Diabetic cardiomyopathy: an educational review

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).

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 non-cardiac 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).

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

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. 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, multi-centre 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.

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

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) multi-centre 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

Conflicts of interest

None declared.

Funding

None.

Patient consent

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

References

1. Cho NH, Shaw JE, Karuranga S et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018;138:271–81. https://doi.org/10.1016/j.diabres.2018.02.023

2. Gulsin GS, Athithan L, McCann GP. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab 2019;10:1–21. https://doi.org/10.1177/2042018819834869

3. The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2013;34:3035–87. https://doi.org/10.1093/eurheartj/eht108

4. Marwick TH, Ritchie R, Shaw JE, Kaye D. Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J Am Coll Cardiol 2018;71:339–51. https://doi.org/10.1016/j.jacc.2017.11.019

5. Haas AV, McDonnell ME. Pathogenesis of cardiovascular disease in diabetes. Endocrinol Metab Clin N Am 2018;47:51–63. https://doi.org/10.1016/j.ecl.2017.10.010

6. Francis GS. Diabetic cardiomyopathy: fact or fiction? Heart 2001;85:247–8. https://doi.org/10.1136/heart.85.3.247

7. Litwin SE. Diabetes and the heart: is there objective evidence of a human diabetic cardiomyopathy? Diabetes 2013;62:3329–30. https://doi.org/10.2337/db13-0683

8. Dandamudi S, Slusser J, Mahoney DW, Redfield MM, Rodeheffer RJ, Chen HH. The prevalence of diabetic cardiomyopathy: a population based study in Olmsted County, MN. J Card Fail 2014;20:304–09. https://doi.org/10.1016/j.cardfail.2014.02.007

9. Lee W-L, Kim J. Diabetic cardiomyopathy: where we are and where we are going. Korean J Intern Med 2017;32:404–21. https://doi.org/10.3904/kjim.2016.208

10. McDonagh TA, Metra M, Adamo M et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2021;42:3599–726. https://doi.org/10.1093/eurheartj/ehab368

11. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol 2018;17:83. https://doi.org/10.1186/s12933-018-0728-6

12. MacDonald MR, Petrie MC, Fumi Varyani et al.; for the CHARM Investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure. Eur Heart J 2008;29:1377–85. https://doi.org/10.1093/eurheartj/ehn153

13. Stratton IM, Adler AI, Neil HAW et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405. https://doi.org/10.1136/bmj.321.7258.405

14. Laverty AA, Bottle A, Kim S-H et al. Gender differences in hospital admissions for major cardiovascular events and procedures in people with and without diabetes in England: a nationwide study 2004–2014. Cardiovasc Diabetol 2017;16:100. https://doi.org/10.1186/s12933-017-0580-0

15. Reaven PD, Emanuele NV, Wiitala WL et al.; for the VADT Investigators. Intensive glucose control in patients with type 2 diabetes – 15-year follow-up. N Engl J Med 2019;380:2215–24. https://doi.org/10.1056/NEJMoa1806802

16. Boonman-de Winter LJM, Rutten FH, Cramer MJM et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia 2012;55:2154–62. https://doi.org/10.1007/s00125-012-2579-0

17. Delbridge LMD, Benson VL, Ritchie RH, Mellor KM. Diabetic cardiomyopathy: the case for a role of fructose in disease etiology. Diabetes 2016;65:3521–8. https://doi.org/10.2337/db16-0682

18. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035–8. https://doi.org/10.1001/jama.241.19.2035

19. Toedebusch R, Belenchia A, Pulakat L. Diabetic cardiomyopathy: impact of biological sex on disease development and molecular signatures. Front Physiol 2018;9:453. https://doi.org/10.3389/fphys.2018.00453

20. Hölscher ME, Bode C, Bugger H. Diabetic cardiomyopathy: does the type of diabetes matter? Int J Mol Sci 2016;17:2136. https://doi.org/10.3390/ijms17122136

21. Rosengren A, Vestberg D, Svensson A-M et al. Long-term excess risk of heart failure in people with type 1 diabetes: a prospective case-control study. Lancet Diabetes Endocrinol 2015;3:876–85. https://doi.org/10.1016/S2213-8587(15)00292-2

22. Lee MMY, McMurray JJV, Lorenzo-Almorós A et al. Diabetic cardiomyopathy. Heart 2019;105:337–45. https://doi.org/10.1136/heartjnl-2016-310342

23. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595–602. https://doi.org/10.1016/0002-9149(72)90595-4

24. The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi.org/10.1093/eurheartj/ehz425

25. Thygesen K, Alpert JS, Jaffe AS et al.; ESC Scientific Document Group. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019;40:237–69. https://doi.org/10.1093/eurheartj/ehy462

26. National Institute for Health and Care Excellence (NICE). Hypertension in adults: diagnosis and management. NG136. London: NICE, 28 August 2019. Available from: https://www.nice.org.uk/guidance/ng136

27. Dollery CT, Perry M Jr., Dustan HP, Lyons RH. Medical management of hypertension. Circulation 1963;28:595–602. https://doi.org/10.1161/01.CIR.28.4.595

28. Moser M. Evolution of the treatment of hypertension from the 1940s to JNC V. Am J Hypertension 1997;10:2S–8S. https://doi.org/10.1016/S0895-7061(97)00016-2

29. de la Sierra A. New American and European hypertension guidelines, reconciling the differences. Cardiol Ther 2019;8:157–66. https://doi.org/10.1007/s40119-019-0144-3

30. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NG28. London: NICE, 28 August 2019. Available from: https://www.nice.org.uk/guidance/ng28

31. van der Meer P, Gaggin HK, Dec GW. ACC/AHA versus ESC guidelines on heart failure: JACC guideline comparison. J Am Coll Cardiol 2019;73:2756–68. https://doi.org/10.1016/j.jacc.2019.03.478

32. Braunwald E. Cardiomyopathies – an overview. Circ Res 2017;121:711–21. https://doi.org/10.1161/CIRCRESAHA.117.311812

33. Elliott P, Andersson B, Arbustini E et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–6. https://doi.org/10.1093/eurheartj/ehm342

34. Evangelista I, Nuti R, Picchioni T, Dotta F, Palazzuoli A. Molecular dysfunction and phenotypic derangement in diabetic cardiomyopathy. Int J Mol Sci 2019;20:3264. https://doi.org/10.3390/ijms20133264

35. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy. An update of mechanisms contributing to this clinical entity. Circ Res 2018;122:624–38. https://doi.org/10.1161/CIRCRESAHA.117.311586

36. Westermeier F, Riquelme JA, Pavez M et al. New molecular insights of insulin in diabetic cardiomyopathy. Front Physiol 2016;7:125. https://doi.org/10.3389/fphys.2016.00125

37. Stern S, Sclarowsky S. The ECG in diabetes mellitus. Circulation 2009;120:1633–6. https://doi.org/10.1161/CIRCULATIONAHA.109.897496

38. de Santiago A, García-Lledó A, Ramos E, Santiago C. Prognostic value of ECGs in patients with type-2 diabetes mellitus without known cardiovascular disease. Rev Esp Cardiol 2007;60:1035–41. https://doi.org/10.1157/13111235

39. Kittnar O. Electrocardiographic changes in diabetes mellitus. Physiol Res 2015;64:S559–S566. https://doi.org/10.33549/physiolres.933230

40. Burch GE, Depasquale N. A study at autopsy of the relation of absence of the Q wave in leads I, aVL, V5, and V6 to septal fibrosis. Am Heart J 1960;60:346. https://doi.org/10.1016/0002-8703(60)90191-5

41. Xiao HB, Gibson DG. Absent septal q wave on electrocardiogram: a forgotten marker of myocardial disease. Int J Cardiol 1996;53:1–4. https://doi.org/10.1016/0167-5273(95)02508-1

42. Schannwell CM, Schneppenheim M, Perings S, Plehn G, Strauer BE. Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology 2002;98:33–9. https://doi.org/10.1159/000064682

43. Hodzic A, Ribault V, Maragnes P, Milliez P, Saloux E, Labombarda F. Decreased regional left ventricular myocardial strain in type 1 diabetic children: a first sign of diabetic cardiomyopathy? J Transl Int Med 2016;4:81–7. https://doi.org/10.1515/jtim-2016-0025

44. Hensel KO. Non-ischemic diabetic cardiomyopathy may initially exhibit a transient subclinical phase of hyperdynamic myocardial performance. Med Hypotheses 2016;94:7–10. https://doi.org/10.1016/j.mehy.2016.06.002

45. Negishi K. Echocardiographic feature of diabetic cardiomyopathy: where are we now? Cardiovasc Diagn Ther 2018;8:47–56. https://doi.org/10.21037/cdt.2018.01.03

46. Chen Z-W, Huang C-Y, Cheng J-F, Chen S-Y, Lin L-Y, Wu C-K. Stress echocardiography-derived E/e’ predicts abnormal exercise hemodynamics in heart failure with preserved ejection fraction. Front Physiol 2019;10:1470. https://doi.org/10.3389/fphys.2019.01470

47. Patel AR, Kramer CM. Role of cardiac magnetic resonance in the diagnosis and prognosis of nonischemic cardiomyopathy. JACC Cardiovasc Imaging 2017;10:1180–93. https://doi.org/10.1016/j.jcmg.2017.08.005

48. Kramer CM, Chandrashekhar Y. Multiparametric CMR in cardiomyopathies beyond diagnosis and toward prognosis. JACC Cardiovasc Imaging 2019;12:1712–14. https://doi.org/10.1016/j.jcmg.2019.07.003

49. Tarquini R, Pala L, Brancati S et al. Clinical approach to diabetic cardiomyopathy: a review of human studies. Curr Med Chem 2017;24:1–15. https://doi.org/10.2174/0929867324666170705111356

50. Kiencke S, Handschin R, von Dahlen R et al. Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome. Eur J Heart Fail 2010;12:951–7. https://doi.org/10.1093/eurjhf/hfq110

51. Young LH, Wackers FJ, Chyun DA et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009;301:1547–55. https://doi.org/10.1001/jama.2009.476

52. Loncarevic B, Trifunovic D, Soldatovic I, Vujisic-Tesic B. Silent diabetic cardiomyopathy in everyday practice: a clinical and echocardiographic study. BMC Cardiovasc Disord 2016;16:242. https://doi.org/10.1186/s12872-016-0395-z

53. Malhotra R, Bakken K, D’Elia E, Lewis GD. Cardiopulmonary exercise testing in heart failure. JACC Heart Fail 2016;4:607–16. https://doi.org/10.1016/j.jchf.2016.03.022

54. Hensel KO, Grimmer F, Roskopf M, Jenke AC, Wirth S, Heusch A. Subclinical alterations of cardiac mechanics present early in the course of pediatric type 1 diabetes mellitus: a prospective blinded speckle tracking stress echocardiography study. J Diabetes Res 2016;2016:2583747. https://doi.org/10.1155/2016/2583747

55. Ha J-W. Diastolic stress echocardiography to quantify the response of diastolic functional indices to dynamic exercise in abnormal relaxation: unmasking diastolic abnormalities is getting ready for prime time. Korean Circ J 2018;48:755–9. https://doi.org/10.4070/kcj.2018.0164

56. Castagno D, Baird-Gunning J, Jhund PS et al. Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J 2011;162:938–48. https://doi.org/10.1016/j.ahj.2011.07.030

57. El Messaoudi S, Rongena GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol 2011;22:445–53. https://doi.org/10.1097/MOL.0b013e32834ae1a7

58. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus impact of glucose-lowering agents, heart failure therapies, and novel therapeutic strategies. Circ Res 2019;124:121–41. https://doi.org/10.1161/CIRCRESAHA.118.311371

59. Zelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S0140-6736(18)32590-X

60. Marso SP, Daniels GH, Brown-Frandsen K et al.; for the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. https://doi.org/10.1056/NEJMoa1603827

61. McMurray JJV, Solomon SD, Inzucchi SE et al.; for the DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303

62. Packer M, Anker SD, Butler J et al.; for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190

63. Wright AK, Carr MJ, Kontopantelis E et al. Primary prevention of cardiovascular and heart failure events with SGLT2 inhibitors, GLP-1 receptor agonists, and their combination in type 2 diabetes. Diabetes Care 2022;45:909–18. https://doi.org/10.2337/dc21-1113

64. Cosentino F, Grant PJ, Aboyans V et al.; ESC Scientific Document Group. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. https://doi.org/10.1093/eurheartj/ehz486. Erratum in: Eur Heart J 2020;41:4317. https://doi.org/10.1093/eurheartj/ehz828

65. McDonagh TA, Metra M, Adamo M et al.; ESC Scientific Document Group. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https://doi.org/10.1093/eurheartj/ehab368. Erratum in: Eur Heart J 2021;42:4901. https://doi.org/10.1093/eurheartj/ehab670

66. Heidenreich PA, Bozkurt B, Aguilar D et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263–e421. https://doi.org/10.1016/j.jacc.2021.12.012

67. Kristensen SL, Rørth R, Jhund PS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/S2213-8587(19)30249-9. Erratum in: Lancet Diabetes Endocrinol 2020;8:e2. https://doi.org/10.1016/S2213-8587(20)30037-1

68. Natali A, Nesti L, Tricò D, Ferrannini E. Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence. Cardiovasc Diabetol 2021;20:196. https://doi.org/10.1186/s12933-021-01385-5

69. Pahud de Mortanges A, Sinaci E, Salvador D Jr et al. GLP-1 receptor agonists and coronary arteries: from mechanisms to events. Front Pharmacol 2022;13:856111. https://doi.org/10.3389/fphar.2022.856111

70. Pfeffer MA, Claggett B, Diaz R et al.; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. https://doi.org/10.1056/NEJMoa1509225

71. Marso SP, Daniels GH, Brown-Frandsen K et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. https://doi.org/10.1056/NEJMoa1603827

72. Marso SP, Bain SC, Consoli A et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/NEJMoa1607141

73. Holman RR, Bethel MA, Mentz RJ et al.; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–39. https://doi.org/10.1056/NEJMoa1612917

74. Hernandez AF, Green JB, Janmohamed S et al.; Harmony Outcomes Committees and Investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519–29. https://doi.org/10.1016/S0140-6736(18)32261-X

75. Gerstein HC, Colhoun HM, Dagenais GR et al.; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121–30. https://doi.org/10.1016/S0140-6736(19)31149-3

76. Husain M, Birkenfeld AL, Donsmark M et al.; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841–51. https://doi.org/10.1056/NEJMoa1901118

77. Gerstein HC, Sattar N, Rosenstock J et al.; AMPLITUDE-O Trial Investigators. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021;385:896–907. https://doi.org/10.1056/NEJMoa2108269

78. Zinman B, Wanner C, Lachin JM et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/NEJMoa1504720

79. Neal B, Perkovic V, Mahaffey KW et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/NEJMoa1611925

80. Wiviott SD, Raz I, Bonaca MP et al.; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389

81. Perkovic V, Jardine MJ, Neal B et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744

82. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al.; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46. https://doi.org/10.1056/NEJMoa2024816

83. McMurray JJV, Solomon SD, Inzucchi SE et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303

84. Packer M, Anker SD, Butler J et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190

85. Cannon CP, Pratley R, Dagogo-Jack S et al.; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425–35. https://doi.org/10.1056/NEJMoa2004967

86. Anker SD, Butler J, Filippatos G et al.; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038

87. Bhatt DL, Szarek M, Steg PG et al.; SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28. https://doi.org/10.1056/NEJMoa2030183

88. Solomon SD, McMurray JJV, Claggett B et al.; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089–98. https://doi.org/10.1056/NEJMoa2206286

89. McHugh K, DeVore AD, Wu J et al. Heart failure with preserved ejection fraction and diabetes: JACC state-of-the-art review. J Am Coll Cardiol 2019;73:602–11. https://doi.org/10.1016/j.jacc.2018.11.033

90. Jhund PS, Kondo T, Butt JH et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat Med 2022;28:1956–64. https://doi.org/10.1038/s41591-022-01971-4

91. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 2022;400:1788–801. https://doi.org/10.1016/S0140-6736(22)02074-8

92. Nakamura K, Miyoshi T, Yoshida M et al. Pathophysiology and treatment of diabetic cardiomyopathy and heart failure in patients with diabetes mellitus. Int J Mol Sci 2022;23:3587. https://doi.org/10.3390/ijms23073587

93. National Institute for Health and Care Excellence. Dapagliflozin for treating chronic heart failure with reduced ejection fraction. TA679. London: NICE, 2021. Available from: https://www.nice.org.uk/guidance/ta679

94. National Institute for Health and Care Excellence. Empagliflozin for treating chronic heart failure with reduced ejection fraction. TA773. London: NICE, 2022. Available from: https://www.nice.org.uk/guidance/ta773

95. Arterburn DE, Telem DA, Kushner RF, Courcoulas AP. Benefits and risks of bariatric surgery in adults – a review. JAMA 2020;324:879–87. https://doi.org/10.1001/jama.2020.12567

96. Basu S, Yoffe P, Hills N, Lustig RH. The relationship of sugar to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data. PLoS ONE 2013;8:e57873. https://doi.org/10.1371/journal.pone.0057873

97. Zheng J, Cheng J, Zheng S et al. Physical exercise and its protective effects on diabetic cardiomyopathy: what is the evidence? Front Endocrinol (Lausanne) 2018;9:729. https://doi.org/10.3389/fendo.2018.00729

98. Stevens JW, Khunti K, Harvey R et al. Preventing the progression to type 2 diabetes mellitus in adults at high risk: a systematic review and network meta-analysis of lifestyle, pharmacological and surgical interventions. Diabetes Res Clin Pract 2015;107:320–31. https://doi.org/10.1016/j.diabres.2015.01.027

99. Dasgupta K, Boulé N, Henson J et al. Remission of type 2 diabetes and improved diastolic function by combining structured exercise with meal replacement and food reintroduction among young adults: the RESET for REMISSION randomised controlled trial protocol. BMJ Open 2022;12:e063888. https://doi.org/10.1136/bmjopen-2022-063888