Do we need biomarkers for diabetics progressing to heart failure?

Do we need biomarkers for diabetics progressing to heart failure?

Accepted Manuscript Do we need biomarkers for diabetics progressing to heart failure? Kyriakos Dimitriadis, Costas Tsioufis, Dimitrios Tousoulis PII: ...

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Accepted Manuscript Do we need biomarkers for diabetics progressing to heart failure? Kyriakos Dimitriadis, Costas Tsioufis, Dimitrios Tousoulis PII:

S1109-9666(18)30125-8

DOI:

10.1016/j.hjc.2018.06.008

Reference:

HJC 313

To appear in:

Hellenic Journal of Cardiology

Received Date: 25 May 2018 Revised Date:

5 June 2018

Accepted Date: 7 June 2018

Please cite this article as: Dimitriadis K, Tsioufis C, Tousoulis D, Do we need biomarkers for diabetics progressing to heart failure?, Hellenic Journal of Cardiology (2018), doi: 10.1016/j.hjc.2018.06.008. 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.

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Title: Do we need biomarkers for diabetics progressing to heart failure?

Authors: Kyriakos Dimitriadis, Costas Tsioufis, Dimitrios Tousoulis

Short title: glycated hemoglobin A1c and heart failure in hypertension

108 Vas. Sofias Ave 11527 Athens, Greece Tel/Fax: +30 213 2089522

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e-mail: [email protected]

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Kyriakos Dimitriadis MD, PhD, FESC

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*Corresponding Author:

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First Cardiology Clinic, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece

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Variability in glycated hemoglobin A1c as predictor of heart failure with preserved ejection fraction in

Abstract

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diabetic hypertensive patients: Integrating the pathophysiology

There is a cardiovascular unfavorable duet consisting of arterial hypertension and diabetes that is related with increased risk of heart failure. The latter is highly prevalent in this setting of dysregulation

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of glucose metabolism and high hemodynamic load and identifying predictors of incidence of heart failure with preserved ejection fraction (HFpEF) is a research and clinical need. Towards this end the

glycemia.

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variability of glucose regulation represent a novel dynamic way to comprehend and study the impact of The results of the published study highlight the independent association of glycated

hemoglobin A1c variability with the development of HFpEF in hypertensive diabetic patients. Based on the above, the effect of diverse antidiabetic therapies on glycemic control variability as well as the

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overall management of these patients in order to reduce the risk of HFpEF remain essential for the

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modern cardiologist.

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The growing epidemic of both diabetes mellitus and heart failure (HF) is an emerging clinical reality.1-3 The prevalence of diabetes mellitus type II has augmented from 4.7% to 8.5% in the last 25 years, whereas heart failure is currently found in 11.8% of the general population.1-4 Hypertension is closely linked to unfavorable overall cardiovascular prognosis via diverse mechanisms including interaction with dysmetabolic pathways, functional and structural cardiac alterations.2,4 Focusing on patients with diagnosed heart failure with preserved ejection fraction, they are commonly diabetic and suffer from long-standing hypertension.4

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In this excellent retrospective cohort study, Gu J et al. demonstrated that the higher glycated hemoglobin A1c (HbA1c) variability is related with higher risk of new-onset symptomatic heart failure with preserved ejection fraction (HFpEF) in diabetic hypertensive patients and most importantly this

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effect of glycemic variation was independent of the mean HbA1c as well as the rest of the established confounders.1 In the same lines the lower the fluctuations of HbA1c the better the functional properties of the LV during follow-up further supporting the concept that glucose dysregulation causes

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maladaptative myocyte alterations. Reports have shown that advanced glycation end-products, toxic effects of the lipids via free fatty acid uptake, mitochondrial fragmantation and rarefication of the

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microcirculation that also characterizes hypertension are potential mechanisms leading to HFpEF with the contribution of neurohormonal dysfunction.2,5,6

One of the critical points is the diagnosis of HFpEF because of the fact that the symptoms are rather mild and can be difficult diagnosed due to the accompanying comorbidities and impairment of physical

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activity especially in the setting of older female patients.3 In the present study HFpEF cases were identified due to the close follow-up and the high clinical suspicion by the investigators.1 Additionally, 7.3 years is an adequate time frame to examine the presence of HFpEF although one could support that

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the final number of patients identified with HF is not the expected one, taking into account that almost half the patients with diabetes develop this condition based on the current evidence.2,3

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There are certain drugs that may promote the development of heart failure.2-4 Sulphonylureas and insulin have been proposed to be the categories that unfavorably impact morbidity and mortality mostly in observational studies but until today the benefit to risk ratio remains largely undetermined. In the study there was no difference in the use of sulphonylureas between the groups of HbA1c variations but the use of insulin was higher in those with higher variability.2-4 This fact can affect the results in two dinstict ways: The insulin may predispose patients to HFpEF as well as to increased HbA1c variability. However, the relation of the latter with the risk of HF was independent of other factors in multivariate

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analysis including insulin therapy.1 In the same lines, high risk patients in large randomized controlled trials have decreased the incident HF by the novel antidiabetic agents such as sodium-glucose cotransporter type 2 inhibitors, empaglifozin and canaglifozin.3,7,8 Contrariwise the other new drugs like

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dipeptidyl peptidase-4 (alogliptin, sitagliptin) and the glucagon-like peptide-1 agents had no effect on HF hospitalization.3 Of note these types of antidiabetic therapy were not provided in the patients of this study thus, their effects on both HFpEF incidence and HbA1c variation cannot be elucidated.1 In the

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future the use of empaglifozin and canaglifozin might be extended as a therapy of HF in diverse subgroups including hypertension and diabetes mellitus but no insights can be provided from the

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present report.

Focusing on the impact of antihypertensive drugs, it is established and stated in the ESC/ESH guidelines that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be preferred in the setting of hypertension and diabetes due to the positive effect on glucose metabolism,

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especially in the presence of renal dysfunction under close monitoring.3,9 B-blockade in hypertension has been challenged mainly because of the negative trials with atenolol-based therapies and the alteration of hypoglycemia awareness and recovery by this category of antihypertensive drugs is a clinical issue. In

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the present study, no differences were also observed in the type of blood pressure lowering therapies along with no data on diuretic use that could potentially influence both glycemic control as well as the

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HFpEF phenotype and diagnosis.9

The main finding of this interesting work by Gu J et al, is that not the once determined level of glucemic load as reflected by the mean HbA1c impacts the incidence of HFpEF but the variability of this parameter providing evidence for the clinical importance of the dynamic dimension of glucose control.1 If the authors had more data available regarding visit-to-visit blood pressure and 24-hour ambulatory data two emerging parameters related to increased cardiovascular risk could be assessed.5,6,10 The problem with variability is the arbitrary cut-off values used and the complexity of estimation that can

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lead to different ways of expressing similar biological phenomena which resulted to contradictory data in the literature not only for blood pressure variability but also for the glucose variations.11 If one is based on the pathophysiology it is evident that fluctuations of glycemia damages the endothelium, the

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mechanisms linked to vascular function and structure, epigenetic changes, disturbed cellular metabolic memory, insulin resistance and pro-inflammatory activation in tandem with sympathetic nervous system overdrive.5,6,12 Additionally, as also commented by the authors the lack of consistency in the diabetic

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therapy due to decreased compliance is associated with the higher HbA1c variability and this could signify that those patients who developed HFpEF were those with a more “unhealthy” behavior

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regarding lifestyle and medication adherence.

In conclusion, this study highlights the important clinical triad of hypertension, diabetes mellitus and HFpEF. As physicians we should take into account the concept of the changes of parameters through time like the HbA1c variability and not merely focus on once measured values. Regarding the possibility

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of improving glucose control in diabetic hypertensive patients apart from guideline based therapies a more strict follow-up is needed in those high risk patients in order to improve overall cardiovascular outcome. As cardiologists we will face a huge “burden” of HFpEF patiens in the years to come and a

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significant proportion of them will be diabetic and hypertensive. We urgently need more studies on time weighting of glucose values in this setting and improve our awareness and management of HFpEF based

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on the novel diagnostic and therapeutic tools.

References

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2. Greene SJ, Vaduganathan M, Khan MS, Bakris GL, Weir MR, Seltzer JH, Sattar N, McGuire DK, Januzzi JL, Stockbridge N, Butler J. Prevalent and Incident Heart Failure in Cardiovascular Outcome Trials of Patients With Type 2 Diabetes. J Am Coll Cardiol. 2018 Mar 27;71(12):1379Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, Paulus WJ, Komajda

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