SGLT2 inhibitors in Diabetic Kidney Disease

SGLT2 Inhibition
in Diabetic Kidney Disease
Christos Argyropoulos MD, MS, PhD, FASN
Assistant Professor
University of New Mexico
Department of Internal Medicine
Division of Nephrology

Disclosures
• Site sub-investigator in the Phase 3 study SONAR
(sponsor AbbVie), examining the safety and efficacy of
the investigational selective endothelin receptor A
antagonist atrasentan v.s. best medical therapy in
patients with Type 2 diabetes and kidney disease
• No financial, research or any other support by any of the
marketing authorization holders of the SGLT2 inhibitors
commercially available in the US (Canagliflozin: Jannsen ,
Dapagliflozin: BMS/AstraZeneca, Empagliflozin:
Boehringer-Ingelheim)
• Research support (access to preclinical data of nonSGLT2i
drug induced kidney injury) from Pfizer (sponsor of
investigational SGLT2i ertugliflozin)

Learning Objectives
• Epidemiological Trends in diabetic chronic kidney
disease
• Role of the kidney in glucose homeostasis
• Outcome trials and clinical studies of SGLT2
inhibitors (SGLT2i) in diabetic kidney disease
• Identify key pharmacological, therapeutic and
safety related properties of FDA approved (summer
2017) SGLT2i for clinical use
Off label use of FDA approved medications will be discussed

Diabetic Nephropathy in
the 21st century
15 years of stagnation, false hopes and dead ends

Diabetic CKD is common and appears to
morph into a non-proteinuric disease
NHANES participants with eGFR <60
ml/min/1.73 m2, by age & risk
factor, 1999-2014
NHANES participants with urine
albumin/creatinine ratio ≥30 mg/g,
by age & risk factor, 1999-2014
2016 Annual Data Report, Vol 1, CKD, Ch 1
~40% of DKD is non-proteinuric

Diabetic CKD + Cardiovascular Disease =
Hospitalization + Death
Data source: Medicare 5 percent sample. January 1, 2014 point prevalent patients aged 66 and older.
Adj: age/sex/race. Ref: all patients, 2014. Abbreviations: CKD, chronic kidney disease; CVD,
cardiovascular disease; DM, diabetes mellitus.
Death Hospitalization

Data Source: Medicare 5% sample. Abbreviations: CKD, chronic kidney disease; CHF, congestive heart failure; DM, diabetes
mellitus; PPPY, per patient per year costs.
Medicare expenditures by DM, CHF, CKD status
U.S. Medicare
Population
Total Costs
(millions, U.S. $)
PPPY Costs
(U.S. $)
Population (%) Costs (%)
All 24,496,020 $254,356 $10,803 100.00 100.00
With CHF or CKD or DM 8,140,540 $130,220 $17,013 33.23 51.20
CKD only (- DM & CHF) 1,023,220 $15,109 $15,673 4.18 5.94
DM only (- CHF & CKD) 4,093,320 $47,846 $12,116 16.71 18.81
CHF only (- DM & CKD) 893,760 $16,955 $20,733 3.65 6.67
CKD and DM only (- CHF) 847,220 $14,856 $18,610 3.46 5.84
CKD and CHF only (- DM) 340,300 $8,829 $30,395 1.39 3.47
DM and CHF only (- CKD) 515,500 $12,599 $26,758 2.10 4.95
CKD and CHF and DM 427,220 $14,025 $38,561 1.74 5.51
No CKD or DM or CHF 16,355,480 $124,136 $7,812 66.77 48.80
All CKD (+/- DM & CHF) 2,637,960 $52,819 $21,857 10.77 20.77
All DM (+/- CKD & CHF) 5,883,260 $89,327 $16,003 24.02 35.12
All CHF (+/- DM & CKD) 2,176,780 $52,409 $26,975 8.89 20.60
CKD and DM (+/- CHF) 1,274,440 $28,882 $24,854 5.20 11.36
CKD and CHF (+/- DM) 767,520 $22,854 $34,935 3.13 8.99
DM and CHF (+/- CKD) 942,720 $26,625 $31,902 3.85 10.47

2016 Annual Data Report, Vol 2, ESRD, Ch 1 8
Data Source: Reference Tables A.1, A.2, A.2(2) and special analyses, USRDS ESRD Database. *Adjusted for age, sex, and race. Abbreviations:
ESRD, end-stage renal disease; n/a, not applicable.
Meanwhile, the incidence of ESRD continues to increase
(don’t believe the #FakeNews of statistical modeling adjustment)
Incident count Unadjusted rate Adjusted rate
Year No. cases
% Change from
previous year
Unadjusted rate (per
million/year)
% Change from
previous year
Adjusted rate (per
million/year)
% Change from
previous year
1996 77,018 n/a 278 n/a 328 n/a
1997 82,116 6.6 293 5.3 343 4.4
1998 87,353 6.4 308 5.3 360 4.8
1999 91,431 4.7 319 3.4 368 2.4
2000 94,662 3.5 327 2.5 374 1.5
2001 98,005 3.5 336 2.6 380 1.8
2002 100,233 2.3 340 1.3 381 0.1
2003 102,770 2.5 345 1.5 382 0.3
2004 104,560 1.7 349 1.2 382 -0.1
2005 106,662 2.0 353 1.2 382 0.0
2006 110,342 3.5 362 2.5 387 1.4
2007 110,381 0.0 359 -0.9 379 -2.1
2008 111,899 1.4 360 0.3 375 -1.0
2009 115,508 3.2 369 2.5 379 1.1
2010 115,920 0.4 367 -0.6 372 -2.0
2011 113,796 -1.8 358 -2.5 358 -3.8
2012 115,602 1.6 360 0.7 355 -0.8
2013 118,119 2.2 366 1.7 355 0.2
2014 120,688 2.2 370 1.1 354 -0.3

ESRD incidence is increasing because of DM
Adjusted prevalence of ESRD
in the US 1996-2014
.. but certain states have it
worse than others
2016 Annual Data Report, Vol 2, ESRD, Ch 1
Fig 1.16 Ground Zero for the
epidemic of diabetic
CKD & ESRD

And so during the last
15 years we tried….
• Intense blood pressure control
• Intense blood sugar control
• ARB + ACEI
• ARB + Direct Renin Inhibitors
• ACEi/ARB + aldosterone antagonists
• Anti-oxidant therapies (e.g. bardoxolone)
• Non-selective endothelin receptor
antagonists …
Hypertension kills
kidneys
Residual Proteinuria
after RAASi kills kidneys
doi:10.1038/nrneph.2013.251
doi: 10.1681/ASN.2014070688
Only to be stopped by poor efficacy and safety
Let’s take a step back and go
back to the basics

Glucose and the kidney
This chapter will be much larger in the next edition of “The
Kidney”

Role of the kidney in glucose
homeostasis
1. Gluconeogenesis (cortex) mainly for utilization in the
medulla
• Fasting post-absorptive state:
• 20-25% of the glucose released into the circulation is derived from
the kidneys (12-55g)
• Kidneys use about 10% of the entire glucose pool (25-35g)
• Post-prandial state (4-5 hours after a meal):
• Kidneys responsible for 60% of endogenous glucose release (70g)
• Renal release of glucose x30% in pts with T2D
2. Reabsorption of filtered glucose by the proximal
tubule
• GFR of 125 ml/min x 90-100 mg/dL = 160-180g filtered
• Nearly all of it is reabsorbed
• Primary renal contribution to glucose homeostasis
DOI: 10.1152/ajpendo.00116.2001
DOI: 10.1113/JP271904
DOI: 10.1016/j.diabres.2017.07.033
DOI: 10.1152/physrev.00055.2009
DOI:10.1016/j.tips.2010.11.011
DOI: 10.1016/j.metabol.2014.06.018

Urinary Glucose Excretion (UGE), Tubular Maximum
Capacity for Glucose (TmG) and Renal Threshold for
Glucose Excretion (RTG)
DOI: 10.1016/j.metabol.2014.06.018
TmG is elevated in poorly
controlled DM
• Kidneys exacerbate
hyperglycemia
• Renal (+50-70 mg/min) >
Hepatic (+24 mg/min) in T2D
Normal values:
TmG 375 mg/min
RTG: 180-200mg/dl

Sodium Glucose Co-Transporters (SGLT)
• SGLTs are responsible for
co-transport of Glu and
Na across epithelia
(except the glucosensor
SGLT3)
• Members of the SLC5
superfamily
• 60-80 kDa proteins – 580-
718 a.a
• Coding sequences for all
SLC5 members are found
in 15 exons
DOI: 10.1152/physrev.00055.2009

Complex Structure 
Complex Kinetics
DOI: 10.1152/physrev.00055.2009

SGLT expression is
tissue specific
FDG = GLUT
DOI: 10.1152/physrev.00055.2009
DOI: 10.1113/JP271904
Me-4FDG = SGLT
Complex
compartmental
kinetics of sugar
reclamation

Renal Glucose Transport
SGLT2 and SGLT1 transport
glucose in different segments
of the nephron
DOI:10.1016/j.tips.2010.11.011

SGLT2 inhibition will lower blood sugar
DOI 10.1007/s40262-013-0104-3
PEES
Can SGLT2i be used to improve
outcomes in diabetic CKD?

Outcome trials and
studies with SGLT2i
Going where no ACEi or ARB has gone before

“Empagliflozin and Progression of Kidney
Disease in Type 2 Diabetes”: EMPA-REG
• Patients with T2D & eGFR>30 ml/min/1.73m2 (N=7,020)
• Randomized to PBO, Empa (10mg) , Empa (25 mg)
• Primary outcome in EMPA-REG: 3 point MACE (death
from CVD, nonfatal MI, nonfatal stroke)
• Non-inferiority design (margin of 1.3 with PBO)
• Microvascular (retinopathy) & renal outcomes
• Incident/worsening nephropathy (1-4)
• Individual components of nephropathy
1. Progression to macroalbuminuria
2. X2 SCr with eGFR<45
3. Renal replacement therapy (RRT)
4. Renal death
• Post-hoc renal outcome (x2 SCr, RRT, renal death)
DOI: 10.1056/NEJMoa1515920

DOI: 10.1056/NEJMoa1515920
EMPA-REG:
Outcomes Patient characteristics
No dose effect

EMPA-REG:
Subgroups The Magnificent Six (Out of Seven)
Time PBO 10mg 25mg
0-4 wk 0.01 ±0.04 -0.62±0.04 -0.82±.04
4-192 wk -1.67±0.13 -0.19±0.11
Washout -0.04±0.04 0.48±0.04 0.55±0.04
eGFR slope
Effect consistent across eGFR/albuminuria
categories
DOI: 10.1056/NEJMoa1515920

Empa seems to work, but how safe is it?
DOI: 10.1056/NEJMoa1515920
Odds for specific AEs by eGFR
• Severe and serious AEs were less
frequent with EMPA than PBO
• Genital infections EMPA > PBO
• HyperK+ EMPA< PBO (contrast RAASi)

DOI: 10.1056/NEJMoa1611925
“Canagliflozin and Cardiovascular and Renal
Events in Type 2 Diabetes” : CANVAS/CANVAS-R
• CANVAS Program consisted of two RCTs:
• CANVAS pre-approval cardiovascular safety RCT
• CANVAS-R: post-approval cardiovascular safety
RCT with a renal endpoint (albuminuria)
• Pts with T2D, high risk risk for CVD, eGFR> 30
(N=10,142)
• Randomized 1:1:1 PBO, Cana (100mg), Cana(300mg)
• Primary outcome: 3 point MACE
• Secondary renal outcome: progression of
albuminuria (normo → micro, micro → macro, ↑
UACR by 30%)
• Exploratory renal composite outcome:
1. Regression of albuminuria
2. 40% ↓ eGFR x 2
3. RRT
4. Renal death
Non-inferiority/sequential
testing analysis plan

Outcomes
Patient characteristics
DOI: 10.1056/NEJMoa1611925

Subgroup analyses
DOI: 10.1056/NEJMoa1611925
Cardiometabolic
effects

Cana works too! Is it safe?
Amputations
Fractures
DOI: 10.1056/NEJMoa1611925

Is dapagliflozin nephroprotective too?
• No prospective randomized
controlled clinical trials
(such as EMPA-REG or
CANVAS) reported
• The corresponding trial
(DECLARE) is still ongoing
• Also DAPA-CKD in
proteinuric CKD with or
without DM
• Secondary, analysis of
existing randomized
controlled trials conducted
to examine short term
safety of dapa
Diabetes, Obesity and Metabolism 18: 590–597, 2016.

Dapagliflozin has an antiproteinuric effect
in short term studies
Antiproteinuric effect Dissociation of effects on A1c
and UACR
Diabetes, Obesity and Metabolism 18: 590–597, 201
Persistent reduction in eGFR

Are the renal effects of dapa
sustained over the long term?
• Analyses of secondary
outcomes in a primary
antidiabetic efficacy
study (A1c)
• Pts with T2D, A1c : 7-
11% & CKD 3a
• Randomized 1:1:1 in
PBO, Dapa (5mg) and
Dapa (10mg)
Kidney International (2014) 85, 962–971

Beware of small, underpowered studies!
Proteinuria Safety
Kidney International (2014) 85, 962–97
eGFR

Meta-analysis of multiple (n=11) under-
powered (for renal outcomes) dapa studies
(N=4,404 pts)
eGFR (relative to PBO) UACR (relative to PBO)
doi: 10.2215/CJN.10180916

What is the mechanism of
nephroprotection?

What is the mechanism of
nephroprotection?
doi: 10.1016/j.amjcard.2017.05.010
doi: 10.1016/j.amjcard.2017.05.012

Are all SGLT2 inhibitors
the same?
Label information of marketed (summer 2017) SGLT2
inhibitors, and emerging preclinical and clinical data

Two operational definitions of
“sameness”
Regulatory (FDA) view: Label
• Indications
• Safety and warnings
• Data from registrational
trials within each drug
(including sponsored RCTs
of head to head
comparisons)
• Pharmacokinetic and
pharmacodynamic analyses
of sponsored registrational
trials
Clinical & basic science view
• Outcomes
• Adverse events
• Indirect comparisons by
payors
• Indication for specific
patients (e.g. glucose
lowering v.s. hard
outcomes)
• Preclinical and clinical data
not reflected in the label

In my humble opinion …..
• … all SGLT2i are AND are not the same
• One can speak of class effects and of each drug in the
class as different from the others
• Similar to Quantum Mechanics we have to “measure”
their clinical “wave function” in studies (that have not
been done yet)
• The viewpoint of the physician using them to treat
diabetes (“high blood sugar”) may differ from the one
of the physician using them to treat diabetes
(“cardiorenal events”) in a safe manner

Current (summer 2017) approved
indications for SGLT2i
• Canagliflozin
• as an adjunct to diet and exercise to improve glycemic control
in adults with type 2 diabetes mellitus
• Dapagliflozin
• Empagliflozin
• to reduce the risk of cardiovascular death in adult patients
with type 2 diabetes mellitus and established cardiovascular
disease.

SGLT2i as glucose
lowering agents:
Network meta-
analyses I
Network diagram
EffectsonA1c(monotherapy)
1. Health Technology Assessment, No. 21.2. NIHR Journals Library; 2017
2. DOI: 10.1111/dom.12670
Cana(300) > Cana(100) ~ Empa(25) >/~ Empa
(10) >/~ Dapa(10) >/~ Dapa(5)

SGLT2i as glucose
lowering agents:
Network meta-
analyses II
Network diagram
Effectsonweightgain(monotherapy)
2. DOI: 10.1111/dom.12670
Cana(300) > Cana(100) ~ Empa(25) ~ Empa
(10) ~ Dapa(10)

SGLT2i as glucose lowering agents:
Network meta-analyses III
Network diagram
Effects on SBP (monotherapy)
2. DOI: 10.1111/dom.12670
Cana(300)~/> ~ Empa(25) ~/> Cana(100) ~
Empa (10) ~ Dapa(10) > Dapa(5)

Cardiovascular outcomes of
marketed SGLT2i: Empagliflozin
Death from CV, nonfatal MI, nonfatal stroke
http://www.nejm.org/doi/pdf/10.1056/NEJMoa1504720 EMPA-REG RCT

marketed SGLT2i: Canagliflozin
http://www.nejm.org/doi/pdf/10.1056/NEJMoa1611925
Data from the integrated CANVAS and CANVAS-R program (RCTs)

marketed SGLT2i: Dapagliflozin
Hospitalization for Heart Failure Cardiovascular death
CVD Real study: a post marketing pooled, propensity score adjusted meta-analysis of
national registry and Medicare data (~300k patients)
NOT a randomized controlled trial
Results broadly similar to EMPA-REG & CANVAS/CANVAS-R
http://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail?id=7f5d0c3c0a2343a3a04b16fc60a883fb

Renal function has a substantial
effect on dosing of SGLT2i
eGFR range Canagliflozin Dapagliflozin Empagliflozin
>60
ml/min/1.73m2
100-300 mg/d 5-10 mg/d 10-25 mg/d
45-60
ml/min/1.73m2
Not to exceed
100 mg/d
Do not initiate 10-25 mg/d
<45
ml/min/1.73m2
Do not initiate Do not initiate Do not initiate
<30
ml/min/1.73m2
Contraindicated Contraindicated Do not initiate
Adjustments
during therapy
Not recommended
when eGFR
declines
persistently below
45 ml/min/1.73m2
Not recommended
when eGFR
declines
persistently
between 30-60
ml/min/1.73m2
Discontinue if
eGFR persistently
falls below 45
ml/min/1.73m2

SGLT2i is a cruel, practical joke played by
pharmacologists on (?non-nephrologist) MDs
PK-PD models link drug
levels to drug effects …meanwhile inside the tubule
Fasting Plasma Glucose (FPG), Urinary
Glucose Excretion (UGE), Area Under
the (concentration) Curve (AUC)
DOI:10.1111/bcp.12453
The differential equations describing the system
SGLT2-SGLT2i will make even the hard core urea
kineticists run for cover (not shown to protect
the innocent)

All flozins are highly selective competitive
inhibitors of the SGLT2 transporter (tubules)
Clin Pharmacokinet (2014) 53:213–225

Fact A nephrology didactic can never be
complete without channel recordings
Extracellular Glucose induces
currents in SGLT(1/2)
expressing cells
Extracellular but
not intracellular
SGLT2i inhibits
glucose uptake
Extracellular
Intracellular
doi: 10.14814/phy2.12058
doi: 10.1124/jpet.116.232025

Pharmacokinetics of the SGLT2i in humans
Canagliflozin Dapagliflozin Empagliflozin
Bioavailability 65% 72% >60%
Peak Plasma time 1-2 hr 2 hr (fasting) – 3hr
(fatty meal)
1.5hr
Protein binding 99% 91% 86.2% (partitions in
red cells by 37%)
Volume of
distribution
119L 118L 73.8L
Half life 10.6-13 hr 12.9 12.4hr
Total body clearance 192 ml/min 207 ml/min 176 ml/min
Hepatic route >50% 21% 41.2%
GI recovery of
parent compound
41.5% 15% >35%
Renal route ~33% 75% 54%
Renal recovery of
parent compound
<1% 1.2% 11-19%
DOI 10.1007/s40262-013-0104-3
DOI 10.1007/s40262-015-0264-4
Hemodialysis in unlikely to be effective in removing
any SGLT2i in case of overdose

Renal function affects the
pharmacokinetics of SGLT2i
DOI 10.1007/s40262-015-0264-4
Even minor degrees of renal impairment leads to substantial
increase in systemic exposure and half life relative to normal eGFR

SGLT2 mediated update of SGLT2i in
vivo and in cell cultures
F-Dapagliflozin sequestration in the kidney requires SGLT2
Cold competition washes out
F-dapa into the circulation
doi: 10.1124/jpet.116.232025.
doi: 10.1681/ASN.2016050510

Renal function affects the
pharmacodynamics of SGLT2i: UGE
DOI 10.1007/s40262-015-0264-4
Even mild CKD (eGFR 60-90) leads to substantial loss of UGE excretion
Pee becomes more and more unsweetened as renal function declines
 dapa appears to lose pharmacodynamic effect faster than the others
(Side comment: I would die to read the IRB submission of the ESRD trials)

Renal function affects the pharmacodynamics
of SGLT2i: A1c, SBP and BW
DOI 10.1007/s40262-015-0264-4
Dapa loses anti-glycemic but not anti-hypertensive or weight less effect when eGFR<60
Cana may retain anti-glycemic effect in this eGFR range

Renal function affects the pharmacodynamics
of SGLT2i: A1c, SBP and BW
DOI 10.1007/s40262-015-0264-4
Empa maintains effect on A1c, body weight reduction and systolic BP even at eGFR 30-60
Blood pressure effect appears to ↑ with dose as eGFR↓
eGFR 60-90
eGFR 15-30
eGFR 30-60

Understanding the effects of renal
function on dosing of the SGLT2i
• Renal function affects both:
1. Pharmacodynamics
• The drugs have to be filtered to work
• Glucose lowering effect depends on SGLT2i activity & filtered
glucose load
2. Pharmacokinetics
• If renal elimination is substantial, then systemic drug exposure
increases
• Systemic Adverse Effects (AE)↑ but ? post-glomerular AE↓
• Dosing recommendations reflect efficacy (glucose
lowering) and benefit vs risk (AE) assessment
• Both refer to the primary indication (anti-diabetic effect)
• May change in the future as the drugs expand their indication to
the cardiometabolic and renal hard outcomes space

Warnings & Precautions in the PI
of marketed SGLT2i (current label)
EmpagliflozinCanagliflozin
Dapagliflozin
Common warnings
Hypotension, AKI, Urosepsis and
pyelonephritis, genital mycotic infections,
hypoglycemia, increases in LDL (4-8%)
Macrovascular outcomes:
Improved with Empa (cardiovascular
death indication), unknown with dapa
and cana (unblinding of the CANVAS site)
Lower limb amputation: Cana
Fracture: Cana
Bladder Ca: Cana

SGLT2i kinetics, pharmacokinetics
and off target effects
Cana inhibits mitochondrial
complex I and activates AMPK
Dapa Empa
Kon (mol-1/min) 1 x 106 1,138.5
Koff (min-1) 0.0067 0.01132
doi:10.1152/ajpcell.00328.2011
DOI: 10.2337/db16-0058
Secker et al SOT2017 Poster 1813
1. Empa disengages fast from the SGLT2 & is recovered
in the urine
2. Dapa disengages slowly and is recycled through the
SGLT2 from the PT in the circulation
3. Cana as slow to disengage as dapa?

Acute Kidney Injury And Changes
In Renal Function
Label Information
All 3 SGLT2i have the
following information
supporting the AKI
warning
1. Postmarketing
reports of AKI
2. Changes in
eGFR noted in
the respective
development
program trials
ΔeGFR
(ml/min/1.73m2)
Placebo Lower dose Higher Dose
Canagliflozin -1.6 -2.3 -3.4
Dapagliflozin 0.8 0.8 0.3
Empagliflozin -0.3 -0.6 -1.4
ΔeGFR
(ml/min/1.73m2)
Placebo Lower dose Higher Dose
Canagliflozin -1.5 -3.6 -4.0
Dapagliflozin -2.6 -4.2 -7.3
Empagliflozin 0.16 - 1.48
All Patients
Moderate renal impairment (eGFR: 30-50/60)
EOT changes in
label suggest EMPA
smaller ΔeGFR Source: Prescribing Information for Jardiance/Invokana/Farxiga

Acute Kidney Injury And Changes In
Renal Function: Network meta-analysis I
Flow-chart Network of trials
DOI: 10.1111/dom.12917
Composite Renal
Events:
↑ Scr, renal events,
↓eGFR
Acute Renal Events:
Investigator Reported
AKI
N=38,079

Acute Kidney Injury And Changes In
Renal Function: Network meta-analysis II
Composite Renal Events Acute Renal Events
DOI: 10.1111/dom.12917
ACT: Active, nonSGLT2 antidiabetic treatment, Cana(gliflozin), Dapa(gliflozin), Empa(gliflozin), Luseo(gliflozin): not available in the US

Acute Kidney Injury And Changes In Renal
Function: Network meta-analysis III
DOI: 10.1111/dom.12917
SUCRA (Surface Under the Cumulative Ranking): parameter used to rank treatments based on their
probability of ranking 1st, 2nd, etc.
Empa < Luseo < NonSGLT2 antiDM < Cana < Dapa
Safest ?

Fracture Risk in SGLT2i Trials:
Network Meta-analysis
Flow-chart Results
OR 1.02 (0.84 – 1.23)
N = 30,384
DOI 10.1111/dom.12742

UTIs and genital infections:
Network meta-analysis I
Flow Chart Network diagrams
DOI 10.1111/dom.12825
Category (drug)
effect
Dose effect

UTIs and genital infections:
Network meta-analysis II
DOI 10.1111/dom.12825
Category Effect
Dose effect
UTI
Genital Infections
Genital infections: higher with empa, dapa, cana. UTI: only with dapa
All doses are associated with genital infections, but only dapa 10 mg is
associated with higher rate of UTI than the other SGLT2i or placebo
Genital Infections
UTI

What about ketoacidosis?
Meta-analysis of RCTs
Market Claims Data –
Propensity Matching
DOI: 10.1016/j.diabres.2017.04.017
DOI: 10.1056/NEJMc1701990
HR ~ 2x
HR ~ 1x

Specific Cancers
Overall Cancer
Diabetologia (2017) 60:1862–1872
• No increase in overall cancer
• Bladder cancer may be increased with SGLT2i

Are all flozins the same?
Yes they are
• Cardiovascular effects broadly
similar (non-FDA view, ?yet)
• They all lower blood sugar (v.s.
placebo)
• Similar renal outcomes
• They all cause genital infections
• They all increase LDL
• They all cause volume
depletion & may increase SCr
• They all lower BP
• They all lower weight
• They may increase bladder
cancer
No they are not
• Only Empagliflozin has the
cardiovascular indication
• Canagliflozin more potent glucose
lowering effect
• Only dapa may cause UTI?
• Empagliflozin appears to be the
safest from an AKI perspective
• Empa may be used at lower levels
of eGFR
• Amputations with cana?
• Drug specific effects of
background therapy
(BB/diuretics/RAASi) on outcomes
• Off-target (AMPK)/glutamine
metabolism effects

Adding SGLT2i to the
armamentarium of the
Nephrologist

SGLT2i in DKD (Summer 2017)
Outcome Cana Dapa Empa
Proteinuria
(short term)
↓ ↓ ↓
Proteinuria
(long term)
↓ ↓ ↓
ΔeGFR (acute) ↑ ↑ ↑
ΔeGFR (chronic) ↓ ? ↓
Hard outcomes (x2
SCr/RRT/renal death)
HR
0.60 (0.47 – 0.77)
Unknown
(DECLARE)
HR
0.61 (0.53 – 0.70)
ARB Hazard Ratio
IDNT composite 0.60 (0.66 – 0.97)
RENAAL composite 0.84 (0.72 – 0.98)
ARB meta ESRD1 0.78 (0.67 – 0.91)
ARB meta x2SCr1 0.79 (0.68 – 0.91)
1doi: 10.1038/ajh.2008.206

How do we treat diabetes ?
By lowering blood sugar
Reduce Cardiovascular & Renal
Risk with drugs that have
antiglycemic effects?
doi: 10.1016/j.tips.2010.11.011

Should SGLT2i be put into the water?
NOT YET
• Patients in the existing
SGLT2i trials had very
high cardiovascular risk
• Proportion of real world
patients with the same
cardiovascular risk profile
as in EMPA-REG:
• ~15.7% in the UK
• 11.1% among new SGLT2i
users
Sweeten my pee PLEASE
Outcome NNT
Nephropathy/CV
Death
14
Nephropathy 16
Albuminuria
progression
20
X2 SCr/eGFR<45 91
X2
SCr+eGFR<45/RRT/
Renal Death
71
RRT 333
DOI 10.1007/s13300-017-0254-7

Practical
Considerations
• Should be using SGLT2i only
for their anti-glycemic effect?
• Should be using the SGLT2i
for reduction of
cardiovascular (label of
empa) and renal (off-label)?
• Who should prescribe?
• Which SGLT2i?
• Level of renal function
• What the insurance will pay
• The copay the patient can
afford
• Will SGLT2i ever be used in
the patients with the low
eGFRs we are more likely to
see?
Am J Physiol. 1985 Sep;249(3 Pt 2):F324-37.

Directions (and suggestions) for
future research
Preclinical
• Intracellular
pharmacokinetics
• Micropuncture experiments
• Bioenergetics
• Compartmental
pharmacokinetics for all
agents
• Off-target exploration (e.g.
AMPK)
Clinical/Translational
• Biomarkers of response (e.g.
n-of-1 RCTs)
• Whole body imaging
• RCTs in patients with low
eGFR
• Direct comparisons between
SGLT2is
• Testing combinations with
anti-hypertensives or other
anti-glycemic agents with
specific SGLT2i

SGLT2 inhibitors in Diabetic Kidney Disease

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