SGLT-2 inhibitors lower blood glucose levels by reducing renal glucose reabsorption and increasing glucose excretion in the urine. Empagliflozin is a selective SGLT-2 inhibitor that lowers both fasting and post-prandial plasma glucose levels. In clinical trials, empagliflozin led to an HbA1c reduction of over 1% compared to placebo when used as both monotherapy and add-on therapy to other glucose-lowering medications. Empagliflozin was also associated with weight loss, reduced blood pressure, and a lower risk of hypoglycemia compared to sulfonylurea therapy.
SGLT2 inhibitors in Heart failure: A prized addition to HF treatment optionsahvc0858
Early Diabetes and Dyslipidaemia Treatment Optimisation.
Presentation by Dr Chan Wan Xian
Cardiologist, Echocardiologist
Heart Failure Intensivist
Asian Heart & Vascular Centre
www.ahvc.com.sg
SGLT2 inhibitors in Heart failure: A prized addition to HF treatment optionsahvc0858
Early Diabetes and Dyslipidaemia Treatment Optimisation.
Presentation by Dr Chan Wan Xian
Cardiologist, Echocardiologist
Heart Failure Intensivist
Asian Heart & Vascular Centre
www.ahvc.com.sg
SGLT2I The paradigm change in diabetes managementPraveen Nagula
Just like ARNI, SGLT2I have changed the face of diabetes management and they have a good profile in multimodality management because of pleiotropic effects
Silvio E. Inzucchi, MD, prepared useful Practice Aids pertaining to type 2 diabetes management for this CME activity titled "The Role of SGLT2 Inhibitors in Type 2 Diabetes: CV, Metabolic, and Renal Considerations." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2l4h3Ss. CME credit will be available until June 27, 2019.
Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ...magdy elmasry
Cardiologists and diabetes.Target organs and action mechanism of antidiabetic drugs.Cardiovascular Outcome Trials
( CVOTs ) in Diabetes.Completed and ongoing CVOTs in type 2 diabetes.Diabetes Medications
and
Cardiovascular Impact.Recommendations for management of diabetes
Cardiovascular safety of anti-diabetic drugs.
SGLT2I The paradigm change in diabetes managementPraveen Nagula
Just like ARNI, SGLT2I have changed the face of diabetes management and they have a good profile in multimodality management because of pleiotropic effects
Silvio E. Inzucchi, MD, prepared useful Practice Aids pertaining to type 2 diabetes management for this CME activity titled "The Role of SGLT2 Inhibitors in Type 2 Diabetes: CV, Metabolic, and Renal Considerations." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2l4h3Ss. CME credit will be available until June 27, 2019.
Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ...magdy elmasry
Cardiologists and diabetes.Target organs and action mechanism of antidiabetic drugs.Cardiovascular Outcome Trials
( CVOTs ) in Diabetes.Completed and ongoing CVOTs in type 2 diabetes.Diabetes Medications
and
Cardiovascular Impact.Recommendations for management of diabetes
Cardiovascular safety of anti-diabetic drugs.
SGLT 2 inhibitors Empagliflozin in Diabetes MellitusGovindRankawat1
Two sodium glucose transporters, cause glucose reabsorption: SGLT-1 and SGLT-2.
SGLT-2 is found in the proximal tubule of the kidney, accounts for 90% of the re-absorption of glucose.
SGLT-1 is found in the gut and other tissues, account for glucose absorption
On top of glycaemic lowering, SGLT2 inhibitors demonstrates additional clinical benefits versus placebo:
Blood pressure lowering
Weight loss
Reduction in major cardiovascular events in patients with established cardiovascular disease1
The mechanisms responsible for the cardiovascular effects are currently unknown
May be a combination of natriuresis, glycosuria (dual inhibition) and/or Na+/H+ exchange
Ongoing mechanistic studies may provide answers
A study published by Elsevier suggest that after 52 weeks of follow-up empagliflozin and dapagliflozin both groups showed significant reductions in HbA1c and FPG, but the reduction was greater in the empagliflozin group (P < 0.001). Hence, empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters than dapagliflozin
GLP-1 is an incretin (hormone that increases insulin secretion in response to a meal), which is a 30-amino acid peptide secreted in response to the oral ingestion of nutrients by intestinal L cells.
GLP-1 receptors (GLP-1R) are located in islet cells, central nervous system, and other organs. GLP-1 is metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4).
Incretin effect is a phenomenon whereby a glucose load delivered orally produces a much greater insulin secretion than the same glucose load administered intravenously.
This presentation is an overview of the entire GLP-1 system, followed by an introduction to leveraging its therapeutic potential using GLP-1 analogues (Exenatide, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide) and DPP-4 inhibitors (Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin).
Shashikiran Umakanth delivered this talk at Manipal on 30th November, 2015
Our aim is to reduce morbidity and mortality related to Non communicable diseases such as hypertension, diabetes, cardiovascular disease, stroke, Obesity, Cancer and lifestyle diseases among those least able to withstand the burden of the disease.
Infertility is defined as the inability of a couple to conceive after at least one year of regular unprotected intercourse.
Male infertility refers to a male's inability to cause pregnancy in a fertile female.
IDD situation in our country has improved
A good number of thyroid disorder patients are either undiagnosed and or untreated
Thyroid disorder in pregnancy- Rate high
As a sound thyroid functioning status is crucial for growth, development in children; reproduction, psychological and general wellbeing in adults, we must be proactive in screening, diagnosing and treating our patients.
Over the past several years it has been proved that maternal thyroid disorder influence the outcome of mother and fetus, during and also after pregnancy. The most frequent thyroid disorder in pregnancy is maternal hypothyroidism. It is associated with fetal loss, placental abruptions, pre-eclampsia, preterm delivery and reduced intellectual function in the offspring.1 In pregnancy, overt hypothyroidism is seen in 0.2% cases2 and sub clinical hypothyroidism in 2.3% cases3. Fetal loss, fetal growth restriction, pre-eclampsia and preterm delivery are the usual complications of overt hyperthyroidism (low TSH and high T3, T4) seen in 2 of 1000 pregnancies whereas mild or sub clinical hyperthyroidism (suppressed TSH alone) is seen in
1.7% of pregnancies and not associated with adverse outcomes4. Autoimmune positive euthyroid pregnancy shows doubling of incidence of miscarriage and preterm delivery. Worldwide more than 20 million people develop neurological sequel due to intra uterine, iodine deprivation5. Other problems of thyroid disorders in pregnancy are post partum thyroiditis, thyroid nodules and cancer, hyper emesis gravidarum etc. Debates and disputes persist regarding several protocol and management plan in this specific spectrum of diseases.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
SGLT2 Inhibitors in Diabetes Management by Dr Shahjada Selim
1. SGLT-2 inhibitors in the
Management of DM
Dr Shahjada Selim
Associate Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: selimshahjada@gmail.com, info@shahjadaselim.com
3. Glucose handling by Kidney in Diabetes Mellitus
Glucose release
Glucose reabsorption
Fasting state release increased
Liver → mainly by increased gluconeogenesis 30%
Kidney→ Gluconeogenesis increased by 300%
Post meal state
Glucose release is more
40% increased release due to renal release by
gluconeogenesis
Renal glucose uptake
increased in both fasting and post meal state
3 folds higher in DM in fasting state
Maximum glucose reabsorption capacity
increased
Renal thresh hold 240mg/dl (13mmol/L )
Maximum capacity increased from
350mg/min to 420mg/min
4. SGLT2i (Empagliflozin) Lowers Renal Threshold
for Glucose Excretion
Adapted with permission from Abdul-Ghani MA, DeFronzo RA.
RTG = renal threshold for glucose excretion.
1. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA:
Butterworths; 1990:653-657. 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 3. Nair S, Wilding JP. J Clin Endocrinol Metab.
2010;95(1):34-42. 4. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 5. Rave K et al. Nephrol Dial Transplant.
2006;21(8):2166-2171. 6. Oku A et al. Diabetes. 1999;48(9):1794-1800.
Type 2 diabetes
(240 mg/dL)
RTG
30025020015010050
25
50
75
100
125
UrinaryGlucose
Excretion(g/d)
Plasma Glucose (mg/dL)
EMPA-gliflozin
Type 2 diabetes
+ Empagliflozin
(70-90 mg/dL)
RTG
Non-diabetic
(180 mg/dL)
RTG
7. Glucose Metabolism in Diabetes
SGLT2
~90%
Glucose
SGLT1
~10%
Urinary
glucose
excretion
Adapted from Bays H. Curr Med Res Opin. 2009;25(3):671-681.
Tm 420mg/min with blood threshold 13mmol/L
8. Empagliflozin - SGLT2 Inhibition Reduces Renal Glucose
Reabsorption and Increases Urinary Glucose Excretion
Decreased glucose reabsorption into
systemic circulation
Glucose SGLT1SGLT2 SGLT2 inhibitor
Glomerulus Proximal Convoluted Tubule
Early Distal
Glucose in urine
9. Metabolic Adaptations following SGLT2-i Therapy
Improved Glycaemia, Insulin sensitivity, β-cell function
Peripheral Tissues Liver
Hyperglycaemia
SGLT2 inhibition
Lowered
Plasma Glucose Renal glucose
excretion
Kidney
Pancreas
Kalra S, Ved J, Baruah M. IJEM. 2017;21(3):482-3.
Del Prato S. Diabet Medicine. 2009;26:1185–1192.
Ferrannini E, et al. J Clin Invest. 2014;124:499–508
Metabolic Switch
Weight Loss Enhanced Insulin
Sensitivity
Improved
Hyperinsulinemia
Weight Loss
10. Empagliflozin - Metformin in Treatment Naïve Patients
Change in HbA1C from Baseline
Hadjadj S et al. Diabetes Care. 2016 Oct;39(10):1718-28.
11. Empagliflozin vs. Glimepiride as Add-on to Metformin
89% Lower Risk of Hypoglycemic Events
Hypoglycemia requiring assistance:
• 5 (0.6%) patients on glimepiride.
• No patients on empagliflozin.
Cochran-Mantel-Haenszel test; treated set (patients who received ≥1 dose of study drug).
*Plasma glucose ≤70 mg/dL and/or requiring assistance. RR, risk ratio.
Adjusted RR 0.112
(95% CI 0.074, 0.169)
p<0.0001
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
12. Renal threshold for glucose
• Plasma level at which the glucose first appears in
the urine in more than the normal minute
amounts.
• Actual renal threshold is about 200 mg/dl of
arterial plasma, which corresponds to a venous
level of about 180 mg/dl.
17. Points Canagliflozin Dapagliflozin Empagliflozin
FDA
approval
March 29, 2013 January 8, 2014 August 1, 2014
Dose range 100-300 mg/day 5 mg-10
mg/day
10-25 mg/day
Half-life (h) 12-15 17 10-19
Administrati
on
Before the first
meal of the day
At any time of
the day with or
without food
In the morning
with or without
food
SGLT2 inhibitors
18. SGLT2-i agents: Characteristics
Empagliflozin Dapagliflozin Canagliflozin
SGLT2 : SGLT1
selectivity@ >2,5001 >1,2001 >2501
Non-specific*
Tissue Distribution
Lowest2 Intermediate2 Highest2
Impaired Glycolysis
in Proximal tubular
epithelium
Not observed3 Not observed3 Observed
in In-vitro study3
Risk of
Hyperkalemia
No imbalance$4 No imbalance$5
Higher in patients
with moderate
renal impairment$6
Risk of Bone
fractures
No imbalance4,7 No imbalance5,8 Increased risk6,9
Risk of lower limb
amputations
No imbalance4,7,11 No imbalance5,8
≈2-fold increase in risk
with canagliflozin
(both doses)10
CV death /
All-cause death
benefit in RCT
Demonstrated12 Not Demonstrated13 Not Demonstrated14
This is Not a
Head-to-Head Comparison
19. FPG (mg/dL) reduction in pivotal trials - 24 week
2014;16:147–158 P: < 0.05
BL, baseline; MET, Metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea. * All data are
Placebo-corrected and statistically significant unless otherwise marked. 1. Hach T, et al. Diabetes.
2013;62(suppl 1A);A21 (P69-LB); 2. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1(3):208–219; 3. Häring H-U, et al. Diabetes Care.
2014 (in press); 4. Kovacs C, et al. Diabetes Obes Metab. 2014;16(2):147–158; 5. Häring H-U, et al. D1ia8betes
Care. 2013;36(11):3396–404; 6. Rosenstock J, et al. Diabetologia. 2013;56(suppl 1);S372 (P931); 7. Barnett A, et al, Lancet Diabetes
Endocrinol. 2014; doi:10.1016/S2213-8587(13)70208-0.
Add-on to
Basal
insulin
Add-on to
PIO
Add-on to
MET+SU
Add-on to
MET
Monotherapy
224 224 217 213 165 168 225 216 169 155
N value
Baseline FPG
152.79 152.61 154.59 149.37 151.92 151.74 150.84 156.42 138 146
0
Adjusted mean
(SE) difference
vs Placebo in
change from
baseline in FPG
(mg/dL)
-10
-20
-30
-29.50-28.65 -28.44* -23.4 -28.44-31.20-40 *
-36.20
*
**
Empagliflozin 10
mg QD
* **
Empagliflozin 25 mg QD
-23.40
-26.49 -28.20
Glycemic Efficacy-Fasting Plasma Glucose
20. EMPA-REG METTM in Type 2 Diabetes
Change in 2-h PPG* at Week 24
Empagliflozin
Comparison with PlaceboPlacebo
(n = 57)
6.0
10 mg QD
(n = 52)
25 mg QD
(n = 58)
20
10
0
-10
-20
-30
-40
-50
-60
-44.5
-46.0
Placebo EMPA 10 mg EMPA 25 mg
264.5 254.6 252.1
(mg/dL)
CI, confidence interval; EMPA, Empagliflozin; PPG, post-prandial glucose; QD, once daily; SE, standard error.
*2-h PPG was evaluated in a subset of 167 randomised patients who had a valid MTT (MTT set).
ANCOVA, MTT (LOCF).
Häring HU, et al. Diabetes Care. 2014;37:1650–1659.
EMPA-REGMET:study1245.23
Adjustedmean(SE)changefrom
baselinein2-hPPG(mg/dL)
Mean baseline 2-h PPG
-
-51.9
(95% CI:
-69.2, -34.6)
P<0.0001
-50.5
(95% CI:
-67.4, -33.5)
P<0.0001
Glycemic Efficacy-Post prandial Plasma Glucose
22. Empagliflozin vs. Glimepiride as Add-on to Metformin
Systolic BP Reduction Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
490
537
394
475
327
427
224
336
191
314
165
289
146
266
739
735
554
579
438
510
358
446
238
361
207
331
177
302
161
284
612
618
4 15665 78 104 130 18291 117 143 169 19512 4028 528 16
650
649
677
669
Glimepiride*
Empagliflozin†
Difference: -6.2 mmHg
(95% CI -8.5 to -4.0)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinSBP(mmHg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
23. Empagliflozin vs. Glimepiride as Add-on to Metformin
Weight-loss Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and
off-treatment values).
743
737
610
642
524
590
458
551
331
443
301
420
269
395
248
368
745
739
15678 104 130 18212 28 52
703
706
Glimepiride
Empagliflozin
Difference: -4.9 kg
(95% CI -5.5 to -4.3)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinweight(kg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
24. Empagliflozin vs. Glimepiride as Add-on to Metformin
Systolic BP Reduction Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
490
537
394
475
327
427
224
336
191
314
165
289
146
266
739
735
554
579
438
510
358
446
238
361
207
331
177
302
161
284
612
618
4 15665 78 104 130 18291 117 143 169 19512 4028 528 16
650
649
677
669
Glimepiride*
Empagliflozin†
Difference: -6.2 mmHg
(95% CI -8.5 to -4.0)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinSBP(mmHg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
25. Empagliflozin vs Glimepiride as Add-on to Metformin
Renal Function (eGFR) Preserved Over 4 years
Baseline: mean (SE) in the treated set; weeks 12–208: adjusted mean (SE) from MMRM in the treated set; LVOT and FU:
adjusted mean (SE) from ANCOVA in patients from the FAS who had a measurement at follow-up. *FU was 4 weeks after
termination of study medication. FU, follow up; LVOT, last value on treatment.
15678 104 130 18212 28 52
503
537
492
525
588
579
751
740
677
679
657
651
478
520
459
510
573
570
707
690
726
713
Glimepiride 757
Empagliflozin 742
LVOT FU*
Difference 5.1;
(95% CI 3.5 to 6.8)
p<0.0001
Week
Mean(SE)eGFR(mL/min/1.73m2)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
26. Empagliflozin Improves UACR Outcomes
in Patients with Albuminuria
Wanner C et al. FR-PO805, American Society of Nephrology Kidney Week, 15–20 November 2016, Chicago, IL, USA.
Empagliflozin
33% Lower Odds of Deterioration
in UACR Status
Empagliflozin
61% Higher Odds of Improvement
in UACR Status
27. Empagliflozin Consistently Reduces
Serum Uric Acid Level
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720. Inzucchi SE et al. Diabetes Care. 2018 Feb;41(2):356-63.
28. Empagliflozin Mediates Sustained
↓se in Plasma Volume
7-8% ↓se in Plasma Volume, Independent of Baseline eGFR
(p <0.0001 at Week 12 and Week 206)
Schou M. M2031; American Heart Association Scientific Sessions 2017, 11–15 November, Anaheim, California, USA
29. Hallow KM et al. Diabetes Obes Metab. 2017 Oct 12. doi: 10.1111/dom.13126.
• SGLT2-i agent ↓ses IF volume by 2-fold greater than blood volume
• Loop diuretic ↓ses IF volume by only 78% of reduction in blood volume
SGLT2-i agent Effect Loop Diuretic Effect
Day
Day
Day
Day
30. Empagliflozin and Cardiac Diastolic Function
Proof of Mechanism
• Diastolic Dysfunction affects at-least 1 of 2 patients with T2DM1-4
• Empagliflozin therapy and Effect on Diastolic Dysfunction5:
Functional Improvement (Early Lateral Annular Tissue Doppler Velocity)
At Baseline: 8.5 (SD 1.6) cm/s
After Empagliflozin therapy: 9.6 (1.3) cm/s
P = 0.002
Structural Improvement (Left Ventricular Mass Index)
At Baseline: 88 (SD 21) g/m2
After Empagliflozin therapy: 75 (SD 19) g/m2
P = 0.01
1. Patil MB et al. J Assoc Physicians India. 2012 May;60:23-6.
2. Patil VC et al. J Cardiovasc Dis Res. 2011 Oct-Dec; 2(4): 213-22.
3. Kumar M et al. J Assoc Physicians India. 2016 Jan;64(1):40.
4. Saichandar P et al. J Assoc Physicians India. 2016 Jan;64(1):33.
5. Verma S et al. Diabetes Care. 2016 Dec;39(12):e212-e213.
31.
32. EMPA-REG OUTCOME Findings
Clinical Inferences for CVD Prevention
#Number Needed to Treat: Number of patients to be treated with empagliflozin for 3 years, to prevent 1 additional event.
32
Clinical
Outcome
Relative Risk Reduction
(Hazard ratio, p-value)
Absolute Risk Reduction
(Number Needed to Treat#)
3-point MACE
14%
(0.86, p = 0.04)
1.6%
(63 patients)
CV Mortality
38%
(0.62, p <0.001)
2.2%
(46 patients)
Hospitalizations for
Heart Failure
35%
(0.65, p = 0.002)
1.4%
(72 patients)
Hospitalizations for HF
or CV Mortality
34%
(0.66, p <0.001)
2.8%
(36 patients)
Incident or Worsening
Nephropathy
39%
(0.61, p <0.001)
6.1%
(17 patients)
≥40% sustained Decline
in eGFR
45%
(0.55, p <0.001)
1.4%
(72 patients)
All-cause Mortality
32%
(0.68, p <0.001)
2.6%
(39 patients)
33. Key Baseline Characteristics
• >50% patients had T2D of >10 years duration
• >25% patients had eGFR <60 ml/min/1.73 m2
• ≈39% patients had albuminuria (Micro- or Macro-albuminuria)
≈99% patients had pre-existing CVD
• >75% patients had Coronary artery disease (CAD)
• >46% patients had a history of MI
• ≈10% patients had Cardiac failure
Background ‘Standard of Care’ therapy:
• >48% patients were receiving insulin
• >80% were on ACE-i/ARB
• >76% were on statins
• ≈89% were receiving Anti-platelet agents
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720
34. All-cause Mortality
Empagliflozin vs. Placebo, On top of Standard of
Care
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
32% RRR
In Death due to
any cause
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720
35. CV Mortality
Empagliflozin vs. Placebo, On Top of Standard of
Care
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
38% RRR
In CV Death
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720
36. Empa-
gliflozin
Placebo
HR (95% CI)
n with event /
N analysed (%)
Main analysis 172/4687
(3.7)
137/2333
(5.9)
0.62
(0.49, 0.77)
Adjusted for control* of blood
pressure
172/4687
(3.7)
137/2333
(5.9)
0.61
(0.49, 0.76)
Adjusted for control* of LDL-
cholesterol
167/4615
(3.6)
136/2308
(5.9)
0.59
(0.47, 0.75)
Adjusted for control* of HbA1c 172/4685
(3.7)
137/2333
(5.9)
0.62
(0.49, 0.78)
Adjusted for control* of blood
pressure, LDL-c, and HbA1c
167/4614
(3.6)
136/2308
(5.9)
0.61
(0.48, 0.76)
CV Mortality Benefit with Empagliflozin is Consistent,
Regardless of Control of HbA1c, BP, LDL-c
*Adjusted for control at baseline and during the trial as time-dependent covariates.
Cox regression analysis in patients treated with ≥1 dose of study drug.
Fitchett D. ESC - 2017
HR (95% CI) for
CV Death
Favours empagliflozin Favours placebo
37. CI, confidence interval; QD, once daily; SE, standard error. ANCOVA (TS). Hach T, et al. Diabetes. 2013;62(suppl 1A):A21(P69-LB). Data on file.
Effect on Uric acid and Lipid profile
40. Genital and Urinary tract infections
Facts :
• Due to glycosuria caused by SGLT-2 inhibitors
• Genital mycotic infections
• Balanitis and balanoposthitis (M) and vulvovaginitis (F)
• Commonly by Candida, treated by local Anti-fungal
• UTIs, Urosepsis and Pyelonephritis
• More common in female, uncircumcised male
Advise to patients :
• Maintain good personal and genital area hygiene
• Washing genital area after each visit to toilet
• Retract the prepuce and wash (uncircumcised male)
• Avoid unusual sexual exposure
• Immediate medical attention if symptoms
41. Volume depletion
Facts :
• Due to glycosuria causing osmotic diuresis
• Increased frequency of urination
• Volume depletion-related effects such as Hypotension,
dehydration, postural dizziness, syncope
Advise to patients :
• Education about measures to avoid volume depletion
• Drink adequate amount of water during exercise, fasting,
starvation or hot weather
42. Hypoglycemia
• Insulin-independent mechanism of action
• Low risk when used as monotherapy
• Comparable to that of metformin or DPP4-inhibitor
• Increased risk with insulin and insulin secretagogues
43. Euglycemic DKA
Facts
• AACE/ACE reported that incidence of DKA in clinical trials of SGLT2i
in T2DM was low and majority of the reported cases were in TIDM
in whom SGLT2i use is not approved.
• SGLT2-inhibitor should be avoided in acute stressful situations
including acute illness, trauma/surgery, significant weight loss,
H/O DKA.
• Also avoided in severely insulinopenic patients and if used
concomitantly with insulin, the dose of insulin must be gradually
down-titrated, avoiding drastic reduction.
Advise to patients :
• Adequate food/carbohydrate intake and proper nutrition
• Maintenance of hydration, avoidance of binge-drinking of alcohol
44. Other rare adverse effects of SGLT-2 inhibitor
• Ischemic events/lower limb amputation (Cangliglozin)
• Bone fractures (Cangliglozin)
• Increased Low-Density Lipoprotein Cholesterol (LDL-C)
• Fournier gangrene
45. Drug interactions
Co-administration of SGLT2-inhibitor with :-
• Diuretics : Resulted in increased urine volume and frequency.
• Insulin or Insulin Secretagogues: Increases the risk for
hypoglycemia.
50. ESC - EASD Guidelines on diabetes, prediabetes, and cardiovascular disease 2019 - Task Force. European Heart Journal. 2019:1-69. doi:10.1093/eurheartj/ehz486
Anti-hyperglycemic Recommendations for T2DM w/CVD
51. Robust indication for SGLT-2 inhibitor
• Overweight/obesity
• Hypertension
• ASCVD predominates
• Heart failure/CKD predominates
• Compelling need to minimize hypoglycemia
• Contraindication to other drugs
• Intolerance to other drugs
52. SGLT2-inhibitor in special populations
Renal impairment/CKD :
1. ADA has updated its diabetes standards of care to incorporate
results from the CREDENCE trial.
2. In the placebo-controlled trial, clinicians should consider using
SGLT2-inhibitor when the eGFR is at or above 30, especially with
albuminuria above 300 mg/g, to lower renal and CV risk.
53. During Ramadan :
1. No dose modification.
2. Dose should be taken with iftar.
3. Extra clear fluids should be ingested during non-fasting
periods.
4. Should not be used in the elderly, patients with renal
impairment, hypotensive individuals or those taking diuretics
SGLT2-inhibitor in special populations…
54. Characteristics Considerations
• Insulin-independent action
• Decrease FPG, PPG, A1c
• Weight loss
• Blood pressure lowering
• Low risk of hypoglycemia
• CV Mortality benefit in T2D with
ASCVD (Empagliflozin)
• MACE benefit in T2D with ASCVD
(Empagliflozin, Canagliflozin)
• Preservation of renal function
(slowing of decline in eGFR)
• Possible reduction in HF risk
• Uro-genital infections
• Ineffective in renal impairment
(eGFR <45mL/min/1.73m2)
• Monitoring of renal function,
volume and electrolyte status
• Volume-depletion related events
in predisposed individuals
• Bone fractures (Canagliflozin)
• Lower-limb amputations
(Canagliflozin)
• Euglycemic Diabetic Ketoacidosis
SGLT2-inhibitors
Considerations for Clinical Use
55. Take home message
• SGLT2 inhibitors are a new strategy for the treatment of T2DM.
• Their action is based on the blockage of SGLT2 of renal tubular cells
which as a result has glycosuria and excess calories' loss.
• The accompanying beneficial effects of this phenomenon are :
Regulation of fasting and postprandial blood glucose levels
HbA1c reduction
Body weight loss
Reduction of SBP and cardiovascular benefit
• However it is associated with genital and urinary tract infections.
• SGLT2 inhibitor can be combined with the existing treatments for
T2DM and can be an effective weapon for the management of
uncontrolled diabetes.