global cv impact of t2dm - pace-cme€¦ · - 70-80 g/day ( - 280-320 kcal/day) increased glucose...
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![Page 1: Global CV Impact of T2DM - PACE-CME€¦ · - 70-80 g/day ( - 280-320 Kcal/day) Increased glucose excretion. Zinman N Engl J Med 2015;373:2117-28 Death from CV Causes HR 0.62 P](https://reader035.vdocument.in/reader035/viewer/2022063011/5fc607c60f4aa4260d63fdc3/html5/thumbnails/1.jpg)
At least 68% of people >65 years with diabetes die of heart disease
Global CV Impact of T2DM
(N 820,900)
IDF Diabetes Atlas. 7th edn. 2015
Seshasal NEJM 2011;364:829
2015 2040
Years
Gregg NEJM 2014;370:1514–1523.
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Disclosures
• Lectures for Merck, Pfizer, Amgen, Sanofi, Aegerion, Kowa, Danone
• Advisory boards: Danone, Merck, Amgen, Aegerion, Verseon
• No relevant research funding
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CV Mortality in T2DMSwedish National Diabetes Register over 4.6 years
Tancredi N Engl J Med 2015;373:1720-32
Hazard Ratio (95% C)
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Constantino et al (2013) Diabetes Care ePub
Long-Term Complications and Mortality
in Young-Onset DiabetesT2DM is more hazardous and lethal than T1DM
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Diabetes, Fasting BG, BP andCholesterol on CHD Risk
Emerging Risk Factors Collaboration Lancet 2010; 375: 2215–22
Fasting Blood Glucose Total / non-HDL Cholesterol Systolic BP
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CARDS: Cumulative Hazard for MI and CV death
Atorvastatin
Cu
mu
lati
ve H
azard
(%
)
Relative Risk -37% (95% CI: -52, -17)
P=0.001
Years
Placebo
0
5
10
15
0 1 2 3 4 4.75
Colhoun Lancet 2004; 364: 685-696
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Time to First Major CV Event in Patients With Diabetes TNT Study : Lower
HR = 0.75 (95% CI 0.58, 0.97)
P=0.026
0 1 2 3 4 5 6
Time (years)
0.20
0.10
0.15
0.05
0
Cu
mu
lati
ve in
cid
en
ce o
f m
ajo
r card
iovascu
lar
even
ts
Relative risk reduction = 25%
Atorvastatin 80mg
Atorvastatin 10mg
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Multiple Risk Factors and CVD Death in Diabetic and Non diabetic Men (MRFIT)
Stamler J et al Diabetes Care 1993;16:434.
Ag
e-a
dju
ste
d C
VD
death
rate
/10,0
00 p
ers
on
-years
140
120
100
80
60
40
20
0
No Diabetes
Diabetes
None One only Two only All three
Number of risk factors
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Multifactorial Intervention in T2DM : Broader
Gaede N Engl J Med 2008;358:580-91
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Benefit of Different Interventions per 200 Diabetes Pts Treated for 5 years
Per 0.9% lowerHbA1c
Per 4mmHg lower SBP
Per 1mmol/L
lower LDL-C
Ray Lancet 2009 Meta-analysis of intensive glucose-lowering trials
CV
Ev
en
ts
5
0
-5
-12.5-15
-20
-10 -8.2
-2.9
Using traditional Glucose lowering treatments
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Intensive Glucose Lowering in T2DM: ACCORD Study : Earlier?
N Engl J Med 2008;358:2545-59
Primary Outcome Death from Any Cause
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Adverse CV events led the FDA to require demonstration of CV safety for new glucose-lowering drugs
UGDP trial: tolbutamide discontinued due to increased CV mortality vs other treatments
1961
2005
2007
2008
2008
2012
Muraglitazar increases CV risk during FDA assessment
Rosiglitazone increased risk for MI and CV-related death
ACCORD trial: intensive glucose lowering increased all-cause mortality
FDA / EMA requirements
New diabetes drugs should
demonstrate CV safety with meta-
analysis and CV outcome trial
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New Diabetes Treatments
Target CV disease mechanisms
Widely applicable
Safer ( eg Hypoglycaemia)
Weight loss
Lifetime CV risk management
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Liraglutide and CV Outcomes in T2DM
Marso N Engl J Med 2016;375:311-22
Pati
en
ts w
ith
an
Even
t (%
)
Primary Outcome Death from Any Cause
Months since Randomisation
HR 0.87
P=0.01
HR 0.85
P=0.02
LEADER Trial
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SGLT2 SGLT
1
Proximal tubule
S1
GlomerulusDistal tubule
Glucosefiltration
S3
Collecting duct
90%
10%
Loop of Henle
Glucosereabsorption
Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18;
Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35;
Han S. Diabetes. 2008;57:1723-1729.
SGLT2 inhibitor Minimal
glucoseexcretion
SGLT2 Inhibition ReducesRenal Glucose Reabsorption
- 70-80 g/day ( - 280-320 Kcal/day)
Increasedglucose
excretion
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Zinman N Engl J Med 2015;373:2117-28
Death from CV Causes
HR 0.62
P<0.01
Empagliflozin, CV Outcomes and Mortality in T2DM
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Mechanisms for CV Benefit From SGLT2
Abdul-Ghani Diabetes Care 2016 May; 39(5): 717-725
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Empagliflozin and Progression of Kidney Disease in T2DM
Wanner N Engl J Med 2016;375:323-34
Incident or Worsening Nephropathy Post Hoc Renal Composite Outcome
Empa
Placebo
Empa
Placebo
HR 0.61, P<0.001 HR 0.54, P<0.001
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CV outcome trials for SGLT2 Inhibitors in Diabetes
CANVAS
(n = 4339)
2015 20172016 2018 2019
EMPA-REG
OUTCOME™
n = 7034
DECLARE-TIMI 58
(n = 17,150)
2020
Dapagliflozin
High risk for CVD
Established CVD
Triple MACE
1390 events
Canagliflozin
Established CVD
or > 2 CVD risk ff
Triple MACE
420 events
Empagliflozin
Established CVD
Triple MACE
691 events
CV mechanisms?
Safety?
Class effect?
Combination therapy?
Opportunity for Prevention?
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New Era for CVD Management in DM:Some thoughts…
In addition to BP and Cholesterol lowering, CVD and renal benefit with two new diabetes drugs especially SGLT2 I
Has changed guidelines for DM care
Novel multiple mechanisms, especially with lack of hypoglycaemia may broaden indications towards early treatment, prevention, even without DM
Diabetologists Cardiologists