**7. Therapeutic considerations of HF in diabetes**

Pharmacotherapy is the cornerstone of HFrEF treatment and should be used in conjunction with non-pharmacological therapies before device therapy is considered [130].

Treatment for patients with HFrEF has three key goals: reduction in mortality, avoiding recurrent hospitalizations due to worsening HF, and improving clinical status, functional capacity, and quality of life [130].

Patients with and without diabetes receive similar treatment for HF. On the other hand, anti-diabetic drugs have different effects in patients with HF, and treatments that are both safe and minimize HF-related events should be prioritized [130].

The 2021 ESC guidelines [91] and 2022 ACC/AHA/HFSA guidelines [120] recommend treatment of HFrEF and HFmrEF with a combination therapy of angiotensinconverting-enzyme inhibitors/angiotensin II receptor blockers (ACE-I/ARB), angiotensin-receptor-neprilysin-inhibitors (ARNI), beta-blockers, mineralocorticoidreceptor antagonists (MRA), and SGLT2i. Since there is currently no therapy for HFpEF subjects [91, 131], HFpEF therapy targets only symptom and well-being improvement [91, 94] and treatment of comorbidities [91]. The recently reported EMPEROR-preserved study provides the first proof of improved outcomes in HFpEF individuals [132].

The 2021 ESC guidelines [91] also recommend that patients with improved LVEF should continue to receive HFrEF treatment [91]. On the other hand, the 2021 ESC guidelines recommend to use ICDs in selected patients with HFrEF of an ischemic etiology and to consider using in those with a non-ischemic etiology [91]. Moreover, CRT-P/D is recommended in those patients with HFrEF, in sinus rhythm, with an LBBB ≥150 ms and should be considered in those with an LBBB ≥130–149 ms or non-LBBB ≥150 ms [91]. Advanced HF strategies, such as heart transplantation or MCS may be appropriate in selected patients [91].

ACE-I and ARB: The effect of the ACE-I enalapril was demonstrated in the SOLVD trial. It was shown that compared to placebo, enalapril diminished the incidence of diabetes in subjects with HF [133]. The 2019 ESC-EASD recommendations suggest blood pressure control with ACE-I or an ARB as a measure to lessen the HF risk in diabetes, especially in conditions such as microalbuminuria, albuminuria, proteinuria, or LV hypertrophy [99].

#### *Diabetes Mellitus Type 2, Prediabetes, and Chronic Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.106391*

The expediency of using ACE inhibitors in patients with insulin resistance is explained by the activation of the RAAS against the background of hyperinsulinemia and hyperglycemia, as well as by common molecular signal transduction pathways used by the insulin and renin-angiotensin systems. When treating diabetic patients with ACE inhibitors or ARBs, continuous monitoring of potassium levels and renal function is necessary to prevent the development of nephropathy [134].

ARNI: In the PARADIGM-HF trial, it was observed that in comparison with enalapril, sacubitril/valsartan is able to substantially reduce the death and hospitalization risk of HF (HHF) in people with HFrEF, demonstrating its blood pressure lowering effect in the long term [135]. However, in people with HFpEF, this trial showed that sacubitril/valsartan was not effective at reducing the total CV death and HHF rate compared to valsartan alone (regardless of diabetes history in HFpEF patients) [136]. Moreover, the positive impact of sacubitril-valsartan in reducing the risk of HHF was comparable among all PARADIGM-HF trial patients with HFrEF and an HbA1c of 5.4–8.4% [19]. Furthermore, sacubitril-valsartan outperforms enalapril in decreasing HbA1c levels and lowering the rate of insulin treatment initiation in individuals with both diabetes and HFrEF over 3 years [137]. Sacubitril-valsartan is thus expected to enhance glycemic control in these individuals [137].

A significant reduction in NT-proBNP levels was observed in the HFpEF group of the PARADIGM-HF trial [138], demonstrating that sacubitril-valsartan therapy reduces risk. This effect occurred regardless of gender, as sacubitril-valsartan equally reduced NT-proBNP levels in men and women in the PARAGON-HF cohort with HFpEF where 50% of subjects were diabetics [139].

There were a few observed side effects of sacubitril-valsartan therapy in the PARADIGM-HF [135] and the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF trial) [136] such as increased prevalence of symptomatic hypertension and angioedema, but this was still lower than with dual inhibition of both ACE and neprilysin, especially in angioedema [135]. In light of these data, the 2019 ESC-EASD Guidelines on diabetes recommend that HF patients with diabetes who remain symptomatic should be treated with sacubitril-valsartan instead of an ACE inhibitor [114].

Beta-blockers: Beta-blockers have been shown to reduce mortality and morbidity in patients with HFrEF, when used together with ACE-I and diuretics [91]. As soon as symptomatic HFrEF is diagnosed, ACE-I and beta-blockers can be started together, according to consensus. However, no evidence proves that starting a beta-blocker before an ACE-I or vice versa is beneficial. Beta-blockers should be given to clinically stable euvolemic patients at low doses and slowly uptitrated to the maximum tolerated dose. Moreover, when patients are admitted with AHF in the hospital, beta-blockers should be given cautiously only after they are hemodynamically stabilized [91].

There is no particular beta-blockade experiment in HFmrEF. The SENIORS trial, in which nebivolol lowered the composite main endpoint of all-cause mortality or CV hospital admissions in the total population, was included in an IPD meta-analysis. There was no interaction between LVEF (35–50% of patients had an LVEF of 35–50%) and the impact of nebivolol on the main outcome. Many patients with HFmrEF may also have another CV reason for a beta-blocker, such as AF or angina. As a result, betablocker therapy may be explored in individuals with HFmrEF [91].

MRA: Assessment of MRA therapy efficacy revealed that compared to non-MRA treatment, it improved the clinical outcome of diabetic patients with HF [140]. To be exact, spironolactone or eplerenone was effective at diminishing CV and all-cause mortality and HHF [140]. A non-steroidal MRA finerenone, on the other hand, was

able to reduce the incidence of death from any cause, CV-related hospitalization or emergency in subjects with HFrEF, CKD, and/or diabetes when compared to eplerenone MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF trial) [141].

Adverse events in the ARTS-HF and other MRA trials included in the aforementioned meta-analysis revealed that MRA treatment increases the risk of hyperkalemia [140, 141].

Also, it has been shown that finerenone at doses of 10–20 mg/day may cause hyperkalemia less frequently [142]. The drugs of this group can cause hyperkalemia and deterioration of renal function, especially in the elderly, patients with diabetic and non-diabetic nephropathy, renal failure; therefore, it is recommended to use them only in patients with adequate renal function, while regular monitoring of plasma electrolytes and renal function is mandatory.

Generally, the 2019 ESC-EASD recommendations [114] indicate that diabetic people with HFrEF should be treated with MRAs if their symptoms persist despite therapy with ACE-I or beta-blockers. In these patients, MRAs and sacubitril-valsartan are indicated to minimize the risk of sudden cardiac death [114].

There is no MRA-specific study in HFmrEF. In a retrospective analysis of the TOPCAT trial, spironolactone reduced hospitalizations for HF in patients with an LVEF of ≥45%, but it increased hospitalizations for HF in those with an LVEF of ≥55%. A comparable trend was observed in CV mortality but not in all-cause mortality [91]. Treatment with an MRA may be considered in patients with HFmrEF [91].

SGLT2 inhibitors: Numerous clinical trials have demonstrated the therapeutic impact of SGLT2 inhibitors on CV outcomes in people with T2D and established HF, demonstrating a cardio-protective effect independent of glycemic status [143].

Inhibition of SGLT2 increases the concentration of circulating ketone bodies, and it can become an alternative source of energy for the diabetic heart with insulin resistance. In addition, other potential mechanisms of action of the drug are possible, such as weight loss of the body, BP, sodium levels, oxidative stress, and sympathetic activation [144]. One evidence comes from the DAPA-HF trial demonstrating that dapagliflozin lowered the risk of progressing HF (HHF) and CV-related death in HFrEF people (NYHA class II–IV) independent of the glycemic status [145] and gender [146]. In addition, The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR)-preserved trial provided the first evidence of a cardio-protective effect of empagliflozin on the combined risk of HHF and CV death in subjects with HFpEF, an effect that is independent of the presence of diabetes [132]. In other studies, for empagliflozin, a lowered risk of CV death and HHF was also shown in the EMPA-REG OUTCOME trial in people with T2D and a history of CVD [59] and in the EMPEROR-Reduced trial in people with HFrEF regardless of the presence of diabetes [147].

One piece of evidence comes from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study, which found that dapagliflozin reduced the risk of progressive HF (HHF) and CV-related death in patients with HFrEF (NYHA class II–IV) regardless of glycemic status [145] or gender [146]. Furthermore, the EMPEROR-preserved study showed the first indication of empagliflozin's cardioprotective benefit on the combined risk of HHF and CV death in people with HFpEF, a result that is independent of diabetes [132]. In additional trials, empagliflozin was associated with a decreased risk of CV mortality and HHF in the EMPA-REG OUTCOME trial in patients with T2D and a history of CVD [59] and in the EMPEROR-Reduced trial in people with HFrEF regardless of diabetes.

#### *Diabetes Mellitus Type 2, Prediabetes, and Chronic Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.106391*

Reducing the risk of CVD in empagliflozin includes combined decrease in blood pressure, body weight (including visceral obesity), albuminuria, glucose levels, stiffness of the arterial wall, activation of the sympathetic part of the autonomic nervous system, oxidative stress, uric acid concentration, and improvement function of the heart [148]. Empagliflozin is able to improve myocardial microvascular perfusion, eNOS activity, and endothelium-dependent relaxation. Empagliflozin may be beneficial by inhibiting induced DM mitochondrial fission dependent on 5'AMP-activated protein kinase (AMPK) way. On the one hand, the action induced by this drug can slow down the aging of endothelial cells by suppressing oxidative stress, which leads to an improvement in their viability and barrier function. On the other hand, empagliflozin-induced migration endothelium as a result of F-actin homeostasis can contribute to angiogenesis [59, 149]. As DM progresses endothelial damage is detected at an early stage. Through these mechanisms, empagliflozin improves myocardial blood supply. Considerable evidence suggests the ability of empagliflozin to reduce systolic blood pressure by facilitating osmotic diuresis, influencing the microvascular diastolic response by stimulation of eNOS phosphorylation, vascular remodeling, reduction of inflammatory proteins, and decrease in collagen synthesis [150]. This drug is promising for the treatment of patients with diabetes and microvascular dysfunction of the heart; this drug can be considered as a drug for protecting the microvascular bed of the heart to maintain its functions and circulatory structures in hyperglycemia [151].

In the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV trial), ertugliflozin was non-inferior to placebo in terms of its important secondary outcome of CV mortality or HHF in participants with T2D and atherosclerotic CVD, but the trial findings did not fulfill the superiority requirements (HR = 0.88, 95% CI 0.75–1.03) [61, 149]. However, there was a 30% reduction in the risk of HHF alone, which was similar to the effects of the other SGLT2 inhibitors on this outcome [149, 152]. A pre-specified analysis in VERTIS CV revealed that the subgroups of patients with the largest decrease in HF-related events had an eGFR of <60 mL/min/1.73 m<sup>2</sup> and albuminuria [62]. Furthermore, another evidence from the SOLOIST-WHF trial shows that simultaneous inhibition of both SGLT1 and SGLT2 in people with T2D may reduce CV fatalities, hospitalizations, and urgent visits for either HFpEF or HFrEF [153]. When started before or shortly after discharge, sotagliflozin avoided CV death, HHF, and urgent HF visits in patients with T2D and recent worsening HF compared to placebo.

SGLT2 inhibitors are cardio-protective in patients with T2D and established CVD, also in people who are at high risk of CV events. The CANVAS study demonstrated that canagliflozin lowered the risk of CV-related events in people with T2D and increased CV risk more effectively than placebo [60]. Furthermore, the DECLARE-TIMI 58 study found that use of dapagliflozin reduces HHF and CV-related death in people with T2D who had or are at risk of atherosclerotic CVD [57].

NT-proBNPs have a predictive value for CV events and death in clinical outcome studies. The decreased NT-proBNP concentration in the canagliflozin arm of the CANVAS trial can be ascribed in part to the reduction in CV-related events in patients with T2D and CV risk [154]. In addition, a sub-analysis of the CANDLE study found a tendency toward decreased NT-proBNP levels in the subgroup with lower LV diastolic function in the canagliflozin treated arm compared to the glimepiride treated arm [155]. Dapagliflozin, like canagliflozin, reduced NT-proBNP levels considerably higher than placebo in the DAPA-HF group [145, 149]. Similarly, empagliflozin significantly lowered NT-proBNP levels 7 days after randomization when delivered as

add-on treatment to T2D patients hospitalized for acute decompensated HF compared to the group treated conventionally with glucose-lowering drugs [149, 156]. However, another dual SGLT1/2 inhibitor, licogliflozin, has been shown to reduce NT-proBNP in individuals with both T2D and HF when compared to placebo 12 weeks following randomization [149, 157].

Because of the class impact of SGLT2 inhibitors, the 2019 ESC-EASD guidelines on diabetes propose the SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin to reduce the risk of HHF in diabetic individuals [114]. Aside from that, the ESC guidelines for 2021 recommend ertugliflozin and sotagliflozin for patients with T2D who are at high risk of CV events to reduce HHF, major adverse CV events (MACE), end-stage renal disease, and CV death, and sotagliflozin in patients with T2D and HFrEF to reduce HHF and CV death [91]. In order to minimize HHF, MACE, and CV death, the 2019 ADA/EASD consensus suggests SGLT2 inhibitors in addition to metformin in adults with diabetes and HF (particularly HFrEF) [158].
