2. outline
2
Introduction
History
Members of class
Chemistry
SGLT Biology
MOA
Pharmacokinetics
Selecting pt for SGT2I
SGT2i in diabetes
SGT2i in heart failure
SGT2i in chronic kidney diseases
SGT2i in cancer
Dose and Indication
Safety profile
Monitoring parameters
Pharmaceutical care
3. Introduction
3
Sodium glucose co-transporter2 inhibitors SGLT2i aslo called
gliflozins are newly discovered class of drug use in management
of type 2 diabetes.
They prevent Glucose and sodium reabsorption in the nephron
Apart from blood sugar control, gliflozins have been shown to
provide significant cardiovascular benefits (usman et al 2018)
They are also found to be useful in chronic kidney disease
(NICE 2021) (NKF 2022)
They are potential anticancer agent ( gergely et al 2020)
4. HISTORY
4
The first gliflozin to be discovered is phlorizin
A natural product extracted by De konnick from the back of apple tree mollus
demostica in 1834 and was later extracted from Salix alba and Cinchona
rubra
Phlorizin was though to have antipyretic, antimalarial and antiphatogenic
activity but was shown to cause increase glucose in urine
In 1880 Merck manual listed Phlorizin as glycoside preceding insulin which
was discovered in 1921
Phlorizin’s potential for clinical use was limited by its effects to reduce
glucose uptake in brain and poor bioavailability
To address these limitations, investigators developed inhibitors specific to
SGLT2, the expression of which is confined to the kidney
Canagliflozin was first approved in 2013, dapagliflozin 2014 followed by
empagliflozin. Ipragliflozin was approved in japan 2014 (Shradha S. et al
2019)
Currently, four SGLT2i (empagliflozin, dapagliflozin, canagliflozin, and
ertugliflozin) are licensed by the European Medicines Agency (EMA) and the
US Food and Drug Administration (FDA). Several other SGLT2i (e.g,
sotagliflozin, remogliflozin, ipragliflozin, and tofogliflozin) have progressed to
5. Members of class
5
Empagliflozin
Dapagliflozin
Canagliflozin
Ertugliflozin
Sotagliflozin
Remogliflozin etabonate
Tologliflozin
Leusogliflozin
Bexaglifloxin
ipragliflozin
9. BIOLOGY OF SGLT
9
Glucose transport is regulated by
two types of protein: the GLUTs
(facilitated transport) and the SGLTs
(active transport).
Sodium glucose transporters
(SGLTs) belong to the mammalian
solute carrier family SLC5.
This family includes 12 different
members in human that mediate the
transport of sugars, vitamins, amino
acids, or smaller organic ions such
as choline.
The SLC5 family belongs to the
sodium symporter family (SSS),
which encompasses transporters
from all kingdoms of life.
Phylogenetic tree of human SLC5 members. And
substrat transported ( Loo DD et al 1991)
https://doi.org/10.1111/j
10. BIOLOGY OF SGLT CONTD.. Receptors, location and actions
10
Recepto
r
Locations physiological role
SGLT1 Intestine and
kidney, heart,
prostate, trachea,
brain, and skeletal
muscle
Absorption of glucose and galactose
across the intestinal brushborder
membrane.
Absorbtion of glucose at the proximal
tuble of the nephrone
SGLT2 Kidney Very high capacity Absorbtion of
glucose at proximal tuble of the
nephrone, responsible for 80-97% of
renal glucose reabsorption
SGLT3 Enteric neurone of
intestine & NMJ
works as a glucose sensor, might
regulate the intestinal motility in
response to glucose in the
lumen.They may regulate skeletal
muscle activity by depolarizing
neuromuscular junction cells in
11. 11
Receptor Locations physiological role
SGLT4 Kidney , intestine
and tumors, of
the kidney,
pancrease and
colon while not
expressed in the
matched normal
tissues
Physiological role not fully understood
SGLT5 Kidney Selective to fructose and mannose,
probably responsible for there
absorptin in the proximal tuble of the
nephrone
12. BIOLOGY OF SGLT.. absorption capacity of SGLT 2 and 1
12
Fig 2: Location of SGT2 SGT1 on the nephron
and glucose absorption capacity (Racheal and
sulman 2020)
13. MECHANISM OF ACTION OF SGLT2
13
SGLT proteins transport
glucose through the
membrane into the cells,
against the concentration
gradient of glucose.
This is done by using the
sodium gradient, produced
by
sodium/potassium ATPase
pumps, so at the same
time glucose is transported
into the cells, the sodium
is too
SGT2i block SGT2
receptor to prevent
glucose and sodium
reabsorption
Dapagliflozin
Empagliflozin
Fig3 medweb.tulane.edu/pharmwiki
17. Sgt2i monotherapy in type2 dm
17
Sgt2i reduce HbA1c, fasting plasma glucose, body weight and
BP (Molly G NLM 2018)
Sgt2i can be use as monotherapy if metformin is contraindicated
or not tolorated
Sgt2i are associated with superior A1C reduction compare to
DPP4 inhibitors especially in marked hyperglycemia but have
similar effect with metformin and sulphonylureas
however sgtis have advantage of body weight reduction over
metformin, sulphonylureas and DPP4i
Risk of hypoglycemia is lower with sgt2i than with insulin and
insulin secretagogues
19. SGT2i combination therapy in type 2 dm
19
SGLT2i as an add-on therapy to metformin
significantly improved outcomes compared with non-
SGLT2i combinations for up to two years of treatment.
Improvement in the change from baseline in HbA1c
was significantly more in SGLT2i therapy than in non-
SGLT2i combinations in the long-term treatment (
fateema saleem 2017)
When combined with insulin sgt2i will reduce the cost
of insulin treatment by reducing daily insulin dose
regiment
21. sgt2i in HF
21
In February 2022, the FDA approved Jardiance
(empagliflozin) to treat heart failure with preserved
ejection fraction (HFpEF).
HFpEF is a form of heart failure that has few
treatment options. empagliflozin provides a new
choice for preventing heart failure complications.
dapagliflozin and empagliflozin, respectively, reduced
the risk of cardiovascular death and Hospitalization in
HF by 26% in patients with HFrEF.
These benefits were observed in those with and
without type 2 diabetes, and resulted in an
improvement in patient reported quality of life indices
(Subodh et al ESC 2020)
22. Mechanism of cardiovascular benefit of
SGLT2i
22
1. Natriuresis, diuresis, and reduction in plasma
volume
2. Improvement of cardiac energy metabolism
3. Weight loss and effects on epicardial fat
4. Reduction in blood pressure
5. Amelioration of endothelial dysfunction and vascular
stiffness
6. Protection of renal function
7. Reduction in serum uric acid level
8. Inhibition of cardiac Na+/H+ exchanger
9. Improvements in cardiac structure and function
10. Attenuation of inflammation
23. 1. Natriuresis, diuresis and reduction in plasma
volume
23
SGLT2i reduce the reabsorption of filtered glucose and sodium by
blocking SGLT2, thus leading to natriuresis and osmotic diuresis.
SGLT2i attenuate congestion, with little effect on arterial perfusion, in
patients with HF. this is because the osmotic diuresis induced by
SGLT2i leads to greater clearance of electrolyte-free water in the
intercellular space than in the blood vessels, causing a greater
reduction in intercellular fluid volume, relative to circulating volume. (
Hallow KM 2018)
The improved quality of life in patients with HF during therapy with
SGLT2i might be partly explain by this mechanism (Boyang Xiang
2021)
25. 2. improvement of cardiac energy metabolism
25
The heart acts as an omnivore under healthy conditions,
metabolizing glucose, fatty acids, ketone bodies, as well as branched
chain amino acids.
Manifestation of heart failure however restricts substrate flexibility
and favors glucose oxidation, which has been attributed to the
reactivation of a fetal [gene] program.
This runs in parallel with a reduced capacity of the insufficient heart
to metabolize fatty acids, branched chain amino acids and ketone
bodies
With greater utilization of the non-glucose fuel, empagliflozin
increased myocardial ATP production and improved myocardial work
efficiency
26. 3. Weight loss and effects on epicardial fat
26
Studies using bioimpedance
spectroscopy showed that the weight
loss during treatment with SGLT2i
could be principally attributed to a
decrease in both visceral and
subcutaneous adipose tissue with no
obvious change in lean tissue mass
It is noteworthy that the decrease in
epicardial adipose tissue mass
observed with SGLT2i is independent
of the antihyperglycemic effects. In
addition to reducing adipose tissue
mass, SGLT2i attenuate systemic and
adipose inflammation (Yagi S 2017)
The accumulation and inflammation of
epicardial fat may promote
inflammation and fibrosis in the
underlying tissues, thereby
contributing to atrial tachyarrhythmias,
ASCVD, and HF with preserved
ejection fraction (HFpEF) (Packer M
2018)
27. 4.Amelioration of endothelial dysfunction and vascular
stiffness
27
Many clinical
studies have
shown that short-
term therapy with
SGLT2i mitigates
aortic stiffness and
improves
endothelial
function (Boyang
Xiang 2021)
Arterial stiffness is
strongly
associated with
hypertension,
cardiovascular
events, HF, and
death, and
endothelial
dysfunction plays
a vital role in the
development of
Laetitia Dou and Stéphane Burtey 2021
https://doi.org/10.1016/j.kint.2021.01.0
08
28. 5. Reduction in serum uric acid
28
Increased uric acid stimulates the proliferation and hypertrophy
of vascular smooth muscle cells promotes intracellular oxidative
stress depletes nitric oxide, activates the vascular
reninangiotensin system, and induces an inflammatory reaction.
Increased uric acid is also associated with hypertension, atrial
fibrillation, and HF.
SGLT2i-induced glycosuria suppresses uric acid absorption in
the proximal tubule, leading to increased uric acid excretion and
reduced plasma levels of uric acid
29. 6. Attenuation of inflammation
29
Low-grade inflammation is recognized to contribute to the
development of atherosclerosis and to be associated with an
increased risk of CVD
SGLT2i slightly decrease circulating levels of inflammatory
factors, including interleukin-6, high‐sensitivity C‐reactive protein,
and tumor necrosis factor-γ and -α, in patients with T2DM
SGLT2i also reduce M1 macrophage accumulation and polarize
M2 macrophages in fat and liver
The antiinflammatory effect of SGLT2i is probably mediated by
many other factors, such as increased levels of ketone bodies
and reduced levels of uric acid
30. Initiation of sgt2i in heart failure
30
When do you start SGLT2 in heart failure?
Initiation of SGLT2 inhibitors in patients hospitalized
for Acute HF should best be during hospitalization or
early post-discharge (within 3 days) reduces the risk
of rehospitalization for heart failure and improves
patient-reported outcomes with no excess risk of
adverse effects
When do you STOP SGLT2 in heart failure
Stop sgti prior to surgery and continue after the
surgery when the pt resume eating and drinking
normally
31. BENEFIT IN CKD
31
Adding dapagliflozin to current standard care has been shown to
significantly reduce the risk of having declining kidney function,
end-stage kidney disease, or dying from causes related to the
kidneys or cardiovascular system. ( NKF 2022)
dapagliflozin significantly reduced risk of kidney failure and
prolonged survival in patients with CKD with or without type2
diabetes (Glenn M Chertow 2021) (Heerspink HJL 2020)
33. reduction in imflamation
33
An SGLT2 inhibitor works by blocking the SGLT2
protein in the kidneys. Blocking this protein alleviates
kidney damage by reducing pressure and
inflammation in the kidneys
35. reduction in albumuniria
35
Reductions in albuminuria are associated with a
subsequent lower risk of kidney failure in patients with
chronic kidney disease. The SGLT2 inhibitor
dapagliflozin significantly reduced albuminuria in
patients with type 2 diabetes and normal or near-
normal kidney function.
In patients with chronic kidney disease with and
without type 2 diabetes, dapagliflozin significantly
reduced albuminuria, with a larger relative reduction
in patients with type 2 diabetes. The similar effects of
dapagliflozin on clinical outcomes in patients with or
without type 2 diabetes, (Jongs N, Greene oct 2021)
36. SGT2i in cancer
36
Sgt2 receptor protein has been found in tumour of the
prostate and bladder
Sgt2 inhibitors prevent uptake or oxidation of glucose
by the tumor cells
SGT2I Can be potential new therapeutic strategies for
cancer treatment by specifically targeting SGLT
further discoveries related to the functional
association of other SGLTs of the SLC5 family to
human pathologies will open the door to potential new
therapeutic strategies for cancer
37. CANDIDATE FOR SGTI
37
Recommended
Type 2 diabetes mellitus patient not responding to oral
antidiabetic agent
Heart Failure Patient with recurrent hospitilization
(ESC 2020) (FDA 2022)
Type 2 diabetes mellitus patient with or at high risk of
cardiovascular disease
Type 2 diabetes patient with Ckd (NICE NOV 2021)
(NKF 2022)
Not recommended
Pt with type 1 diabetes
Any one with ketoacidosis
Dm with Severe kidney diseases
38. dapagliflozin
38
Dose and Indication
Type 2 diabetes 5 – 10mg PO daily
Heart failure 10mg PO daily
Ckd 10mg PO daily
Dose Modification
At eGRF 25 – 45mL/min/1.73m2 No dose adjustment in HF and ckd,
not recommended for dm without risk of cvs or ckd
eGFR <25 mL/min/1.73 m2 Initiation not recommended. Patients with HF
or CKD may continue 10 mg/day to reduce risk of eGFR decline, ESKD, CV
death, and HF hospitalization
Price
48000 naira 28 tablet forxiga
39. emfagliflozin
39
Dose and indication
Type 2 diabetes 10 – 25mg
Heart failure 10mg
Dose modification
eGFR <30 mL/min/1.73 m2 Not recommended for dm without
cardiovascular risk factors
eGFR ≥20 mL/min/1.73 m2: No dosage adjustment required
Price
50000 naira 30 tablet jadiance
40. canagliflozins
40
Dose and indication
Type 2 diabetes 100 mg PO daily
Dosing consideration
eGRF must be above 30mL/min/1.73m2). to initiate
Dose may be increase to 300 mg daily in patients who have eGFR ≥60
mL/min/1.73 m² and require additional glycemic control
Dose modification
eGFR 30 to <60 mL/min/1.73 m2: 100 mg daply
eGFR <30 mL/min/1.73 m2 with albuminuria >300 mg/day: 100 mg daily
to reduce the risk of end-stage kidney disease, doubling of serum
creatinine, CV death, and hospitalization for heart failure
Price
60000 naira 30 tablet of ivokana 100mg
41. Safety profile
41
Pregnancy : contraindicated in second and third trimester ,
animal studies shows adverse renal changes
Lactation: limited data available; trace found in breast milk in
animal studies
Infant: safety and efficacy not established
Geriatrics : generally safe but may experienced symptomatic
hypotention
Hepatic impirement: avoid in severe hepatic impirement
Renal insufficiency: adjust the dose
43. Interaction
43
Diuretics with sgt2i result in increase urine volume,
may enhance the potential of volume depletion and
hemoconcentration
Canagliflozin and drugs that increase serum
potassium ( eg aliskiren, amiloride, captopril )
Canagliflozin increases level of digoxin
The risk or severity of hypoglycemia can be increased
when Acetylsalicylic acid is combined with
Dapagliflozin.
Gliflozin classically interact with more than 300 drugs,
a moderatee interaction that slightly increase or
decrease it activity or the activity of the interacting
drug.
44. contraindications
44
contraindicated in patients with a known serious
hypersensitivity reaction e.g angioedema, urticaria
Patient on dialysis
Breastfeeding
Type 1 dm
46. Pharmaceutical care
46
Taking with meal
Take before the first meal of the day
Avoid high fat mealhygiene when taking dapagliflozin
Dose missed
Take the subsequent dose, do not double dose
Pt counseling
Genital/perineal
Regular Foot exams
Watch for symptoms of DK acidosis
Reduce alcohol intake
type 2 dm pt taking dual therapy should be closely
monitore for hypoglycaemia
Adequate fluid intake
48. Previously asked question
48
eGFR sharp decline with dapagliflozin before maintaining a
steady level
Can sgt2i alone sustain glycemic control given that it is
independent of insulin
Safety in pregnancy
Cost and comparism with the innovator brand forxiga
Weigth lost and life style modification wth sgt2i
Is sgt2i recommended in pt with badground cvs disoder, dm and
hiv
49. Referrence
49
Stefan D. Anker,Muhammad Shahzeb Khan,Izza Shahid,Gerasimos
Filippatos,Andrew J.S. Coats,Javed Butler Sodium–glucose co-transporter 2
inhibitors in heart failure with preserved ejection fraction: reasons for optimism 26
June 2021 https://doi.org/10.1002/ejhf.2279
Rachel J. Perry1 and Gerald I. Shulman1 Sodium glucose cotransporter-2
inhibitors: Understanding the mechanisms for therapeutic promise and persisting
risks; August 12, 2020
Usman, Muhammad Shariq; Siddiqi, Tariq Jamal; Memon, Muhammad Mustafa;
Khan, Muhammad Shahzeb; Rawasia, Wasiq Faraz; Talha Ayub, Muhammad;
Sreenivasan, Jayakumar; Golzar, Yasmeen (2018). "Sodium-glucose co-
transporter 2 inhibitors and cardiovascular outcomes: A systematic review and
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Rachel J. Perry Gerald I. Shulman Sodium-glucose cotransporter-2 inhibitors:
Understanding the mechanisms for therapeutic promise and persisting risks
Open AccessDOI:https://doi.org/10.1074/jbc.RE medweb.tulane.edu/pharmwiki/
(access 5:30 am 26 – 05 – 2022)
Husam M. Salah, Subhi J. Al’Aref, Muhammad Shahzeb Khan, Malek Al-
Hawwas, Srikanth Vallurupalli, Jawahar L. Mehta, J. Paul Mounsey, Stephen J.
Greene, Darren K. McGuire, Renato D. Lopes & Marat Fudim : Efficacy and
safety of sodium-glucose cotransporter 2 inhibitors initiation in patients with acute
heart failure, with and without type 2 diabetes: a systematic review and meta-
analysis : febuary 2022
50. 50
Carlos G. Santos-Gallego, Juan Antonio Requena-Ibanez, Rodolfo San
Antonio, Kiyotake Ishikawa, Shin Watanabe, Belen Picatoste, Eduardo
Flores, Alvaro Garcia-Ropero, Javier Sanz, Roger J. Hajjar, Valentin Fuster,
and Juan J. Badimon: Empagliflozin Ameliorates Adverse Left Ventricular
Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics:
Journal of american collage of cardiology : April 2019
Subodh Verma, 1 Stefan D. Anker, 2 Javed Butler, 3 and Deepak L. Bhatt :Early
initiation of SGLT2 inhibitors is important, irrespective of ejection fraction:
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• Laetitia Dou, Stéphane Burtey Reversing endothelial dysfunction with
empagliflozin to improve cardiomyocyte function in cardiorenal syndrome
VOLUME 99, ISSUE5, P1062-1064, MAY 01
DOI:https://doi.org/10.1016/j.kint.2021.01.008
• Bjornstad, Petter - Cherney, David - - Renal Hyperfiltration in Adolescents with
Type 2 Diabetes: Physiology, Sex Differences, and Implications for Diabetic
Kidney Disease2018/03/19 VL - 18 DO - 10.1007/s11892-018-0996-2
