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17-Aug-16
1
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
17-Aug-16
2
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
17-Aug-16
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
18
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
17-Aug-16
4
What are James’ treatment priorities?*
Weight Sustainability
No HYPO
Lower HbA1c
Complications
Compliance
Tolerability Cost
*an actor, not a real spy or patient
What are James’ treatment priorities?*
Weight Sustainability
No HYPO
Lower HbA1c
Complications
Compliance
Tolerability Cost
*an actor, not a real spy or patient
40 RCT (n=17795): 6-12 months trials, added-on after MFM failure
McIntosh B et al. Open Med 2011; 5:E35-E48
23
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
17-Aug-16
5
Sustainability
No HYPO
Lower HbA1c
Complications
Compliance
Weight
CostTolerability
What are James’ treatment priorities?*
*an actor, not a real spy or patient
Meta-analysis: Overall hypoglycemia for medications added-on metformin
34 RCT (n=16704): 6-12 months trials, added-on after metformin failure
McIntosh B et al. Open Med 2011; 5:E35-E48
27
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 ?
What are James’ treatment priorities?*
Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Weight Control
*an actor, not a real spy or patient
Meta-analysis: Body weight change for medications added-on metformin
30 RCT (n=15265): 6-12 months trials, added-on after MFM failure
McIntosh B et al. Open Med 2011; 5:E35-E48
–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
17-Aug-16
6
What are James’ treatment priorities?*
Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Weight
CostTolerability
*an actor, not a real spy or patient
DKA
PolyuriaeGFR<45
Benefits
arthralgia
?BMD
What are James’ treatment priorities?*
Sustainability
No HYPO
Lower HbA1c
CVD Risk
Weight loss
Tolerability Cost
COMPLIANCE
*an actor, not a real spy or patient
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?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
50 y.o.
36
Exhaustion (nike effect)
17-Aug-16
7
Weight Sustainability
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
8
Weight Sustainability
No HYPO
Lower HbA1c
Cost
Compliance
Tolerability
CVD risk
Changing treatment priorities?*
*an actor, not a real spy or patient
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?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Changing treatment priorities?*
*an actor, not a real spy or patient
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
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
What are James’ treatment priorities?*
*an actor, not a real spy or patient
Weight
CVD Risk
Compliance
Tolerability
Sustainability
No HYPO
Lower HbA1c
Cost