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.
Disclosures
• Lectures for Merck, Pfizer, Amgen, Sanofi, Aegerion, Kowa, Danone
• Advisory boards: Danone, Merck, Amgen, Aegerion, Verseon
• No relevant research funding
CV Mortality in T2DMSwedish National Diabetes Register over 4.6 years
Tancredi N Engl J Med 2015;373:1720-32
Hazard Ratio (95% C)
Constantino et al (2013) Diabetes Care ePub
Long-Term Complications and Mortality
in Young-Onset DiabetesT2DM is more hazardous and lethal than T1DM
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
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
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
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
Multifactorial Intervention in T2DM : Broader
Gaede N Engl J Med 2008;358:580-91
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
Intensive Glucose Lowering in T2DM: ACCORD Study : Earlier?
N Engl J Med 2008;358:2545-59
Primary Outcome Death from Any Cause
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
New Diabetes Treatments
Target CV disease mechanisms
Widely applicable
Safer ( eg Hypoglycaemia)
Weight loss
Lifetime CV risk management
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
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
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
Mechanisms for CV Benefit From SGLT2
Abdul-Ghani Diabetes Care 2016 May; 39(5): 717-725
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
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?
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
