D E N C E t o

n g C R E
Givi L 2 i s t o r y
g e r S G T
the big beti c
diane p h r o p a thy
Benefits in
and beyond

Dr Davy Ip SSRNH 29th July

 OUTLINE OF THE TALK

Diabetes, the kidneys and SGLT2 Inhibitors

A global and local perspective

A look at…

Where we have come from

How are we doing now

Where are we going?

 History of Diabetes

1552 BC – Written on a 3rd 500 BC — Ancient Hindu 475–221 BC - The

Dynasty Egyptian papyrus, writings from Sushruta Huángdì Nèijīng mentions
physician Hesy-Ra and Charaka note that xiāo kě ( "wasting-thirst"):
mentions frequent urination ants are attracted to the excessive thirst, excessive
as a symptom. This is the urine (madhumeha) of hunger, excessive urine,
earliest known record of people with a mysterious and weight loss
diabetes. emaciating disease.
 History of Diabetes

259 BC – The creation of 164 AD - A Greek 1025 Persian polymath

the term “diabetes” is physician, Galen of Avicenna (Ibn Sina)
credited to Apollonius of Pergamum, theorises that publishes “The Canon of
Memphis, which refers to a diabetes is an affliction of Medicine” providing a
disease which drains the kidneys. After this detailed account on
patients of more fluid than period, diabetes is rarely diabetes mellitus including
they can consume. mentioned sweet urine, abnormal
appetite, gangrene and
sexual dysfunction
 History of Diabetes

1798 -
John Rollo

1776 - Matthew Dobson 1869 - Paul Langerhans, 1889 Minkowski and von
evaporates diabetic urine while a medical student in Mering (University of
and finds substance like Berlin, describes islands Strasbourg) find that
brown sugar in appearance of cells in the pancreas. removing the pancreas
and taste. Also finds a These were later found to from dogs results in
sweetish taste of sugar in be the source of insulin, diabetes.
the blood of diabetics. and were called the
Observes that diabetes is "islets of Langerhans."
fatal in < 5 weeks in some,
and is a chronic condition in
others
 History of Diabetes

1910-1920 Dr Frederick 1869 -1962 – Elliott P. 1921 - Frederick Banting

Allen publishes a book, Joslin. First diabetic and his student assistant
“Total Dietary Restriction in registry. Predicted Charles Best successfully
the Treatment of Diabetes”, diabetes epidemic.First in isolate insulin (initially
which describes the hospital glucose called "iletin) from dog
‘starvation diet’. The monitoring. Preconised pancreases at the
treatment helps extend the patient education,tight University of Toronto
lives of diabetes patients diabetes control. First James Collip works on
(Type 2) , but many of his diabetes textbook purifying it. Findings
patients (type 1) die as a published 1922, Nobel
result of starvation. prize 1923
History of Diabetes
History of Diabetes
 Estimates and projections in millions of
the global prevalence of DM in the 20–79y
The diabetes pandemic
Number of people (20-79 years) with diabetes
globally and by IDF Region
World diabetes rankings
Country/Territory 2010 2019 2030 2045
Marshall Islands 9.1 30.5 33 34.1
Kiribati 6.6 22.5 23.6 23.9
Sudan 4.2 22.1 23.5 24.2
Tuvalu 13.9 22.1 23.9 24.7
Mauritius 16.2 22 24.3 25.3
New Caledonia 7.2 21.8 23.2 23.9
Pakistan 9.1 19.9 21 21.5
French Polynesia 13.8 19.5 20.5 20.9
Solomon Islands 3.3 19 20.6 21.3
Guam 6.7 18.7 20.6 21.6
Palau 9.1 17.9 19.3 20
Papua New Guinea 3 17.9 18 18
Egypt 11.4 17.2 18.8 19.5
Belize 9.8 17.1 18.6 19.4
Malaysia 11.6 16.7 18 18.7
World IGT rankings
Country/Territory 2010 2019 2030 2045
Papua New Guinea 9.4 29.2 30.4 31.2
Indonesia 11 17.8 18.3 18.5
New Zealand 5.9 17.5 18.9 19.6
Burundi 8.6 15.9 17 17.6
Eritrea 8.6 15.9 17 17.6
Ethiopia 8.6 15.9 17 17.6
Rwanda 8.6 15.9 17 17.6
Somalia 8.6 15.9 17 17.6
Uganda 8.6 15.9 17 17.6
United Republic of Tanzania 8.6 15.9 17 17.6
Maldives 12.7 15.8 15.9 16
Mauritius 13.5 15.8 15.9 16
Djibouti 2.9 15.7 16.8 17.4
Kenya 8.6 15.7 16.8 17.4
Brunei Darussalam 17.9 15.5 15.8 16
Mauritius diabetes prevalence
Mauritius diabetes control
 Natural history of diabetes

Piya et al. 2010. British journal of clinical pharmacology

 From the Triumvirate...
The Triumvirate = Beta-cell dysfunction, muscle, and hepatic insensitivity to insulin

The Dysharmonious Quartet = Add adipocyte dysfunction

The Quintessential Quintet = Add Incretin effect

The Setaceous Sextet = Add hyperglucagonemia

The Septicidal Septet = Add altered renal glucose handling

The Ominous Octet = Add central Nervous System dysfunction

From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus.
DeFronzo RA (2009) Diabetes 58:773–795
 … to the Ominous Octet

DeFronzo RA (2009)
 20

Targeting the Ominous Octet

 … to the Egregious Eleven

Schwartz SS et al (2016) The Time Is Right for a New Classification System for Diabetes:
Rationale and Implications of the β-Cell–Centric Classification Schema. Diabetes Care 39:179–186
Pathogenesis
 ‘Classical’ natural history of diabetic nephropathy

ESR
Pre DN Early DN Overt DN
F

Glomerular
hyperfiltration GFR 100 ml/min Nephrotic range proteinuria

GFR

Albuminuria MICROALBUMINURIA RANGE

0 5 15 25 years
Longitudinal study since 1965
Age related decline in kidney
function
Natural rate of decline in kidney function in DKD
 ‘Alternative’ natural history of diabetic nephropathy

ESR
F

GFR 100 ml/min Nephrotic range proteinuria

GFR

Albuminuria MICROALBUMINURIA RANGE

0 5 15 25 years
Detection of DKD in T2 DM
Number of People Receiving Renal Replacement Therapy
Is Projected to Double

Worl Regio
8. 3.
0 d 0 n
7.
0
Number of RRT

Number of RRT
6. Asia
0 (0.97→2.16)
(×million)

(×million)
5.4 2.
5.
4 0
0 4.5
4. 3
3.7 North
0 8 America
3. 3.1 Latin
(0.64
0 2.6 3
1.
America
→1.26)
2. 2 0 Europe
(0.37
0 (0.53
→0.90)
1. Africa
→0.83)
0 (0.08
0 0 Oceania
→0.24)
(0.03→0.05)
20 20 20 20 20 20 20 20 20 20
10 15 20 25 30 10 15 20 25 30
Ye Ye
ar ar

Liyanage T, et al. Lancet.

2015;385(9981):1975-1982.
Diabetes Is the Leading Cause of Kidney Failure: US Data

60,000

Diabetes
50,000 Hypertension
Number of patients

Glomerulonephritis
40,000
Cystic kidney

30,000

20,000

10,000

0
1980 1985 1990 1995
199 2000 2005 2010
5

United States Renal Data System (USRDS). USRDS Annual Report, Chapter 1.
https://www.usrds.org/2012/pdf/v2_ch1_12.pdf.
Accessed March 15, 2019.
 Die or dialyse in DKD?

Go et al. NEJM 2004

Dialysis Survival Compared to Common Cancers

Wom Me
10
0
en 10
0
n
9 9
0 0
8 8
Survival probability

Survival probability
0 0
7 7
0 0 Breast/Prostate
6 6 Cancer
0 0 Colorectal
5 5
Cancer
0 0
4 4 Dialysis
0 0
(%)

(%)
3 3 Lung Cancer
0 0
2 2
Pancreatic Cancer
0 0
1 1
0 0
0 0
1997-20 2002-20 2007-20 1997-20 2002-20 2007-20
01 06 11 01 06 11
Er Er
a a
Unadjusted 10-year survival for all-cause mortality in Canada
N = 33,500 incident maintenance dialysis patients; 532,452 incident
cancer patients
Naylor KL, et al. Am J Kidney Dis. 2019. Epub ahead of print.
doi:10.1053/j.ajkd.2018.12.011.
Dialysis patients in Mauritius
How many CKD patients in Mauritius?
Global, regional, and national burden of CKD 1990–2017
Global, regional, and national burden of CKD 1990–2017

Age-standardised Prevalence in 2017 Deaths in 2017

rate per 100 000

1 Fiji 14399 El Salvador 71.4

2 Mauritius 13768 Mauritius 67

3 Tonga 13491 Marshall Is 65.4

4 Kiribati 13265 American samoa 64.6

5 American Samoa 13217 Micronesia 62.6

6 Micronesia 12990 Mexico 58.1

7 Russia 12832 Tonga 50.9

8 eSwatini 12568 Phillipines 50.3

9 Samoa 12455 Nicaragua 49.4

10 Salomon Is 12402 Guatemala 47.8

Lancet 2020; 395: 709–33

Mauritius
540pmp/y

Incidence rate
of treated
ESRD (per
million
population), by
country, 2016

USRS 2018 Annual Data Report

Volume 2 ESRD, Chapter 11
Prevalence of treated
ESRD (per million
population), by
country, 2016

Mauritius 1250pmp

USRS 2018 Annual Data Report

Volume 2 ESRD, Chapter 11
Incidence of treated
ESRD due to diabetes
as the assigned
primary cause of
ESRD cause, by
country, 2016

Mauritius?

USRS 2018 Annual Data Report

Volume 2 ESRD, Chapter 11
 Beware of data
Morrell et al, BMC Public Health.
2019; 19: 481.
 History of SGLT2 inhibitors

De Koninck LG (1835) Über das Phloridzin (Phlorrhizin) Annalen der Pharmacie. Heidelberg 15(1):75–77
 47

SGLT2 inhibitors mechanism

Glomerular haemodynamics
Tubuloglomerular feedback
 Trials of Diabetic Nephropathy

3867 T2DM

Intensive vs standard glycemic control

3 years FU

Intensive glycemic control versus

1993 (2014) standard control (HbA1c 7.0 versus
DCCT EDIC/DCCT 7.9%) led to 33% risk reduction for
micro-albuminuria.

1441 T1DM
1998
Intensive vs standard glycemic control
UKPDS
6.5 years FU 18 years FU
Intensive glycemic control versus Renoprotective efficacy of intensive
standard control (HbA1c 7.3 versus glycemic control persisted and resulted
9.1%) reduced incident micro- and in 45% risk reduction of
macro-albuminuria by 39 and 54%. micro-albuminuria at 18 years

Chan et al NTD 2016, Devonald et al JRSM 2012

 Trials of Diabetic Nephropathy

409 T1DM

Captopril v placebo

2013 2008 10 years FU

ADVANCE ACCORD Captopril reduced risk of doubling
creat by 48%

11140 T2DM 10251 T2DM

1993
Intensive vs standard glycemic control Intensive vs standard glycemic control
Lewis et al
5 years FU Terminated at 3.5 years

Intensive glycemic control versus Targeting HbA1c 6.0 versus 7.0–7.9%

standard control (HbA1c 6.5 versus resulted in excess mortality (HR 1.22;
7.3%) reduced risk of micro-, 95% CI 1.01–1.46; P = 0.04).
macro-albuminuria and ESRD by 9, 30
and 65%. For those with
macro-albuminuria, number needed to Chan et al NTD 2016, Devonald et al JRSM 2012
treat to prevent one ESRD = 41.
 Trials of Diabetic Nephropathy
1513 T2DM 590 T2DM

Losartan versus placebo Irbesartan versus placebo

3.4 years FU 2 years

Multivariate analysis: every 10 mmHg Irbesartan demonstrated renoprotective

SBP rise increased risk of ESRD or efficacy with reduction in disease
2000 death by 6.7%. Losartan led to progression compared with placebo
decrement of proteinuria (35%), risk independent of BP lowering effect
MICRO-HOPE reduction of serum creatinine doubling
(25%) and ESRD (28%)

3577 almost all T2DM

2001 2001
Ramipril v placebo
RENAAL IRMA-2
Stopped at 4.5 years

Reduced risk of progression to overt

nephropathy; decreased risk of
combined microvascular outcomes by
16%; decreased risk of major CV
outcomes by 25-30%

Chan et al NTD 2016, Devonald et al JRSM 2012

 Trials of Diabetic Nephropathy

1715 T2DM 332 T2DM

Irbesartan vs amlodipine vs placebo Valsartan versus amlodipine

2.6 years FU 24 weeks FU

Irbesartan was renoprotective with Reduction of micro-albuminuria with

lower risk of serum creatinine doubling valsartan (44%) greater than amlodipine 2002
(33%; P = 0.003) and ESRD (23%; P = (8%) CALM
0.07) compared with placebo.

199 T2DM
2001 2002
Candesartan/lisinopril combo versus
IDNT MARVAL candesartan versus lisinopril

12 weeks FU

Combination therapy more effective

with greater reduction in urinary
albumin: creatinine ratio (50%)
compared with candesartan (24%) or
lisinopril (39%) alone
Chan et al NTD 2016, Devonald et al JRSM 2012
 Trials of Diabetic Nephropathy
599 T2DM

Losartan vs aliskiren/losartan combo

6 months FU

2013 Aliskiren (direct renin inhibitor)/losartan

2008 combo led to reduction of urinary
VA albumin: creatinine ratio by 20% (95%
ONTARGET NEPHRON-D CI 9–30; P < 0.001) independent of
blood pressure control.

25 620 T1&2DM 1448 T2DM

2008
Telmisartan/ramipril combo vs Losartan/lisinopril combo vs losartan
telmisartan vs ramipril
AVOID
Terminated at 2.2 years
55 months FU
Combination therapy offered no renal
Combination therapy was associated benefit but resulted in excessive risk of
with increased composite outcome of hyperkalemia (6.3 vs 2.6 events/100
dialysis, serum creatinine doubling and person years) and acute kidney injury
death (HR 1.09, P ≤ 0.037) (12.2 vs 6.7 events/100 person years).

Chan et al NTD 2016

 Trials of Diabetic Nephropathy
8561 T2DM

RAS blockade plus aliskiren versus

placebo

Terminated at 2.7 years

Addition of aliskiren to maximal ARB 2002 2012

offered no additional benefit.
Hyperkalemia and hypotension were
Di. N. .AS SUN - MACRO
significantly increased in the aliskiren
arm.

223 T1&2DM 1248 T2DM

2012
Sulodexide versus placebo Maximum ARB plus sulodexide versus
ALTITUDE placebo
8 months FU
Terminated
4 months of sulodexide (200 mg/day)
significantly reduced albuminuria. Effect No significant benefit observed in end
persisted after 8 months with 62% points of serum creatinine doubling and
reduction compared with placebo ESRD.

Chan et al NTD 2016

 Trials of Diabetic Nephropathy

227 T2DM
2185 T2DM
11392 T2DM
Bardoxolone methyl vs placebo
Bardoxolone methyl versus
Avosentan versus placebo
placebo
52 weeks FU
Terminated at 4 months
Terminated at 9 months
Bardoxolone methyl at 25, 75
Avosentan reduced proteinuria
2012 and 150 mg resulted in a
Bardoxolone methyl led to a
significant increase in
compared with placebo, but, VITAL higher GFR compared with
cardiovascular morbidity (HR
had excess adverse placebo at 52 weeks.
1.83)
cardiovascular events

1281 T2DM
2010 2011 2013
RAS inhibition plus paricalcitol
ASCEND versus placebo BEAM BEACON
24 weeks

Paricalcitol at 2 μg/day reduced

albuminuria (20% compared
with placebo). However, 2
μg/day was poorly tolerated
and patients often reduced the
dosage.
Chan et al NTD 2016
 The Road to Credence

2013 2019
2015 2017
CANTATA DECLARE-TIM
EMPA-REG CANVAS
SU I

1450 T2DM

Canagliflozin versus glimepiride 52 weeks FU

Canagliflozin caused initial decrease in GFR but subsequently stabilized while

individuals in the glimepiride arm had progressive GFR decline (–1.7 versus –5.1 Chan et al NTD 2016
mL/min/1.73 m2 after 52 weeks).
 Early canagliflozin trials

∙ Pre-Marketing Study Results:

✔ Average decrease in A1C levels 1%
✔ Weight Loss average 2-5 kgs
✔ Decrease in systolic blood pressure approximately 4%
✔ Increase HDL approximately 7.6%
✔ Decrease LDL approximately 11.7%
✔ Low risk of hypoglycemia
 2015 EMPA-REG
Modest A1c reduction Modest reduction (14%) in primary outcome

CV Death reduced by 38% HF Hospitalization reduced by 35%

N Engl J Med 2015;373:2117-2128.

 64

2017 CANVAS
 65

2017 CANVAS
 66

2017 CANVAS
 67

2017 CANVAS
 68

2017 CANVAS
69
70
71
NephJC
DECLARE-TIMI
 BP lowering vs Hba1c lowering in CKD with SGLT2 i

Cherney, David Z.I. et al.

Kidney International,
Volume 93, Issue 1, 231 - 244
 Effect on loss of KF, ESKD or renal death

SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis
Neuen, Brendon L et al. The Lancet Diabetes & Endocrinology, Volume 7, Issue 11, 845 - 854
SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis
Neuen, Brendon L et al. The Lancet Diabetes & Endocrinology, Volume 7, Issue 11, 845 - 854
2019 CREDENCE
2019 CREDENCE
2019 CREDENCE
2019 CREDENCE
2019 CREDENCE
2019 CREDENCE
High risk population in CREDENCE
 Renal
Renal Safety safety of canagliflozin
Number of participants
with an event, n

Canagliflozi Placebo Hazard ratio

n (N = (95% CI)
(N = 2200) 2197)

All renal-related AEs 290 388 0.71 (0.61–0.82)

Hyperkalemia 151 181 0.80 (0.65–1.00)

Acute kidney injury 86 98 0.85 (0.64–1.13)

0.5 1. 2.0
0
Favors Favors
Canagliflozin Placebo

Includes all treated participants through 30 days after last dose.

SGLT2 inhibitors and AKI
 OtherAdverse
AEs of Interest
effects of canagliflozin
Number of participants
with an event, n
Canagliflozin Placebo Hazard ratio
(N = 2200) (N = 2197) (95% CI)

Male genital mycotic infections* 28 3 9.30 (2.83–30.60)

Female genital mycotic infections† 22 10 2.10 (1.00–4.45)

Urinary tract infections 245 221 1.08 (0.90–1.29)

Volume depletion–related AEs 144 115 1.25 (0.97–1.59)

Malignancies‡ 98 99 0.98 (0.74–1.30)

Renal cell carcinoma 1 5 0.20 (0.02–1.68)

Breast† 8 3 2.59 (0.69–9.76)

Bladder 10 9 1.10 (0.45–2.72)

0.1250.2 0. 1. 2.0 4.0 8.0 16. 32.
Acute pancreatitis 5 2 2.44 (0.47–12.59)
5 5 0 0 0
Favors Favors
Diabetic ketoacidosis 11 1Canagliflozin Placebo 10.80 (1.39–83.65)
Lower Extremity Amputation
Lower extremity amputation
Participants with an event IRD per Hazard ratio
per 1000 patient-years 1000 (95% CI)
(n/N) patient-ye
Canagliflozin Placebo ars
(95% CI)

CREDENCE 12.3 11.2 1.16 1.11

(70/2200) (63/2197) (–2.87, 5.18) (0.79–1.56)
CANVAS 6.3 3.4 2.93 1.97
Program1
(140/5790) (47/4344) (1.50, 4.36) 0.5 1.0 2.0 (1.41–2.75)
4.0

Favors Favors
Canagliflozin Placebo

Whether the increased risk of lower limb amputation in the CANVAS Program was due to differing trial populations
IRD, incidence rate difference.
1. or protocols, or to chance remains unclear
Neal B, et al. N Engl J Med.
2017;377(7):644-657.
Rate of decline in kidney function by BP from clinical trials

Trials included in figure:

Captopril Trial, N Engl J Med. 1993; IDNT, N Engl J Med. 2001;
Hannadouche et al, BMJ. 1994; RENAAL, N Engl J Med. 2001;
Bakris et al, Kidney Int. 1996; CREDENCE, N Engl J Med. 2019 (orange glow).
Bakris et al, Hypertension. 1997; X represents no treatment.
Bakris AJKD 2019 .
©2020 by American Diabetes Association
 Proposed renal effects of SGLT2 inhibitors

↓Energy Rq

↓Hypoxia ↑ Hct
SGLT2 Inhibitors as a diuretic
The Thrifty Gene Hypothesis
Barry Brenner father of hyperfiltration
 The start of the Barker hypothesis

Barker DJ, Osmond C. Infant mortality, childhood

nutrition, and ischaemic heart disease in England and
David J P Barker CBE 1938-2013 Wales. Lancet 1986; 1: 1077 –1081.
 Evidence for Barker hypothesis in kidneys

Cumulative risk for ESRD in men and women, by age and birth weight.
Norway, births 1967 to 2004, ESRD 1980 to 2005

Vikse et al, J Am Soc Nephrol. 2008 Jan; 19(1): 151–157.

The ‘Brenner-Barker’ Hypothesis
Developmental theory of metabolic disease
Trials of Diabetic Nephropathy
National Institutes of Health
 Epigenetics

Epigenetics and Epigenomics: Implications for Diabetes and Obesity

Rosen et al Diabetes Oct 2018, 67 (10) 1923-1931
Barker hypothesis and evolution

Nature Review | Cancer

Key trials to come

DELIVER SCORED
Dapagliflozin Sotagliflozin
Cardiovascular Cardiovascular
‘ Dapa HF
NephJC
EPA-KIDNEY enrolled a broad CKD population
 More SGLT2i pleiotropy

Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells:

Multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT)

Empagliflozin-Mediated Lithium Excretion: A Case Study and Clinical Applications

Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the
Syndrome of Inappropriate Antidiuresis

SGLT2 Inhibitors for Treatment of Refractory Hypomagnesemia: A Case Report of 3 Patients

Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: A common comorbidity
associated with severe complications
Who owns the SGLT2 inhibitors?
How to lower the rate of decline further?

.
Mineralocorticoid receptor antagonists
Thank You!

renal.mu

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