Dapagliflozin and sacubitril on myocardial microperfusion in patients with post-acute myocardial infarction heart failure and type 2 diabetes

Abstract

BACKGROUND

Coronary heart disease and type 2 diabetes mellitus (T2DM) frequently coexist, creating a complex and challenging clinical scenario, particularly when complicated with acute myocardial infarction (AMI).

AIM

To examine the effects of dapagliflozin combined with sakubactrovalsartan sodium tablets on myocardial microperfusion.

METHODS

In total, 98 patients were categorized into control (n = 47) and observation (n = 51) groups. The control group received noxital, while the observation group was treated with dapagliflozin combined with noxital for 6 months. Changes in myocardial microperfusion, blood glucose level, cardiac function, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, growth differentiation factor-15 (GDF-15) level, and other related factors were compared between the two groups. Additionally, the incidence of major adverse cardiovascular events (MACE) and adverse reactions were calculated.

RESULTS

After treatment, in the observation and control groups, the corrected thrombolysis in myocardial infarction frame counts were 37.12 ± 5.02 and 48.23 ± 4.66, respectively. The NT-proBNP levels were 1502.65 ± 255.87 and 2015.23 ± 286.31 pg/mL, the N-terminal pro-atrial natriuretic peptide (NT-proANP) levels were 1415.69 ± 213.05 and 1875.52 ± 241.02 ng/mL, the GDF-15 levels were 0.87 ± 0.43 and 1.21 ± 0.56 g/L, and the high-sensitivity C-reactive protein (hs-CRP) levels were 6.54 ± 1.56 and 8.77 ± 1.94 mg/L, respectively, with statistically significant differences (P < 0.05). The cumulative incidence of MACEs in the observation group was significantly lower than that in the control group (P < 0.05). The incidence of adverse reactions was 13.73% (7/51) in the observation group and 10.64% (5/47) in the control group, with no statistically significant difference (P > 0.05).

CONCLUSION

Dapagliflozin combined with nocinto can improve myocardial microperfusion and left ventricular remodeling and reduce MACE incidence in patients with post-AMI heart failure and T2DM. The underlying mechanism may be related to the reduction in the expression levels of NT-proANP, GDF-15, and hs-CRP.

Key Words: Dagelin, Nocinto, Acute myocardial infarction, Type 2 diabetes, Heart failure, Myocardial microperfusion

Core Tip: This study explored the efficacy of combining dapagliflozin and sakubactrovalsartan (noxinto) in improving myocardial microperfusion and reducing major adverse cardiovascular event incidence in patients with post–acute myocardial infarction (AMI) heart failure and type 2 diabetes mellitus (T2DM). Results indicated that compared with the control group, significant improvements in myocardial perfusion, blood glucose levels, and cardiac function along with reductions in N-terminal pro-atrial natriuretic peptide, growth differentiation factor-15, and high-sensitivity C-reactive protein levels were noted in the observation group. These findings revealed that this combination therapy may offer a novel approach for managing complex cases of post-AMI heart failure and T2DM, highlighting its potential benefits and mechanisms of action.

INTRODUCTION

Coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM) frequently coexist, creating a complex and challenging clinical scenario, especially when complicated with acute myocardial infarction (AMI)[1,2]. Immediate intervention following AMI, which typically involves percutaneous coronary intervention (PCI), is crucial for rapidly alleviating vessel obstruction and restoring myocardial blood flow[3]. However, even with successful revascularization, some patients may experience complications such as microvascular dysfunction and subsequent heart failure. To mitigate these risks, adjunctive therapy with antiplatelet agents and myocardial protection drugs is essential. Telmisartan (micardis) is known for its dual action, as it exerts antihypertensive effects and reduces cardiovascular mortality while slowing the progression of heart failure. This makes it a preferred choice in the post-PCI setting[4,5]. Additionally, dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, offers a novel approach for managing patients with T2DM and post-AMI complications. It effectively regulates postprandial blood sugar levels without the risk of hypoglycemia and has shown potential as a therapeutic option for heart failure, including benefits for patients with mildly reduced ejection fraction and implications for arrhythmia prevention[6]. The applications of dapagliflozin are expanding, with clinical trials of dapagliflozin being recently completed for chronic kidney disease[7]. Despite these advancements, the precise mechanisms underlying its cardioprotective effects warrant further elucidation[8,9].

Consequently, this study aimed to explore the impact and potential mechanisms underlying the combined administration of dapagliflozin and telmisartan on microvascular perfusion in individuals experiencing post-AMI complications and T2DM[10,11]. By examining the interplay between these medications and their effects on microvascular dynamics, this study can provide novel insights into optimizing therapeutic strategies for this high-risk patient population. To achieve this, the study employed a rigorous research methodology, with a prospective, randomized, open-label, controlled, single-center design. Ninety-eight patients diagnosed with AMI complicated with T2DM and subsequent heart failure were enrolled, after obtaining ethical approval from the Medical Ethics Committee and written informed consent from the participants. Diagnosis and inclusion criteria were based on the established guidelines for AMI, T2DM, and heart failure[12]. Exclusion criteria were defined to ensure the homogeneity of the study population and mitigate confounding factors. Treatment allocation was randomized, with patients assigned to either the control group receiving telmisartan or the observation group receiving a combination of dapagliflozin and telmisartan. Both groups received standard secondary prevention measures for CHD, glucose-lowering therapy, and anti-heart failure treatment[13]. The efficacy and safety of the treatment regimens were assessed over a 6-month period based on various clinical and biochemical parameters, including myocardial microcirculation indicators, cardiac function parameters, and biochemical markers of heart failure and inflammation. Additionally, the incidences of MACEs and treatment-related adverse reactions were recorded and analyzed[14].

This study can significantly improve our understanding of the therapeutic synergies between dapagliflozin and telmisartan in managing post-AMI complications and T2DM. By elucidating the underlying mechanisms and assessing their clinical implications, the findings could pave the way for developing more effective and tailored therapeutic strategies for this vulnerable patient population[15].

MATERIALS AND METHODS

Study design

In this study, blinding was appropriately implemented to minimize subjective bias. Examiners (typically physicians or assessors) were unaware of the treatment regimen received by patients during assessment or data collection. This ensured reliability and credibility of the research findings.

Randomization was conducted using the envelope method, wherein treatment allocation for clinical trial participants is concealed within opaque envelopes. Each envelope contains a random assignment to either the observation or control group. Before the study, envelopes were prepared with randomized treatment assignments based on a predetermined allocation ratio. Upon participant enrollment, the investigators randomly selected an envelope and allocated the corresponding treatment to the participant. This method ensures allocation concealment and helps minimize selection bias, thus enhancing the validity of the study results.

Patient selection

Ninety-eight patients with post-AMI heart failure and T2DM between October 2019 and June 2022 were enrolled. This study was approved by the Medical Ethics Committee, and written informed consent was obtained from the participants.

Diagnosis and inclusion criteria: This study utilized criteria specified in the guidelines for acute ST-segment elevation myocardial infarction, Chinese guidelines for T2DM, and Chinese guidelines for heart failure[12].

Exclusion criteria: Patients with hypotension, prior coronary artery bypass grafting, allergies to dapagliflozin or telmisartan, severe diabetes complications, unstable hemodynamics, a history of chronic heart failure, severe hepatic or renal dysfunction, or mental illness were excluded.

Drugs, reagents, and instruments

Dapagliflozin tablets (10 mg) were manufactured by AstraZeneca Pharmaceuticals Co., Ltd., and approved by the China Food and Drug Administration under the registration number J20170040. Telmisartan sodium tablets (100 mg), marketed as micardis, were manufactured by Beijing Novartis Pharma Ltd., and approved by the China Food and Drug Administration under the registration number J20190002.

A fully automated biochemical analyzer was obtained from Siemens AG (Germany, model ADVIA2400). An enzyme immunoassay analyzer was procured from Thermo Fisher Scientific Inc. (United States, model Multiskan FC), and a color Doppler ultrasound scanner was obtained from Shenzhen Kaili Biomedical Co., Ltd. (model M30). A special protein analyzer was purchased from Sysmex Corporation (Japan, model PA-900).

Grouping and treatment methods

Both groups received standard secondary prevention measures for CHD, glucose-lowering therapy, and anti-heart failure treatments. The control group received telmisartan, starting at a dose of 50 mg twice daily (bid) and titrated to 200 mg bid. The observation group received dapagliflozin combined with telmisartan, starting at a dose of 5 mg once daily (qd) and titrated to 10 mg qd. Both groups were treated for 6 months.

Observation indicators

Myocardial microcirculation parameters, including corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC), TIMI myocardial perfusion grade (TMPG), coronary flow velocity reserves (CFVR), and cardiac function indicators, were assessed. Blood samples were collected for biochemical analyses, and the incidences of MACEs were recorded over the 6-month treatment period.

Statistical analysis

SPSS 19.0 was used for statistical analysis. Normally distributed quantitative variables were presented as mean ± SD and analyzed using t-tests. Categorical variables were compared using χ² tests. The statistical significance was set at P < 0.05.

RESULTS

General information

This study compared general demographic data, including sex, T2DM duration, time from onset to surgery, and Killip classification, between the observation and control groups. When comparing disease duration and cardiac function grading, this study specifically focused on patients with significant T2DM. In both the groups, cardiac function grading was predominantly grade III, which was observed in 56.86% and 59.57% of the respective total populations. However, no statistically significant differences were observed (P > 0.05) (Table 1).

Table 1 Comparison of general characteristics between the two groups.

Item	Control group (n = 47)	Observation group (n = 51)	t/F	P value
Sex (M/F)	26 (55.32)/21 (44.68)	28 (54.90)/23 (45.10)	0.002	0.967
Age (year)	63.92 ± 9.85	65.01 ± 10.21	-0.537	0.593
BMI (kg/m2)	26.12 ± 2.56	26.64 ± 2.67	-0.982	0.328
HR (beat/min)	80.11 ± 9.14	78.95 ± 8.78	0.641	0.523
T2DM course (years)	8.96 ± 2.47	8.74 ± 2.19	0.467	0.641
Time from onset to operation (hours)	5.21 ± 1.91	5.04 ± 1.97	0.433	0.666
Killip classification (I-IV)			0.703	0.704
Grade II	11 (23.40)	10 (19.61)
Grade III	28 (59.57)	29 (56.86)
Grade IV	8 (17.02)	12 (23.53)

Control group: Noxital treatment; Observation group: Dapagliflozin combined with noxital; BMI: Body mass index; HR: Heart rate.

Comparison of myocardial microperfusion indicators between the two groups

Comparison of myocardial microperfusion indicators before treatment showed no statistically significant differences between the two groups (P > 0.05). Compared with baseline, both groups exhibited significant reductions in CTFC and TMPG post-treatment, with the observation group exhibiting lower values than the control group (P < 0.05). Conversely, the post-treatment CFVR increased significantly in both groups, with the observation group exhibiting higher values than the control group (3.32 ± 0.51 vs 2.98 ± 0.47; P < 0.05) (Table 2).

Table 2 Comparison of myocardial micro perfusion indexes between the two groups.

Item	Control group (n = 47)		t	P value	Observation group (n = 51)		t	P value
	Before treatment	After treatment			Before treatment	After treatment
CTFC	80.25 ± 4.89	48.23 ± 4.66a	32.05	< 0.01	78.98 ± 5.47	37.12 ± 5.02a,c	42.07	< 0.01
TMPG	130.14 ± 7.85	105.25 ± 6.11a	19.65	< 0.01	128.97 ± 10.04	96.12 ± 5.78a,c	19.04	< 0.01
CFVR	2.25 ± 0.41	2.98 ± 0.47a	-6.52	< 0.01	2.20 ± 0.46	3.32 ± 0.51a,c	-13.53	< 0.01

^aP < 0.05 vs before treatment.

^cP < 0.05 vs control group.

CTFC: Thrombolysis in myocardial infarction frame count; TMPG: Thrombolysis in myocardial infarction myocardial perfusion grade; CFVR: Coronary flow velocity reserves.

Comparison of blood glucose indicators between the two groups

Comparison of blood glucose indicators before treatment showed no statistically significant differences between the two groups (P > 0.05). Compared with baseline, both groups exhibited significant reductions in fasting blood glucose (FBG), 2-h postprandial glucose (2hPG), and glycated hemoglobin (HbA1c) levels post-treatment, with the observation group showing lower values than the control group (P < 0.05) (Table 3).

Table 3 Comparison of blood glucose indicators between the two groups.

Item	Control group (n = 47)		t	P value	Observation group (n = 51)		t	P value
	Before treatment	After treatment			Before treatment	After treatment
FBG (mmol/L)	11.12 ± 1.77	7.47 ± 1.08a	12.89	< 0.01	10.98 ± 1.84	6.33 ± 0.87a,c	16.23	< 0.01
2hPG (mmol/L)	15.21 ± 2.56	10.41 ± 2.01a	12.16	< 0.01	15.34 ± 2.17	8.41 ± 1.81a,c	16.20	< 0.01
HbA1c (%)	12.25 ± 2.74	8.02 ± 1.96a	12.16	< 0.01	11.98 ± 2.83	6.84 ± 1.54a,c	13.31	< 0.01

^aP < 0.05 vs before treatment.

^cP < 0.05 vs control group.

FBG: Fasting blood glucose; 2hPG: 2-h postprandial glucose; HbA1c: Glycated hemoglobin.

Comparison of cardiac function–related indicators between the two groups

Comparison of cardiac function–related indicators before treatment showed no statistically significant differences between the two groups (P > 0.05). Compared with baseline, both groups exhibited significant reductions in left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left ventricular mass index (LVMI), and left ventricular remodeling index (LVRI) post-treatment, with the observation group exhibiting lower values than the control group (P < 0.05). Conversely, left ventricular ejection fraction (LVEF) significantly increased in both groups post-treatment, with the observation group demonstrating higher values (P < 0.05) (Table 4).

Table 4 Comparison of indexes related to cardiac function between the two groups.

Item	Control group (n = 47)		t	P value	Observation group (n = 51)		t	P value
	Before treatment	After treatment			Before treatment	After treatment
LVEF (%)	43.26 ± 5.21	50.25 ± 5.78a	-5.60	< 0.01	42.97 ± 5.74	55.69 ± 6.01a,c	-10.86	< 0.01
LVESD (mm)	44.21 ± 3.89	38.95 ± 3.41a	9.38	< 0.01	44.11 ± 4.03	34.41 ± 3.26a,c	15.70	< 0.01
LVEDD (mm)	59.78 ± 4.41	54.63 ± 4.05a	7.24	< 0.01	60.23 ± 4.52	51.78 ± 3.69a,c	9.17	< 0.01
LVMI (g/m2)	115.02 ± 16.45	102.89 ± 13.04a	4.68	< 0.01	113.87 ± 17.14	95.36 ± 10.47a,c	7.51	< 0.01
LVRI (g/mL)	1.61 ± 0.15	1.46 ± 0.12a	4.92	< 0.01	1.59 ± 0.18	1.37 ± 0.11a,c	7.21	< 0.01

^aP < 0.05 vs before treatment.

^cP < 0.05 vs control group.

LVEF: Left ventricular ejection fraction; LVESD: Left ventricular end-systolic diameter; LVEDD: Left ventricular end-diastolic diameter; LVMI: Left ventricular mass index; LVRI: Left ventricular remodeling index.

Comparison of other related factors between the two groups

Comparison of other related factors before treatment showed no statistically significant differences between the two groups (P > 0.05). Compared with baseline, both groups exhibited significant reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), growth differentiation factor-15 (GDF-15), and high-sensitivity C-reactive protein (hs-CRP) levels post-treatment, with the observation group showing lower values than the control group (P < 0.05) (Table 5).

Table 5 Comparison of correlation factors between two groups.

Item	Control group (n = 47)		t	P value	Observation group (n = 51)		t	P value
	Before treatment	After treatment			Before treatment	After treatment
NT-proBNP (pg/mL)	3624.74 ± 475.69	2015.23 ± 286.31a	20.00	< 0.01	3652.05 ± 439.87	1502.65 ± 255.87a,c	26.28	< 0.01
NT-proANP (ng/mL)	3526.02 ± 412.05	1875.52 ± 241.02a	24.39	< 0.01	3498.74 ± 397.86	1415.69 ± 213.05a,c	31.17	< 0.01
GDF-15 (g/L)	3.02 ± 0.85	1.21 ± 0.56a	12.91	< 0.01	2.97 ± 0.93	0.87 ± 0.43a,c	15.19	< 0.01
hs-CRP (mg/L)	13.56 ± 2.58	8.77 ± 1.94a	10.20	< 0.01	13.42 ± 2.67	6.54 ± 1.56a,c	20.60	< 0.01

^aP < 0.05 vs before treatment.

^cP < 0.05 vs control group.

NT-proBNP: N-terminal prohormone of brain natriuretic peptide; NT-proANP: N-terminal pro-atrial natriuretic peptide; GDF-15: Growth differentiation factor-15; hs-CRP: High-sensitivity C-reactive protein.

Comparison of MACE incidences between the two groups

The cumulative incidence of MACEs was significantly lower in the observation group than in the control group [7.84% (4/51) vs 25.53% (12/47); P < 0.05] (Table 6).

Table 6 Comparison of major adverse cardiovascular events incidence rates between the two groups [n (%)].

Item	Control group (n = 47)	Observation group (n = 51)
Recurrent myocardial infarction	3 (6.38)	1 (1.96)
Heart failure	2 (4.26)	1 (1.96)
Angina pectoris	6 (12.77)	2 (3.92)
Cardiogenic death	1 (2.13)	0 (0.00)
Cumulative MACE incidence	11 (25.53)	4 (7.84)a
F value	0.446
P value	0.979

^aP < 0.05 vs control group.

MACE: Major adverse cardiovascular events.

Safety comparison between the two groups

During the treatment period, the observation group reported two cases of hypoglycemia, one case each of urinary tract infection and vascular edema, and three cases of gastrointestinal reaction. Meanwhile, the control group reported one case each of hypotension, dizziness, and ketoacidosis and two cases of urinary tract infection. Comparison of the incidences of adverse reactions between the observation (13.73%) and control (10.64%) groups showed no statistically significant difference (P > 0.05).

DISCUSSION

AMI occurs due to the rupture of unstable plaques and thrombosis in coronary arteries, leading to sustained narrowing or occlusion of blood vessels and subsequent myocardial ischemic necrosis. It is a major cause of sudden death, particularly among middle-aged and older individuals. AMI is characterized by rapid onset and high mortality rates. Timely PCI can reduce the size of infarcts and proportion of myocardial cells as well as improve patient prognosis[16,17]. However, patients with AMI and concomitant T2DM face a more complex condition that directly impacts the efficacy of PCI, possibly due to hyperglycemia-induced microcirculatory dysfunction[18,19]. Valsartan (sacubitril/valsartan) is commonly used as an adjuvant therapy post-PCI. Sacubitril, a neprilysin inhibitor, protects the cardiovascular and renal systems. Valsartan blocks type 1 angiotensin II receptors, inhibits aldosterone release, and exerts antihypertensive effects. Clinical evidence has confirmed the pharmacological benefits of valsartan, including blood pressure reduction, cardiovascular protection, and anti-heart failure properties[20].

Dapagliflozin, an SGLT2 inhibitor, acts on SGLT2 expressed in the proximal renal tubules, where it participates in glucose reabsorption[21,22]. By inhibiting SGLT2, dapagliflozin reduces glucose reabsorption, thereby enhancing urinary glucose excretion. Related researches have demonstrated that dapagliflozin can promote post-PCI glycemic control and inhibit ventricular remodeling and myocardial microcirculation disorders in patients with AMI and T2DM[22]. In the current study, both groups showed significant decreases in CTFC and TMPG after treatment, with the observation group exhibiting lower values than the control group. Compared with baseline, CFVR was significantly increased in both groups after treatment, with the observation group exhibiting higher values. Furthermore, LVESD, LVEDD, LVMI, and LVRI were significantly decreased in both groups after treatment, with the observation group showing lower values. LVEF was also significantly increased in both groups after treatment, with the observation group showing higher values. Compared to baseline, FBG, 2hPG, and HbA1c levels were significantly decreased in both groups after treatment, with the observation group showing lower values. Our results suggested that dapagliflozin combined with valsartan can improve myocardial micro-perfusion and cardiac function and better control blood glucose levels in patients with post-AMI complications and T2DM. This is because dapagliflozin can promote urinary glucose excretion by inhibiting SGLT2, thereby maintaining blood glucose stability. Dapagliflozin can promote fat breakdown as well as alleviate inflammation and oxidative stress, thereby inhibiting microvascular lesions, improving local and myocardial microcirculation, and ultimately enhancing cardiac function.

NT-proBNP is primarily secreted by ventricular muscle cells, while NT-proANP is mainly secreted by atrial muscle cells. Both are released in large quantities during myocardial damage, leading to vasodilation and reduced water and sodium retention[23]. A previous study confirmed that NT-proBNP and NT-proANP levels are positively correlated with heart failure severity. GDF-15 is a myocardial protective factor highly expressed during myocardial injury, safeguarding damaged myocardium. Its serum level is related to the diagnosis, risk stratification, and prognosis of cardiovascular diseases[24]. Furthermore, hs-CRP reflects the body’s microinflammatory state and is associated with pathological processes such as unstable plaques and microvascular constriction[25,26]. In the current study, both groups showed significantly decreased levels of NT-proBNP, NT-proANP, GDF-15, and hs-CRP after treatment, with the observation group exhibiting lower values. These findings suggest that dapagliflozin combined with valsartan can reduce NT-proANP, GDF-15, and hs-CRP levels, potentially contributing to the treatment of patients with post-AMI heart failure and T2DM.

The occurrence of MACEs post-PCI poses significant risks to patient outcomes, potentially leading to adverse consequences, including mortality. This study revealed that the cumulative incidence of MACE was significantly lower in the observation group than in the control group. Notably, there was no statistically significant difference in the incidence of adverse reactions between the two groups. These results highlight the potential therapeutic benefits of dapagliflozin combined with valsartan in mitigating the risk of MACE in patients with post-AMI complications and T2DM, without increasing the risk of adverse reactions. The multifaceted mechanisms of action of dapagliflozin, including promoting urinary glucose excretion and fat breakdown, contribute to this favorable outcome. Furthermore, dapagliflozin possesses anti-inflammatory and antioxidative properties, which help alleviate inflammation and oxidative stress in the cardiovascular system, thereby enhancing plaque stability and reducing MACE incidence in high-risk patients, such as those with T2DM. However, due to sample size limitations in the current study, future research should focus on larger clinical studies to further demonstrate the pharmacological mechanism of dapagliflozin in reducing inflammation and oxidative stress in the cardiovascular system.

CONCLUSION

Dapagliflozin combined with valsartan can improve myocardial microperfusion and left ventricular remodeling as well as reduce MACE incidence. Its mechanism of action may be related to the reduction in NT-proANP, GDF-15, and hs-CRP levels.