Diabetes Mellitus Type 2, Prediabetes, and Chronic Heart Failure

Abstract

Impaired glucose metabolism and its consequence diabetes mellitus is still challenging the health care system worldwide. According to the International Diabetes Federation in 2021, the number of adult people living with diabetes was approximately 537 million and 860 million adults had prediabetes. It is predicted that numbers will rise in the future. Numerous researches have shown that prediabetes and diabetes mellitus are serious risk factors for cardiovascular diseases. Lots of epidemiological evidence figured out that diabetes mellitus is associated with the risk of developing heart failure. Diabetes mellitus is highly prevalent among patients with heart failure. Moreover, several anti-diabetics (anti-prediabetic) medications are contributing their share into developing heart failure by increasing risk of mortality and hospitalization for heart failure. This chapter will discuss the connection between prediabetes, diabetes mellitus, and chronic heart failure.

1. Introduction

Diabetes mellitus (DM) is one of the major healthcare problems worldwide. According to the International Diabetes Federation (IDF) 2021 Atlas, 537 million adults (20–79 years) are living with diabetes. This number is predicted to rise to 783 million by 2045 [1]. Of persons with diabetes, 21.4% were not aware of or did not report having diabetes, and only 15.3% of persons with prediabetes reported being told by a health professional that they had this condition [2]. The prevalence of DM type 2 (T2D) is overwhelming. It is accounted for more than 90% of diabetes cases all over the world [1]. High incidence of T2D is thought to be because of population aging, lack of physical activity, urbanization, and obesity [3].

DM is diagnosed by using following criteria: fasting plasma glucose level of ≥126 mg/dl, glycated hemoglobin (HbA1c) level of ≥48 mmol/mol, and 2-hour plasma glucose after 75 g oral glucose load (oral glucose tolerance test-OGTT) level of ≥11.1 mmol/l. Diabetes should be diagnosed if one or more diagnostic criteria are met [1]. Symptoms of diabetes include thirst, fatigue, polyuria, hunger, weight loss, blurred vision, etc.

The classification of DM is not unified and there are some differences between proposed classification by the American Diabetes Association (ADA) [4], IDF [1], and the World Health Organization (WHO) [3]. Precise classification is important for identifying the individual treatment approach since sometimes it is quite difficult to distinguish types of DM [4].

Variety of genetic and environmental factors can lead to the progressive loss of ß-cell mass and/or function that manifest as hyperglycemia which result in DM. Deficient ß-cell insulin secretion, often on the background of insulin resistance, appears to be the common pathophysiological factor for T2D. T2D is associated with insulin secretory defects related to genetics, inflammation, and metabolic stress [4].

2. Risk factors for diabetes mellitus

Risk factors for DM include adults, with a history of cardiovascular disease (CVD), hypertension (≥140/90 mmHg or on therapy for hypertension), HDL cholesterol level < 35 mg/dL (0.90 mmol/L) and/or a triglyceride level > 250 mg/dL (2.82 mmol/L), physical inactivity, and other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) and etc. Also, patients with prediabetes and women who were diagnosed with gestational diabetes mellitus are at risk of diabetes [4]. People living with diabetes are at risk of macrovascular complications such as CVD and microvascular complications (such as diabetic kidney disease, diabetic retinopathy, and neuropathy). These complications lead to increased mortality, blindness, kidney failure, and decreased quality of life in individuals with diabetes [5]. T2D is a common metabolic disease leading to diabetic myocardiopathy and atherosclerotic cardiovascular disorder. These conditions may induce heart failure through a range of mechanisms along with myocardial infarction (MI) and chronic pressure overload [6].

Atherosclerotic cardiovascular diseases are determined as coronary artery disease, cerebrovascular disease, and peripheral artery diseases. Among patients with DM atherosclerotic CVD remains the main cause of death and disability [7]. This results in $37.3 billion in cardiovascular-related spending in patients with diabetes per year [8]. CVD and T2D share several common pathophysiological features such as insulin resistance, inflammation, oxidative stress, hypercoagulability, high blood pressure (BP), dyslipidemia, and obesity. Classical cardiovascular risk factors, such as dyslipidemia, hypertension, and obesity can also raise the risk of T2D [6].

Although T2D and heart failure (HF) are each individually associated with morbidity and mortality, they often occur together, which further worsens adverse patient outcomes, quality of life, and costs of care [9].

Observational studies of patients with DM (predominantly type 2) have identified an approximately two to fourfold risk of HF compared to individuals without DM [10]. While the relative risk of HF in patients with DM compared with patients without DM is higher in younger individuals [11], the frequency of HF is higher in older adults with DM who were ≥ 65 years of age [12].

Although studies have shown an association between poor glycemic control and risk of HF, improved glucose control has not been shown to reduce incident HF. A meta-analysis including 27,049 patients with T2D found that more intensive glucose control, compared with less intensive control, did not decrease incident HF or mortality, although major cardiovascular events (primarily MI) were decreased [13].

Glycemic control is assessed by HbA1c level measurement, continuous glucose monitoring (CGM) using either time in range and/or blood glucose monitoring. In a clinical scenario HbA1c measurement is used more often. The HbA1c measurement should be performed in all diabetes patients at initial assessment and once in every 3 months. Measurement of HbA1c every 3 months determines whether patients’ glycemic targets have been achieved and maintained. The HbA1c checking may have limitations in patients with medical conditions that can affect red blood cell turnover (hemodialysis, erythropoietin therapy, etc.). In such cases plasma blood glucose measurements are conducted by using BGM by fingerstick and CGM. Glycemic targets should be determined individually in each diabetes patient. There is evidence that more intensive glycemic control in newly diagnosed diabetes patients can be beneficial in reducing long-term CVD [14]. However, available data show that strict glycemic control in patients with established DM does not eliminate the risk of developing HF [15]. Overall, there is obscurity on choosing glycemic targets in diabetes mellitus with HF.

Prognosis in patients with HF and DM having DM led to worse outcomes in comparison with those who did not have DM among patients with HF. This was also demonstrated by randomized trial data in patients with HF with reduced ejection fraction (HFrEF; LVEF ≤40%) or HF with preserved ejection fraction (HFpEF) [9, 16, 17, 18, 19, 20, 21, 22].

A study of data from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and morbidity (CHARM) program on outcomes in patients with HF found that concurrent DM was associated with a greater increased risk of cardiovascular death or HF hospitalization in patients with LVEF >40% than in patients with LVEF ≤40% [21]. The risk by DM was similar in the two groups for all-cause mortality.

In the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial with patients with HFrEF, there was an increased risk of the primary outcome of HF hospitalization or cardiovascular mortality in patients with previously undiagnosed DM or known DM [19].

It has been shown that, there is disturbingly high prevalence, incidence, and mortality for HF in individuals with diabetes [12]. DM patients who developed HF had poor prognosis.

It has been shown that, there is disturbingly high prevalence, incidence, and mortality for heart failure in individuals with diabetes [12]. DM patients who developed HF had poor prognosis.

3. Management of DM type in patients with HF

The initial management of blood glucose as well as the general medical care in adults with T2D or type 1 DM and HF is similar to that for other adults. In selecting initial therapy, patient presentation should be considered (e.g., presence or absence of symptoms of hyperglycemia, comorbidities, baseline HbA1c level). Treatment plans should include individualized treatment goals and preferences. The glucose-lowering efficacy of individual drugs, their adverse effect profile, tolerability, and cost should be considered individually for each patient. In the absence of specific contraindications, metformin should be suggested as initial therapy for patients with newly diagnosed T2D who are asymptomatic. Metformin is the preferred initial therapy because of glycemic efficacy, absence of weight gain and hypoglycemia, general tolerability, and favorable cost. Metformin does not have adverse cardiovascular effects, and it appears to decrease cardiovascular events [23, 24, 25]. The cost of metformin is more affordable and practically it has more experience than glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2i) inhibitors. Metformin usage instigates less episodes of hypoglycemia compared with sulfonylureas, and less edema, congestive HF, and weight gain compared with thiazolidinediones. The benefit of metformin in HFpEF has been studied. It has been shown that, metformin was beneficial in reduction of mortality in both preserved and reduced EF after adjustment with HF therapies such as angiotensin converting enzyme inhibitors (ACEi) and beta-blockers. Metformin treatment along with insulin, ACEi, and beta-blocker therapy were also shown to have a reduction in mortality, whereas female gender was associated with worse outcomes [26].

Sulfonylurea medications are commonly used in DM as second- or third-line treatment if needed, especially when the cost is the issue for a patient [27]. They are the oldest class of antidiabetic medications [28]. Sulfonylureas are classified as first and second generation, as second generation of sulfonylureas are the most prescribed (glibenclamide, glimepiride, gliclazide, etc.) [29]. The pharmacokinetic and pharmacodynamic features of sulfonylureas differ [30]. Not all sulfonylureas are selective for pancreas, they can also bind to cardiac myocytes and vascular smooth muscle. This can lead to ischemia and deterioration of the cardiovascular outcome. It has been suggested that gliclazide is selective for pancreas, while glimepiride and glibenclamide are non-selective [31]. Usage of sulfonylurea is complicated with hypoglycemia [32]. Hypoglycemia is associated with a higher risk of CVD [33]. One of the meta-analyses demonstrated significant associations between hypoglycemia and death, dementia, macrovascular and microvascular complications, and CVD [34]. Therefore, there is clinical uncertainty on the usage of sulfonylurea medications in diabetic patients with CVD. It also has been shown that the use of sulfonylureas in T2D increases mortality and risk of stroke, although the overall incidence of major adverse cardiovascular events (MACE) seems to be unchanged [35]. In another cardiovascular outcomes trial assessing linagliptin with glimepiride in patients with T2D and increased cardiovascular risk, the nonfatal MI and nonfatal stroke outcome was similar in both groups. It was demonstrated that hospitalization for HF was the same in patients who received glimepiride in comparison with linagliptin. Episodes of hypoglycemia events occurred in both groups and the rate was low, although it was higher in the glimepiride group [36]. Widely used sulfonylurea, gliclazide was associated with a lower risk of all-cause and cardiovascular mortality [37]. Although the data regarding long-acting sulfonylureas may be conflicting [38]. There are no randomized control trials assessing their effects on outcomes.

Thiazolidinediones are insulin sensitizing glucose-lowering medication which shows their effect by activating PPAR-gamma (peroxisome proliferator–activated receptor γ) [39]. Their effects regulate glucose, lipids, and protein metabolism. They are hugely effective in insulin resistance [39]. The commonly used thiazolidinediones are rosiglitazone and pioglitazone, which are indicated as FDA black box warning [27]. In diabetic patients their use is moderated by concerns over cardiovascular safety, weigh gain, edema, fracture risk, and bladder cancer [27]. The randomized clinical trials demonstrated that rosiglitazone and pioglitazone increase the risk of HF [40, 41, 42].

GLP-1 are efficient glucose-lowering medications used for the treatment of T2D. GLP-1 RA include liraglutide once daily, semaglutide once weekly, dulaglutide once weekly, exenatide twice daily, exenatide once weekly, lixisenatide once daily, which are injectable medications. Recently semaglutide has been introduced also in oral form which can be taken once daily.

GLP-1 have a reliable safety and tolerability profile in the management of the T2D [43]. As it has been shown in numerous studies and trials, this class of glucose-lowering medication proved itself as an effective tool in blood glucose and weight management [44, 45, 46]. The class effect is based on glucose-dependent insulin secretion. They also delay gastric emptying and increase satiety [47]. GLP-1 improve lipid levels with decreased triglyceride levels and increase high-density lipoprotein levels and provide low risk of hypoglycemia [9]. They significantly reduce HbA1c levels and systolic BP [48]. GLP-1 usage is proved to be beneficial in T2D and established atherosclerotic CVD and is recommended as part of the cardiovascular risk reduction and/or glucose-lowering medication [49]. Semaglutide demonstrated decrease in the rate of cardiovascular death, MI, and stroke by 26% [50]. Overall GLP-1 have no effect on HF hospitalization [9] and are not recommended for the prevention of HF events in patients with T2D.

Dipeptidyl peptidase-4 inhibitors (DPP4) are oral glucose-lowering medications that inhibit native enzyme dipeptidyl peptidase [51]. This enzyme is expressed on the surface of the most cell types that affects native gastrointestinal peptides and GLP-1. DPP4 inhibit the degradation of native GLP1 and enhance the incretin effect [52]. The commonly used DPP4 are sitagliptin, vildagliptin, linagliptin, alogliptin, and saxagliptin. It should be noted that, saxagliptin demonstrated the increased risk of hospitalization in patients with DM and HF [53]. Sitagliptin, linagliptin, and alogliptin showed no effect on HF events. However, in another trial vildagliptin increased the left ventricular volumes [54]. Overall, DPP4 are not recommended to reduce cardiovascular events in T2D with HF [55].

SGLT2i are one of the effective glucose-lowering drugs used in the treatment of DM. Their effect is based on reducing renal tubular glucose reabsorption [56]. They decrease blood glucose levels without stimulation of insulin secretion which makes them very useful in patients with a long duration of diabetes [56]. SGLT2i include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. The usage of dapagliflozin and canagliflozin has been associated with reduced incidence of HF [57, 58]. Those T2D patients with a high risk of cardiovascular events who received empagliflozin demonstrated reduction of the primary composite cardiovascular outcome and of death from any cause [59]. Empagliflozin and canagliflozin reduced the primary composite endpoint of major CV adverse events, including CV death or non-fatal MI or non-fatal stroke, and HF hospitalizations [59, 60]. Dapagliflozin demonstrated a lower rate of cardiovascular death or hospitalization for HF in T2D in the DECLARE-TIMI 58 trial [57]. The other SGLT2i, ertugliflozin, showed statistically significant reduction in HF hospitalization and repeated hospitalizations, although it did not reduce the primary major CV event endpoint and key secondary outcome of cardiovascular death or HF hospitalization [61, 62]. Meta-analysis of Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME), Canagliflozin Cardiovascular Assessment Study (CANVAS), Dapagliflozin Effect on CardiovasculAR Events (DECLARE-TIMI 58), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated the significant reduction in HF and cardiovascular hospitalization [49, 55].

Therefore, it is recommended to use SGLT2i as first-line therapy in diabetes as well as add on to patients with T2D with or at high risk of HF or chronic kidney disease (CKD) and ASCVD [49]. Additionally, the SGLT2i canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin are recommended to prevent HF and CV death and worsening kidney function in patients with T2D and CV disease and/or CV risk factors, or CKD. Dapagliflozin and empagliflozin are also indicated for the treatment of patients with T2D and HFrEF [55].

Insulin is one of the effective and oldest glucose-lowering medications in the management of DM. In cases when glycemic treatment goals are not achieved, adding of insulin therapy should not be delayed. Insulin treatment can be added to oral and injectable anti-diabetic medications. Insulin usage is associated with high efficacy and improved glycemic control [27]. Despite the high efficacy insulin treatment can lead to hypoglycemia and weight gain [27]. Both acute and chronic hypoglycemia increase CVD risk [63, 64]. Moreover, severe hypoglycemia was shown to be an independent risk factor for heart failure incidence [65]. Another trial also demonstrated that insulin usage is associated with deterioration in patients with HFpEF [64]. Therefore, patients with HF should be monitored thoroughly after starting insulin treatment [55].

4. Prediabetes and chronic heart failure

4.1 Definition, prevalence, diagnostics, and types of prediabetes

Prediabetes (PD) is a serious health condition where blood sugar levels are higher than normal, but not enough yet to be diagnosed as T2D [66]. IDF estimates that, worldwide, 541 million individuals aged 20–79 years have impaired glucose tolerance (IGT) and 319 million have impaired fasting glucose. These numbers are projected to increase to 730 million and 440 million, respectively by 2045 [1].

According to the 2022 National Diabetes Statistics Report, in 2019, 96 million (38.0%) adults age 18 and older in the United States were diagnosed with PD. This means that 1 in 3 people have PD, but 8 in 10 are unaware of their carbohydrate metabolism disorder. Meanwhile, 26.4 million (48.8%) people age 65 and older have PD. 10.8% of American adults had PD based on both elevated fasting plasma glucose and A1C levels. Based on fasting glucose or A1C levels, PD was more common in men (41.0%) than in women (32.0%). For example, in the United States, 1 in 3 people have PD and 1 in 10 people have DM, i.e., the prevalence of PD is several times higher than that of DM [67].

DM does not appear suddenly. Every person diagnosed with diabetes first goes through a PD stage [68]. PD not only is associated with high risk of progression to T2D; it also confers an increased risk of cardiovascular morbidity and mortality [69], microangiopathy [70], and neuropathy [71]. An essential difference between PD and DM is the possibility of early detection, proper diagnosis, and an optimal management; PD can be returned to normal glucose metabolism (NGM) or its progression to diabetes may be slowed [72]. The medical and social significance of PD and DM requires the earliest detection of these conditions. The diagnostic criteria for diabetes are generally accepted [73, 74, 75, 76, 77, 78, 79], but the community of experts has not yet been able to fully agree on diagnostic criteria for PD.Table 1 presents the diagnostic criteria for PD in accordance with international and national recommendations [73, 74, 75, 76, 77, 78, 79].

Source of recommendations	Diagnostic criteria
	FG	OGTT	HbA1c
ADA	100–125 (mg/dl); 5.6–6.9 (mmol/l)	140–199 (mg/dl); 7.8–11.0 (mmol/l)	5.7–6.4 (%); 39–47 (mmol/mol)
WHO/IDF	110–125 (mg/dl); 6.1–6.9 (mmol/l)	140–199 (mg/dl); 7.8–11.0 (mmol/l)	Not recommended
Canada/UK/Australia	110–125 (mg/dl); 6.1–6.9 (mmol/l)	140–199 (mg/dl); 7.8–11.0 (mmol/l)	6.0–6.4 (%); 42–47 (mmol/mol)
AAEDTE	110–125 (mg/dl); 6.1–6.9 (mmol/l)	140–199 (mg/dl); 7.8–11.0 (mmol/l)	5.7–6.4 (%); 39–47 (mmol/mol)

Table 1.

Comparative characteristics of diagnostic criteria for prediabetes based on the recommendations of different societies.

Note: ADA—American Diabetes Association, WHO—World Health Organization, IDF—International Diabetes Federation, Canada—The Canadian Diabetes Association, UK—The British Diabetic Association, Australia—Diabetes Australia, AAEDTE—Azerbaijan Association of Endocrinology, Diabetology and Therapeutic Education, FG—fasting glucose, OGTT—oral glucose tolerance test, HbA1c—glycohemoglobin.

A range of risk scores are used for screening diabetes and PD [80, 81]. The relationship between PD and types of PD as IGT, IFG, elevated HbA1c (or their various combinations) with heart failure (HF) has been studied [82, 83, 84, 85]. In one of the studies, it was demonstrated that, for all-cause mortality risk, the association was stronger for IGT- than for IFG- or HbA1c-defined prediabetes, suggesting that OGTT is more useful for identifying high-risk individuals [82].

In a recently published article in the journal Cardiovascular Diabetology, Sinha et al. analyzed 40,117 participants from 6 population-based cohorts in the United States. They found that PD (defined as an FPG concentration of 100–125 mg/dL) was associated with a higher lifetime risk of HF in middle-aged white adults and black women, while the association was less pronounced in older black women. It was observed that middle-aged adults with prediabetes had a higher lifetime risk of HF and, on average, lived fewer years without HF than adults with normoglycemia. This difference was seen in all racial-gender groups except for middle-aged black men with PD, where the difference was not consistently significant, but the trend was similar. The results can probably be explained by two mechanisms that are not mutually exclusive. First, cumulative effects on glucose levels in the PD range in middle-aged and older men may contribute to cardiac dysfunction and the development of chronic HF. This explanation is supported by mechanistic and clinical studies demonstrating direct and indirect effects of insulin resistance and hyperglycemia on myocardial energetics, fibrosis, and subclinical cardiac dysfunction. Second, middle-aged adults with PD are more likely to develop diabetes later in life, leading to a greater lifetime risk of HF [83].

In the study about glucose abnormalities and heart failure among participants with normal glucose metabolism, HF was diagnosed in 3.2% compared with IGT and IFG in 6.0%, respectively. Also, IGT and IFG and HF were in 0.7% of men and in 0.6% of women. In this study, it is proved once again that there is a relationship between impaired glucose metabolism (IGM) and HF [84]. In one of the studies it was demonstrated that, PD with high levels of HbA1c is associated with an increased risk of HF [85].

4.2 HF as a risk factor for PD

The 5-year risk of HF was assessed among participants with diabetes and PD by biomarker assessment groups (0–4). The primary outcomes included 6799 patients with dysglycemia (diabetes: 33.2%; PD: 66.8%). The 5-year risk of HF increased stepwise with a rising biomarker score, with the highest risk seen in patients with scores ≥3 (diabetes: 12.0%; PD: 7.8%). Therefore, the study demonstrated that among adults with IGM (DM + PD), a biomarker score would stratify HF [86].

4.3 Management of PD in heart failure

Until now there is no information on the usage of Metformin and DPP4 inhibitors in the treatment of PD and HF. Thiazolidinediones are contraindicated with HF. One of the studies had showed, orlistat which is used for the treatment of PD had lower rates of first-time HF [87].

SGLT2i are recommended in HF; however, there are no effective data on the reversing PD to NGM by using SGLT2i. Various studies have examined the effects of GLP1 in the treatment of PD on HF. Based on the results of trials as Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) [88] and LIVE [89], the effect of the glucagon-like peptide-1 analogue in HF patients without diabetes was demonstrated. The effect of Liraglutide on left ventricular function in chronic heart failure patients with and without type 2 diabetes (LIVE) study has noticed that, Liraglutide had no effect on left ventricular systolic function compared with placebo in patients with stable HF with and without diabetes. Liraglutide resulted in weight loss, improved glycemic control, and improved physical performance [89].

5. Chronic heart failure and diabetes mellitus

5.1 Classification and epidemiology of heart failure

LVEF is the criterion that is taken into consideration when diagnosing HF in groups. Based on the ‘Report on the Universal Definition and Classification of HF’ [90] and the last 2021 European Society of Cardiology (ESC) guidelines [91], there are three major categories of HF proposed: HF where EF is preserved (HFpEF, LVEF ≥50%), HF where EF is mildly reduced (HFmrEF, LVEF between 41 and 49%), and HF where EF is reduced (HFrEF, LVEF ≤40%). Improved LVEF is used to describe patients who have been previously diagnosed with HFrEF whose LVEF is now >40%.

Approximately 50% of all HF instances are caused by HFpEF, and its prevalence is rising—making this category of HF the most common one in the future [92, 93]. HFrEF has distinct risk factors including male gender and CVD history (for example, MI) [94]. In comparison with HFpEF, patients with HFrEF have a greater mortality rate [92, 95]. HF with mildly reduced EF, previously named “HF with mid-range EF” since similar therapies work for both patients with HFmrEF and HFrEF, is the latest type of HF (introduced by ACCF/AHA in 2013 [96] and by the ESC in 2016 [91, 94]).

Hypertension, CKD, obesity, and diabetes are all important predictors of HF [97, 98]. The etiological relationship between DM and HF is mutually directed. Prolonged diabetes contributes to the development of myocardial dysfunction and HF [99]. This is due to potentiation of endothelial dysfunction, dyslipidemia, and hypercoagulability, and is also the result of a direct effect of hyperglycemia on myocardial function and morphology. On the other hand, HF can be complicated by the development of DM as a result of organ hypoperfusion and hyperactivation of neurohumoral systems, which contribute to an increase in blood glucose concentration as a result of a decrease in glucose consumption by muscle tissue, increased gluconeogenesis in the liver, and the contra-insular effect of catecholaminemia [100]. Also, HF in patients with DM is considered direct damage to the heart muscle as a result of prolonged hyperglycemia. Myocardial damage against the background of hyperglycemia is mediated by microangiopathy, impaired calcium transport, and fatty acid metabolism [101]. A classic example of the myocardial effect of hyperglycemia is diabetic cardiomyopathy.

Diabetic cardiomyopathy describes impaired cardiac function as a result of decreased glucose metabolism and increased fatty acid (FA) metabolism [102]. It also includes myocardial structural and performance anomalies in people with diabetes not diagnosed with coronary artery disease, valvular disease, or other CV risk factors such as hypertension and dyslipidemia [103]. Irregularities that are usually seen in diabetes, such as hyperglycemia, hyperinsulinemia, systemic insulin resistance, and inflammation, are the factors that directly lead to the development of cardiomyopathy in people with diabetes (CMiPD) [103]. Regardless of LVEF or HF etiology, insulin therapy may be linked with higher mortality compared to oral hypoglycemic agents [104].

Insulin therapy in type 1 diabetes improves hyperglycemia and increases myocardial ischemia and death of cardiomyocytes, thereby inducing HF. There is evidence of a direct relationship between myocardial tissue perfusion, oxygen supply, energy substrate availability, and myocardial function in patients with DM, suggesting microcirculatory damage as a cause of diabetic cardiomyopathy [105]. Thus, the prevalence of CMiPD is increasing at the same rate as T2D [103].

As CMiPD advances from the first stage through the last, muscle contraction is impaired and fibrosis develops [102]. Stage I is characterized by abnormal myocardial relaxation, however normal EF [102]. During stage IV, HF is developed due to overt ischemia and infarct [102]. Hyperglycemia, hyperinsulinemia, inflammation, and hyperlipidemia due to diabetes can lead to cardiac dysfunction along with changes in the structure of the heart [106]. In the case of CMiPD, insulin resistance causes glucose metabolism in the cardiac myocyte to be altered; more specifically, glucose uptake, glycolytic activity, and oxidation of pyruvates are decreased [102]. In CMiPD while glucose is available in small amounts, there is an accumulation of circulating FAs that act as an energy source for the cardiomyocytes [102]. As a result of overactive FA oxidation and metabolic inflexibility, the heart is exposed to a variety of secondary pathways making it less capable of dealing with increased workloads [102].

An increase in free FA and hyperglycemia leads to an undesirable accumulation of lipids in the heart. Cardiomyocytes are not adapted to the accumulation of large amounts of lipids that have a direct cytopathic effect on them, and lipid fragments lead to the activation of inflammatory signaling pathways, including protein kinase C, which interfere with insulin signaling. As a result, insulin resistance develops, which limits the consumption of glucose by cells and a shift happens toward fatty acid oxidation [107].

Particularly, as FA-rich cardiomyocytes produce ATP less effectively and accumulate diverse toxic intermediates and lipids, pro-inflammatory and profibrotic responses are induced [102]. These processes ultimately lead to CMiPD through cardiac hypertrophy and diastolic dysfunction [102].

The accumulation of end products is the driving force behind microvascular damage in DM and is associated with myocardial stiffness and collagen accumulation in the myocardium. The gradual increase in myocardial stiffness also leads to diastolic dysfunction, decreased myocardial tension, and atrial dilatation, which is associated with an increased prevalence of atrial fibrillation in patients with DM [108].

Mitochondrial dysfunction can also lead to CMiPD development. This happens because of excessive mitophagy causing an imbalance between mitophagy and mitochondrial biogenesis. As a result, myocardial cells are destructed more intensively [109].

It has been established that ketone metabolism can be an alternative to the energy supply of the heart muscle [110]. The concentrations of circulating ketone bodies increase in HF and they enter the cell as an insulin-independent energy substrate. The appearance of ketone enzymes in a hypertrophied and damaged heart leads to energy consumption for the oxidation of ketones with insufficient possibilities for oxidation of fatty acids [111]. The presence of DM contributes to the development of myocardial dysfunction and CHF due to the development and maintenance of endothelial dysfunction, dyslipidemia, hypercoagulation, and the direct effect of hyperglycemia on myocardial function and morphology [112]. At the same time, in HF, as a result of organ hypoperfusion and hyperactivation of neurohumoral systems (decrease in glucose consumption by muscle tissue, increased gluconeogenesis in the liver, contra-insular effects of catecholaminemia), blood glucose levels increase.

Thus, the development of HF in DM is due to the progression of atherosclerosis with subsequent progression of myocardial ischemia and immediate myocardial damage as a result of prolonged hyperglycemia. Myocardial damage against the background of hyperglycemia is mediated by microangiopathy, impaired calcium transport, and fatty acid metabolism. The presence of DM increases the risk of developing HF compared with that in the general population, and there is a significantly higher mortality among DM patients with HF. In addition, an increased risk of developing HF was found in individuals with elevated values of morning glycemia even in the absence of DM. Patients with HF have high insulin resistance and an increased risk of developing DM [113].

6. Screening and diagnosing HF in people with diabetes

6.1 Electrocardiography (ECG)

According to the 2021 ESC guidelines’ recommendations, when patients’ symptoms signal the presence of acute or chronic HF, ECG is one of the measures used to evaluate their condition [91]. If acute HF is detected, it is recommended to produce an ECG when patients are admitted to the hospital, during their stay, and before they are discharged [91]. Performing electrocardiography is mainly a step toward HF detection, such as changes in the ECG show higher chances of HF in patients and vice versa: HF is not plausible when ECG is normal [91]. Moreover, by looking at the ECG, it is possible to learn about the causes of HF and how to proceed with future treatment [91]. Based on the 2019 ESC-EASD recommendations, ECG is also proposed for “patients with diabetes who have been diagnosed with hypertension” [114].

6.2 Echocardiography

A cardiac injury manifests itself as structural changes and echocardiography is the most effective and non-invasive measure to detect those changes [115], assessing systolic and diastolic dysfunction [116]. Echocardiography is recommended by the 2021 ESC guidelines [91] and the 2019 ESC-EASD recommendations as the first-choice tool for structural and functional evaluation of the heart of diabetic people since it can detect higher LV mass (LVM) and/or diastolic dysfunction when no symptoms of HF are present [114]. It is widely known that LVM is directly proportional with common risk factors for T2D such as age, obesity, and dyslipidemia [117], but it also relies on gender and body size [118]. It is worth mentioning that, LV hypertrophy is a common anomaly seen in asymptomatic T2D patients, such that even after omitting silent coronary disease, it was observed in one-third of individuals without hypertension [119]. Indexed LVM/bovine serum albumin (BSA) enables for the establishment of reference values for comparing subjects of various body sizes [118]. The American Society of Endocrinology defines normal LVM/BSA levels as 43–95 g/m² for women and 49–115 g/m² for men [118].

6.3 Assessment of biomarkers

The 2021 ESC guidelines [91] and the 2022 AHA/ACC/HFSA updated guidelines [120] recommend natriuretic peptide biomarker screening (either NT-proBNP or BNP) to identify diabetic patients with pre-HF. The 2022 AHA/ACC/HFSA guidelines also recommend routine assessment of circulating biomarkers in general for supporting a diagnosis or exclusion of HF, risk stratification, and prognosis of patients with diabetes [120]. Since HF stages are defined by increased natriuretic peptide levels by the universal definition [90], routine screening of NT-proBNP or BNP is recommended in patients without current or prior HF symptoms or signs. The cut-off levels for BNP and NT-proBNP as settled by the universal definition were as following: 35 pg/mL and 125 pg/mL for ambulatory HF patients and 100 pg/mL and 300 pg/mL for hospitalized/decompensated HF patients, respectively [90]. Nevertheless, natriuretic peptide levels are not sufficient to diagnose HF since CV and non-CV factors diminish explanatory values of those levels under conditions such as AF, increasing age, obesity, and kidney disease [91]. In order to contribute to the informative diagnostic utility of natriuretic peptides, other new biomarkers, such as independent biomarkers for myocardial fibrosis or risk stratification in HF (secreted Frizzled-related proteins) or gut microbiota-derived trimethylamine N-oxide (TMAO), are required [121, 122, 123, 124].

6.4 Assessment of glycemic parameters in HF patients

When dysglycemia in patients with HFrEF remains undiagnosed, it is hard to determine a solid prognosis [125]. As a solution, the 2019 ESC-EASD guidelines advise testing HbA1c and FPG levels for detecting diabetes in patients previously diagnosed with CVD [114]. Furthermore, if the aforementioned tests do not yield a concrete result, it is recommended to perform OGTT [114]. The 2021 ESC guidelines recommend to consistently check fasting glucose and HbA1c levels if chronic HF is suspected, to find its treatable causes and related comorbidities [91].

6.5 Strategies in people with diabetes to reduce the risk of HF

The 2019 ESC-EASD guidelines recommend regular microalbuminuria and eGFR screening to identify patients at high risk of renal dysfunction or future CVD. On the other hand, the Standards of Care 2021 from the ADA [126], and the 2019 ESC-EASD guidelines [114] recommend a BP target of <130/80 mmHg (but not <120 mmHg). Moreover, even though the 2021 ESC guidelines [91] do not recommend a target, the 2022 AHA/ACC/HFSA guidelines [120] do recommend a more stringent target of systolic BP of <120 mmHg in individuals with diabetes at CV risk since hypertension control is associated with a lower HF risk. It is worth noting that masked hypertension (meaning only home, but not office BP levels are hypertensive) [127] is common in T2D patients [128], making out-of-office BP monitoring a viable screening method for this clinical condition [129, 130]. Diabetic and hypertensive patients should have their ECGs checked at rest to identify silent MI, which happens in 4% of diabetic patients and adds an insult to HF [114]. Additionally, for pre-diabetics and hypertensive patients with diabetes, lifestyle adjustments and the use of RAAS blockers as first-line therapy for BP management are advised [114]. RAAS blockers also diminish the incidence of new-onset diabetes and the risk of sudden cardiac death in HFrEF patients [114]. Aside from hypertension, a higher body mass index is thought to be a risk factor for HF, which is why the ESC recommendations for 2021 [91] propose that obesity should be controlled to avoid or delay the onset of HF.

7. Therapeutic considerations of HF in diabetes

Pharmacotherapy is the cornerstone of HFrEF treatment and should be used in conjunction with non-pharmacological therapies before device therapy is considered [130].

Treatment for patients with HFrEF has three key goals: reduction in mortality, avoiding recurrent hospitalizations due to worsening HF, and improving clinical status, functional capacity, and quality of life [130].

Patients with and without diabetes receive similar treatment for HF. On the other hand, anti-diabetic drugs have different effects in patients with HF, and treatments that are both safe and minimize HF-related events should be prioritized [130].

The 2021 ESC guidelines [91] and 2022 ACC/AHA/HFSA guidelines [120] recommend treatment of HFrEF and HFmrEF with a combination therapy of angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers (ACE-I/ARB), angiotensin-receptor-neprilysin-inhibitors (ARNI), beta-blockers, mineralocorticoid-receptor antagonists (MRA), and SGLT2i. Since there is currently no therapy for HFpEF subjects [91, 131], HFpEF therapy targets only symptom and well-being improvement [91, 94] and treatment of comorbidities [91]. The recently reported EMPEROR-preserved study provides the first proof of improved outcomes in HFpEF individuals [132].

The 2021 ESC guidelines [91] also recommend that patients with improved LVEF should continue to receive HFrEF treatment [91]. On the other hand, the 2021 ESC guidelines recommend to use ICDs in selected patients with HFrEF of an ischemic etiology and to consider using in those with a non-ischemic etiology [91]. Moreover, CRT-P/D is recommended in those patients with HFrEF, in sinus rhythm, with an LBBB ≥150 ms and should be considered in those with an LBBB ≥130–149 ms or non-LBBB ≥150 ms [91]. Advanced HF strategies, such as heart transplantation or MCS may be appropriate in selected patients [91].

ACE-I and ARB: The effect of the ACE-I enalapril was demonstrated in the SOLVD trial. It was shown that compared to placebo, enalapril diminished the incidence of diabetes in subjects with HF [133]. The 2019 ESC-EASD recommendations suggest blood pressure control with ACE-I or an ARB as a measure to lessen the HF risk in diabetes, especially in conditions such as microalbuminuria, albuminuria, proteinuria, or LV hypertrophy [99].

The expediency of using ACE inhibitors in patients with insulin resistance is explained by the activation of the RAAS against the background of hyperinsulinemia and hyperglycemia, as well as by common molecular signal transduction pathways used by the insulin and renin-angiotensin systems. When treating diabetic patients with ACE inhibitors or ARBs, continuous monitoring of potassium levels and renal function is necessary to prevent the development of nephropathy [134].

ARNI: In the PARADIGM-HF trial, it was observed that in comparison with enalapril, sacubitril/valsartan is able to substantially reduce the death and hospitalization risk of HF (HHF) in people with HFrEF, demonstrating its blood pressure lowering effect in the long term [135]. However, in people with HFpEF, this trial showed that sacubitril/valsartan was not effective at reducing the total CV death and HHF rate compared to valsartan alone (regardless of diabetes history in HFpEF patients) [136]. Moreover, the positive impact of sacubitril-valsartan in reducing the risk of HHF was comparable among all PARADIGM-HF trial patients with HFrEF and an HbA1c of 5.4–8.4% [19]. Furthermore, sacubitril-valsartan outperforms enalapril in decreasing HbA1c levels and lowering the rate of insulin treatment initiation in individuals with both diabetes and HFrEF over 3 years [137]. Sacubitril-valsartan is thus expected to enhance glycemic control in these individuals [137].

A significant reduction in NT-proBNP levels was observed in the HFpEF group of the PARADIGM-HF trial [138], demonstrating that sacubitril-valsartan therapy reduces risk. This effect occurred regardless of gender, as sacubitril-valsartan equally reduced NT-proBNP levels in men and women in the PARAGON-HF cohort with HFpEF where 50% of subjects were diabetics [139].

There were a few observed side effects of sacubitril-valsartan therapy in the PARADIGM-HF [135] and the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF trial) [136] such as increased prevalence of symptomatic hypertension and angioedema, but this was still lower than with dual inhibition of both ACE and neprilysin, especially in angioedema [135]. In light of these data, the 2019 ESC-EASD Guidelines on diabetes recommend that HF patients with diabetes who remain symptomatic should be treated with sacubitril-valsartan instead of an ACE inhibitor [114].

Beta-blockers: Beta-blockers have been shown to reduce mortality and morbidity in patients with HFrEF, when used together with ACE-I and diuretics [91]. As soon as symptomatic HFrEF is diagnosed, ACE-I and beta-blockers can be started together, according to consensus. However, no evidence proves that starting a beta-blocker before an ACE-I or vice versa is beneficial. Beta-blockers should be given to clinically stable euvolemic patients at low doses and slowly uptitrated to the maximum tolerated dose. Moreover, when patients are admitted with AHF in the hospital, beta-blockers should be given cautiously only after they are hemodynamically stabilized [91].

There is no particular beta-blockade experiment in HFmrEF. The SENIORS trial, in which nebivolol lowered the composite main endpoint of all-cause mortality or CV hospital admissions in the total population, was included in an IPD meta-analysis. There was no interaction between LVEF (35–50% of patients had an LVEF of 35–50%) and the impact of nebivolol on the main outcome. Many patients with HFmrEF may also have another CV reason for a beta-blocker, such as AF or angina. As a result, beta-blocker therapy may be explored in individuals with HFmrEF [91].

MRA: Assessment of MRA therapy efficacy revealed that compared to non-MRA treatment, it improved the clinical outcome of diabetic patients with HF [140]. To be exact, spironolactone or eplerenone was effective at diminishing CV and all-cause mortality and HHF [140]. A non-steroidal MRA finerenone, on the other hand, was able to reduce the incidence of death from any cause, CV-related hospitalization or emergency in subjects with HFrEF, CKD, and/or diabetes when compared to eplerenone MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF trial) [141].

Adverse events in the ARTS-HF and other MRA trials included in the aforementioned meta-analysis revealed that MRA treatment increases the risk of hyperkalemia [140, 141].

Also, it has been shown that finerenone at doses of 10–20 mg/day may cause hyperkalemia less frequently [142]. The drugs of this group can cause hyperkalemia and deterioration of renal function, especially in the elderly, patients with diabetic and non-diabetic nephropathy, renal failure; therefore, it is recommended to use them only in patients with adequate renal function, while regular monitoring of plasma electrolytes and renal function is mandatory.

Generally, the 2019 ESC-EASD recommendations [114] indicate that diabetic people with HFrEF should be treated with MRAs if their symptoms persist despite therapy with ACE-I or beta-blockers. In these patients, MRAs and sacubitril-valsartan are indicated to minimize the risk of sudden cardiac death [114].

There is no MRA-specific study in HFmrEF. In a retrospective analysis of the TOPCAT trial, spironolactone reduced hospitalizations for HF in patients with an LVEF of ≥45%, but it increased hospitalizations for HF in those with an LVEF of ≥55%. A comparable trend was observed in CV mortality but not in all-cause mortality [91]. Treatment with an MRA may be considered in patients with HFmrEF [91].

SGLT2 inhibitors: Numerous clinical trials have demonstrated the therapeutic impact of SGLT2 inhibitors on CV outcomes in people with T2D and established HF, demonstrating a cardio-protective effect independent of glycemic status [143].

Inhibition of SGLT2 increases the concentration of circulating ketone bodies, and it can become an alternative source of energy for the diabetic heart with insulin resistance. In addition, other potential mechanisms of action of the drug are possible, such as weight loss of the body, BP, sodium levels, oxidative stress, and sympathetic activation [144]. One evidence comes from the DAPA-HF trial demonstrating that dapagliflozin lowered the risk of progressing HF (HHF) and CV-related death in HFrEF people (NYHA class II–IV) independent of the glycemic status [145] and gender [146]. In addition, The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR)-preserved trial provided the first evidence of a cardio-protective effect of empagliflozin on the combined risk of HHF and CV death in subjects with HFpEF, an effect that is independent of the presence of diabetes [132]. In other studies, for empagliflozin, a lowered risk of CV death and HHF was also shown in the EMPA-REG OUTCOME trial in people with T2D and a history of CVD [59] and in the EMPEROR-Reduced trial in people with HFrEF regardless of the presence of diabetes [147].

One piece of evidence comes from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study, which found that dapagliflozin reduced the risk of progressive HF (HHF) and CV-related death in patients with HFrEF (NYHA class II–IV) regardless of glycemic status [145] or gender [146]. Furthermore, the EMPEROR-preserved study showed the first indication of empagliflozin’s cardioprotective benefit on the combined risk of HHF and CV death in people with HFpEF, a result that is independent of diabetes [132]. In additional trials, empagliflozin was associated with a decreased risk of CV mortality and HHF in the EMPA-REG OUTCOME trial in patients with T2D and a history of CVD [59] and in the EMPEROR-Reduced trial in people with HFrEF regardless of diabetes.

Reducing the risk of CVD in empagliflozin includes combined decrease in blood pressure, body weight (including visceral obesity), albuminuria, glucose levels, stiffness of the arterial wall, activation of the sympathetic part of the autonomic nervous system, oxidative stress, uric acid concentration, and improvement function of the heart [148]. Empagliflozin is able to improve myocardial microvascular perfusion, eNOS activity, and endothelium-dependent relaxation. Empagliflozin may be beneficial by inhibiting induced DM mitochondrial fission dependent on 5’AMP-activated protein kinase (AMPK) way. On the one hand, the action induced by this drug can slow down the aging of endothelial cells by suppressing oxidative stress, which leads to an improvement in their viability and barrier function. On the other hand, empagliflozin-induced migration endothelium as a result of F-actin homeostasis can contribute to angiogenesis [59, 149]. As DM progresses endothelial damage is detected at an early stage. Through these mechanisms, empagliflozin improves myocardial blood supply. Considerable evidence suggests the ability of empagliflozin to reduce systolic blood pressure by facilitating osmotic diuresis, influencing the microvascular diastolic response by stimulation of eNOS phosphorylation, vascular remodeling, reduction of inflammatory proteins, and decrease in collagen synthesis [150]. This drug is promising for the treatment of patients with diabetes and microvascular dysfunction of the heart; this drug can be considered as a drug for protecting the microvascular bed of the heart to maintain its functions and circulatory structures in hyperglycemia [151].

In the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV trial), ertugliflozin was non-inferior to placebo in terms of its important secondary outcome of CV mortality or HHF in participants with T2D and atherosclerotic CVD, but the trial findings did not fulfill the superiority requirements (HR = 0.88, 95% CI 0.75–1.03) [61, 149]. However, there was a 30% reduction in the risk of HHF alone, which was similar to the effects of the other SGLT2 inhibitors on this outcome [149, 152]. A pre-specified analysis in VERTIS CV revealed that the subgroups of patients with the largest decrease in HF-related events had an eGFR of <60 mL/min/1.73 m² and albuminuria [62]. Furthermore, another evidence from the SOLOIST-WHF trial shows that simultaneous inhibition of both SGLT1 and SGLT2 in people with T2D may reduce CV fatalities, hospitalizations, and urgent visits for either HFpEF or HFrEF [153]. When started before or shortly after discharge, sotagliflozin avoided CV death, HHF, and urgent HF visits in patients with T2D and recent worsening HF compared to placebo.

SGLT2 inhibitors are cardio-protective in patients with T2D and established CVD, also in people who are at high risk of CV events. The CANVAS study demonstrated that canagliflozin lowered the risk of CV-related events in people with T2D and increased CV risk more effectively than placebo [60]. Furthermore, the DECLARE-TIMI 58 study found that use of dapagliflozin reduces HHF and CV-related death in people with T2D who had or are at risk of atherosclerotic CVD [57].

NT-proBNPs have a predictive value for CV events and death in clinical outcome studies. The decreased NT-proBNP concentration in the canagliflozin arm of the CANVAS trial can be ascribed in part to the reduction in CV-related events in patients with T2D and CV risk [154]. In addition, a sub-analysis of the CANDLE study found a tendency toward decreased NT-proBNP levels in the subgroup with lower LV diastolic function in the canagliflozin treated arm compared to the glimepiride treated arm [155]. Dapagliflozin, like canagliflozin, reduced NT-proBNP levels considerably higher than placebo in the DAPA-HF group [145, 149]. Similarly, empagliflozin significantly lowered NT-proBNP levels 7 days after randomization when delivered as add-on treatment to T2D patients hospitalized for acute decompensated HF compared to the group treated conventionally with glucose-lowering drugs [149, 156]. However, another dual SGLT1/2 inhibitor, licogliflozin, has been shown to reduce NT-proBNP in individuals with both T2D and HF when compared to placebo 12 weeks following randomization [149, 157].

Because of the class impact of SGLT2 inhibitors, the 2019 ESC-EASD guidelines on diabetes propose the SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin to reduce the risk of HHF in diabetic individuals [114]. Aside from that, the ESC guidelines for 2021 recommend ertugliflozin and sotagliflozin for patients with T2D who are at high risk of CV events to reduce HHF, major adverse CV events (MACE), end-stage renal disease, and CV death, and sotagliflozin in patients with T2D and HFrEF to reduce HHF and CV death [91]. In order to minimize HHF, MACE, and CV death, the 2019 ADA/EASD consensus suggests SGLT2 inhibitors in addition to metformin in adults with diabetes and HF (particularly HFrEF) [158].

8. Conclusion

HF is still a significant factor in life expectancy, especially among diabetic patients. HF can be viewed as both a cause and a complication of DM at the same time. Evidence strongly suggest that there is negative predictive effect of DM in the course of HF. Therapy for this category of patients should be characterized by a holistic approach, including a thorough glycemic control, as well as an effective blockade of neurohumoral changes. New pharmacological options, such as SGLT2 inhibitors, are allowing for better control of this life-threatening T2D condition. Biomarkers like NT-proBNP can help identify HF early and predict prognosis and therapeutic efficacy of HF or/and diabetes treatment. As a result, NT-proBNP testing should be used early in the monitoring of subjects with diabetes with a high CV risk.

Acronyms and abbreviations

AAEDTE

Azerbaijan Association of Endocrinology, Diabetology and Therapeutic Education

ACC

American College of Cardiology

ACCF

The American College of Cardiology Foundation

ACE-I

angiotensin-converting-enzyme inhibitors

ADA

American Diabetes Association

AF

atrial fibrillation

AHA

American Heart Association

AHF

acute heart failure

AMPK

5′AMP-activated protein kinase

ARB

angiotensin II receptor blockers

ARNI

angiotensin-receptor-neprilysin-inhibitors

ATP

adenosine triphosphate

BNP

brain natriuretic peptide

BP

blood pressure

BSA

bovine serum albumin

CKD

chronic kidney disease

CMiPD

cardiomyopathy in people with diabetes

CRT-P/D

cardiac resynchronization therapy with pacemaker/defibrillator

CVD

cardiovascular disease

DM

diabetes mellitus

DPP4

dipeptidyl peptidase 4 inhibitors

EASD

European Association for the Study of Diabetes

ECG

electrocardiography

eGFR

estimated glomerular filtration rate

eNOS

endothelial nitric oxide synthase

ESC

European Society of Cardiology

FA

fatty acid

FG

fasting glucose

FPG

fasting plasma glucose

GLP-1

glucagon-like peptide 1 receptor agonist

HbA1c

glycohemoglobin

HF

heart failure

HFmrEF

heart failure with mildly reduced ejection fraction

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

HFSA

Heart Failure Society of America

HHF

hospitalization for HF

HR

hazard ratio

ICD

implantable cardioverter defibrillator

IDF

International Diabetes Federation

IGM

impaired glucose metabolism

IGT

impaired glucose tolerance

IPD

individual patient data

LBBB

left bundle branch block

LVEF

left ventricular ejection fraction

LVM

left ventricle mass

MACE

major adverse cardiovascular events

MCS

mechanical circulatory support

MI

myocardial infarction

MRA

mineralocorticoid-receptor antagonists

NGM

normal glucose metabolism

NT-proBNP

N-terminal pro-b-type natriuretic peptide

NYHA

New York Heart Association

OGTT

oral glucose tolerance test

PD

prediabetes

RAAS

renin-angiotensin-aldosterone system

SGLT1

sodium-glucose cotransporter 1

SGLT2

sodium-glucose cotransporter 2

SGLT2i

sodium glucose co-transporter 2 inhibitors

T2D

type 2 diabetes

TMAO

trimethylamine N-oxide