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Incretin Based Therapies
Sanjay Kalra, Rakesh Sahay, Ambika G Unnikrishnan
SECTION 1: INCRETINS: AN INTRODUCTION
1:
History of Incretins
INTRODUCTION
EARLY YEARS: HYPOTHESIS THAT INTESTINAL FACTORS INFLUENCE PANCREATIC SECRETORY RESPONSE (1902–1906)
SEARCH FOR GUT-DERIVED FACTORS INFLUENCING INSULIN SECRETION (1921–1930)
INCRETINS FIRST DEFINED (1932)
DEMONSTRATION AND QUANTIFICATION OF THE INCRETIN EFFECT (1961–1970)
DISCOVERY OF GASTRIC INHIBITORY POLYPEPTIDE (GIP) (1970) AND ITS INSULINOTROPIC ACTION IN HUMANS (1973)
DISCOVERY OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AND ITS INSULINOTROPIC EFFECT IN HUMANS (1979–1987)
DEMONSTRATION OF THE REDUCED INCRETIN EFFECT IN TYPE 2 DIABETES AND THE POTENTIAL OF GLP-1 TO NORMALIZE BLOOD GLUCOSE CONCENTRATIONS (1986–2002)
INCRETIN THERAPY APPROVED FOR THE MANAGEMENT OF TYPE 2 DIABETES (2005)
CURRENT STATUS AND FUTURE RESEARCH
CONCLUSION
2:
Physiology of Incretins
INTRODUCTION
INCRETIN SYNTHESIS, STRUCTURE, AND PHARMACOKINETICS
INCRETIN PHYSIOLOGY
Physiological Actions of GIP
Action on Insulin Secretion
Other Actions of GIP
Physiological Actions of GLP-1
Effects on Insulin Secretion
Other Actions
POTENTIAL NEW APPLICATIONS FOR GLP-1 THERAPY
CONCLUSION
3:
Incretin Hormones: Effects Beyond Glycemic Control
INTRODUCTION
GLP-1R AGONISTS ENHANCE β-CELL PROLIFERATION AND SURVIVAL
EFFECTS ON GASTRIC EMPTYING AND GASTRIC SECRETION
EFFECTS ON CARDIOVASCULAR SYSTEM AND POSTPRANDIAL METABOLIC MILIEU
EFFECTS ON CENTRAL NERVOUS SYSTEM (CNS)
Neuroprotection
EFFECTS ON LIVER AND SKELETAL MUSCLE
EFFECTS ON BONE
OTHER ACTIONS OF INCRETIN HORMONES
CONCLUSION
SECTION 2: CLINICAL PHARMACOLOGY OF GLP-1 ANALOGUES
4:
GLP-1 Analogues: An Overview
INTRODUCTION
CLASSIFICATION
EXENATIDE
EXENATIDE EXTENDED-RELEASE
LIRAGLUTIDE
LIXISENATIDE
ALBIGLUTIDE
TASPOGLUTIDE
CONCLUSION
5:
GLP-1 Analogues: Monotherapy
INTRODUCTION
EXENATIDE
Side Effects
EXENATIDE LONG-ACTING RELEASE (LAR)
LIRAGLUTIDE
ALBIGLUTIDE
LIXISENATIDE
DULAGLUTIDE
CONCLUSION
6:
GLP-1 Analogues: Combination Therapy
INTRODUCTION
APPROVED GLP-1 ANALOGUES IN COMBINATION THERAPY
Exenatide in Combination Therapy
Exenatide and Metformin
Exenatide and Sulfonylureas
Exenatide, Metformin, and Sulfonylurea Combination
Exenatide and Thiazolidinediones
Exenatide with Thiazolidinediones and Metformin
Exenatide vs. Sulfonylureas as an Addition to Metformin
Liraglutide in Combination Therapy
Liraglutide Effect and Action in Diabetes (LEAD) Trials
Liraglutide vs. Other Incretin Based Drugs as an Add-on Therapy
Liraglutide vs. Exenatide
Liraglutide vs. Sitagliptin
GLP-1 ANALOGUES UNDER DEVELOPMENT IN COMBINATION THERAPY
Exenatide LAR
Lixisenatide
Taspoglutide with Metformin
CONCLUSION
7:
GLP-1 Analogues and Insulin Combination
INTRODUCTION
GLP-1 ANALOGUES NONINFERIOR TO INSULIN THERAPY
RATIONALE BEHIND COMBINATION OF GLP-1 ANALOGUES AND INSULIN THERAPY
BENEFICIAL EFFECTS OF GLP-1 ANALOGUES
CONCLUSION
SECTION 3: CLINICAL PHARMACOLOGY OF DPP-4 INHIBITORS
8:
DPP-4 Inhibitors: An Overview
INTRODUCTION
BIOLOGY OF DPP-4 ENZYME
Structure of DPP-4 Enzyme
DPP-4 Enzyme Family
Localization of the DPP-4 Enzyme
In vitro/In vivo (Physiological) Ligands for DPP-4 Action
DPP-4 and the Inactivation of the Incretin Hormones
DPP-4 Enzyme Action
PHYSIOLOGICAL ROLE OF DPP-4 ENZYME
Fischer 344 Rat
Targeted DPP-4 Gene Knockout Mice (DPP-4 –/–)
Physiological DPP-4 Enzyme Substrates
Nonglycemic Physiological Properties of DPP-4 Enzyme
Physiological Role of the Cleavage Products of Incretin Hormones
BIOLOGICAL CHEMISTRY AND DEVELOPMENT OF DPP-4 INHIBITORS
History
Types of DPP-4 Inhibitors
CLINICAL PHARMACOLOGY OF DPP-4 INHIBITORS
Mechanism of Action
Improvements in β-cell Mass and Survival in Rat Studies
Pharmacokinetics of DPP-4 Inhibitors
SAFETY OF THE DPP-4 INHIBITORS
CONCLUSION
9:
DPP-4 Inhibitors: Monotherapy
INTRODUCTION
VILDAGLIPTIN AS MONOTHERAPY
Vildagliptin vs. Placebo
Vildagliptin vs. Rosiglitazone
Vildagliptin vs. Metformin
Vildagliptin vs. Gliclazide
Vildagliptin vs. Acarbose
Vildagliptin vs. Voglibose
SITAGLIPTIN AS MONOTHERAPY
Sitagliptin vs. Placebo
SAXAGLIPTIN AS MONOTHERAPY
Sitagliptin vs. Placebo and Other Comparators
CONCLUSION
10:
DPP-4 Inhibitors: Combination Therapy
INTRODUCTION
RATIONALE BEHIND COMBINING DPP-4 INHIBITORS WITH METFORMIN
RATIONALE BEHIND COMBINING DPP-4 INHIBITORS WITH THIAZOLIDINEDIONES
CLINICAL STUDIES WITH COMBINATION THERAPY
Vildagliptin as an Add-on Therapy
Combination with Metformin
Combination with a Thiazolidinedione
Combination with Glimepiride
Comparison of Vildagliptin and Metformin vs. Thiazolidinedione and Metformin
Comparison of Sulfonylurea and Metformin vs. Vildagliptin and Metformin
Combination with Insulin
Sitagliptin as an Add-on Therapy
Combination with Metformin
Combination with Pioglitazone
Comparison of Sitagliptin and Metformin vs. Glipizide and Metformin
Saxagliptin as an Add-on Therapy
Combination with Metformin (In Treatment-naïve Patients)
Saxagliptin as an Add-on Therapy to Metformin (In Treatment-experienced Patients)
Combination with Sulfonylureas
Combination with Thiazolidinedione
Conclusion
SECTION 4: PLEIOTROPIC EFFECTS OF INCRETINS
11:
Cardiovascular Effects of Incretins
INTRODUCTION
INCRETIN
Tissue Distribution of GLP-1 Receptors
GLP-1 Agonism and Cytoprotection
Mechanism of Action of GLP-1 on Cardiovascular System
Direct GLP-1 Receptor Dependent Cardiac Effects
Indirect GLP-1 Receptor Independent Cardiac Effects
Potential Benefits
CONCLUSION
12:
Neurological Effects of Incretins
INTRODUCTION
TISSUE DISTRIBUTION OF GLP-1 RECEPTORS IN THE BRAIN
MECHANISM OF ACTION IN GLP-1 IN NEUROLOGICAL SYSTEM7–11
POTENTIAL BENEFITS
Neuroprotection and Neurobehavioral
Weight Reduction
Taste Modulation
Appetite Suppression
CONCLUSION
13:
Gastrointestinal and Hepatobiliary Effects of Incretins
INTRODUCTION
Mechanism Of Action Of Glp On Gastrointestinal System2–5
POTENTIAL BENEFITS
Weight Reduction
Taste Modulation
Appetite Suppression
Delayed Gastric Emptying
Insulinotropic Effect
Glucagon Suppression
Hepatosteatosis
CONCLUSION
14:
Incretins and Insulin Sensitivity
INTRODUCTION
ASSESSMENT OF INSULIN RESISTANCE
Clinical Indicators
Biochemical Indicators
Other Indicators
NEED TO ADDRESS INSULIN RESISTANCE
ROLE OF INCRETINS AS INSULIN SENSITIZERS
CONCLUSION
15:
Incretins and Obesity
INTRODUCTION
REGULATION OF ENERGY INTAKE
Central Regulation
First and Second Order Neurons
ROLE OF INCRETINS IN APPETITE REGULATION
EVIDENCE OF TOTAL BODY FAT REDUCTION
CONCLUSION
SECTION 5: COMPARATIVE PHARMACOLOGY
16:
GLP-1 Analogues vs. DPP-4 Inhibitors
INTRODUCTION
GLP-1 ANALOGUES
Exenatide: Once a Week or Twice a Day?
Exenatide vs. Liraglutide
DPP-4 INHIBITORS
Sitagliptin vs. Saxagliptin
Sitagliptin vs. Vildagliptin
THE BIG QUESTION: GLP-1 ANALOGUE VERSUS DPP-4 INHIBITOR
Exenatide vs. Sitagliptin
Liraglutide vs. Sitagliptin
GLP-1 ANALOGUES AND DPP-4 INHIBITORS: SIMILARITIES AND DIFFERENCES
Similarities between GLP-1 Analogues and DPP-4 Inhibitors
Differences between GLP-1 Analogues and DPP-4 Inhibitors
SIDE EFFECT PROFILE
FUTURE TRENDS
CONCLUSION
17:
Choosing a GLP-1 Analogue
INTRODUCTION
OVERVIEW OF LICENSED GLP-1 ANALOGUES
Absorption, Distribution, Metabolism, Excretion, and Dosing
Exenatide
Liraglutide
Clinical Efficacy
Exenatide
Liraglutide
Safety and Tolerability
OVERVIEW OF GLP-1 RECEPTOR ANALOGUES IN DEVELOPMENT
Clinical Efficacy
HbA1C
Weight Loss
Systolic Blood Pressure
Safety and Tolerability
Hypoglycemia
GI Side Effects
Antibodies
OVERVIEW OF LONG-ACTING VS. SHORT-ACTING GLP-1 ANALOGUES
CONCLUSION
18:
Choosing a DPP-4 Inhibitor
ROLE OF GUT PEPTIDES (INCRETINS) IN GLUCOSE DISPOSAL
INCRETINS
CURRENTLY AVAILABLE GLIPTINS/DPP-4 INHIBITORS
Efficacy
Adverse Effects
Pleiotropic Effects
Cardiovascular
Nervous System
Hepatobiliary
CURRENT POSITION OF GLIPTINS IN TREATMENT OF DIABETES AND RELATIONSHIP TO PATHOGENESIS
CONCLUSION
19:
Future of Incretin Therapies
INTRODUCTION
BREAKING THE DURATION BARRIER
INCRETINS AND BONE
GLP-1 ANALOGUES AND CALCITONIN
GLP-1 AND PANCREATITIS
INCRETINS AND OBESITY
CAN INCRETINS MIMIC THE EFFECTS OF METABOLIC SURGERY?
CARDIOVASCULAR EFFECTS OF INCRETINS
MICROVASCULAR COMPLICATIONS AND INCRETIN THERAPY
INDEX
TOC
Index
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