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Cardiovascular Complications Related to Lower Limb Revascularization and Drug-Delivering…
DOI: http://dx.doi.org/10.5772/.107973
[81]
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Teichgräber U,Ingwersen M,
Platzer S, Lehmann T,Zeller T,
Aschenbach R, etal. Head-to-head
comparison of sirolimus- versus
paclitaxel-coated balloon angioplasty
in the femoropopliteal artery: Study
protocol for the randomized controlled
SIRONA trial. Trials. 2021;:665
[82]
Gray WA, Jaff MR, Parikh SA,
Ansel GM, Brodmann M, Krishnan P,
etal. Mortality assessment of paclitaxelcoated balloons: Patient-level metaanalysis of the ILLUMENATE clinical
program at 3 years. Circulation.
2019;:1145-1155
[83]
Schahab N, Prengel A-K, Mahn T,
Schaefer C, Fimmers R, Nickenig G,
etal. Long-term clinical outcome and
mortality risks after paclitaxel-coated
balloon angioplasty in patients
with peripheral artery disease: An
observational clinical study. Health
Science Reports. 2021;:e236-e236
[84]
Schneider PA, Laird JR, Doros G,
, Ansel G, Brodmann M, etal.
Gao Q
Mortality not correlated with paclitaxel
exposure: An independent patient-level
Meta-analysis of a drug-coated balloon.
Journal of the American College of
Cardiology. 2019;:2550-2563
[85]
Zeller T, Micari A, Scheinert D,
Baumgartner I, Bosiers M, Vermassen
Frank EG, etal. The IN.PACT DEEP
clinical drug-coated balloon trial.
JACC. Cardiovascular Interventions.
2020;:431-443
[86]
Schneider PA, Brodmann M,
Mauri L, Laird J, Soga Y, Micari A, etal.
Paclitaxel exposure: Long-term safety
and effectiveness of a drug-coated
balloon for claudication in pooled
randomized trials. Catheterization
and Cardiovascular Interventions.
2020;:1087-1099
Chapter 9
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Diabetes Mellitus Type 2,
Prediabetes, and Chronic Heart
Failure
Valeh Mirzazada, Sadagat Sultanova, Natavan Ismayilova,
Aygun Huseynova, Gulnara Nurmammadova,
Sevil Ismayilova and Aygun Aliyeva
Abstract
Impaired glucose metabolism and its consequence diabetes mellitus is
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.
Keywords: diabetes mellitus type 2, prediabetes, chronic heart failure, diabetes risk
factors, diabetes management
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 pl asma glucose
after 75 g oral glucose load (oral glucose tolerance test-OGTT) level of ≥11.1 mmol/l.
still
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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].
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Glycemic control is assessed by HbA1c level measurement, continuous glucose moni-
toring
(CGM) using either time in range and/or blood glucose monitoring. In a clinical
scenario
performed
Measurement
have
patients
erythropoietin
conducted
mined
mic
CVD
established
obscurity
HbA1c measurement is used more often. The HbA1c measurement should be
in
all diabetes patients at initial assessment and once in every 3 months.
of
HbA1c every 3 months determines whether patients’ glycemic targets
been achieved and maintained. The HbA1c checking may have limitations in
with medical conditions that can affect red blood cell turnover (hemodialysis,
therapy, etc.). In such cases plasma blood glucose measurements are
by
using BGM by fingerstick and CGM. Glycemic targets should be deter-
individually in each diabetes patient. There is evidence that more intensive glyce-
control in newly diagnosed diabetes patients can be beneficial in reducing long-term
[14]. However, available data show that strict glycemic control in patients with
DM
does not eliminate the risk of developing HF [15]. Overall, there is
on
choosing glycemic targets in diabetes mellitus with HF.
Prognosis in patients with HF and DM having DM led to worse outcomes in
comparison
demonstrated
fraction
[9,
16–22].
with those who did not have DM among patients with HF. This was also
by
randomized trial data in patients with HF with reduced ejection
(HFrEF; LVEF ≤40%) or HF with preserved ejection fraction (HFpEF)
A study of data from the Candesartan in Heart Failure-Assessment of Reduction in
Mortality
that
death
≤40%
and morbidity (CHARM) program on outcomes in patients with HF found
concurrent DM was associated with a greater increased risk of cardiovascular
or HF
hospitalization in patients with LVEF >40% than in patients with LVEF
[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
HFrEF,
cardiovascular
and Morbidity in Heart Failure (PARADIGM-HF) trial with patients with
there was an increased risk of the primary outcome of HF hospitalization or
mortality in patients with previously undiagnosed DM or known DM [19].
It has been shown that, there is disturbingly high prevalence, incidence, and
mortality
poor
for HF in individuals with diabetes [12]. DM patients who developed HF had
prognosis.
It has been shown that, there is disturbingly high prevalence, incidence, and
mortality
oped
for heart failure in individuals with diabetes [12]. DM patients who devel-
HF
had poor prognosis.
3. Management
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
efficacy
be
tions,
nosed
of glycemic efficacy, absence of weight gain and hypoglycemia, general tolerability,
and
appears
3
include individualized treatment goals and preferences. The glucose-lowering
of
individual drugs, their adverse effect profile, tolerability, and cost should
considered individually for each patient. In the absence of specific contraindica-
metformin should be suggested as initial therapy for patients with newly diag-
T2D who are asymptomatic. Metformin is the preferred initial therapy because
favorable cost. Metformin does not have adverse cardiovascular effects, and it
to
decrease cardiovascular events [23–25]. The cost of metformin is more
of DM
type in patients with HF
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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.
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GLP-1 have a reliable safety and tolerability profile in the management of the T2D
As it
[43].
lowering
management
tion.
levels
and
systolic
atherosclerotic
and/or
rate
HF
on
patients with T2D.
in
has been shown in numerous studies and trials, this class of glucose-
medication proved itself as an effective tool in blood glucose and weight
[44–46]. The class effect is based on glucose-dependent insulin secre-
They also delay gastric emptying and increase satiety [47]. GLP-1 improve lipid
with decreased triglyceride levels and increase high-density lipoprotein levels
provide low risk of hypoglycemia [9]. They significantly reduce HbA1c levels and
BP
[48]. GLP-1 usage is proved to be beneficial in T2D and established
CVD and is recommended as part of the cardiovascular risk reduction
glucose-lowering medication [49]. Semaglutide demonstrated decrease in the
of
cardiovascular death, MI, and stroke by 26% [50]. Overall GLP-1 have no effect
hospitalization [9] and are not recommended for the prevention of HF events
Dipeptidyl peptidase-4 inhibitors (DPP4) are oral glucose-lowering medications
inhibit native enzyme dipeptidyl peptidase [51]. This enzyme is expressed on the
that
surface
DPP4
commonly
saxagliptin.
hospitalization
showed
left
vascular
of
the most cell types that affects native gastrointestinal peptides and GLP-1.
inhibit the degradation of native GLP1 and enhance the incretin effect [52]. The
used DPP4 are sitagliptin, vildagliptin, linagliptin, alogliptin, and
It
should be noted that, saxagliptin demonstrated the increased risk of
in
patients with DM and HF [53]. Sitagliptin, linagliptin, and alogliptin
no
effect on HF events. However, in another trial vildagliptin increased the
ventricular volumes [54]. Overall, DPP4 are not recommended to reduce cardio-
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
them
canagliflozin,
of
[57,
empagliflozin
come
primary
fatal
strated
DECLARE-TIMI
significant
did
cardiovascular
Cardiovascular
COME),
Effect
Events
trial
[49,
blood glucose levels without stimulation of insulin secretion which makes
very useful in patients with a long duration of diabetes [56]. SGLT2i include
dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. The usage
dapagliflozin and canagliflozin has been associated with reduced incidence of HF
58]. Those T2D patients with a high risk of cardiovascular events who received
demonstrated reduction of the primary composite cardiovascular out-
and of death from any cause [59]. Empagliflozin and canagliflozin reduced the
composite endpoint of major CV adverse events, including CV death or non-
MI or
non-fatal stroke, and HF hospitalizations [59, 60]. Dapagliflozin demon-
a
lower rate of cardiovascular death or hospitalization for HF in T2D in the
58
trial [57]. The other SGLT2i, ertugliflozin, showed statistically
reduction in HF hospitalization and repeated hospitalizations, although it
not reduce the primary major CV event endpoint and key secondary outcome of
death or HF hospitalization [61, 62]. Meta-analysis of Empagliflozin,
Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUT-
Canagliflozin Cardiovascular Assessment Study (CANVAS), Dapagliflozin
on
CardiovasculAR Events (DECLARE-TIMI 58), and Canagliflozin and Renal
in
Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE)
demonstrated the significant reduction in HF and cardiovascular hospitalization
55].
Therefore, it is recommended to use SGLT2i as first-line therapy in diabetes as well
add on to patients with T2D with or at high risk of HF or chronic kidney disease
as
(CKD)
empagliflozin,
CV
and ASCVD [49]. Additionally, the SGLT2i canagliflozin, dapagliflozin,
ertugliflozin, and sotagliflozin are recommended to prevent HF and
death and worsening kidney function in patients with T2D and CV disease and/or
5
Novel Pathogenesis and Treatments for Cardiovascular Disease
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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 ca n 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 mon itored 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].
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DOI:
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.
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100ADA –125 (mg/dl)
5.6–6.9 (mmol/l)
110WHO/IDF –125 (mg/dl)
6.1–6.9 (mmol/l)
110Canada/UK/Australia –125 (mg/dl)
6.1–6.9 (mmol/l)
110AAEDTE –125 (mg/dl)
6.1–6.9 (mmol/l)
Diagnostic criteriaSource of recommendations
140–199 (mg/dl)
7.8–11.0 (mmol/l)
140–199 (mg/dl)
7.8–11.0 (mmol/l)
140–199 (mg/dl)
7.8–11.0 (mmol/l)
140–199 (mg/dl)
7.8–11.0 (mmol/l)
HbA1cOGTTFG
5.7–6.4 (%)
39–47 (mmol/mol)
Not recommended
6.0–6.4 (%)
42–47 (mmol/mol)
5.7–6.4 (%)
39–47 (mmol/mol)
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
7
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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
8
Diabetes
180
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DOI:
Mellitus Type 2, Prediabetes, and Chronic Heart Failure
http://dx.doi.org/10.5772/.106391
gluconeogenesis
HF in
Also,
result
of
prolonged hyperglycemia. Myocardial damage against the background of
hyperglycemia
metabolism [101]. A classic example of the myocardial effect of hyperglycemia is
acid
diabetic
cardiomyopathy.
in
the liver, and the contra-insular effect of catecholaminemia [100].
patients with DM is considered direct damage to the heart muscle as a
is
mediated by microangiopathy, impaired calcium transport, and fatty
Diabetic cardiomyopathy describes impaired cardiac function as a result of
decreased
includes
diagnosed
as
hypertension and dyslipidemia [103]. Irregularities that are usually seen in diabetes,
inflammation,
in
people with diabetes (CMiPD) [103]. Regardless of LVEF or HF etiology, insulin
therapy
agents
glucose metabolism and increased fatty acid (FA) metabolism [102]. It also
myocardial structural and performance anomalies in people with diabetes not
with coronary artery disease, valvular disease, or other CV risk factors such
such as hyperglycemia, hyperinsulinemia, systemic insulin resistance, and
are the factors that directly lead to the development of cardiomyopathy
may be linked with higher mortality compared to oral hypoglycemic
[104].
Insulin therapy in type 1 diabetes improves hyperglycemia and increases myocar-
ischemia and death of cardiomyocytes, thereby inducing HF. There is evidence of
dial
direct relationship between myocardial tissue perfusion, oxygen supply, energy
a
substrate
microcirculatory
prevalence
availability, and myocardial function in patients with DM, suggesting
damage as a cause of diabetic cardiomyopathy [105]. Thus, the
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
relaxation,
ischemia
hyperlipidemia
the
glucose
uptake,
while
that
oxidation
pathways
and fibrosis develops [102]. Stage I is characterized by abnormal myocardial
however normal EF [102]. During stage IV, HF is developed due to overt
and infarct [102]. Hyperglycemia, hyperinsulinemia, inflammation, and
due to diabetes can lead to cardiac dysfunction along with changes in
structure of the heart [106]. In the case of CMiPD, insulin resistance causes
metabolism in the cardiac myocyte to be altered; more specifically, glucose
glycolytic activity, and oxidation of pyruvates are decreased [102]. In CMiPD
glucose is available in small amounts, there is an accumulation of circulating FAs
act as an energy source for the cardiomyocytes [102]. As a result of overactive FA
and metabolic inflexibility, the heart is exposed to a variety of secondary
making it less capable of dealing with increased workloads [102].
An increase in free FA and hyperglycemia leads to an undesirable accumulation of
in
lipids
amounts
lead
which
limits
oxidation
the heart. Cardiomyocytes are not adapted to the accumulation of large
of
lipids that have a direct cytopathic effect on them, and lipid fragments
to
the activation of inflammatory signaling pathways, including protein kinase C,
interfere with insulin signaling. As a result, insulin resistance develops, which
the consumption of glucose by cells and a shift happens toward fatty acid
[107].
Particularly, as FA-rich cardiomyocytes produce ATP less effectively and
accumulate
responses
cardiac
diverse toxic intermediates and lipids, pro-inflammatory and profibrotic
are induced [102]. These processes ultimately lead to CMiPD through
hypertrophy and diastolic dysfunction [102].
The accumulation of end products is the driving force behind microvascular
damage
in
in DM
the myocardium. The gradual increase in myocardial stiffness also leads to diastolic
dysfunction,
an
with
increased prevalence of atrial fibrillation in patients with DM [108].
and is associated with myocardial stiffness and collagen accumulation
decreased myocardial tension, and atrial dilatation, which is associated
9
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