Blood Pressure Disorders in Diabetes Mellitus

Preface
Contents
Part I: Introduction
1: Coexistence of Diabetes Mellitus and Hypertension
1.1 Introduction
1.2 Hypertension–Diabetes Mellitus: A Bidirectional Relationship
1.2.1 Definition
1.2.2 Epidemiology
1.3 Classification of Hypertension–Diabetes-Associated Phenotypes
1.3.1 Hypertension in Diabetes Mellitus
1.3.1.1 Type 2 Diabetes Mellitus
1.3.1.2 Type 1 Diabetes Mellitus
1.3.2 Diabetes Mellitus in Hypertension
1.4 New-Onset Diabetes Mellitus and Antihypertensive Medications
1.5 Gestational Diabetes Mellitus and Pregnancy-Induced Hypertension Association
1.6 Hypertension—Diabetes Mellitus Coexistence and COVID-19 Relationship
1.7 Conclusion
References
Part II: Epidemiological Aspects
2: Blood Pressure Disorders in Diabetic Children and Adolescents
2.1 Characteristics of Blood Pressure Measurement in the Pediatric Age
2.2 Type 1 Diabetes Mellitus
2.2.1 Introduction
2.2.2 Prevalence of Hypertension and Risk Factors
2.2.3 Pathophysiology of HTN
2.3 Type 2 Diabetes Mellitus
2.3.1 Introduction
2.3.2 Prevalence of Hypertension and Risk Factors
2.3.3 Pathophysiology
2.4 Management
2.4.1 Lifestyle Approach
2.4.2 Optimal Treatment
2.4.3 Therapeutic Approach for HTN
2.5 Conclusions
References
3: Hypertension and Type 2 Diabetes
3.1 Introduction
3.2 Epidemiology of Hypertension in T2DM
3.3 Mechanisms of BP Elevation in T2DM
3.3.1 Endothelial Dysfunction
3.3.2 RAAS Overactivity
3.3.3 Sympathetic Overactivity
3.3.4 Abnormal Sodium Handling
3.3.5 Renal Dysfunction
3.3.6 Vascular Stiffness
3.3.7 Genetic Association
3.4 Characteristics of High BP in T2DM
3.4.1 Isolated Systolic Hypertension
3.4.2 High Variability
3.4.3 Non-Dipping Pattern
3.4.4 Salt Sensitivity
3.4.5 Toward Hyperkalemia
3.4.6 Resistant Hypertension
3.5 Impact of HTN on the Organ Damage in T2DM Patients
3.6 Treatment Strategies to Reduce CV Risk
3.7 BP Treatment in T2DM
3.7.1 Class of Antihypertensive Drugs
3.7.2 New GLDs, When and for Whom?
3.7.3 Intensive vs Standard Antihypertensive Treatment
3.7.4 Diabetic Nephropathy: What About Goals for Diabetic CKD
3.7.5 Use of 24-h ABPM
3.8 Future Trends
References
4: Diabetes Complicating Pregnancy and Hypertension
4.1 Introduction
4.2 Diabetes Mellitus in Pregnancy
4.3 Hypertensive Disorders of Pregnancy
4.4 Classification of Hypertension
4.5 Treatment of Hypertension in Pregnancy
4.6 Insulin Resistance and Diabetes in Pregnancy
4.7 Increased Risk for Hypertension with Gestational Diabetes
4.8 Treatment of Gestational Diabetes Decreases the Risk of Hypertension
4.9 The Role of Aspirin in Prevention of Hypertension
4.10 The Effect of Hypertensive Treatment on Diabetes
4.11 Weight Loss to Reduce Risk
4.12 Hypertensive Disorders Complicating Diabetes Worsen the Maternal Fetal Outcome
4.13 Management of Diabetic Patient with Chronic Hypertension
4.14 Management of Diabetic Patient with Preeclampsia
4.15 Conclusion
References
Part III: Screening and Diagnostic Approaches in Diabetic Hypertensive Patients
5: Office/Out-of-Office Blood Pressure Measurements
5.1 Introduction
5.2 Masked Hypertension
5.2.1 Masked Hypertension and Organ Damage
5.2.2 Masked Hypertension and Outcome
5.3 White-Coat Hypertension
5.4 24-Hour Day-Night BP Changes
5.4.1 Relationship with Organ Damage
5.4.2 Relationship with Outcome
5.4.3 Impact on Chronotherapy
5.5 Self-Measured Home Blood Pressure
5.6 Blood Pressure Variability
5.7 Blood Pressure Targets
5.8 Conclusions
References
6: Laboratory Indices/Bioimaging
6.1 Laboratory Indices
6.2 Other Circulating Biomarkers
6.3 Bioimaging
6.3.1 Electrocardiography
6.4 Imaging Techniques
6.4.1 Echocardiography
6.4.2 Cardiac Magnetic Resonance
6.4.3 Coronary Calcium Score
6.4.4 Carotid Intima-Media Thickness
6.4.5 Aortic Stiffness
6.4.6 Ankle–Brachial Index (ABI)
6.5 Conclusions
References
Part IV: Pathophysiological Mechanisms
7: Molecular Mechanisms Underlying Vascular Disease in Diabetes
7.1 Introduction
7.2 Macrovascular and Microvascular Disease in Diabetes
7.3 Pathophysiology of Vascular Disease in Diabetes
7.3.1 Insulin Resistance
7.3.2 Endothelial Dysfunction
7.3.3 Vascular Remodeling
7.4 Molecular Mechanisms of Vascular Dysfunction and Damage During Diabetes
7.4.1 Advanced Glycation End Products (AGEs) and Activation of the AGE-Receptor AGE (RAGE) System
7.4.2 Oxidative Stress and Vascular Injury in Diabetes
7.4.3 Hyperglycaemia and Vascular Signalling
7.4.4 Inflammation and Vascular Injury in Diabetes
7.5 MicroRNAs, Diabetes and Vascular Complications
7.6 Conclusions
References
8: Insulin and Blood Pressure Relationships
8.1 Observational Studies: Epidemiology
8.2 Mechanistic Studies Linking Insulin, Insulin Resistance and Blood Pressure Regulation
8.2.1 Insulin Resistance Facilitates Elevated Blood Pressure
8.2.2 Elevated Blood Pressure Facilitates Insulin Resistance
8.2.3 Factors Able to Induce Simultaneously Insulin Resistance and Elevated Blood Pressure
8.3 Intervention Studies
8.3.1 Lifestyle Intervention: Weight Loss and Physical Exercise
8.3.2 Drug Effects on Insulin and Blood Pressure
8.4 Summary
References
9: Mechanisms of Diabetic Nephropathy in Humans and Experimental Animals
9.1 Introduction
9.2 Pathology
9.3 Clinical Course
9.3.1 Normoalbuminuria
9.3.2 Microalbuminuria
9.3.3 Overt Nephropathy
9.4 Metabolic Dysregulation of Diabetic Nephropathy
9.4.1 Advanced Glycation Reactions
9.4.2 Protein Kinase C Signaling
9.4.3 Oxidative Stress
9.5 Glomerular Hemodynamics
9.6 Cellular and Molecular Mechanisms of Glomerulopathy
9.7 Tubulopathy in Diabetes
9.8 Inflammation
9.9 Conclusion
References
10: Diabetes and Sympathetic Nervous System
10.1 Introduction
10.2 Epidemiology
10.3 Prediabetes and Diabetes
10.4 Pathophysiological Mechanisms
10.5 Insulin Resistance and Sympathetic Nervous System
10.6 Adrenergic Tone and Diabetes
10.7 Drugs May Help to Reduce Adrenergic Tone?
10.8 Conclusions
References
11: Diabetes and Microcirculation
11.1 Introduction
11.2 Mechanisms of Microvascular Alterations in Diabetes
11.3 Endothelial Dysfunction
11.4 Structural Alterations
11.4.1 Small Resistance Arteries
11.4.2 Capillaries
11.5 Vascular Structural Alterations, End-Organ Damage, and Cardiovascular Events
11.6 Treatment
11.6.1 Effect of Antihypertensive Drugs
11.6.2 Effect of Antidiabetic Drugs
11.7 Conclusions
References
Part V: Target Organ Damage in Hypertensive Diabetic Patient
12: Endothelial Dysfunction and Large Artery Stiffness
12.1 Introduction
12.2 Endothelial Function and Large Artery Stiffness in Health and Disease
12.3 The Interplay Between Hypertension, Type 2 Diabetes, Endothelial Function and Large Artery Stiffness
12.3.1 Hypertension and Endothelial Dysfunction
12.3.2 Hypertension and Large Artery Stiffness
12.3.3 Type 2 Diabetes and Endothelial Dysfunction
12.3.4 Type 2 Diabetes and Large Artery Stiffness
12.4 Summary and Conclusion
References
13: The Heart in Diabetic Hypertensive Patients
13.1 Introduction
13.2 Epidemiology
13.3 Mechanisms of Myocardial Dysfunction in Type 2 Diabetes Mellitus and Hypertension
13.3.1 Type 2 Diabetes Mellitus
13.3.2 Hypertension
13.4 Coronary Artery Disease in Hypertensive Diabetic Patients
13.4.1 Pathophysiology
13.4.2 Clinical Features
13.4.3 Imaging Findings
13.4.4 Treatment
13.4.4.1 Lifestyle Modifications
13.4.4.2 Primary Prevention
13.4.4.3 Secondary Prevention
13.4.4.4 Invasive Management
13.5 Cardiomyopathy in Hypertensive Diabetic Patients
13.5.1 Pathophysiology
13.5.2 Clinical Features
13.5.3 Imaging Findings
13.5.4 Treatment
13.5.4.1 Blood Pressure Management
13.5.4.2 Diabetes Management
13.5.4.3 Heart Failure Management
13.6 Conclusions
References
14: Cerebrovascular Structural Alterations/Dysautonomic Disorders in Diabetes Mellitus
14.1 Introduction
14.2 Cerebrovascular Structural Alterations
14.2.1 Atherosclerosis and Stroke
14.2.2 Imaging Studies on Diabetes and Brain Structure
14.3 Cognitive Function
14.3.1 Type 1 Diabetes
14.3.2 Type 2 Diabetes
14.3.3 Depression
14.4 Dysautonomic Disorders
14.4.1 Definition
14.4.2 Cardiovascular Autonomic Neuropathy
14.4.3 Other Clinical Manifestations of DAN
14.4.4 Pathogenesis
14.4.5 Prevention and Treatment
14.5 Conclusions
References
15: Diabetic Nephropathy in Type 1 Diabetes Mellitus
15.1 Epidemiology
15.1.1 Prognosis of Microalbuminuria
15.1.2 Prognosis of Diabetic Nephropathy
15.2 Clinical Course and Pathophysiology
15.2.1 Normoalbuminuria
15.2.2 Microalbuminuria
15.2.3 Diabetic Nephropathy
15.3 Treatment
15.3.1 Glycemic Control
15.3.1.1 Nephropathy
15.3.2 Blood Pressure Control
15.3.2.1 Primary Prevention
15.3.2.2 Secondary Prevention
15.3.2.3 Nephropathy
15.3.3 Lipid-Lowering Therapy
15.3.4 Dietary Protein Restriction
15.3.5 New Treatment Options
References
16: Diabetic Chronic Kidney Disease in Type 2 Diabetes Mellitus (Albuminuric/Non-albuminuric)
16.1 Overview of Clinical Epidemiology
16.2 Pathophysiology, Risk Factors, and Novel Biomarkers
16.2.1 Hyperglycemia, AGEs, Asymmetric Dimethyl Arginine, and the PKC Pathway
16.2.2 Phosphofructokinase and the Hexosamine Pathway
16.2.3 Systemic Hypertension and Alterations in Renal Hemodynamics
16.2.4 Autophagy
16.2.5 Sodium Glucose Cotransporter (SGLT) and Cell Hypoxia
16.2.6 Urinary microRNAs and the Mitochondria
16.3 Novel Biomarkers of DKD
16.4 Therapeutic Advancements
16.4.1 SGLT2 Inhibitors
16.4.2 GLP-1RA and DDP-4 Inhibitors
16.4.3 Endothelin-1 Antagonists
16.4.4 Patiromer
16.4.5 Finerenone
References
17: Diabetic Retinopathy
17.1 Epidemiology
17.2 Hypertension: The Risk Factor for Retinopathy in Diabetics
17.3 Similarities and Differences in Early Retinal Phenotypes in Diabetes and Hypertension
17.3.1 The Morphological Correlations
17.3.2 The Pathophysiology
17.4 Metabolic Memory: Reversibility, Inertia, and Irreversibility of Diabetic Retinopathy and Hypertensive Retinopathy
17.5 Diabetic Choroidopathy
17.6 The Role of Endothelial Dysfunction: A Journey from the Static Fundoscopy to the Dynamic Vessel Analysis
17.7 Diabetic Retinopathy Seeing Beyond Glucose-Induced Microvascular Disease, New Imaging Technologies, and Digital Models of Care
References
Part VI: Diabetes and Benefit of Blood Pressure Lowering Treatment
18: Blood Pressure-Lowering Treatment and Macrovascular Events
18.1 Stating the Problem
18.2 BP-Lowering Treatment and Macrovascular Outcomes in DM
18.3 Macrovascular Outcomes Following BP-Lowering Treatment in Patients With or Without DM
18.4 BP Thresholds and Macrovascular Outcomes in Patients with DM
18.5 Systolic BP Targets and Macrovascular Outcomes in Patients with DM
18.6 Blood Pressure-Lowering Treatment and Renal Failure in Patients With or Without DM
18.7 BP-Lowering Treatment and Macrovascular Outcomes by Different Drug Classes in Patients With DM
18.8 BP-Lowering Independent Effects of Different Drug Classes on Major Cardiovascular Events in Patients With DM
18.9 Are the Independent BP-Lowering Effects of Various Drug Classes Different Between Patients With and Without DM?
18.10 Conclusions
References
19: Blood Pressure Lowering and Microvascular Complications of Diabetes
19.1 Introduction
19.2 Diabetic Neuropathy
19.3 Diabetic Retinopathy
19.4 Diabetic Nephropathy
19.5 Conclusion
References
20: New Antidiabetic Agents: Relevance to Cardiovascular Outcomes
20.1 Sodium Glucose Cotransporter Type 2 (SGLT2) Inhibitors
20.1.1 Physiology of SGLT2 and Its Pharmacological Inhibition
20.1.2 Effects of SGLT2 Inhibitors on CV Outcomes
20.1.3 Effects of SGLT2 Inhibitors on Renal Outcomes
20.1.4 Mechanisms of Cardiorenal Protection of SGLT2 Inhibitors
20.2 Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs)
20.2.1 Physiology of GLP-1 and Pharmacological Activation of GLP-1 Receptors
20.2.2 Characteristics of Available GLP-1RAs
20.2.3 Effects of GLP-1 RAs on CV Outcomes
20.2.4 Effects of GLP-1 RAs on Renal Outcomes
20.2.5 Potential Mechanisms of CV Protection
References
21: Advances on Long-Term Antihypertensive Treatment and Diabetes
21.1 Establishing Personalized Goals in the Treatment of Hypertension
21.1.1 Building Antihypertensive Therapies with Single-Pill Combinations (SPC) for People with Diabetes
21.1.2 Moving Toward the Use of Low-Dose SPC for Lowering Blood Pressure
21.1.3 Management of Multiple Risk Factors and Potential for Combination Hypertension-Diabetes Polypill
21.1.4 Long-Term Blood Pressure and Glucose Control, with a Focus on Treatment Adherence
21.2 Conclusions
References
Part VII: Strategies for Blood Pressure Control
22: Lifestyle Modifications
22.1 Introduction
22.2 Weight Reduction
22.2.1 Caloric Restrictions
22.3 Increased Physical Activity
22.4 Sodium Intake Reduction
22.5 Increased Consumption of Fruits and Vegetables
22.6 Avoiding Excessive Alcohol Consumption
22.7 Smoking Cessation
22.8 Conclusions
References
23: Blood Pressure Thresholds for Initiation of Drug Treatment: Blood Pressure Targets in Diabetes
23.1 Introduction
23.2 Review of Data on Blood Pressure Targets
23.3 Nuanced Approach to BP Management: In Search of the “Sweet Spot”
23.4 Diastolic Blood Pressure: Is It Important?
23.5 Barriers to Achieving the Desired Blood Pressure Targets
23.6 Conclusion
References
24: Choice of Antihypertensive Drugs and Antihypertensive Drug Combination in Diabetes
24.1 Introduction
24.2 Initial Therapy
24.2.1 Approach to Treatment
24.2.2 Renin-Angiotensin System Blockers
24.2.3 Calcium Channel Blockers
24.2.4 Thiazide and Thiazide-Like Diuretics
24.2.5 Beta-Blockers
24.2.6 Mineralocorticoid Receptor Antagonists
24.2.7 Antihypertensive Drug Combinations
24.3 Summary
References
Part VIII: Antihypertensive Drugs and Diabetes Mellitus: Special Problems
25: Adverse Reactions in Renal Function and Electrolytes Associated with Antihypertensive and Antidiabetic Therapy
25.1 Introduction
25.2 Adverse Renal Reactions to Renin–Angiotensin–Aldosterone System Blockade
25.2.1 Renin–Angiotensin–Aldosterone System Blockade Associated Decline in Renal Function: General Features
25.2.2 Determinants of Impairment of Renal Function Associated with Renin–Angiotensin–Aldosterone System Blockade Therapy
25.2.3 Role of Renin–Angiotensin–Aldosterone System in Pathogenesis of Chronic Kidney Disease
25.2.4 Initiation/Withdrawal of Renin–Angiotensin–Aldosterone System Blockade Therapy in Advanced Stages of Chronic Kidney Disease
25.2.4.1 De Novo Initiation of Renin–Angiotensin–Aldosterone System Blockade Therapy in Advanced Stages of Chronic Kidney Disease
25.2.4.2 Indication for Continuation/Cessation of Renin–Angiotensin–Aldosterone System Blockade Therapy in Advanced Chronic Kidney Disease
25.3 Hyperkalemia-Antihypertensive Drugs Association
25.3.1 Definition/Frequency
25.3.2 Predictors of Hyperkalemia
25.3.2.1 Reduced Glomerular Filtration Rate
25.3.2.2 Diabetes Mellitus
25.3.2.3 Antihypertensive Pharmacotherapy
Renin–Angiotensin–Aldosterone System Inhibitors
Mineralocorticoid Receptor Antagonists
Beta-Blockers
25.3.3 Clinical Manifestations and Outcomes of Hyperkalemia
25.3.4 Mechanisms of Development of Hyperkalemia
25.3.5 Principles of Management of Hyperkalemia
References
26: Diabetogenic Effects of Antihypertensive Drugs and Statins
26.1 Effects of Antihypertensive Drugs on NOD
26.2 Effects of Statin on NOD
26.3 Increased NOD by Antihypertensive Drugs and Statins: Mechanisms
26.4 Drug-Induced NOD and Cardiovascular Risk
26.5 Future Studies
References
27: Management of Diabetic Hypertensive Patient during Ramadan Fasting
27.1 Introduction
27.2 Effects of Ramadan Fasting on Blood Pressure
27.2.1 Nondiabetic Normotensive/Hypertensive Subjects
27.2.2 Diabetic Normotensive/Hypertensive Subjects
27.3 Liquorice and Blood Pressure Changes
27.4 Effects of Blood Pressure Changes on Renal Function in Ramadan Fasting
27.4.1 Normal Renal Function
27.4.1.1 Nondiabetes
27.4.1.2 Diabetes
27.4.2 Impaired Renal Function/Chronic Kidney Disease
27.5 Impacts of Fasting/Refeeding Cycles on Blood Pressure Regulation
27.6 Management of Diabetic Hypertensive Fasting Subjects
27.6.1 General Principles
27.6.2 Treatment of Hypertension
27.6.3 Treatment of Diabetes Mellitus
27.6.4 Drug–Drug Interactions
27.6.4.1 Sulfonylureas
27.6.4.2 Thiazolidinediones
27.6.4.3 Metformin
27.6.4.4 Cardiovascular Drugs
References
Part IX: Other Therapeutic Modalities
28: Control of Blood Glucose and Cardiovascular Risk Profile
28.1 Introduction
28.2 Glycemic Control and Cardiovascular Complications
28.2.1 Diabetes Control and Complications Trial (DCCT)
28.2.2 The UK Prospective Diabetes Study (UKPDS)
28.2.3 Action to Control Cardiovascular Risk of Diabetes (ACCORD)
28.2.4 Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)
28.2.5 The Veteran Affairs Diabetes Trial (VADT)
28.2.6 Meta-Analytic Assessment and Interpretation
28.3 Changing the Focus of Regulatory Agencies and Clinical Trials
28.3.1 Lifestyle Intervention
28.3.2 Metformin
28.3.3 Insulin
28.3.4 Thiazolidinediones (TZDs)
28.3.5 Dipeptidyl Peptidase-4 Inhibitors (DPP4-I)
28.3.6 Sulfonylureas (SUs)
28.3.7 GLP1-Receptor Agonists (GLP1-RA)
28.3.8 Sodium Glucose Transporter 2 Inhibitors (SGLT2-I)
28.3.9 The Impact on International Guidelines
28.4 Additional Measures of Glycemic Control
28.5 Final Remarks
References
Part X: Hypotensive Disorders
29: Orthostatic Hypotension and Diabetes
29.1 Introduction
29.1.1 Pathigenetic Mechanisms
29.2 Prevalence
29.3 Prognostic Significance
29.4 Drug-Induced OH
29.4.1 Antihypertensive Drugs
29.4.2 Drugs Acting on Central Nervous System
29.4.3 Antidiabetic Drugs
29.5 Clinical Aspects and Treatment
29.6 Conclusions
References