**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 [23–25]. 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 [40–42].

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.

#### *Diabetes Mellitus Type 2, Prediabetes, and Chronic Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.106391*

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 glucoselowering medication proved itself as an effective tool in blood glucose and weight management [44–46]. 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 nonfatal 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 OUT-COME), 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 [73–79], 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 [73–79].

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 [82–85]. 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].


*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.*

#### **Table 1.**

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

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].
