2. Chronic kidney disease is an important contributor to illness and is associated with a diminished
quality of life and a reduced life expectancy
Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-
term treatments are available.
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. SGLT2 INHIBITORS AND THEIR CLINICAL
EFFECTS
Mechanism of action of SGLT2 inhibitors
Glucose lowering effects SGLT2is inhibit 50-60% of reabsorption of glucose in PCT
HbA1c reduction is 0.6 to 1%
HAEMODYNAMIC EFFECTS
Sustained reduction SBP(3-6mm Hg)
DBP(1 to 2 mm Hg)
resulting in a diuresis (approximately 400 mls/d) and potential
modest intravascular volume depletion
Improved arterial stiffness-
cardiovascular benefit Glucosuria osmotic diuresis intravascular volume
depletion reducing ventricular preload and myocardial oxygen
consumption
Body sodium depletion
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.
weight loss (2 to 3 kg per year) 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
4. Renoprotective pathways
In patients with T2D, eGFR changes are characterized by acute, dose-dependent reductions of ≈5
mL·min–1·1.73 m–2 over several weeks
After this initial dip, eGFR subsequently tends to return toward baseline and remains stable over
time
The impact of SGLT2 inhibition on eGFR is consistent in patients with and without CKD, in those
with established cardiovascular disease, and is observed after treatment for 3 to 4 weeks
eGFR dip is reversible within 2 weeks of drug discontinuation,an effect also observed in the EMPA-
REG OUTCOME trial.
5. The initial decline in eGFR observed with SGLT2 inhibitors is likely related to afferent arteriolar
vasoconstriction through a tubuloglomerular feedback mechanism.
In nondiabetic conditions, SGLT2 is responsible for ≈5% of total renal NaCl reabsorption.
In hyperglycemia, SGLT2 and SGLT1 mRNA expression increase by 36% and 20%,
respectivelySGLT1/2 activity accounts for as much as 14% of total renal NaCl reabsorption ->
marked reduction in distal NaCl delivery to the macula densa
6. SGLT2 inhibitor has been associated with
10% to 15% reduction in plasma uric acid levels
Increased glycosurialeading to secretion of uric acid in exchange for glucose reabsorption via the
GLUT9 transporter
7.
8.
9. an increase in NaCl delivery to the macula densaincreased uptake of NaCl by macula densa
cells occurs via the Na/K/2Cl cotransporter(which is an energy-requiring process) leading to
breakdown of adenosine triphosphate to adenosineAdenosine then acts in a paracrine fashion
via adenosine type 1 receptors on afferent arteriolar vascular smooth muscle cells causing
vasoconstriction
As increase in intraglomerular pressure and resultant increase in glomerular wall tension are
associated with glomerular fibrosis and inflammationSGLT2 inhibitor–mediated reductions in
hyperfiltration would suppress markers of inflammation and fibrosis
12. EMPA-REG Outcome trial
to assess the CV safety of empagliflozin, in patients with type 2 DM at high risk for CV events.
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).
Total no: 7,028
Duration : 3.1 years
13. Inclusion
criteria
Age ≥18 years
DM2
HbA1c) of ≥7.0% to10%
BMI ≤45 kg/m2
GFR >30
Established CVD
Results (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
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.
14.
15.
16. DECLARE-TIMI 58
to assess the CV safety of dapagliflozin in patients with type 2 DM2 and either established CVD
or multiple risk factors.
Patients were randomized in a 1:1 fashion to either dapagliflozin 10 mg (n = 8,582) or matching
placebo (n = 8,578)
Total number : 17,160
Duration : 4.2 years
Inclusion citeria
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)
17. DECLARE-TIMI 58
(2018)
Primary outcome 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
Secondary outcome 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
Renal end points: >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
18. Canagliflozin and Renal Events in Diabetes
With Established Nephropathy Clinical
Evaluation - CREDENCE
To assess the effect of canagliflozin on renal outcomes among patients with type 2 diabetes
mellitus (DM2) and chronic kidney disease (CKD).
Double-blind, randomized trial
Total number of : 4,401, randomized in a 1:1 fashion to either canagliflozin 100 mg daily (n = 2,202)
or matching placebo (n = 2,199).
Duration of follow-up: 2.62 years, Mean patient age: 63.0 years, female: 33.9%
19. The trial stopped early due to overwhelming benefit.
The primary outcome(end-stage renal disease (ESRD), doubling of serum creatinine, renal or
cardiovascular (CV) death) for canagliflozin vs. placebo, was 43.2 vs. 61.2 per 1,000 patient-years
(P-Y) (p = 0.00001).
Secondary outcomes for canagliflozin vs. placebo
All-cause mortality: 29.0 vs. 35.0/1,000 P-Y (p > 0.05)
CV death, myocardial infarction, stroke, hospitalization for heart failure/unstable angina: 27.0 vs.
40.4/1,000 P-Y (p < 0.001)
Amputation: 12.3 vs. 11.2/1,000 P-Y (p > 0.05)
Reduction in HbA1c at 13 weeks: 0.31%
20. CANAGLIFLOZIN iwas found to be
superior to placebo in improving glycemic control and reducing adverse renal events
among patients with DM2 and established CKD.
Reduced CV events in this patient population.
Benefits were independent of baseline HbA1c.
Risk of complications, including amputation, was similar between the two groups.
21. Trial Measure of renal outcome Results
CANVAS-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)
22.
23.
24.
25.
26. Adverse effects of SGLT2 inhibitors
1
2.
Adverse events with SGLT2 inhibitors
Ketoacidosis without significant hyperglycemia
More common in type I DM
Hypoglycemia Risk of hypoglycemia is low
Usually occurs when used with insulin/insulin secretagogues
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
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%)
Bone Fractures higher with canagliflozin (2.7%) compared with non-canagliflozin groups (1.9%)
falls because of volume depletion
possible SGLT2 inhibitor-associated effects on bone metabolism
Cancer greater proportion of patients treated with dapagliflozin
Fournier’s Gangrene
lower limb
amputations
2-fold increased risk of lower limb amputation (LLA) associated with canagliflozin compared with
placebo observed in the CANVAS Program trials
27. 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
28.
29. Study rationale
SGLT2 inhibitors have emerged as powerful agents to reduce the incidence of renal events, as well
as cardiovascular events, in patients with type 2 diabetes
apparent ability to slow the progressive decline in renal function over time is not completely
explained by improved glycaemic control
30. Other non-glycemic pathways
natriuretic/osmotic diuresis
restoration of tubuloglomerular feedback leading to glomerular afferent
vasoconstriction with the reduction in single-nephron hyperfiltration
amelioration of renal tissue hypoxia
attenuation of inflammation and fibrosis
31. If one or more of these mechanisms
are operative, then SGLT2 inhibitors
may also be beneficial in patients
with CKD without diabetes
32. Concerns regarding use of SGLT2
inhibitors
HYPOGLYCAEMIA
-glycosuria induced by SGLT2 inhibitors diminishes with diminishing
blood glucose concentrations and filtered glucose load
-a compensatory increase in basal hepatic glucose production
following urinary glucose loss helps maintain fasting plasma glucose at
euglycaemic levels in individuals without diabetes
-filtered glucose load is reduced due to decreased glomerular glucose
filtration
33. AKI
the haemodynamic actions of SGLT2 inhibitors may lead to an initial reduction in
eGFR, similar to that seen with an ACEi or ARB (i.e. afferent arteriolar constriction)
fewer episodes of AKI were reported with SGLT2 inhibition in the DECLARE-TIMI
58, EMPA-REG OUTCOME, CANVAS and CREDENCE
34. Thus, the DAPA-CKD study is the first
dedicated clinical trial to explore the potential
benefits and risks of SGLT2 inhibitors in
patients across multiple CKD stages both with
and without diabetes who are already receiving
evidence-based renoprotective therapy.
35.
36. Trial Design and Oversight
Randomized, double-blind, placebo-controlled, multicenter clinical trial
The trial was sponsored by AstraZeneca and conducted at 386 sites in 21 countries from
February 2, 2017, through June 12, 2020
38. Exclusion criteria
Type 1 diabetes mellitus
Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-
associated vasculitis
Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or
secondary renal disease within 6 months prior to enrolment
New York Heart Association Class IV congestive heart failure
Myocardial infarction, unstable angina, stroke or transient ischaemic attack within 8 weeks prior to
enrolment
Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or
valvular repair/replacement within 8 weeks prior to enrolment
39. Any condition outside the renal and cardiovascular study area with a life expectancy of less than 2
years based on investigator’s clinical judgement
Hepatic impairment [aspartate transaminase or alanine transaminase >3 times the upper limit of
normal (ULN) or total bilirubin >2 times the ULN at the time of enrolment ]
40. Trial Procedure
Participants were randomly assigned to receive dapagliflozin (10 mg once daily) or matching placebo
Randomization was stratified according to the diagnosis of type 2 diabetes (yes or no) and the
urinary albumin-to-creatinine ratio (≤1000 or >1000)
After randomization, in-person trial visits were performed at 2 weeks, at 2, 4, and 8 months, and at 4-
month intervals thereafter
41. At each follow-up visit
vital signs were recorded
blood and urine samples were sent for laboratory assessment
information on potential trial outcomes, adverse events, concomitant therapies, and adherence to
the trial regimen was collected.
Dapagliflozin or placebo was to be discontinued if pregnancy or diabetic ketoacidosis occurred
42. Outcomes
Primary composite endpoint assessed in a time-to-event analysis, was the first occurrence of any of
the following:
A decline of at least 50% in the estimated GFR (confirmed by a second serum creatinine
measurement after ≥28 days)
The onset of end-stage kidney disease (defined as maintenance dialysis for ≥28 days, kidney
transplantation or an estimated GFR of <15 ml per minute per 1.73 m2 confirmed by a second
measurement after ≥28 days)
Death from renal or cardiovascular causes.
43.
44. Safety outcomes
These included serious adverse events, adverse events resulting in the discontinuation of
dapagliflozin or placebo
Adverse events of interest (symptoms of volume depletion, renal events, major hypoglycemia,
bone fractures, amputations, and potential diabetic ketoacidosis)
45. Statistical Analysis
Event-driven trial
With the recruitment of at least 4000 patients, the trial will have 90% power to detect a relative risk
reduction of 22% in the primary endpoint based on primary events being observed in 681 patients and a
two-sided P-value of 0.05
Assumptions underlying the sample size calculation included a placebo event rate of 7.5% events per
year (based on event rates observed in relevant patients in prior trials), an annual drug discontinuation
rate of 6%, 1% loss to follow-up, a recruitment period of 24 months and a total study duration of 45
months.
The primary efficacy analysis was based on the intention-to-treat population, which included all the
participants who had undergone randomisation
46. a formal interim analysis was originally planned when 75% of primary outcome events had
occurred. However, during the conduct of the trial it became apparent that the interim analysis
would occur close to the end of the trial. The executive committee therefore decided to remove the
interim analysis from the protocol
47.
48. Results
From February 2017 through October 2018, a total of 7517 participants were screened, of whom
4094 underwent randomization.
49.
50.
51. The baseline characteristics, including medications for type 2 diabetes and kidney disease, were
balanced between the dapagliflozin and placebo groups
After a regular review meeting on March 26, 2020, the independent data monitoring committee
recommended to the two coprincipal investigators that the trial be discontinued because of clear
efficacy, on the basis of 408 primary outcome events.
At the conclusion of the trial, the median follow-up was 2.4 years
61. The number of participants who needed to be treated during the trial period to prevent one primary
outcome event was 19 (95% CI, 15 to 27)
The effect of dapagliflozin on the primary outcome was generally consistent across prespecified
subgroups
62.
63.
64.
65.
66.
67. During the first 2 weeks, there was a greater reduction in the estimated GFR in the dapagliflozin
group than in the placebo group (–3.97±0.15 vs. –0.82±0.15 ml per minute per 1.73 m2 ).
Thereafter, the annual change in the mean estimated GFR was smaller with dapagliflozin than with
placebo (–1.67±0.11 and –3.59±0.11 ml per minute per 1.73 m2 , respectively), for a between-
group difference of 1.92 ml per minute per 1.73 m2 per year (95% CI, 1.61 to 2.24)
68.
69. Safety Outcomes and Adverse Events
The incidences of adverse events and serious adverse events were similar overall in the
dapagliflozin and placebo groups
Diabetic ketoacidosis was not reported in any participants who received dapagliflozin and in two
participants who received placebo
Neither diabetic ketoacidosis nor severe hypoglycemia was observed in participants without type 2
diabetes.
There was one confirmed case of Fournier’s gangrene in the placebo group and none in the
dapagliflozin group.
70.
71. Discussion
Participants with chronic kidney disease, with or without type 2 diabetes, who were randomly
assigned to receive dapagliflozin had a lower risk of the primary composite outcome of a sustained
decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or
cardiovascular causes than participants who were assigned to receive placebo
In contrast to the CREDENCE trial, the present trial examined the effects of an SGLT2 inhibitor in
patients with chronic kidney disease of whom 32.5% did not have type 2 diabetes and 14.5% had
an estimated GFR below 30 ml per minute per 1.73 m2 .
72. The lower risk of hospitalization for heart failure or death from cardiovascular causes in the
dapagliflozin group than in the placebo group is consistent with the results of two previous trials of
dapagliflozin, the DECLARE–TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis
in Myocardial Infarction 58) and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in
Heart Failure) trials
Dapagliflozin had an acceptable safety profile in this population, which included participants with an
estimated GFR as low as 25 ml per minute per 1.73 m2 .
There were no cases of diabetic ketoacidosis with dapagliflozin, and hypoglycemic episodes did not
occur in participants without diabetes
73. As in other trials of SGLT2 inhibitors, there was an initial dip in the estimated GFR, followed by a
stabilization of kidney-function decline. This dip in the estimated GFR reflects favorable
hemodynamic changes in the glomerulus
74. Limitations
Type 1 DM patients were excluded, thus the safety profile of dapagliflozoin regarding DKA could
not be excluded for sure
Patients on ESRD and on HD were excluded, so that its is not clear whether dpagliflozin can be
used in such patients
