Ueda2016 symposium - pathophysiology of diabetes - abbas orabi

Pathophysiology of Diabetes: The Ominous Octet

Etiology of -cell dysfunction in type 2 diabetes

-Celldysfunction

LipotoxicityFree

Fatty Acids

GlucoseToxicity

Age

InsulinResistance

Amyloid Deposition

Genetics(TCF 7L2)

IncretinEffect

Adapted from De Fronzo RA. Diabetes 2009;58:773-95.

The Ominous Octet

– Multiple defects contribute to the progression of T2D

Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.

Hyperglycaemia

DecreasedInsulin

Secretion

IncreasedGlucagonSecretion

NeurotransmitterDysfunction

DecreasedIncretin Effect

IncreasedHGP

DecreasedGlucose Uptake

IncreasedGlucoseReabsorption

IncreasedLipolysis

Islet-a cell

The Role of the Kidney in Diabetes

Glomerular Filtration and Glucose Reabsorption

Marsenic, O. (2009) Am J Kidney Dis. 53(5):875-83Gerich, J.E. (2010) Diabet Med. 27(2):136-42

SGLT2• Primarily expressed in kidney• Responsible for majority of renal

glucose reabsorption

SGLT1• Responsible for small portion of

renal glucose reabsorption• Prominent role in intestinal glucose

absorption

Major SGLT Glucose Transporters

Modified from Lee YJ. et al. Kidney Int Suppl. 2007;72:S27-S35.

Characteristic SGLT1 SGLT2

Major sites of expression Intestine & kidney Kidney

Sugar specificity Glucose or galactose Glucose

Main role

Dietary absorption of glucose and galactose

Renal glucose reabsorption

Renal glucose reabsorption

Renal locationLate proximal straight tubule

(distal S2/3 segment)Early proximal convoluted tubule

(S1/S2 segment)

Affinity for glucose (Km) High (0.4 μM) Low (2 μM)

Capacity for glucose transport

Low High

% Renal glucose reabsorption

10% 90%

Glucose Reabsorption in a Nondiabetic Person (Plasma Glucose <10 mmol/L)

Glomerulus Proximal Convoluted Tubule

Glucose reabsorption into tissue

Early Distal

Glucose SGLT1SGLT2

Urine

Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose linked co-transporter.Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden

Glucose Reabsorption in a Person With T2DM (Plasma Glucose >10 and <13.3 mmol/L)

Glomerulus Proximal Convoluted Tubule

Increased glucose reabsorption into tissue compared to normal

Early Distal

Urine

Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose linked co-transporter.Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden

Glucose SGLT1SGLT2

Urin

ary G

luco

se

Excreti

on

(g/d

)

0

100

50

25

0

Plasma Glucose (mmol/L)

150

75

125

1412108642

Below RTG

Minimal Glucosuria OccursAbove RTG

Glucosuria Occurs

Healthy RTG

~10 mmol/L

The Renal Glucose Threshold (RTG) Concept

• Maximum plasma glucose concentration at which kidneys reabsorb glucose back into the blood

• When glucose levels exceed the RTG, excess glucose is eliminated from the body through urinary glucose excretion

• Usual RTG in healthy subjects reported to be up to 10-11 mmol/L

Polidori D et al.. Poster presented at EASD 2010; Stockholm, Sweden

Urin

ary G

luco

se E

xcreti

on

(g/d

ay)

0

75

100

50

150


125

25

4 6 8 1610 14

Below RTG minimal glucosuria occurs

12

Healthy RTG

T2DMRTG

Above RTG glucosuria occurs

~13.8 mmol/L~10 mmol/L

The Renal Glucose Threshold (RTG) is Increased in Subjects with Type 2 Diabetes

Polidori D et al. Poster presented at ADA 2010; Orlando, Florida.Polidori D et al. Poster presented at EASD 2010; Stockholm, Sweden.

• Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

HbA1c≥9%

Me orminintoleranceorcontraindica on

Uncontrolledhyperglycemia

(catabolicfeatures,BG≥300-350mg/dl,HbA1c≥10-12%)

Insulin (basal)

+

or

or

or

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Urin

ary G

luco

se E

xcreti

on

(g/d

ay)

0

75

100

50

150


125

25

4 6 8 1610 14


12

Healthy RTG

T2DMRTG


~13.8 mmol/L~10 mmol/L

The Renal Glucose Threshold (RTG) is Increased in Subjects with Type 2 Diabetes

Polidori D et al. Poster presented at ADA 2010; Orlando, Florida.Polidori D et al. Poster presented at EASD 2010; Stockholm, Sweden.

• Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels

Urin

ary

Glu

co

se

Excreti

on

(g/d

)

0

100

50

25

0


150

75

125

1412108642



RTGRTG

Untreatedhealthy

SGLT2i-treatedT2DM

UntreatedT2DM

SGLT2, sodium glucose co-transporter 2; RTG, renal threshold for glucose excretion; UGE, urinary glucose excretion.

SGLT2 inhibition lowers RTG

Appreciable UGE occurs only when plasma glucose exceeds RTG

Polidori D et al. Poster presented at ADA 2010; Orlando, Florida.Polidori D et al. Poster presented at EASD 2010; Stockholm, Sweden

SGLT2 Inhibition Lowers RTG

Phase 3 Clinical Development Programme: 9 Studies Conducted

Canagliflozin Head to Head StudiesAdd-on to MET Study: Canagliflozin vs Sitagliptin (DIA3006)

16

Screening Visit

Week–2

Day 1Baseline

AHA Adjustment Period Start

• On protocol-specified doses of MET• A1C ≥7% and ≤10.5%

Week52

CANA 300 mg

SITA 100 mg

PBO

A1C≥7% and ≤10.5%

R

SITA 100 mg

SITA 100 mg

CANA 300 mg

Week26

CANA 100 mg CANA 100 mg

• On below protocol-specified doses of MET• A1C ≥7.5% and ≤11%

1. Titrate MET (up to 2 weeks)

2. Stable MET dose (8 weeks)

• On MET/SU• A1C ≥6.5% and ≤9.5%

Add-on to MET vs Sitagliptin (DIA3006): Study Design

Pretreatment PeriodPBO/Active-

controlled, Double-blind Treatment Period

Active-controlled, Double-blind

Treatment Period

PBO

Continue stable protocol-specified dose of MET

2-week, single-blind PBO

run-in

Discontinue SU

17

Lavalle González, et al. Poster presented at ADA 2013 Chicago, Illinois,

Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print]

Add-on to MET vs Sitagliptin (DIA3006):

Change in HbA1c

SITA 100 mg CANA 100 mg CANA 300 mg

Time point (wk)

LS m

ean c

hange (±SE)

from

baseline (

%)

Baseline (%) 7.9 7.9 8.0

LS meanchange

0%(95% Cl: –0.12, 0.12)

–0.73%

–0.73%

–0.88%–0.15%(95% Cl: –0.27, –0.03)

0 6 12 18 26 34 42 52

0.2

0

–0.2

–0.4

–0.6

–0.8

–1.0

–1.2mITT, LOCF

Lavalle González FJ et al. Data presented ADA 2013; Chicago, Illinois.Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print]

• CANA 100 and CANA 300 mg demonstrated non-inferiority to SITA 100 mg in HbA1c-lowering;

• CANA 300 mg showed statistical superiority to SITA 100 mg in HbA1c-lowering


Change in FPG


LS m

ean c

hange (±SE)

from

baseline (

mm

ol/

L)

Baseline (mmol.L) 168.9 168.6 172.7

LS mean change

–0.5 mmol/LP <0.001

–1.0 mmol/LP <0.001

–1.0 mmol/L

–1.5 mmol/L

–2.0 mmol/L

Time point (wk)

0 6 12 18 26 34 42 52

0

–0.5

–1.0

–1.5

–2.0

–2.5

mITT, LOCF



Percent Change in Body WeightLS m

ean %

change (±SE)

from

baseline

Baseline (kg) 87.6 88.7 85.4

LS mean % change

–2.4% (–2.1 kg)P <0.001

–2.9% (–2.5 kg)P <0.001

–1.3%(–1.2 kg)

–3.8%(–3.3 kg)

–4.2%(–3.7 kg)

Time point (wk)

-5

-4

-3

-2

-1

0


0 6 12 18 26 34 42 52

–4

–5

–3

–2

–1

mITT, LOCF



Change in Systolic BP

• With CANA 100 and 300 mg and SITA 100 mg, LS mean changes from baseline in diastolic BP were −1.8, –1.8, and –0.3 mmHg, respectively

• No notable changes in pulse rate were observed across groups

LS m

ean c

hange (±SE)

from

baseline (

mm

Hg)


–2

–4

–6

2

0

–8

Baseline (mmHg) 128.0 128.0 128.7

LS mean change

–2.9 mmHgP <0.001

–4.0 mmHgP <0.001

–0.7 mmHg

–3.5 mmHg

–4.7 mmHg

Time point (wk)

0 6 12 18 26 34 42 52

mITT, LOCF


Canagliflozin Head to Head StudiesAdd-on to MET Study: Canagliflozin vs Glimepiride (DIA3009)

Add on to Metformin vs Glimepiride (DIA3009): Study Design

R, randomisation; AHA, antihyperglycaemic agent.*Protocol-specified = ≥2,000 mg (or ≥1,500 mg, if unable to tolerate higher dose).†To be discontinued before titrating MET.

Pretreatment PeriodCore Double-blind Treatment Period

Screening visit

Week –2Run-in start

Day 1Baseline

AHA adjustment period start

• On protocol-specified doses* of MET• HbA1c ≥7.0% and ≤9.5%

Week 104

Continue stable protocol-specified* dose of MET

CANA 300 mg

CANA 100 mg

GLIM (titrated)

Not on protocol-specified doses* of MET

- Low-dose MET: A1C ≥7.5 and ≤10%

- MET + another AHA†: HbA1c ≥6.5 and ≤9%

1. Titrate MET(up to 2 weeks)

2. Stable MET dose (10 weeks)

A1C≥7.0% and ≤9.5%

2-week, single-blind

placebo run-in

R

Extension Double-blind Treatment

Period

Week 52Primary endpoint

Cefalu WT et al. Lancet. 2013; 382(9896):941-50. Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois, (65-LB).

Add on to Metformin vs Glimepiride (DIA3009): Change in HbA1c (MMRM)*

24

GLIM CANA 100 mg CANA 300 mg

0 8 12 18 26 36 44 52

Time point (wk)

Baseline (%)

64 78 88 104

LS meanchange

–0.68%

–0.58%

–0.38%–0.20%(95% CI: –0.34, –0.06)

–0.30%(95% CI: –0.44, –0.16)

7.8 7.8 7.8

*Mixed-Effect Model Repeated Measure Model

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0

LS m

ean c

hange (±SE)

from

baseline (

%)

104 week data

Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois, (65-LB).

• Both CANA doses showed a reduction in HbA1c vs GLIM at 104

weeks when assessed using MMRM

Add on to Metformin vs Glimepiride (DIA3009):Proportion of Subjects With Documented HypoglycaemiaEpisodes Through Weeks 52 and 104

25

40.9

6.8 8.2

0

20

40

60

80

100

Perc

enta

ge o

f subje

cts

104 week data

Cefalu WT et al. Lancet. 2013; 382(9896):941-50. Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois.

34

6 5

0

20

40

60

80

100

GLIM

CANA 100 mg

CANA 300 mg

Perc

enta

ge o

f subje

cts

52 week data

Add on to Metformin vs Glimepiride (DIA3009):

Percent Change in Body Weight (LOCF)*

26

LS m

ean %

change (

±SE)

from

baseline


0 8 12 18 26 36 44 52

Time point (wk)

Baseline (kg)

64 78 88 104

LS mean% change

–4.2%(–3.6 kg)

–4.1%(–3.6 kg)

0.9%(0.8 kg)

–5.1% (95% CI: –5.6, –4.5)(–4.3 kg)([95% CI: –4.8, –3.8])

–5.2% (95% CI: –5.7, –4.6)(–4.4 kg)([95% CI: –4.9, –3.9])

86.6 86.8 86.6

4

*N = 1,450 (Baseline); N = 1,425 (Week 4); N = 1,436 (Week 8); N = 1,438 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104).

–6

–5

–4

–3

–2

–1

0

1

2

104 week data


Add on to Metformin vs Glimepiride (DIA3009): Change in Systolic BP (LOCF)*

27

LS m

ean c

hange (

±SE)

from

baseline (

mm

Hg)


0 8 12 18 26 36 44 52

Time point (wk)

Baseline (mmHg)

64 78 88 104

LS meanchange

–3.1 mmHg

–2.0 mmHg

1.7 mmHg

–3.7 mmHg(95% CI: –5.2, –2.3)

–4.8 mmHg(95% CI: –6.2, –3.4)

129.5 130.0 130.0

4

Reductions in diastolic BP with CANA 100 and 300 mg and GLIM were –1.3, –2.2, and –0.02 mmHg, respectively, with no notable changes in pulse rate.

*N = 1,450 (Baseline); N = 1,429 (Week 4); N = 1,438 (Week 8); N = 1,440 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104).

–6

–5

–4

–3

–2

–1

0

1

2

3

104 week data


Add on to Metformin vs Glimepiride (DIA3009): % Change in HDL-C


• Both Canagliflozin doses associated with increases in HDL-C and LDL-C that were stable from 26 weeks to 104 weeks

• HDL-C LS mean % change:• GLIM: 0.7%, CANA 100: 9.4%; CANA 300: 10.0%

• LDL-C LS mean % change• GLIM: 6.3%; CANA 100: 11.2%; CANA 300 14.3%

SGLT2 Inhibitors modulate several factors related to CV risk

Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100

BPArterial stiffness

GlucoseInsulin

Albuminur

ia

Uric

acid

Other

↑LDL-C↑HDL-C

Triglycerid

es

Oxidative stress

Sympatheti

c nervous system activity

WeightVisceral

adiposity

AHA Study name N Aim

Canagliflozin CANVAS1 4330 • Evaluate effect of canagliflozin on CV outcomes & safety/tolerability in T2DMpts at increased CV risk

Supported by CV part of CANVAS-R2

5700 • Study effects of canagliflozin on renal endpoints in T2DM pts at elevated CV risk

• MACE-plus is an additional outcome measure

Dapagliflozin DECLARE-TIMI-583

17,150 • Evaluate impact of dapagliflozin (vsplacebo) on incidence of CV events in T2DM pts with established CV disease or ≥2 risk factors

Empagliflozin4 EMPA-REG Outcome4

7034 • Assess long-term CV safety of empagliflozin (vs placebo) and benefits on macro/microvascular outcomes in pts at high risk of CV events

MACE – Major adverse cardiovascular events (composite of CV death, non-fatal MI or non-fatal stroke)MACE-plus – Composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalisation for unstable angina

CV Outcome Studies -SGLT2 Inhibitors

1. Neal B, et al. (2013). Am Heart J; 166(2):217-223.2. Clinicaltrials.gov. http://clinicaltrials.gov/show/NCT01989754. Accessed 4.11.143. Clinicaltrials.gov. http://clinicaltrials.gov/show/NCT01730534. Accessed 4.11.144. Zinman B, et al. (2014) Cardiovascular Diabetology;13:102.

http://clinicaltrials.gov/show/NCT01989754

http://clinicaltrials.gov/show/NCT01730534

John M Lachin, ScD

Professor of Biostatistics and Epidemiology, and Statistics, The George Washington University,

Rockville, USA

31

EMPA-REG OUTCOME®

• Randomised, double-blind, placebo-controlled CV outcomes trial

•ObjectiveTo examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events

32

Trial design

• The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

33

Randomised

and treated

(n=7020)

Empagliflozin 10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)

Placebo

(n=2333)

Screening

(n=11531)

Key inclusion and exclusion criteria

• Key inclusion criteria

– Adults with type 2 diabetes

– BMI ≤45 kg/m2

– HbA1c 7–10%*

– Established cardiovascular disease

• Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease

• Key exclusion criteria

– eGFR <30 mL/min/1.73m2 (MDRD)

34

Pre-specified primary and key secondary outcomes

• Primary outcome

– 3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke

• Key secondary outcome

– 4-point MACE: Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina

35

EMPA-REG OUTCOME®: Summary

• Risk reduction for 3-point MACE by 14%

• Reduction in HbA1c without an increase in hypoglycaemia, reductions in weight and blood pressure, and small increases in LDL cholesterol and HDL cholesterol

• Increase in genital infections but was otherwise well tolerated

• Reduced hospitalization for heart failure by 35%

• Reduced CV death by 38%

• Improved survival by reducing all-cause mortality by 32%

36

SUMMARY

New MOA:

• Canagliflozin work in Insulin Independent manner. • SGLT2 inhibition reduces Glucose Reabsorption and increases Urinary Glucose Excretion.

Safety:

• A Low Risk of Hypoglycaemia when used as monotherapy or as add-on to metformin. GMI’s were mild to moderate in severity & infrequently led to discontinuation.

• Manageable side effect (UTI, MGI, Polyuria)

Additional Benefit

• Significant Weight loss and Blood Pressure Reductions.

Used in wide-range of patients

• Used in patients developing renal impairment (eGFR 45>60)• Used in older patients (>75 yrs)• Used either alone or in combination with other type 2 diabetes medications, including pioglitazone

Tolerability:

• The 100 mg and 300 mg Once-Daily Doses allow tailoring of dosing to individual needs in a wide range of patients.

Sustained Efficacy:

• Significant reduction of HbA1c across 9 Phase III trials including 3 head-to-head trials with

active comparators. .• Greater and sustained HbA1c reductions with Canagliflozin 300mg Vs Sitagliptin as add on to

metformin and as add on to metformin + Sulphonylurea.• Greater and sustained HbA1c reductions with Canagliflozin 300mg Vs Glimeperide as add on

to metformin

Thank you

Health & Medicine

Ueda2016 symposium - pathophysiology of diabetes - abbas orabi