Diabetes mellitus: associations with atherosclerosis, myocardial fibrosis, and implications for heart failure

Salvador, Dante Jr. (2023). Diabetes mellitus: associations with atherosclerosis, myocardial fibrosis, and implications for heart failure (Unpublished). (Dissertation, University of Bern, the Faculty of Medicine and the Faculty of Human Sciences)

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ABSTRACT

INTRODUCTION. Diabetes mellitus is a growing pandemic, and its adverse effects on cardiovascular
health have put an impetus to reduce morbidity and mortality through preventive measures. Although
several preventive approaches such as screening, lifestyle modifications, and treatment have improved
overall outcomes during the past decades, excess risk of cardiovascular disease remains. Therefore,
further understanding of the associations and mechanisms between diabetes and cardiovascular disease
could improve risk stratification and early management.

AIMS. The overall aim of the thesis is to provide novel and contemporary insights on diabetes, its
associations with atherosclerosis, myocardial fibrosis (MF), and heart failure (HF). Specific aims of the
thesis are: (1) To investigate the prospective association of changes in fasting plasma glucose (FPG) on
the development and progression subclinical atherosclerosis; (2) To review the effects of sodium
glucose cotransporter 2 inhibitors (SGLT2is) from mechanisms to subclinical and clinical
atherosclerosis; (3) To review the effects of glucagon-like peptide 1 receptor agonists (GLP1-RAs) on
coronary arteries from mechanisms, subclinical measures, and clinical outcomes and events; (4) To
investigate the associations between diabetes, glycemic control, and novel antidiabetic medications (i.e.
SGLT2is and GLP1-RAs) with MF, and; (5) To assess the impact of type 2 diabetes on mortality risk
and influence of chronic kidney disease (CKD) on life expectancy among hospitalized patients with
heart failure.

METHODS. In Chapter 3.1 we conducted a secondary analysis of the VIPVIZA trial which included
1897 participants. In this analysis, we aimed to investigate the prospective association of changes in
fasting plasma glucose (FPG) with the development of subclinical atherosclerosis assessed by
ultrasonographic assessment of the incident carotid plaque (CP) or progression of carotid intima media
thickness (CIMT) over time. In Chapter 3.2 we reviewed the effects of SGLT2is from 1) mechanisms
observed in animal and human studies, to 2) subclinical measures, and 3) atherosclerotic cardiovascular
disease (ASCVD) events and outcomes. In Chapter 3.3 we reviewed the effects of GLP1-RAs from 1)
mechanisms on coronary atherosclerosis, coronary vasospasm, and coronary microvasculature, to 2)
subclinical measures and 3) clinical acute and chronic coronary events and coronary revascularization.
In Chapter 3.4, we conducted a systematic review and meta-analysis summarizing evidence on the
association of diabetes, glycemic control, and SGLT2is and GLP1-RAs with MF histologic and
cardiovascular magnetic resonance (CMR) parameters. In Chapter 3.5, we investigated the association
of type 2 diabetes (T2D) with mortality risk and life expectancy and the influence of chronic kidney
disease (CKD) in 10,532 inpatients with HF at a tertiary cardiovascular referral centre in Switzerland.

RESULTS. This thesis presented results in five subchapters. Chapter 3.1 showed that changes in FPG
over 3 years was positively associated with 40% higher odds of developing CP, but not with CIMT
progression among 60-year old individuals with low to moderate cardiovascular risk. These associations
were independent of sex, smoking, alcohol, physical activity, systolic blood pressure, serum lipid
parameters, and medications for hypertension and dyslipidemia. Chapter 3.2 reviewed SGLT2is and
showed anti-atherosclerotic impacts on atherosclerotic pathways through dyslipidemia, endothelial
dysfunction, oxidative stress, inflammation, leucocyte adhesion and transmigration, plaque composition
and instability. SGLT2is have demonstrated downstream effects of reducing the risk of largely
atherosclerotic events such as: myocardial infarction (MI), major adverse cardiovascular out events
(MACEs), cardiovascular (CV) mortality, HF, and CKD. Chapter 3.3 reviewed GLP1-RAs potential
mechanisms underlying development of coronary events, including 1) coronary atherosclerosis, 2
coronary vasospasm and 3) impairment of coronary microvascular function. GLP1-RAs have been
observed to reduce CV mortality, MACE, and MI among individuals mostly with type 2 diabetes.
Chapter 3.4 showed that diabetes was associated with higher degrees of MF estimated through histology
and CMR T1 mapping. Those with poor glycemic control had significantly higher degrees of MF.
Included studies were mostly cross-sectional, and had low (25%), moderate (25%), or high (50%) risk
of bias. Overall findings remained similar when studies with high risk of bias were excluded in the
analyses. In Chapter 3.5, we demonstrated that type 2 diabetes (T2D) was associated with a 22% higher
mortality rate and a decrease in life expectancy among inpatients with HF. Moreover, the presence of
CKD further amplified these risks. Specifically, compared to patients without T2D nor CKD whom an
average of 55 months (4.6 years) from first day of hospital admission, those with T2D survived 6 months
less, those with CKD survived 9 months less, and those with both T2D and CKD survived 15 months
less. These associations were independent of age, sex, presence of ASCVD, hypertension, dyslipidemia,
atrial fibrillation, and COPD.

CONCLUSION. This thesis has extended knowledge on the associations between diabetes with
atherosclerosis and MF, and demonstrated mortality and life expectancy impacts in patients with heart
failure. We provided new insights on CV risk reduction investigating how monitoring changes in fasting
plasma glucose may play a role in atheroma prevention in middle-aged individuals with low to moderate
cardiovascular risk. Further research should focus on utilizing monitoring glycemic parameters,
including but not limited to fasting plasma glucose and 2-hour postprandial glucose, or incorporating
these in composite measures of risk over longer periods to improve CV risk prediction. SGLT2is were
documented to reduce atherosclerotic CV outcomes such as MI, MACE, HF, and CKD, but has not
been shown to reduce the risk of unstable angina, stroke, TIA, arterial revascularization, and PAD.
Specific effects on these ASCVD events need to be further studied. Furthermore, the comparative and
long-term effects of SGLT2is according to diabetes status, age, sex, and comorbidities need to be
investigated. GLP1-RAs have been shown to exert beneficial effects on coronary arteries, but it is still
unknown whether the observed long-term benefits were mediated through 1) the mechanisms elucidated
in the short term, or 2) glycemic control, weight loss, and blood pressure reduction. Further research is
needed regarding these mechanisms, and whether these effects can be used for primary prevention
among individuals with normoglycemia and lower cardiovascular risks. We summarized key evidence
on the potential of MF as a therapeutic target in preventing adverse outcomes, particularly non-ischemic
HF, among patients with diabetes. Investigation of the causal association of diabetes with MF is
warranted, and if MF mediates the association between diabetes and HF. We observed that T2D,
potentiated by CKD, increases mortality risk among inpatients with HF. Using the relative risk
parameters generated from our models, we estimated life expectancy measures, which then could be
more informative for clinicians and patients. Future studies should look at the potential modifying
effects of glycosylated hemoglobin (HbA1c), ejection fraction (EF), MF, and estimated glomerular
filtration rate (eGFR) in these associations.

Item Type:	Thesis (Dissertation)
Division/Institute:	04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology 04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)
Graduate School:	Graduate School for Health Sciences (GHS)
UniBE Contributor:	Salvador, Dante Jr., Muka, Taulant, Bano, Arjola, Wilhelm, Matthias
Subjects:	600 Technology > 610 Medicine & health 300 Social sciences, sociology & anthropology > 360 Social problems & social services
Language:	English
Submitter:	Beatrice Minder Wyssmann
Date Deposited:	07 Aug 2023 09:30
Last Modified:	07 Aug 2023 09:30
Additional Information:	PhD in Health Sciences (Epidemiology and Biostatistics)
URI:	https://boris.unibe.ch/id/eprint/185251