Treatment of Hyperglycemia in Type 2 Diabetes: Focus on...

Treatment of Hyperglycemia in Type 2

Diabetes: Focus on New

Recommendations/Studies

Carol H. Wysham, MDClinical Associate Professor of Medicine

University of WashingtonSection Head, Rockwood Center for Diabetes and Endocrinology

Disclosure Information

• Consultant: Amylin Pharmaceuticals, Boerhinger Ingelheim,

Eli Lilly & Co, Johnson and Johnson, Sanofi U.S.

• Research funding (paid to institution): Amylin

Pharmaceuticals, Boerhinger Ingelheim, Eli Lilly & Co,

Intarcia, Johnson and Johnson, Merck, NovoNordisk, Sanofi

U.S.

• Speakers Bureau: Amylin Pharmaceuticals, Boerhinger

Ingelheim, Eli Lilly & Co, Johnson and Johnson, Merck,

NovoNordisk, Sanofi U.S.

What’s New in Diabetes

• New ADA/EASD Position Statement for Management of Type

2 Diabetes Mellitus

• More strigent recommendations for individualization of targets

and treatments of diabetes

– More emphasis on avoiding weight gain and hypoglycemia

• New BP target for diabetes

• Publication of LOOKAHEAD study

• Publication of study on Mediterranean Diet

• New class of medcations

• Newer data on quality of care in US

• Newer data on outcomes of patients

0

5

10

15

20

25

0

1

2

3

4

5

6

7

8

1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09

Num

be

r w

ith D

iabe

tes (

Mill

ions)

Perc

en

tag

e w

ith

Dia

be

tes

Year

Percentage with Diabetes

Number with Diabetes

Number and Percentage of U.S. Population with Diagnosed

Diabetes, 1958–2010

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available athttp://www.cdc.gov/diabetes/statistics

Direct Health Care Cost of Diabetes (2012) =

$176 billion

ADA. Published ahead of print. Diabetes Care, March 6, 2013

Management of Hyperglycemia in Type 2

Diabetes: A Patient-Centered Approach

Position Statement of the American Diabetes Association (ADA) and

the European Association for the Study of Diabetes (EASD)

Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

+

-

-

Peripheralglucose uptake Hepatic

glucose production

Pancreatic Insulin/amylinsecretion

Pancreatic glucagonsecretion

Main Pathophysiological Defects in

Type 2 Diabetes

Gutcarbohydratedelivery &absorption

Incretineffect

Hyperglycemia ?

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Glycemic targets

- HbA1c < 7.0% (mean PG 150-160 mg/dl)

- Pre-prandial PG <130 mg/dl

-Post-prandial PG <180 mg/dl

-Individualization is key:

Tighter targets (6.0 - 6.5%) - younger, healthier

Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc.

- Avoidance of hypoglycemia

PG = plasma glucose Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

Figure 1Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

(Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)

<6% <8%

Individualizing Glycemic

Goal Setting

Favors Intensive Therapy

• No CVD, few

comorbidities

• HbA1c ≤8%

• Glycemic control more

readily attained

• Younger age

• Shorter duration of

diabetes

• Lower hypoglycemia risk

Favors Standard Therapy

• CVD, neuropathy, other

comorbidities

• Glycemic control difficult

• History of hypoglycemia

• Older age/shorter life

expectancy

Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]

Healthy eating, weight control, increased physical activity

12

2008 Oldways Preservation & Exchange Trust

The Mediterranean Diet

The Mediterranean Diet CarttoKitchen.potm

Mediterranean Diet Beats Low Fat Diet in Reducing

Cardiovascular Events

Estruch R et al. NEJM 2013: published online Feb 25, 2013

50% had Type 2 DM, 50% were on statins

Patient with diabetes had a 29% reduction in events

Inci

den

ce o

f C

om

po

site

En

dp

oin

t (M

I, C

VA

, Dea

th)

Look AHEAD: Study design

Usual medical care+ lifestyle intervention* for 4 years, with maintenance

counseling thereafter

*≥7% mean weight loss with hypocaloric diet ±pharmacologic therapy + ≥175 min/week moderate physical activity Diet = 1200-1500 kcal/day (<250 lbs) or1500-1800 kcal/day (≥250 lbs)

Primary endpoint: CV death, nonfatal MI, nonfatal stroke

Look AHEAD Research Group. Control Clin Trials. 2003;24:610-28; Obesity. 2006;14:737-52.

Look Action for Health in Diabetes

N = 514545-74 years with T2DM, BMI ≥25 kg/m2 (≥27 kg/m2 if taking insulin)

Usual medical care + diabetes support and education for 4 years

Total follow-up 11.5 years

Source: www.myhealthywaist.org

Ch

an

ge in

we

igh

t(%

)Weight

Average effect across visits: -5.27 (p<0.001)

LOOK AHEAD: Changes in Weight

Adapted from the Look AHEAD Research Group. Arch Intern Med 2010;170:1566-75

ILIDSE

0

-7

-8

-9

0 1 2 3 4

-1

-2

-3

-4

-5

-6

Years

Look AHEAD

Source: www.myhealthywaist.org

Systolic blood pressure Average effect across visits: -2.36 (p<0.001)

Ch

an

ge in

sys

tolic

blo

od

pre

ss

ure

(m

m H

g)

Changes in Systolic Blood Pressure (SBP)

Adapted from the Look AHEAD Research Group. Arch Intern Med 2010;170:1566-75

ILIDSE

0

-7

-8

-9

0 1 2 3 4

-1

-2

-3

-4

-5

-6

Years

Look AHEAD

LOOK AHEAD STUDY

• Was stopped early (after 11 years) due to lack of difference in

primary cardiovascular endpoint (nonfatal I, stroke, death,

hospitalization for angina)

• Overall very low event rate

• Other positive outcomes

– Decrease in medications

– Decrease in rate of sleep apnea

– Decrease in urinary incontinence

• Further analyses may show subsets of people who may

benefit

Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]

780 intolerant

23%

Portland Kaiser Permanente Metformin Study

3388 Metformin Monotherapy Starts

2608 to Assess Initial Treatment Response

809 Initial A1c >7.0%

1799Initial A1c <7.0%

53% of All Starts

Brown JB, Conner C, Nichols G. Diabetes Care 33:501–506, 2010

1

Faction Remaining Under 7.5%

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

Healthy eating, weight control, increased physical activity

Metformin

high

low risk

neutral/loss

GI / lactic acidosis

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+

Insulin (usually basal)

+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high

GLP-1 receptor agonist

Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):

T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012

[Epub ahead of print]

Hanefeld (n=500)

Charbonnel (n=630)

CHICAGO (n=462)

ADOPT (n=2897)

UKPDS (n=1573)

-2

-1

0

1

Ch

an

ge in

A1

C (

%)

Time (yrs)

0 1 2 3 4 5 6 10

GlimepirideGlyburide

Glyburide

Glyburide

Gliclazide

Mazzone T. JAMA. 2006;296:2572-2581. Hanefeldd M. Cur Med Res Opin. 2006;22:1211-1215.

Nissen SE. JAMA. 2008;299:1567-1573. UKPDS Study Group. Lancet.1998;352:837-853

Charbonnel B. Diabetoogia. 2005;48(6):1093-1104.

Durability of Glycemic Control with Sulfonylurea

Therapy

Exenatide BID Associated with Slower Failure Rate than Glimepiride

Baptiste B. Lancet 379:2270-2278

Date of download:

11/11/2012

Copyright © The American College of Physicians.

All rights reserved.

From: Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in

Type 2 Diabetes Mellitus: A Cohort Study

Ann Intern Med. 2012;157(9):601-610. doi:10.7326/0003-4819-157-9-201211060-00003

Treatment with Sulfonylurea Associated with

Increased Risk for CVD Events

ADA-EASD Position Statement: Concern

about Hypoglycemia

• Hypoglycemia

• Emerging concerns regarding association withincreased mortality

• Associated with prolonged QT and arrhythmias

• Associated with increased risk for injury due to falls, etc.

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Hypoglycemia Is a Common Occurrence

in Patients With Diabetes

Survey of 409 US patients with nonsevere hypoglycemic events

(NSHE), T1DM (n = 200) and T2DM (n = 209). Brod M, et al. Value Health. 2011;14:665-671.

64.5

24.923.5

34.9

12

40.2

0

10

20

30

40

50

60

70

80

90

100

T1DM T2DM

Fre

qu

en

cy o

f N

SHE

(%)

Daily to about 1/wk

1/mo to several times/mo

Only a few times/y or very rarely

Severe Hypoglycemia Increases the

Risk of Mortality and CV Events

Zoungas S, et al; ADVANCE Collaborative Group. N Engl J Med. 2010;363:1410-1418.

Duckworth W, et al; VADT Investigators. VA Diabetes Trial (VADT) Update. ADA 69th Scientific Sessions, 2009.

http://webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?type=0&lid=9473&pv=2&preview=False&idcl=0.

0.1 1 10

Macrovascular events3.45 (2.34-5.08); P < .001

Death—any cause3.30 (2.31-4.72); P < .001

Death—non-CV cause2.86 (1.67-4.90); P < .001

Death—CV cause3.78 (2.34-6.11); P < .001

0.1 1 10

Macrovascular events1.88 (1.03-3.34); P = .04

Hazard Ratio (95% CI)

Death—any cause6.37 (2.57-15.79); P = .0001

Death—CV cause3.73 (1.34-10.36); P = .0117

Increased riskDecreased risk

ADVANCE Trial Results

VADT Results

Risk Factors for Hypoglycemia

DeSouza CV, et al. Diabetes Care. 2010;33:1389-1394.

UK Hypoglycemia Study Group. Diabetologia. 2007;50:1140-1147.

American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S11-S63.

Risk Factors

Increasing age

Increasing duration of T2DM

Decreased or delayed food intake

Recent or previous hypoglycemic episode

Cognitive impairment

Increasing duration of insulin therapy

Recent hospitalization

Infection

Alcohol intake

Renal dysfunction

Hypoglycemic Risk of Antihyperglycemic

Agents Added to Metformin

Liu S, et al. Diabetes Obes Metab. 2012;14:810-820.

17.8

10.5

8.9

4.8

1.1 0.9 0.5 0.40

5

10

15

20

25

Biphasicinsulin

Glinide SU Basal insulin DPP-4i GLP-1 RA TZD AGI

Od

ds

Rat

io v

s P

lace

bo

Increased risk vs placebo

No increased risk vs placebo

Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]

When Goal is to Avoid Hypoglycemia

“Weight” Has Negative Impact Beyond

Therapeutic Goals for Individuals With T2DM

• Worry about weight has been associated with poorer outcomes, such as greater likelihood of1

– Symptomatic hyperglycemia

– Suboptimal therapy adherence

– Poor psychological well-being

– Diabetes-specific stress

• Weight gain has been associated with2

– Lower treatment satisfaction

– Lower health-related quality of life

1. Peyrot M, et al. Curr Med Res Opin. 2009;25:1985-1993.

2. Marrett E, et al. Diabetes Obes Metab. 2009;11;1138-1144.

Potential Clinical Benefits Associated

With Weight Loss

Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.

6% weight loss over 4 years

•Decreased A1C (0.4%)

•Decreased SBP (5 mm Hg)

•Increased HDL-C (4 mg/dL)

•Decreased triglycerides (26 mg/dL)

Patients Are Willing to Pay More to

Avoid Weight Gain or to Lose Weight

Patients value

– Weight loss/avoiding

weight gain

– Avoiding

hypoglycemia

– Avoiding injection

– Efficacy

– Avoiding nausea

Jendle J, et al. Curr Med Res Opin. 2010;26:917-923.

11

13

17

24

26

35

0 5 10 15 20 25 30 35 40

↓Weight (1 kg)

Avoid hypoglycemia

Avoid 1 kg wt ↑

Avoid injection

↓A1C (1%)

Avoid nausea

Willingness-to-Pay (USD/month)

Meta-Analysis: Weight Changes With

Antihyperglycemic Agents Added to Metformin

Liu SC, et al. Diabetes Obes Metab. 2012;14:810-820.

3.41

2.462.17

1.40 1.38

0.23

-1.01

-1.66

-5

-4

-3

-2

-1

0

1

2

3

4

5

BiphasicInsulin

TZD SU Glinide BasalInsulin

DPP-4i AGI GLP-1 RA

∆ W

eig

ht

(kg)

Significantly greater loss vs all other classes

GLP-1 RAs and DPP-4 inhibitors highlighted for

avoiding weight gain

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

Healthy eating, weight control, increased physical activity

Metformin

high

low risk

neutral/loss

GI / lactic acidosis

low

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+

Insulin (usually basal)

+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high

GLP-1 receptor agonist

Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

When Goal is to Avoid Weight Gain

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

Healthy eating, weight control, increased physical activity

Metformin

high

low risk

neutral/loss

GI / lactic acidosis

low

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+

Insulin (usually basal)

+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high

GLP-1 receptor agonist

Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):

When Goal is to Minimize Costs

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ORIGIN Study

Evaluated use of glargine insulin in patients with pre-diabetes or early type 2 diabetes

Goal was to test hypothesis that early insulin therapy would reduce risk of CV events

Answer: there was no difference in CV outcomes

However, there was no difference in cancer risk, either

Presented at 72nd Annual Sessions of ADA, Philadelphia, PA

ORIGIN Trial: Median A1C Levels

Presented at 72nd Annual Sessions of ADA, Philadelphia, PA

Median Glargine Dose & IQR (U/kg)

Median 40 U/d in 100 Kg Person

Hypoglycemia & Weight (6 -7 years)

Glargine(N=6264)

Standard(N=6273)

P

% /100py % /100py

Any Non-severe1 or more episodes 57 17 25 5 <0.001

Severe 1 or more episodes 6 1.0 2 0.3 <0.001

Glargine Standard P

Weight Change Since Randomized

1.6 kg (3.5 lbs) -0.5 kg (1 lb) <0.001

Presented at 72nd Annual Sessions of ADA, Philadelphia, PA

Diabetes Care, Diabetologia. 19 April 2012 .[Epub ahead of print]

What about combined GLP-1 and Basal Insulin?

Adding Exenatide BID to Optimized Glargine in T2DM Improves

Glycemic Control Without Increasing Hypoglycemia

Incidence of hypoglycemia was similar in both groups; 1 patient in GLAR + PBO group had severe hypoglycemia

a P < .001 between-group difference.b P < .01 between-group difference.

Results from 30-week RCT in 259 patients with T2DM. Buse J, et al. Ann Intern Med. 2011;154:103-112.

Parameter GLAR + EXN BID vs

GLAR + PBO

P

A1C, % −0.69 < .001

Weight, kg −2.74 < .001

b

aa

a

a

a

234

216

198

180

144

126Glu

cose

Le

vel (

mg

/dL)

162

108

GLAR + EXN BID, baselineGLAR + PBO, baselineGLAR + EXN BID, 30 wkGLAR + PBO, 30 wk

Liraglutide QD With Detemir QD Improves Glycemic

Control in T2DM Over 38 Weeks

Incidence of hypoglycemia was similar in both groups; no major hypoglycemia occurred in either group

No major hypoglycemia occurred in any group during weeks 12

to 38.

Transient nausea occurred in 21% of patients during weeks 0 to 12, 4%

of patients during weeks 12 to 38.

DeVries JH, et al. Diabetes Care. 2012 May 18. [Epub ahead of print];

Rosenstock J, et al. Diabetes. 2011;60(suppl 1):A76 [abstr 276-OR].

Parameter LIRA + DET + MET vs

LIRA + MET

P

A1C, % −0.52 < .0001

Weight, kg 0.79 .03

LIRA + DET + MET (n = 162)

LIRA + MET (n = 161)

234

198

180

162

108

90

Self

-Me

asu

red

Pla

sma

Glu

cose

(m

g/d

L)

126

144

216

P = .0003P = .0244

P = .0141

GLP-1 RAs Added to Basal Insulina,b

• Hypoglycemia generally similar vs PBO in absence of SU (≈ 20%‒35%)1-3

• ALBI noninferior vs LISPRO with lower hypoglycemia (32.6% vs 49.8%,

respectively)4

a ALBI and LIXI are not FDA-approved; b Insulin glargine except insulin

glargine, insulin detemir, NPH, or premixed (≤ 2%) for LIXI GetGoal-L

trials; c P ≤ .002 vs comparator.

1. Rosenstock J, et al. ADA 72nd Scientific Sessions. 2012;62-OR.2. Riddle M, et al. ADA 72nd Scientific Sessions. 2012;983-P.

3. Seino Y, et al. Diabetes Obes Metab. 2012;14:910-917.4. Rosenstock J, et al. ADA 72nd Scientific Sessions. 2012;55-OR.

-0.4 -0.4

0.1

-0.7-0.7 -0.7 -0.8 -0.8

-3

-2

-1

0

1

2

3

LIXIGetGoal-Duo 1

LIXIGetGoal-L

LIXIGetGoal-L-Asia

ALBI

∆ A

1C

(%

)

c c c c

PBO LIXI LISPRO ALBI

1 2 3

4

AACE 2013 Prediabetes Algorithm

AACE 2013 A1c Goals

AACE 2013 Glycemic Control Algorithm

SGLT2 Inhibitors

• Dapaglifozin

• Canagliflozin

• Empagliflozin

• Ipragliflozin

• Tofogliflozin

Renal Glucose Transport

• Kidneys filter ≈ 180 g glucose from circulation/24 h– Glucose is reabsorbed and returned to circulation

– Urinary glucose excretion = 0 g

• SGLT1 and SGLT2—Renal sodium glucose cotransporters that actively transport glucose from the renal tubular lumen into the renal tubule cell

• GLUT1 and GLUT2—Glucose transporters in the kidney that facilitate passive transport from the renal tubule cell to circulation

Marsenic O. Am J Kidney Dis. 2009;53:875-883.

SGLT2 Inhibitors: Mechanism of Action

Rothenberg PL, et al. Diabetologia. 2011;54(suppl 1):876.

Bowman’scapsule

Circulation

Urinary excretion

Glucose

SGLT2

Rationale for Inhibiting SGLT2 to

Manage Hyperglycemia in Diabetes

• Novel insulin-independent mechanism1,2

– Low-affinity, high-capacity glucose transporter in the S1

and S2 segments of proximal renal tubules3

– Responsible for 90% of renal glucose reabsorption3

• Glycemic efficacy anticipated even with worsening β-cell

failure and insulin resistance2

• Potential to complement available antihyperglycemic agents,

including insulin4

• Low risk of hypoglycemia4

• Negative energy balance due to glucosuria (≈ 200-300

kcal/day) = potential for weight loss5

1. Chao E, Henry R. Nat Rev Drug Discov. 2010;9:551-559.2. Abdul-Ghani M, DeFronzo R. Endocr Pract. 2008;14:782-790.

3. Marsenic O. Am J Kidney Dis. 2009;53(5):875-883.4. Basile J. Postgrad Med. 2011;123:38-45.

5. List J, et al. Diabetes Care. 2009;32:650-657; 3.

• Canagliflozin 1st SGLT-2 inhibitor, approved March 2013

• Once daily dosing before 1st meal of day, 100mg or 300mg tablets

• MOA: Inhibition of SGLT2 reduces reabsorption of glucose in the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss.

• Blocks approximately 50-80 grams of glucose per day from being reabsorbed

SGLT-2 Inhibitor - Canagliflozin

-10

69

113

88

-20

0

20

40

60

80

100

120

PBO CANA30 mg QD

CANA 400mg QD

CANA 300mg BID

Δ 2

4-H

ou

r U

GE,

Day

1 t

o 1

6 (

g)

Glycemic Efficacy of SGLT2 Inhibitors

As Monotherapy

1. Inagaki N, et al. Diabetes. 2011;60(suppl 1):999-P.2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.3. Ferrannini E, et al. Diabetologia. 2010;53(suppl 1):877.4. Kashiwagi A, et al. Diabetologia. 2011;54(suppl 1):149.

0.1

-0.2

0.1

0.5

-0.8

-0.6

-0.4

-0.8-0.8 -0.8

-0.5

-0.9 -0.9

-0.6

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

Δ A

1C

(%

)

-3 -4

1

6

-33

-15

-23

-40

-36

-24

-29

-38

-29-31

-50

-40

-30

-20

-10

0

10

ΔFP

G (

mg

/dL)

PBO 2.5 5 10 PBO

e e

e ee

e

PBO5 10 25 50

Dapagliflozin2,b Empagliflozin3,c Ipragliflozin4,d

eee

ee

ee e

e

Canagliflozin1,a

PBO 100 200 300

e ee

a 12 weeks, N = 383, baseline A1C = 8.1%.b 24 weeks, N = 274, baseline A1C = 7.8%-8.0%.c 12 weeks, N = 408, baseline A1C = 7.9%.d 16 weeks, N = 129, baseline A1C = 8.3%.e P < .05 vs PBO.

SGLT2 Inhibitors: Efficacy as

Add-on to Metformin Therapy

• FPG reductions from baseline also statistically significant vs PBO (P < .05)

• Dapagliflozin efficacy sustained for at least 102 weeks4,5

a 24 weeks, N = 534, baseline A1C = 7.9%-8.2%.b 12 weeks, N = 451, baseline A1C = 7.75%.c Mean PBO-subtracted change from baseline.d 12 weeks, N = 495, baseline A1C = 7.9%.e P < .05 vs PBO.

1. Bailey C, et al. Lancet. 2010;375:2223-2233.2. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.

3. Seman L, et al. Diabetologia. 2011;54(suppl 1):147.4. Bailey C, et al. Diabetologia. 2011;54(suppl 1):146.

5. Del Prato S, et al. Diabetologia. 2011;54(suppl 1):852.

-0.22

-0.30

-0.79

-0.24

-0.67

-0.76

-0.39

-0.70 -0.70 -0.71

-0.84

-0.92

-0.70

-0.95

-0.64

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

Δ A

1C

(%

)

50 QD

100 QD

200QD

Canagliflozin2,b

300QD

300BID

Empagliflozin3,c,d

1 5 10 25 50

Dapagliflozin1,a

PBO 2.5 5 10

e e

e e ee

e e

e

e

e ee

PBO

Efficacy of SGLT2 Inhibitors

Added to Insulin ± Oral Agents

• Serious AEs were balanced across groups1,2

• Discontinuations were balanced across groups for DAPA vs PBO,1 but higher for CANA 300 mg

(5.3%) than CANA 100 mg or PBO (both 1.9%)2

• Hypoglycemia: 54%-60% vs 52% for DAPA vs PBO at 52 wk1 and 48%-49% vs 37% for CANA vs

PBO2

a N = 808, BL A1C = 8.46%-8.62%, PBO-subtracted results shown.b N = 1718, baseline A1C = 8.3%, PBO-subtracted results shown.

1. Wilding JP, et al. Ann Intern Med. 2012;156:405-415.

2. Matthews DR, et al. Diabetologia. 2012;55(suppl 1): [abstract 764].

-0.40

-0.65

-0.49

-0.73

-0.57

-0.8

-0.6

-0.4

-0.2

0.0

Δ A

1C

(%

)

2.5QD

5QD

10QD

100 QD

Dapagliflozin (24 wk)1,a Canagliflozin (18 wk)2,b

300 QD

Potential Weight Loss Has Been Associated With SGLT2

Inhibitors In Combination With Metformin

a PBO-subtracted values.b P ≤ .01 vs PBO.c P < .001 vs PBO.d P < .002 vs MET.

1. Bailey C, et al. Lancet. 2010;375:2223-2233.

2 . Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.

3. Rosenstock J, et al. Diabetes. 2011;60(suppl 1):989-P.

4. Henry RR, et al. Int J Clin Pract. 2012;66:446-456.

5. Bailey CJ, et al. Diabetologia. 2011;54(suppl 1):146.

6. Cefalu WT, et al. Diabetes. 2012;61(suppl 2): 38-LB..

-0.9-1.1 -1.2

-1.4

-2.2

-2.6

-2.3

-2.7

-3.0

-3.4

-2.7

-3.3

-2.9

-3.4

-2.9

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Δ W

eig

ht

(kg)

Dapagliflozin Add-on (24 wk)1

Canagliflozin Add-on (12 wk)2

Empagliflozin Add-on (12 wk)3

PBO 2.5 5 10100QD

300QD

300BID PBO 5 10 50

c

c c

b

bb

b

b b

Clinically relevant loss also observed with DAPA at 102 wk (2.2-3.4 kg) and CANA at 52 wk (4.2%-4.7% of body weight)5,6

METonly

10only

MET + 10

Dapagliflozin Initial (24 wk)4

d

d

PBO

Rates of Hypoglycemia of SGLT2 Inhibitors

Combined With Metformin Are Comparable to

Placebo

• Across phase 3 trials, hypoglycemia rates with dapagliflozin were6:

– Similar to PBO when used as monotherapy or with metformin

– Higher than PBO when added to SU (10%-11% vs 7%) or insulin (54%-60% vs 52%)

a None were major and none led to discontinuation.b Continuation of 24-wk study.c 1% with major event and 1.5% with event leading to discontinuation in

GLIM group only.

1. Bailey CJ, et al. Lancet. 2010;375:2223-2233; 2. Bailey CJ, et al. Diabetologia. 2011;54(suppl 1):146; 3. Nauck M, et al. Diabetes Care.

2011;34:2015-2022. 4. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238; 5. Cefalu WT, et al. Diabetes. 2012;61(suppl 2):38-LB. 6. Seman L, et al.

Diabetologia. 2011;54(suppl 1):147; 7. Rohwedder K, et al. Diabetologia. 2011;54(suppl 1):853.

AgentHypoglycemia (% of Participants)

SGLT2 Inhibitor Comparator

DAPA (24 wk)1,a 2-4 3 PBO

DAPA (102 wk)2,b 4-5 6 PBO

DAPA (52 wk)3,c 3 40 GLIM

CANA (12 wk)4 0-6 2 PBO

CANA (52 wk)5 4.9-5.6 34.2 GLIM

EMPA (12 wk)6 Similar for EMPA and PBO

SGLT2 Inhibitors Are Associated With Favorable

Blood Pressure Effects When Added to Metformin

1. Nauck M, et al. Diabetes Care. 2011;34:2015-2022.2. Bailey C, et al. Lancet. 2010;375:2223-2233.

3. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.4. Cefalu WT, et al. Diabetes. 2012;61(suppl 2):38-LB.

5. Hach T, et al. Diabetologia. 2012;55(suppl 1):770.

Agent/Study Δ SBP (mm Hg) Δ DBP (mm Hg)

Dapagliflozin1

(Titrated dose, 52 weeks)-4.3 -1.6

Dapagliflozin2

(10 mg, 24 weeks)-5.1 -1.8

Canagliflozin3

(50-600 mg, 12 wk)-4.9 to -0.9 -2.4 to -0.1

Canagliflozin4

(100 mg or 300 mg, 52 weeks)-4.6 to -3.3 NR

Empagliflozin5

(10 mg or 25 mg, 12 weeks)-4.5 to -3.8 -2.7 to -2.3

Genital Infections: SGLT2 Inhibitors With Metformin

• Most events mild to moderate1,3,4

– Most resolved with conventional intervention

– Rarely led to study discontinuation

a One discontinuation.b One severe and 3 led to discontinuation in DAPA group.

1. Bailey CJ, et al. Lancet. 2010;375:2223-2233.2. Bailey CJ, et al. Diabetologia. 2011;54(suppl 1):146.3. Nauck M, et al. Diabetes Care. 2011;34:2015-2022.

4. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.5. Cefalu WT, et al. Diabetes. 2012;61(suppl 2):38-LB.6. Seman L, et al. Diabetologia. 2011;54(suppl 1):147.

AgentGenital Infections (% of Participants)

SGLT2 Inhibitor Comparator

DAPA (24 wk)1 8-13 5 PBO

DAPA (102 wk)2,a 12-15 5 PBO

DAPA (52 wk)3,b 12 3 GLIM

CANA (12 wk)4 3-8 2 PBO

CANA (52 wk)5 7-24 1-4 GLIM

EMPA (12 wk)6 2.5 0 PBO

Urinary Tract Infections:

SGLT2 Inhibitors With Metformin

• Occurrence of urinary tract infection signs/symptoms was similar across

treatments

• Reports indicate that urinary tract infections:1,3,4

– Were generally mild to moderate and not recurrent

– Responded to standard treatments

– Rarely led to discontinuationa One discontinuation.b P < .05 for DAPA vs GLIM based on post hoc analysis.

1. Bailey CJ, et al. Lancet. 2010;375:2223-2233.2. Bailey CJ, et al. Diabetologia. 2011;54(suppl 1):146.3. Nauck M, et al. Diabetes Care. 2011;34:2015-2022.

4. Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.5. Cefalu WT, et al. Diabetes. 2012;61(suppl 2):38-LB.6. Seman L, et al. Diabetologia. 2011;54(suppl 1):147.

AgentUrinary Tract Infections (% of Participants)

SGLT2 Inhibitor Comparator

DAPA (24 wk)1 4-8 8 PBO

DAPA (102 wk)2,a 8-13 8 PBO

DAPA (52 wk)3 11b 6 GLIM

CANA (12 wk)4 3-9 6 PBO

CANA (52 wk)5 6 4 GLIM

EMPA (12 wk)6 3 3 PBO

Summary

• Management of hyperglycemia in patients with type 2

diabetes should be individualized

– Glycemic targets

– Antihyperglycemic therapies

• Choice of antihyperglycemic therapies

– Consideration of patient characteristics & values

– Risk of hypoglycemia

– CV risk

– Consideration of long-term effects on beta cells

• Treatment should include comprehensive reduction of CV

Risk Factors

Guidelines for Glycemic, Blood Pressure

and Lipid Control

HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.

ADA. Diabetes Care. 2012;35:S11-63.

American Diabetes Association Goals

A1c < 7.0% (individualization)

Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/L)

Postprandial glucose < 180 mg/dL

Blood pressure < 140/80 mmHg (<130/80 with macroalbuminuria)

Lipids

LDL: < 100 mg/dL (2.59 mmol/L)

< 70 mg/dL (1.81 mmol/L) (with overt CVD)

HDL: > 40 mg/dL (1.04 mmol/L)

> 50 mg/dL (1.30 mmol/L)

TG: < 150 mg/dL (1.69 mmol/L)

Intensive versus standard blood pressure control and (A) all-cause

mortality and (B) cardiovascular mortality.

Bangalore S et al. Circulation 2011;123:2799-2810

Copyright © American Heart Association

Metaanalysis: BP Targets for Patients with Type 2 Diabetes Mellitus

Bangalore S et al. Circulation 2011;123:2799

0

5

10

15

20

25

30

35

40

STENO-2: No Other Clinical Trial of Patients With Type 2 Diabetes Has Shown Such a Dramatic Reduction in Cardiovascular Events With a Pharmacologic Intervention

Intensive Therapy

Conventional Therapy

Num

ber

of

Card

iovascula

r Events

Amputation

Revascularization

Percutaneus

Coronary

Intervention

Myocardial Infarction

Stroke

Death from Cardiovascular

Causes

Coronary

Artery

Bypass

Graft Surgery

Reprinted from Gaede P, et al. N Engl J Med. 2003;358:580−591.Copyright © 2003 Massachusetts Medical Society. All rights reserved.

0

20

40

60

80

100

120

140

160

180

STENO-2: Fasting Glucose, Low-Density Lipoprotein, and Blood Pressure at 7.8 Years With Intensive Treatment

Intensive Therapy

Conventional Therapy

Valu

e a

t 7.8

Years

FPG(mg/dL)

LDL(mg/dL)

HDL(mg/dL)

Systolic BP(mm Hg)

Diastolic BP(mm Hg)

129

178

83

126

47 45

131

146

7378

HbA

1c 7

.9%

HbA

1c9.0

%

P < .01

P < .01

P < .01 P < .01

Reprinted from Gaede P, et al. N Engl J Med. 2008;358:580−591.Copyright © 2008 Massachusetts Medical Society. All rights reserved.

BP = blood pressure; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein

0

20

40

60

80

STENO-2: Risk-Factor Targets Attained at 7.8 Years With an Intensive Treatment Program

Intensive Therapy

Conventional Therapy

Patients

(%

)

Hemoglobin

A1c <6.5%Cholesterol<175 mg/dL

Triglycerides<150 mg/dL

Systolic

Blood Pressure

<130 mm Hg

Diastolic Blood

Pressure<80 mm Hg

A Message

to

ACCORD?

p = 0.06

p < .001

p = 0.19

p = 0.001

p = 0.21

Reprinted from Gaede P, et al. N Engl J Med. 2003;348:383−393.Copyright © 2003 Massachusetts Medical Society, All rights reserved.

SystolicBlood

Pressure

0

20

40

60

80

Perc

ent

of Tota

l Calc

ula

ted R

isk

Reduction in C

ard

iovascula

r D

isease-R

ela

ted E

vents

Lipids

STENO-2: Lipid-Lowering Therapy Accounted for More Than 70% of Cardiovascular Risk Reduction

Analysis of STENO-2 data based on the risk engine from the United Kingdom Prospective Diabetes Study (UKPDS)

HemoglobinA1c

Reprinted with permission from Gaede P, Pederson O. Diabetes. 2004;53(Suppl 3):S39−S47. Copyright © 2004 American Diabetes Association.

Diabetes Care in US: How Well Are We Doing?

Published on line prior to print February 26, 2013: Diabetes Care

What To Do With the Statin Intolerant Patient

• Dispel misgivings (Dr. Oz et al)

• Review data:

– Decrease stroke, MI, dementia

• Make sure they are vitamin D replete

• Try at least three statins

– Atorvastatin

• Three times per week

– Pravastatin

– Rosuvastatin

• Once weekly

• Cholesevelam

Incidence of Diabetic End-Stage Renal Disease

per 100,000 People with Diabetes, U.S., 1980 -

2008

National Diabetes Surveillance System, U.S. Renal Data System, National Health Interview Survey

Amputation Rates per 1000 People with

Diabetes, U.S., 1988 - 2008

National Diabetes Surveillance System, National Health Interview Survey, National Vital Statistics System

Age-Adjusted Percentage of Adults with Diabetes

Reporting Visual Impairment, United States, 1997–

2010

Data Source: Centers for Disease Control and Prevention (CDC), National Center for Health Statistics, Division of Health Interview

Statistics, data from the National Health Interview Survey. Data computed by personnel in the CDC's Division of Diabetes Translation,

National Center for Chronic Disease Prevention and Health Promotion.

Summary

• A1c target should still be < 7.% for the majority of patients, the

current emphasis is on individualization of targets and

therapies

– Selection of medications in elderly to avoid hypoglycemia

– Patients should be involved in medical decision making

• ADA BP target is < 140/80, lower in patients with proteinuria.

Individualization is appropriate (ie, high risk for CVA).

– Perform orthostatic BP in older individuals and those with

neuropathy

• LDL target has not changed < 100 mg/dl in most, < 70 in

highest risk