The double burden: type 1 diabetes and heart failure—a comprehensive review

One of the most well established mechanisms linking DM, including T1D, to HF is chronic hyperglycemia. Both preclinical and clinical evidence strongly suggests that hyperglycemia plays a causal role in diabetes-related HF, including in T1D [19, 23, 40, 41]. In experimental models of T1D diabetic cardiomyopathy, the improvement of hyperglycemia mitigates diabetes-associated diastolic dysfunction [42]. Chronic hyperglycemia results in the exacerbation of two potentially pathological molecular processes: non-enzymatic glycation with the formation of advanced glycation end products (AGEs) and oxidative stress, both intricately linked. AGEs may play a pivotal role in the development and progression of DCM by stimulating collagen expression and accumulation, contributing to myocardial fibrosis and stiffness, and diastolic dysfunction [43, 44].

Additionally, chronic hyperglycemia increases mitochondrial activity, promoting the production of reactive oxygen species (ROS) and elevated oxidative stress. These effects trigger an inflammatory process in the myocardium, leading to fibrosis and cardiac remodeling, disruption of calcium homeostasis, endothelial dysfunction, and ultimately a reduction in cardiac contractility and relaxation [36, 39]. In several mouse models of T1D, therapeutic targeting focused on oxidative stress was associated with suppressed high glucose-induced superoxide generation and enhanced mitochondrial function, with an effect in preventing cardiac remodeling and dysfunction in a setting of DM [45‐47].

Mitochondrial dysfunction plays a pivotal role in DCM and is usually found in cardiac tissue in T1D [37, 48, 49]. Decreased mitochondrial oxidative capacity is caused by altered mitochondrial ultrastructure, proteomic remodeling, and oxidative damage to proteins and mitochondrial DNA [47, 50]. Additional mechanisms for mitochondrial dysfunction comprise perturbed mitochondrial Ca2+dynamics, mitochondrial uncoupling in T2D, and decreased cardiac insulin signaling in T1D [48, 49].

On the other hand, chronic inflammation plays a key role in the pathogenesis of HF in diabetes, especially in HF with preserved ejection fraction [49, 51‐53]. It is well established that DM is a pro-inflammatory state [54]. This inflammatory milieu can cause direct damage to cardiac myocytes, leading to myocardial dysfunction. Additionally, inflammation contributes to the formation and progression of atherosclerosis, a key factor in HF development. Several systemic inflammatory biomarkers have been described as being associated with CVD, including HF [55]. In particular, in a study by Puig et al., the systemic pro-inflammatory molecule GlycA, a novel biomarker of protein glycan N‐acetyl groups, was associated with the presence of myocardial dysfunction in T1D subjects [21].

In relation to cardiac inflammation, studies using experimental models of diabetes have identified a critical role for increased myocardial inflammation in the progression of DCM [56]. Hearts from T1D mice and rats showed increased infiltration by leukocytes, such as macrophages, which raised levels of pro-inflammatory cytokines (TNFα, IL-1β, IL-6), increased the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, and decreased the activity of the collagen-degrading matrix metalloproteinase (MMP), leading to profibrotic responses and cardiac remodeling [51, 57]. Therapies that target proinflammatory signaling have been shown to attenuate the development of experimental diabetic cardiomyopathy associated with a reduction in myocardial inflammation and cardiac fibrosis [56‐58]. Nevertheless, clinical trials of anti-inflammatory and anti-cytokine therapies have shown limited cardioprotective benefits, in some cases even inducing adverse effects [52]. Moreover, studies in mouse models of T1D have detected higher T-cell infiltration in the myocardium, and certain efforts to mitigate cardiac fibrosis by reducing T-cell movement have proven effective [59, 60].

Lipotoxicity and cardiac lipid accumulation in the heart have also been implicated in the development of DCM [61‐63]. Studies on myocardial metabolism have demonstrated reduced glucose uptake and increased fatty acid (FA) uptake in individuals with T1D. In T1D, the deficiency of insulin promotes the release of FAs from adipose tissue, leading to a heightened presence of excess FAs in various tissues, including the myocardium. Under physiological conditions, the myocardium can utilize fatty acids and glucose as energy substrates, being able to switch energy sources depending on their relative availability, a condition known as metabolic flexibility. When an excessive amount of FAs exceeds the cell’s oxidative capacity, the FAs will accumulate, leading to a rise in metabolic stress and a significant reduction in cardiac efficiency and function. Additionally, the accumulation of FAs stimulates the production of intermediate products (ceramides, diacylglycerol, and ROS) which accumulate in the cardiomyocyte’s cytoplasm and lead to its apoptosis [64‐66].

Microangiopathy has been shown to be present in the myocardium of diabetic patients. Autopsy samples of ventricular myocardium analyzed through traditional histological methods have revealed signs such as capillary basement membrane thickening, arteriole medial thickening, and perivascular fibrosis [37, 67, 68]. The possible mechanisms promoting microangiopathy in DCM are hyperglycemia, hyperlipidemia, and activation of the neurohormonal system. These factors may act either independently or synergistically, giving rise to oxidative stress, alterations in cellular signaling, and gene transcription. The microvascular changes result in reduced myocardial perfusion, subsequently compromising energy levels and leading to alterations in calcium handling, apoptosis, and diminished cardiac contractile strength [69].

Impaired endothelial function is a typical finding in DCM. In subjects with T1D hyperglycemia and oxidative stress impair endothelial function [70]. This endothelial dysfunction results in reduced bioavailability of nitric oxide, a molecule responsible for vasodilation and maintaining blood vessel health. With compromised endothelial function, there is an increased risk of hypertension and atherosclerosis, both of which are risk factors for HF. In the clinical settings, a link between coronary microvascular dysfunction and concurrent albuminuria has been reported. In T1D patients without a known history of heart disease, both microalbuminuria and macroalbuminuria have been associated with the presence of subclinical myocardial dysfunction [71].

Activation of the renin–angiotensin–aldosterone system (RAAS) contributes to myocardial dysfunction [72‐74]. Therefore, significantly more impaired cardiac sympathetic nervous system activity has been reported in HF patients with DM compared with HF patients without [75], and this is associated with adverse outcomes [76, 77]. Activation of the adrenergic system increases β-adrenergic expression and signaling, promoting myocyte hypertrophy, interstitial fibrosis, myocyte apoptosis, and contractile dysfunction [78]. In experimental models of T1D, an elevation in angiotensin-II receptor density and synthesis has been observed [57, 79].

On the other hand, although cardiovascular autonomic neuropathy (CAN) is one of the least understood of all serious complications of diabetes, cardiac sympathetic signals play an important role in the perfusion of myocardial injury [80]. CAN is associated with imbalance between sympathetic and parasympathetic components of the autonomic nervous system. For instance, heightened cardiac sympathetic tone may lead to a decrease in myocardial vascularity, induce vascular hyperreactivity, heighten mitochondrial production of reactive oxygen species, disrupt intracellular signaling, trigger myocardial apoptosis, and encourage myocardial remodeling [39, 81]. Clinically it is associated with rest tachycardia, exercise intolerance, orthostatic hypotension and silent myocardial ischemia.

CAN is known to occur in individuals with T1D, correlating with increased CVD and mortality [79, 80]. It is suggested that cardiac neuropathy may affect up to 40% of individuals with T1D [82, 83]. However, CAN is more commonly associated with T2D, and it has been independently associated with LV diastolic dysfunction, even in asymptomatic T2D patients without any history of CVD [82]. In the study conducted by Maddaloni et al., it was observed that the prevalence of CAN is significantly higher in individuals with T2D compared to those with autoimmune diabetes (LADA and T1D) (64% vs. 40% vs. 26%; p < 0.001) [84]. Moreover, the study showed that individuals with LADA are 2.7 times less likely to develop CAN than those with T2D, even with a similar disease duration, irrespective of age and gender [84]. Conversely, after adjusting for pre-specified confounders and age, the risk of CAN in LADA was found to be similar to that in T1D. Long-standing diabetes and poor glycemic control are considered the main risk factors for the development of CAN in T1D [81, 85]. Strict glycemic control can prevent the development or delay the progression of CAN in subjects with T1D [86]. Some observational studies suggest that the presence of CAN is associated with the impairment of systolic and diastolic LV function [87].

A role for autoimmune mechanisms in the development of DCM is another point of recent interest. In observational studies, the presence of autoantibodies against heart muscle proteins is associated with subclinical myocardial dysfunction in subjects with T1D, independent of traditional CV risks. A study published by Sousa et al. involving 892 subjects with T1D being followed in the DCCT observed higher levels of cardiac autoantibodies in those who had inadequate glycemic control. Subjects who tested positive for two cardiac autoantibodies were more likely to have subclinical myocardial dysfunction and had an increased risk of higher cardiovascular disease. Using cardiac magnetic resonance indices, subjects with ≥ 2 autoantibodies were shown to have markedly greater LV end-diastolic volume (EDV), end-systolic volume (ESV), and LV mass, as well as a lower LVEF [88]. Chronic hyperglycemia causes myocardial damage and is associated with the release of myocardial proteins into the circulation. This could potentially result in the exposure of previously sequestered cardiac antigens, including α-myosin, to the immune system. Previous experimental studies have shown that the immune system is normally enriched in autoreactive CD4 + T cells specific for cardiac myosin due to loss of immunological tolerance [89].

A newly identified pathway in the development of DCM is the concept of autophagy [46]. Autophagy is a highly conserved cellular process that recycles long-lived proteins and organelles to uphold cellular equilibrium. Dysregulated autophagy has been linked to the pathogenesis of numerous ailments, including infectious diseases, cancer, obesity, and various cardiac conditions, such as DCM [90‐92].

Several investigations have explored the potential connection between disrupted autophagy and the onset of DCM [91]. Within heart tissue, the elimination of damaged mitochondria through autophagy plays a vital role in preserving the well-being of cardiomyocytes. Damaged mitochondria resulting from cardiac injuries can generate ROS and release factors that induce cell death, thereby exacerbating cardiac harm. Nevertheless, excessive or prolonged autophagy can prove detrimental if it leads to cardiac atrophy [91]. Research findings in the context of DCM have yielded contradictory results. There is sufficient evidence from rodent model studies to indicate that cardiac autophagy is reduced in T1D [90, 93‐95]. However, the functional consequence of this reduction in autophagy remains unclear. One suggested hypothesis is that impaired autophagy plays a role in causing cardiac damage by reducing the removal of dysfunctional organelles and protein aggregates. It is believed that enhancing autophagy could potentially mitigate damage in the hearts of subjects with T1D. On the contrary, Xu et al. have proposed that the reduced cardiac autophagy observed in T1D mice is actually an adaptive response aimed at preventing excessive autophagic degradation of cellular components [90]. However, autophagy may play a different role in T2D. Results from experimental T2D studies involving animals are less consistent, showing that cardiac autophagy can be either unchanged [96], reduced [97, 98], or even increased [99, 100]. Additional research is required to explore the underlying mechanisms responsible for the differences in autophagy observed in T1D compared to T2D.

Pharmacological treatment is the cornerstone of HF management and should be implemented concurrently with other non-pharmacological interventions. Classically, therapies in HF focused on the renin–angiotensin and sympathetic nervous system. Regarding HFrEF, large well-designed randomized controlled clinical trials have shown that angiotensin-converting enzyme inhibitors (ACEI) [117], angiotensin II receptor blockers (ARBs) [118], β-blockers [119, 120], mineralocorticoid receptor antagonists (MRAs) [121, 122], and, more recently sacubitril/valsartan (a neprilysin inhibitor/ARBs) [123] and ivabradine [124] have all resulted in significant reductions in CV events in terms of mortality and hospitalizations.

A significant breakthrough in contemporary management of HF was the finding that treatment with SGLT2 inhibitors was associated with a lower risk of HF hospitalization in patients with T2D and CV disease or at high risk thereof. A meta-analysis of six CV and renal outcome trials of four SGLT2 inhibitors (empagliflozin [125], canagliflozin [126], dapagliflozin [127] and ertugliflozin [128]) in patients with T2D (EMPA-REG OUTCOME, CANVAS Programme, DECLARE-TIMI-58, CREDENCE, VERTIS CV) demonstrated a 32% reduction in HF hospitalization [129]. These results indicated a potential benefit of SGLT2 inhibitors in treating individuals with established HF, although it should be noted that HF-related outcomes were not the primary focus of the study. Taking into account these findings, recent randomized clinical trials (RCTs) have been conducted involving patients with HFrEF (DAPA-HF [130] and EMPEROR-Reduced trials [131]) and HFpEF (EMPEROR-Preserved and DELIVER trials [130, 132]), in which HF outcomes were the primary objective, and including patients both with and without DM (almost 50% had T2D). In these large trials, treatment with SGLT2 inhibitors in combination with optimal medical therapy (ACEI/ARNI, β-blockers, and MRAs) in patients with symptomatic chronic HF is associated with a reduction in the risk of hospitalization for HF and cardiovascular mortality, regardless of the presence of DM and across all LVEF. Furthermore, there have also been reported improvements in symptoms and quality of life among patients with HF. Recent trials with SGLT2 inhibitors have also shown benefits concerning HF-related hospitalization and CV mortality in subjects admitted to the hospital due to acute decompensated HF (SOLOIST-WHF trial: sotagliflozin and EMPULSE trial: empagliflozin) [133, 134]. This positive effect was also observed regardless of LVEF or the presence of DM. Thus, based on strong evidence, the SGLT2 inhibitors dapagliflozin, empagliflozin, and more recently sotagliflozin (currently approved for the treatment of HF in the United States but not in the European Union) are recommended as first line therapy in patients with T2D and HF to reduce CV death and HF hospitalization [108].

Another pharmacological group of interest in terms of cardioprotective effects is the glucagon-like peptide 1 agonists (GLP1-RAs). Despite positive outcomes in reducing major cardiovascular events, studies have shown most GLP-RAs having a neutral effect on the risk of HF hospitalization in patients with T2D who had, or were at high risk of, CVD [135, 136]. Future studies are needed to investigate the effects of GLP1-RAs in HF and T2D as primary outcomes and as well as its benefits in certain populations such as non-diabetic or T1D subjects. Recently, treatment with a GLP1-RA (semaglutide) was associated with improved symptoms and exercise capacity in patients with HFpEF and obesity [137]. Moreover, in patients with preexisting cardiovascular disease and overweight or obesity, treatment with semaglutide resulted in a 20% reduction in the risk of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (HR 0.80; 95% CI, 0.72 to 0.90). Noteworthy, an 18% reduction for the HF composite endpoint (HR 0.82; 95% CI, 0.71 to 0.96) and a 21% reduction in hospitalization or urgent medical visit for HF (HR 0.79; 95% CI, 0.60 to 1.03) were observed [138].

In relation to T1D, it is worth noting that most large-scale trials involving medications (ACEI, ARBS, β-blockers, MRAs and sacubitril/valsartan) and medical devices for HF have had limited participation from individuals with T1D, often excluding them or lacking detailed information about this specific subgroup. As a result, the choice of treatment for individuals with T1D is primarily extrapolation from results observed in individuals with T2D. Thus, though the therapies employed for preventing and managing HF in T1D are similar, there is no strong evidence to support this approach [4, 114].

Moreover, it is important to note that in all of the large RCTs with SGLT2 inhibitors, patients with HF and T1D were consistently excluded. To our knowledge, there are no studies that have assessed the effects of SGLT2 inhibitor treatment in patients with T1D and HF, resulting in a lack of evidence and specific recommendations for this subgroup. In experimental models of T1D, treatment with dapagliflozin prevents intimal thickening, cardiac inflammation, and fibrosis [139]. Regarding glycemic control, several clinical trials have evaluated the efficacy and safety of the use of SGLT2 inhibitors in T1D [140‐143]. Treatment with SGLT2 inhibitors added to adjunctive therapy with basal-bolus regimen insulin have demonstrated reduced HbA1c and lower glucose variability with increased time in optimal glucose range as well as additional benefits in terms of reductions in weight and insulin dose without increasing the incidence of hypoglycemia. Based on these positive results, dapagliflozin was the first SGLT2 inhibitor to have its marketing authorization extended to T1D with a BMI ≥ 27 kg/m². However, ‘euglycemic ketoacidosis’ has been reported in 2–3% of patients with T1D taking SGLT2 inhibitors. The careful selection of individuals with T1D for SGLT2 inhibitor treatment is crucial for minimizing the risk of diabetic ketoacidosis (DKA). This treatment may be considered for subjects between the ages of 18 and 74 who are overweight or obese, have been on stable and optimized insulin therapy (not recently diagnosed), require a high dose of insulin (i.e., > 0.5 units/kg per day), presentation with ketone levels < 0.6 nmol/L, and have demonstrated adherence to their insulin regimen as well as the ability to understand and apply relevant education regarding the risk of DKA [140]. In our opinion, when weighing the use of SGLT2 inhibitors in T1D for the treatment of asymptomatic HF, it is essential to establish strategies to reduce the risk of DKA, ideally with the involvement of specialized multidisciplinary units. This entails providing comprehensive education to both individuals with T1D and healthcare professionals about the potential risk of DKA and, if it arises, the methods by which it can be mitigated. It is crucial to closely monitor ketone levels and consider recommendations for temporary suspension in specific circumstances (such as during fasting, vigorous physical activity, concurrent medical illness, recurrent vomiting, alcoholism, etc.).