Novel Insights on SGLT-2 Inhibitors Rajeev Chawla, Shalini Jaggi
INDEX
Page numbers followed by ‘f’ indicate figures respectively.
A
Acetyl-CoA derived 41
Adenosine triphosphatase 9
Adipokine 42
kinetics besides effects 40
levels of anti-inflammatory 42
paracrine regulation of 42
reducing proinflammatory 42
Adipose tissue 31
Albuminuria, effects on 91f
Alpha-glucosidase inhibitors 73
American College of Endocrinology, guidelines 66
American Diabetes Association 64
Antianaphylactic 4
Antiasthmatic 4
Antiatherogenic properties 59
Antidiabetic agents 4
doses, adjusting of 76f
drugs 72, 73, 77
Antihypertensive
agents doses, adjusting of 76f
therapy 75
Anti-inflammatory, antitumor 4
Antimicrobial and immunoregulatory 4
Atherosclerotic cardiovascular disease 22, 35, 63, 69
Atherosclerotic events 87
B
Bacteria, increased adherence of 50
Basolateral membrane 9, 15
Beta-carboxy-telopeptide 57
Beta-cell function 63
Beta-hydroxybutyrate 38
Biguanides 73
Blood pressure 35, 76
changes 54
diastolic 54
lowering 38
reduction 48, 73, 40
systolic 54
Body mass index 32
Bone effects and fractures 56
Bowman's capsule 17
Breast cancer, rates of 61
C
Canagliflozin 3, 25, 26-28, 32, 35-37, 48-50, 57-59, 57, 64, 74, 83, 88
bladder cancer, trial with 61
breast cancer, trial with 61
Cardiovascular Assessment Study 22, 23, 24f, 28f, 34
metabolism of 60
Cancer risk 60
Candida glabrata 49
Cardiac
fibroblasts results 41
metabolism and bioenergetics, improvement in 41
structural remodeling 41
Cardioprotection 60
Cardioprotective action 40
Cardiorenal
benefits 66
pleiotropic benefits 68
Cardiovascular
benefits: implications of 35
death 93
composite of 89
disease 25
prevalence of 35
event 22
primarily 40
thrombolysis 37
thrombolysis in myocardial infarction 58 trial with dapagliflozin 26
Outcome Trials 23, 29, 87
with SGLT-2 inhibitors 21, 27
protective effects 4
Catabolic state 75
Coronary artery disease 23, 25, 36
Credence trial
exploratory outcomes 92
interpretation 93
limitations 94
methodology 88
outcomes 89
primary outcomes 89
safety evaluations 89
secondary outcomes 89, 92
Cytokine 42
Cytokine interleukin-6 42
D
Dapagliflozin 3, 22, 25-28, 34, 35, 37, 40, 49, 50, 57, 59, 64, 80, 81, 85
antifibrotic effects of 41
cardiovascular safety of 26
effect on cardiovascular events-thrombolysis 23, 28f
reported for 60
versus placebo 61
Dehydration 73
Dehydration-related dyshidrotic eczema 60
Diabetes mellitus
and cardiovascular disease 21
management of 63
treatment of type 2 diabetes 7
type 1 diabetes 75, 78
controlled 81
need for adjuvant therapies in 79
type 2 diabetes 4, 11, 14, 52, 63, 75, 78, 87
management of 21
patients trial with empagliflozin 23
Diabetic foot ulcers 74
Diabetic ketoacidosis 53
associated increased risk of 84
essential pathophysiology of 53f
euglycemic 34, 48, 52, 53, 75
incidence of 34
increased risk for 34
Diabetic kidney 7, 8
Diabetic nephropathy 14
development of 18
Diabetic tubulointerstitial fibrosis 15
Diabetologia 40
Dihydrochalcone compound isolated 2
Dipeptidyl peptidase 4 inhibitors 69, 73, 76
Distal tubular sodium delivery 45
Diuresis leads 73
Dizziness 66
Drug interactions 60
Dyselectrolytemia 56
Dysentery 4
Dyslipidemia 21
E
Empagliflozin 21, 22, 25, 26, 28, 32, 35, 36, 40-41, 49-51, 56, 58, 59, 64, 80, 83
cardiovascular outcome event trial 23
in type 2 diabetes mellitus 24, 28, 34
causes inhibition 41
dose of 56
reported for 60
treatment blocks proximal tubule glucose 45
Endogenous 65
glucose production 33, 53
Epicardial adipose tissue mass 42
Epidermal growth factor receptor 46
Ertugliflozin 4
Euglycemic insulin clamp 53
European Medicines Agency's CHMP regulatory committee 85
Exogenous 65
Eythropoietin levels leading 56
F
Fabaceae 4
Familial renal glucosuria 12, 18
Fasting blood glucose 19, 81
Fatty acid 39
FDA Advisory Committee 60
Fever 4
treatment option for 2
Flavescens 4
Formononetin 4
Free fatty acid 84
G
Gastrointestinal 76
epithelial cells 18
Genital infections 49, 64
Genital mycotic infections 77
Gliflozin 3, 4, 49
Glimepiride 32
Glimpse 1
Glitazones 79
Glomerular filtration rate 17, 26, 37, 45, 54, 74, 87, 91
baseline estimated 28
estimated 69, 73
spectrum of estimated 42
Glomerular hyperfiltration 14, 39, 45, 46, 55
Glucagon
levels
increased 55
stimulating neoglucogenesis 84
like peptide-1 receptor agonist 69, 76, 79
production 52
secretion 33
improements in 32
Glucose
conservation 8, 17
deficiency 31
diffuses 16
excretion 10
galactose malabsorption 18
homeostasis, regulation of 12
levels, postprandial 31
lowering medication in type 2 diabetes 69f
lowering therapies 49
oxidation 33
reabsorption 17, 18
inhibition of 31
mechanics of 10
physiology of 17
threshold for 17
toxicity, improvements in 32
transport in tubular epithelial cells 9f
transporter 2, 9, 15
Glucoside analogs 2
Glucosuria 49
condition of natural 12
in uncontrolled T2DM 50
Glucotoxicity 31, 46, 65
reduction in 53
Glycated hemoglobin 73, 76
Glycemic control 79
Glycosuria 14
H
Hazard ratio 24
Heart failure 65, 69
development of 41
hospitalization for 22
prevention of 40
Hemoconcentration 56
manifested 40
Hemodynamic 44
effects 38-39
Hemoglobin A1c 3, 19, 23, 39, 66, 69
Hepatic
gluconeogenesis 8
neoglucogenesis 53
Heterozygous FRG in benign condition 18
Hydroxyl functional group 4
Hyperglycemia
chronic 1
management of 13
mild 35
worsening 7
Hyperkalemia 73
Hypertension 21
management, case for aggressive 35
Hypoglycemia 49
risk of 72, 79
agents 49
I
Immunoreactive insulin 39
Incretin axis 1
Infectious diseases, treatment option for 2
Inhibiting histone deacetylase 41
Inhibitory constant values 2
Insulin 4
add-on to 66
doses, careful titration of 79
resistance 65
secretion, improvements in 32
sensitivity 32
using triple combination therapy of 80
Insulinopenia 83
degree of 53
Interstitial fibrosis 18
Intracellular sodium concentration 16
Intraglomerular hypertension in patients 46
Ipragliflozin 4, 26
efficacy 60
Isoflavanoid
glycosides 4
based structures 4
J
Jaundice 4
K
Ketogenesis 46
Ketone 38
body production, clinical significance of increased 34
oxidation 41
Kidney disease 88
chronic 65, 69, 87
epidemiology collaboration equation 88
failure, risk of 88
progression 42
Kidney interstitium 16
Kidneys filter 17
Kurarinone 4
L
Lavandulyl functional 4
Leukorrhea 4
Lifestyle, management of 63
Lipids effects on 59
Lipoprotein cholesterol
high-density 38, 39
low-density 59
Liraglutide 80
Luseogliflozin 4, 26
M
Maackiain 4
Malaria, treatment option for 2
Malignancy risk 61
Meglitinides 73
Metabolic syndrome 79
Metformin 49, 53, 65, 66, 67, 72, 79
Mitochondrial
biogenesis 40
enzymes, hyperacetylation of 41
Monotherapy, agent of choice for 67
Multifactorial metabolic 39
Mycotic infections 73
Myocardial
glucose metabolism 41
infarction 23, 28f, 37, 58, 89, 93
metabolism 40
Myocardium, direct effects on 40
N
Natriuresis diuresis 40
Necrosis, reduction of 41
Nephroprotection 44
Neurohormonal derangement 1
Nonesterified fatty acids 38
North American inTandem1 Study 82
O
Obesity epidemic 78
Obesity-related comorbid issues 65
Orthostatic hypotension 73
Osmotic diuresis 40, 73
Osteocalcin 57
P
Pain 4
Pancreatic beta-cells 49
Paracrine insulin inhibition 53
Parathyroid hormone increases bone resorption 57
Peripheral artery disease 25, 27
Peripheral vascular disease 59, 74, 83
Phenobarbital 60
Phenytoin 60
Phlorizin 2, 3
Phosphate 56
Pioglitazone 79
Placebo 36, 82
Plasma glucose 17
Pramlintide 79
Prohypertrophic transcription pathways 41
Proximal
convoluted tubule 74
straight tubule 15
tubular cells, basolateral membrane of 16
tubular sodium reabsorption 45
tubules 49
Pyogenic skin infections 4
R
Real-World
data with canagliflozin 25
practice 25
Remogliflozin 3, 80
Renal
death 42
components, effect on primary outcome 90
disease 38
end stage 42, 87
progression of 27, 29, 42 65
effects
acute kidney injury 54
with blood pressure 35
function 19
gluconeogenesis in postabsorptive state 7
glucose
reabsorption in diabetes, alterations of 17
release in the postprandial state 8
transport genetic defects in 11, 18
transport upregulation of 8
glycogenesis 8
glycosuria 18, 75
drugs water 73
hemodynamic effects associated with SGLT-2 inhibition 45f
impairment 65
insufficiency 73
plasma flow 45
threshold for glucose excretion 10
tubular factors, overactivation of 14
tubules 7, 9
Renin–angiotensin–aldosterone system 14, 18, 55
Rifampicin 60
Ritonavir 60
S
Scabies 4
Sedentarism 78
Sergliflozin 3
Serum calcium 56
SGLT-2 inhibitors 1, 9, 11, 21, 31, 39, 45, 56, 66, 69, 73
advantages and disadvantages in use of 28f
adverse effects and safety of 48
current evidences 80
dosage adjustments based on renal function 74
effect of 54
glycemic efficacy of 31
in diabetes 63
intrarenal effect of 14
in therapy, positioning of 64
in type 1 diabetes: emerging evidences 78
induced hematocrit 56
mechanism of action of 15
mediated glucose transportation 15
metabolic
and hemodynamic effects of 31
effects of 32
offer renoprotection 18
on fracture risk 58
physiology of 7
potential mechanism for 84
role of kidneys in glucose homeostasis 7
safety concerns 83
treatment with 31, 33
type 2 diabetes mellitus 7
use of 65
caution in 72, 73
clinical beneficial effects 72
clinical pearls 72, 74
contraindications 72
of indications 72
Skin disorders 60
SLC5A2 gene 12, 18
Small intestine 64
Sodium
electrochemical potential gradient 9
glucose cotransporters 15, 64
glucose linked transporter T2DM (SGLT-2) inhibitors, effect of 51
glucose cotransporter-2 87
potassium adenosine triphosphatase 9, 90, 16
reabsorption 45
Sophora flavescens 4
Sotagliflozin 4, 81, 82, 83
Stroke 56, 93
Sulfonylureas 49, 66, 73, 76
dose of 49
Swelling 4
T
Target glycemic range 82
Thiazolidinediones 66, 69, 73
Thiophene derivative of C-glucoside 3
Tissue glucose disposal 53
Tofogliflozin 4, 26
Total daily insulin, dose of 82
Tubular
cells 16
glucose reabsorption, mechanism of 16
intracellular space 16
lumen 16
Tubuloglomerular, restoration of impaired 55
Tubulointerstitial fibrosis 18
U
United States Food and Drug Administration 3
Urinary albumin-to-creatinine ratio 88
Urinary glucose
clearance rate 53
excretion 17, 64
Urinary tract infections 19, 48, 50, 51, 77
Urothelium 50
USA Food and Drug Administration 22
V
Variabilin 4
Vasodilatation, potential induction of 41
Voltage-gated potassium, activation of 41
Vulvovaginal candidiasis 73
W
Weight gain 79
insulin-induced 66
Weight loss 48, 68
significant 73
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Chapter Notes

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_fm1Novel Insights on SGLT-2 Inhibitors_fm2
_fm3Novel Insights on SGLT-2 Inhibitors
Authors Rajeev Chawla MD FRSSDI FACP (USA) FRCP (Edin) FACE (USA) Senior Consultant Diabetologist and Director North Delhi Diabetes Centre New Delhi, India Shalini Jaggi Dip Diab (UK) Dip Endo (UK) FRSSDI FRCP (London, Glas, Edin) FACE (USA) Consultant and Head Department of Diabetology Dr Mohans' Diabetes Specialities Centre New Delhi, India Foreword Paresh Dandona
_fm4
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Novel Insights on SGLT-2 Inhibitors / Rajeev Chawla, Shalini Jaggi
First Edition: 2020
9789352706808
Printed at
_fm5Foreword
We are in the golden era of innovation with respect to the discoveries in the field of diabetes over the past two decades. With the appropriate use of the drugs currently available, no patient with type 2 diabetes should remain uncontrolled and thus be vulnerable to diabetic complications. In this respect, three classes of drugs stand out: pioglitazone, a thiazolidenedione, and an insulin sensitizer, the glucagon like peptide-1 (GLP-1) receptor agonists and SGLT-2 inhibitors. All three have potent glucose lowering effects. However, it is remarkable that all have cardio-protective effects and may, therefore, potentially find use in prediabetic and non-diabetic populations. SGLT-2 inhibitors were launched into the market as glucose lowering agents exerting their action through the inhibition of glucose reabsorption at level of the proximal convoluted tubule in the kidney and the induction of glycosuria. Little did we realize that this action would be associated with other unique properties, including lowering of systolic blood pressure, cardioprotection and nephroprotection. The cardioprotective effect is the most marked in terms of cardiac failure. This action is so impressive that prospective clinical trials have been set up to assess this potential beneficial effect in non-diabetic populations. We still do not understand the mechanisms underlying these beneficial effects. Ketosis and ketonemia have been proposed as one mechanism leading to beneficial metabolic changes in the myocardium. However, further investigations and discoveries are still required to complete the mosaic related to the action of these drugs.
This book, edited by Drs Rajeev Chawla and Shalini Jaggi, provides an excellent opportunity for both the uninitiated and the specialist to learn about this class of drugs. I wish this book and the authors all the best wishes so that it can contribute to the translation of the golden age of innovation into a golden age of scientific and rational clinical practice.
Paresh Dandona MD PhD
SUNY Distinguished Professor
Head of Endocrinology, Diabetes and Metabolism
State University of New York and Kaleida Health
Director, Diabetes Endocrinology Center of Western New York_fm6
_fm7Preface
The scientific advancements over the last few decades have revolutionized the field of medicine, bringing in a much better understanding of the disease processes and their management. The growing epidemic of diabetes and obesity in current times pose a major challenge globally and is associated with a huge burden of comorbidities and complications. Last two decades have seen the advent of newer therapies, designer insulins as well as newer technologies and gadgets for management of diabetes, but unfortunately with the best of our efforts a vast majority of our patients are still not on optimum glycemic targets.
Type 2 diabetes is a progressive disease and there is always scope for newer agents that can address its multiple pathophysiological etiologies. One such class of new agents to be added to our armamentarium in recent times is the sodium-glucose transporter-2 inhibitors. These novel agents have changed the paradigm for diabetes management by inducing glycosuria in hyperglycemic patients to restore glycemia besides the added advantage of weight loss and reduction in BP. Hence, from being the conventional victim of hyperglycemia the kidney now has become a partner in the management of hyperglycemia. This book “Novel Insights on SGLT-2 Inhibitors” is an effort on our part to present to the readers an insight into how these agents came into being and have fast evolved today as potent antidiabetic drugs occupying the coveted place of preferred agents in all diabetes management algorithms globally owing to their efficacy, durability as well as pleiotropic benefits and cardiorenal protective effects. This book is a humble effort on our part to update the busy internists and primary physicians who because of their busy practices cannot find enough time to update themselves with the current concepts and placement as well as the future prospects of these new drugs in the management of diabetes. This book offers a crisp and balanced overview of all that we need to know about these agents not only for the beginners, but also for the established clinicians having a thirst for research and detail into this drug class. Every attempt has been made to highlight the clinically relevant _fm8points that serve as a quick referral guide on the topic concerned by means of a crisp introduction and conclusion encompassing each topic being discussed in the various chapters.
Rajeev Chawla
Shalini Jaggi
_fm9Acknowledgment
We have been associated on many platforms for the last few years and that is where we identified our common passion in writing which has finally brought us together in bringing out this first joint book. Each chapter is a joint effort—one prepared a skeleton and the other gave it shape and we tossed it to and fro multiple times, fine-tuning, layer by layer, till both of us were satisfied with the end result. In spite of our chronological differences in age, seniority and experience, the mutual respect and an eye for perfection that we share made this book eventually see light of the day in its current form.
It gives us extreme pleasure to express our gratitude to Mr Jitendar P Vij (Chairman), Jaypee Brothers Medical Publishers (P) Ltd, who not only prompted us to write this book, but also served as a catalyst throughout the project. Without his pursuance, it would not have been possible to write this book with our busy schedules. Himani Pandey, Development Editor, provided us the editorial support and helped us shape our writings into a concrete book. Their commitment and dedication to this endeavor is praiseworthy. We thank the publishers and the entire publication team for putting their tireless efforts to make this project possible.
We shall be failing in our duty if we don't acknowledge the contribution made by our families—spouses, parents and children in allowing us to take away precious hours from their kitty and spending them in researching and writing this book. Their support and good wishes along with their faith in us encouraged us to work together on this project.
We are equally grateful to all our patients who have provided us insights into diabetes and helped us master the practical tips in day-to-day management blessing us with such a vast clinical experience.