Diabetes-Induced Cardiomyopathy: Updates in Epidemiology, Prevention, and Management

Abstract

Diabetes mellitus (DM) is a condition of abnormal carbohydrate metabolism, leading to persistent hyperglycemia. It is defined as a fasting blood glucose over 7.0 mmol/L, a 2-hour plasma post-meal of 11.1 mmol/L, or HbA1C values over 6.5% (48 mmol/L). DM affects almost 600 million people globally with an annual cost of around three trillion US dollars. These data indicate that DM is a global health burden that warrants attention. Complications of DM include nephropathy, retinopathy, neuropathy, and cardiomyopathy. DM-induced hyperglycemia causes oxidative stress, inflammation, endothelial and mitochondrial abnormality, and subsequently, cardiomyopathy. Hyperglycemia stimulates many signaling pathways including polyol, and hexokinase, resulting in the formation of vascular endothelial lesions, free radicals and carbonyl anions, transforming growth factor-β1, fibronectin, and nuclear factor kappa-B, which increase fibrosis and inflammation in the myocardium. All of these pathological processes lead to defective vascular permeability and hypoxia in cardiac tissue, ischemia, and eventually heart failure, and sudden cardiac death. The onset of diabetic cardiomyopathy could be delayed with a healthy lifestyle (balanced diet, physical activity, sleep, low stress, non-smoking). GLP-1 receptor agonists with or without SGLT2i are beneficial additions for the treatment of diabetic cardiomyopathy.

1. Introduction

1.1 Diabetes (DM): epidemiology and associated complications

DM is a complex condition currently having an impact on over 600 million individuals aged 20–78 years worldwide, with 250 million undiagnosed and 2 billion with prediabetes [1, 2]. The disorder is divided into two main groups: Type 1 diabetes mellitus (T1-DM) and Type 2 or non-insulin dependent diabetes (T2-DM). T1-DM arises by the demolition of the endocrine β-cells of the islet of Langerhans by immune cells, resulting in inadequate insulin release, while T2-DM is due to lifestyle habits including unhealthy diets and physical inactivity. This results in insulin resistance (IR) where insulin molecules cannot be imbibed into skeletal muscle. DM is now a global pandemic with a global widespread presence that will rise to 800 million people in 2045 [1, 3].

The annual cost of treating and managing diabetic patients in 2021 in the US was estimated at one trillion US dollars and three trillion US dollars globally [4]. The high prevalence and the amount of funds for managing DM and its associated complications have posed severe distress to healthcare providers and individuals with the disorder worldwide (Table 1).

		DM cases in 2021 (millions)	Projected DM cases in 2045; (millions)	% Increase from 2021 to 2045	Ref
1	Worldwide	537	784	46	[1]
2	Africa (Nigeria, South Africa, Kenya, etc.)	24	55	134	[1]
3	South-East Asia (India, Bangladesh, Indonesia, etc.)	90	152	68	[1]
4	Europe (UK, France, Germany, Italy, etc.)	61	69	13	[1]
5	North America & Caribbean (United States of America, Mexico, Canada, etc.)	51	63	24	[1]
6	Middle East & North Africa (Egypt, Pakistan, Iran, Saudi Arabia, Sudan, etc.)	73	136	87	[5]
7	South and Central America (Brazil, Argentina, Chile, etc.)	32	49	50
8	Western Pacific (China, Japan, Australia, Philippines, Malaysia, Vietnam, etc.)	206	260	27

Table 1.

The pattern of distribution of diabetes mellitus type 2 cases among those between the ages of 20 and 79 years, in different WHO zones in 2021 and 2045 (projected).

WHO = World Health Organization.

The ten nations with the highest widespread occurrence of diabetes mellitus, from the highest to lowest, are: Pakistan-Islamic Republic (30.80%), Kuwait-State (24.90%), Republic of Nauru (23.40%), New Caledonia Islands (23.40%), Islands of Northern Mariana (23.40%), Marshall Islands of the US (23.00%), Republic of Mauritius (22.60%), Arab Republic of Egypt (20.90%), Qatar (19.50%), Malaysia (19.00%) [1]. Unfortunately, most of the increases in the number of people with DM are found in poorer countries.

1.2 Gender, ethnicity, and diabetic cardiomyopathy

Diabetes affects ethnic groups differentially, striking some ethnic groups more severely than others. For example, the Pima Indians of the USA acquire T2-DM at a rate that is double that seen in Caucasians. Other ethnic groups that are also at higher risk include Latinos, Asians, and African Americans [5].

Several epidemiological investigations have indicated that the widespread occurrence of T2-DM is four times in people from South Asian countries compared to Caucasians. In addition, people from Southern Asia nations become diabetic at an earlier age compared to Caucasians [6]. Women with DM, on the other hand, are relatively more susceptible to developing cardiovascular events when compared to men [7]. The reason for this is unknown, but hormonal interference may contribute to this difference. Since DM is as twice as high in Pima Indians compared to Caucasians, the prevalence of DCM will most likely be higher in this ethnic group.

The reasons for these ethnic differences may be due to some or all of the following: a): access to optimal health care, b): standard of living, c): awareness about illnesses in general and DM in particular, d): social coherence, e): eating habits, and f): physical exercise. In addition to genetics and environmental factors, it is also likely that the opportunity to use health services and other social factors that determine health (SDOH) could explain some of the disparities in the pathophysiological manifestations and severity of DM and its associated complications [8].

The majority of Caucasians will likely have better access to the above-listed items compared to their non-Caucasian counterparts.

Other ethnic groups including Latinos, Asians, and African Americans are more likely to develop DM and its complications (including DCM) when compared to their Caucasian counterparts [8]. It is worth noting, however, that inherited and modifiable external factors also contribute to the pathogenicity and severity of DM, and its associated co-morbidities and complications [8].

2. Pathophysiological considerations in diabetic cardiomyopathy

DM is a dysfunction of the pancreas to regulate the metabolism of carbohydrates. The inability of insulin to effectively control carbohydrate metabolism also leads to disturbances in lipid, and protein metabolisms, also associated with diabetic cardiomyopathy [3, 8]. Figure 1 illustrates the pathological pathways leading to diabetic cardiomyopathy (DCM). 35–50% of all cases of cardiomyopathies cause arrhythmias, HF, and subsequently, SCD (sudden death of the heart).

Figure 1.

Illustrates the pathological conditions contributing to the initiation of diabetic cardiomyopathy. ROS = Reactive oxygen free radical species; RCS = reactive carbonyl free radical species; MGO = methylglyoxal.

Many factors put people at risk of getting T2DM. They include unhealthy diets, obesity or overweight, aging, genetic factors, physical inactivity, ethnicity, polycystic ovary syndrome, and others. These risk factors can act synergistically to elicit diabetes-induced hyperglycemia (HG). HG is the insulting factor, which works in tandem with protein and lipid metabolic pathways to generate certain reactive species that induce oxidative stress (OS). OS has a direct insulting, and damaging effect on mitochondria, cells, nerves, and tissues within the myocardium. These eventually precipitate a reduced heart rate and force of contraction.

These pathological processes are due to derangements in cation-transporting proteins, and contractile proteins, thereby compromising the excitation-contraction (ECC) process. With time, the myocardium develops diastolic dysfunction due to delayed contraction and relaxation (filling), reduced cardiac output, and subsequently arrhythmias, HF, and SCD [9, 10, 11, 12].

This review will now concentrate on how hyperglycemia can induce structural changes in the myocardium, OS (oxidative stress) and inflammation, lesions of the mitochondria and endothelial lining, cardiac energy metabolism, extracellular matrix (ECM), and development of cardiac fibrosis, remodeling of the heart and abnormalities in calcium signaling and contractile proteins. In addition, the review will describe the roles of potential biochemical markers, signature proteins, and other factors associated with the development of DCM, since they play significant roles in its development. Figure 1 shows the different pathological events leading to diabetic cardiomyopathy. These events include, but are not limited to, hyperglycemia, insulin resistance emanating from obesity, unfolded protein response, physical inactivity, and dyslipidemia. Hyperglycemia can cause glucotoxicity and OS that enhance extracellular matrix restructuring, myocardium fibrosis, and eventually DCM.

3. DM-induced oxidative stress, inflammatory chain reaction, and dysfunction of mitochondria

T2-DM-induced hyperglycemia (HG) leads to oxidative stress and inflammatory reactions, which elicit a switch of metabolic homeostatic processes in the heart leading to glucose intolerance. Mitochondrial damage leads to the overproduction of ROS and RCS in diabetic subjects leading to increased fatty oxidation and lipotoxicity in cardiomyocytes. This is coupled with increased levels of superoxide anion radicals, AGE (advanced-glycation-end-products), and enhancement of the receptors for AGE.

These oxidants also induce oxidative distress within the mitochondrion culminating in disaggregation, reduction in number, height, length, and width, and formation of blebs or vesicles and marked elevation in cristae number to compensate for mitochondria damage, and loss in DCM [13, 14, 15, 16]. It is now well established that mitochondria damage and dysfunction are determinant factors in the development of cardiac insufficiency-progression, and subsequently, diabetes-induced cardiomyopathy. This pathophysiological event is due to abnormally elevated high-energy phosphates release and increased production of ROS and RCS [17]. Once the mitochondrion is in distress due to damage by oxidants such as ROS and RNS and unable to produce energy, the myocyte and conductive tissue damage ensues [12, 14, 18].

3.1 How do chronic hyperglycemia and oxidative stress induce cardiomyocyte dysfunction?

It is paramount to stress the effect of chronic HG, a major sign of DM, in the initiation of cardiomyocyte dysfunction. HG induces oxidative stress (OS) at the cellular, tissue, and systemic levels. The OS induced by HG can then cause the release of several noxious biological factors such as cytokines that promote inflammation, ROS, and RCS [19, 20]. In addition, calcium and other signaling pathways are impaired after the onset of DM. These factors, in addition to other DM-induced pathologies, contribute to the dysfunction of the cardiomyocyte that eventually leads to the development of DCM (Figure 2).

Figure 2.

Pathophysiology of hyperglycemic-induced cardiac damage. EC = Cells of the endothelium cell; ROS = Reactive oxygen free radical species; RNS = Reactive nitrogen free radical species.

4. Endothelial cell dysfunction in DM

The endothelium maintains homeostasis of the vascular bed through blood flow regulation, and vascular tone, and prevents bleeding and thrombosis formation [21]. The endothelial cells (ECs) are located on the endothelial layer or the internal tunic of blood vessels. Therefore, any pathological changes in the EC may result in abnormal function in ECs, leading to vascular disease of the myocardium [22, 23]. When the endothelium within the myocardium is exposed to chronic hyperglycemia due to diabetes, it induces a cascade of dysfunctions leading to the induction of myocardial diseases including diabetes-induced cardiomyopathy [23, 24].

5. Derangement in calcium signaling in DM

Diabetes-induced cardiomyopathy (DCM) is a major pathological disease of the heart, where cardiomyocytes become weak and frail. DCM also damages the conductive tissues and cation-transporting proteins in the heart [12, 25]. Hyperglycemia generates oxidants such as ROS and RCS, which have direct adverse effects on the homeostasis of cellular calcium and other cations including potassium. Calcium is the second messenger, initiator, modulator, and promoter of the coupling excitation-contraction process in the myocardium [11, 14, 22, 23]. It has been shown that the coupling process can be damaged by factors such as hyperglycemia associated with DM [11, 14, 25, 26, 27, 28].

Methylglyoxal (MGO), an α-di-carbonyl RCS, is the main inducer of “carbonyl stress” [14, 29]. RCS are free radicals (reactive molecules) that cause conformational changes to biological macromolecules through AGE action [14, 30]. RCS, ROS, and RNS impair cell organelle function to induce autophagy and apoptosis [29, 30, 31, 32].

The dysfunction of RyR and SERCA to regulate cytosolic calcium transport during diabetes leads to an elevation in diastolic calcium, which in turn results in delayed contraction and relaxation of the heart. These events play a part in the initiation of heart diseases like cardiomyopathy [14, 33]. Recent studies have revealed that gene therapy can be used successfully to delay the occurrence of diabetes-induced cardiomyopathy by targeting the synthesis of the glyoxylate-1 enzyme that breaks down MGO, a major RCS in the myocardium [33]. There is also evidence that regular daily exercise can control diabetes by increasing the beta cell mass of the endocrine pancreas and insulin release [34]. In addition to gene therapy and daily exercise, it is equally important to develop novel drugs to inhibit vascular adhesion protein that synthesizes MGO and other drugs, which can inhibit the breakdown of glyoxylase-1.

6. Extracellular matrix (ECM) development (fibrosis) and remodeling of the myocardium in DM

Most of the morbid and mortal events associated with DM are due to the DM-induced conditions of the cardiovascular apparatus such as the disease of the blood vessels supplying the heart and DCM [35]. Fibrosis, observed in the diabetic heart, is a biochemically induced morphological process, which involves the excessive tissue levels of ECM components. These components include fibrin, fibrinogen, fibronectin, laminins, collagens, elastin, myosin, and other connective tissue matrices. The accumulation of these ECM components can contribute to organ dysfunctions [10, 36].

HG, lipotoxicity, and insulin resistance (IR) activate molecules responsible for the deposition of fibers in the myocardium.

DM-induced hyperglycemia can also stimulate several fibrogenic pathways to generate ROS and RCS to induce neurohumoral responses and activate growth factor formation and downstream cascades. One such major growth factor is TGF-β1, which can induce the enlargement of the myocardium and upregulate fibro-genic matricellular proteins to form more pronounced and clinically significant fibrosis [13, 35, 36].

Diabetes-induced fibrosis impairs the contractile function and the electrophysiological properties of the heart, resulting in ventricular stiffness, delayed conduction, heart failure/cardiomyopathy, arrhythmogenesis, and SCD [36].

At an earlier stage of all these events, the myocardium undergoes a physiological remodeling process to enable the pumping of blood until the organ is repaired naturally or treated with drugs.

7. Other metabolic factors and protein signatures associated with diabetes-induced cardiomyopathy

Several metabolic factors, signature proteins, biomarkers, and cellular mediators contribute to the pathogenesis of DCM. This section briefly describes the involvement of these components. Figure 3 illustrates the roles of some typical metabolic factors, signature proteins, biomarkers, and cellular mediators in the progression of DCM. The renin angiotensin aldosterone system abbreviated as RAAS is enhanced in people with DM [37]. The RAAS in turn stimulates NF-κB release. This promotes the release of TNF-alpha, MCP-1, IL-6, and IL-8 [38, 39]. DM promotes increased tissue levels of NF-κB in the myocardium to increase NADP oxidase-mediated release of ROS, superoxide, and peroxynitrite radicals. This process consumes the available nitric oxide, an important signaling molecular for the vasculature of the myocardium. Abnormal profiles of cAMP-responsive element modulator [40], free fatty acid [41], transcription factor Nrf2 [42], PKC (protein kinase-C) [19], cardiac Poly(ADP-ribose) polymerase 1 [43], miRNA [44], MAPK and JNK [45], SGLT2 [46], AMPK [46], O-GlcNAC [46], and autonomic neuropathy [47] also take part in determining whether DCM occurs (Figure 3).

Figure 3.

Signature proteins and other biomarkers implicated in the etiopathogenesis of DCM. CREM = cAMP-responsive element modulator, FFA = Free fatty acid, NrF2 = nuclear factor erythroid 2-related-factor-2; PKC = protein kinase-C.

8. How does diabetes mellitus contribute to coronary artery disease?

T2-DM predisposes patients to developing coronary artery disease (CAD). Indeed, it is estimated that people with T2-DM are more likely to have CAD [48, 49]. As described earlier, people with DM have an increased tendency for atherosclerosis. There are many factors, which predispose diabetic patients to developing atherosclerosis. These factors include insulin resistance, chronic hyperglycemia, elevated plasma concentrations of lipid molecules, OS, inflammatory reactions, and the dysfunction of EC, the coagulation process, and vascular smooth muscle [50, 51, 52]. Many other elements of dysmetabolic syndrome, like obesity, and high blood pressure also contribute to the etiology of CAD [53, 54, 55].

Severe obesity, IR, and chronic hyperglycemia enhance the release of inflammatory cytokines. Obesity, by itself, can induce many of the components (DM, hyperlipidemia, atherosclerosis, cardiovascular diseases) of Syndrome-X [56, 57]. These factors and hyperlipidemia hasten the deposition of atherosclerotic plaques in blood vessels [58] including coronary arteries. The deposition of lipid- and macrophage-laden plaques causes stenosis of the blood vessels of the heart bringing about a poor blood flow to the myocardial layer of the heart. Insufficient blood supply to the myocardium will cause hypoxia and injury of cardiomyocytes. All of these are risk factors for DCM. DM causes impaired blood coagulation, leading to increased formation of micro-thrombi in coronary arteries because of the enhanced function of platelets and the affinity of blood to clot [59].

In DM patients, there is an elevated circulating level of osteonectin. The plasma level of osteonectin has a direct correlation with the manifestation and severity of atherosclerotic deposition in coronary artery endothelium [60, 61] Figure 4.

Figure 4.

Factors leading to the initiation of diabetes-induced coronary artery lesions.

9. Prevention of diabetes (DM) and diabetic cardiomyopathy (DCM)

The surest way to avoid DCM is to prevent DM. There are numerous ways and activities that, if applied effectively, can delay the onset of DM and hence DCM Table 2.

		Effect on DM/DCM	Ref
1	Healthy and balanced diet	Reduces blood glucose and HbA1c levels.	[62, 63]
2	Physical activity: aerobic and anaerobic	Increases insulin sensitivity and reduces blood glucose and HbA1c levels.	[3]
3	Sleep	Loss of sleep increases blood glucose level.	[64]
4	Reduction of stress	Stress increases blood glucose level.	[65]
5	Avoid cigarette smoking	Increases blood glucose via nicotine.	[66]
6	Avoid excessive alcohol intake	Increases in blood glucose levels in well-nourished individuals may cause pancreatitis.	[67]
7	Weight reduction	Improves diabetes signs and cardiac functions.	[68, 69]
8	Hypoglycemic agents	Reduces blood glucose level.	[70, 71, 72, 73, 74]

Table 2.

List of activities that can help to prevent and/or manage diabetic cardiomyopathy.

9.1 Healthy and balanced diet

A healthy and well-balanced diet will deliver the necessary micronutrients, vitamins, proteins, and carbohydrates required for normal body function. A diet with a lot of greens, nuts, and fresh fruits, with a balanced proportion of protein, carbohydrates, and fat, will not only bring the needed micronutrients and trace elements but an optimal dose of energy to complete our daily tasks. Micronutrients and trace elements, including zinc and magnesium, are crucial for the function of several enzymes and biological pathways that regulate our energy homeostasis. The fine regulation of energy homeostasis determines whether an individual becomes diabetic. Literature reports have indicated that a balanced and individualized diet may reduce the level of HbA1c in diabetic patients [62, 63].

9.2 Physical activity

Physical activity such as resistance, aerobic exercise, and high-intensity interval exercise can reduce the body’s total weight and increase the body’s sensitivity to insulin and blood glucose in DM patients. The prospect of developing DCM is grossly reduced if the blood sugar concentration is optimal. In addition, long-term physical exercise (PE) can increase the mass of skeletal musculature. Since voluntary muscle cells uptake glucose molecules, increased skeletal muscle mass and activity will consume blood glucose levels, thereby lowering plasma sugar concentration [3]. PE also increases fat oxidation and reduces fat deposition in both the hepatic and adipose tissues. PE also reduces triglycerides and inflammation in tissues, both of which can complicate the management of DM and CDM [3].

9.3 Sleep

Adequate sleep has long been shown to contribute to optimal glucose homeostasis. During the sleep phase, blood glucose levels remain fairly constant. However, loss of sleep leads to abnormal glucose metabolism, more appetite for food, and a tendency to eat any type of food, and more time available to consume food [64]. All of these indicate that loss of sleep could result in poor sugar control and worsen the outcome of DM and DCM. Therefore, a crucial part of the management of DM must not be limited to the ingestion of food or pharmaceutical treatment alone, it must include lifestyle patterns such as sleep deprivation and sleep cycles.

9.4 Reduction of stress

Several reports have shown that diabetes can be induced by either psychological or physical stress. Stress, through the activation of the nervous systems, can increase the level of stress hormones including but not limited to catecholamines and glucocorticoids. These hormones are known inducers of insulin resistance [65]. These hormones can also increase blood glucose level leading to chronic hyperglycemia, with a sequelae of oxidative stress. All of these factors lead to a more severe DCM. Therefore, clinicians and advocates must investigate the relationship between the onset and complications of DM and the stressors in the lives of their patients or clients.

9.5 Cigarette smoking

In one experiment examining the effect of cigarette smoking on diabetes, a group of 26 diabetic and 24 non-diabetic subjects were asked to smoke two sticks of cigarettes. The plasma sugar concentrations were later measured before cigarette smoking and at 15, 30, and 60 min post cigarette smoking. These observations suggest that the blood sugar level increased markedly after cigarette smoking in both control, non-diabetic, and diabetic groups, but more profound in diabetic subjects. The culprit for the increase in blood glucose levels is nicotine, which has been reported to stimulate the release of hormones (catecholamines, glucocorticoids) capable of increasing the circulating blood level of glucose [66]. In addition to all other known cardiac-related consequences of cigarette smoking, patients with diabetes must be informed about their heightened risk of complications.

9.6 Excessive alcohol intake

Excessive intake of alcohol increases blood glucose levels in well-fed diabetic patients. In contrast, it may cause hypoglycemia in a poorly nourished diabetic patient. In addition, excessive alcohol consumption can lead to the occurrence of hypertriglyceridemia and vascular (retinopathy, neuropathy) diseases of diabetes [67]. Therefore, the management of DM must also include a holistic approach that integrates nutrition and pharmaceuticals into the functional aspects of the life of individuals with DM or those at risk.

10. Treatment and management of diabetic cardiomyopathy

The flow diagram in Figure 5 illustrates some interventions to treat and manage diabetic cardiomyopathy with the help of counseling for compliance, depression, and personal care. The standards in the treatment of diabetic cardiomyopathy are related to lifestyle modification, euglycemia, and mitigation of predisposing factors for cardiovascular diseases. Smoking cessation and alcohol consumption, healthy eating habits by decreasing carbohydrates and sugar consumption, reduction in body weight by eating a moderate amount daily, and daily aerobic exercise are the cornerstones in terms of lifestyle change (Figure 5).

Figure 5.

A flow chart illustrating the interventions to manage and treat diabetic cardiomyopathy. GLP-1 = Glucagon-like-peptide-1.

10.1 Hypoglycemic agents

Several anti-diabetic drugs such as sulfonylureas, biguanides, inhibitors of α-glucosidase, thiazolidinediones, meglitinides, agonists of GLP-1 receptor, amylin analogs, and SGLT inhibitors are currently available for treating diabetes. These hypoglycemic agents can reduce blood glucose and HbA1c levels and enhance the well-being and the living standard of diabetic patients [70, 71, 72, 73, 74].

10.1.1 Sulfonylureas (SU)

Although some studies have shown that SU, when used alone, may elevate the risk of cardiovascular conditions, [75] a large clinical trial (CAROLINA Trial), conducted over 6 years, showed that the newer generation of SU (glimepiride) reduces the risk of major adverse cardiac events.

10.1.2 Biguanides

Several studies have shown that metformin can protect the heart, especially in DM patients. One study (UKPDS 34) reported that metformin mitigated MI in DM patients by almost 33%. Metformin can also alleviate the risk associated with MI, SCD, angina pectoris, and peripheral vascular disease by up to 30% in people suffering from DM because it can prevent inflammation and OS of the myocardium, and enhance microcirculation in the myocardial compartment of the heart [74, 76, 77].

10.1.3 α-glucosidase inhibitors

The beneficial effect of acarbose (an α-glucosidase inhibitor) in managing diabetic cardiomyopathy is controversial. Some studies (STOP-NIDDM multicenter, The meta-analysis of Risk Improvement under the use of Acarbose study) indicated that this α-glucosidase inhibitor can reduce MI, hypertension, and other cardiovascular risks by up to 34–64% [78, 79]. These observations contrasted those reported by the Acarbose Cardiovascular Evaluation Trial (ACET) on more than 6500 patients. ACET conducted in 176 centers showed that acarbose has no major beneficial effect on the heart. [80].

10.1.4 Thiazolidinedione

The role of rosiglitazone and pioglitazone in the myocardium of the diabetic patient is controversial. Some reports (DREAM trial) have shown that these medications can cause HF [3, 81]. Although some reports have shown that this class of drugs can reduce stroke and MI [82], the consensus is that this group of anti-diabetic drugs can cause HF [83].

10.1.5 Meglitinides

Meglitinides have no marked effect on diabetic cardiomyopathy and have been reported to be subordinate to dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and antagonists of GLP-1 receptors regarding the pharmacotherapy of cardiovascular conditions in DM patients [84, 85].

10.1.6 Dipeptidyl peptidase 4 inhibitors (DPP4i)

Several drugs such as vildagliptin, sitagliptin, denagliptin, and saxagliptin belong to the DPP4i class of drugs. Reports (CARMELINA, EXAMINE, TECOS) have shown that DPP4 inhibitors have no major effect on the heart and may even cause HF [86, 87, 88, 89].

10.1.7 GLP-1 receptor agonists

Large clinical trials such as REWIND, HARMONY, PIONEER-6 reported that agonists of GLP-1 receptors curtail the risk for MI and the rate at which patients are hospitalized for heart HF [90].

10.1.8 SGLT inhibitors

SGLT2i displays a strong and significant reduction in cardiovascular events (MI, HF, stroke, hypertensive HF, and the rate of hospital stay for HF) in DM patients. This indicates that SGLT2i is non-hazardous and beneficial in DM patients and those with diabetes-induced cardiomyopathy [91, 92].

11. Structural treatment of the disease of coronary artery

Coronary artery lesions significantly contribute to the development, progression, and severity of DCM. One of the most important and recurring pathological lesions is atherosclerotic plaque. These plaques narrow the coronary artery lumen, which prevents adequate blood flow to the heart. Coronary artery stenosis may be so severe that revascularization may be needed to restore the perfusion of the myocardium.

In addition to treating the underlying DM and intensive medical therapy, currently, there are three major approaches to restoring the patency of a blocked or narrowed coronary artery. They include: a) graft bypass for coronary artery (CABG), or b) targeted vessel revascularization or PCI. PCI may employ either stents that elute drugs (DES) or naked metal stents. All of these procedures attempt to restore the function of coronary arteries and prevent stenosis and cardiovascular events.

In addition, it is also crucial to keep healthy nutrition, have a healthy total body weight and good lipid levels, achieve normal blood pressure and glucose levels, be active physically, and abstain from tobacco smoking [55, 93, 94, 95, 96, 97, 98].

11.1 Which coronary artery restoration therapy is better?

While the use of medical treatment (anti-platelet, statins) and lifestyle changes (maintenance of healthy body weight, diet, good lipid profile, healthy blood pressure, and glucose concentrations, being active physically, and abstaining from tobacco smoking) is well agreed by all experts as being beneficial to patients with CAD, the restoration of the patency of coronary arteries is controversial. In a recent review comparing CABG with PCI, most experts believe that CABG is superior to PCI when restoring multiple coronary artery blockades. This is because CABG has a lower death rate and saves the patient from repeated revascularization compared to PCI, especially in patients with DM [55, 98].

Regarding PCI, drug-eluting stents are better than naked metal or balloon stents because of their ability to release medication, especially in DM patients. Patients with DES are unlikely to have recurring stenosis of the coronary artery when compared to those with balloon or bare metal stents [55].

12. What is new in the treatment of DCM?

12.1 Weight loss medications

Over the past few years, a new group of hypoglycemic medications, like antagonists to GLP-1 receptor (GLP-1 RA), have been utilized to treat overweight and obesity. These drugs are usually administered subcutaneously, however, oral formulations are also available for some classes of this medication. Many GLP-1R agonists (dulaglutide, exenatide, semaglutide) have now been manufactured for treating DM patients. Of these drugs, semaglutide has proved to be very effective in weight reduction. Semaglutide at a dose of 0.25 to 0.5 mg (sc; per os) per week can make significant reduction in total body weight. Millions of people worldwide now use semaglutide (Wegovy, Ozempic) for weight loss. In one study, semaglutide was able to induce a reduction of up to 15.8% of total body weight in 68 weeks [68, 69]. Despite the dramatic success of semaglutide in reducing body weight, the long-term adverse consequences of this “magic” drug are yet to be determined.

In an evaluation of RCTs of a large cohort of patients suffering from heart failure, GLP-1RA caused a significant improvement in cardiac function [99].

Consensus statements from several professional organizations, including the ACC Expert Consensus Panel on Novel Therapies for DM, EASD, ESC Guidelines on Diabetes, ACC/AHA on Primary Prevention of Cardiovascular Guidelines, and ADA, have suggested that GLP-1RA should be included as an “add-on” to the treatment of DCM [100]. Large RTCs have also pointed to the fact that GLP-1RAs markedly reduced cardiovascular outcomes in DM patients [70]. The rationale behind this consensus statement is that GLP-1RA can reduce obesity, insulin resistance, and inflammatory reactions [68], which predispose DM patients to developing DCM.

12.2 Sodium-glucose cotransporter-2 inhibitors (SGLT2i)

Several reports have shown that SGLT2i when given alone or with GLP-1RA possesses a strong cardio-protective effect, especially in DM patients. In many RCTs, including CREDENCE, EMPA-REG, and CANVAS, it was reported that SGLT2i significantly reduces fatal cardiovascular events and the rate of hospital visits due to HF [70, 101, 102]. The EMPEROR-Reduced RCT and VERTIS, which reviewed more than 10, 000 patients, reported that SGLT2i markedly mitigated the degree of severity of T2-DM-induced cardiovascular diseases [98, 103]. SGLT2i can alleviate the signs and symptoms of DCM because they improve microcirculation and the function of mitochondria. They also reduce the degree of cardiac fibrosis, oxidative stress, and ER stress [104].

13. Consensus in the management of diabetes-induced cardiomyopathy

The ADA and the EASD have recommended guidelines for the treatment of DM patients with cardiovascular diseases. In addition to PE, the first drug of choice should be metformin. The second recommended stage of treatment is a combination of metformin and GLP-1 R agonists. Other classes of drugs may be added in more severe cases of DCM [105].

14. Disability and quality of life (QoL) in DCM

DCM is a leading trigger of disability, along with a marked loss in quality of life. People with DM and DCM have a heightened risk of morbidity, severe loss of physical activity and function, including the incapability to perform daily tasks, as well as experiencing sexual and erectile dysfunctions. The estimated loss of activity could be as high as 80% of total capacity [106].

15. Ultrastructural changes in the diabetic heart

Diabetes mellitus (DM) causes severe morphological changes to the ultrastructure of the heart. The longer the duration of DM, the more destructive and drastic the alterations become. Nearly all of the cytoplasmic organelles are damaged by the impact of DM [15, 16, 107]. The mitochondria are swollen and turn into casts of organelles in severe cases. In addition, the myofibrils of the myocardium undergo marked degeneration with loss or thinning of structure. The discs of Eberth also suffer immense degeneration, resulting in loose contact between two adjacent cardiomyocytes (Figure 6).

Figure 6.

TEM images of the myocardium of (a) control Wistar rat heart and (b) diabetic Wistar rat heart. Note the thinness of myofibrils and loss of mitochondria in diabetic hearts. Magnification: X27,500. TEM—Transmission electron microscope.

16. Conclusion

In summary, the cellular events illustrated in Figure 6 reveal how diabetes, if diagnosed late or left untreated, can induce heart disease such as cardiomyopathy. These pathophysiological processes are due to several metabolic, ultrastructural, and physiological changes in the myocardial layer of the heart. Recent research studies have helped significantly in understanding the pathophysiology of cardiac muscles, fibrosis infiltration, remodeling, derangement in cellular calcium homeostasis and contractile proteins, involvement of signature proteins and biomarkers and mediators, and physiological changes within the heart during DM. Further research on fatty acid metabolism, glucotoxicity, protein acetylation, and roles of potential biochemical markers for diabetic myocardiopathy including galectin-3 is required. As such, further studies are very important to comprehend the precise subcellular, cellular, and signaling cascades that take part in the initiation and progression of DCM. Furthermore, people must alter their lifestyle habits via diet modification by consuming lesser amount of carbohydrates and sugar but more green vegetables, participate in daily exercise, maintaining the correct basal metabolic index, adhere to medicine intake, and moreover, seek psychological intervention to adhere to these changes. In addition, there is an urgent need for further studies of the illness process and the discovery of more reliable clinical biomarkers of the disease. Moreover, to reduce mortality among diabetic patients, clinical practitioners must identify diabetic cardiomyopathy at an early stage and begin treatment.

Conflict of interest

The authors declared no conflict of interest.