetic control did not affect the observed associations between DPP-4I use and risks of outcomes.

Sensitivity analyses

DPP-4I use remained associated with significantly lower risks of all outcomes when only DPP-4I users who had DPP-4I use at the time of ADT initiation were compared against patients who never used DPP-4I (N=1,336; p<0.001 for all; Supplementary Table 6). This suggested that the aforementioned associations were not confounded by DPP-4I use at the time of ADT initiation.

By using a population-based database, we showed that patients with PCa receiving ADT in the metformin and DPP-4I combination group had significantly lower mortality risks compared to those in the metformin group. Such associations were independent of diabetic control. Moreover, the association between DPP-4I use and risks of PCa-specific mortality was independent of chemotherapy or androgen receptor signaling inhibitor use.

Potential mechanisms

While the precise role of DPP-4 in tumor biology is unclear, there are several proposed mechanisms. DPP-4 increases secretion of cytotoxic granzymes such as tumour necrosis factor-α, interferon-γ, and FAS-ligand through the activation of resting T cells, costimulatory effects on T cells, and signal transduction [18]. Moreover, DPP-4 cleaves N-terminal dipeptides from cytokines involved in the regulation of immune system, altering their chemotactic potency, impairing their signaling effects, and modifying their receptor specificity [19]. Furthermore, DPP-4 biochemical activity is twice as high in PCa compared to benign prostate hyperplasia tissues. DPP-4 activity is also increased in benign prostate hyperplasia glands associated with PCa [20]. In addition, a high expression of DPP-4 was associated with poor prognosis in a study of PCa tissue samples [21]. Complementing the aforementioned is the expression profile of DPP-4. Antibody staining showed that PCa displayed moderate to strong positivity to antibody to DPP-4, while most other cancers did not [22]. Taken all together, DPP-4I could have improved survival in patients with PCa in our analysis through immune modulation and antitumor activity. In our analysis, the lower risks of PCa-specific mortality associated with DPP-4I use was independent of chemotherapy or androgen receptor signaling inhibitor use. This may imply that the anti-cancer activity of DPP-4I is consistent regardless of metastatic disease or not. DPP-4 has a role in metastasis because of its intrinsic peptidase activity and ability to bind key molecules. As a receptor for plasminogen 2ϵ, DPP-4 can upregulate the expression of matrix metalloproteinase-9, which is responsible for the degradation of the extracellular matrix, allowing cancer invasion and metastasis [23, 24]. Another way DPP-4 assists in metastasis is through fibroblast activation protein-α, activating signals that lead to various effects, such as forming invadopodia-like protrusions with matrix metalloproteinase activation [25] and suppressing antitumor immunity [26]. Moreover, through binding extracellular matrix proteins, collagen, and fibronectin, DPP-4 can directly promote tumor invasion [2, 27]. Additionally, DPP-4 could increase susceptibility to metastasis by cleaving CXCL10 and CXCL12, ligands that assist in lymphocyte chemotaxis and migration necessary for tumor immune surveillance [28, 29].

Prior studies and future directions

Prior studies that investigated the link between DPP-4I exposure and PCa outcomes present a mixed picture. A multi-center retrospective analysis found that DPP-4I use compared to metformin use did not show a significant progression-free survival benefit in advanced-stage PCa [9]. However, it was limited by a small sample size of DPP-4I users (n = 41), while our study is better powered. Meanwhile, another study showed that patients with PCa on DPP-4I had better survival compared to those who were not on DPP-4I, with the benefit independent of metformin [10]. Nonetheless, it only showed the survival benefits of metformin and metformin/DPP-4I combination groups in patients with PCa without comparing them. To the best of our knowledge, our study is the first to directly compare the two treatment groups in PCa, suggesting possibly synergistic survival benefits of DPP-4I and metformin. Indeed, the use of metformin has been associated with lower risks of new-onset PCa [12], but its interacting effects with DPP-4I on mortality in patients with established PCa need to be investigated in the future. Further in vivo experiments are needed to definitively establish if there is any synergistic activity of these two drugs in treatment of PcC. Moreover, the effects of glycemic control were not thoroughly accounted for by Shah et al. Recognizing the bias that differences in glycemic control may bring about, our study balanced HbA1c level between the two treatment groups and further observed that the survival advantage of DPP-4I use is independent of HbA1c level and insulin use. Given DPP-4’s role in tumor biology, it may be a novel therapeutic target in cancer therapy. Both in vitro and in vivo studies showed that anti-DPP-4 monoclonal antibody IF7 inhibits the growth of 1 T-cell lymphoma [30]. Additionally, the first in human phase I clinical trial of humanized anti-DPP-4 monoclonal antibody YS110 reported prolonged disease stabilization with good drug tolerance in patients with mesothelioma [5]. Based on studies conducted on anti-DPP-4 monoclonal antibodies, our findings should further prompt clinicians to study the use of DPP-4I as an adjunct therapy in prostate cancer. Moreover, our data may aid providers in choosing among various antidiabetic medications given the high prevalence of PCa. Further interest in the impact of antidiabetic medications on PCa should be considered in terms of optimization of T2D treatment among patients with PCa concerning the metabolic effect of ADT and their possible use in the management of PCa in patients without T2D. Although prospective trials are needed to confirm our findings, retrospective data may aid in shared decision-making.

Strengths and limitations

To the best of our knowledge, our study is the first to evaluate the impact of DPP-4I use on mortality risks in patients with PCa in an ADT setting. This study used a representative population-based database with long follow-up duration. Our results are thus likely to be widely generalizable and reflect real-world practice. Sensitivity analysis was performed showing consistent results, indicating robustness. However, several limitations should be noted. Firstly, as an observational study, residual confounding cannot be excluded. Secondly, cancer staging details were unavailable due to the nature of the data. We addressed this by using chemotherapy or androgen receptor signaling inhibitors as the surrogate for metastatic PCa. Lastly, since all diagnoses were identified using ICD-9 codes as recorded by CDARS, the data could not be adjudicated individually. Nonetheless, all diagnostic codes were input by treating clinicians independent of the authors, and previous studies of CDARS have shown good coding accuracy [31].

DPP-4I use concurrent with ADT in patients with T2D and PCa was associated with significantly lower risks of PCa-specific mortality and all-cause mortality. Such associations were independent of metformin use and diabetic control. Moreover, the association between DPP-4I use and risks of PCa-specific mortality was independent of chemotherapy or androgen receptor signaling inhibitor use. Prospective trials are necessary to confirm these findings.

Conflicts of interest: ECD is funded in part through the Cancer Center Support Grant from the National Cancer Institute (P30 CA008748). All other authors have no conflict of interest to report.

Ethics approval: This study was performed in accordance with the Declaration of Helsinki, and has been approved by the Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee.

Data availability: All data underlying this study are available on reasonable request to the corresponding authors.

Sources of funding: None.

Authorship:

JMHH: conceptualization, methodology, data curation, formal analysis, visualization, writing – original draft, writing – review and editing

YHAL: conceptualization, methodology, data curation, writing – original draft, writing – review and editing

SSYL, KL: investigation, data curation, writing – review and editing

ECD, KN, JSKC: methodology, supervision, writing – review and editing

GT, CFN: supervision, project administration, resources, writing – review and editing

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Table 1. Baseline characteristics with standardized mean differences (SMD) before and after inverse probability treatment weighting (IPTW).

	DPP-4I users (n= 286)	DPP-4I non-users (n= 1,179)	Unweighted SMD	SMD with IPTW
Age, years	75.0±7.6	76.2±7.9	0.16	0.05
Use of GnRH agonist or antagonist, n (%)	224 (78.3)	773 (65.6)	0.27	0.08
Bilateral orchidectomy, n (%)	106 (37.1)	544 (46.1)	0.18	0.04
ADT duration, years	5.0±3.3	5.5±4.3	0.10	0.03
Hypertension, n (%)	155 (54.2)	559 (47.4)	0.14	0.07
Ischaemic heart disease, n (%)	65 (22.7)	220 (18.7)	0.10	0.04
Myocardial infarction, n (%)	17 (5.9)	52 (4.4)	0.07	0.01
Heart failure, n (%)	27 (9.4)	105 (8.9)	0.02	0.04
Stroke, n (%)	41 (14.3)	162 (13.7)	0.02	0.01
Chronic kidney disease, n (%)	28 (9.8)	60 (5.1)	0.30	0.06
Anaemia, n (%)	24 (8.4)	134 (11.4)	0.10	0.09
Atrial fibrillation, n (%)	23 (8.0)	79 (6.7)	0.05	0.10
Chronic liver disease, n (%)	13 (4.5)	23 (2.0)	0.17	0.04
Chronic obstructive pulmonary disease, n (%)	6 (2.1)	54 (4.6)	0.13	0.06
Any malignancy, n (%)	22 (7.7)	174 (14.8)	0.21	0.11
Hyperlipidaemia, n (%)	67 (23.4)	260 (22.1)	0.03	0.03
Ever underwent radical prostatectomy, n (%)	71 (24.8)	392 (33.2)	0.18	0.10
Ever underwent radiotherapy, n (%)	39 (13.6)	210 (17.8)	0.07	0.06
Ever underwent chemotherapy, n (%)	39 (13.6)	123 (10.4)	0.10	0.10
Androgen receptor antagonist use, n (%)	161 (56.3)	485 (41.1)	0.31	0.11
ACEI/ARB use, n (%)	202 (70.6)	732 (62.1)	0.18	0.13
Beta blocker use, n (%)	150 (52.4)	553 (46.9)	0.11	0.04
Dihydropyridine calcium channel blocker use, n (%)	191 (66.8)	797 (67.6)	0.02	0.13
Metformin duration, years	12.1±5.4	7.9±5.1	0.77	0.14
Sulphonylurea use, n (%)	245 (85.7)	729 (61.8)	0.51	0.14
GLP1RA use, n (%)	1 (0.3)	0 (0)	0.13	0.05
Insulin use, n (%)	92 (32.2)	275 (23.3)	0.20	0.05
Statin use, n (%)	192 (67.1)	729 (61.8)	0.11	0.02
Corticosteroid use, n (%)	51 (17.8)	207 (17.6)	0.01	0.14
Antiplatelet use, n (%)	117 (40.9)	440 (37.3)	0.07	0.09
Anticoagulant use, n (%)	21 (7.3)	62 (5.3)	0.09	0.10
HbA1c, %	7.5±1.4	6.9±1.2	0.50	0.06

ACEI, angiotensin-converting-enzyme inhibitors. ADT, androgen deprivation therapy. ARB, angiotensin II receptor blockers. DPP-4I, dipeptidyl peptidase-4 inhibitors. GLP1RA, glucagon-like peptide 1 receptor agonists. GnRH, gonadotropin-releasing hormone.

Table 2. Weighted comparisons of outcomes by DPP-4I use with subgroups for chemotherapy or androgen receptor signaling inhibitor use. Weighted hazard ratios (wHR) [95% confidence interval (CI)] were referenced against DPP-4I non-users.

	Chemotherapy or androgen receptor signaling inhibitor use (n=287)		No chemotherapy or androgen receptor signaling inhibitor use (n=1,178)		p-value for interaction
	wHR [95% CI]	p-value	wHR [95% CI]	p-value	p-value for interaction
Prostate cancer-specific mortality	0.43 [0.24-0.78]	0.005	0.36 [0.21-0.63]	<0.001	0.629
All-cause mortality	0.79 [0.51-1.22]	0.287	0.54 [0.43-0.69]	<0.001	0.164

DPP-4I, dipeptidyl peptidase-4 inhibitors.

Yes there is potential conflict of interest.

Dipeptidyl peptidase-4 inhibitors and mortality risks in patients with prostate cancer receiving androgen deprivation therapy: a population-based cohort study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Source of data

Study design and population

Follow-up and outcomes

Covariates

Subgroup analyses

Sensitivity analysis

Statistical analyses

Results

Discussion

Potential mechanisms

Prior studies and future directions

Strengths and limitations

Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1