Heart Failure in Diabetes: A Complex Interplay

https://meditropics.com/heart-failure-in-diabetes-a-complex-interplay/ 

* Navita Jain, **Vivek Suman

* Post Graduate Resident, Department of Medicine, Lady Hardinge Medical College, New Delhi

**Professor, Department of Medicine, Lady Hardinge Medical College, New Delhi

 

Abstract:

Introduction: The coexistence of heart failure (HF) and diabetes mellitus poses significant modern healthcare challenge The bidirectional interplay between HF and diabetes mandates a comprehensive diagnostic and management approach due to their mutual impact on various physiological systems.

Pathophysiology: The intricate relationship between HF and diabetes stems from the convergence of metabolic, molecular, and systemic disruptions. Hyperglycemia, central to diabetes, fosters cardiovascular complications through advanced glycation end-products (AGEs) and oxidative stress, exacerbating fibrosis and cardiac tissue dysfunction. Insulin resistance, prominent in type 2 diabetes, extends to cardiovascular systems, promoting inefficient cardiac function. Neurohormonal imbalances in HF further worsen insulin resistance, while shared chronic inflammation disrupts insulin signaling pathways. Structural and functional shifts within the myocardium, known as diabetic cardiomyopathy, contribute to HF development, often preceding clinical manifestations.

Clinical Implications: The symbiotic HF-diabetes relationship elevates hospitalization rates, cardiovascular events, and compromises quality of life. Overlapping symptoms complicate precise diagnosis, necessitating comprehensive evaluations encompassing cardiac and metabolic aspects.

Therapeutic Considerations: Navigating the HF-diabetes challenge necessitates a comprehensive, multidisciplinary strategy. Lifestyle interventions including heart-healthy diets and regular exercise assume crucial roles in managing both conditions. Guideline-directed medical therapy (GDMT) combines sodium-glucose cotransporter 2 inhibitors (SGLT2is), sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists (MRAs) to address both conditions’ unique aspects. A combination of SGLT2is and ARNI demonstrates cardiovascular protection and superior outcomes through diverse mechanisms. Beta-blockers and MRAs, aside from their cardiac benefits, contribute to glycemic control. Personalized medicine’s potential lies in optimized treatment strategies informed by genetics, metabolism, and clinical traits.

Conclusion: The intricate HF-diabetes interaction underscores the need for comprehensive, tailored management. Understanding their intertwined pathophysiology, diagnostic challenges, and evolving therapies is pivotal for healthcare providers. Holistically addressing both conditions can enhance patient outcomes, enrich quality of life, and alleviate the HF burden in diabetes. Ongoing research promises innovative and effective therapeutic breakthroughs.

1.0 Introduction:

Heart failure (HF) and diabetes mellitus are two of the most prevalent chronic conditions globally, representing significant challenges in modern healthcare. (1) The convergence of these conditions amplifies their individual burdens, creating a complex clinical scenario with distinctive pathophysiological mechanisms and therapeutic considerations.

Heart failure, characterized by the heart’s inability to effectively pump blood, and diabetes, marked by hyperglycemia due to insulin dysfunction, often coexist, leading to a symbiotic relationship that worsens patient outcomes.(2) The bidirectional interplay between HF and diabetes forms a multifaceted web of interactions, affecting various physiological systems and requiring a comprehensive approach to diagnosis and management.

Shared mechanisms underlie the relationship between these conditions. Hyperglycemia, a central feature of diabetes, contributes to cardiovascular complications by fostering oxidative stress, inflammation, and endothelial dysfunction.(2) Conversely, the neurohormonal imbalances and systemic inflammation in HF promote insulin resistance and glucose dysregulation, fueling a cycle of metabolic and cardiac deterioration.

This narrative review explores the intricate connection between HF and diabetes, delving into their intertwined pathophysiology, the diagnostic challenges arising from overlapping symptoms, and the evolving landscape of therapeutic strategies. By understanding the mutual reinforcement of these conditions, healthcare providers can refine their clinical approaches, adopting tailored interventions that address both HF and diabetes, ultimately improving patient outcomes and quality of life.

2.0 Pathophysiology:

The pathophysiological nexus between heart failure (HF) and diabetes mellitus represents a dynamic and intricate relationship that arises from a convergence of metabolic, molecular, and systemic perturbations.

2.1 Hyperglycemia and Oxidative Stress:

Hyperglycemia, a hallmark of diabetes, serves as a cornerstone in the development of cardiovascular complications, including HF. (3) Elevated glucose levels contribute to the formation of advanced glycation end-products (AGEs), which accumulate in the extracellular matrix of cardiac tissues and blood vessels. AGEs promote cross-linking of collagen fibers, resulting in fibrosis, increased tissue stiffness, and impaired contractility of the heart. Furthermore, hyperglycemia-driven oxidative stress leads to increased production of reactive oxygen species (ROS) and decreased antioxidant defenses. This imbalance not only damages cardiomyocytes but also exacerbates inflammation and endothelial dysfunction, key contributors to the pathogenesis of HF. (4)

2.2 Insulin Resistance and Neurohormonal Dysregulation:

Insulin resistance, a hallmark of type 2 diabetes, is characterized by reduced cellular responsiveness to insulin’s glucose-lowering effects. This resistance extends beyond metabolic tissues to impact the cardiovascular system, particularly the heart. Insulin resistance alters myocardial metabolism, favoring fatty acid utilization over glucose, leading to impaired cardiac efficiency. (3,4) The accompanying dysregulation of intracellular signaling pathways influences cardiomyocyte growth, contractility, and apoptosis, contributing to the development of HF.

The neurohormonal dysregulation commonly observed in HF further exacerbates insulin resistance and glucose metabolism. Activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) leads to elevated levels of norepinephrine, angiotensin II, and aldosterone. These neurohormones promote systemic vasoconstriction, sodium retention, and fluid overload, leading to increased cardiac workload and reduced cardiac output. Additionally, RAAS activation has been linked to insulin resistance, further compromising glucose utilization.

2.3 Inflammation and Cellular Dysfunction:

Chronic inflammation is a shared feature of both HF and diabetes, contributing to the progression of each condition. In HF, systemic inflammation is driven by the release of proinflammatory cytokines from the stressed myocardium. (4,5) These cytokines contribute to endothelial dysfunction, increased vascular permeability, and impaired vasodilation, collectively promoting HF development. In the context of diabetes, inflammation is fueled by hyperglycemia-induced oxidative stress and the accumulation of AGEs. Inflammatory mediators such as C-reactive protein (CRP) and interleukin-6 (IL-6) disrupt insulin signaling pathways, aggravating insulin resistance and impairing glucose uptake. (6)

2.4 Cardiac Remodeling and Diabetic Cardiomyopathy:

The cumulative effects of hyperglycemia, oxidative stress, insulin resistance, and inflammation manifest in structural and functional changes within the myocardium, termed diabetic cardiomyopathy. This distinct form of cardiomyopathy is characterized by myocardial fibrosis, impaired diastolic function, and alterations in cardiomyocyte calcium handling. (7) These changes collectively lead to reduced cardiac compliance, impaired relaxation, and ultimately, HF development. Importantly, diabetic cardiomyopathy often precedes the overt clinical manifestations of HF, highlighting the need for early detection and intervention.

3.0 Clinical Implications:

3.1 Complex Intersection of Heart Failure and Diabetes

The confluence of heart failure and diabetes leads to worse clinical outcomes and increased mortality with almost 44% of patients being hospitalized for HF come out to be diabetic (1,8) Patients with both conditions are at a higher risk of hospitalizations, cardiovascular events, and reduced quality of life compared to those with either condition alone.(8)  Diabetic cardiomyopathy, a distinct form of heart failure, is recognized as a consequence of the intricate interplay between diabetes and heart failure. (7)  It involves structural and functional alterations in the myocardium that are independent of coronary artery disease or hypertension. Diabetic cardiomyopathy contributes to impaired diastolic function, which may precede systolic dysfunction, highlighting the importance of early detection and intervention.

3.2 Diagnostic Challenges:

The overlap of symptoms between heart failure and diabetes, such as fatigue, dyspnea, and exercise intolerance, can complicate accurate diagnosis and appropriate management. (9) It is crucial for healthcare providers to recognize the potential coexistence of both conditions and conduct comprehensive assessments that encompass both cardiac and metabolic evaluations. Tools like echocardiography, cardiac biomarkers, and hemoglobin A1c measurements are invaluable in aiding diagnosis and guiding treatment decisions.

Natriuretic peptides, namely BNP and NT-proBNP, are acknowledged as reliable indicators of intracardiac volumes and filling pressures. These biomarkers are currently regarded as the foremost tools for the prevention, diagnosis, and prediction of heart failure. (10) Patients with T2DM also tend to have worse structural and fractionation dimensions in echocardiography including but not limited to diastolic dysfunction, LV mass and higher filling pressures. (11) When it comes to HbA1c levels, surprisingly, among a group of outpatient individuals with confirmed heart failure who were undergoing medical therapy for diabetes, there existed a U-shaped correlation between mortality and HbA1C levels.(12)

3.3 Risk of Complications and Hospitalizations:

The intersection of HF and diabetes amplifies the risk of complications and adverse events. Patients with both conditions are predisposed to a higher likelihood of hospitalizations, cardiovascular events, and overall mortality compared to those with either condition alone. (8,10,11) Diabetic cardiomyopathy, marked by structural and functional changes within the myocardium, contributes to HF progression and is an independent risk factor for morbidity and mortality. Additionally, the shared risk factors of obesity, hypertension, and dyslipidemia further compound the burden of these conditions, necessitating meticulous monitoring and management.

4.0 Therapeutic Considerations:

The intricate interplay between heart failure (HF) and diabetes mellitus presents a unique set of challenges that require a comprehensive and tailored therapeutic approach thus Managing heart failure in the presence of diabetes requires a comprehensive and multidisciplinary approach.

4.1 Lifestyle Modifications:

Lifestyle interventions play a pivotal role in managing heart failure in the presence of diabetes. Encouraging patients to adopt a heart-healthy diet, engage in regular physical activity, and achieve and maintain a healthy weight can have profound positive effects. A balanced diet that limits sodium and saturated fats can help control blood pressure and fluid retention, easing the workload on the heart. Engaging in regular aerobic exercise can improve cardiovascular fitness, reduce insulin resistance, and promote weight loss, all of which contribute to better glycemic control and cardiac function. (13)

4.2 Pharmacological Approaches:

Pharmacotherapy remains a cornerstone in the management of heart failure and diabetes. However, selecting appropriate medications requires careful consideration of their impact on both conditions. Individuals diagnosed with heart failure with reduced ejection fraction (HFrEF) experience notable advantages through guideline-directed medical therapy (GDMT) that encompasses a foundational regimen comprising four distinct drug categories: (1) sodium-glucose cotransporter 2 inhibitors (SGLT2is), (2) sacubitril/valsartan, (3) beta-blockers, and (4) mineralocorticoid receptor antagonists (MRAs) These agents exert their effects, at least in part, by influencing the renin-angiotensin-aldosterone and sympathetic nervous systems. However, the mechanisms of benefit for SGLT2is appear to extend through hemodynamic adjustments or other cellular influences. Extensive trials on a large scale have underscored the efficacy of these agents, particularly when employed in combination, in enhancing survival rates, mitigating the risk of heart failure hospitalizations, alleviating symptoms, and fostering favorable reverse cardiac remodeling. (14)

SGLT2 inhibitors exhibit effectiveness in both primary and secondary prevention of heart failure, encompassing a diverse range of patient demographics and healthcare environments. Evidence underscores the capacity of SGLT2 inhibitors to diminish the likelihood of heart failure occurrences, without being influenced by either the presence of diabetes or the patient’s heart failure status. The overall safety profile of these inhibitors is reassuring, as there is a dearth of substantial evidence pointing to major safety concerns. Our analysis reveals the utility of these medications in both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), regardless of the patient’s diabetic status. Moreover, these medications are generally well-tolerated and pose minimal safety risks. It is important to note, however, that there is a slightly heightened susceptibility to genitourinary infections and euglycemic ketoacidosis associated with their use. (15)

As a novel addition to the pharmacological armamentarium for heart failure, Angiotensin Receptor-Neprilysin Inhibitor (ARNI) has recently emerged as a superior alternative to Angiotensin-Converting Enzyme Inhibitors (ACEI) in terms of curbing the risk of cardiovascular events among patients with heart failure with reduced ejection fraction (HFrEF). In a direct comparison with enalapril, ARNI showcased its prowess by inducing a 20% reduction (HR 0.8, 95% CI 0.73–0.87) in the composite endpoint of cardiovascular death or hospitalization for heart failure, and a 16% reduction (HR 0.84, 95% CI 0.76–0.93) in all-cause mortality within the PARADIGM-HF trial. This effect has also been corroborated by investigations conducted in real-world scenarios. (16)

Given the disparate mechanisms through which Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) and ARNI exert their effects, the notion of synergizing their cardiovascular protective effects while potentially minimizing adverse effects has ignited considerable interest. Studies demonstrate that the combination therapy outperformed ARNI monotherapy in the context of patients afflicted by HFrEF. (15, 16)

Beta-blockers, another class of medications commonly used in HF management, provide benefits beyond their cardiac effects. They can improve insulin sensitivity and glycemic control, making them suitable choices for patients with diabetes and heart failure. (17) Additionally, mineralocorticoid receptor antagonists (MRAs) have shown to reduce morbidity and mortality in HF patients and have the potential to enhance glycemic control. (14)

4.3 Personalized Medicine:

Advancements in genetic and biomarker research hold promise for personalized therapeutic strategies. Tailoring treatments based on individual genetic profiles, metabolic markers, and clinical characteristics could optimize outcomes for patients with heart failure and diabetes. This approach could guide medication selection, dosing, and timing, resulting in more effective and targeted interventions. (18)

5.0 Conclusion:

The symbiotic relationship between heart failure and diabetes underscores the importance of a holistic approach to patient care. Recognizing the bidirectional interactions, shared pathophysiology, and overlapping clinical implications is essential for healthcare providers to deliver optimal management. Advances in pharmacological therapies, along with lifestyle modifications, offer hope for improving outcomes in individuals burdened by these complex and interrelated conditions. As research progresses, a more comprehensive understanding of the underlying mechanisms will undoubtedly unveil new avenues for intervention and pave the way for better outcomes and improved quality of life for affected patients.

References

  1. Jerkins T, McGill JB, Bell DS. Heart Failure and Diabetes: Clinical significance and epidemiology of this two‐way association. Diabetes, Obesity and Metabolism. 2023 Jul;25:3-14.
  2. Sabbour H, Ahmad A. Management of Heart Failure in Patients with Diabetes Mellitus in the UAE: A Call to Action. Journal of Cardiovascular Pharmacology and Therapeutics. 2023 Apr 17;28:10742484231162248.
  3. Kasznicki J, Drzewoski J. State of the art paper heart failure in the diabetic population–pathophysiology, diagnosis and management. Archives of Medical Science. 2014 Jun 30;10(3):546-56.
  4. Longo M, Scappaticcio L, Cirillo P, Maio A, Carotenuto R, Maiorino MI, Bellastella G, Esposito K. Glycemic control and the heart: the tale of diabetic cardiomyopathy continues. Biomolecules. 2022 Feb 8;12(2):272.
  5. Chrysohoou C, Fragoulis C, Leontsinis I, Gastouniotis I, Fragouli D, Georgopoulos M, Mantzouranis E, Noutsou M, Tsioufis KP. Cardiometabolic Care: Assessing Patients with Diabetes Mellitus with No Overt Cardiovascular Disease in the Light of Heart Failure Development Risk. Nutrients. 2023 Mar 13;15(6):1384.
  6. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. European cytokine network. 2006 Mar 1;17(1):4-12.
  7. Bando YK, Murohara T. Diabetes-Related Heart Failure–Does Diabetic Cardiomyopathy Exist?–. Circulation journal. 2014;78(3):576-83.
  8. Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, Bhatt DL, Hernandez AF, Heidenreich PA, Fonarow GC. Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: Findings from Get With The Guidelines–Heart Failure registry. American heart journal. 2016 Dec 1;182:9-20.
  9. Aneja A, Tang WW, Bansilal S, Garcia MJ, Farkouh ME. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. The American journal of medicine. 2008 Sep 1;121(9):748-57.
  10. Seferović P, Farmakis D, Bayes‐Genis A, Ben Gal T, Böhm M, Chioncel O, Ferrari R, Filippatos G, Hill L, Jankowska E, Lainscak M. Biomarkers for the prediction of heart failure and cardiovascular events in patients with type 2 diabetes: a position statement from the Heart Failure Association of the European Society of Cardiology. European journal of heart failure. 2022 Jul;24(7):1162-70.
  11. Kristensen SL, Mogensen UM, Jhund PS, Petrie MC, Preiss D, Win S, Køber L, McKelvie RS, Zile MR, Anand IS, Komajda M. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-Preserve Trial (Irbesartan in Heart Failure With Preserved Ejection Fraction). Circulation. 2017 Feb 21;135(8):724-35.
  12. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. Journal of the American College of Cardiology. 2009 Jul 28;54(5):422-8.
  13. Staimez LR, Weber MB, Gregg EW. The role of lifestyle change for prevention of cardiovascular disease in diabetes. Current atherosclerosis reports. 2014 Dec;16:1-1.
  14. Lee MM, Sattar N. A review of current key guidelines for managing high risk patients with diabetes and heart failure and future prospects. Diabetes, Obesity and Metabolism. 2023 Apr 11.
  15. Wahinya M, Khan Z. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor Therapy for the Primary and Secondary Prevention of Heart Failure in Patients With and Without Type 2 Diabetes Mellitus: A Systematic Review. Cureus. 2023 Apr 10;15(4).
  16. Yan Y, Liu B, Du J, Wang J, Jing X, Liu Y, Deng S, Du J, She Q. SGLT2i versus ARNI in heart failure with reduced ejection fraction: a systematic review and meta‐analysis. ESC heart failure. 2021 Jun;8(3):2210-9.
  17. Wai B, Kearney LG, Hare DL, Ord M, Burrell LM, Srivastava PM. Beta blocker use in subjects with type 2 diabetes mellitus and systolic heart failure does not worsen glycaemic control. Cardiovascular diabetology. 2012 Dec;11(1):1-5.
  18. Gori M, D’Elia E, Iorio A, Iacovoni A, Senni M. Clinical application of personalized medicine: heart failure with preserved left ventricular ejection fraction. European Heart Journal Supplements. 2020 Nov;22(Supplement_L):L124-8.