XU Lin-hui, WANG Wan-hong?, ZHANG Yi, SHI Bo

1.Department of Cardiology, Suqian Hospital of Nanjing Drum Tower Hospital Group, Suqian 223800, China

2.Department of Cardiology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian 223800, China

3.Department of Cardiology, Suqian Traditional Chinese Medicine Hospital, Suqian 223800, China

Keywords:

ABSTRACT Objective: To observe the clinical efficacy of dapagliflozin in the treatment of type 2 diabetes mellitus(T2DM) complicated with heart failure with mildly reduced ejection fraction (HFmrEF,40%≤LVEF＜50%).Methods: A total of 84 patients with T2DM complicated with HFmrEF hospitalized in our hospital from October 2019 to October 2021 were selected, and random number table method was used to divide into the control group and the study group each 42 cases.Both groups used basal hypoglycemic and standardized anti-heart failure therapy,and the study group was treated with dapagliflozin simultaneously.Nine months later, the following indexes were compared between the two groups before and after treatment: the cardiac function indicators: N-terminal pro brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF); exercise endurance: 6-minute walk distance (6MWD),NYHA cardiac function class, the score of the Minnesota living with heart failure questionnaire(MLHFQ) and the incidence of major adverse cardiovascular events (MACE).Results: Nine months later, the two groups showed decreased NT-proBNP level, increased LVEF, prolonged 6MWD, improved NYHA cardiac function grade, decreased MLHFQ score, and statistically significant differences within both groups compared with before treatment (P＜0.05), after treatment significant differences were displayed between the two groups (P＜0.05).Less patients had MACE events and adverse drug reactions in the study group compared with the control group.Conclusion: Dapagliflozin in the treatment of T2DM patients with HFmrEF can improve cardiac function indicators, improve exercise endurance, improve NYHA cardiac function class, improve patient's quality of life, and reduce the incidence of MACE events, with no obvious side effects.

1.Introduction

According to statistics, there are about 64 million patients with heart failure[1] worldwide, while China has about 8.9 million[2].In 2016, the European Society of Cardiology (ESC) first defined the heart failure with mid-range ejection fraction (HFmrEF) as heart failure with left ventricular ejection fraction (LVEF) in 40%-49%.Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2018[3] also adopted this classification method.The 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure, redefined HFmrEF as “heart failure with mildly reduced ejection fraction”, or heart failure with mildly reduced ejection fraction.According to statistics[4], HFmrEF accounted for 22.43% -24.83% of heart failure in China in the past four years.

The prevalence of heart failure in patients with diabetes is as high as 22%, and the incidence is increasing[5].In recent years,it has been found that the new hypoglycemic drug sodiumdependent glucose transporters 2 inhibitor (SGLT2i), not only has a hypoglycemic effect, but also can protect the cardiovascular system effectively.The DAPA-HF[6] study showed that the addition of SGLT2i dapagliflozin to the underlying drug for heart failure reduced the risk of cardiovascular death or hospitalization in patients with heart failure with reduced ejection fraction (HFrEF)by 26%.However, the understanding of HFmrEF is not deep enough domestic and overseas, and its pathogenesis, treatment and prognosis are not clearly.The study aims to evaluate the clinical efficacy of dapagliflozin in patients with type 2 diabetes mellitus (T2DM) with HFmrEF and to provide a better solution for the treatment of such patients.

2.Data and Methods

2.1Object of Study

T2DM complicated with HFmrEF 84 patients hospitalized in Suqian Hospital of Nanjing Drum Tower Hospital Group from October 2019 to October 2021 were selected.Inclusion criteria:①According to the T2DM diagnostic criteria for Guidelines for the Prevention and Treatment of Type 2 Diabetes Mellitus in China(2017 Edition)[7]; ② HFmrEF diagnostic criteria according to the 2018 China Guidelines for the Diagnosis and Treatment of Heart Failure[3].Exclusion criteria: ①Type 1 diabetes mellitus; ②T2DM complicated with lactic acidosis and ketoacidosis nearly 6 months;③severe liver and kidney insufficiency; ④heart failure caused by congenital heart and heart valve disease; ⑤repeated and severe hypoglycemia; ⑥chronic lung disease and stroke; ⑦unable to cooperate.All the enrolled patients voluntarily signed the informed consent form.Using random numbers table, the participants were divided into the control and study group each 42 cases.This study has been approved by the Ethics Committee of Suqian Hospital of Nanjing Drum Tower Hospital Group.

2.2 Therapeutic Method

Both groups gave a lifestyle intervention and standard treatment,①T2DM treatment: glemepiride, acarbose, repaglinide, insulin,etc.; ②HF treatment: ARB/ACEI/ARNI,β receptor blockers,spironolactone, necessarily, diuretics, nitrates, digitalis and other drugs were used to improve symptoms.The study group added dapagliflozin (AstraZeneca, National Drug Approval No.J20170040,size 10 mg), 10 mg/time, 1 time/d, morning service.

2.3 Observational Indicators

The following indicators were recorded before and 9 months after treatment: ①cardiac function indicators: 2 mL of fasting venous blood was drawn, centrifuged (3000 r/min, 6 min), and then the upper serum was collected for detecting the serum N-terminal pro brain natriuretic peptide (NT-proBNP) by Electrochemical luminescence immunoassay method.The LVEF was checked using a Philips iu22 color doppler ultrasound diagnostic instrument.②blood glucose indexes: 2 mL of venous blood was drawn, and used automatic biochemical analyzer to detect glycosylated hemoglobin (HbA1c), 2 h postprandial blood glucose (2 h PBG), and fasting plasma glucose(FPG).③cardiac function classification was recorded according to the NYHA cardiac function grade.④sports endurance and quality of life: 6 min walking distance (6 MWD): longer distance, indicating better exercise endurance; Minnesota Living with Heart Failure Questionnaire (MLHFQ) score: lower score, better QoL.⑤major adverse cardiac events (MACE): malignant arrhythmia, heart failure readmission, and sudden cardiac death.⑥adverse drug reactions:blood glucose, urine routine, renal function and other indicators were monitored regularly during the medication.

2.4 Statistical Method

Measurement data were used (±s ).Frequency (rate) was used for count data, and χ2test was used for comparison between groups.A rank-sum test was used to compare the rank data.Comparisons between two data groups were performed using independent sample t-test, and comparisons between data before and after treatment were performed using paired sample t-test.All data analysis was performed using the SPSS 17.0 statistical software.P＜0.05 was considered as statistically significant.

3.Results

3.1 Comparison of the general data

Before treatment, there was no significant difference between the two groups in gender, age, blood pressure, etiology, medication,blood glucose index, cardiac function index, 6 MWD, MLHFQ score and so on(P＞0.05).Showed in Table 1.

3.2 Comparison of changes in blood glucose indexes

After treatment, the levels of HbA1c, 2 hPG and FPG were lower than before treatment, and the study group was lower than the control group, showing a statistically significant difference (P＜0.05).Comparing the decreasing levels of HbA1c, 2 hPG and FPG before and after treatment, the study group was larger than the control group (P＜0.05).Showed in Table 2.

3.3 Comparison of cardiac function indicators and 6MWD

After treatment, NT-proBNP levels decreased, LVEF and 6MWD levels increased, and NT-proBNP levels in the study group were lower than the control group, LVEF and 6MWD were higher than the control group, all statistically significant (P＜0.05).Comparison of the decreasing level of NT-proBNP before and after treatment and the improvement level of LVEF and 6MWD, the study group was larger than the control group (P＜0.05).Showed in Table 3.

Tab 1 Comparison of general data between two groups [±s , n(%)]

Tab 1 Comparison of general data between two groups [±s , n(%)]

BMI: Body mass mass index, 1 mmHg=0.133 kPa, DCM: dilated cardiomyopathy, ICM: ischemic cardiomyopathy, HbA1c: glycosylated hemoglobin, FPG:fasting plasma glucose, 2 hPG: 2 h postprandial blood glucose, ACEI: angiotensin converting enzyme, ARB: angiotensin receptor blocker, ARNI: Angiotesin receptor-neprilysin inhibitor, NT-proBNP: N-terminal pro brain natriuretic peptide, LVEF: left ventricular ejection fraction, 6MWD: 6 min walking distance,MLHFQ: Minnesota Living with Heart Failure Questionnaire.

Characteristic Study Group(n=42) Control Group(n=42) t/χ2 P Gender (male/female) 28/14 26/16 0.207 0.649 Age (year) 63.48±9.35 62.56±10.12 0.480 0.632 BMI(kg/m2) 22.43±4.23 22.39±3.65 0.090 0.928 Heart rate (times/min) 66.37±7.24 65.46±8.33 -0.721 0.473 Systolic blood pressure (mmHg) 123.56±10.89 125.61±12.76 -0.476 0.635 Diastolic blood pressure (mmHg) 63.58±10.98 64.44±11.12 0.650 0.518 Etiology DCM 8(19.05) 7(16.67) 0.081 0.776 ICM 34(80.95) 35(83.33)Course of heart failure (years) 2.76±0.42 2.89±0.33 -1.871 0.065 Course of diabetes mellitus (years) 9.98±6.30 10.13±6.47 0.292 0.771 Medication Diuretic 18(42.86) 20(47.62) 1.213 0.271 ACEI/ARB/ARNI 32(76.19) 35(83.33) 0.664 0.415 β receptor blockers 30(71.43) 28(66.67) 0.223 0.637 Antisterone 35(83.33) 37(88.1) 0.389 0.533 Digitalis 8(19.05) 7(16.67) 0.081 0.776 Repaglinide 10(23.81) 8(19.05) 0.283 0.595 Acarbose 10(23.81) 12(28.57) 0.246 0.620 Insulin 15(35.71) 16(38.10) 0.051 0.821 Glimepiride 12(28.57) 10(23.81) 0.246 0.620 Blood glucose index FPG(mmol/L) 8.63±2.25 8.75±1.96 -0.019 0.985 2hPG(mmol/L) 14.27±1.51 14.36±1.42 0.253 0.801 HbA1c(%) 8.11±1.42 8.28±1.66 -0.801 0.426 Cardiac function index NT-proBNP(pg/ml) 1 528.25±416.78 1 488.51±364.78 -0.022 0.982 LVEF(%) 45.05±2.92 45.01±2.83 0.075 0.941 6MWD(m) 314.62±58.33 308.34±60.41 1.572 0.120 MLHFQ grade Body field 22.25±2.23 22.76±2.25 -1.414 0.161 Emotional field 11.26±1.75 11.58±1.64 -0.474 0.637 Other fields 20.86±2.27 21.05±2.35 -0.904 0.369

Tab 2Contrast of blood glucose indexes before and after treatment between the two groups(±s )

Tab 2Contrast of blood glucose indexes before and after treatment between the two groups(±s )

Differences showed the degree of change in values before and after treatment, similarly hereinafter.*: Compared with this group before treatment (P＜0.05).

Group n FPG(mmol/L) 2hPG(mmol/L) HbA1c(%)post-treatment Differences post-treatment Differences post-treatment Differences study group 42 4.98±0.65* 3.39±2.06 6.70±0.98* 7.31±1.78 6.33±0.66* 1.55±1.25 control group 42 6.26±0.68* 2.12±2.33 8.00±1.68* 5.92±2.34 7.50±0.51* 0.65±1.81 t-8.801 2.651 -4.359 3.054 -9.127 2.632 P 0.000 0.010 0.000 0.003 0.000 0.010

Tab 3 Contrast of cardiac function and 6MWD before and after treatment between the two groups (±s )

Tab 3 Contrast of cardiac function and 6MWD before and after treatment between the two groups (±s )

*: Compared with this group before treatment (P＜0.05).

Group n NT-proBNP(pg/ml) LVEF(%) 6MWD(m)post-treatment Differences post-treatment Differences post-treatment Differences study group 42 916.68±328.62* 641.89±455.89 51.44±3.77* 6.29±4.64 442.62±66.54* 122.95±84.72 control group 42 1 028.45±412.58* 367.57±579.91 47.88±4.85* 2.63±5.59 356.36±52.63* 47.19±91.32 t-3.266 2.410 3.753 3.263 6.939 3.941 P 0.002 0.018 0.000 0.002 0.000 0.000

3.4 Comparison of NYHA cardiac function grade

Before treatment, the NYHA grade was compared between the two groups, there was no statistically significant difference (P＞0.05).After treatment, the NYHA was better than before treatment, and the NYHA was better in the study group, with statistically significant differences (P＜0.05).Showed in Table 4.

Tab 4 Contrast of cardiac function grades before and after treatment between the two groups (n)

3.5 Comparison of the quality of survival

After treatment, both MLHFQ scores were better than before treatment, and the study group was better than the control (P＜0.05).Comparing the decline levels of body, emotional, and other fields before and after treatment, the study group was larger than the control, and the difference was statistically significant (P＜0.05).Showed in Table 5.

Tab 5 Contrast of MLHFQ scores before and after treatment between the two groups(±s )

Tab 5 Contrast of MLHFQ scores before and after treatment between the two groups(±s )

*: Compared with this group before treatment (P＜0.05).

Group Body field Emotional field Other fields post-treatment Differences post-treatment Differences post-treatment Differences study group 15.50±2.12* 6.71±2.84 5.92±1.82* 5.61±2.53 15.62±3.02* 5.33±4.40 control group 18.82±2.09* 4.17±3.46 8.37±1.79* 3.03±1.92 18.23±2.78* 3.17±3.30 t-7.118 3.680 -8.418 5.255 -3.988 2.535 P 0.000 0.000 0.000 0.000 0.000 0.013

3.6 Currence of MACE events and adverse drug reactions

After treatment, the MACE event in the study group, three patients experienced malignant arrhythmia and heart failure rehospitalization,while 11 patients in the control group, all improved after treatment,and no sudden cardiac death occurred in either group.Adverse drug reactions in the study group, one case experienced hypoglycemia,and three cases had hypoglycemia and urinary tract infection in the control group, all of which improved after treatment, and no renal inadequacy occurred in either group.

3.Discussion

Left ventricular ejection fraction is not invariable in heart failure patients, studies had showed that[8,9], 73% of heart failure with preserved ejection fraction (HFpEF) worsened to HFmrEF , 17%of HFrEF improved to HFmrEF, and 10% constantly HFmrEF.The occurrence of HFmrEF may be related to the increased inflammation, metabolic disorders, neuroendocrine activation and other mechanisms.HFmrEF is a transitional state between HFpEF and HFrEF, it is not independent exist.If without effective intervention is taken at the early stages of the disease, there is a strong chance that HFmrEF will progress to HFrEF.Therefore, it is very important to take effective treatment for HFmrEF patients,but there is no clear and consistent best regimen for the treatment of HFmrEF[10,11].

Diabetes mellitus is closely related to the occurrence, development and death risk of heart failure.It mainly causes a series of pathophysiological changes through hyperglycemia and insulin resistance, which cause the heart contraction and diastolic dysfunction, thus causing heart failure.Mainly manifested in: 1.myocardial energy metabolism dysfunction: hyperglycemia induces epigenetic changes and mitochondrial damage; Insulin resistance leads to reduced glucose oxidation, increased myocardial oxygen demand, free oxygen radicals cause lipotoxicity and sarcoplasmic calcium uptake disorders, low fatty acid metabolism efficiency,cardiomyocyte fuel depletion, altered myocardial energy substrate utilization, and thus diastolic dysfunction[12].2.Na+/Ca2+imbalance:increased intracellular sodium levels in diabetic myocardium and mitochondria activation of the Na+/Ca2+exchanger cause reduced mitochondria calcium levels, a mechanism that also increases the risk of arrhythmias and oxidative stress[13].3.Autonomous neuropathy: 25%-75% of patients with T2DM complicated with diabetic cardiovascular autonomic neuropathy, the increase of blood glucose causes the increase of reactive oxygen species in mitochondria, oxidative stress and the generation of glycation substances, and eventually make neurons dysfunction and death,causing tachycardia in static state, postural hypotension, QT interval extension, decreased heart rate variability, etc[14,15].4.Cardiomyocyte apoptosis and autophagy: the production of reactive oxygen species, increased inflammatory cytokines and chemokines,ER stress, enhanced transformation growth factor signaling pathway activity, cause cardiomyocyte death and apoptosis;Reduced phosphatidylinositol 3 kinase/protein kinase B signaling leads to autophagy in the myocardium[16].5.renin angiotensin aldosterone system (RAAS): RAAS can be activated by insulin resistance, which can induce such as cardiac hypertrophy, fibrosis and aggravate diastolic dysfunction[13].However, simple intensive control of blood glucose levels does not reduce the prevalence of heart failure, nor can it benefit patients with heart failure, and sometimes even increase the cardiovascular events and mortality.In addition to effectively reducing blood glucose, SGLT2i also reduces cardiovascular mortality and heart failure hospitalization rate in patients with T2DM[17].The DAPA-HF study[6] showed that SGLT2i dapagliflozin not only effectively reduced blood glucose, but also decreased worsened heart failure in HFrEF patients and the risk of death from cardiovascular events, regardless of diabetes mellitus, it suggests that dapagliflozin may also have an independent effect on improving cardiac function without increasing adverse reactions,and long-term use is safe.For the treatment of HFpEF, 12 weeks of dapagliflozin treatment can improve the symptoms and activity restriction, and enhance the motor function of patients[18].

Dapagliflozin has many cardioprotective mechanisms.In addition to the direct reduction of blood glucose levels and the toxic damage to myocardial and cardiovascular damage of hyperglycemia, it is also manifested in: 1.reduce pre and post cardiac load: dapagliflozin acts on proximal convoluted tubules, suppresses sodium and glucose cotransport, sodium and glucose drainage cause plasma osmolarity changes, and exerts osmotic diuresis through the Frank-Starling mechanism.The diuretic effect of SGLT2i is to reduce intertissue fluid without activating the sympathetic nervous system or the RAAS axis, affecting small on vascular content[19].Dapagliflozin exerts vasodilatory effects through protein kinase G and voltagegated potassium channels[20].2.Improve the myocardial energy metabolism: in heart failure and hyperglycemic stress state,myocardial energy metabolism substrate metabolism disorders, fuel depletion.At this time, ketone bodies are a good alternative substrate for increasing cardietabolic efficiency.SGLT2i stimulates lipolysis by lowering blood sugar levels, thereby increasing free fatty acids and triggering an increase in circulating ketone bodies.At the same time, it reduces the renal excretion of ketone body, maintains the high ketone body state, promotes the utilization of β-hydroxybutyrate,improves the myocardial energy supply at the mitochondrial level,and increases the energy level of the heart muscle[12,21].3.Improve the myocardial remodeling: suphibit inflammatory factors, relieve vascular oxidative stress, delay myocardial fibrosis, decrease ventricular wall thickness at end-diastole and promote the return of normal ejection fraction, thus producing protective effects on the heart[21].4.Inhibition of myocardial Na+/H+exchanger (NHE): when diabetes and heart failure coexist, NHE in cardiomyocytes and the concentration of Na+and Ca2+in the cytoplasm increases, while the concentration of Ca2+in mitochondria and myocardial excitationcontraction coupling decreases, causing myocardial dysfunction,accelerating the progression of heart failure and increasing the risk of malignant arrhythmia.SGLT2i can inhibit NHE, increase Ca2+concentration in mitochondria, promote ATP generation, and improve mitochondria and myocardial function[22].Dai Rixin et al.[23] found that after 6 months of treatment for T2DM patients with HFmrEF, dapagliflozin can effectively reduce the level of blood glucose, heart failure and inflammatory markers, and improve the cardiac function grade, which may be related to the mechanisms of its anti-inflammatory and myocardial protection, but there is no significant difference in LVEF before and after treatment.

In this study, it was found that compared with the control group,dapagliflozin in the treatment of T2DM patients complicated with HFmrEF can effectively reduce the level of blood glucose and NTproBNP, prolong by 6MWT, improve NYHA cardiac function classification, and improve the exercise endurance of patients, which is consistent with Dai Rixin et al.[23].However, in this study, LVEF was better than before treatment, and the improvement was more obvious in the dapagliflozin group.The possible reason is that Dai Rixin et al.had a small sample size and a shorter follow-up time of 6 months, while this study had a larger sample size and a longer observation time of 9 months, with relatively small bias.In addition,the oral dose of dapagliflozin in their study was 5 mg/d, while that in this study was 10 mg/d.The improvement of cardiac function in different therapeutic doses of dapagliflozin is worthy of further study.At the same time, this study also found that after treatment, the MLHFQ scores in the body field, the emotional field and other fields were decreased comprehensively in the dapagliflozin group, and patients showed better quality of life.Moreover, the study group had fewer MACE events, suggesting that dapagliflozin may improve the prognosis of T2DM patients with HFmrEF.In terms of safety, longterm oral dapagliflozin did not significantly increase adverse drug reactions.There was no statistical comparison because of the too few MACE events and adverse drug reactions in the two groups.In conclusion, dapagliflozin treatment in T2DM patients with HFmrEF has good clinical efficacy, good patient tolerance and high safety profile.

This study has some limitations: the number of samples is small,and further large-scale studies with large samples and longer followup are needed to confirm whether it can reduce mortality, MACE and the prognosis of patients.The mechanism of dapagliflozin improving cardiac function in HFmrEF patients still needs to molecular biological studies.The effect of different therapeutic doses of dapagliflozin on experimental results deserves further study.

4.Discussion

In conclusion, dapagliflozin is a safe and effective drug for the treatment of T2DM complicated with HFmrEF, which can effectively reduce blood glucose, improve patients’ activity ability,optimize patients’ quality of life, and reduce adverse cardiac events.For patients with heart failure, the addition of dapagliflozin to standard anti-heart failure therapy may produce better efficacy, but further confirmation is needed in large population studies.

Author contribution: Wang Wanhong is responsible for the guidance of the academic direction and academic views, and the specific design of the experiment; Xu Linhui participated in the implementation of case collection and follow-up process, wrote and revised the paper; Zhang Yi and Shi Bo participated in the collection and analysis of the data and the interpretation of the results.

There is no conflict of interest in this article.