Silvio E. Inzucchi MDYale University

New Haven, Connecticut, USA

Managing Diabetes & CVD: Exploring New Evidence & OpportunitiesESC Congress, London, UK

30 August, 2015

SGLT2 Inhibition in the Management of T2DM:

Potential Impact on CVD Risk

+

-

-

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple Complex Pathophysiological Abnormalities in T2DM

+

-

-

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

DA agonists

T Z D sMetformin

S U sGlinides

DPP-4 inhibitors

GLP-1Ragonists

A G I s

Amylinmimetics

Insulin

Bile acidsequestrants

SGLT-2 inhibitors

Multiple Pathophysiologically-Based Therapies for T2DM

+

-

-

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

T Z D sMetformin

DPP-4 inhibitors

GLP-1Ragonists

SGLT-2 inhibitors

Major Glucose-Lowering AgentsUsed in T2DM

S U s

Insulin

Renal Glucose Handling*

Schematic representation of the typical titration curve for renal glucose reabsorption in man.Adapted from Silverman M, Turner RJ. Handbook of Physiology, Oxford University Press; 1992:2017-2038.

600

400

200

00 200 400 600 800

Rat

e o

f G

luco

seFi

ltra

tio

n/

Re

abso

rpti

on

/Exc

reti

on

(mg/

min

)

Plasma Glucose (mg/dL)

Tm

Reabsorbed

Filtered Excreted

Threshold

Tmax

Threshold (TmGlu ) =maximal resorptivecapacity of the proximal tubule

*Filters & reabsorbs 140-180 g glucose / day

Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42.

Active (SGLT2) and Passive (GLUT2) Glucose Transport in a Renal Proximal Tubule Cell

SGLT2

GLUT2

InterstitiumTubular lumen

Na+

Glucose

Na+/K+

ATPase PumpNa+

K+

Glucose

SGLT2 SGLT1

Normal Physiology of Renal Glucose Homeostasis

Proximal tubule

S1

GlomerulusDistal tubule

Glucosefiltration

Minimalglucose

excretion

S3

Collecting duct

90%

10%Glucose

reabsorption

Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35; Han S. Diabetes. 2008;57:1723-1729.

Loop of Henle

SGLT2 SGLT1

Proximal tubule

S1

GlomerulusDistal tubule

Glucosefiltration

Increasedglucose

excretion

S3

Collecting duct

90%

10%

Loop of Henle

Glucosereabsorption

Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35; Han S. Diabetes. 2008;57:1723-1729.

SGLT2 inhibitor

- 70-80 g/day ( - 280-320 Kcal/day)

SGLT2 Inhibition ReducesRenal Glucose Reabsorption

SGLT2 Inhibitors Currently Available

Canagliflozin (100, 300 mg)

Dapagliflozin (5, 10 mg)

Empagliflozin (10, 20 mg)

Ipragliflozin, Luseogliflozin, Tofogliflozin (Japan)

Ertugliflozin (investigational)

-1,25

-1,00

-0,75

-0,50

-0,25

0,00

Ad

just

ed m

ean

(9

5%

CI)

dif

fere

nce

ver

sus

pla

ceb

o

in c

han

ge f

rom

bas

elin

e in

Hb

A1

c(%

)

Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin Luseogliflozin

Pooled results for 22 dapagliflozin, 11 empagliflozin, 9 canagliflozin, 7 ipragliflozin and 3 luseogliflozin studies with ≥ 12 weeks durationfrom published and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med.2013;159(4):262-274]. Results are presented for the group allocated to the highest, most common dose across studies. SGLT2: sodiumglucose cotransporter 2, CI: confidence interval, HbA1c: haemoglobin A1c.

Placebo-corrected change from baseline in HbA1cIn

verse

-variance w

eigh

ted

rand

om

effects m

eta-an

alysis

Dapagliflozin(~ 6000 patients)

Canagliflozin(~ 3500 patients)

Empagliflozin(~ 4000 patients)

Ipragliflozin(~ 1000 patients)

Luseogliflozin(~ 500 patients)

–0.56(–0.64 to –0.48)

–0.81(–0.93 to –0.69)

–0.65(–0.74 to –0.56)

–0.97(–1.23 to –0.70)

–0.70(–0.85 to –0.55)

Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74.

-2,50

-2,00

-1,50

-1,00

-0,50

0,00

Ad

just

ed m

ean

(9

5%

CI)

dif

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nce

ver

sus

pla

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ch

ange

fro

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asel

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t (k

g)Overall Monotherapy Add-on treatment

Pooled results for 18 studies of SGLT2 inhibitors as monotherapy and 28 studies as add-on treatment with ≥ 12 weeks duration frompublished and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med.2013;159(4):262-274]. Results are presented for the group allocated to the highest, most common dose across studies. SGLT2: sodiumglucose cotransporter 2, CI: confidence interval.

Placebo-corrected change from baseline in body weightIn

verse

-variance w

eigh

ted

rand

om

effects m

eta-an

alysis

Overall Monotherapy Add-on treatment

–1.87 (–2.05 to –1.70) –1.72 (–1.92 to –1.52) –2.02 (–2.28 to –1.75)

Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74.

Ridderstrale M et al. Lancet Diabetes Endocrinol. 2014;2(9):691-700

Empagliflozin vs. glimepiride as add-on to metformin

• After 2 years (n = 1,549):

– More durable reduction in HbA1c (–0.11 %; 95% CI –0.19, –0.02).

– Significant body weight reduction of –4.5 kg (95% CI –4.8, –4.1).

– Lowering effect on SBP was –5.6 mm Hg (95% CI –6.8, –4.4).

– Fewer hypoglycemic events with empagliflozin (4%) than with

glimepiride (25%).

– Similar rates of urinary tract infections but increased incidence

of genital mycotic infections for empagliflozin (12%) compared

with glimepiride (2%).

-6,00

-5,00

-4,00

-3,00

-2,00

-1,00

0,00

Ad

just

ed m

ean

(9

5%

CI)

dif

fere

nce

ver

sus

pla

ceb

o in

ch

ange

fro

m b

asel

ine

in S

BP

(m

m H

g)Overall Monotherapy Add-on treatment

Pooled results for 16 studies of SGLT2 inhibitors as monotherapy and 29 studies as add-on treatment with ≥ 12 weeks duration frompublished and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med.2013;159(4):262-274]. Results are presented for the group allocated to the highest, most common dose across studies. SGLT2: sodiumglucose cotransporter 2, CI: confidence interval.

Placebo-corrected change from baseline in systolic blood pressure (SBP)In

verse

-variance w

eigh

ted

rand

om

effects m

eta-an

alysis

Overall Monotherapy Add-on treatment

–4.19 (–4.77 to –3.61) –4.74 (–5.52 to –3.95) –3.91 (–4.68 to –3.14)

Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74.

-3,00

-2,50

-2,00

-1,50

-1,00

-0,50

0,00

Ad

just

ed m

ean

(9

5%

CI)

dif

fere

nce

ver

sus

pla

ceb

o in

ch

ange

fro

m b

asel

ine

in D

BP

(m

m H

g)Overall Monotherapy Add-on treatment

Pooled results for 14 studies of SGLT2 inhibitors as monotherapy and 27 studies as add-on treatment with ≥ 12 weeks duration frompublished and gray literature sources through June 30, 2014 [search strategy adapted from Vasilakou et al. Ann Intern Med.2013;159(4):262-274]. Results are presented for the group allocated to the highest, most common dose across studies. SGLT2: sodiumglucose cotransporter 2, CI: confidence interval.

Placebo-corrected change from baseline in diastolic blood pressure (DBP)In

verse

-variance w

eigh

ted

rand

om

effects m

eta-an

alysis

Overall Monotherapy Add-on treatment

–2.02 (–2.30 to –1.74) –2.03 (–2.56 to –1.50) –2.03 (–2.38 to –1.68)

Courtesy, A. Tsapas MD, Aristotle Univ, Thessaloniki, Greece Vasilakou D, et al. Ann Intern Med. 2013;159:262-74.

Additional Potential Benefit:Blood Pressure Reduction

Well-documented, consistent reduction of systolic blood pressure in clinical trials

Irrespective of background anti-HTN therapy

Appears to occur even in those with decreased GFR, where glycemic efficacy is reduced

Probably triggered by osmotic diuresis

Role of tubulo-glomerular feedback (?)

Clinical value

Improved BP control

Reduction in use/dose of anti-hypertensives?

Cardiovascular risk reduction?

Weight

Visceral

adiposity

BP

Arterial

stiffness

Glucose

Insulin

Albuminuria

Uric Acid

Novel

Pathways (?)

↑LDL-C

↑HDL-C

Triglycerides

Oxidative

stress

SNS

activity(?)

Potential pathways to CV benefits of SGLT2-inhibitors

based on clinical and mechanistic studies

Inzucchi SE et al.

Diab Vasc Dis Res 2015;12:90-100

“Will They Hurt the Kidney?”

Small, reversible decreases in GFR.

Decreases albuminuria

Loss of glucose reabsorption appears to be safe in

non-diabetic patients with normal eGFR (i.e. FRG.)

Unclear what long-term effect of persistent glucosuria

will be in people with diabetes

Less effective when kidney function is reduced.

Don’t use when eGFR <60 (dapa) or <45 (cana, empa)

Scheen AJ. Clin Pharmacokinet 2015, PMID: 25805666

“FRG”: An Experiment of Nature

Familial renal glucosuria

– Due to SGLT2 gene mutations

– Rare kidney disorder

Benign

No corresponding kidney complications

– Absence of glucose reabsorption indicated by higher urinary glucose excretion

– Urinary glucose excretion up to 170 g/d

– Appear protected vs. obesity, T2DM

Wright EM. J Intern Med. 2007;261:32-43.

SGLT2 Inhibitors: Risks & Benefits

Kim Y et al. Diabetes Metab Syndr Obes. 2012;5:313-327.Inzucchi SE et al. Diabetes Care 2015;38:140-159

• Genital mycotic infections • ? UTIs• DKA• Polyuria/ Dehydration• Reversible GFR • Small Hgb/Hct• Small LDL-C• Urinary Ca+ losses (?)

• Insulin-independent glucose lowering effect (irrespective of DM duration)

• Low hypoglycemia rates• Modest weight, BMI, WC• Modest BP• Albumin:Cr Ratio• Modest TGs• Small HDL-C

RISKSBENEFITS

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

Metforminhigh

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 denoteany 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-ior

or

or GLP-1-RA

high

low risk

loss

GI

high

GLP-1 receptoragonist

Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptoragonist

+

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

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

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 denoteany 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, addbasal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin+

Combinationinjectabletherapy‡

GLP-1-RAMealtime Insulin

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

2015 ADA-EASD PositionStatement on Management of Hyperglycemia in T2DM

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

Metforminhigh

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 denoteany 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-ior

or

or GLP-1-RA

high

low risk

loss

GI

high

GLP-1 receptoragonist

Sulfonylurea

high

moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate

low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptoragonist

+

SGLT-2 Inhibitor

+SU

TZD

Insulin§

Metformin+

Metformin+

or

or

or

or

or

or

or

SGLT2-i

Mono-therapy

Efficacy*

Hypo risk

Weight

Side effects

Costs

Dualtherapy†

Efficacy*

Hypo risk

Weight

Side effects

Costs

Tripletherapy

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 denoteany 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, addbasal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin+

Combinationinjectabletherapy‡

GLP-1-RAMealtime Insulin

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

SGLT2-i

SGLT2 Inhibition, T2DM Management & CVD Impact

SUMMARY

• The SGLT 2 inhibitors are the latest category of drugs used for type 2 diabetes; they lower glucose by increasing urinary glucose excretion. They are effective at any stage of disease, so long as there is sufficient renal function. No hypoglycemia.

• Additional advantages include modest reductions in body weight & BP. There are small beneficial changes in TGs & HDL. Long-term CVD effects are under study.

• Side effects stem directly from their mechanism of action –increased urination, possible dehydration, and increase in GU infections. LDL-C is increased by 5%.

• Interesting recent reports of DKA - predominately in T1DM (off-label use) and in some (presumably highly insulin-deficient) patients with T2DM.

Silvio E. Inzucchi MDYale University

New Haven, Connecticut, USA

Managing Diabetes & CVD: Exploring New Evidence & OpportunitiesESC Congress, London, UK

30 August, 2015

SGLT2 Inhibition in the Management of T2DM:

Potential Impact on CVD Risk