2. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a newly developed class of oral anti-
diabetic drugs (OADs) with a unique mechanism of action and having various pleotropic effects in
addition to lowering the blood sugars
3. ROLE OF SGLT2 AND SGLT1 IN RENAL
AND GI GLUCOSE TRANSPORT AND THE
EFFECTS OF DIABETES
In the kidneys, glucose is freely filtered by the glomeruli
Glucose reasorption (99% of filtered) occurs in PCT by active transport (SGLT1/2)
Approximately, 90% by the high capacity, low affinity SGLT2 with the low capacity, high affinity SGLT1
transporter, in the distal segment, responsible for the remaining 10%.
These transporters bind with both sodium ions (Na+) and glucose in the tubular filtrate, then these are
translocated across the cell membrane.
This process is driven by the electrochemical Na+ gradient between the tubular filtrate and the
intracellular space and is called secondary active-transport
Glucose in the tubular epithelial cell is then transported down a concentration gradient across the
basolateral membrane to the systemic circulation by GLUT2.
When the blood glucose concentration rises above about 10 mmol/L, filtered glucose load exceeds the
tubular maximum reabsorptive capacity (TmG, approximately 375 mg/min [425 g/d] in healthy individuals)
excess glucose is excreted in the urine.
4.
5.
6.
7. In the presence of chronic hyperglycaemia, there is paradoxically excessive glucose reabsorption,
due to compensatory up-regulation of SGLT2 and/or SGLT1 expression in response to increased
urinary glucose filtration, exacerbating hyperglycaemia.
Mediated via induction of hepatic nuclear factor-1 (HNF1) alpha by the increased energy demands
of increased glucose transport
9. Glucose lowering effects
By causing glucosuria
SGLT2is inhibit 50-60% of reabsorption of glucose in PCT
HbA1c reduction is 0.6 to 1%
Action is independent of other glucose lowering drugs, can be combined with other OHAs and
insulin
Effects to lower HbA1c are reduced in renal impairment
Usually not recommended if GFR is <45ml/min
10.
11. Proposed mechanisms underlying
cardiovascular benefit of SGLT2 inhibitors
1. Glucosuric effect
Glucosuria osmotic diuresis intravascular volume depletion reducing ventricular preload
and myocardial oxygen consumption
Glucosuria altered insulin:glucagon ratio favours hepatic ketone production (especially β-
hyrdoxybutyrate) used as highly efficient fuel source for oxidative ATP production by the
cardiomyocyte
2. Body sodium depletion:
may reduce blood pressure and improve ventricular function.
12. 3. Inhibition of the NHE:
There are two isoforms of the NHE:-NHE1 isoform in the heart and vasculature, NHE3 isoform in
the kidneys. In the cardiomyocytes
blockade of NHE1 reduced sodium and calcium entry into the cytosol increased calcium entry
into the mitochondria activating mitochondrial ATP generation and antioxidant enzyme defences.
There is evidence that both effects in the kidney, and possibly in the heart (perhaps due to SGLT2i
binding the NHE1 isoform, as SGLT2 is not expressed in the heart), might partially explain the
benefits seen in heart failure
13.
14. METABOLIC EFFECTS OF SGLT2
INHIBITION
1. Effects on energy balance
The glucosuria and osmotic diuresis associated with SGLT2 inhibition can help in reducing glycaemia and weight loss
causes significant glucosuria of 75 g glucose/d which is equivalent to energy loss of 300 kcal/d and osmotic diuresis of
~400 mL/d
Reduceds insulin requirement
clinical trial data with SGLT2i has revealed that the observed weight loss is in the range of 2 to 3 kg per year
can exert effects on body weight as early as 7 days and have been shown to persist in clinical trials of up to 4 years
duration although weight loss reaches a plateau after about 6 months of treatment
the reduction in hepatic glycogen stores and osmotic diuresis contributes to early onset weight loss, the reduction in
steatosis, visceral and subcutaneous adipose tissue accounts for the late effects on body weight
The weight reduction is lesser than expected, may be because of compensatory increased appetite( as was observed in
animal models)
15.
16. 2. Effects on pancreas, liver and adipose tissue metabolism
Glucosuria reduction of fasting and post-prandial glucose concentrations reduction in insulin
secretion and increase in glucagon secretion increased endogenous glucose production
(mediated by hepatic glycogenolysis and gluconeogenesis) increased lipolysis and circulating
free fatty acids increased ketogenesis ( energy substrate for heart- one of the cardioprotevtive
mechanism)
In the long term, SGLT2is improved β cell function and insulin sensitivity, despite the fall in insulin
secretion
Chronic dosing shifted substrate utilization from carbohydrate to lipid.
17. HAEMODYNAMIC EFFECTS OF SGLT2
INHIBITION
Sustained reduction in systolic(3-6mm Hg) and diastolic (1 to 2 mm Hg) BP.
Mechanisms-
Inhibition of sodium reabsorption resulting in a diuresis (approximately 400 mls/d) and potential
modest intravascular volume depletion
Improved arterial stiffness-
hyperglycaemia, increased fatty acids and insulin resistance can lead to changes in nitric oxide, the
renin-angiotensin-aldosterone system (RAAS) and sympathetic system activity leading to
hypertension and arterial stiffness
Thus, improved glycaemic control, weight loss and the direct effects on vascular smooth muscle
relaxation after induction of a negative sodium balance, all lead to improve arterial stiffness.
24. Trial Measure of renal outcome Results
CAVAS-R Albuminuria
Renal composite-
Progression/Regression of albuminuria
40% decrease in GFR
End-stage renal disease
HR-0.87 (0.74-1.01)
HR- 0.6 (0.47-0.77)
DECLARE
TIMI58
Renal composite-
Progression/Regression of albuminuria
40% decrease in GFR
End-stage renal disease
Dapagliflozin (3.7%) vs
placebo(7%)
HR-0.53 (0.43-0.66)
25.
26.
27. The renal-cardio hypothesis for cardiovascular protection with
SGLT2 inhibition: a nephrocentric perspective
28.
29.
30. Adverse effects of SGLT2 inhibitors
1. ketoacidosis
o without significant hyperglycemia
o More common in type I DM
2. Hypoglycemia
o Risk of hypoglycemia is low
o Usually occurs when used with insulin/insulin secretagogues
31. 3. Genital Mycotic Infection and Urinary Tract Infection
particularly in patients with a history of genital mycotic infection and in uncircumcised males.
Genital mycotic infections occur more frequently in females than males
4. Volume Depletion-Related Adverse Events
hypotension, syncope, and dehydration
Pooled data from SGLT2 inhibitor RCTs show increased rates of volume depletion-related adverse
events (range 0.3%-4.4%) compared with placebo groups (range 0%-1.5%)
32. 5. Bone Fractures
In a pooled analysis, the incidence of fractures was higher with canagliflozin (2.7%) compared with
non-canagliflozin groups (1.9%) in the overall population
Reason is unknown
proposed mechanism-
falls because of volume depletion
possible SGLT2 inhibitor-associated effects on bone metabolism
33. 6. Cancer
bladder cancer were reported in a greater proportion of patients treated with dapagliflozin
7. Fournier’s Gangrene
8. lower limb amputations
An approximately 2-fold increased risk of lower limb amputation (LLA) associated with canagliflozin
compared with placebo observed in the CANVAS Program trials
34.
35. 9. Renal Safety
Urosepsis and pyelonephritis
Proposed mechanisms are
osmotic diuresis causing an increased risk of hyperosmolarity and dehydration
exchange of urinary glucose for uric acid leading to uricosuria and tubular injury via crystal-
dependent
local inflammation and tubular injury resulting from fructose generation and metabolism.
Renal function should be assessed before initiation of SGLT2 inhibitor treatment
40. Trial name EMPA-REG outcome trial
(2016)
CANVAS DECLARE-TIMI 58
(2018)
DAPA-HF
(2019)
Discription to assess the CV safety of
empagliflozin, in patients
with type 2 DM at high risk
for CV events.
To evaluate the
canagliflozin
compared with
placebo among
patients with type 2
diabetes.
to assess the CV
safety of
dapagliflozin in
patients with type 2
DM2 and either
established CVD or
multiple risk
factors.
to evaluate
dapagliflozin)
compared with
placebo among
patients with heart
failure with reduced
ejection fraction
(HFrEF
Design Patients were randomized in
a 1:1:1 fashion to either
empagliflozin 10 mg (n =
2,345)
25 mg (n = 2,342), or
matching placebo (n =
2,333).
Patients with type 2
DM were randomized
to canagliflozin (n =
5,795) versus placebo
(n = 4,347).
canagliflozin arm
received 300 mg daily
or 100 mg daily.
Patients were
randomized in a 1:1
fashion to either
dapagliflozin 10 mg
(n = 8,582) or
matching placebo
(n = 8,578)
Patients with HFrEF
(irrespective of
diabetes status)
were randomized to
dapagliflozin 10 mg
daily (n = 2,373)
versus placebo (n =
2,371)
Total no: 7,028
Duration : 3.1 years
Total number: 10,142
Duration: 188 weeks
Total number :
17,160
Duration : 4.2 years
Total no. : 4,744
Duration : 18.2 mts
Percentage with
diabetes: 42%
41. EMPA-REG outcome
trial
CANVAS DECLARE-TIMI
58
DAPA-HF
Inclusion
criteria
Age ≥18 years
DM2
HbA1c) of ≥7.0%
to10%
BMI ≤45 kg/m2
GFR >30
Established CVD
-type 2 diabetes and
high CV risk
-≥30 yrs and h/o
symptomatic
atherosclerotic
cardiovascular
disease,
or≥50 yrs of age and
2+ of the following:
DM >10 years,
SBP>140 mm Hg on
antihypertensive
therapy,
current smoking,
albuminuria, or
HDL<38.7 mg/dl
Age ≥40 years
DM2
HbA1c) ≥6.5% to
≤12%
GFR of >60
Established CVD
or multiple r/f (men
≥55 years or
women ≥60 years
with HTN, DL, or
tobacco use)
Symptomatic heart
failure
LVEF ≤40%
NTpro BNP≥600
pg/ml (if
hospitalized for
heart failure within
last 12 months
≥400 pg/ml; if
atrial
fibrillation/flutter
≥900 pg/ml)
42. EMPA-REG outcome
trial
CANVAS DECLARE-TIMI
58
(2018)
DAPA-HF
Primary
outcome
(CV death, nonfatal
MI, or stroke) for
empagliflozin vs.
placebo: 10.5% vs.
12.1%, HR 0.86,
95% CI 0.74-0.99,
p < 0.001 for
noninferiority; p =
0.04 for superiority
(CV death, MI, or
stroke, occurred in
26.9 participants per
1,000 patient-years
of the canagliflozin
group vs 31.5
participants per
1,000 patient-years
of the placebo
group (p = 0.02 for
superiority, p <
0.001 for
noninferiority).
The benefit for
canagliflozin
appeared to be
similar for pts with
HFrEF and those with
HFpEF.
MACE for
dapagliflozin vs.
placebo: 8.8% vs.
9.4%,
HR 0.93, 95% CI
0.84-1.03,
p < 0.001 for
noninferiority;
p = 0.17 for
superiority
(CV death,
hospitalization
for HF, or urgent
HF) visit
occurred in
16.3% of the
dapagliflozin
group compared
with 21.2% of the
placebo group (p
< 0.001).
43. Secondary outcomes
EMPA-REG
outcome
trial
All-cause mortality: 3.8% vs. 5.1%, p < 0.01
CHF hospitalization: 2.7% vs. 4.1%, p = 0.002 (results were similar in patients
with and without CHF at baseline); time to first CHF episode: HR 0.70 (0.57-0.87)
CHF hospitalization or CV death: 5.7% vs. 8.5%, p < 0.001
All-cause hospitalization: 36.8% vs. 39.6%, p = 0.003
Coronary revascularization: 7% vs. 8%, p = 0.11
Mean change in HbA1c at 12 wks for 10 mg empagliflozin vs. placebo: -0.54%
Mean change in HbA1c at 12 wks for 25 mg empagliflozin vs. placebo: -0.6%
Confirmed hypoglycemic event: 27.8% vs. 27.9%
Urinary tract infection: 18% vs. 18.1%, p > 0.05; genital infection: 6.4% vs. 1.8%, p <
0.001
CANVAS Amputation: 6.3 participants per 1,000 patient-years versus 3.4 participants per
1,000 patient-years (p < 0.05)
Progression of albuminuria: 89.4 participants per 1,000 patient-years versus 128.7
participants per 1,000 patient-years (p < 0.05)
44. DECLARE-
TIMI 58
(2018)
Reduction in HbA1c with dapagliflozin: 0.42%
CV death or heart failure (HF) hospitalization: 4.9% vs. 5.8%, p = 0.005
HF hospitalization: 2.5% vs. 3.3%, p < 0.005
All-cause mortality: 6.2% vs. 6.6%, p > 0.05
>40% decrease in GFR, end-stage renal disease, or death due to renal or CV
causes: 4.3% vs. 5.6%, p < 0.05
Diabetic ketoacidosis: 0.3% vs. 0.1%, p = 0.02
Genital infections: 0.9% vs. 0.1%, p < 0.001
Amputation: 1.4% vs. 1.3%, p = 0.53
DAPA-HF Cardiovascular death: 9.6% with dapagliflozin vs. 11.5% with placebo
Hospitalization for heart failure: 9.7% with dapagliflozin vs. 13.4% with placebo
Worsening of renal function: 1.2% with dapagliflozin vs. 1.6% with placebo (p = 0.17)
Findings were similar in DM vs Non DM pts
45. EMPA-REG outcome trial CANVAS DECLARE-TIMI 58 DAPA-HF
conclusion Patients with type 2 DM
at high risk for CVevents
who received
empagliflozin, as
compared with placebo,
had a lower rate of the
primary composite CV
outcome and of death
from any cause when the
study drug was added to
standard care.
patients treated
with canagliflozin
had a lower risk of
cardiovascular
events than those
who received
placebo but a
greater risk of
amputation,
primarily at the
level of the toe or
metatarsal.
In patients with type 2
DM who had or were at
risk for atherosclerotic
cardiovascular
disease, treatment with
dapagliflozin did not
result in a higher or
lower rate of MACE
than placebo but did
result in a lower rate of
cardiovascular death or
hospitalization for heart
failure, a finding that
reflects a lower rate of
hospitalization for heart
failure.
Among patients with
HFrEF, the risk of
worsening heart
failure or death from
cardiovascular
causes was lower
among those who
received
dapagliflozin than
among those who
received placebo,
regardless of the
presence or
absence of
diabetes.
55. Directions for future development
In T2DM, new onset HF is common and is associated with a high mortality.
Further subgroup analyses of existing trials should be conducted to confirm that SGLT2 inhibitors
do indeed prevent new-onset of HF for patients who did not have HF at baseline.
The results of clinical trials of patients with prevalent and well defined HFrEF and HFpEF (with and
without T2DM being present at baseline) are awaited before recommending these agents for the
management of HF itself, rather than only for the treatment of T2DM
