SGLT2 INHIBITORS are very new therapeutic agents for the management of Type2 DM.They are very unique molecules and they donot cause hypoglycaemia or weight gain unlike many other OADs

1. NIDM Vs. NIDDM
CURRENT THERAPEUTIC
APPROACH TO TYPE2DM
DR.RISHIKESAN K.V
SPECIALIST PHYSICIAN
VENNIYIL MEDICAL CENTRE
SHARJAH,UAE

4. A HUGE PROBLEM
 DIABETES IS A HUGE
PROBLEM
 WORLDWIDE 371 MILLION
INDIVIDUALS LIVE WITH TYPE 2
DIABETES
 THE MOST RECENT NHANES
REPORT INDICATES THAT LESS
THAN 50% AMERICANS WITH
DIABETES ACHIEVE A HbA1C
GOAL LESS THAN 7%

6. PREVALENCE OF
DIABETES
 THERE IS A DRAMATIC
INCREASE IN THE
PREVALENCE OF DIABETES
GLOBALLY
 MANY PEOPLE WITH DIABETES
FAIL TO MEET GLYCAEMIC
TARGETS
 A JOINT STATEMENT BY ADA ,
AHA , & ACC URGES A TARGET
HbA1C LEVEL OF < 7%

8. COMMON BARRIERS
COMMON BARRIERS TO
THE ACHIEVEMENT OF
TARGET HbA1C ARE SIDE
EFFECTS WITH
CURRENTLYAVAILABLE
DRUGS PARTICULARLY
HYPOGLYCAEMIA AND
WEIGHT GAIN

9. AN UNMET NEED….
 REMAINS FOR IMPROVED
GLYCAEMIC CONTROL IN
PATIENTS WITH TYPE 2 DM
 CURRENT APPROACHES ARE
ASSOCIATED WITH
LIMITATIONS
 NEW THERAPIES WOULD BE
OF VALUE

11. PATHOPHYSIOLOGY IN
T2DM
THERE IS A BUNCH OF DEFECTS
AND DIFFERENT MECHANISMS OF
ACTION IN DIABETIC INDIVIDUAL AS
SUGGESTED IN THE FAMOUS
OMINOUS OCTET MODEL BY PROF.
DE FRONZO.
WE HAVE TO APPRECIATE THAT ALL
OF THESE ORGANS COMMUNICATE
WITH EACH OTHER.
WHAT WE DO TO TREAT 1 ORGAN
MAY HAVE EFFECTS ON THE
RESPONSE OF OTHER TARGET

12. The increasing prevalence of T2DM, in combination with
limitations of current therapies, has led to the search for newer
alternatives. SGLT2 inhibitors represent a novel 'glucuretic'
therapeutic strategy for the treatment of T2DMs.

13. PROS AND CONS
Existing therapies focus on
*Reducing insulin resistance, *Increasing
insulin secretion, *Slowing CHO digestion,
Restraining glucagon production, and
*Supplying exogenous insulin.
LIMITATIONS OF TRADITIONAL AGENTS : (metformin, SUs
and insulin) GI side effects, wt. gain and
hypoglycaemia.
TZDs : CV safety concerns, wt. gain, increased
fractures and fluid retention.
DPP-4 inhibitors well tolerated, but merely weight
neutral.
GLP-1analogues result in moderate wt. loss, are
injectables and their use is limited by GI side effects

14. NEW TREATMENT
OPTIONS

15. RENAL GLUCOSE TRANSPORT
MAY PRESENT A RATIONAL
TARGET

16. FILTRATION AND
REABSORPTION
MOST OF US HAVE A GFR OF ~
180L/DAY AND OUR GLUCOSE IS 90-
100 MG/D .
WE FILTER ABOUT 160GM. PER DAY
90% OF THIS IS REABSORBED IN THE
S1 SEG. OF PCT BY SGLT2
THE REMAINING 10% BY SGLT1 OF
S3 SEGMENT
SGLT1 ALSO PRESENT IN THE GUT
BLOCKING SGLT1 LEADS TO
DIARRHOEA

17. GLUCOSE
TRANSPORTERS
SGLTs 4-6 ROLES
NOT YET
DETERMINED

18. A CLOSER VIEW
SGLT2
TRANSPORTS
GLUCOSE IN
CONCERT WITH
Na+
Na+ IS PUMPED
OUT BY Na+ K+
ATP- ase
GLUT2 , ANOTHER
TRANSPORTER
GETS THE
GLUCOSE FROM
THE CELL BACK

19. A DRUG THAT SEEMS TO BE SO
FAR REMOVED FROM OUR
CONCPEPTS ABOUT THE CORE
DEFECTS IN T2DM, CAN
CORRECT THE CORE DEFECT

20. We have a drug that
will work in those
who have good renal
function, causing
glycosuria, with
weight loss and a
low risk of
hypoglycemia. That
is a very attractive
class.

21. INSULIN RESISTANCE
IN INDIVIDUALS
WITH T2DM
INSULIN
RESISTANCE IS
MAXIMALLY
ESTABLISHED
AND
> 50% OF BETA
CELL FUNCTION
HAS BEEN LOST
AT THE TIME OF
DIAGNOSIS

22. AS GLUCOTOXICITY IS REVERSED…
GLUCOSE TRANSPORT
SYSTEM IN THE
MUSCLE IS IMPROVED
MORE OF ACTIVATED
GLUT4 TRANSPORT
PROTEIN ARE
TRANSLOCATED TO
THE CELL MEMBRANE
THERE IS
ENHANCEMENT OF
INSULIN-SIGNALING
TRANSDUCTOR
SYSTEM
G 6
PHOSPHATASE,
THE RATE LIMITING
ENZYME IS INHIBITED
SO THAT LESSER
AMOUNT OF GLUCOSE
GET OUT OF THE LIVER
HEPATIC GLUCOSE
PRODUCTION IS
MODULATED.
THERE IS DECREASE
IN THE CRITICAL
ENZYMES OF
GLUCONEOGENESIS

23. INSULIN SENSITIVITY
With the use of SGLT2 inhibitor , glucose
reabsorption is inhibited from the renal
tubules. Approx.70 g of glucose a day is now
excreted in the urine, independent of insulin
sensitivity, and serum insulin levels.
FBS goes down , overall glucose tolerance
improves with a reduction in A1C, and some
wt loss . In doing so, there may be some
improvement in peripheral insulin sensitivity.
The reduced insulin secretory demand by
lowering ambient glucose, may help conserve
beta cell function.

24. A DELICATE AND
WELL BALANCED
SYSTEM OF
GLUCOSE INPUT
AND
UTILISATION

25. GLUCOSE HOMEOSTASIS &
KIDNEY
The total glucose
stored in the body is
450g.
The brain and the rest
of the body use almost
same (125+125=250g)
amount of glucose.
Glucose prodn. is 70 g.
Glucose Production
(Gluconeogenesis
Typical western diet
Glycogenolysis)
-70g/d
contains 180g. glucose
The kidney filters and
reabsorbs 140 -180 g/d
.

26. KIDNEY,AN
DN
EOGLUCO
G-ENESIS
Glucose production
happens in the
renal cortex. The
renal medulla as an
obligate consumer
affects glucose
utilization. FFA -the
main energy source
of renal cortex
gluconeogenesis .
20-25% of the total
body glucose is
released by kidney.

27. KIDNEYS IN T2DM
*Increased baseline
gluconeogenesis,
*Insulin resistance ,
and *Increased FFA
in diabetes stimulate
gluconeogenesis in
the kidney.
The liver down-regulates,
there is a
reduction in hepatic
glucose release.
However the kidney
has an increase in
glucose release.
These different
organs have different
responses to
diabetes.

28. KIDNEY’S CONTRIBUTION
Glucose control is
altered in people with
T2DM.
Gluconeogenesis is
increased in the
postprandial and post
absorptive state.
There exists the renal
contribution to hyper-glycemia
with a 3-fold
increase relative to
patients without
diabetes.

29. TRANSPORT MAXIMUM :T max
As the glucose level
rises in the blood
more glucose is
filtered but much of
it is reabsorbed.
However as we reach
T max. tubule can’t
reabsorb more. Once
we cross that point we
start excreting more
and more glucose.
That level is 180-200
The magic number is approx.180 mg/d L. mg/ dl

31. THE PATHOPHYSIOLOGY
The magic number is approx.180
mg/d L.
However, normally resorption
levels off and more and more
filtered glucose is excreted when
levels exceed 180 mg/d L .
In pts. with diabetes, T Max for
Glucose changes, because these
SGLT2 receptors change.

32. THE ABILITY OF THE
DIABETIC KIDNEY
TO CONSERVE
GLUCOSE
MAY BE AUGMENTED
IN ABSOLUTE TERMS
BY AN INCREASE IN
THE RENAL Tm FOR

35. GLUCOSE TRANSPORT IN
DIABETES
 IN EVERY ANIMAL MODEL OF TYPE
1 AND TYPE 2 DIABETES THERE IS
AN INCREASE IN THE Tm FOR
GLUCOSE.
 WE HAVE PTs. WITH FBS 180
MG.THEY EAT A MEAL , IT GOES TO
300 MG; STILL THEY HAVE NO
GLUCOSE IN THE URINE
 THIS IS BASICALLY TELLING THAT
THEIR Tm IS SET UPWARDS

36. HIGHER SGLT2 mRNA /
GLUT2 EXPRESSION…

37. SGLT2 LEVELS IN T2DM
There is increased
SGLT2 expression
and activity in the
renal epithelial
cells of the
proximal tubule.
This proves that the renal
SGLT2 levels, are increased
in patients with type 2 diabetes

38. SGLTs
2 types : the SGLT2s and
the SGLT1s.
The SGLT2s are found almost
exclusively in the kidney.
These low affinity but high
capacity glucose transporters
are the ones that are doing the
majority of the work in the kidney.
The SGLT1s are mostly found in
the intestine.
They handle glucose or
galactose.
They have high affinity and low
capacity for glucose, in contrast
to the SGLT2s.
These co transporters work
together in PCTs

39. The kidney is very dynamic and produces a large
number of sensors. It is so important in the
homeostatic mechanisms of the body . There are
many SGLTs -- many of which are sensors,

41. CHANGE THE MINDSET
We need to change our mind set
regarding the adversarial relationship
clinicians have with the kidney.
The kidney is actually an ally in
managing T2DM
We as clinicians should understand
and actually utilize , the KIDNEY.
KIDNEY has the ability to handle
glucose and help the patients to
achieve glycemic control.

42. The kidney is actually an ally in
managing T2DM

43. By reducing the activity of these
transporters – (SGLT2 ) by around
30%, we are able to flush out
approx.60-70 gm. of glucose out
into the urine/day.
This, of course, not only reduces
hyperglycemia, but it also reduces
calories therefore, assists weight
loss via a non-insulin dependent
mechanism, so it is not associated
with hypoglycemia.

44. GENETIC MODEL OF SGLT2
INHIBITION
NATURE HAS PROVIDED
US WITH A BEAUTIFUL
GENETIC MODEL OF SGLT2
INHIBITION THAT TELLS US
FOR SURE THAT THE
APPROACH OF BLOCKING
THE SGLT2 TRANSPORTER
WILL WORK EFFICIENTLY TO
DUMP OUT EXCESS GLUCOSE

45. AR DEFICIENCY OF THE SGLT2
TRANSPORTER

46. ABSOLUTELY
ASYMPTOMATIC
RENAL GLUCOSURIC PERSONS
ARE ASYMPTOMATIC , DON’T
BECOME HYPOVOLEMIC AND
DEHYDRATED, DON’T DEVELOP
HYPOGLYCAEMIA
RENAL Bx. HAVE BEEN DONE :
THEY HAVE NORMAL RENAL
HISTOLOGY , NO INCREASED
INCIDENCE OF CRF, UTI OR
DIABETES AND THEY ARE NEVER
OBESE

47. WE HAVE MULTIPLE
GENERATIONS OF
HUMAN DEFECT. WE
CANNOT GET BETTER
TOXICOLOGY

48. WE HAVE MULTIPLE GENERATIONS OF
HUMAN DEFECT. WE CANNOT GET BETTER
TOXICOLOGY

49. PHLORIZIN
This is the molecule
called Phlorizin , the
prototype of an SGLT
inhibitor.
It is toxic to humans ,
was first described in
the mid-19th century.
It is isolated from the
root of the bark of the
apple tree and is
utilized for exploration
of SGLT function.

50. PHLORIZIN IN RATS

51. Here is the representation .They work by blocking the
transporter –SGLT2.Those dots in the middle of what is
supposed to be a proximal tubule represent glucose.
As the transporters are blocked, very little glucose comes back
to the body . The glucose reabsorption is decreased and the majority
of the glucose is excreted in the urine. Glucose levels fall.
Calories are lost, Less insulin is required.
Sugar levels improve

52. OPEN THE SPIGOT
WE ARE JUST GOING TO OPEN
THE SPIGOT IN THE KIDNEY
AND LET THE GLUCOSE FLOW
OUT.
This alleviates glucotoxicity by
dumping the excess in the
urine.
NOW WE SHOULD FEEL
COMFORTABLE WITH THIS
APPROACH OF SGLT2

53. SMART MOLECULES..
When SGLT2 inhibitors reduce the
amount of glucose that is coming back
into the body the signals to the kidney
suggest that the SGLT2 receptors now
have less glucose to handle .
As a result they readjust ; and the TM
for glucose falls.
It does not fall to 20 or 30 mg/dL and
induce hypoglycemia, but it falls to
levels of approx. 70 mg/d L.

55. SMART MOLECULES.THEY READJUST THEMSELVES TO A T
MAX.OF APPROX. 70MG/DL.

56. There are 2 SGLT2 inhibitors that are approved in
the United States and Europe: canagliflozin and
dapagliflozin. There is one on the horizon,
empagliflozin, which may be available within the
next year, and there are others in development.

57. POTENTIAL CLINICAL
BENEFITS
 OSMOTIC DIURESIS LEADS TO
INITIAL WEIGHT LOSS
 LOSS OF EXCESS CALORIES IN THE
URINE LEADS TO SUSTAINED
WEIGHT LOSS
 GLUCOSE LOWERING WITH A LOW
RISK OF HYPOGLYCAEMIA
 NON INSULIN DEPENDENT
MECHANISM (NIDM CHALLENGES
NIDDM)

58. EFFICACY AND
TOLERABILITY

59. N
MONOTHERA
PY
CANAGLIFLOZIN USED AS
MONOTHERAPY IN T2DM WHO
ARE INADEQUATELY
CONTROLLED WITH DIET AND
EXERCISE , AGAIN OVER A
PERIOD OF 52 WEEKS.
THERE IS A DOSE RESPONSE
REDUCTION OF HbA1C
APPROXIMATELY .8% WITH
100MG AND 1.1% WITH 3OOMG
.
MORE THAN 50% PTS.
REACHING HbA1C LESS THAN
7%.
BODY WEIGHT CHANGES BY
3-4KG

60. COMBINATION
WITH SU &
METFORMIN
The changes in
hemoglobin A1c, are
consistent and
durable over a period
of 52 weeks.
There is a dose
response whereby the
average drop in A1C
was in the order of
0.7%, with the lower
dose of canagliflozin
and 0.9% with the
higher dose of
canagliflozin.

61. W e h a v e data from different
compounds of this new class.
It shows that it is
beneficial to add an SGLT2
inhibitor even with a long,
15-years’ duration of diabetes,
where the patient has been on 70-
90 units/day of insulin for 6 years.
This causes an HbA1c reduction
from a baseline of 8.5% down to
7.4% .
A reduction of 25% insulin use and
good effect on weight.

62. Wilding J, et al. EASD 2013 Poster 946
The study showed that at week 26 a greater proportion of
patients with T2D who had received canagliflozin achieved
an HbA1c of <7% or an HbA1c of ≤6.5%, SBP <140 mm Hg,
body weight reduction 4%, with canagliflozin 100 and 300
mg compared with placebo.

64. Clinically
meaningful
drop in SBP
were seen
with
canagliflozin
over 26
weeks 25
The diastolic blood pressure, likewise, drops between
2 -3 mm Hg.
The BP effects are thought to be related to the osmotic
diuretic effect and very mild natriuresis.
SGLT2 Inhibitors may affect nitric oxide, and it is
currently under investigation.

65. NATRIURESIS
The effect on BP is in all
likelihood the combined result of
the reduction in body weight but
also the loss of sodium through the
urine.
The natriuretic effect-because
the compounds block, the
sodium glucose cotransport at the
level of the tubular nephron.

66. LIPIDS AND SGLT2
INHIBITORS
The proportion of patients with LDL-C <100 mg/dL at
week 26 was modestly lower with both canagliflozin
doses compared with placebo

67. SAFETY & EFFICACY
Increased urination
has been reported
particularly in women,
but also in men.
Women are likely to
get vulvo vaginal
infections. The
people who tend to
get those infections
are ones that had the
infections before the
drugs were given in
the first place

69. EFFICACY AND SAFETY in
ELDERLY T2D TREATED OVER 2
YEARS
Emerging Role of SGLT2 Inhibitors: Updates From ADA 2014 CME
Ages 55 to 80 yrs. Canagliflozin 100 mg or 300 mg
vs placebo.
HbA1c decrease as being relatively modest.
UTIs : 10%(placebo ), 15% in 100 mg and 17% in the
300 mg group .
The osmotic diuresis symptoms 6% (placebo) , 100
mg had 9%, and 300 mg was 12%.
The AE of dizziness , hypotension , was mainly seen
in the 300-mg group at 2%-4% . The SBP decreased
significantly at 5 to 7 mm Hg vs placebo.
There are always mycotic infections in this
population.
No Hypoglycemia in the canagliflozin arm.

70. Caution should be exercised in elderly patients, with renal
impairment. These are patients with an estimated GFR
between 45 and 60. Dapagliflozin is not indicated in those
patients and Canagliflozin is.

71. There are at least 3 major studies running right now.
We will have the results by 2017 and 2018.
Then we will have much more information regarding long-term safety,
efficacy, and possible effects on both macro/ microvascular
outcomes.

72. GU INFECTIONS
The extensive clinical program with this class
of agents has shown that:
There is a clear signal regarding the
increase of genital infections, occurring
in 4-10% of patients; mostly in elderly,
female patients. Generally, these infections
are easy to treat with standard methods.
There is a low rate of recurrence, and very
rarely are discontinued the treatment.
Discontinuation of therapy occurred at a
frequency of about 1 in 500 in the clinical
development program

74. REFRESHER COURSE FOR
PATIENTS
Women should have proper hygiene
and keep the area dry and clean.
Circumcised males do not
have any significant issues.
Non circumcised males need to keep
the area clean because balanitis has
been reported in men with these
agents.
The side effects are rare ;generally well
tolerated if they are properly educated

76. SGLT2 INHIBITORS…
SUMMARY
A NOVEL NON INSULIN DEPENDENT
MECHANISM .
They can be used at any stage in
the natural history of T2DM.
They can be used as monotherapy or in
combination with insulin, metformin ,
DPP4inh.
Treatment is associated with mean weight
loss , small reduction in BP, which may also
be beneficial to patients with co-existing CVD.
Trials regarding long-term cardiovascular
outcomes are ongoing.

77. BOTTOM LINE
By the very mechanism of action, these
drugs can also potentially be used in type 1
diabetes, because they do not depend on the
presence of endogenous insulin or beta cell
function. Therefore, in association with
insulin, obviously, they might find a place in
the treatment of type 1 diabetes
#To stabilize the glucose swing.
#To limit the weight gain that occurs with
satisfactory insulin treatment in type 1 DM.
This application is being actively
investigated.

78. KEY TAKEAWAYS
The kidney contributes to
gluconeogenesis and
hyperglycemia in patients with type
2 diabetes.
SGLT2 inhibitors act by a novel
mechanism and are useful in
patients to achieve goal HbA1c
SGLT2 inhibitors lower HbA1c levels
They have the benefit of wt.
reduction in pts with T2DM

80. THANK YOU …
ANY ?????????