Date of Award
2024
Degree Name
Master of Philosophy (School of Medicine)
Schools and Centres
Medicine
First Supervisor
David Playford
Second Supervisor
Wendy Davis
Third Supervisor
Geoff Strange
Abstract
Background
Diabetes is a common disorder in the general population with most studies focusing on its role on the left ventricle and coronary artery disease, however it effects on pulmonary hypertension (PH) have not been fully studied. There is a pressing need to more completely explore the cardiovascular impacts of diabetes. The impact of diabetes might vary according to the various forms of PH, their predominant contribution is likely to be in PH due to left heart disease (group II, the most common form of PH).
Thus far, most studies have offered a focussed perspective with data from specialised referral centres, hospital admissions database and targeted community studies. Critically incidence and mortality data has often not been presented. The studies frequently suffer from referral bias, and may not represent true prevalence and prognosis. A large population-based study with clinical information, echocardiographic parameters and mortality data is thus needed to systematically characterise PH in diabetes participants with or without obesity.
Objectives:
1. To determine the relative incidence and predictors of pulmonary arterial hypertension (Group 1) in participants/patients with type 2 diabetes. 2. To determine the incident and prevalent epidemiology of all-cause pulmonary hypertension in a large community-based diabetes cohort linked with echocardiographic data and mortality according to three separate diagnostic criteria: a. Pulmonary hypertension coded using ICD-10 coding system at hospitalisation, with sub-code for WHO group of pulmonary hypertension. b. High probability of pulmonary hypertension based on echocardiographic data, using an estimated right ventricular systolic pressure >40mmHg. c. Intermediate or greater probability of pulmonary hypertension based on echocardiographic data, using an estimated right ventricular systolic pressure >30mmHg.
3. To determine the risk of a) mortality over prolonged follow-up and b) rehospitalisation during the cohort follow-up.
4. To explore the clinical and echocardiographic phenotype of patients with diabetes, with or without pulmonary hypertension according to the three diagnostic criteria described above.
Methodology
1. Hospitalisation for/with and death from/with PAH, and all cause-mortality were ascertained from validated databases for participants with type 2 diabetes from the longitudinal, community-based Fremantle Diabetes Study Phase 1 (n = 1287) and age-sex-and zip codematched people without diabetes (n=5153) between entry (1993-1996) and end 2017. Incidence rates and incidence rate ratios were calculated. Cox proportional hazards and competing risk models generated cause-specific and sub-distribution hazard ratios for incident PAH.
2. Data from 1,430 participants with type 2 diabetes (mean age 65.5 years, 51.5% males) in the Fremantle Diabetes Study Phase 2 (FDS2) were linked with the National Echocardiographic Database of Australia (NEDA) to ascertain the prevalence and incidence of PH using an estimated right ventricular systolic pressure (eRVSP) >30 mmHg (new suggested threshold) or the conventional >40 mmHg) over a 12-year period. PH prevalence in FDS2 was compared with that in NEDA overall and a geographically close sub-population. Multivariable analyses identified associates of prevalent/incident PH in the FDS2 cohort.
3. We linked data from 1732 participants in the Fremantle Diabetes Study Phase 2 (FDS2) with NEDA. Of these, 417 (mean age 70.5 years, 47.2% males) had an eRVSP measured and 381 (91.4%) had type 2 diabetes. To ascertain the optimum eRSVP cut-off for mortality, ROC analyses for all-cause mortality by diabetes type were undertaken. For homogeneity, only those with T2D diagnosed before the first measured eRVSP (n=350) had survival analyses performed. Multiply-imputed Cox regression identified clinical and echocardiographic associates of all-cause mortality.
Results
1. In the pooled cohort (mean age 64.0 years, 49% males), 49 (3.8%) of the type 2 diabetes participants and 133 (2.6%) of those without diabetes developed PAH during 106,556 personyears of follow-up (incident rate (IR) (95% CI) 262 (194–346) and 151 (127–179) /100,000 person-years, respectively; incident rate ratio (IRR) 1.73 (1.22–2.42), P=0.001). Type 2 diabetes was associated with an unadjusted csHR of 1.97 (1.42–2.74) and sdHR of 1.44 (1.04–2.00) (P ≤ 0.03); after adjustment for age, sex, and co-morbidities, these were 1.43 (0.83–2.47) and 1.36 (0.97–1.91), respectively (P ≥ 0.07).
2. Of 275 FDS2 participants (19.2%) with pre-entry echocardiography, 90 had eRVSP >30 mmHg and 35 had eRVSP >40 mmHg (prevalences 32.7% (95% CI 27.3–38.7%) and 12.7% (9.1–17.4%), respectively), prevalences that are 35–50% greater than national/local NEDA general population estimates. Moreover, 70 (5.0%) and 123 (9.2%) FDS2 participants were identified with incident PH at the respective eRVSP thresholds (incidence (95% CI) 7.6 (6.0– 9.7) and 14.2 (11.8–17.0)/1000 person-years), paralleling data from recognised high-risk conditions such as systemic sclerosis. The baseline plasma N-terminal pro-brain natriuretic peptide concentration was the strongest independent associate of prevalent/incident PH. Approximately 1 in 8 people with type 2 diabetes have PH using the eRVSP >40 mmHg threshold.
3. There were 141 deaths (40.4%) during 2,348 person-years (6.7±4.0 years) of follow-up. In unadjusted Kaplan-Meier (K-M) analysis, mortality rose with higher eRVSP (log rank test, P<0.001). In unadjusted pairwise comparisons, eRVSP >30-35, >35-40, and >40mmHg had significantly increased mortality compared with eRVSP £30mmHg (P=0.025, P=0.001, P<0.001, respectively). There were 50 deaths in the 173 individuals (29.5%) with eRVSP £30mmHg, and 91 deaths in the 177 (51.4%) with eRVSP >30mmHg, log rank test, P<0.001. In fully adjusted models (including age, Aboriginal descent, body mass index, diabetes duration and left heart disease), eRVSP>30mmHg was associated with 2.5 times higher allcause mortality.
Conclusions
Type 2 diabetes is associated with an increased risk of PAH but this is no longer significant after adjustment for other explanatory variables and the competing risk of death. However, the more common forms of PH (including PH due to left heart disease, Group 2) is more common in the setting of type 2 diabetes than the general population, and PH should be considered as part of regular clinical assessment of individuals with type 2 diabetes. Lastly, the presence of PH (at an eRVSP threshold >30mmHg) is associated with a significant risk for mortality in this group of patients, underlying the importance of screening for PH in type 2 diabetes, and instituting appropriate preventative or treatment measures to decrease the risk of mortality.
Publication Details
Nundlall, N. (2024). Uncovering the Link Between Diabetes and Pulmonary Hypertension [Master of Philosophy (School of Medicine)]. The University of Notre Dame Australia. https://researchonline.nd.edu.au/theses/447
