T2 Diabetes in 2016 · CI, confidence interval; CV, cardiovascular; HR, hazard ratio. MarsoSP et...
Transcript of T2 Diabetes in 2016 · CI, confidence interval; CV, cardiovascular; HR, hazard ratio. MarsoSP et...
22-Sep-16
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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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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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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
(%)
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; 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
(%)
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; HR, hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.
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
(%)
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; HR, hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.
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
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 exposure.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.
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HbA1c
Time from randomisation (months)
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
Time from randomisation (months)
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
Number of patients at each visit
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.
Number of patients at each visit
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
)
Time from randomisation (months)
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
Hazard ratio (95% CI)
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?
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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
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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?