ask the expert 7 mct and mk have received honoraria for ... · vvvvvvvv muscle adipose tissue...

17-Aug-16

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Professor Merlin Thomas (Baker IDI )A/Prof Mark Kennedy (University of Melbourne)

7%ASK THE EXPERT

2

MCT and MK have received honoraria for educational symposia conducted on behalf of pharmaceutical companies

marketing anti-diabetic medications including BI, Lilly, MSD, Servier, Novartis, Takeda, &Astra Zeneca

Motivated/adherent

Good self-care

Short duration

Low hypo risk

Long life expectancy

No co-morbidity

Good resources

Non-compliant

Poor self-care

Longstanding

High hypo risk

Short life expectancy

Co-morbidity

Limited resources

<7 COMPROMISE

TARGET?

The right target...

Motivated/adherent

Good self-care

Short duration

Low hypo risk

Long life expectancy

No co-morbidity

Good resources

Non-compliant

Poor self-care

Longstanding

High hypo risk

Short life expectancy

Co-morbidity

Limited resources

Standard ?

….with the right agent

200

100

0

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

Perfect Balance

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

FASTING

VVVVVVVVVVVVV Perfect Control

VVVVVVVVVliver

pancreas

glucagon

VVVVVVVV

α

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11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

Perfect Balance

VVVVVVVVV

FEEDINGpancreas

insulin

liver

VVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+ β

L/K

α-

glucagon

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

Out of Control

VVVVVVVVV

DIABETES

pancreas

INSUFFICIENTinsulin

liver VVVVVvVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+

X

X

Increased thresholdX

Anarchic neogenesis

β

L/K

RESISTENCEto insulin

anarchicglucagon

α

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

Back inBalance

VVVVVVVVV

DIABETES

pancreas

insulin

liver VVVVVvVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+

XX

X

MET

MET

β

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

VVVVVVVVV

DIABETES

pancreas

insulin

liver

VVVVVvVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+

X

SU

Back inBalance

β

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

VVVVVVVVV

DIABETES

pancreas

Moreinsulin

liver

VVVVVvVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+

DPP4

DPP4i

Back inBalance

β

α

supressedglucagon

GLIPTINS11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

VVVVVVVVV

DIABETES

pancreas

insulin

liver

VVVVVvVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+

TZD

Back inBalance

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3

11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

0-

Back inBalance

VVVVVVVVV

pancreas

insulin

liver VVVVVvVVVVVVV

muscle

adiposetissue

Incretins GLP1/GIP

+SGLT2i

glycosuria

β

Laboratory parameters HbA1c 7.9%

Total cholesterol: 3.8 mmol/L

Normal albuminuria and eGFR

James presents to his GPPatient history• Age 48 years

• Widowed

• Works in Import/Export

• BP 132/85 mmHg

• BMI 27 kg/m2

• Occasional smoker

• Diet and lifestyle are not optimal

Medical history

• Diabetes diagnosed 2 years ago

• Dyslipidaemia and hypertension

diagnosed 5 years ago

James*, aged 48

Current Medications• Metformin 1500 mg/day• Rosuvastatin 20 mg/day• Telmisartan/hydrochlorothiazide

80/12.5 mg fixed dose combination

*an actor, not a real spy or patient

DIDN’T SOMEONE

SAY “STOP”?

RACGP General practice management of type 2 diabetes (2014-2015)

17

EXCLUDE /TREAT REASONS FOR CONTROL

NON –COMPLIANCE (pills,diet,lifestyle)

SIDE EFFECTS (real or perceived risk for)

STRESS & DEPRESSION

BULLET WOUNDS or other INFECTION

EXCESSIVE WEIGHT GAIN

OTHER DRUGS

HYPOTHYROIDISM

RACGP Guidelines 2014-5

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o When the treatment goal of HbA1C <7 % with metformin plus lifestyle intervention is not achieved within 3-6 months

o In order to achieve the HbA1C <7 % these glucose goals are usually necessary:

Fasting glucose 4-7 mM

Postprandial glucose (<10 mM)

o If more than 20% are greater than this in a two week period you are not in control

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What are James’ treatment priorities?*

Weight Sustainability

No HYPO

Lower HbA1c

Complications

Compliance

Tolerability Cost




No HYPO

Lower HbA1c

Complications

Compliance

Tolerability Cost


40 RCT (n=17795): 6-12 months trials, added-on after MFM failure

McIntosh B et al. Open Med 2011; 5:E35-E48

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0.06

–0.39p<0.0001

–0.52p<0.0001

–0.55p<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 m

ean

(SE

) ch

ang

e fr

om

b

asel

ine

in H

bA

1c(%

)

EM

PA

-RE

G M

ON

O: stu

dy

1245.20

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

24

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 m

ean

(SE

) ch

ang

e fr

om

bas

elin

e in

Hb

A1c

(%)

EM

PA

-RE

G M

ON

O: stu

dy

1245.20–0.38

(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

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Sustainability

No HYPO

Lower HbA1c

Complications

Compliance

Weight

CostTolerability



Meta-analysis: Overall hypoglycemia for medications added-on metformin

34 RCT (n=16704): 6-12 months trials, added-on after metformin failure


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Don’t use agents that increase insulin when it is not needed

Priority in high risk groups Priority in patients with CVD Priority in drivers Behavioral changes + action plan Self monitoring ?


Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Weight Control


Meta-analysis: Body weight change for medications added-on metformin

30 RCT (n=15265): 6-12 months trials, added-on after MFM failure


–0.33

–2.26–2.48

0.18

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Placebo(n=228)

10 mg(n=224)

25 mg(n=224)

Sitagliptin(n=223)

Ad

just

ed m

ean

(SE

) ch

ang

e fr

om

bas

elin

e in

bo

dy

wei

gh

t (k

g)

Roden M, et al. Lancet Diabetes Endocrinol. 2013;1(3):208–219

E

MPA

-RE

G M

ON

O: stu

dy 124

5.20

–2.15(95% CI,

–2.63, –1.67)p<0.0001

0.52(95% CI,

0.04, 1.00)p=0.0355

–1.93(95% CI,

–2.41, –1.45)p<0.0001

Mean baseline

78.23 78.35 77.80 79.31

Comparison with placeboEmpagliflozin

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Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Weight

CostTolerability


DKA

PolyuriaeGFR<45

Benefits

arthralgia

?BMD


Sustainability

No HYPO

Lower HbA1c

CVD Risk

Weight loss

Tolerability Cost

COMPLIANCE


34

Side effects (real or perceived risk for)

Complexity (timing, frequency, delivery route, polypharmacy, coordination, convenience, ease, etc)

Cost Lack of efficacy (real or perceived)

Invulnerability (relevance/threat)

Confidence (sense of control)

What are James’ treatment priorities?


No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

50 y.o.

36

Exhaustion (nike effect)

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No HYPO

Lower HbA1c

CVD

Compliance

Tolerability Cost

What are James’ treatment priorities?Non-significant (10%) in all MI

BMJ 2011;343:d6898

39

Glucose related:- Fewer hypos- Fewer and briefer highs- Smoother control- Reduced insulin levels

Pleiotropic:- Lower BP- Lower weight- Lower fat- Lower uric acid- Reduced inflammation- Better recovery

Direct cardioprotective? 40

HR 0.62(95% CI 0.49, 0.77)

p<0.0001

NEJM (2015) Cumulative incidence function. HR, hazard ratio

41

NEJM (2015) Cumulative incidence function. HR, hazard ratio 42

0.25 0.50 1.00 2.00

Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

42

Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI

17-Aug-16

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No HYPO

Lower HbA1c

Cost

Compliance

Tolerability

CVD risk

Changing treatment priorities?*


Comorbidity44

Metformin : accumulation, GI effects, lactic acidosis

SU : accumulation , inflexibility, hypoglycemia 1st Gen SUs, Glyburide and Glimepiride should not be used

Gliclazide and Glipizide are the preferred SU

both still require careful dose adjustment below 60 and are contraindicated <15

TZD: CHF, bone thinning and anemia

Insulin : variable accumulation , hypoglycemia

GLP-1 agonists : accumulation, poorly tolerated

SGLT2i : lack efficacy, hypovolaemic ARF

DPP4 i : dose adjustment (except linagliptin)

All classes have challenges in low eGFR?


No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Changing treatment priorities?*


Laboratory parameters HbA1c 8.2%

Total cholesterol: 5.8 mmol/L

eGFR 125 ml/min/1.73m2

James presents to his GPPatient history• Age 48 years

• BP 142/75 mmHg

• BMI 37 kg/m2

• Occasional smoker

• Diet not optimal

Medical history

• Diabetes diagnosed 5 years ago

• Failed oral therapy

Now on insulin injections

• But control is still suboptimal

James*aged 48

Current Medications• Metformin 2g/day• Insulin 100U/day• Rosuvastatin 20 mg/day• Telmisartan/hydrochlorothiazide

80/12.5 mg fixed dose combination*an actor, not a real spy or patient


No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost



Weight

CVD Risk

Compliance

Tolerability

Sustainability

No HYPO

Lower HbA1c

Cost

ask the expert 7 mct and mk have received honoraria for ... · vvvvvvvv muscle adipose tissue...

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