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Am J Cardiol. Author manuscript; available in PMC Dec 15, 2012.
Published in final edited form as:
PMCID: PMC3324944
NIHMSID: NIHMS328836
A Propensity-Matched Study of the Association of Diabetes Mellitus with Incident Heart Failure and Mortality among Community-Dwelling Older Adults
Brita Roy, MD, MPH, MS,a Pushkar P. Pawar, MBBS, MPH,a Ravi V. Desai, MD,b Gregg C. Fonarow, MD,c Marjan Mujib, MBBS, MPH,a Yan Zhang, MS, MPH,a Margaret A. Feller, MPH,a Fernando Ovalle, MD,a Inmaculada B. Aban, PhD,a Thomas E. Love, PhD,d Ami E. Iskandrian, MD,a Prakash Deedwania, MD,e and Ali Ahmed, MD, MPHaf
aUniversity of Alabama at Birmingham, Birmingham, AL
bLehigh Valley Hospital, Allentown, PA
cUniversity of California, Los Angeles, CA
dCase Western Reserve University, Cleveland, OH
eUniversity of California, San Francisco, CA
fVeterans Affairs Medical Center, Birmingham, AL
* Correspondence: Ali Ahmed, MD, MPH, University of Alabama at Birmingham, 1530 3rd Avenue South, CH-19, Suite 219, Birmingham AL 35294-2041. Telephone: 1-205-934-9632; Fax: 1-205-975-7099; aahmed/at/uab.edu
Diabetes mellitus (DM) is a risk factor for incident heart failure (HF) in older adults. However, to what extent this association is independent of other risk factors remains unclear. Of the 5464 community-dwelling adults ≥65 years in the Cardiovascular Health Study without baseline HF, 862 had DM (fasting plasma glucose levels ≥126 mg/dl, or treatment with insulin or oral hypoglycemic agents). Propensity scores for DM were estimated for each of the 5464 participants and were used to assemble a cohort of 717 pairs of participants with and without DM, who were balanced on 65 baseline characteristics. Incident HF occurred in 31% and 26% of matched participants with and without DM, respectively, during over 13 years of follow-up (hazard ratio {HR} when DM was compared with no DM, 1.45; 95% confidence interval {CI}, 1.14–1.86; p=0.003). Among the 5464 pre-match participants, unadjusted and multivariable-adjusted HRs for incident HF associated with DM were 2.22 (95% CI, 1.94–2.55; p<0.001) and 1.52 (95% CI, 1.30–1.78; p<0.001), respectively. All-cause mortality occurred in 57% and 47% of matched participants with and without DM respectively (HR, 1.35; 95% CI, 1.13–1.61; p=0.001). Among matched participants, DM-associated HRs for incident peripheral arterial disease, incident acute myocardial infarction and incident stroke were 2.50 (95% CI, 1.45–4.32; p=0.001), 1.37 (95% CI, 0.97–1.93; p=0.072), and 1.11 (95% CI, 0.81–1.51; p=0.527), respectively. In conclusion, the association of DM with incident HF and all-cause mortality in community-dwelling older adults without HF is independent of major baseline cardiovascular risk factors.
Keywords: heart failure, diabetes mellitus, mortality, older adults, propensity-matched
Diabetes mellitus (DM) is a major risk factor for incident heart failure (HF).1, 2 However, DM is also associated with many traditional cardiovascular risk factors.3 To what extent the association of DM with incident HF is independent of other cardiovascular risk factors remains unclear. Although traditional multivariable risk adjustment models can account for baseline differences in the distribution of such risk factors, they cannot guarantee that they would be balanced.4 Propensity score matching, on the other hand, can be used to for outcome-blinded assembly of study cohorts in which exposed and unexposed groups are balanced on all measured baseline characteristics.57 Therefore, we conducted a propensity-matched study of the association of DM with incident heart failure, mortality, and incident cardiovascular events.
The Cardiovascular Health Study (CHS) is a National Heart, Lung, and Blood Institute (NHLBI)-funded prospective study designed to assess the traditional and non-traditional cardiovascular risk factors among community-dwelling older adults.8 The CHS recruited 5888 Medicare-eligible community-dwelling adults ≥65 years of age from four US communities in two phases. A mostly white initial cohort of 5201 participants (1989–1990) was later supplemented by 687 African-Americans from three of those four communities (1992–1993). We used a de-identified public-use copy of the CHS dataset obtained from the NHLBI which contained information on 5795 participants who consented to be included in that dataset. After excluding 63 participants without data on DM status and 268 participants with prevalent HF at baseline, the final sample size for the current analysis was 5464 participants.
Baseline DM was defined by fasting plasma glucose (FPG) level >126 mg/dl or treatment with insulin or hypoglycemic drugs, and 16% (862/5464) of the CHS participants had DM. Data on socio-demographic, clinical, sub-clinical, and laboratory variables including serum insulin, triglyceride, interleukin-6 (IL-6), and C-reactive protein (CRP) levels were measured at baseline.8 If the value of a continuous variable was found to be missing, then predicted values based on age, sex and race were imputed. The primary outcome for this study was incident HF, which was centrally adjudicated by the CHS Events Committee. Data on self-reports of physician diagnosis of HF were obtained during semi-annual visits, which was then verified via review of medical records.2, 9, 10 Secondary outcomes included all-cause and cause-specific mortalities, acute myocardial infarction (AMI), stroke, and peripheral arterial disease (PAD).
Propensity scores, or the conditional probability of having DM, were estimated for each of the 5,464 participants using a non-parsimonious multivariable logistic regression model in which DM was the dependent variable and the 65 baseline characteristics were covariates.1114 We then used the propensity scores to match 717 (83% of the 862) individuals with DM with 717 of those without DM who had similar propensity scores.1518 Pre- and post-match absolute standardized differences for all 65 covariates were estimated and presented as a Love plot (Figure 1).1923 An absolute standardized difference of less than 10% indicates inconsequential imbalances, while 0% indicates no between-group imbalances on that covariate.24, 25
Figure 1
Figure 1
Absolute standardized differences comparing 65 baseline characteristics between CHS participants with and without diabetes mellitus, before and after propensity score matching.(ACE = angiotensin-converting enzyme; COPD = chronic obstructive pulmonary (more ...)
For between-group comparisons for pre- and post-match data, we used Pearson chi-square tests, Wilcoxon rank-sum tests, McNemar’s tests and paired sample t-tests, as appropriate. Kaplan-Meier and matched Cox proportional hazard analyses were used to estimate the associations between DM and outcomes. Formal sensitivity analyses were conducted to determine the impact of a potential hidden confounder on the association between DM and incident HF in the matched cohort.26 Subgroup analyses were performed to determine the homogeneity of this association. Two-tailed statistical tests with 95% confidence intervals were employed with a p-value <0.05 considered to be significant. All data analysis was completed using SPSS for Windows (Version 15).
Our matched cohort had a mean (±SD) age of 73 (±6) years, 51% were women, and 21% were African American (Table 1). Before matching, participants with DM were more likely to have a history of CAD, hypertension, stroke, and higher mean serum insulin, triglyceride, IL-6 and CRP levels. These and other imbalances were balanced in the matched cohort (Table 1 and Figure 1).
Table 1
Table 1
Baseline characteristics of patients by diabetes before and after propensity matching
Incident HF occurred in 31% and 26% of matched participants with and without DM, respectively, during over 13 years of follow-up (hazard ratio {HR}, 1.45; 95% confidence interval {CI}, 1.14–1.86; p=0.003; Table 2, Figure 2). A hidden binary covariate that is a near-perfect predictor of incident HF would need to increase the odds of DM by 23% to explain away this association. This association was homogeneous across various subgroups of matched participants except that it was stronger in those without hypertension than in those with hypertension (Figure 3). Pre-match associations of DM with incident HF are displayed in Table 2.
Table 2
Table 2
Association of baseline diabetes mellitus and incident heart failure among community-dwelling older adults without heart failure, before and after propensity matching
Figure 2
Figure 2
Kaplan-Meier plots for (a) incident heart failure and (b) mortality due to all causes by presence or absence of diabetes mellitus (DM) in a propensity-matched cohort of CHS participants (HR=hazard ratio; CI=confidence interval)
Figure 3
Figure 3
Association of diabetes mellitus (DM) with incident heart failure in subgroups of propensity-matched CHS participants (CI=confidence interval; HR=hazard ratio)
All-cause mortality in the post-match cohort occurred in 57% and 47% of participants with and without DM, respectively (HR, 1.35; 95% CI, 1.13–1.61; p=0.001; Table 3, Figure 2). Associations of DM with cardiovascular and non-cardiovascular mortality are displayed in Table 3. Associations of DM with other incident cardiovascular outcomes are displayed in Table 4. Of those who developed incident HF, only 25 (8%) patients had incident AMI prior to HF, which occurred in 1% (6 of 630) and 3% (19 of 632) of those with and without DM, respectively (p=0.009).
Table 3
Table 3
Association of baseline diabetes mellitus and all-cause and cause-specific mortalities among community-dwelling older adults without heart failure, before and after propensity matching
Table 4
Table 4
Association of baseline diabetes mellitus and other outcomes among community-dwelling older adults without HF, before and after propensity matching
Findings from the current propensity-matched study of community-dwelling older adults demonstrate that DM had a strong association with incident HF and all-cause mortality, and these associations were independent of most traditional and non-traditional cardiovascular risk factors at baseline. The results from the current study also demonstrate that the higher incidence of HF among those with DM was in large part due to a higher incidence of AMI in those individuals. In contrast to prior studies of the association of DM and cardiovascular outcomes,1, 2731 to the best of our knowledge, this is the first propensity-matched population based study of older adults that demonstrated an independent association of DM with incident HF and mortality.
The independent association of DM with incident HF and all-cause mortality observed in our propensity-matched cohort cannot be explained by any of the 65 balanced baseline characteristics. Therefore, there are two potential explanations for these associations: confounding by unmeasured covariates or a true intrinsic association. Findings from our sensitivity analysis suggest that the association of DM with incident HF is unlikely to be due to potential unmeasured confounders. Potential mechanistic explanations for an intrinsic association include DM-associated neurohormonal activation, impaired calcium homeostasis, oxidative stress, mitochondrial dysfunction, protein kinase C activation, microangiopathy, collagen accumulation, and formation of advanced glycation end-products, all of which may lead to diabetic cardiomyopathy.3236 Our findings suggest that the higher incidence of HF in those with DM was in large part due to a higher incidence of AMI in those individuals.
The confounding role of the cardiovascular risk factors and mediating role of incident AMI suggest that optimal management of cardiovascular risk factors in those with DM may play an important role in the secondary prevention of HF in community-dwelling older adults with DM. Whether a more aggressive management of DM would further reduce the risk adverse cardiovascular events remains unclear. While intensive DM management has been shown to reduce the risk of microvascular complications, it has no effect on adverse cardiovascular events,37 and may even be associated with increased risk of overall mortality.38 A meta-analysis of 5 prospective trials also found no evidence that more intensive glycemic control resulted in lower risk of incident HF.39 Therefore, prevention efforts may need to focus on the primary prevention of DM.
Our study has several limitations. While propensity matching allowed us to balance many confounding comorbid conditions, we were not able to account for the duration, severity, or extent of many of these comorbid conditions. Additionally, we had no data on HF etiology or left ventricular systolic function for those with incident HF. It is also possible that those without DM at baseline developed DM during follow-up. This regression dilution may have underestimated the association of DM with outcomes in our study.40 In conclusion, DM is independently associated with incident HF and all-cause mortality in community-dwelling older adults without HF. .
Acknowledgments
Funding: Dr. Ahmed is supported by the National Institutes of Health through grants (R01-HL085561 and R01-HL097047) from the National Heart, Lung, and Blood Institute and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama.
The Cardiovascular Health Study (CHS) was conducted and supported by the NHLBI in collaboration with the CHS Investigators. This manuscript was prepared using a limited access dataset obtained by the NHLBI and does not necessarily reflect the opinions or views of the CHS Study or the NHLBI.
Funding Sources:
Dr. Ahmed is supported by the National Institutes of Health through grants from the National Heart, Lung, and Blood Institute (5-R01-HL085561-02 and P50-HL077100), and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama.
Footnotes
Disclosures:
None.
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