Diabetic cardiomyopathy: an educational review

Abstract

This educational review provides information about the epidemiology of diabetes and heart failure (diabetic cardiomyopathy) and the challenges in diagnosis and screening. Details on how to investigate patients with imaging and other modalities are discussed, as well as an update regarding the efficacy and safety of novel agents for treatment of diabetic cardiomyopathy.

Introduction

Diabetes mellitus is a major global health burden, with type 2 diabetes representing approximately 90% of cases. It is estimated that there were 451 million people with diabetes worldwide in 2017, and there will be 690 million by 2045.^1–3 Unfortunately, almost half (49.7%) of the patients with diabetes remain undiagnosed. Diabetes accounts for 10% of global all-cause mortality and is a major risk factor for numerous cardiovascular diseases, including coronary artery disease, hypertension, peripheral vascular disease and heart failure.¹ The link between diabetes and cardiovascular disease appears to be at both macrovascular and microvascular levels.^4,5 Although its association with heart failure, the final common pathway of cardiovascular disease, may well be beyond a single mechanism,² the co-existence of the two has long stimulated interest and gradually resulted in the concept of diabetic cardiomyopathy. The existence of diabetic cardiomyopathy as a pathological entity has been questioned;^6,7 but in the last few years there has been a surge in the number of both publications in the literature and patients with diabetic cardiomyopathy.^8,9 It is, therefore, reasonable to expect that this condition will soon be a cause for concern if it is not appropriately recognised and treated, or perhaps more importantly, prevented.

As separate entities, diabetes and heart failure are common, and can be challenging to treat effectively. The combination of the two undoubtedly causes new challenges in practice. It is, therefore, essential to have a concise update on diabetic cardiomyopathy for all healthcare professionals in both primary and secondary care. This is the aim of the current review.

The size of the challenge

Heart failure and diabetes incidence are increasing, with significant impact on mortality and morbidity.^1,10 Heart failure is a clinical syndrome and its aetiology is not always clear, though cardiovascular pathology is the main cause. In clinical practice, we encounter many patients with heart failure in whom no compatible cardiac aetiology can be identified, other than diabetes alongside treated hypertension or minor coronary artery disease.

It is clear that there is a close link between diabetes and cardiovascular disease. One third of patients with diabetes have cardiovascular disease, and about half of deaths in those with diabetes are reportedly caused by cardiovascular disease.¹¹ In patients with heart failure, the prevalence of diabetes ranges from 10% to 30%, reaching 40% in the acutely hospitalised patients, and this figure is expected to grow in the coming years with an ageing population.¹² Furthermore, the presence of heart failure can even be an independent risk for developing type 2 diabetes.² We, therefore, anticipate that cases of diabetic cardiomyopathy are likely to increase and pose a challenge to the healthcare system.

In order to assess objectively the size of the challenge of diabetic cardiomyopathy, we performed a literature search in English through PubMed, which can also be considered as a measure of professional interest in this field. We searched for “diabetic cardiomyopathy” in titles and in all fields, respectively. The increase in the number of publications has been exponential. The term diabetic cardiomyopathy arose in the 1970s. In the 10 years that followed, there were three articles with “diabetic cardiomyopathy” in the title and 21 articles associated with diabetic cardiomyopathy. In 2019 alone, the numbers were 380 and 2,510, respectively (table 1).

Table 1. Numbers of publications on diabetic cardiomyopathy in English.

Period	In all fields	In title
1970–1979	21	3
1980–1989	161	32
1990–1999	249	38
2000–2009	706	148
2010–2018	2,430	555
2019 Jan–Dec	2,510	380

While we believe that diabetic cardiomyopathy is already a real clinical entity and is imposing a significant challenge, the true prevalence of diabetic cardiomyopathy has not been established due to challenges in diagnosis.

The contributory factors of the challenge

The increase in publications on the topic not only indicates a growing interest in diabetic cardiomyopathy, but also begs the question of what specific factors contribute to the development of diabetic cardiomyopathy. First, risk factors for diabetes itself must be contributory for developing diabetic cardiomyopathy. Second, the high prevalence may be attributed to the widely available investigating tools that help gain insights into the relationship between diabetes and heart failure, such as echocardiography (echo) and cardiac magnetic resonance imaging (CMR).² As a result, diabetic cardiomyopathy is increasingly identified as an independent clinical diagnosis. Finally, the long duration of diabetes and inadequate control of glycaemia could be involved in the development of diabetic cardiomyopathy.^13–15 Nevertheless, there are other factors that are contributory to the development of diabetic cardiomyopathy in specific groups of patients.

Age

The prevalence of type 2 diabetes increases with age in the general population. In people aged over 65 years, the prevalence of diabetes is four times that in those under 40 years in the middle- to high-income countries according to the World Bank.¹ Similarly, heart failure increases with age in patients with or without diabetes. Direct observations of the relationship between age and the prevalence of diabetic cardiomyopathy have yet to be ascertained. The possibility exists that age may be a significant contributor to the development of diabetic cardiomyopathy.¹⁶

Obesity

Obesity and being overweight is one of the main risk factors for developing diabetes, and cardiovascular disease in patients with pre-existing diabetes.¹¹ Heart failure is more common in those with a body mass index (BMI) over 30 kg/m² (39% in BMI ≥30 vs. 23% in BMI <30 kg/m²).¹⁶ Increased weight, therefore, may represent a significant risk factor for developing diabetic cardiomyopathy.

Lifestyle

Excess dietary sugar is responsible for dysregulation of systemic metabolism. Recent laboratory studies suggested that increased dietary fructose could lead to the loss of cardiomyocytes and an increase in collagen deposition, and, hence, myocardial fibrosis. Fructose could, therefore, be considered as a specific cardiopathogenic agent in diabetes,¹⁷ and excessive consumption of sugar-rich fruits by diabetic patients may need to be treated as an unrecognised risk factor for the development of diabetic cardiomyopathy.

Gender

Type 2 diabetes is more prevalent in men than in women, but cardiovascular complications, particularly heart failure, are higher in diabetic women than in men, and so is cardiovascular mortality.¹⁸ This suggests that diabetic women may take a quicker path to cardiomyopathy and heart failure. It has been observed that pre-menopausal women have a lower risk of cardiovascular diseases than age-matched men. This advantage, however, is lost in pre-menopausal women with diabetes, which suggests that diabetes diminishes the protective effects of oestrogen from the increased risk of cardiovascular disease.¹⁸ Worse still, there is a four to six times increased admission rate for coronary intervention,¹⁴ and five times higher risk for heart failure in female than in male diabetic patients.¹⁸ The recognition of gender differences may help understand the development of diabetic cardiomyopathy and its treatment.¹⁹

Type of diabetes

Compared with the general population, the risk of heart failure is increased by two and a half times in patients with type 2 diabetes, on average, 5.5 years earlier in occurrence. In type 1 diabetes, the risk does not appear to differ from the general population.²⁰ However, epidemiologic literature is more limited in type 1 than in type 2 diabetes. When inadequate glycaemic control and renal dysfunction are present, type 1 diabetes is a significant risk factor for heart failure.²¹ It has been suggested that insulin resistance and insulin deficiency may have different effects on the myocardium, but the understanding of such differences and diabetic cardiomyopathy is still in its infancy, and further study is needed.

Challenges in diagnosis

At first sight, diabetic cardiomyopathy is simply the combination of diabetes and heart failure and/or myocardial pathology, and its diagnosis is reasonably simple. The reality is far less straightforward and the diagnosis remains a challenge, for which the main reason is the lack of a universally accepted definition.²²

Due to the highly prevalent comorbidities of diabetes, the certainty of the diagnosis of diabetic cardiomyopathy depends on the diagnostic criteria and how strictly they are applied. As originally proposed by Rubler et al.,²³ diabetic cardiomyopathy was defined as the combination of long-term diabetes, heart failure and myocardial fibrosis that cannot be attributed to coronary artery disease, hypertension, valvular disease, other heart disease or common non-cardiac causes, including alcohol excess and chronic renal disease. According to their definition, there were four such cases out of 3,234 autopsies in a period of eight years. If the definitions and treatment of coronary artery disease and other conditions had remained unchanged in the last few decades, the proposed diagnostic criteria by Rubler et al. would still be valid today.

As medical science has evolved, there have been significant developments in the diagnosis and treatment of coronary artery disease and hypertension. Coronary artery disease can now be readily diagnosed and treated,^24,25 and remains the main cause for myocardial damage and ventricular dysfunction. On the other hand, hypertension, one of the most prevalent conditions, has been redefined with significant modification,^26–29 as has the threshold for antihypertensive treatment.^27–29 The lower threshold for treating hypertension today has potentially prevented ventricular disease caused by hypertension. So it is high time to update the diagnostic criteria of diabetic cardiomyopathy. We would suggest that coronary artery disease remains an exclusion, but it would be reasonable and necessary to include treated hypertension in the diagnostic criteria of diabetic cardiomyopathy.

We, therefore, propose the diagnostic criteria of diabetic cardiomyopathy as follows:

• Established diabetes.^3,30

• Heart failure either newly diagnosed or established.¹⁰

• Hypertension²⁶ under appropriate control (<130/80 mmHg).

• Myocardial pathology confirmed either by non-invasive imaging or biopsy.^31–33

• Other causes for heart failure have been excluded: significant coronary artery disease, significant valvular heart disease, established cardiomyopathy, chronic arrhythmias including atrial fibrillation that might cause cardiac dysfunction, and noncardiac conditions known to cause cardiac dysfunction including alcohol excess, chronic renal disease, thyroid disease, prior chemotherapy, systemic connective tissue disease.

Investigations

There is no specific test available to establish the diagnosis of diabetic cardiomyopathy with certainty. Alongside clinical assessment, some biochemical and cardiac tests are helpful to confirm the diagnosis of diabetic cardiomyopathy (cases 1 and 2).

Case 1

A 50-year-old woman was admitted with congestive heart failure. She had been treated for type 2 diabetes and hypertension. Her electrocardiogram (ECG) showed sinus rhythm, borderline broad QRS duration (100 ms) and absence of septal q wave (figure 1). Her echocardiogram showed a dilated and poorly functioning left ventricle: left ventricular end-diastolic dimension was 7.4 cm, end-systolic dimension 6.6 cm and left ventricular ejection fraction of 20%. Her coronary angiography did not reveal any coronary artery disease. Her cardiac magnetic resonance (CMR) scan was suggestive of dilated cardiomyopathy without any evidence of myocardial infarction or inducible ischaemia. She improved clinically with medication and the left ventricular ejection increased to 40–45% but end-diastolic dimension did not change. She has been managed medically and remained stable for six years now.

Case 2

A 36-year-old man was admitted to the hospital five years ago for acute breathlessness and abdominal pain on the background of type 2 diabetes and asthma. His ECG showed sinus rhythm, slightly reduced QRS voltage and possible left atrial dilatation. His initial echocardiogram showed normal left ventricular size, poor function with an ejection fraction of 10–15%, global hypokinesia, left atrial dilatation corrected by body surface area, but no valvular disease. His CMR scan showed normal left ventricular cavity size with severely impaired function, but no evidence of myocardial infarction or fibrosis. The CMR concluded as “nondilated and nonischaemic cardiomyopathy”. The patient was treated in the hospital and made much clinical improvement, but his echocardiogram on discharge only showed mild improvement in ejection fraction (20–25%). He has remained clinically stable and echocardiograms have remained unchanged since (figure 2).

Biomarkers

Natriuretic peptides are helpful in detecting heart failure and identifying diabetic cardiomyopathy. It has been reported that serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) is increased in patients with type 2 diabetes and isolated diastolic dysfunction before they develop any symptoms of heart failure. At present, NT-proBNP is used in routine practice, however, natriuretic peptide levels can be influenced by other factors, some of which are prevalent in diabetes. These include obesity, old age, renin-angiotensin-aldosterone-system inhibitors and renal dysfunction. As such, NT-proBNP is mainly used in the initial assessment of heart failure.^2,10

Figure 1. A 12-lead ECG recorded in a 50-year-old woman showing sinus rhythm, borderline prolonged QRS duration (110 ms) and the absence of septal q wave.

In more recent years, microRNAs (miRs), a class of non-coding RNA, have been proposed as another diagnostic tool. It is hoped that they may provide valuable information on diagnosis, prognosis and even the assessment of therapeutic effects on heart failure.^34–36

Finally, the potential role of exosomes in the development of diabetic cardiomyopathy has also been explored, although their practical application is not known.^35,36

Cardiac imaging

Electrocardiography

Electrocardiography (ECG) is the most commonly used cardiac test and has much to offer in the prediction and diagnosis of diabetic cardiomyopathy. Some of the common ECG abnormalities, such as ST-T changes, long QT interval, pathological Q waves, left ventricular hypertrophy and atrial fibrillation are highly predictive of cardiac abnormalities in patients with diabetes.^37–39 The earliest sign could be the absence of the normal septal q wave that is a marker of myocardial fibrosis.^40,41

Echocardiography

Echocardiography is a widely used, readily available, useful imaging tool to assess cardiac structure and ventricular function.

Figure 2. Echocardiograms recorded in parasternal long-axis view showing a non-dilated and poorly functioning left ventricle in a 36-year-old man who has been treated for type 2 diabetes and heart failure in comparison with images in a normal subject (51-year-old man).

In diabetic cardiomyopathy, there are changes in myocardial interstitium resulting in abnormal contractile function. In the early stages of the disease, diastolic dysfunction may be the only abnormality, but systolic dysfunction occurs in the later stages with impaired left ventricular ejection fraction.⁴² Transmitral Doppler echocardiography is usually used to demonstrate global diastolic dysfunction, but tissue Doppler imaging can detect regional diastolic dysfunction, as well as general diastolic dysfunction. Tissue Doppler imaging has been reported to detect subtle abnormalities in patients before the full development of heart failure symptoms.^4,43

We believe that two-dimensional stress echocardiography would be a helpful tool to reveal subclinical functional abnormalities of the heart in patients with diabetes, particularly when combined with the newer imaging modalities based on tissue Doppler imaging. It would be reasonable to suggest that stress echocardiography could be used to detect cardiac dysfunction in patients with diabetes and clinical suspicion of heart failure, similar to using stress echocardiography to detect ischaemia in patients with suspected coronary artery disease.^44–46

Cardiac magnetic resonance imaging

Cardiac magnetic resonance (CMR) imaging has been increasingly used for early detection of cardiomyopathy of various types.^47,48 Microvascular pathology seems to be the link between diabetes and cardiomyopathy and may manifest as myocardial abnormalities detected by CMR.⁴⁹ Indeed, CMR is able to quantify myocardial fibrosis in patients with cardiomyopathy regardless of aetiology. CMR imaging may be able to reveal myocardial changes, including fibrosis, prior to any symptoms developing in patients at risk of diabetic cardiomyopathy.^47,48

Challenges in screening

The optimal way to manage diabetic cardiomyopathy is to prevent it. The second best opportunity would be to detect it early and treat it before heart failure symptoms develop.

Screening patients with type 2 diabetes for pre-clinical diabetic cardiomyopathy has been conducted and valuable information gathered, but whether such a programme is practical is difficult to ascertain.⁵⁰ With more established screening tools, a similar programme was conducted to screen for coronary artery disease in asymptomatic but high-risk patients during the DIAD (Detection of Ischemia in Asymptomatic Diabetics) study. However, the outcome was somewhat discouraging. It was concluded that screening for coronary artery disease in asymptomatic patients with nuclear myocardial imaging is unhelpful in early detection of cardiac events.⁵¹

It has been proposed that various screening tools, including B-type natriuretic peptide (BNP) and echocardiography, could be used to identify subclinical ventricular dysfunction in diabetic patients.^35,50 The sensitivity of these tools has yet to be established. Tissue Doppler imaging was suggested to be sensitive, which may be helpful in detecting cardiac abnormalities, hence, subclinical diabetic cardiomyopathy. For instance, based upon two-dimensional echocardiography and tissue Doppler imaging, significant changes in left ventricular size and longitudinal myocardial deformation have been observed in 30 consecutive asymptomatic children with type 1 diabetes, in comparison with 30 age-and sex-matched healthy subjects. The left ventricular mass index and septal thickness were significantly increased and the global longitudinal systolic strain and strain rate were decreased in diabetic children, but left ventricular ejection fraction and mitral flow pattern on Doppler did not differ.⁴³

In adult diabetic patients without hypertension and coronary artery disease, the left ventricular (LV) mass was increased, LV relaxation, LV ejection fraction (EF) and mitral annular plane excursion (MAPSE) were decreased.⁵² In a multi-variate analysis, with diabetes, hypertension, coronary artery disease, age, gender and BMI as covariance, diabetes alone was an independent factor for the increased LV mass, decreased EF, systolic excursion of mitral annulus, peak global longitudinal strain and early diastolic longitudinal strain rate.⁵² Diabetes per se is, therefore, an independent risk factor for LV abnormality in both structure and function that can be readily detected by echocardiography, even in patients without symptoms of heart failure.

CMR is considered as a powerful tool to assess structural remodelling, functional abnormalities, and myocardial fibrosis.^47,48 It undoubtedly has great potential to be a screening tool.

In an ideal world, screening for diabetic cardiomyopathy should be a part of our daily clinical practice, utilising ECG, echocardiography and CMR. Due to the high technical demand and cost, CMR may not be a practical tool for screening for diabetic cardiomyopathy in the foreseeable future. If a stress protocol is taken into consideration, ECG and echocardiography are definitely tools of choice, as they are widely available and easily portable.^53–55

Treatment challenges

The treatment for patients with diabetic cardiomyopathy brings new challenges to both cardiologists and diabetologists. There has been rapid and continuing development in this area.

It would be logical to assume that glycaemic control is the key to treating diabetic cardiomyopathy, but previous, large, multicentre and randomised-controlled trials did not demonstrate any significant benefit in macrovascular outcomes with tight glycaemic control.² Further, a meta-analysis of randomised trials in a patient population of 37,229 with type 2 diabetes did not show any significant benefit from intensive glycaemic control on heart failure-related outcomes.⁵⁶

Metformin has been shown to have significant cardioprotective effects by increasing glucose utilisation and reducing myocardial infarction and cardiomyocyte degenerative changes in animal models. Reduction in incidence of heart failure has been observed in patients with diabetes, although the mechanism remains unclear.^57,58

Newer glucose-lowering agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to improve glycaemic control and to reduce cardiovascular mortality in patients with type 2 diabetes. They appear to be safe and well tolerated.² The development is fast and the outlook is hopeful.^59–62 Real-world analysis of primary care data (n=411,206) of patients with type 2 diabetes mellitus, concluded that SGLT2 inhibitors, GLP-1 receptor agonists, or a combination thereof, was associated with improved adjusted pooled odds ratio in terms of heart failure occurrence.⁶³ This is reflected by the stance adopted by the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD), whereby SGLT2 inhibitors and GLP-1 receptor agonists should be considered as first-line therapy for type 2 diabetes mellitus patients with known cardiovascular disease or those at high risk.⁶⁴ Table 2 summarises the two classes of agent.

Table 2. Comparison between sodium–glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.

	SGLT2 inhibitors	GLP-1 receptor agonists
Hypoglycaemic effects	Yes	Yes
Reduce atherosclerotic disease	Yes	Yes
Renal protection	Yes	Yes
Reduce cardiovascular mortality	Yes	Yes
Treat heart failure with reduced ejection fraction	Yes	No
Prevent diabetic cardiomyopathy	Potentially	Potentially

GLP-1 receptor agonists

Data regarding GLP-1 receptor agonists have been promising, with a number of trials suggesting improved cardiovascular outcomes, especially in terms of major adverse cardiovascular events; nonetheless, evidence relevant to heart failure is not as clear cut. This is mirrored by the ESC guidelines 2021, where such preparations are not recommended for the prevention/treatment of heart failure, with no mention in the American Heart Association (AHA) guidelines.^65,66 Nonetheless, in terms of heart failure, a systemic review and meta-analysis of seven randomised-controlled trials (RCTs), incorporating a variety of GLP-1 receptor agonists, indicated a modest but significant improvement in rate of hospitalisations associated with heart failure in patients with type 2 diabetes on GLP-1 receptor agonists (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 0.99, p=0.028).⁶⁷ Besides a reduction in blood glucose, systolic blood pressure, body weight and lipids, GLP-1 receptor agonists may also be associated with a reduction in the development of atherosclerotic plaques and improved cardiac remodelling.^68,69 The mechanisms of these remain unclear. Authorised GLP-1 receptor agonists in the UK are injectable. The main adverse effect of GLP-1 receptor agonists is gastrointestinal intolerance. Healthcare providers should also be aware of its potential side effect of pancreatitis, and, in terms of cardiac pathology, the induction of sinus tachycardia. Table 3 summarises studies relevant to GLP-1 receptor agonists in terms of heart failure outcomes.^70–88

Table 3. Studies including GLP-1 receptor agonists or SGLT2 inhibitors and outcomes relevant to heart failure admissions.

Medication used	Study name	Number	Population	Heart failure hospitalisation
GLP-1 receptor agonist
Lixisenatide	ELIXA70	6,068	Type 2 DM and ACS	HR: 0.96 (95%CI 0.75 to 1.23); p=0.75
Liraglutide	LEADER71	9,340	Type 2 DM and CVD/high risk	HR: 0.87 (95%CI 0.73 to 1.05); p=0.14
Semaglutide (injectable)	SUSTAIN-672	3,297	Type 2 DM and CVD/high risk	HR: 1.11 (95%CI 0.77 to 1.61); p=0.57
Exenatide	EXSCEL73	14,742	Type 2 DM	HR: 0.94 (95%CI 0.78 to 1.13); p=0.51
Albiglutide	HARMONY74	9,463	Type 2 DM and CVD	HR: 0.71 (95%CI 0.53 to 0.94); p<0.001
Dulaglutide	REWIND75	9,901	Type 2 DM and CVD/high risk	HR: 0.93 (95%CI 0.77 to 1.12); p=0.46
Semaglutide (oral)	PIONEER 676	3,183	Type 2 DM and CVD/high risk	HR: 0.86 (95%CI 0.48 to 1.44); p=0.59
Efpeglenatide	AMPLITUDE-O77	4,076	Type 2 DM and either a history of CVD or current CKD	HR: 0.61 (95%CI 0.38 to 0.98); p value not stated
SGLT2 inhibitors
Empagliflozin	EMPA-REG Outcome78	7,020	Type 2 DM	HR: 0.65 (95%CI 0.50 to 0.85); p=0.002
Canagliflozin	CANVAS79	10,142	Type 2 DM and CVD/high risk	HR: 0.67 (95%CI 0.52 to 0.87); p value not stated
Dapagliflozin	DECLARE-TIMI-5880	17,160	Type 2 DM and CVD/high risk	HR: 0.73 (95%CI 0.61 to 0.88); p value not stated
Canagliflozin	CREDENCE81	4,401	Type 2 DM and CKD	HR: 0.54 (95%CI 0.39 to 0.75); p<0.001
Dapagliflozin	DAPA-CKD82	4,304	CKD	HR: 0.40 (95%CI 0.23 to 0.70) without prior heart failure; HR: 0.62 (95%CI 0.35 to 1.10) with prior heart failure; p value not stated
Dapagliflozin	DAPA-HF83	4,744	HFrEF (EF<40%)	HR: 0.70 (95%CI 0.59 to 0.83); p value not stated
Empagliflozin	EMPEROR REDUCED84	3,730	HFrEF (EF<40%)	HR: 0.69 (95%CI 0.59 to 0.81); p value not stated
Ertugliflozin	VERTIS85	8,246	Type 2 DM and CVD	HR: 0.70 (95%CI 0.54 to 0.90); p value not stated
Empagliflozin	EMPEROR-PRESERVED86	5,988	HFpEF (EF>40%)	HR: 0.73 (95%CI 0.61 to 0.88); p<0.001
Sotagliflozin	SOLOIST-WHF87	1,222	Type 2 DM and worsening HF (both HFpEF and HFrEF)	HR: 0.64 (95%CI 0.49 to 0.83); p<0.001
Dapagliflozin	DELIVER88	6,263	HFpEF (EF>40%)	HR: 0.77 (95%CI 0.67 to 0.89); p value not stated

Key: ACS = acute coronary syndrome; CI = confidence interval; CKD = chronic kidney disease; CVD = cardiovascular disease; DM = diabetes mellitus; EF = ejection fraction; GLP-1 = glucagon-like peptide 1; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HR = hazard ratio; SGLT2 = sodium–glucose co-transporter 2

SGLT2 inhibitors

In an era of precision medicine, it is rare for a newly designed drug to express pleiotropic effects. Although primarily developed to treat type 2 diabetes, SGLT2 inhibitors have become increasingly important in the treatment of heart failure. Given the landmark studies of EMPA-REG Outcome, CANVAS (CANagliflozin cardioVascular Assessment Study) and DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events), SGLT2 inhibitors gained a prominent role in the treatment of heart failure with reduced ejection fraction as evident in both ESC and AHA guidelines on heart failure.^65,66 Like GLP-1 receptor agonists, SGLT2 inhibitors reduce major cardiovascular events and cardiovascular death, and offer renal protection in patients with type 2 diabetes. In addition, they reduce the risk of heart failure-related events and reduce hospitalisation due to heart failure.^10,59,61,62 Intriguingly, SGLT2 inhibitors appear to have efficacy in the treatment of heart failure with preserved ejection fraction as well, a clinical entity which can be linked to type 2 diabetes.⁸⁹ This has been further reflected in a pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER randomised, placebo-controlled trials (n=11,007), where dapagliflozin was associated with a statistically significant decrease in hospitalisation for heart failure irrespective of ejection fraction (HR 0.71, 95%CI 0.65 to 0.78, p<0.001).⁹⁰

Dapagliflozin has been approved in the European Union to extend the indication for heart failure with reduced ejection fraction (HFrEF) to cover individuals across the full spectrum of left ventricular ejection fraction (LVEF), including heart failure with mildly reduced and preserved ejection fraction.

The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use in December 2022 and was based on the positive results from the DELIVER Phase III trial.⁸⁸

In addition, SGLT2 inhibitors appear to have beneficial effects in patients with chronic kidney disease, both in terms of disease progression and cardiovascular outcomes, even in the absence of diabetes.⁹¹ This is particularly important given the intricate interplay between heart failure, renal disease and diabetes.

The possible mechanism for this is that the increased urinary glucose and sodium excretion leads to a reduction in intravascular volume and in systolic blood pressure, while maintaining interstitial volume. This in turn reduces both cardiac preload and afterload, leading to the improvement in myocardial oxygen supply and vascular function. They may also shift myocardial metabolism towards ketones, a favourable effect on cardiac energy utilisation.¹ Additionally, SGLT2 inhibitors may have additive metabolic effects, including weight loss, decrease in insulin and insulin resistance. They may also be implicated directly in the cardiac cycle by decreasing sympathetic nerve activity and attenuation of the late I_Na channels.⁹² National Institute for Health and Care Excellence (NICE) guidelines in the UK have authorised two SGLT2 inhibitors (dapagliflozin and empagliflozin) in the treatment of heart failure with reduced ejection fraction.^93,94 Clinicians should be aware of potential side effects, which include urinary tract infections and genital infections (secondary to glycosuria) and an increased propensity to ketoacidosis. Table 3 summarises studies relevant to SGLT2 inhibitors in terms of heart failure outcomes.

Non-medical therapy

Non-medical approaches are important for treating, as well as preventing diabetes, hence, diabetic cardiomyopathy. Weight loss, either with low-calorie diets or bariatric surgery, is an attractive option for reversing diabetes and the risk of heart failure, but the latter is expensive and not universally available, and further studies are needed for more definitive conclusions.^2,95,96

Prevention

There is considerable overlap between prevention and treatment of diabetic cardiomyopathy. Ideally, prevention should start with the general population from a young age, and risk factors should be modified in all patients with diabetes. There can never be too much emphasis on educating the general public in order to prevent diabetes and its complications, one of which is diabetic cardiomyopathy.

At a national or international level, excess sugar consumption must be addressed, as the relationship between sugar availability and the prevalence of diabetes has been clearly shown.^95–97 Cutting down on sugar content in the food industry may well be an effective way to prevent diabetes, which can only be achieved with governments’ support.

At an individual level, in addition to lifestyle changes such as aerobic exercise, weight control is a very effective approach to both prevention and treatment of diabetic cardiomyopathy.³⁵ Even in established diabetes, exercise can still protect the myocardium by improving its metabolism, alleviating oxidative stress damage, reducing myocardial fibrosis, inhibiting apoptosis, and limiting microvascular disorders. Exercise should, therefore, be considered as essential in the management of type 2 diabetes and in the prevention of diabetic cardiomyopathy.⁹⁸ The RESET for REMISSION (REmission of diabetes and improved diastolic function by combining Structured Exercise with meal replacemenT and food reintroduction) multicentre randomised-controlled trial is currently examining the effect of combining structured exercise with meal replacement and food reintroduction among young adults, in terms of type 2 diabetes remission and diastolic function.⁹⁹

Finally, the upcoming agents, GLP-1 receptor agonists and SGLT2 inhibitors, may have a significant role to play in preventing the development of diabetic cardiomyopathy as well as atherosclerotic cardiovascular disease.^59–62

Conclusion

Diabetic cardiomyopathy is not uncommon and its prevalence is increasing rapidly. It remains challenging to the medical care profession, as well as medical science. The likely best way to curb it is effective prevention, which relies on public education and government policy, with the aim to both slow and reverse the globally increasing prevalence of diabetes. The recent development in antidiabetic drugs brings some hope that both diabetes and heart failure may be treated and even prevented with the same medicines.

Key messages

• With the ever increasing prevalence of diabetes mellitus, diabetic cardiomyopathy has become more and more common

• The diagnosis and management of this emerging condition can be a clinical challenge

• The proposed diagnostic criteria for diabetic cardiomyopathy include:

  1. Established diabetes

  2. Heart failure either newly diagnosed or established

  3. Hypertension under appropriate control (<130/80 mmHg)

  4. Myocardial pathology confirmed either by non-invasive imaging or biopsy

  5. Absence of other causes of heart failure: significant coronary artery disease, significant valvular heart disease, established cardiomyopathy, chronic arrhythmias, alcohol excess, chronic renal disease, thyroid disease, prior chemotherapy, systemic connective tissue disease

• Apart from the conventional treatment for both diabetes and heart failure, combining lifestyle changes with the use of newer glucose-lowering agents (SGLT2 inhibitors and GLP-1 receptor agonists) is probably the best option for managing patients with diabetic cardiomyopathy

Patient consent

Patients included in the case studies provided consent for publication. All attempts were made to ensure patient confidentiality was maintained.

Funding Statement

Funding None.