CES2 Expression in Pancreatic Adenocarcinoma Is Predictive of Response to Irinotecan and Is Associated With Type 2 Diabetes

PURPOSE The combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has provided clinically meaningful improvement for pancreatic ductal adenocarcinoma (PDAC). We previously uncovered a role for the serine hydrolase carboxylesterase 2 (CES2) in mediating intratumoral activation of the prodrug irinotecan, a constituent of FOLFIRINOX. We aimed to further test the predictive value of CES2 for response to irinotecan using patient-derived xenograft (PDX) models and to elucidate the determinants of CES2 expression and response to FOLFIRINOX treatment among patients with PDAC. METHODS PDXs were engrafted subcutaneously into nude mice and treated for 4 weeks with either saline control or irinotecan. CES2 and hepatocyte nuclear factor 4 alpha (HNF4A) expression in PDAC tissues was evaluated by immunohistochemical and Western blot analysis. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and hemoglobin A1C (HbA1C) levels in patients who underwent neoadjuvant FOLFIRINOX treatment. RESULTS High CES2 activity in PDAC PDXs was associated with increased sensitivity to irinotecan. Integrated gene expression, proteomic analyses, and in vitro genetic experiments revealed that nuclear receptor HNF4A, which is upregulated in diabetes, is the upstream transcriptional regulator of CES2 expression. Elevated CES2 protein expression in PDAC tissues was positively associated with a history of type 2 diabetes (odds ratio, 4.84; P = .02). High HbA1C levels were associated with longer overall survival in patients who received neoadjuvant FOLFIRINOX treatment ( P = .04). CONCLUSION To our knowledge, we provide, for the first time, evidence that CES2 expression is associated with a history of type 2 diabetes in PDAC and that elevated HbA1C, by predicting tumor CES2 expression, may represent a novel marker for stratifying patients most likely to respond to FOLFIRINOX therapy.

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Gestational Diabetes Mellitus and the Risks of Overall and Type-Specific Cardiovascular Diseases: A Population- and Sibling-Matched Cohort Study

10.2337/figshare.16826482 ◽

2021 ◽

Author(s):

Yongfu Yu ◽

Melissa Soohoo ◽

Henrik Toft Sørensen ◽

Jiong Li ◽

Onyebuchi A. Arah

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cohort Study ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Cox Regression ◽

Maternal History ◽

History Of ◽

The Impact

OBJECTIVE To evaluate associations between gestational diabetes mellitus (GDM) and various incident cardiovascular disease (CVD) endpoints, considering the effects of mediating role of type 2 diabetes and shared environmental/familial factors. RESEARCH DESIGN AND METHODS This population-based cohort study included 1002486 parous women in Denmark during 1978-2016. We used Cox regression to (i) examine the associations of GDM with overall and type-specific CVDs using full-cohort and sibling-matched analysis; (ii) quantify the impact of type 2 diabetes after GDM using mediation analysis; and (iii) assess whether these associations were modified by pre-pregnancy obesity or maternal history of CVD. RESULTS Women with a history of GDM had a 40% increased overall CVD risk (hazard ratio [HR]: 1.40, 95% confidence interval [CI]: 1.35-1.45). Sibling-matched analyses yielded similar results(HR, 1.44; 95%CI, 1.28-1.62). Proportion of association between GDM and overall CVD explained by subsequent type 2 diabetes was 23.3%(15.4%-32.8%). We observed increased risks of specific CVDs, including 65% increased stroke risk and more than two-fold risks for myocardial infarction, heart failure, and peripheral artery disease. The elevated overall risks were more pronounced among women with GDM and pre-pregnancy obesity or maternal history of CVD. CONCLUSIONS A history of GDM was associated with increased risks of overall and specific CVDs. Increased risks were partly explained by subsequent type 2 diabetes and the need to identify other pathways remains important. Continuous monitoring of women with a history of GDM, especially those with pre-pregnancy obesity or maternal history of CVD, may provide better opportunities to reduce their cardiovascular risk.

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P6270Empagliflozin reduces the total burden of first and recurrent hospitalisations in patients with type 2 diabetes and established cardiovascular disease

European Heart Journal ◽

10.1093/eurheartj/ehz746.0869 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

D McGuire ◽

B Zinman ◽

S E Inzucchi ◽

S D Anker ◽

C Wanner ◽

...

Keyword(s):

Type 2 Diabetes ◽

Recurrent Events ◽

Negative Binomial ◽

Cox Regression ◽

Standard Of Care ◽

History Of ◽

Outcome Trial ◽

Cv Disease ◽

Total Burden

Abstract Background and aims The EMPA-REG OUTCOME trial included patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular (CV) disease. Empagliflozin reduced the risk of 3-point major adverse CV events (MACE; composite of CV death, myocardial infarction [MI], or stroke) by 14%, CV death by 38% and hospitalisation for heart failure (HF) by 35% vs placebo in analyses of time to first event. We assessed the effect of empagliflozin on all-cause hospitalisation in post-hoc analyses of all (first and recurrent) events. Materials and methods Patients were randomised to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care. We assessed the effects of empagliflozin pooled vs placebo on first event of all-cause hospitalisation using Cox regression and all (first and recurrent) events of all-cause hospitalisation using a negative binomial model. Results A total of 7020 patients were treated (4687 empagliflozin; 2333 placebo, mean [SD] age 63 [9] years, 71% male, 47% with history of MI, 23% with history of stroke, 10% with HF). In this analysis, 1725/4687 (36.8%) empagliflozin patients and 925/2333 (39.6%) placebo patients experienced an event leading to hospitalisation. The adjusted hazard ratio (HR; 95% CI) vs placebo for first all-cause hospitalisation using the Cox regression model was 0.89 (0.82, 0.96; p=0.0033; Figure); In analyses of all (first and recurrent) hospitalisation events, there were 3168 events in the empagliflozin group and 1863 in the placebo group. The adjusted event rate ratio (95% CI) vs placebo was 0.83 (0.76, 0.91; p<0.0001; Figure). Conclusion In the EMPA-REG OUTCOME trial, risk reductions with empagliflozin were seen in both first and all hospitalisation events and were numerically more favourable in analyses of all events vs analyses of first events. These analyses expand on the favourable CV effects of empagliflozin by also showing a reduction in the total burden of hospitalisation events in patients with T2D and established CV disease. Acknowledgement/Funding Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance

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Skin autofluorescence predicts cancer in subjects with type 2 diabetes

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001312 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001312

Author(s):

Ninon Foussard ◽

Alice Larroumet ◽

Marine Rigo ◽

Kamel Mohammedi ◽

Laurence Baillet-Blanco ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cox Regression ◽

Skin Autofluorescence ◽

Cox Regression Analysis ◽

Screening Programs ◽

Biological Studies ◽

History Of ◽

Risk Of Cancer

IntroductionSubjects with type 2 diabetes have an excess risk of cancer. The potential role of advanced glycation end products (AGEs) accumulated during long-term hyperglycemia in cancer development has been suggested by biological studies but clinical data are missing. AGEs can be estimated by measuring the skin autofluorescence. We searched whether the skin autofluorescence could predict new cancers in persons with type 2 diabetes.Research design and methodsFrom 2009 to 2015, we measured the skin autofluorescence of 413 subjects hospitalized for uncontrolled or complicated type 2 diabetes, without any history of cancer. The participants were followed for at least 1 year and the occurrences of new cancers were compared according to their initial skin autofluorescences.ResultsThe participants were mainly men (57.9%), with poorly controlled (HbA1c 72±14 mmol/mol or 8.7%±1.8%) and/or complicated type 2 diabetes. Their median skin autofluorescence was 2.6 (2.2–3.0) arbitrary units. Forty-five new cancer cases (10.9%) were registered during 4.8±2.3 years of follow-up: 75.6% of these subjects had skin autofluorescence higher than the median (χ2: p=0.001). By Cox regression analysis adjusted for age, gender, body mass index, history of smoking and renal parameters, skin autofluorescence >2.6 predicted a 2.57-fold higher risk of cancer (95% CI 1.28 to 5.19, p=0.008). This association remained significant after excluding the eight cancers that occurred in the 4 years after inclusion (OR 2.95, 95% CI 1.36 to 6.38, p=0.006). As a continuous variable, skin autofluorescence was also related to new cancers (OR 1.05, 95% CI 1.01 to 1.10, p=0.045).ConclusionsSkin autofluorescence, a potential marker of glycemic memory, predicts the occurrence of cancer in subjects with type 2 diabetes. This relation provides a new clinical argument for the role of AGEs in cancer. Their estimation by measuring the skin autofluorescence may help select subjects with diabetes in cancer screening programs.

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Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

Diabetes Care ◽

10.2337/dc21-1744 ◽

2022 ◽

Author(s):

Avivit Cahn ◽

Stephen D. Wiviott ◽

Ofri Mosenzon ◽

Erica L. Goodrich ◽

Sabina A. Murphy ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Cox Regression ◽

Cardiovascular Death ◽

Atherosclerotic Cardiovascular Disease ◽

Baseline Hba1c ◽

Renal Outcomes ◽

Increased Risk ◽

Hba1c Levels

OBJECTIVE Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models. RESULTS In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06–1.19], 1.08 [1.04–1.13], and 1.17 [1.11–1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05). CONCLUSIONS Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%.

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Gestational Diabetes Mellitus and the Risks of Overall and Type-Specific Cardiovascular Diseases: A Population- and Sibling-Matched Cohort Study

10.2337/figshare.16826482.v1 ◽

2021 ◽

Author(s):

Yongfu Yu ◽

Melissa Soohoo ◽

Henrik Toft Sørensen ◽

Jiong Li ◽

Onyebuchi A. Arah

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cohort Study ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Cox Regression ◽

Maternal History ◽

History Of ◽

The Impact

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Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

10.2337/figshare.17118962 ◽

2022 ◽

Author(s):

Avivit Cahn ◽

Stephen D. Wiviott ◽

Ofri Mosenzon ◽

Sabina A. Murphy ◽

Erica L. Goodrich ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Cox Regression ◽

Major Adverse Cardiovascular Events ◽

Atherosclerotic Cardiovascular Disease ◽

Baseline Hba1c ◽

Renal Outcomes ◽

Increased Risk ◽

Hba1c Levels

Objective: Current guidelines recommend prescribing SGLT-2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. Methods: In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population, and with dapagliflozin vs. placebo in HbA1c subgroups were studied by Cox regression models. Results: In the overall population, increasing HbA1c was associated with higher risk of cardiovascular death or hospitalization for heart failure (CVD/HHF), major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) and of the cardiorenal outcome (adjusted HR [95% CI] 1.12 [1.06-1.19], 1.08 [1.04-1.13] and 1.17 [1.11-1.24] per 1% increase respectively). Elevated HbA1c was associated with an increased risk for MACE and for the cardiorenal outcome significantly more in patients with multiple risk factors (MRF), vs. patients with established ASCVD (P-interaction 0.0064 and 0.0093 respectively). Dapagliflozin led to a decrease in the risk of CVD/HHF, HHF and the cardiorenal outcome vs. placebo with no heterogeneity by baseline HbA1c (P-interaction >0.05). Conclusions: High HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c<7%.

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Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus

Tumori Journal ◽

10.1177/0300891620976945 ◽

2020 ◽

pp. 030089162097694

Author(s):

Andrea Pretta ◽

Pina Ziranu ◽

Marco Puzzoni ◽

Eleonora Lai ◽

Giulia Orsi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Overall Survival ◽

Validation Cohort ◽

Medical Oncology ◽

Univariate Analysis ◽

University Hospital ◽

Ductal Adenocarcinoma ◽

Diabetic Patients

Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months ( p = 0.03). Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.

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Association between Metformin Use and Clinical Outcomes Following Pancreaticoduodenectomy in Patients with Type 2 Diabetes and Pancreatic Ductal Adenocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm9061953 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1953

Author(s):

Daegwang Yoo ◽

Nayoung Kim ◽

Dae Wook Hwang ◽

Ki Byung Song ◽

Jae Hoon Lee ◽

...

Keyword(s):

Type 2 Diabetes ◽

Overall Survival ◽

Pancreatic Ductal Adenocarcinoma ◽

Clinical Outcomes ◽

Ductal Adenocarcinoma ◽

Time Varying ◽

Start Date ◽

Metformin Group ◽

Time Varying Covariates

Retrospective studies on the association between metformin and clinical outcomes have mainly been performed on patients with non-resectable pancreatic ductal adenocarcinoma and may have been affected by time-related bias. To avoid this bias, recent studies have used time-varying analysis; however, they have only considered the start date of metformin use and not the stop date. We studied 283 patients with type 2 diabetes and pancreatic ductal adenocarcinoma following pancreaticoduodenectomy, and performed analysis using a Cox model with time-varying covariates, while considering both start and stop dates of metformin use. When start and stop dates were not considered, the metformin group showed significantly better survival. Compared with previous studies, adjusted analysis based on Cox models with time-varying covariates only considering the start date of postoperative metformin use showed no significant differences in survival. However, although adjusted analysis considering both start and stop dates showed no significant difference in recurrence-free survival, the overall survival was significantly better in the metformin group (Hazard ratio (HR), 0.747; 95% confidence interval (CI), 0.562–0.993; p = 0.045). Time-varying analysis incorporating both start and stop dates thus revealed that metformin use is associated with a higher overall survival following pancreaticoduodenectomy in patients with type 2 diabetes and pancreatic ductal adenocarcinoma.

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History of lower-limb complications and risk of cancer death in people with type 2 diabetes

Cardiovascular Diabetology ◽

10.1186/s12933-020-01198-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Kamel Mohammedi ◽

Stephen Harrap ◽

Giuseppe Mancia ◽

Michel Marre ◽

Neil Poulter ◽

...

Keyword(s):

Type 2 Diabetes ◽

Peripheral Neuropathy ◽

Lower Limb ◽

Cox Regression ◽

Cancer Death ◽

Advance Study ◽

Increased Risk ◽

History Of ◽

Risk Of Cancer

Abstract Background Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes. Methods We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models. Results Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th–75th percentile, 4.7–5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3–6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21–1.94), p = 0.0004], PAD [1.32 (1.02–1.70), p = 0.03] or neuropathy (1.41 (1.11–1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers. Conclusions PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.

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Developing a Prediction Model for 7-Year and 10-Year All-Cause Mortality Risk in Type 2 Diabetes Using a Hospital-Based Prospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10204779 ◽

2021 ◽

Vol 10 (20) ◽

pp. 4779

Author(s):

Sherry Yueh-Hsia Chiu ◽

Ying Isabel Chen ◽

Juifen Rachel Lu ◽

Soh-Ching Ng ◽

Chih-Hung Chen

Keyword(s):

Type 2 Diabetes ◽

Prediction Model ◽

Prospective Cohort ◽

Prediction Models ◽

Cox Regression ◽

Predictive Performance ◽

Mortality Prediction ◽

All Cause Mortality ◽

History Of

Leveraging easily accessible data from hospitals to identify high-risk mortality rates for clinical diabetes care adjustment is a convenient method for the future of precision healthcare. We aimed to develop risk prediction models for all-cause mortality based on 7-year and 10-year follow-ups for type 2 diabetes. A total of Taiwanese subjects aged ≥18 with outpatient data were ascertained during 2007–2013 and followed up to the end of 2016 using a hospital-based prospective cohort. Both traditional model selection with stepwise approach and LASSO method were conducted for parsimonious models’ selection and comparison. Multivariable Cox regression was performed for selected variables, and a time-dependent ROC curve with an integrated AUC and cumulative mortality by risk score levels was employed to evaluate the time-related predictive performance. The prediction model, which was composed of eight influential variables (age, sex, history of cancers, history of hypertension, antihyperlipidemic drug use, HbA1c level, creatinine level, and the LDL /HDL ratio), was the same for the 7-year and 10-year models. Harrell’s C-statistic was 0.7955 and 0.7775, and the integrated AUCs were 0.8136 and 0.8045 for the 7-year and 10-year models, respectively. The predictive performance of the AUCs was consistent with time. Our study developed and validated all-cause mortality prediction models with 7-year and 10-year follow-ups that were composed of the same contributing factors, though the model with 10-year follow-up had slightly greater risk coefficients. Both prediction models were consistent with time.

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