I have devoted the last few days to sharing information on diabetes. The feedbacks have been good. There was one that I would like to share with you, dear reader.Can diabetes on its own cause heart disease in a person? The response is yes. There is actually a condition known as diabetic cardiomyopathy.

Diabetes mellitus and the associated complications represent a global burden on human health and economics. Cardiovascular diseases are the leading cause of death in diabetic patients, who have a 2–5 times higher risk of developing heart failure than age-matched non-diabetic patients, independent of other comorbidities. This suggests a specific intrinsic mechanism that drives the pathological cardiac remodeling in this population. The United Kingdom Prospective Diabetes Study (Group) indicated an association between the risk of cardiovascular complications and glycaemia, observing that for every 1% decrease in HbA1c there was an 18% reduction in myocardial infarction (MI) events.

Diabetic cardiomyopathy is defined as the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease (Borghetti et al. Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front. Physiol. 2018:9:1514)

Heart failure is a multifactorial disease in diabetic patients. Both type 1 diabetes mellitus (T1DM) and T2DM are associated with an increase in macrovascular and microvascular dysfunction, resulting in ischemic events and altered vascular permeability. Atherosclerosis and hypertension are often present in diabetic patients and contribute to coronary artery disease (CAD) and peripheral vascular disease, both of which affect the heart. Apart from these well-known pathological triggers, diabetes contributes to the development of heart failure (HF) through a more disease-specific variety of mechanisms, which are mostly driven by hyperglycaemia, hyperinsulinemia, metabolic changes, and oxidative stress .

Metabolic dysfunction, hyperinsulinemia, oxidative stress, and inflammation are among the prevalent causes of this increase in left ventricular (LV) mass seen in diabetic patients.Cardiac remodeling occurs in several different phases during the progression of diabetic cardiomyopathy, which is often asymptomatic during the early stages.

Currently, there are no specific morphological changes, biochemical markers, or clinical manifestations needed to secure a diabetic cardiomyopathy diagnosis. The pathology is often asymptomatic throughout the early stages and usually overlaps with other complications in diabetic patients, making a definitive diagnosis challenging. Significant improvements have been made in non-invasive imaging technologies, such as echocardiography and magnetic resonance imaging (MRI), which provide detailed information about cardiac morphology and functions. Both transmitral Doppler and Tissue Doppler imaging are used to quantify the functional myocardial abnormalities.

Hyperglycemia and chronic sustained hyperinsulinemia cause microvascular complications leading to renal failure, retinopathy, and nerve damage. Lowering blood glucose levels is therefore fundamental in the treatment regimen for diabetes. However, several observational studies fail to demonstrate a reduction in HF hospitalizations in diabetic patients treated with anti-hyperglycemic therapy.This is a normal course of action for researchers. Identifying a molecule (anti-diabetic) with cardiovascular benefit will be a huge advantage in the long term treatment of the person affected by diabetes. 

Glucagon-like peptide 1 (GLP-1) is a gut-derived peptide hormone primarily secreted after food intake. This so-called incretin has the ability to decrease glycaemia by increasing the release of insulin and repressing glucagon expression in a glucose-dependent manner. Besides this, activation of the GLP-1 receptor in different tissues leads to a broad spectrum of effects, including deceleration of gastric emptying, suppression of appetite with consequent weight loss, reduction of circulating lipoprotein, and a decrease in blood pressure. However, endogenous secreted GLP-1 [GLP-1 (7–36)] has a very short half-life, which is approximately 2–3 min in the circulation. This active isoform is rapidly degraded primarily by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9–36), a receptor antagonist. Thus, several synthetic GLP-1 receptor agonists (GLP-1RAs) have been developed to provide prolonged action and subsequently have beneficial effects for T2DM patient. These drugs are able to increase insulin release only in the context of hyperglycaemia and therefore with a very low risk of inducing severe hypoglycaemia. Thus, GLP-1RAs potential cardioprotective effects are derived from their ability to attenuate established cardiovascular risk factors, such as hyperglycaemia, obesity, high blood pressure, and dysfunctional lipid profile.

The cardiovascular safety of liraglutide was evaluated in the LEADER trial, in which 9,340 diabetic patients at high risk for cardiovascular events (having established cardiovascular disease, either CAD or chronic HF, and/or cerebrovascular disease, peripheral vascular disease, and chronic kidney disease) were enrolled. This study showed not only the safety but also the beneficial cardiovascular effect of this drug. Liraglutide was associated with a significant reduction in the primary composite endpoint, which includes CV mortality, non-fatal MI, non-fatal stroke as well as in all-cause mortality. Hospitalizations for HF were not different between the liraglutide and the placebo group. The subgroup analysis revealed that patients with more severe kidney disease, older or with established cardiovascular disease may have greater benefit from liraglutide treatment in comparison with other patient groups

Dipeptidyl peptidase-4 is expressed in most parts of cells/tissue and exhibits exopeptidase activity against GLP-1 and several other peptide hormones and chemokines. Thus its activity is not only limited to glucose metabolism but also regulates several processes, including inflammation, vascular function, cell homing, and survival. Dipeptidyl peptidase-4 plasma activity correlates with cardiac dysfunction in humans indicating a direct link between the DPP-system and cardiovascular health. Three DPP-4 inhibitors have been tested in large clinical trials: sitagliptin, alogliptin, and saxagliptin. The use of these drugs was not associated with any increase (but neither a decrease) in the composite primary outcome, including CV mortality, non-fatal MI, and non-fatal stroke.

Since regulatory agencies began requiring cardiovascular outcome trials for newly developed anti-hyperglycaemic drugs, the EMPA-REG-OUTCOME trial was the first to report remarkably improved CV outcomes including all-cause mortality in patients treated with one particular anti-diabetic drug. This double-blind, placebo-controlled trial randomized 7,020 patients with T2DM at high CV risk to either once-daily empagliflozin treatment (10 or 25 mg) or placebo treatment.

The investigators reported a significant 14% reduction of the combined primary endpoint encompassing CV death, non-fatal MI, and non-fatal stroke in patients treated with empagliflozin (pooled analysis) during a mean follow-up of 3.1 years, which was mainly driven by a reduction in CV deaths. Furthermore, a 35% relative reduction in the rate of HF hospitalization was observed in the empagliflozin group. An explanation for the beneficial CV effects of sodium-glucose transport protein 2 (SGLT-2) inhibition is a modulation of myocardial energy metabolism. The myocardium of diabetic HF-patients loses the ability to properly oxidize fatty acids and metabolize glucose.  SGLT-2 inhibition slightly increases levels of ketone bodies independent of the presence of diabetes, which can then be oxidized in preference to fatty acids. This metabolic substrate shift might improve myocardial work efficiency and oxygen consumption.

Oxidative stress is one of the major contributors in the pathogenesis of the diabetic heart. A number of studies have evaluated different strategies to decrease ROS accumulation.The prevalence of Type 2 diabetes mellitus is rising worldwide, accompanied by an increasing risk of hypertension, cardiovascular disease, and mortality. Observational studies have shown that physical activity, weight loss, and diet can prevent diabetes and its complications.Diet is a major lifestyle factor that can greatly influence the incidence and the progression of chronic diseases such as cancer, cardiovascular disease, and diabetes.Incorporation of polyphenol-rich cocoa in the regime will be very useful for these patients.




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