|Year : 2020 | Volume
| Issue : 4 | Page : 100-108
Emerging role of natriuretic peptides in diabetes mellitus: New approaches for risk stratification
Alexander E Berezin1, Alexander A Berezin2
1 Internal Medicine Department, State Medical University, Ministry of Health of Ukraine, Zaporozhye, Ukraine
2 Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine, Zaporozhye, Ukraine
|Date of Submission||16-Jan-2020|
|Date of Acceptance||24-Aug-2020|
|Date of Web Publication||13-Oct-2020|
Prof. Alexander E Berezin
Internal Medicine Department, State Medical University, 26, Mayakovsky Av., Zaporozhye, Postcode 69035
Source of Support: None, Conflict of Interest: None
Keywords: Biomarkers, cardiovascular risk, natriuretic peptides, prediabetes, type 2 diabetes mellitus
|How to cite this article:|
Berezin AE, Berezin AA. Emerging role of natriuretic peptides in diabetes mellitus: New approaches for risk stratification. Heart Mind 2020;4:100-8
| Introduction|| |
Diabetes mellitus (DM) remained the most common metabolic disorder worldwide occupying the 8th leading cause of death. The global statistics of DM yielded about 382 million people had this disease in 2013 and by 2030 the number of diabetics will reach 500 million people. According to the Reduction of Atherothrombosis for Continued Health registry, patients with type 2 DM (T2DM) had a higher risk of cardiovascular (CV) death, nonfatal myocardial infarction, or nonfatal stroke in comparison with the patients without T2DM. Therefore, T2DM was independently associated with a 33% greater risk of hospitalization for heart failure (HF), HF-related outcomes, and CV death., In addition, T2DM and CV diseases frequently coexist and CV risk factors influence significantly on manifestation and progression of both conditions. Although CV factors are affected by some antidiabetic medications, there is not complete correspondence between a control for conventional CV risk factors including glycemic status by lifestyle modification, drug prescription, and diminishing risk of T2DM-related outcomes and CV complications.,, Moreover, T2DM patients without established CV disease may have even at a greater mortality risk to non-T2DM patients with known CV disease. In this context, advanced risk stratification strategy among the patients with prediabetes and known T2DM requires to be personally modified by used biomarker prediction scores.
Among numerous circulating biomarkers and multiple biomarker-based models reflecting various pathophysiological stages of the development of both T2DM and HF natriuretic peptides (NPs) continue to be a core element in the strategy of CV risk assessment and molecular target for guided therapy of HF. However, serious variability of circulating levels of NPs in the patients with metabolic diseases, including abdominal obesity, metabolic syndrome, and T2DM, requires an adjustment of the diagnostic and predictive cutoff points for NPs, whereas the NPs remain useful biomarker for HF diagnosis and prediction of all-cause mortality, CV death, and HF. The aim of the mini review is to accumulate current knowledge toward controversial prognostic role of circulating NPs in patients with prediabetes and established T2DM.
| Myocardial Biomechanical Stress in Type 2 Diabetes Mellitus|| |
Previous magnetic resonance imaging studies have revealed that alterations in glucose metabolism were independently associated with left ventricular (LV) concentric remodeling, less spherical shape, and reduced systolic myocardial shortening in the general population.,,.
[Figure 1] reports the principal molecular mechanisms that correspond to T2DM-induced cardiomyopathy and HF.
|Figure 1: Pathophysiological mechanisms of the development of T2DM.induced cardiomyopathy and HF. CV = Cardiovascular, FFA = Free fatty acids, AGEs = Advanced glycation end products, RAGEs = Receptors for advanced glycation end products, GDM = Gestational diabetes mellitus, T2DM = Type 2 diabetes mellitus, CMP = Cardiomyopathy|
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However, T2DM-induced cardiomyopathy is heterogenic term that includes several conditions, such as autonomic cardiomyopathy, cardiac hypertrophy, adverse cardiac remodeling, and HF [Figure 2]. At early stage of T2DM-induced cardiomyopathy, isolated diastolic dysfunction and autonomic cardiomyopathy can be determined, whereas at the late stage HFpEF is the most common condition., The speckle-tracking echocardiography studies have yielded that myocardial shortening, LV torsion and myocardial strain was progressively decreased with higher HOMA-IR and torsion was increased only with less severe insulin resistance in individuals with prediabetes., In the coronary artery risk development in young adults study, patients with established T2DM had lowered LV ejection fraction (LVEF), longitudinal systolic strain, and early diastolic strain rate when compared with patients having normal glucose metabolism. The population STAAB cohort study has demonstrated that LV global longitudinal strain and torsion were inversely associated with glycosylated hemoglobin and insulin resistance and that these parameters were found significant lowered in diabetics in compared with nondiabetics without known CV disease.
|Figure 2: Types of T2DM-induced cardiomyopathy and key pathophysiological mechanisms. T2DM = Type 2 diabetes mellitus, HFrEF = Heart failure with reduced ejection fraction, HFpEF = Heart failure with preserved ejection fraction|
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In fact, glucose abnormalities, lipid toxicity, altered tissue reparation, accelerating atherosclerosis, and coexisting conventional CV risk factors are causes to develop diabetic cardiomyopathy as well as HF related to ischemia causes., In addition, atherosclerosis, systemic and microvascular inflammation, myocardial fibrosis, myocardial infarction, or LV contractile/diastolic dysfunction due to microvascular obstruction are the main causes for myocardial remodeling, for which myocardial biomechanical stress is discussed as crucial pathogenetic mechanism, leading to HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Indeed, several molecular mechanisms, such as renin–angiotensin system activation, cardiac autonomic neuropathy, alterations in calcium homeostasis, generation of reactive oxygen or nitrogen species lead to mitochondrial dysfunction, which contributes to ischemic myocardial injury in T2DM. Moreover, mitochondrial dysfunction represents the major cause of death in diabetics regardless of presence of coronary artery disease (CAD) and hypertension. Having evidence that conventional CV risk factors, CAD, and diabetic cardiomyopathy influence negatively on mortality rate and quality-of-life among T2DM patients, there is a suggestion that cardiac biomarkers reflecting various stages of adverse cardiac remodeling and HF advance, such as NPs, would ensure add-on incremental value for the prediction of clinical outcomes (death, major adverse cardiac events [MACEs], hospital admission, and HF-related events) in the patient population. Moreover, the levels of NPs may exhibit personifying predictive information that would be able to yield the greatest predictive potency beyond conventional CV risk factors.
| Natriuretic Peptides: biological Role and Function|| |
Biological role of NPs' system as a core element of water and sodium homeostasis is well established and pervasively known. Indeed, predominantly atrial (atrial natriuretic peptide) and brain natriuretic peptide (BNP) and rarely C-type of NP are embedded onto a regulation of cardiorenal homeostasis through appropriate receptor A (NPRA). Clearance of NPs is mediated by their proteolysis by endogenous endopeptidase called neprilysin that activates physiological pathways by which NPs are effectively removed from circulation through receptor-mediated internalization by the NP receptor C (NPRC). In fact, both circulating levels of neprilysin and the NPs' receptors (NPRA and NPRC) ensure the NP bioactivity.
[Table 1] contains data regarding the primary and additional biological function of the NPs.
|Table 1: Biological role, function and origin of various natriuretic peptides|
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The main triggers for NPs' secretion are myocardial stretching, fluid overload, ischemia/hypoxia, inflammation, and renin–angiotensin–aldosterone system (RAAS). Although system of the NPs is a physiological antagonist of RAAS, there is a wide range of evidence regarding that the NPs through adipose tissue-expressed NPRA and NPRC reciprocally regulate lipolytic activity of adipocytes similar to catecholamine-derived effect that is mediated by the β-adrenergic receptors. In addition, NPs via p38 MAP kinase act as a trigger for overexpression of brown fat genes to increase energy expenditure and regulate adaptive thermogenesis. Therefore, in human cells, including adipocytes, muscle cell, and hepatocytes, NPs promote transcriptional regulation of genes involved in mitochondrial biogenesis, uncoupled respiration (peroxisome proliferator-activated receptor-γ coactivator-1α, and uncoupling protein 1), lipid oxidation, as well as glucose tolerance insulin resistance., Overall, activation of NPRA signaling system in skeletal muscle and hepatocytes is crucial for the maintenance of long-term insulin sensitivity and this phenomenon can link a transformation of prediabetes to T2DM as well as ensures rockets of CV risk., Both C-type of NP and urodilatin provide cardiac and renal protection, reduce blood pressure, induce diuresis, and regulate water and electrolyte homeostasis.,,,
| Circulating Levels and Expression of Receptors for Natriuretic Peptides in Prediabetes and Type 2 Diabetes Mellitus|| |
Previous studies have shown that the patients with abdominal obesity, metabolic syndrome, and T2DM had low levels of NPs in comparison with healthy volunteers and that this finding related to increased clearance of NPs. Indeed, NPs are degraded by neprilysin, an activity of which was found to be elevated among the majority of the patients with prediabetes., In addition, insulin may upregulate the NPRC expression in white adipose tissue in obese individuals, while the difference between healthy volunteers and obese patients in the circulating levels of NPs has not been determined by several investigators., Therefore, kidney clearance of NPs was found to be worse in T2DM with nephropathy due to altered glomerular filtration and that was associated with increased circulating levels of BNP and N-terminal prohormone BNP (NT-pro-BNP). However, the reasons for NP level fluctuation in patents with metabolic disease remain uncertain.
Besides being reduced circulating levels of NPRA in obese patients and prediabetics, the expression of the skeletal muscle NPRA is downregulated?. In contrast, it has been found that the number of NP clearance receptors, which are expressed on the surface of the skeletal muscle cells, increased in individuals with either established impaired glucose tolerance or T2DM. Collectively, altered NP receptor/cyclic GMP signaling in skeletal muscle was associated with downregulation of lipid oxidative capacity, increased mitochondrial stress, and increase in IR., Perhaps, NP receptor signaling system is essential for skeletal muscle energy metabolism and downregulation of the NPRA influences muscle weakness and decreased tolerability to physical exercise. Taken together, NP system acts as a powerful endogenous regulator of biomechanical coupling in skeletal muscle mediating glucose tolerance and lipid oxidation and thereby prevents obesity and T2DM. Manifestation of prediabetes often corresponds to NPRA dysfunction and low circulating NP levels in peripheral blood.
| Natriuretic Peptides in Heart Failure Associated with Abnormalities of Glucose Status|| |
Current clinical guidelines have been recommended to measure NP levels to diagnose HF when diagnosis is uncertain, to stratify patients from general population into group at higher CV risk and HF manifestation, as well as to prognosticate risks of HF advance and 60-day readmission regardless of the presentation of abdominal obesity, prediabetes, and T2DM., However, asymptomatic patients from general population should have higher circulating levels of NT-proBNP (>300 pg/mL) when compared to individuals having signs and symptoms of HF (125 pg/mL) to be stratified at a risk of death and HF onset. In fact, increased age requires rechecking diagnostic NT-proBNP cutoff point for patients suspecting cardiac dysfunction., Interestingly, among patients without T2DM, elevated levels of NPs yielded greater predictive accuracy for CAD, MACEs, CV mortality, and HF manifestation in comparison with T2DM patients., Although the circulating levels of NT-proBNP did not differ between male and female in general population, elevated NT-proBNP concentrations conferred a higher risk of mortality due to HFpEF in women only, but not in male. However, T2DM patients have demonstrated more pronounced LV hypertrophy and adverse cardiac remodeling, but systolic and diastolic LV function parameters and NT-proBNP serum levels were found to be similar in T2DM and non-T2DM patients. Therefore, serum levels of NPs were found to be independent predictors for atherosclerosis, albuminuria, atrial fibrillation, pulmonary hypertension, and sudden death in patients with abdominal obesity, metabolic syndrome and T2DM, but among patient with HFrEF predictive value of NPs for these outcomes related to the presentation of prediabetes and T2DM.,,, Patients with overweight and abdominal obesity not having T2DM had lower NT-proBNP levels to T2DM patients with and without obesity and higher levels of NT-proBNP to healthy volunteers. In fact, elevated NT-proBNP levels remain a powerful predictive tool to diagnose cardiac abnormalities regardless of glucose status. Moreover, multiple biomarkers' models including NPs occurred to be more prognostically accurate for HF manifestation in non-T2DM patients that in prediabetics with abdominal obesity and T2DM patients.,
There are several controversies regarding predictive abilities of elevated levels of NPs in patients with metabolically healthy obesity and metabolic syndrome. First controversy affects evidence of the fact that NPs were not better to conventional cardiac biomarkers, such as cardiac troponins, soluble ST2, ischemia-modified albumin, in prediction of the occurrence of future microvascular and macrovascular complications in obese/ prediabetes patients without known CV disease. In contrast, metabolic biomarkers (adiponectin, resistin, chemerin, and visfatin) sufficiently increased predictive value of NT-proBNP levels for MACEs in patients with various glucose statuses and established HF.,, The next controversy ties to inverted association between serum levels of NPs (atrial and brain pro-NPs) and the number of components of the metabolic syndrome in young people without established CV disease.
Finally, elevated levels of NT-proBNP remain a strong predictor for CV death among patients with established CV diseases including CAD and HF, even with the confounding effect of prediabetes and T2DM, but cutoff points for serum levels of BNP/NT-proBNP require to be elucidated thoroughly. However, it is still uncertain whether the discriminative potency of NPs for CV death and events in prediabetes and T2DM populations beyond CV disease would be independent from traditional CV risk factors.
| Controversial Prognostication Abilities of Natriuretic Peptides in Clinical Trials among Type 2 Diabetes Mellitus Patients|| |
Recently completed EMPEROR-Reduced trial has elucidated that SGLT-2 inhibitor empaglyflosin was better to placebo in improvement of mortality and HF-related clinical outcomes in connection with NT-proBNP dynamics. In the SGLT-2 inhibitor canaglyflosin in the CANVAS trial led to reduce the occurrence of CV death, myocardial infarction, HF, or stroke along with a decrease in serum levels of NT-proBNP when compared to placebo. [Table 2] is summarizes randomized clinical study design, the number of participants, antidiabetic care, CV outcomes, and NP level changes among patients having prediabetes and T2DM.
|Table 2: Natriuretic peptide measure I connection with cardiovascular clinical outcomes in prediabetes and type 2 diabetes mellitus patients clinical trials|
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The SAIS2 (Sapporo Athero-Incretin Study 2) has revealed that GLP-1 liraglutide and insulin glargine demonstrated similarity in glycemic improvement without changes in NP levels. The T2DM patients with stable CAD and normal values of LVEF who were treated with SGLT-2 inhibitor empagliflozin or placebo were recruited in the EMPA-HEART CardioLink-6., The results of the study have shown that adverse cardiac remodeling was significantly improved by empagliflozin, while circulating levels of NT-proBNP in both patient cohorts were similar. The Empire HF (Empagliflozin in HF Patients With Reduced Ejection Fraction) is now ongoing and the results have not still published.
In contrast, among patients with prediabetes and T2DM without HF serum levels of NT-proBNP remained unaltered regardless of improving glucose homeostasis and decreased CV risk. Interestingly, the change in NT-proBNP serum levels correlated negatively with baseline NT-proBNP levels in T2DM. In addition, in the DEFINE-HF Trial SGLT-2 (sodium-glucose cotransporter 2), inhibitor dapagliflozin did not affect changes in NT-proBNP serum levels, but increased the proportion of patients (as diabetics, as well as nondiabetics) experiencing clinically meaningful improvements in HFrEF-related clinical status. DAPA-HF (dapagliflozin in patients with HF and reduced ejection fraction) trial has yielded a superiority of SGLT2 inhibitor dapagliflozin to placebo in reduction of the MACEs and HF-related outcomes in patients with established HFrEF, but circulating levels of NPs including NT-proBNP were not significantly modified. The authors of the study concluded that the therapy with SGLT-2 inhibitors did not modulate the actions of NP and probably was not associated with decrease in preload and stimulation of diuresis. In contrast, SGLT-1 and -2 inhibitor licogliflozin significantly decreased the levels of NT-proBNP when compared to placebo in patients with T2DM and HFrEF, but there was no sufficient difference between circulating NT-proBNP levels in patients treated with licogliflozin and empagliflozin. Soga et al. reported that SGLT02 inhibitor dapagliflozin influenced positively on adverse cardiac remodeling, but there were no significant changes in BNP over 6-month administration. However, the authors found that the only high concentrations of BNP (≤100 pg/mL) demonstrated a significant decrease over time. Recently completed EMPEROR-Reduced trial has elucidated that SGLT-2 inhibitor empaglyflosin was better to placebo in improvement of mortality and HF-related clinical outcomes in connection with NT-proBNP dynamics. In the SGLT-2 inhibitor canaglyflosin in the CANVAS trial led to reduce the occurrence of CV death, myocardial infarction, HF, or stroke along with a decrease in serum levels of NT-proBNP when compared to placebo. Moreover, this drug was effective in patients with either HFrEF or HFpEF.
It is difficult to speculate a plausible mechanistic reason why GLP-1 analogs and SGLT2 have demonstrated a controversial effect on NP circulating levels in patients with T2DM having HF or no having HF. Perhaps, SGLT-2 inhibitors demonstrated cardiac and kidney protective effects improving metabolic control, oxidative stress, systolic and diastolic functions, and endothelial function, whereas GLP-1 analogs did not have such a variable spectrum of positive impacts on the target organs. As a result of improvement of adverse cardiac remodeling and kidney function, SGLT-2 inhibitors demonstrated an ability to reduce circulating levels of NT-proBNP when they were elevated, while normal and near normal levels of NPs were not modified by these drugs. Thus, high variability of the impact of SGLT-2 inhibitors on NP changes during serial measures may relate to heterogeneity of study patient populations and hyperglycemia controls with antidiabetic drugs. In addition, older people with T2DM at high CV risk treated with SGLT-2 inhibitors during 6 months had lowered levels of NT-proBNP over time, but the signs of decreased preload (tendency to decrease in diameter of the inferior vena cava and intravascular collapse) were not observed. However, the main cause why serum levels of NPs exhibited high variability in numerous clinical trials remained to be uncertain.
Interestingly, dipeptidyl peptidase (DPP)-4 inhibitors had been reported to have neutral effect than deteriorating impact on myocardium in preclinical studies and early large-scale trials.,, The EXAMINE (Examination of CV Outcomes with Alogliptin versus Standard of Care) trial was included T2DM patients with known CAD treated with DPP-4 inhibitor alogliptin or placebo. The authors found that increase in NT-proBNP plasma levels or persistently high NT-proBNP levels over 6 months were strongly associated with the occurrence of major CV events, whereas low levels of the biomarker accompanied with improved clinical outcomes. However, on the one hand, DPP-4 inhibitors may increase the ability of GLP-1 to stimulate cyclic adenosine monophosphate in cardiac myocytes, and on the other hand, they potentiate the effects of stromal cell-derived factor-1 aggravating cardiac fibrosis and indirectly increase in circulating levels of NPs. Finally, an increased risk of HF progression appeared to be a class effect of DPP-4 inhibitors, even in patients without a history of HF. However, other antidiabetic drugs, i.e., metformin and thiazolidinediones, did not demonstrate predictably clear impact on circulating levels of NPs. Indeed, metformin did not increase the concentration of NPs, but thiazolidinediones through fluid retention acted as triggers for NP level elevation.
| Conclusions|| |
NPs are a useful tool for CV risk stratification among patients with prediabetes and T2DM regardless of HF presentation.Occurrence HFrEF / HFpEF in T2DM patients requires the modification of NP cut-off points to establish primary diagnosis of HF and determine HF-related risks. There are several controversies between clinical outcomes and dynamic of circulating levels of NPs in diabetics treated with GLP-1 agonists and SGLT2 inhibitors that needs to be elucidated in large clinical studies in the future.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]