Noncardiovascular deaths are more common than cardiovascular deaths in patients with cardiovascular disease or cardiovascular risk factors and impaired glucose tolerance: Insights from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial

    Non-Cardiovascular Deaths Are More Common than Cardiovascular Deaths in Patients with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial Abhinav Sharma, Fl´avio de Souza Brito, Jie-Lena Sun, Laine Thomas, Steven Haffner, Rury R. Holman, Renato D. Lopes PII: DOI: Reference:

S0002-8703(16)30292-7 doi: 10.1016/j.ahj.2016.12.011 YMHJ 5345

To appear in:

American Heart Journal

Received date: Accepted date:

15 June 2016 22 December 2016

Please cite this article as: Sharma Abhinav, de Souza Brito Fl´ avio, Sun Jie-Lena, Thomas Laine, Haffner Steven, Holman Rury R., Lopes Renato D., Non-Cardiovascular Deaths Are More Common than Cardiovascular Deaths in Patients with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial, American Heart Journal (2016), doi: 10.1016/j.ahj.2016.12.011

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Non-Cardiovascular Deaths Are More Common than Cardiovascular Deaths in Patients with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance:

PT

Insights from the NAVIGATOR Trial

RI

Abhinav Sharma, MD1,2; Flávio de Souza Brito, MD1; Jie-Lena Sun, MSc1; Laine Thomas, PhD1; Steven

Clinical Research Institute, Duke University, Durham, NC, USA; 2Mazankowski Alberta Heart

NU

1Duke

SC

Haffner, MD3; Rury R. Holman, FRCP, FMedSci4; Renato D. Lopes, MD, PhD, MHS1

MA

Institute, University of Alberta, Edmonton, Alberta, Canada; 3Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA; 4Diabetes Trials Unit, University of Oxford,

TE

D

Oxford, UK

AC CE P

Short title: Cause of death in patients with impaired glucose tolerance

Word count: 6351 (all-inclusive)

Address for correspondence: Renato D. Lopes, MD, PhD, MHS, Duke Clinical Research Institute, Box 3850, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC 27705. Phone: (919) 668-8241, Fax: (919) 668-7056. Email: [email protected].

ACCEPTED MANUSCRIPT ABSTRACT Background: Patients with impaired glucose tolerance (IGT) have an elevated risk of

PT

cardiovascular (CV) death; however, the causes and risk factors associated with non-CV deaths are poorly understood.

RI

Methods: The NAVIGATOR trial enrolled 9306 participants with IGT and CV disease or at high CV

SC

risk, with a median follow-up of 6.4 years. Using this population, we identified (1) the proportion of deaths attributed to CV, non-CV, and unknown causes, and (2) the risk factors associated with non-

NU

CV death.

MA

Results: During the NAVIGATOR trial follow-up, 622 patients died. Investigators reported 244 (39.2%) CV deaths, 313 (50.3%) non-CV deaths, and 65 (10.4%) deaths of unknown cause.

D

Myocardial infarction was the leading cause of investigator-reported death (57/622 [9.2%]).

TE

Among non-CV deaths, the most commonly identified cause related to malignancy (193/313 [61.7%]). Using adjudicated causes of death, Cox proportional hazard models identified three

AC CE P

independent prognostic markers that increased the risk of non-CV death: history of non-melanoma skin cancer (HR 2.67 [95% CI 1.64–4.32]; p<0.0001); white blood cell count (1 unit above 5000/mm3; 1.09 [1.02–1.18]; p=0.011); and serum potassium levels (per 1 mmol/L above any value; 1.67 [1.29–2.15]; p<0.0001).

Conclusions: Despite the high baseline CV risk among patients in the NAVIGATOR trial, the most common cause of death was non-CV. The high burden of non-CV death in this population has potential implications for future CV-event-driven trials. Key words: cardiovascular death, non-cardiovascular death, impaired glucose tolerance, risk factors

ACCEPTED MANUSCRIPT INTRODUCTION Diabetes is an established marker of cardiovascular (CV) disease.1 People with dysglycemia,

PT

including impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), are at increased risk for developing type 2 diabetes.2 Furthermore, the spectrum of risk for CV events extends into the

RI

IGT and IFG populations. Previous analyses have demonstrated that both IGT and IFG can increase

SC

the risk of CV events by up to 20%.2,3

There is growing recognition that diabetes increases the risk of non-CV causes of death,

NU

especially cancer. In a large prospective cohort of 1,053,831 U.S. adults enrolled in the Cancer

MA

Prevention Study-II, those with diabetes had a higher risk of all-cause mortality, including death from cancer; respiratory, digestive, and genitourinary diseases; and external/accidental deaths.4

D

Diabetes was also an independent predictor of death due to a variety of cancers (such as pancreatic

TE

and colon cancer) in both men and women.5 Furthermore, patients with diabetes and CV disease were at significantly higher risk of infection-related mortality.6

AC CE P

It is unclear whether IGT increases the risk of non-CV causes of death in a manner similar to diabetes, as the factors that predict non-CV death are not well elucidated in this population. In addition, the relative burden of non-CV death compared with CV death is unclear. The objective of this study was to evaluate the causes and risk factors associated with non-CV death in patients with IGT using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.

METHODS The NAVIGATOR trial The NAVIGATOR trial was a double-blind, multinational, placebo-controlled study involving patients with IGT and CV disease or CV risk factors.7,8 Its primary purpose was to evaluate whether the use of nateglinide and valsartan could reduce the risk of new-onset diabetes and/or CV events

ACCEPTED MANUSCRIPT in this population. Participants were randomized to treatment with nateglinide (up to 60 mg orally three times a day) or placebo and to valsartan (up to 160 mg orally daily) or placebo in a 2×2

PT

factorial design. They also received instructions about lifestyle intervention aimed at reducing body weight and dietary fat intake. Key inclusion criteria included IGT, a fasting plasma glucose level ≥95

RI

mg/dL (5.3 mmol/L) but <126 mg/dL (7.0 mmol/L), and one or more CV risk factors (if 55 years of

SC

age or older) or known CV disease (if 50 years of age or older). Key exclusion criteria included laboratory abnormalities or conditions that could interfere with safety or efficacy assessment of

NU

study drug, use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for

MA

treatment of hypertension, and use of an anti-diabetic medication within the previous 5 years. All patients enrolled in NAVIGATOR provided written informed consent.

D

A total of 9306 participants from 40 countries were randomized and followed for a median

TE

of 6.4 years. Valsartan reduced the risk of developing diabetes (relative risk reduction 14%, P<0.001) but did not reduce the risk of CV outcomes. The design, rationale, and other key results

AC CE P

have been previously described.7,8

Clinical events classification

An independent clinical endpoint committee (CEC), blinded to study medication allocation, adjudicated all endpoints and their dates of onset.7 These endpoints included new-onset diabetes, death, hospitalization, and potential CV events. For the current study, all variables used to make the regression models for CV death, non-CV death, and unknown cause of death came from CECadjudicated endpoints. Amongst non-CV death, the specific causes of death were identified by individual investigators and were not formally adjudicated.

ACCEPTED MANUSCRIPT Definition of CV death CV death was defined as sudden cardiac death and death due to an acute myocardial infarction,

PT

heart failure, stroke, or other CV causes (see Appendix Table 1 for event definitions). Deaths due to arrhythmia, pulmonary embolism, CV intervention (including complications of cardiac surgery or

RI

non-surgical revascularization), aortic aneurism rupture, and peripheral artery disease were also

SC

classified as CV deaths.

NU

Definition of non-CV death

MA

Non-CV deaths, defined as any death not due to a CV cause, were divided into 2 subgroups: (1) malignant deaths and (2) non-malignant deaths. Deaths resulting directly from cancer, a

D

complication of cancer (e.g., infection, complication of surgery, chemotherapy, or radiotherapy), or

TE

withdrawal of other therapies because of concerns related to poor prognosis associated with cancer were classified as malignant deaths. Non-malignant deaths were those resulting from pulmonary,

AC CE P

renal, gastrointestinal, hepatobiliary, or pancreatic disease; infection (including sepsis); and noninfectious causes (e.g., systemic inflammatory response syndrome); hemorrhage (not intracranial); non-CV system organ failure (e.g., hepatic failure); non-CV trauma; suicide; and drug overdose (see Appendix Table 1 for event definitions).9 Deaths not attributable to a CV or non-CV cause were classified as unknown deaths.

Statistical analysis Baseline patient characteristics were assessed based on 4 adjudicated cause-of-death groups: survivors, CV death, non-CV death, and unknown death. Continuous variables were reported as medians with 25th and 75th percentiles, and categorical variables were reported as frequencies and percentages. Fifty-four variables collected at baseline—including demographics, clinical measurements, medical history, laboratory results, and investigator-reported electrocardiogram

ACCEPTED MANUSCRIPT results—were tested. Using data from adjudicated causes of death, Cox proportional hazards regression models were developed to identify the prognostic risk factors associated with CV and

PT

non-CV death (which included the unknown death category). The competing risks were handled by estimating cause-specific hazards. Variables were selected for inclusion by forward selection with

RI

an alpha <0.05. Covariates were tested for linearity, and non-linear relationships were handled by

SC

fitting linear splines. The proportional hazards assumption was tested with a Kolmogorov-type supremum test. There was no violation for all covariates. The unknown death and CV death

NU

categories were combined; however, a sensitivity analysis was performed to assess model results if

MA

unknown death was combined with the non-CV death category instead of the CV death category. Less than 3% of data were missing for all variables except hemoglobin A1c, where 15%

Role of the funding source

TE

D

were missing. Missing data were handled by the multiple imputation method.

AC CE P

The NAVIGATOR study and this secondary analysis was sponsored by Novartis Pharma. The study sponsor did not contribute to the statistical analysis, interpretation, or creation of this manuscript. The manuscript was prepared by the coauthors. Renato D. Lopes and Rury R. Holman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

RESULTS Baseline characteristics and causes of death Baseline characteristics for are shown in Table 1. A total of 622 participants died during the trial. Those patients were older; more often male; more often smokers; and had more electrocardiogram abnormalities, renal dysfunction, chronic obstructive pulmonary disease, and atrial fibrillation/flutter. Across almost all country regions, CV deaths were outweighed by non-CV

ACCEPTED MANUSCRIPT deaths: Asia (7 vs. 18), Europe (107 vs. 152), Latin America (67 vs. 79), and North America (51 vs. 64). Of participants who died from non-CV causes, 193 deaths (61.6% of investigator-reported non-

PT

CV death) were attributed to malignancy (Table 2). The most frequent individual causes of death included myocardial infarction (9.2%), heart failure (6.6%), sudden cardiac death (6.6%), lung

RI

cancer (6.6%), stroke (6.4%), and non-specific cancer death (5.0%) (Table 3). We evaluated the

SC

cumulative incidence of CV and non-CV death over the duration of the trial (Figure 1). While the proportion of CV and non-CV deaths were equal, near the end of the trial, the proportion of non-CV

MA

NU

deaths becomes greater than the proportion of CV deaths.

Risk factors associated with non-CV and CV death In both the primary and sensitivity analyses, risk factors independently associated with non-CV

TE

D

death (Table 4a and 4b) were: presence of non-melanoma skin cancer (HR 2.67, 95% CI 1.64–4.32), increased white blood cell (WBC) count for high values above 5000/mm3 (HR per 1 unit above

AC CE P

5000/mm3; 1.09, 95% CI 1.02–1.18), and WBC count (HR per 1 unit up to 5000/mm3; 0.63, 95% CI 0.45–0.90), platelet count (per 10,000/mm3 above any value; HR 0.97, 95% CI 0.95–0.99), and increased potassium level (per 1 mmol/L above any value; HR 1.67; 95% CI 1.29–2.15). A history of cancer and HbA1c were significantly associated with non-CV mortality in the primary analysis but not in the sensitivity analysis, whereas body mass index was significant in the sensitivity analysis but not in the primary analysis. Risk factors independently associated with CV death in both the primary and sensitivity analyses (Table 4a and 4b) were: presence of atrial fibrillation/flutter (HR 1.72, 95% CI 1.21–2.45); cerebrovascular disease (HR 1.65, 95% CI 1.21–2.24); coronary disease (HR 2.01, 95% CI 1.56– 2.60); renal dysfunction (HR 2.37, 95% CI 1.38–4.08); and non-North American regions (Australia + New Zealand + South Africa) vs. North America (HR 1.88, 95% CI 1.04–3.38).

ACCEPTED MANUSCRIPT There are a number of risk factors that independently predict the risk of both CV and nonCV death, including age, female sex, enrollment in a Latin American country, smoking status, history

PT

of heart failure, urine albumin/creatinine ratio, and hemoglobin per 10 g/L up to 140 g/L.

RI

DISCUSSION

SC

In our study of patients enrolled in the NAVIGATOR trial with IGT and CV disease or at high CV risk, myocardial infarction, heart failure, and sudden cardiac death were the most common individual

NU

causes of death. However, in totality, the most frequent cause of death was non-CV. Amongst these

MA

non-CV causes of death, the most common was malignancy.

D

Causes of death

TE

Compared with non-CV causes of death, there is a higher proportion of CV-related risk factors and associated comorbidities (such as male sex, family history of premature coronary disease, and

AC CE P

history of CV disease) among those who died of CV causes (Table 1). Given the presence of IGT and the enrollment of patients with CV risk factors, it is not unexpected that myocardial infarction, heart failure, and sudden cardiac death were the most common individual causes of death; however, nonCV causes compared with CV causes contributed to the significant burden of all-cause mortality. In the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab), 10,428 patients with varying degrees of hyperglycemia were prospectively followed for a median of 5.2 years.10 Compared with normal glucose tolerance (n=7662), IGT (n=1298) was associated with an increased risk of non-CV mortality (HR 1.6, 95% CI 1.1–2.3) but not CV mortality (HR 1.2, 95% CI 0.7–2.2). In total, 67 patients with IGT died, 16 (23.9%) due to CV causes and 51 (76.1%) due to non-CV causes. While limited by inadequate sample size, it was proposed that IGT increased the risk of malignant death, as 59.3% of non-CV deaths were due to malignancy. While diabetes mellitus has been shown to increase the risk of cancer-related death,4,5 there

ACCEPTED MANUSCRIPT is increasing recognition of IGT’s role in cancer-related mortality. For example, in 3056 patients from the Second National Health and Nutrition Examination Survey (NHANES II) and the NHANES II

PT

Mortality Study, adults with IGT had the greatest adjusted relative hazard of cancer mortality (relative HR 1.87, 95% CI 1.06–3.31).11 The proportion of deaths associated with cancer in the

RI

NHANES II study were 5.4% in those with normal glucose tolerance and 9.8% in those with IGT.

SC

These findings are lower than in our study (31%); this likely reflects the inclusion criteria of NAVIGATOR, which selected for older patients with more comorbidities.

NU

The Emerging Risk Factor Collaboration study (which included cause-specific mortality

MA

outcomes in 820,900 people from 97 prospective studies) demonstrated that patients with diabetes and elevated fasting glucose are at higher risk of cancer and other non-CV related mortality.12

D

Altogether, 40% of the years of life lost from diabetes can be attributed to nonvascular causes, and

TE

this includes a 10% contribution from cancer.12 Our findings parallel these results as the extensive burden of non-CV death, especially due to cancer, is also present in patients with IGT, despite

AC CE P

having prior CV disease or CV risk factors. The DREAM trial was a double-blind, randomized clinical trial with a 2×2 factorial design in 5269 participants without CV disease but with IFG or IGT. These patients received ramipril or placebo (and rosiglitazone or placebo). In total, 63 patients died, 22 of CV causes, implying the majority of deaths in this patient population were due to non-CV causes. These results parallel our results, suggesting that the burden of non-CV death increased substantially in patients with pre-diabetes. The associations between cancer risk and mortality and diabetes mellitus have been recognized,4,5,13 and mechanisms linking these conditions include hyperinsulinemia, hyperglycemia, and inflammation.9 The pre-diabetic phase is also a proinflammatory state14 with associated hyperglycemia and hyperinsulinemia, which may contribute to the cancer burden seen in this population. Several specific mechanisms linking insulin resistance and cancer have been proposed.13 Insulin resistances is known to increase tumor necrosis factor alpha (TNFα) and

ACCEPTED MANUSCRIPT interleukin 6 (IL-6) levels. Both of these inflammatory molecules up-regulate reactive oxygen species, which are established drivers of cancer development through increased DNA damage.13 In

PT

addition, chronic hyperinsulinemia increases bioavailability of insulin-like growth factor 1 (IGF1).13,15 IGF-1 has been implicated in triggering multiple intra-cellular signaling cascades known to

RI

induce tumor production.15 While we do not have a control non-IGT population, our results, in

SC

context of the totality of evidence, would suggest that patients with IGT might benefit from being more aggressively screened for cancer by guideline-recommended investigations. Whether these

MA

NU

patients need more frequent or earlier screening remains to be evaluated in prospective studies.

Predictors of mortality

D

Predictors of CV causes of death in NAVIGATOR have been previously described in detail,16 and our

TE

analysis (Table 4a and 4b) aligns with these results. Subtle differences in HRs likely arise from differences in the selected candidate variables. Our study identified three risk factors that

AC CE P

independently increased the risk of non-CV related mortality: presence of non-melanoma skin cancer, WBC count, and serum potassium level. We also identified two risk factors that independently decreased the risk of non-CV death: hemoglobin and platelet count (Table 4a and 4b). We hypothesize that these variables are likely identifying risk markers for cancer mortality and have been shown to predict cancer mortality in other populations. A population of 5766 elderly (aged >65 years) community dwellers of the Cardiovascular Health Study in the United States demonstrated that platelet count was significantly associated with a risk of non-CV and cancer mortality.17 In the population-based New Hampshire Skin Cancer study, non-melanoma skin cancer in 3584 participants was associated with an increased risk of a subsequent cancer, specifically basal cell carcinoma (adjusted HR 1.40, 95% CI 1.15–1.71).18 Increases in WBC count have also been associated with increases in cancer mortality. For example, 7674 patients in NHANES II with 16 years of follow-up demonstrated that patients within the highest quartile of WBC count had a

ACCEPTED MANUSCRIPT significant increase in the risk of all-cause cancer death (adjusted HR 1.66, 95% CI 1.08–2.56).19 Another prospective cohort of 3189 people free of cancer demonstrated an increased risk of cancer

PT

mortality in those within the highest quartile of WBC count (HR 1.73, 95% CI 1.18–2.55).20 Serum potassium has also demonstrated an association with cancer mortality. In 7636 middle-aged British

RI

men followed prospectively for 11.5 years, increased potassium (>5.2 mml/L) in those who smoked

SC

increased the risk for adjusted all-cause mortality (relative risk [RR] 1.7, 95% CI 1.2–2.5), cancer death (RR 1.8, 95% CI 1.0–3.2), and lung cancer death (RR 2.5; 95% CI 1.1–5.6).21 While caution

NU

should be given to our results as non-CV mortality includes heterogeneous causes of death, the

MA

association of these variables to non-CV cause of death in patients with IGT are hypothesis-

D

generating.

TE

Implications for future trials

Our results have potential implications for clinical trial conduct in patients with IGT. Given that the

AC CE P

NAVIGATOR trial enriched for patients with CV events, the high burden of non-CV deaths was an unexpected finding. Future trials that may attempt to reduce CV death in an IGT population with known CV disease or CV risk factors need to consider that many of these patients will be dying of causes that likely cannot be modified by the therapy being evaluated. For example, while antihypertensive drugs, including angiotensin receptor blockers,22 have not been shown to increase cancer-related deaths, future therapies will have to carefully evaluate cancer-related mortality given that dysglycemic patients are at increased risk for cancer-related deaths.4,5,11 In trials primarily focused on CV outcomes, less attention has been given to non-CV outcomes, including non-CV death. Our results suggest that since non-CV deaths contribute to a significant burden of overall mortality, formal adjudication and adequate importance of these events should be considered in trials of patients with IGT. The long follow-up of the NAVIGATOR trial allows us to evaluate how the proportions of CV and non-CV death change over time. We have

ACCEPTED MANUSCRIPT shown that the cumulative incidence event rate increased more for non-CV death as compared with CV death near the end of the trial. This has significant implications for long-term CV trials in this

PT

patient population as the burden of non-CV death becomes a dominant component of all-cause

RI

death.

SC

Limitations

Our patient population included those who either had or were at high-risk of having a CV event;

NU

therefore, we cannot generalize our findings to all patients with IGT. Our data came from one large,

MA

randomized trial and was not validated against other studies. The lack of a non-IGT comparator limits analysis. Misclassification of events through the adjudication process may have occurred.

D

While an extensive number of baseline variables were included in the Cox proportional model,

TE

other significant variables not available may significantly influence results. Lack of adjudication for cancer-specific death limits our ability to identify factors associated with cancer death. Investigator

AC CE P

assessments of cause of death were used in the descriptive assessment of specific cause of death, especially in non-CV death, as there was no formal adjudication for these types of death. Adjudicated cause of death was used in the Cox models, and unknown causes of death were added to the CV death category, which may have altered the risk profile in this population. However, based on our sensitivity analysis, the predictors of CV and non-CV death were relatively similar if the unknown causes of death were added to the non-CV group. No adjustment was made for multiple hypothesis testing. Finally, a causal relationship cannot be concluded from the present data, and the hypothesis-generating results should be confirmed in separate analyses.

ACCEPTED MANUSCRIPT CONCLUSIONS In patients with IGT and CV risk factors, non-CV deaths formed the main cause of death. Malignancy

PT

was the most common cause of non-CV death. Studies will have to identify strategies to risk-stratify patients with IGT with regards to cause-specific death in order to initiate appropriate medical

RI

screening and interventions. Furthermore, future studies evaluating therapies to reduce CV death

SC

in patients with IGT and CV disease or CV risk factors will need to consider the high burden of non-

AC CE P

TE

D

MA

NU

CV death in this population.

ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS Disclosures:

Alberta Innovates Health Solution Clinician Investigator award.

PT

A.S: Supported by the Canadian Cardiovascular Society Bayer-Vascular research grant and an

RI

R.D.L: Disclosures available at https://www.dcri.org/about-us/conflict-of-interest.

SC

R.R.H. has received grants and personal fees from Merck; grants from Bayer and AstraZeneca;

GlaxoSmithKline, Janssen, and Takeda.

MA

All remaining authors have nothing to disclose.

NU

personal fees from Amgen, Bayer, Intarcia, Novartis, and Novo Nordisk; and other support from

D

Funding

TE

This work and the NAVIGATOR trial were funded by Novartis Pharmaceuticals.

AC CE P

Data Access and Responsibility:

Renato D. Lopes and Rury R. Holman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

ACCEPTED MANUSCRIPT References 1. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident

PT

cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233–240.

RI

2. Grundy SM. Pre-diabetes, metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol

SC

2012; 59: 635–643.

3. Ford ES, Zhao G, Li C. Pre-diabetes and the risk for cardiovascular disease. J Am Coll Cardiol

NU

2010; 55: 1310–1317.

MA

4. Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million US adults. Diabetes Care 2012: 35: 1835–

D

1844.

TE

5. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004; 159: 1160–1167.

AC CE P

6. Bertoni AG, Saydah S, Brancati FL. Diabetes and the risk of infection-related mortality in the U.S. Diabetes Care 2001; 24: 1044–1049. 7. Califf RM, Boolell M, Haffner SM, et al. Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. Am Heart J 2008; 156: 623–632. 8. NAVIGATOR Study Group, McMurray JJ, Holman RR, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362: 1477–1490. 9. Spranger J, Kroke A, Möhlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52: 812–817. 10. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in

ACCEPTED MANUSCRIPT individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 2007;

PT

116: 151–157. 11. Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Abnormal glucose tolerance and the risk of

RI

cancer death in the United States. Am J Epidemiol 2003; 157: 1092–1100.

SC

12. Emerging Risk Factors Collaboration, Seshasai SRK, Kaptoge S, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364: 829–841.

NU

13. Arcidiacono B, Iiritano S, Nocera A, et al. Insulin resistance and cancer risk: an overview of

MA

the pathogenetic mechanisms. Exp Diabetes Res 2012; 2012: 789174. 14. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report.

D

Diabetes Care 2010; 33: 1674–1685.

TE

15. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000;21:215–244.

AC CE P

16. Preiss D, Thomas LE, Sun JL, et al. Predictors of cardiovascular events in a contemporary population with impaired glucose tolerance: an observational analysis of the Nateglinide and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial. BMJ Open 2012; 2: pii: e001925.

17. van der Bom JG, Heckbert SR, Lumley T, et al. Platelet count and the risk for thrombosis and death in the elderly. J Thromb Haemost 2009; 7: 399–405. 18. Rees JR, Zens MS, Gui J, Celaya MO, Riddle BL, Karagas MR. Non melanoma skin cancer and subsequent cancer risk. PLoS One 2014; 9: e99674. 19. Erlinger TP, Muntner P, Helzlsouer KJ. WBC count and the risk of cancer mortality in a national sample of U.S. adults: results from the Second National Health and Nutrition Examination Survey mortality study. Cancer Epidemiol Biomarkers Prev 2004; 13: 10521056.

ACCEPTED MANUSCRIPT 20. Shankar A, Wang JJ, Rochtchina E, Yu MC, Kefford R, Mitchell P. Association between circulating white blood cell count and cancer mortality: a population-based cohort study.

PT

Arch Intern Med 2006; 166: 188–194. 21. Wannamethee SG, Lever AF, Shaper AG, Whincup PH. Serum potassium, cigarette smoking,

RI

and mortality in middle-aged men. Am J Peidemiol 1997; 145: 598–606.

SC

22. Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from

AC CE P

TE

D

MA

NU

randomised trials. Lancet Oncol 2011; 12: 65–82.

ACCEPTED MANUSCRIPT Figure Legend Figure 1. Cardiovascular and non-cardiovascular death over time. The widths of the blue and red

AC CE P

TE

D

MA

NU

SC

RI

non-CV death as compared with CV death near the end of the trial.

PT

areas reflect the 95% confidence intervals. The cumulative incidence event rate increased more for

ACCEPTED MANUSCRIPT

Survivors

CV death

Non-CV death

Unknown cause

(N=9306)

(N=8684)

(N=244)

(N=322)

(N=56)

63.0

63.0

67.0

68.5

69.0

4711 (50.6)

4493 (51.7)

78 (32.0)

121 (37.6)

19 (33.9)

White

7734 (83.1)

7213 (83.1)

201 (82.4)

274 (85.1)

46 (82.1)

Black

236 (2.5)

219 (2.5)

8 (3.3)

6 (1.9)

3 (5.4)

Asian

613 (6.6)

583 (6.7)

9 (3.7)

18 (5.6)

3 (5.4)

Other*

723 (7.8)

669 (7.7)

26 (10.7)

24 (7.5)

4 (7.1)

552 (5.9)

525 (6.0)

7 (2.9)

18 (5.6)

2 (3.6)

Age, yrs Female sex

MA

NU

Race/nationality

PT ED

Region Asia

SC

Characteristic

PT

Total

RI

Table 1: Baseline characteristics according to survivors and adjudicated CV death, non-CV death, and unknown cause of death

4909 (52.8)

4623 (53.2)

107 (43.9)

152 (47.2)

27 (48.2)

Latin America

1406 (15.1)

1253 (14.4)

67 (27.5)

79 (24.5)

7 (12.5)

North America

2146 (23.1)

2013 (23.2)

51 (20.9)

64 (19.9)

18 (32.1)

293 (3.1)

270 (3.1)

12 (4.9)

9 (2.8)

2 (3.6)

Other+ Current smoker

1025 (11.0)

920 (10.6)

41 (16.8)

53 (16.5)

11 (19.6)

Family history of diabetes

AC

Risk factors

CE

Europe

3547 (38.1)

3361 (38.7)

69 (28.3)

105 (32.6)

12 (21.4)

Family history of premature coronary

1544 (16.6)

1465 (16.9)

39 (16.0)

32 (9.9)

8 (14.3)

Body mass index, kg/m2

29.7

29.7

28.8

29.2

29.3

Waist circumference, cm

100.0

100.0

101.5

102.0

102.0

2933 (31.5)

2606 (30.0)

157 (64.3)

142 (44.1)

28 (50.0)

Atrial fibrillation/flutter

356 (3.8)

283 (3.3)

37 (15.2)

30 (9.3)

6 (10.7)

PE/DVT

129 (1.4)

116 (1.3)

7 (2.9)

4 (1.2)

2 (3.6)

disease

Diseases CV composite†

ACCEPTED MANUSCRIPT

Survivors

CV death

Non-CV death

Unknown cause

(N=9306)

(N=8684)

(N=244)

(N=322)

(N=56)

COPD/emphysema/chronic bronchitis

451 (4.8)

379 (4.4)

34 (13.9)

28 (8.7)

10 (17.9)

Renal dysfunction‡

90 (1.0)

61 (0.7)

18 (7.4)

6 (1.9)

5 (8.9)

Height, cm

165.0

165.0

168.0

168.0

169.5

Weight, kg

82.0

82.0

82.1

82.0

83.5

Systolic blood pressure, mmHg

140.00

140.0

140.0

139.0

140.0

Diastolic blood pressure, mmHg

82.0

82.0

80.0

80.0

80.0

Pulse, bpm

70.0

70.0

68.5

71.0

70.0

RI

Characteristic

PT

Total

NU

MA

4525 (48.6)

4344 (50.0)

54 (22.1)

112 (34.8)

15 (26.8)

Clinically insignificant abnormality

3326 (35.7)

3067 (35.3)

100 (41.0)

132 (41.0)

27 (48.2)

Clinically significant abnormality

1455 (15.6)

1273 (14.7)

90 (36.9)

78 (24.2)

14 (25.0)

HbA1C, %

5.8

5.8

5.9

5.9

6.0

Fasting glucose, mmol/L

6.10

6.10

6.05

6.10

6.10

9.00

9.00

9.20

9.20

9.05

147.0

147.0

146.5

147.0

151.0

6.700

6.700

6.800

6.800

7.100

252.00

252.00

235.00

242.50

236.5

5.36

5.37

5.20

5.18

5.04

HDL

1.24

1.24

1.15

1.18

1.28

LDL

3.22

3.23

3.08

3.13

3.06

Triglycerides

1.69

1.70

1.70

1.59

1.63

79.8

80.1

72.6

75.9

72.9

2-hour glucose, mmol/L Hemoglobin, g/L White blood cell count,

/mm3

Platelet, /mm3 Total cholesterol, mmol/L

eGFR, mL/min/1.73 m2

CE

Laboratories exams

PT ED

Normal

AC

Electrocardiogram

SC

Physical findings

ACCEPTED MANUSCRIPT

Data presented as no. (%) or median (25th, 75th percentiles), unless otherwise indicated. Abbreviations: bpm, beats per minute; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; DVT, deep vein thrombosis; eGFR, estimated

PT

glomerular filtration rate; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PE, pulmonary embolism.

RI

*Other is a composite of Australia, New Zealand, and South Africa.

†CV composite: history of myocardial infarction, unstable angina, coronary revascularization, history of stroke, and history of heart failure.

SC

‡Defined using a combination of preferred and low-level MedDRA terms of the patient records selected by medically qualified personnel and includes renal death; renal transplant; initiation of dialysis; serum creatinine >530 μmol/L, doubling from baseline in serum creatinine; eGFR 30 mL/min per

NU

1.73m2 or less; hospitalization for renal failure; or MedDRA preferred terms renal transplant, renal failure acute, renal failure chronic, renal failure,

AC

CE

PT ED

MA

renal and pancreas transplant rejection, renal and pancreas transplant, renal and liver transplant, dialysis, and renal graft loss.

ACCEPTED MANUSCRIPT Table 2: Cause of death by CV, non-CV, and unknown classifications Cause of death

Total N=622 244 (39.2)

Non-CV death

332 (51.8)

Malignant*

177 (28.5)

Non-malignant*

145 (23.3) 65 (10.4)

SC

Undetermined/unknown

RI

CV death

PT

N (%)

Data presented as no. (%). *Investigator reported.

AC CE P

TE

D

MA

NU

Abbreviations: CV, cardiovascular.

ACCEPTED MANUSCRIPT Table 3: Investigator-reported cause of death by specific cause

57 (9.2)

Heart failure

41 (6.6)

Sudden cardiac death

41 (6.6)

Lung cancer

41 (6.6)

Stroke

40 (6.4)

Non-specific cancer

31 (5.0)

Pneumonia

23 (3.7)

Cardiac arrest

18 (2.9)

Pancreatic cancer

18 (2.9)

NU

SC

Myocardial infarction

Sepsis

17 (2.7) 13 (2.1)

MA

Respiratory failure Colon cancer

13 (2.1)

Pulmonary embolism

12 (1.9)

Aortic aneurysm rupture

11 (1.8)

Renal cancer Gastric cancer Arrhythmia Lymphoma Rectal cancer

TE AC CE P

Brain cancer Breast cancer

D

Cardiogenic shock Renal failure

9 (1.4) 9 (1.4) 8 (1.3) 7 (1.1) 7 (1.1) 7 (1.1) 7 (1.1) 6 (1.0) 6 (1.0)

Multiple organ failure

6 (1.0)

Biliary tract cancer

6 (0.1)

Trauma

5 (0.8)

Chronic obstructive pulmonary disease

5 (0.8)

Peritonitis

5 (0.8)

Suicide

4 (0.6)

Ovarian cancer

4 (0.6)

Leukemia

4 (0.6)

Bladder cancer

4 (0.6)

Undetermined/unknown cause of death

65 (10.4)

Others causes

72 (11.5)

Total

PT

Total (%)

RI

Cause of death

622

ACCEPTED MANUSCRIPT Table 4a. Predictors of CV death plus unknown cause of death and non-CV death: multivariable Cox proportional hazards model Risk factors

CV death* and unknown

Non-CV death

P-Value

Age per 10 years

1.91 (1.61– 2.26)

<0.0001

2.12 (1.80–2.49)

<0.0001

Female

0.59 (0.44–0.77)

0.0002

0.62 (0.47–0.81)

0.0005

Asia

0.58 (0.28–1.18)

0.1337

Europe

0.94 (0.69–1.28)

Latin American

2.13 (1.49–3.04)

Other

1.88 (1.04–3.38)

P-Value

0.3509

0.7207

1.32 (0.97–1.80)

0.0768

<0.0001

2.32 (1.63–3.30)

<0.0001

0.0342

1.48 (0.73–3.00)

0.2768

2.06 (1.50–2.81)

<0.0001

1.89 (1.38–2.59)

<0.0001

—

—

1.82 (1.03–3.22)

0.0391

—

—

2.67 (1.64–4.32)

<0.0001

0.70 (0.54–0.91)

0.0078

—

—

—

—

0.68 (0.47–0.98)

0.0431

—

—

1.00 (1.00–1.01)

0.0419

2.11 (1.49–2.99)

<0.0001

1.90 (1.27–2.84)

0.0017

Coronary heart disease†

2.01 (1.56–2.60)

<0.0001

—

—

Atrial fibrillation/flutter

1.72 (1.21–2.45)

0.0024

—

—

1.65 (1.21–2.24)

0.0014

—

—

2.06 (1.39–3.06)

0.0003

1.56 (0.98–2.49)

0.0574

2.37 (1.38–4.08)

0.0017

—

—

1.98 (1.00–3.90)

0.0481

—

—

Insignificantly abnormal

1.60 (1.18–2.17)

0.0024

—

—

Significantly abnormal

1.88 (1.34–2.63)

0.0002

—

—

eGFR below 60 mL/min/1.73 m2

0.97 (0.95–0.99)

0.0119

—

—

eGFR above 60 mL/min/1.73 m2

1.00 (0.99–1.01)

0.5597

—

—

Urine albumin/creatinine ratio, log units

1.14 (1.05–1.24)

0.0014

1.19 (1.10–1.29)

<0.0001

—

—

1.67 (1.06–2.64)

0.0266

Hemoglobin per 10 g/L above 140 g/L

1.01 (0.88–1.15)

0.8660

0.91 (0.79–1.04)

0.1919

Hemoglobin per 10 g/L up to 140 g/L

0.77 (0.63–0.93)

0.0084

0.75 (0.62–0.92)

0.0053

—

—

0.97 (0.95–0.99)

0.0064

NU

Risk factors Current smoker All cancers, excluding skin cancer Skin cancer, excluding melanoma Family history of diabetes

Diseases

disease‡

COPD Renal dysfunction PE/DVT

AC CE P

Congestive heart failure

TE

Waist circumference, cm

D

Family history of premature CHD

Cerebrovascular

SC

1.30 (0.74–2.28)

MA

RI

Region, vs. North America

HR (95% CI)

PT

HR (95% CI)

Electrocardiogram, vs. normal

Laboratory exams

HbA1c per 1% above 6%

Platelet per 10,000/mm3 above any value

ACCEPTED MANUSCRIPT Risk factors

CV death* and unknown

Non-CV death

P-Value

HR (95% CI)

P-Value

—

—

1.09 (1.02–1.18)

0.0124

WBC per 1 unit up to 5000/mm3

—

—

0.63 (0.45–0.90)

0.0107

Potassium per 1 mmol/L above any value

—

—

WBC per 1 unit above

PT

HR (95% CI) 5000/mm3

1.67 (1.29–2.15)

<0.0001

Data presented as median (25th, 75th percentiles), unless otherwise indicated. Dash lines indicate non-

RI

significant results.

SC

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; CHD coronary heart disease; CV, cardiovascular; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; HR, *The Cox models used adjudicated cause of death.

NU

hazard ratio; PE, pulmonary embolism; WBC, white blood cell.

†Coronary heart disease composite: history of myocardial infarction, unstable angina, coronary

MA

revascularization.

AC CE P

TE

D

‡Cerebrovascular disease composite: stroke, transient ischemic attack, history of cerebrovascular disease.

ACCEPTED MANUSCRIPT Table 4b. Predictors of CV death and non-CV death plus unknown cause of death: multivariable Cox proportional hazards model Risk factors

CV death

Non-CV death and unknown P-Value

Age per 10 years

1.78 (1.48–2.16)

<0.0001

2.27 (1.95–2.64)

<0.0001

Female sex

0.54 (0.4–0.73)

<0.0001

0.60 (0.47–0.77)

<0.0001

RI

P-Value

0.33

1.16 (0.69–1.96)

0.56

SC

Region, vs. North American

HR (95% CI)

PT

HR (95% CI)

0.65

1.24 (0.93–1.64)

0.13

2.7 (1.82–4.01)

<0.0001

1.95 (1.40–2.71)

<0.0001

2.23(1.17–4.25)

0.01

1.43 (0.76–2.72)

0.26

1.97 (1.39–2.80)

0.0001

1.97 (1.48–2.63)

<.0001

—

—

2.38 (1.53–3.70)

0.0001

—

—

1.05 (1.01–1.10)

0.01

—

—

1.0 (0.97–1.03)

0.94

2.21 (1.51–3.22)

<0.0001

1.79 (1.23–2.59)

0.0021

2.09 (1.57–2.79)

<0.0001

—

—

1.78 (1.21–2.60)

0.0029

—

—

Cerebrovascular disease composite†

1.71 (1.22–2.39)

0.0016

—

—

COPD

1.97 (1.26–3.07)

0.0028

1.81 (1.21–2.71)

0.0037

Peripheral artery disease

1.66 (1.08–2.55)

0.0205

—

—

Renal dysfunction

1.88 (1.03–3.41 )

0.0377

—

—

Significantly abnormal

2.00 (1.37–2.91)

0.0003

1.41 (1.06–1.88)

0.0164

Insignificantly abnormal

1.59 (1.12–2.24)

0.0086

1.37 (1.08–1.75)

0.0088

eGFR below 60 mL/min/1.73m2

0.96 (0.94–0.98)

0.003

—

—

eGFR above 60 mL/min/1.73m2

1.0 (0.99–1.01)

0.91

—

—

Urine albumin/creatinine ratio, log units

1.15 (1.05–1.26)

0.0019

1.18 (1.09–1.27)

<0.0001

Hemoglobin per 10 g/L above 140 g/L

0.94 (0.80–1.09)

0.42

0.96 (0.85–1.09)

0.6

Hemoglobin per 10 g/L up to 140 g/L

0.76 (0.61–0.93)

0.01

0.74 (0.62–0.89)

0.0015

WBC per 1 unit above 5000/mm3

—

—

1.09 (1.02–1.17 )

0.0089

WBC per 1 unit up to 5000/mm3

—

—

0.64 (0.46–0.89)

0.008

any value

—

—

0.97 (0.96–0.99)

0.02

Potassium per 1 mmol/L above any value

—

—

1.59 (1.26–2.0)

<0.0001

0.67 (0.30–1.51)

European

1.08 (0.76–1.54)

Latin American Others

NU

Asian

Risk factors

MA

Current smoker Non-melanoma skin cancer BMI above 35 kg/m2

D

BMI up to 35 kg/m2 Diseases

TE

Congestive heart failure Coronary disease composite*

AC CE P

Atrial fibrillation/flutter

Electrocardiogram, vs. normal

Laboratory exams

Platelet per

10,000/mm3 above

ACCEPTED MANUSCRIPT Data presented as median (25th, 75th percentiles), unless otherwise indicated. Dash lines indicate nonsignificant results. Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; WBC, white blood cell.

PT

*Coronary heart disease composite: history of myocardial infarction, unstable angina, coronary revascularization.

AC CE P

TE

D

MA

NU

SC

RI

†Cerebrovascular disease composite: stroke, transient ischemic attack, history of cerebrovascular disease.

ACCEPTED MANUSCRIPT

AC CE P

TE

D

MA

NU

SC

RI

PT

Figure 1.

ACCEPTED MANUSCRIPT Appendix: Table 1: Definition of death classification Cause of death

Classification

PT

Cardiovascular Sudden cardiac death

Death that occurs instantaneously or within 60 minutes of onset of symptoms and the cause of the death is unknown. Unobserved

RI

death within 60 minutes of last contact will be classified as sudden

SC

death. Sudden death may occur in the hospital. This category will also include post-resuscitation death, defined as follows: patients in whom a cardiac and/or respiratory arrest occurs within 60

NU

minutes of the onset of cardiac or suspected cardiac symptoms but a) are resuscitated, and b) do not regain normal vital functions, and

MA

c) die after more than 60 minutes from the onset of symptoms leading to the arrest. Myocardial infarction death

Definite: Death that occurs during the hospitalization for the MI

D

and is related to a cardiac complication (e.g., congestive heart failure, arrhythmia, shock) of the acute event. MI is documented by

TE

clinical, electrocardiographic, and enzyme criteria or angiographic

AC CE P

or pathological findings. If a patient has a documented MI and then dies "suddenly" while making an otherwise normal recovery, the death will be classified in this category. Probable: As above, but MI is documented by two of three criteria (ECG, enzyme, clinical setting); or patient presentation is in a typical clinical setting with chest pain or other findings suggestive of acute MI in the absence of diagnostic enzyme or ECG changes; or the attending physician states that the patient died from an MI but does not provide documentation.

Congestive heart failure

Death from intractable congestive heart failure (class III or IV) not associated with an acute event.

Stroke

Death for which the primary cause is stroke

Other cardiovascular cause

Death for which there is evidence of a primary cardiovascular etiology and does not clearly meet the criteria for the categories outlined above. This category also includes arrhythmogenic death, cardiac rupture, and vascular death (arterial embolism, pulmonary embolism, spontaneous aortic dissection/rupture, and bleeding).

Presumed cardiovascular death

Death occurring when the patient was last seen >60 minutes

ACCEPTED MANUSCRIPT before death and is presumed to be cardiovascular. Cardiovascular procedure-related

Death during or within 24 hours following a surgical or

death

percutaneous cardiovascular procedure (e.g., PCI, CABG) and

PT

considered related to the procedure. Non-cardiovascular cause of death

Death due to an identifiable renal etiology (e.g., renal failure).

Cancer

Death due to an identified cancer.

Other non-cardiovascular cause

Specific diagnoses may include respiratory failure, pneumonia,

SC

RI

Renal

trauma, suicide, or any other non-cardiovascular-defined causes (e.g., liver disease, etc.) not included in the previous categories. A case will be classified as “unknown” if the circumstances of death

NU

Death from unknown cause

are totally unknown and assessment of a CV or non-CV cause is not

AC CE P

TE

D

MA

possible.