Heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus: pathophysiology and treatment options

Introduction

Heart failure (HF) and diabetes mellitus (DM) are considered to be the diseases representing the most important problem of modern healthcare. The prevalence of these pathologies is progressively increasing every year; more and more often they are increasingly accompanying each other. Thus, more than 40% of patients with HF suffer from DM [1], while the HF phenomena are observed in 10–23% of cases in patients with DM [2].

DM is one of the main risk factors for HF development, as it contributes to the damage of both the coronary bed and the structural myocardium components, leads to diabetic cardiomyopathy development.

DM also affects the prognosis of patients suffering from HF, which is mainly associated with the development of macro- and microvascular complications. Thus, according to a large registry, the three-year survival rate in patients with HF and DM, being hospitalized for decompensation of HF, was 28% lower than in patients without diabetes [3].

Heart failure with preserved ejection fraction

The concept of heart failure with preserved ejection fraction (HFpEF) has appeared relatively recently. The first publications [4, 5] on this problem were presented in the American Journal of Cardiology in 1984 and 1985. Nevertheless, today more than 50% of all the patients suffering from HF also have a preserved ejection fraction [6], and the prevalence of HFpEF keeps on increasing every year [7].

It is important to note that at this very moment, there is no treatment improving the prognosis of patients with HFpEF. The standard HF treatment aimed at suppressing the neurohumoral triad, which has proven itself well in patients with a reduced ejection fraction, does not have any significant effect on the prognosis of patients suffering from HFpEF. This issue was studied within four large randomized studies: CHARM-PRESERVED [8], PEP-CHF [9], I-PRESERVE [10], and TOPCAT [11], but no statistically significant improvement in prognosis was observed in any of them.

Heart failure with preserved ejection fraction and diabetes mellitus

Unfortunately, the combination of HFpEF and DM is becoming more and more common, and each of the diseases worsens the prognosis of another one. Thus, it became clear that patients with HFpEF suffering from DM were younger and more prone to obesity, arterial hypertension, and renal failure than HFpEF patients without DM [12]. Patients with DM were also characterized by a large thickness and mass of the cardiac walls and a larger volume of cardiac chambers. Despite the fact that some parameters of systolic and diastolic functions were similar in patients with and without DM, the former ones demonstrated a tendency to increase the filling pressure of the left ventricle [12]. Patients with HFpEF suffering from DM are also characterized by a lower level of life quality, an increased frequency of hospitalizations, and a high risk of cardiovascular complications [13].

Molecular mechanisms underlying the pathogenesis of HFpEF in patients suffering from DM

DM plays an important role in HFpEF development and progression, as it leads to structural changes in the heart and blood vessels (endothelial dysfunction, fibrosis, and hypertrophy of cardiomyocytes, as well as the concretion of advanced glycation end products (AGEs) in the myocardium) [14]. In addition, diabetes, as well as often accompanying obesity and hypertension, contribute to maintaining a chronic low-intensity proinflammatory body status. Usually, it is accompanied by the activation of reactive oxygen species, disturbance of oxide synthesis, increased myocardial stiffness and hypertrophy [15]. The loss of the “metabolic flexibility” of the myocardium also has a great influence on the disease course.

 Metabolic myocardium flexibility

The main energy substrate of a healthy person’s myocardium is fatty acids (FAs); their beta-oxidation provides 70–90% of the total energy demand of the myocardium. The remaining 10–30% accounts for glucose oxidation. Such “metabolic flexibility”, due to the presence of different substrates for energy production, is extremely important for the adequate functioning of the myocardium, especially during physical exertion.

There is a transition from the use of glucose to the full or almost complete use of FAs in the myocardium of a patient suffering from DM, which leads to a metabolically “inflexible” FA-dependent state. These changes are largely due to an increase in the level of FAs, triglycerides, and non-esterified FAs in the myocardium of patients suffering from DM [12]. This fact can be explained by the point that the FA capture by cardiomyocytes is not hormonally regulated, therefore high amounts of FAs enter the heart disproportionately according to a concentration gradient, suppressing the glucose capture. As a result, the necessary level of adenosine triphosphate is provided only by beta-oxidation of FAs. Although it is able to provide cardiomyocytes with the necessary amount of energy, anyway, it requires one and a half times more oxygen than glucose oxidation, which ultimately inevitably leads to oxidative stress.

Myocardial stiffness and advanced glycation end products

Hyperglycemia is an inherent condition that accompanies the course of diabetes. Due to the increased blood glucose level in the myocardium, the glycation process (non-enzymatic glycosylation) of interstitial proteins begins, which plays a key role in HFpEF pathogenesis in patients with DM. The glycation end products then are covalently bound to the protein amino groups, forming the intercollagen compounds [16]. Such collagen connections lead to an increase in myocardial stiffness and a violation of the diastolic heart function.

The ability of the myocardium to diastolic relaxation is determined by the rigidity of its two departments: the extracellular matrix and cardiomyocytes [17]. The stiffness of the extracellular matrix is determined by the total amount of collagen, the proportion of type 1 collagen and intercollagen bonds, the number of which increases significantly due to AGEs.

Therefore, AGE deposition occurs not only in the myocardium. The connections formed between type 1 collagen and elastin in blood vessels lead to an increase in their stiffness and contribute to the formation of systemic arterial hypertension [18]. It also contributes to HFpEF development and progression.

Titin isoforms

Violation of the myocardium diastolic function is also closely related to the ratio of various titin isoforms in it. Titin is one of the largest proteins in the human body, which plays a significant role in the myocardial relaxation process. In cardiomyocytes, titin is expressed in two main isoforms: N2BA and N2B; the second one is of greater rigidity. The ratio of titin isoforms in cardiomyocytes is controlled by PHI-3K/PKB signaling pathways (phosphatidylinositol-3-kinase/protein kinase B), which are regulated by thyroid hormones. However, it has been shown that these same pathways can be activated by hyperinsulinemia [17] accompanying the type 2 diabetes course. As a result, the ratio of titin isoforms shifts in favor of a larger amount of the rigid N2B form. It leads to an increase in the rigidity of cardiomyocytes and thereby, as was discussed earlier, to a violation of the myocardium diastolic function.

In addition to the mechanism which has been already described, it is important to note that an even greater increase in the stiffness of cardiomyocytes is possible in patients with DM. It happens due to the formation of disulfide bonds inside the titin molecule [19]. This process is potentiated by the oxidative stress accompanying the course of diabetes mellitus.

Pro-inflammatory status, oxidative stress, and lipotoxicity

According to modern concepts, the main role in HFpEF pathogenesis is assigned to systemic inflammation. The main diseases that contribute to maintaining the pro-inflammatory body status are diabetes, as well as obesity and arterial hypertension accompanying it. The inflammation supported by these diseases leads to the activation of reactive oxygen species, slows down the nitric oxide (NO) synthesis, and triggers a true cascade of events leading to increased myocardial stiffness and hypertrophy [15].

As has been discussed above, the total amount of free FAs and non-esterified fatty acids (NEFAs) in the myocardium increases. An important NEFA feature is the point that such acids do not undergo beta-oxidation and accumulate in the intracellular space of cardiomyocytes. The reaction of the intermediate NEFA product (palmitoyl-CoA) and the serine amino acid forms ceramide. It is known that ceramide triggers the process of cell apoptosis [20] through the activation of caspase-3 and cytochrome C. It also plays an important role in HFpEF pathogenesis.

The increased levels of free FAs and NEFAs, as well as hyperglycemia, lead to the activation of protein kinase C (PKC) through insulin signal modification. PKC is involved in the regulation of cell membrane permeability in the myocardium, as well as in the cardiomyocyte contractility and extracellular matrix homeostasis. In patients suffering from DM, the functions of all of the above-mentioned processes are disrupted.

PKC is also able to activate substances such as transforming growth factor beta (TGF-β) and connective tissue growth factor (CTGF). PKC promotes the synthesis of nuclear factor kappa B (NF-kB), atrial natriuretic peptide, and c-Fos oncogene [21]. In some studies, it has been noted that a specific isoform of PKC – PKC-β is activated in patients with DM. Overexpression of this PKC form in mice led to an increase in the levels of atrial natriuretic peptide, transforming growth factor beta-1 (TGFß-1), and collagens of types IV and VI. It is assumed that all of the above-mentioned substances are somehow involved in HFpEF pathogenesis. Currently, the direct inhibitors of PKC-β have been invented, and ruboxistaurin is one of them. In a DM and HFpEF model on rodents, the use of ruboxistaurin led to the improvement of the diastolic function, a decrease in the mass of the left ventricular (LV) myocardium, and a decrease in the extracellular matrix volume [22]. The effect was achieved due to the inhibition of TGF-β.

Changes in insulin signaling pathways

The glucose uptake by cardiomyocytes is regulated by insulin, a hormone produced by the beta cells of the pancreas. Insulin implements this function with the help of transporters of types 1 and 4 (GLUT-1 and GLUT-4), among which GLUT 4 is most common for the myocardium. It is known that the synthesis of GLUT-4 slows down significantly in patients with diabetes, which leads to a decrease in glucose uptake. It in turn leads to an increase in insulin synthesis and hyperinsulinemia. Hyperinsulinemia activates the PHI-3K/PKB signaling pathways by activating the protein kinase B (PKB) [23]. It triggers processes that lead to an increase in the size of cardiomyocytes. The excessive stimulation of this pathway may possibly lead to the development of myocardial hypertrophy.

At the same time, hyperinsulinemia also leads to PKC activation, which activates TGF-β [23]. The activation of these signaling pathways contributes to the development of myocardial hypertrophy and interstitial fibrosis, which are characteristic of patients with HFpEF and DM [24].

Endothelial dysfunction

Currently, it is well known that the endothelium not only performs a barrier function but also represents an important regulatory system that functions through autocrine and paracrine mechanisms. The endothelial dysfunction is considered to be the central mechanism of HFpEF pathogenesis. The main manifestations of endothelial dysfunction are impaired vasodilation, increased vasoconstriction, increased arterial stiffness, and accelerated atherogenesis [25].

The endothelium produces an enzyme-endothelial NO synthase, which is necessary for NO synthesis. In patients with DM, as has been already mentioned, PKC has high activity. It activates the NF-kB signaling pathway, leading to a decrease in the synthesized NO, which, as it has been already described above, leads to an increase in myocardial stiffness [26].

A special role in the implementation of intercellular interaction is played by transmembrane integrin proteins that are important adhesion receptors in the extracellular substance [27].

Such biological processes as proliferation, hypertrophy of cardiomyocytes, the transformation of endothelial cells into mesenchymal cells, migration and proliferation of fibroblasts, as well as differentiation of myofibroblasts, are regulated within the participation of integrins [27].

In patients with DM, structural and mechanical changes in the glycated extracellular matrix lead to a change in the frequency of integrin activation, thereby triggering the above-mentioned processes, as well as leading to a change in the expression rate of some biologically active substances (in particular TGF-β).

Thus, an increased expression of integrin α-11 was detected in experimental models of DM, which led to the stimulation of myofibroblast differentiation and ultimately to myocardial fibrosis through the activation of TGF-β [28].

The main therapy ways for patients suffering from HFpEF and DM

It is known that HFpEF is much more common among patients with type 2 diabetes (as opposed to patients with type 1 diabetes), and therefore it is assumed that there are mechanisms other than hyperglycemia complications that contribute to HF development [29].

Currently, no drug has proven its effectiveness in HFpEF treatment [30], and therefore, the treatment of such patients is mainly reduced to the treatment of concomitant pathologies.

Renin-angiotensin-aldosterone system

An increase in the activity of the renin-angiotensin-aldosterone system (RAAS) is observed in both DM and HFpEF [31]. The RAAS triggers a number of hypertrophic and profibrotic cascades through angiotensin II and aldosterone, which leads to ventricular fibrosis and hypertrophy, vasoconstriction, and vascular remodeling. All of the above-mentioned problems contribute to HFpEF development. In this regard, most patients receive either angiotensin-converting enzyme inhibitors (so-called ACE inhibitors) or angiotensin receptor blockers in order both to slow the progression of HFpEF and to treat hypertension. However, the data on the RAAS contribution to inhibition in order to reduce the frequency of hospitalizations and mortality in patients with HFpEF and DM are ambiguous (according to the results of various studies and meta-analyses). Therefore, elderly people with HF, who took this medicine, demonstrated a decrease in both the frequency of hospitalizations and mortality (according to the results of a major study about the effect of ACE inhibitors, perindopril, and PEP-CHF). However, the study included a smaller number of patients than it had been planned; thus, the necessary level of statistical significance was not achieved. According to the data obtained in the study of candesartan in patients suffering from HF, CHARM-preserved, the use of the medicine moderately reduced the frequency of hospitalizations for the cases of HF. However, similar results were not obtained in the study of irbesartan, I-PRESERVE. In some clinical studies, it has been proven that the use of mineralocorticoid receptor antagonists leads to a decrease in mortality and hospitalization frequency in patients with HFpEF [32]. However, in the TOPCAT study, the use of spironolactone in patients with HFpEF did not lead to a decrease in mortality from cardiovascular causes, nor to a decrease in the frequency of HF hospitalizations. Anyway, it can be noted (upon a more detailed review of the TOPCAT study results) that in Russia and Georgia, the frequency of reaching the primary endpoint was significantly lower than in other participating countries. According to some experts’ opinion, it happens due to the study inclusion of less severe patients in Russia and Georgia than it was required. The statistical significance of the primary endpoint was achieved while excluding the data of these countries from the analysis, but it is hardly legitimate to form any conclusions from the results of such manipulations. Thus, the final result of the TOPCAT program is still considered a negative one. It is worth noting that at this very moment, a new spironolactone study is being conducted in patients suffering from HFpEF; it is a kind of TOPCAT 2.0 – the SPIRRIT-HFPEF study (NCT02901184), which is expected to be completed in the summer of 2022.

Thus, at this moment, the results of studies concerning the use effectiveness of RAAS inhibitors in HFpEF are contradictory.

The anti-proliferative effects of RAAS are of particular interest, especially those carried out, in particular, by ACE-2 and angiotensin 1-7 [33]. ACE-2 is widely distributed in the human body and participates in the regulation of biological processes in fibroblasts, cardiomyocytes, and endothelial cells [34]. This enzyme works as a counterweight to ACE. Thus, ACE converts angiotensin I-converting enzyme into a vasoconstrictor (angiotensin II), while ACE-2 hydrolyzes angiotensin II into a vasodilator (angiotensin 1-7).

Recent studies have demonstrated a link between ACE-2 inhibition and the development of HFpEF in mice with type 1 diabetes [34]. In this study, a decrease in the ACE-2 activity led to a deterioration of systolic and vascular functions. Currently, recombinant human ACE-2 (rhAPF2) is considered a potential medicine for HF treatment. The recombinant human ACE-2 slowed angiotensin II-dependent myocardial remodeling while reducing pressure overload (which was shown in a study on mice with HFpEF) [34]. The action of angiotensin 1-7 is carried out by activating the Mass receptor conjugated with the G-protein, as a result of which the opposite effects of angiotensin II are realized [33]. Currently, synthetic analogs of angiotensin 1-7 and substances capable of ACE-2-stimulating have been created. Both groups of these substances in the future can make a significant contribution to the formation of a strategy for HFpEF treatment in patients with diabetes, but at this very moment, clinical studies of potential medicines have not yet been conducted.

Cascade activated by nitrogen oxide

The endothelial dysfunction is an important part of DM pathogenesis and contributes to HFpEF formation through the pathway activated by NO [35]. The NO pathway activation leads to the formation of cyclic guanosine monophosphate (cGMP), which has an antihypertrophic and antifibrotic effect on the heart [35]. Treatment with organic nitrates and NO is of no value due to the formation of tolerance and a decrease in preload. Now there are several medicines aimed at the NO cascade links that can affect microvascular dysfunction. Recent studies have evaluated the effect of soluble guanylate cyclase stimulants and non-lysine inhibitors to activate the cGMP pathway [36]. In early clinical trials, the stimulant of soluble guanylate cyclase, vericiguat, was well tolerated by patients and was also associated with an improvement in the quality of life and the absence of an increase in NT-proBNP (N-terminal propeptide of the natriuretic B-type hormone) [37]. As for patients with HFpEF, vericiguat showed efficacy compared to placebo in reducing the risk of cardiovascular death and HF hospitalizations [38]. At the same time, the Phase 2B study (VITALITY-HFpEF) did not show the advantages of vericiguat over placebo in improving the quality of life or functional activity in patients with HFpEF [39].

Neprilysin inhibitors are also of great interest as potential medicines for HFpEF treatment. The action of neprilysin inhibitors is based on an increase in the number of biologically active natriuretic peptides, which lead to the activation of cGMP through the stimulation of guanylate cyclase. The only non-lysine inhibitor currently used in clinical settings is sacubitril, being used only in combination with valsartan. In clinical trials, its effectiveness in reducing mortality in HFpEF patients was shown [40]. In the 3^rd phase of the PARADIGM-HF study, where ACE inhibitors and angiotensin receptor and non-lysine inhibitors were compared, the advantage of sacubitril/valsartan compared to enalapril in reducing mortality and the frequency of hospitalizations for HF in patients with HFpEF was shown. Also, as for the sacubitril/valsartan group, better glycemic control was observed in DM patients, as evidenced by a lower level of glycated hemoglobin (HbA1c). The possibility of using this medicine for HFpEF patients was evaluated in the PARAGON-HF study, according to the results of which the statistical significance of the main endpoint could not be achieved. However, a detailed analysis of the research results raises many questions as was the case with the TOPCAT program. First, 6–7 events in the valsartan group were not enough to achieve the statistical significance of the primary program endpoint as a whole, since p = 0.059 was close to significant in this work. Second, if a subgroup analysis is performed, it will be possible to find out that the statistical significance of the main endpoint was achieved in different subgroups of patients; in particular, it happened in patients older than 65 years, in patients with an LV ejection fraction below the median (57%) and in women. Thus, the result of the PARAGON HF program may not be considered as a strictly negative one, so it is necessary to study in more detail what subgroups became the ones where the medicine showed an advantage and why this happened.

Beta blockers

The main effect of beta-blockers on the cardiovascular system is a decrease in the heart rate and a weakening of sympathetic tone. Despite the fact that such effects may seem extremely useful in HFpEF, the study data on the use of this medicine group are also contradictory. Thus, the effectiveness of bisoprolol and carvedilol was shown in HFpEF patients with newly diagnosed diabetes, which was manifested in a decrease in both mortality from cardiovascular diseases and the frequency of HF hospitalizations [41]. In a meta-analysis, the use of beta-blockers in HFpEF cases led to a decrease in mortality from all the causes but did not affect the frequency of hospitalizations [42]. At the same time, the carvedilol effectiveness in HFpEF treatment was not noted in another study [41].

Diuretics

Diuretics are used for the treatment of HF patients regardless of the LV ejection fraction, with preference usually given to loop diuretics [43]. Among such loop diuretics, torasemide is one of those having the greatest interest due to its antialdosterone effects. However, no studies of torasemide have been conducted in the group of HFpEF patients [43].

Glycemic control

In order to determine the role of glycemic control in DM patients, it is worth paying attention to the data of several major studies. Thus, it was shown in the UKPDS study that a 1% decrease in the HbA1c level in DM patients led to a 16% decrease in the frequency of HF development. At the same time (according to the ACCORD and ADVANCE studies), it was not possible to prove that glycemic control is the only factor, which reduces the frequency of cardiovascular complications. Moreover, more severe complications were observed in patients with an HbA1c level of less than 7% [44]. Thus, it is difficult to talk about the positive effect of glycemic control alone on the cardiovascular prognosis at the moment. At the same time, the role of glycemic control in HFpEF and DM patients has not been studied.

New antihyperglycemic medicines

As for the previous studies, medicines such as metformin, sulfonylureas, insulin, and thiazolidinediones were used. Currently, new antihyperglycemic medicines have been produced and they are widely used in combination with metformin. They are also actively being investigated for their effect on the development of cardiovascular complications. These are medications of dipeptidyl peptidase-4 inhibitors (iDPP-4), glucagon-like peptide 1 agonists (GLP-1), and sodium-glucose cotransporter inhibitors of type 2 (iSGC-2).

Metformin

Metformin is one of the main medicines used for the treatment of HFpEF and DM patients [45]. Its main effect is to increase the adenosine monophosphate-dependent protein kinase, which increases the uptake of glucose by cells and prevents cardiomyocyte hypertrophy [45]. Different observational studies have shown that metformin improves the prognosis for HF patients, but the specific mechanisms provoking such an effect are not completely clear. It is assumed that the use of metformin leads to the formation of low-energy states, weight loss, and sympathetic activity.

A recent meta-analysis demonstrated a positive effect of metformin on the prognosis for HFpEF patients, but all the studies included in the analysis were observational, and most of them were retrospective [46]. However, it is hardly legitimate to talk about the impact on the prognosis in the absence of large randomized controlled studies.

Type 4 dipeptidyl peptidase inhibitors

Type 4 Dipeptidyl peptidase inhibitors (DPP4) are a relatively new class of medicines for the treatment of diabetes. Their glycemic effect is achieved by affecting the incretin activity and GLP-1, as well as changes in gluconeogenesis in the liver. In the SAVOR-TIMI 53 study, the DPP-4 inhibitor, saxagliptin, was compared with a placebo in a group of patients with type 2 diabetes (about 10.5% of them suffered from HF). It was not possible to prove the effect of saxagliptin on the main study endpoints (mortality from cardiovascular causes, myocardial infarction, stroke), moreover, the use of the medicine was associated with a higher frequency of HF hospitalizations [47]. Two more studies were conducted as well: EXAMINE, where alogliptin was compared with standard therapy, and TECOS, where sitagliptin was compared with a placebo. In both studies, the effect of DPP-4 inhibitors on the same endpoints was not shown, the frequency of HF hospitalizations in the EXAMINE study was slightly increased in the group of patients receiving the medicine, while in the TECOS study remained unchanged. Due to the results of SAVOR-TIMI 53, it is currently not recommended to use saxagliptin for the treatment of HF patients.

Type 1 glucagon-like peptide agonists

The effect of type 1 glucagon-like peptide (GLP-1) agonists was evaluated in four studies: ELIXA, LEADER, SUSTAIN-6, and EXSCEL. In the ELIXA and EXSCEL studies, it was shown that GLP-1 agonists do not affect the frequency of cardiovascular complications and hospitalizations for HF. Other results were obtained in the LEADER and SUSTAIN-6 studies, where the use of GLP-1 agonists was associated with a decrease in the incidence of cardiovascular complications. Indicators of the frequency of HF hospitalizations in the LEADER study did not differ between the liraglutide and placebo groups. Moreover, the use of liraglutide was associated with a worse prognosis in HFpEF patients in the FIGHT study. Due to the fact that there is currently insufficient data on the use of GLP-1 agonists in the case of HFpEF; their effect on the prognosis concerning HFpEF patients also suffering from DM remains unexplored.

Type 2 sodium-glucose cotransporter inhibitors (iSGC-2)

Inhibitors of type 2 sodium-glucose cotransporter (iSGC-2) block the reabsorption of glucose and sodium in the proximal convoluted nephron tubule, resulting in a decrease in the glycemic level and blood pressure decrease [48]. The medicine effects of this group were evaluated in the studies such as EMPA-REG OUTCOME (empagliflozin), CANVAS Program (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin); their data were used for meta-analysis [49]. According to its results, iSGC-2 intake has reliable advantages in influencing the frequency of HF hospitalizations and the progression of kidney disease. It happens regardless of whether patients suffer from cardiovascular diseases due to atherosclerosis or have HF in the medical history. The specific mechanisms of iSGC-2 action that cause such results are not completely clear. It is suggested that when iSGC-2 is used, a decrease in the glucose reabsorption level leads to the fact that ketone bodies begin to be used as the main source of energy [50]. Compared with glucose and FAs, ketone bodies are the most effective source of energy; they are associated with a positive effect on the myocardium in patients with HFpEF and DM [51]. It is also assumed that the positive iSGC-2 effects can be achieved partly due to a decrease in arterial stiffness and blood pressure.

The positive effect of iSGC-2 on the prognosis of patients suffering from HFpEF has been confirmed in several large studies, such as EMPEROR-Reduced and DAPA-HF. The results of the EMPEROR-Preserved study are expected in the near future, which assesses the effect of empagliflozin on the prognosis for HFpEF patients, regardless of their glycemic status.

Currently, a randomized clinical trial is being conducted at the National Medical Research Center of Cardiology in order to evaluate the functional and hemodynamic effects of empagliflozin in comparison with standard therapy for patients with HFpEF and type 2 diabetes. The study examined 70 patients: 35 were in the empagliflozin group and 35 were in the standard therapy group for type 2 diabetes. According to the results of this test, 6-month medicine administration was accompanied by an increase in the distance (21 meters) covered during the test with a six-minute walk (95% of confidence interval (CI) [ 6; 34], p = 0.004), a decrease in the LV filling pressure (according to E/e’) at rest (12.4[ 7.6;17.3], 10.7[ 6.5;14.9], p < 0.001) and at the peak of physical activity (16.9[ 11;22.8], 13.8[ 8.9;18.8], p < 0.001), a decrease in the LA volume index (37.3[ 33.6;39.4], 34.5[ 32.0;35.2], ml/m², p = 0.007) and a decrease in the mitral E/A ratio (0.91[ 0.80;1.02], 0.87[ 0.76;0.97], p = 0.04). Thus, a positive effect of empagliflozin on exercise tolerance and LV diastolic function was shown in patients with HFpEF and type 2 diabetes.

Conclusion

The prevalence of HFpEF is increasing at an alarming rate. According to the current prognosis, about 80% of patients with HF will have a preserved LV ejection fraction by 2030. At the same time, the HFpEF prognosis remains extremely unfavorable. If in the case of HF with low ejection fraction, there is a tendency to improve it during treatment, then in HFpEF patients, the prognosis has not practically changed over the past two decades.

One of the significant factors contributing to the progression of HFpEF is diabetes. In addition to maintaining the pro-inflammatory status underlying the pathogenesis of HFpEF, DM has a direct damaging effect on the myocardium by accumulating oxygen free radicals and glycation end products in it. Thus, DM leads to the development of LV dysfunction [50] and, in general, to a deterioration in the HFpEF prognosis [52].

Due to the fact that currently, the main goal of DM treatment is shifting from glycemic control to cardiovascular risk control, iSGC-2 and GLP-1 medicines are beginning to be of great interest for patients with HFpEF and DM. These groups of medicines are the ones that scientists place the greatest hopes on both in improving the course of HFpEF and in potentially improving the prognosis.

HFpEF is already a fairly widespread disease, and still very little is known about it. More studies on the pathogenesis of HFpEF are needed since it will allow developing new approaches to this disease treatment. Currently, HFpEF therapy is reduced to the control of concomitant diseases, which only improves the quality of the patient’s life. Improving the prognosis for these patients is the goal that is most in demand, but unfortunately, it has not yet been achieved.