T2 Diabetes in 2016 · CI, confidence interval; CV, cardiovascular; HR, hazard ratio. MarsoSP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827. Non-fatal myocardial infarction

22-Sep-16

1

T2 Diabetes in 2016Exciting new era

Or

More of the same

Stephen Leow Disclosures

I have received honoraria, sat on the advisory boards

or received grants from Novo Nordisk, Sanofi Aventis,

Eli Lilly, Boehringer Ingleheim, Jansenn Cilag, Mundipharma, BioCSL, Rickett Benkiser, AstraZeneca,

GlaxoSmithKlein, Pfizer, Takeda and Grunenthal

Agenda

Why do we treat glycaemia?

Do we treat to target?

Is aggressive treatment always good?

The case for early vs late treatment

Beyond Glycaemia

EMPHA-REG

LEADER

More tools for our toolbox

Why do we treat diabetes?

Is it to prevent complications?

Nephropathy

Neuropathy

Retinopathy

Is it to increase lifespan?

What do diabetics die from?

Association between mean HbA1c and complications: UKPDS

Adapted from Stratton IM et al. on behalf of the UK Prospective Diabetes Study Group. BMJ 2000; 321:405–412.

Targets

What are HbA1c targets in 2016?

Is it 7% (53 mmol/mol)?

Is lower better?

Is lower always better?

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ADS recommended targets for HbA1c

*Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia, especially among older

people. †In an older adult, long duration might be

considered to be >10–20 years, but for a person who develops type 2 diabetes at a young age, it may be considerably longer.

‡ Examples of major comorbidities include chronic medical conditions, such as chronic

kidney disease stages 4 or 5; heart failure stages III or IV (New York Heart Association grading); incurable malignancy; and

moderate to severe dementia.§Where practical, suggest blood glucose

target level <15 mmol/L to help minimise risk of infection.

Adapted from Cheung NW et al. Med J Aust 2009; 191: 339–44.

Are we doing enough

already?

Early intensive multifactorial therapy: STENO-2

Adapted from Gaede PG et al. N Engl J Med 2009; 358: 580-91.

Does glycaemic control

alone save lives?

The argument for

early aggressive treatment

The Legacy Effect

UKPDS Trial showed the advantage of treating

glycaemia

After the trial, the HbA1c of the control group and the

intervention group were the same

In the10 year follow up of the trial, the benefits of the

intervention group continued, despite the glycaemic

control being the same

Early intensive glycaemic control: UKPDS

Adapted from UKPDS Group Lancet 1998; 352: 837–53. Holman RR et al. N Engl J Med 2008; 359: 1577–89.

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Is glucose lowering always a good thing?

• There is an established benefit to treating Blood Glucose early

• How about treating Blood Glucose later on in the progression of the disease?

• Should we treat all diabetic patients aggressively?

• If achievable, are lower targets always better?

Intensive versus standard glucose control: VADT, ACCORD, ADVANCE

Duckworth W et al. for the VADT investigators. N Engl J Med 2009; 360: 129–39. The ADVANCE Study Group. N Engl J Med 2008; 358: 2560–72. The ACCORD Study Group. N Engl J Med 2008; 358: 2545–59.

CVD: cardiovascular disease. MI: myocardial infarction. CHF: coronary heart failure.

In the light of the ACCORD Trial, the ADS HbA1c targets

are different for early and late stage diabetes

*Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia, especially among older

people. †In an older adult, long duration might be

considered to be >10–20 years, but for a person who develops type 2 diabetes at a young age, it may be considerably longer.

‡ Examples of major comorbidities include chronic medical conditions, such as chronic

kidney disease stages 4 or 5; heart failure stages III or IV (New York Heart Association grading); incurable malignancy; and

moderate to severe dementia.§Where practical, suggest blood glucose

target level <15 mmol/L to help minimise risk of infection.

Adapted from Cheung NW et al. Med J Aust 2009; 191: 339–44.

How do you treat diabetes?

First line

Second line

Third line

Wonderful Metformin

Lowers BGLs

Few hypos

Weight loss

Lower rates of cancer

1st line treatment in most, if not all, guidelines

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Rosiglitazone, the game

changer

In 2007, Steve Nissen published a metanalysis showing

that Rosiglitazone was associated with increased

myocardial infarctions

This caused a lot of controversy, with GSK defending

Rosiglitazone in the ADOPT trial

This resulted in the FDA mandating a “Black Box”

warning on Rosiglitazone

The Black Box warning was removed after publication

of the RECORD trail in 2008

Cardiovascular Outcomes

Since Rosiglitazone, the FDA has mandated that all

new diabetes medication undergo cardiovascular

safety trials

There are many cardiovascular trials currently

underway

All are powered to show non inferiority ie no

cardiovascular risk

However, the “Holy Grail” with these trials is to show

cardiovascular benefit

Most trials prior to 2015 have showed no

cardiovascular risk

Do you expect there to be

better cardiovascular outcomes with

hypoglycaemics?

All the FDA mandated trials are

powered to show NON INFERIORITY

If a drug actually

showed a

cardiovascular benefit beyond

glycaemic control

Would this be a game changer?

In Stockholm, on September

2015, the game changed

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5

0.06

–0.39

p<0.0001

–0.52

p<0.0001–0.55

p<0.0001-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

Placebo

(n=131)

10 mg

(n=142)

25 mg

(n=136)

Sitagliptin

(n=129)

Ad

just

ed

me

an

(SE)

ch

an

ge

fro

m

ba

selin

e i

n H

bA

1c

(%)

Change in HbA1c, in patients with good

control (HbA1c<8%; post-hoc analysis)

EM

PA

-REG

MO

NO

: stud

y 1

245.2

0

0.04(95% CI, –0.15, 0.22)

p=0.7118

0.17(95% CI,

–0.02, 0.35)p=0.0808

Mean baseline

7.37 7.33 7.32 7.31

Empagliflozin

Comparison with sitagliptin

0.06

–1.13 –1.16

–0.78

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Placebo

(n=97)

10 mg

(n=82)

25 mg

(n=88)

Sitagliptin

(n=94)

Ad

just

ed

me

an

(SE)

ch

an

ge

fro

m b

ase

line

in

Hb

A1

c(%

)

EM

PA

-REG

MO

NO

: stud

y 1

245.2

0

–0.38(95% CI,

–0.61, –0.15)p=0.0010

–0.35(95% CI,

–0.58, –0.12)p=0.0031

Mean baseline

8.65 8.83 8.7 8.6

Empagliflozin

Comparison with sitagliptin

Change in HbA1c, in patients with poor

control (HbA1c> 8%; post-hoc analysis)

EMPHA-REG

Myocardial Infarcts

EMPHA-REG

Heart Failure

In New Orleans, LEADER

added more fuel to the fire

LEADER

Large clinical trial looking at the cardiovascular safety

of Liraglutide (Victoza)

Coincidentally, Liraglutide has been released as an a

weight loss medication under the trade name

SAXENDA

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6

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

2

4

6

8

L ira g lu t id e

P la ce b o

CV death

4668

4672

4641

4648

4599

4601

4558

4546

4505

4479

4445

4407

4382

4338

4322

4267

1723

1709

484

465

HR=0.78

95% CI (0.66 ; 0.93)p=0.007

Patients at risk

Liraglutide

Placebo

Pa

tie

nts

with

an

eve

nt

(%)

Time from randomisation (months)

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Non-fatal myocardial infarction

4668

4672

4609

4613

4531

4513

4454

4407

4359

4301

4263

4202

4181

4103

4102

4020

1619

1594

440

424

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

2

4

6

8

L ira g lu t id e

P la ce b o

HR=0.88

95% CI (0.75 ; 1.03)p=0.11

Patients at risk

Liraglutide

Placebo

Pa

tie

nts

with

an

eve

nt

(%)


The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; HR, hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

1

2

3

4

5

L ira g lu t id e

P la ce b o

Non-fatal stroke

4668

4672

4624

4622

4564

4558

4504

4484

4426

4405

4351

4314

4269

4228

4194

4141

1662

1648

465

445

HR=0.89

95% CI (0.72 ; 1.11)p=0.30

Patients at risk

Liraglutide

Placebo

Pa

tie

nts

with

an

eve

nt

(%)



Hazard ratio(95% CI) p-value

Liraglutide Placebo

N % R N % R

Number of patients 4668 100.0 4672 100.0

CV death 0.78 (0.66 ; 0.93) 0.007 219 4.7 1.2 278 6.0 1.6

Non-fatal MI 0.88 (0.75 ; 1.03) 0.11 281 6.0 1.6 317 6.8 1.8

Non-fatal stroke 0.89 (0.72 ; 1.11) 0.30 159 3.4 0.9 177 3.8 1.0

Individual components of the primary endpoint

Hazard ratio (95% CI)

Favours PlaceboFavours Liraglutide

10 .5 1 .5

Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.%, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 100 patient-years of observation. Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

All-cause death

4668

4672

4641

4648

4599

4601

4558

4546

4505

4479

4445

4407

4382

4338

4322

4268

1723

1709

484

465

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

5

1 0

1 5

2 0

P la ce b o

Patients at risk

Liraglutide

Placebo

Pa

tie

nts

with

an

eve

nt

(%)



HR=0.85

95% CI (0.74 ; 0.97)p=0.02

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

5

1 0

1 5

2 0

L ira g lu t id e

0 6 12 18 24 30 36 42 48 540

5

10

15

20

Hazard ratio

(95% CI) p-value

Liraglutide Placebo

N % R N % R

Number of patients 4668 100.0 4672 100.0

All-cause death 0.85 (0.74 ; 0.97) 0.02 381 8.2 2.1 447 9.6 2.5

CV death 0.78 (0.66 ; 0.93) 0.007 219 4.7 1.2 278 6.0 1.6

Non-CV death 0.95 (0.76 ; 1.18) 0.66 162 3.5 0.9 169 3.6 1.0

All-cause, CV and non-CV death


Favours PlaceboFavours Liraglutide

10 .5 1 .5

Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.%, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 100 patient-years of exposure.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

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HbA1c


Hb

A1c

(%)

Hb

A1c

(mm

ol/

mo

l)

ETD at month 36: -0.40%

95% CI (-0.45 ; -0.34)

Number of patients at each visit

3705101809234938103877403441354295435544024668Liraglutide

356187756230336403742390540304235435544134672Placebo

5 .0

6 .0

7 .0

8 .0

9 .0

3 0

3 5

4 0

4 5

5 0

5 5

6 0

6 5

7 0

7 5

0 6 1 2 2 4 3 6 4 8

L ira g lu t id e

P la ce b o

3 5 41 8 3 0 4 2 E O T

Data are estimated mean values from randomisation to EOT. CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; HbA1c, glycosylated haemoglobin.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Body weight


Bo

dy

we

igh

t (k

g)

Bo

dy

we

igh

t (l

b)

8 4

8 6

8 8

9 0

9 2

9 4

9 6

1 9 2

1 9 4

1 9 6

1 9 8

2 0 0

2 0 2

2 0 4

0 1 2 2 4

L ira g lu t id e

P la ce b o

6 3 6 E O T4 8

ETD at month 36: -2.3 kg

95% CI (-2.5 ; -2.0)

370882438354088432444344667

355576636803970428544234671


Liraglutide

Placebo

Data are estimated mean values from randomisation to EOT.CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Blood pressure

SBP

ETD at month 36: 1.2 mmHg 95% CI (1.9 ; 0.5)

DBP

ETD at month 36: 0.6 mmHg 95% CI (0.2 ; 1.0)

Data are estimated mean values from randomisation to EOT; *EOT may be any time from month 42 onwards.CI, confidence interval; DBP, diastolic blood pressure; EOT, end of trial; ETD, estimated treatment difference; SBP, systolic blood pressure.Marso SP et al. N Engl J Med 2016. In press.


Liraglutide

Placebo

372282338594107433244454668

357076736993975429544354672

1 3 0

1 3 5

1 4 0

P l a c e b o

L i r a g l u t i d e

7 0

7 5

8 0

0 6 1 2 2 4 3 6 4 8

P l a c e b o

L i r a g l u t i d e

E O T *0 6 12 24 36 48 EOT*

Blo

od

pre

ssu

re (

mm

Hg

)


Rate ratio

(95% CI) p-value

Liraglutide Placebo

N % N %

Confirmed hypoglycemia0.80

(0.74 ; 0.88) <0.001 2039 43.7 2130 45.6

Severe hypoglycemia0.69

(0.51 ; 0.93)0.016 114 2.4 153 3.3

Hypoglycemia

Favours Liraglutide Favours Placebo

10 .5 1 .5


Confirmed hypoglycaemia was defined as plasma glucose level of less than 56 mg per decilitre (3.1 mmol per litre) or a severe event. Severe hypoglycaemia was defined as hypoglycaemia for which the patient required assistance from a third party. Analysed using a negative binomial regression model.CI, confidence interval.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

EMPHA-REG

38% Relative Risk Reduction for Myocardial Infarcts

35% Relative Risk Reduction for Hospitalisation for Heart Failure

LEADER

22% Risk Reduction for Myocardial Infarcts

11% Risk Reduction for Non Fatal Strokes

But theres more

Both these agents areasspciated with Weight Loss

Bith these agents have low rates of hypoglycaemia

Summary Class Effect or Unique

Actions?

Do all SGLT2 inhibitors have the same effect?

Do all GLP1 agonists have the same effect?

22-Sep-16

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Not to forget that some old trials have shown cardiovascular

benefit

Pioglitazone

Thought to be due to the positive benefit on lipids

Acarbose

Thought to be due to the effect on post prandial

hyperglycaemia

Metformin

Teasers

New Oral FDCs

Smart Insulin

Closed loop CGM/Pumps

Flash Glucometer

Nano technology

Insulin/GLP1 FDC

High concentration basal insulin

SGLT2/DPP4i combination

Closed Loop Insulin Pump Freestyle Libre

Flash Glucometer

22-Sep-16

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Insulin Nanotechnology Insulin/GLP1 combo

High concentration

Basal Insulin

Summary

Early aggressive treatment benefits our patients

Late aggressive treatment may be detrimental

The RACGP STOP Rule helps us implement this

Certain medications confer cardiovascular benefits

beyond glucose lowering

The End

Any Questions?Will this change the way you treat diabetes?

Documents

T2 Diabetes in 2016 · CI, confidence interval; CV, cardiovascular; HR, hazard ratio. MarsoSP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827. Non-fatal myocardial infarction