managing the hyperglycemia of diabetes:...
TRANSCRIPT
MANAGING THE HYPERGLYCEMIA OF
DIABETES: SHOULD CVOTs IMPACT MEDICATIONS?
Ralph A. DeFronzo, M.D.Professor of Medicine
Chief, Diabetes DivisionUniversity of Texas Health
Science CenterSan Antonio, Texas
HYPERGLYCEMIA AND MICROVASCULAR COMPLICATIONS
Retinopathy Nephropathy
Neuropathy
UKPDS: EPIDEMIOLOGIC ANALYSIS –MICROVASCULAR ENDPOINTS
Stratton et al, BMJ 321:405-412, 2000
HbA1C (%)
Haz
ard
Rat
io
1
1037% decrease per 1% reduction in HbA1C
P<0.0001
5 6 7 8 9 10
adjusted for age, sex, smoking,albuminuria, BP, LDL, HDL, TG
5
MACROVASCULAR DISEASE*
Heart attack
Stroke
PVD (Amputation)*accounts for ~80% of all mortality in T2DM
NDDG; Diabetes in America, 1995
WHAT ROLE DOES HYPERGLYCEMIA PLAY IN THE PATHOGENESIS OF ATHEROSCLEROSIS
IN T2DM?
Stratton et al, BMJ 321:405-412, 2000
UKPDS: EPIDEMIOLOGIC ANALYSIS –CARDIOVASCULAR ENDPOINTS
HbA1C (%)
Haz
ard
Rat
io
MYOCARDIAL INFARCTION
1
1014% decrease per 1%
reduction in HbA1C
P<0.0001
5 6 7 8 9 10
5 2.2
STROKE
1
1012% decrease per 1%
reduction in HbA1C
P<0.035
5 6 7 8 9 10
5 1.8
UKPDS, Lancet 352:837-853, 1998
MI
-14% -12%
STROKE
UKPDS: RISK REDUCTION IN DIABETES-RELATED COMPLICATIONS FOR 1%
DECLINE IN HbA1C
Micro-vascular
-37%**-40
-30
-20
-10
0
Ris
k R
educ
tion
(%)
P=NS
If hyperglycemia does not play a major role in the
development of ASCVD in T2DM, what factors are
responsible for the accelerated atherogenesis?
INSULIN RESISTANCE SYNDROMEObesity (visceral)
Diabetes/IGTHypertensionDyslipidemia
Increased PAI-1Endothelial Dysfunction
LipotoxicityNAFLD/NASHInflammation
ASCVDHyperinsulinemia
INSULIN RESISTANCE
INSULIN SENSITIVITY IN THE IRS
CON
Glu
cose
Upt
ake
(mg/
m2 -m
in)
HTNObeseNGT
LeanT2DM
0
300
200
100
Hyper-Trigly
Bressler & DeFronzo, Diabetologia 39:1345-50, 1996
* p < 0.001 vs CON** p < 0.01 vs CON
* * * ***
CAD
*
PREDICTIVE (%) VALUE OF FRAMINGHAM CARDIOVASCULAR RISK ENGINE IN MEN
D’Agostino RB et al, JAMA 286:180-87, 2001
MEAN
69%
0
25
50
75
100
FHS ARIC ARIC FHS HHP PR SHS CHS
PER
CEN
T (%
)
Japa
nese
Am
er
His
pani
c
Nat
ive
Am
er
Whi
te (M
)
Whi
te
Whi
te (F
)
Whi
te
Bla
ckUNEXPLAINED RISK=31%
ALL CAUSE MORTALITY AND CARDIOVASCULAR DEATH IN T2DM (N=2,287,362) AND MATCHED CONTROLS (N=457,473) IN SWEDISH
NATIONAL DIABETES REGISTRYRawshani et al, NEJM 376:1407-18, 2017
Inci
denc
e R
ate
(per
10,
000
pers
on-y
r)
T2DM
- - - -
300 -
350 -
250 -
-
400 -
- -Death from any Cause
Controls200 -0 -
Death from Cardiovascular Disease
150 -
200 -
100 -
250 -
50 -
0 - - --- -
T2DM
ControlsInci
denc
e R
ate
(per
10,
000
pers
on-y
r)
- - - - - -
ANTIDIABETIC MEDICATIONS WITH DOCUMENTED CARDIOVASCULAR
BENEFIT
Pioglitazone
GLP-1 RAs
SGLT2 INHIBITORS
EFFECT OF THIAZOLIDINEDIONES ON INSULIN-MEDIATED GLUCOSE DISPOSAL
mg/
kg F
FM•m
in
Before PIO ROSI0
4
6
8
10* *
Miyazaki & DeFronzo, Diabetologia 44: 2210, 2001Diabetes Care 24: 710, 2001
GLYSYNTH
GOX
EFFECT OF TZD AND PLACEBO TREATMENT ON ISR IN RELATIONSHIP TO INSULIN RESISTANCE
IS
R (A
UC
)
Glu
cose
(AU
C)
1 IRx
*
**
Before RxAfter Rx
2500
0
2000
1500
1000
500
Gastaldelli, DeFronzo et al, AJP 292:E871-83, 2007
PROACTIVE
In high risk type 2 diabetics:
● To examine whether pioglitazone reduces total mortality and macrovascular morbidity
19 European Countries
5238 Type 2 Diabetics
TIME (months)
PROACTIVE (n=5238):TIME TO DEATH, MI, OR STROKE
LANCET 366:1279-89,2005
Placebo
Pioglitazone
Kap
lan-
Mei
er E
vent
Rat
e 0.15
0.10
0.05
00 12 24 36
PlcPIO
358301
14.4%12.3%
# Events 3 YearEstimate
P=0.027
HR =0.84
0
0.02
0.04
0.06
40 80 120 160
Comparator
Pioglitazone
0TIME (weeks)
CI = 0.55-1.02
HR=0.75
(n = 5,203)
(n = 5,944)
CARDIOVASCULAR OUTCOMES FROM PIOGLITAZONE META-ANALYSIS OF
CLINICAL TRIALS FDA and Center for Drug Evaluation &Research; July 30,2007
PIOGLITAZONE REDUCES CARDIOVASCULAR EVENTS
HR = 0.7695% CI = 0.62 – 0.93
P = 0.007
EFFECT OF PIOGLITAZONE VERSUS PLACEBO ON RECURRENT STROKE / MI IN IRIS STUDY
0.95 -
0.90 - -
100 -
1 2 3
0.85 -
Years since Randomization
Placebo
0 - 4
Pioglitazone
0.80 -Cum
ulat
ive
Prob
abili
ty
of E
vent
s-fr
ee S
urvi
val
5Number at risk
0
1939 1793 1701 1491 1196481
1937 1778 1690 1476 1182459
Placebo
Pioglitazone
Kernan et al, NEJM, February 17, 20016
N = 3,876
ANTIDIABETIC MEDICATIONS WITH DOCUMENTED CARDIOVASCULAR
BENEFIT
Pioglitazone
GLP-1 RAs
SGLT2 INHIBITORS
Glucagon-like Peptide 1 (GLP-1)and
Glucose-Dependent Insulinotrophic Polypeptide (GIP)
account for ~90% of the incretin effect and 60-70% of insulin
secreted during a meal
INCRETINSIn response to equivalent hyperglycemic stimuli, ORAL glucose elicits a greater
insulin response than IV glucose
GLP-1 ANALOGUES● Exenatide BID● Liraglutide● Exenatide QW● Albiglutide QW● Dulaglutide QW● Lixisenatide● Semaglutide QW● Intarcia 650● Semaglutide - oral
Rad 03/20/00
GLP-1 RECEPTOR AGONISTSGLP-1 RECEPTOR AGONISTS● Effectively reduce HbA1c
● Preserve beta cell function● Promote weight loss● Correct known pathophysiologic
defects in T2DM● Do not cause hypoglycemia● Have an excellent safety profile● Reduce cardiovascular events
Triplitt & DeFronzo, Expert Rev Endo Metab 1:329-41, 2006
Open-Label Extension
Baseline HbA1C=8.3%
TIME COURSE OF EFFECT OF EXENATIDEON HbA1c
Time (weeks)
H
bA1c
(%)
0 20 40 60 80 156
-2.0
-1.0
0
0.5
Placebo-ControlledTrials
Exenatide-10 g bid
Placebo
Klonoff et al, Curr Med Res Opin 24:275-285, 2008
Exenatide-10 g bid
DeFronzo et al, Diabetes Care28:1092-1100, 2005
MOLECULAR ACTIONS OF GLP-1 ON BETA CELL
● increased GLUT2 and Glucokinase● restores glucose responsitivity to resistant beta cells
● replenishes beta cell insulin stores● prevents beta cell exhaustion
INSULIN SECRETION – Glucose Dependent
INSULIN GENE TRANSCRIPTION – Pdx-1
BETA CELL GLUCOSE SENSITIVITY
cAMPPKA
Epac2
IC Ca++
PI-3KInsulin
Secretion
● PI-3K/Akt inhibition of caspase activation
BETA CELL APOPTOSIS
Increa sedHG P
Hype rglyc emia
ETI OLO GY O F T2 DM
DEFN7 5-3/99 Decrea sed G lucoseU ptake
Imp aired Insul inSecre tion Inc rease d Lip olysis
HYPERGLYCEMIAHYPERGLYCEMIA
DecreasedIncretin Effect
DecreasedIncretin Effect
Decreased InsulinSecretion
IncreasedHGP
Islet–cellIslet–cell
IncreasedGlucagonSecretion
OMINOUS OCTET
IncreasedLipolysis
IncreasedGlucose
Reabsorption
NeurotransmitterDysfunction
Decreased GlucoseUptake
Diabetes 58:773-795, 2009
GLP-1
GLP-1
GLP-1GLP-1
GLP-1
GLP-1
Placebo
Liraglutide
Years
Patie
nts
with
Eve
nts
(%)
10 -
15 -
5 -
-
12
-
24
-
0
- - - -
20 -
0
36
-
54
-
N = 9,340HR = 0.8795% Cl, 0.78-0.97P=0.01
Weeks
Semaglutide
2
N = 14,752HR = 0.9195% CI =0.83-1.00P=0.06
6 -
0 -
12 -
18 -
-
- - -- -
0 1 3 4 5
Exenatide
Placebo
320 64 96 109
8 -
6 -
4 -
0
2 -
Placebo
10 - N = 3297 HR = 0.7495% Cl, 0.58-0.95P = 0.02
- - - - - - - -
EFFECT OF ONCE WEEKLY EXENATIDE ON MACE IN EXSCEL
Years
EFFECT OF SEMAGLUTIDE
ON MACE IN SUSTAIN-6
Marso et al, NEJM, Sept 16, 2016
EFFECT OF LIRAGLUTIDE ON MACE IN LEADER
Marso et al, NEJM June 13, 2016 Holman et al, NEJM, Sept 13, 2017
DPP-4 INHIBITORS
EFFECT OF SAXAGLIPTIN ON HbA1c: CHANGE FROM PLACEBO (BASELINE HbA1c ≈ 8.0%)
Int J Clin Prac 63:1395, 2009; Diab Ob Metab 10:376, 2008Diab Care 32:1649, 2009; JCEM 94:4810, 2009
-1
-0.5
0
DRUG NAIVE METFORMIN
ADDITION OF SAXAGLIPTIN TO:GLYBURIDE PIO/ROSI
H
bA1c
(%)
-0.63-0.76
-0.83
-0.64
KAPLAN-MEIER PLOT TO TIME OF OCCURRENCE OF PRIMARY (MACE) ENDPOINT WITH
SAXAGLIPTIN (N=16,492)
HR = 1.00 (95% CI, 0.89-1.12)P<0.001 for non-inferiorityP=0.99 for superiority
Scirica et al, NEJM 369:1317-26, 2013
2 – yr Kaplan-Meier rate:Saxagliptin, 7.3%Placebo, 7.2%
12 -
8 -
4 -
09007205403501800
- - - - -
Days
Placebo
SAXA increased risk of hospitalization for heart failure and hypoglycemia
Saxagliptin
Patie
nts
with
End
Poi
nt (%
)
ANTIDIABETIC MEDICATIONS WITH DOCUMENTED CARDIOVASCULAR
BENEFIT
Pioglitazone
GLP-1 RAs
SGLT2 INHIBITORS
SGLT2 INHIBITION:A NOVEL TREATMENT
STRATEGY FOR TYPE 2 DIABETES MELLITUS
Dapagliflozin Canagliflozin Empagliflozin
SGLT 2 INHIBITION: MEETING UNMETNEEDS IN DIABETES CARE
Corrects a Novel Pathophysiologic
Defect
ReducesHbA1c
Promotes Weight Loss
ComplementsAction of Other
AntidiabeticAgents
Reduces Blood
Pressure NoHypoglycemia
Improves GlycemicControl
and CVRFs
Reversal ofGlucotoxicity
Hazard ratio=0.86 (95% CI, 0.74- 0.99)p=0.004
Placebo
Empagliflozin
Months
10 -
15 -
5 -
-
12
-
24
-
0 48
- - - -
20
036
-
N = 7,020
4 -
6 -
0
8 -
-
-
2 -
-
- - - - - - - -0 12 24 36 48
Months
Hazard ratio = 0.62(95% Cl, 0.49-0.77)P<0.00l
Placebo
Empagliflozin
-
-
Hazard ratio = 0.65 (95% Cl, 0.50- 0.85)P=0.002
Placebo
Empagliflozin
Months
4 -
3 -
5 -
2 -
1 -
-
12
-
24
-
0 48
- - - -
6 -
7
036
-
EFFECT OF EMPAGLIFLOZIN ON
HOSPITALIZATION FOR HEART FAILURE
Zinman et al, NEJM, Sept 20, 2015
EFFECT OF EMPAGLIFLOZIN ON CV
DEATH IN EMPA-REG
EFFECT OF Empagliflozin ON MACE
IN EMPA-REG
Zinman et al, NEJM, Sept 20, 2015
Patie
nts
with
Eve
nts
(%)
KEY OUTCOMES IN CANVAS AND EMPA REG OUTCOME
CV death, nonfataI MI, nonfatal stroke
CV death
Nonfatal myocardial infarction
Hospitalization for heart failure
CV death or hospitalization for heart failure
All-cause mortality
Progression to macroalbuminuria*
Renal composite
Nonfatal stroke
Hazard ratio (95% CI)
*CANVAS Program endpoints comparable withEMPA-REG OUTCOME.
CANVAS Program EMPA-REG OUTCOME
0.25 0.5 1.0 2.0Favors SGLT2i Favors placebo
Zinman B et al. N Engl J Med. 2015; 373:2117-2128Wanner K et al. N Engl J Med. 2016; 375:323-334
CONTRIBUTION OF SGLT-2 INHIBITORS TOALL-CAUSE DEATH AND HHF IN CVD-REAL
(N=309,046)
CANA42.3%
CANA75.4%
CANA1.5
DAPA51.0%
DAPA19.3%
DAPA90.1%
EMPA 6.7% EMPA 5.3% EMPA 8.3%
0
20
40
60
80
100
All countriescombined
US only Europeancountriescombined
Prop
ortio
n of
Expo
sure
Tim
e (%
)Kosiborad et al, Circulation 136:249-259, 2017
ALL-CAUSE DEATH IN CVD-REAL
US
Norway
Denmark
Sweden
UK
# of Events
250
364
323
317
80
Number
143,264
25,050
18,468
18,378
10,462
HR
0.38
0.55
0.46
0.47
0.73
Total 215,622 1334 0.49 (P<0.001)
Favor SGLT2i Favor OGLD
Hazard Ratio: 0.05 0.25 0.5 1.0 2.0
‐ ‐ ‐ ‐ ‐ ‐
‐‐
HOSPITALIZATION FOR HEART FAILURE IN CVD REAL
US
Norway
Denmark
Sweden
UK
Germany
# of Events
298
278
167
191
16
11
Number
233,798
25,050 191
18,468
18,378
10,462
2900
HR
0.55
0.62
0.77
0.61
0.36
0.14Total 309,056 961 0.61 (P<0.001)
Favor SGLT2i Favor OGLD
Hazard Ratio: 0.05 0.25 0.5 1.0 2.0
‐ ‐ ‐ ‐ ‐ ‐
‐‐
KAPLAN–MEIER CURVES FOR MACE AND HHF IN CV-REAL NORDIC
Persson F et al, Diab Ob Metab, 2017HR=0.79P=0.006
1.0 2.01.50.5
Dapagliflozin (n=10,227)
DPP4i (n=30,681)
4 -
0 -
2 -
0Years
Cum
Inci
denc
e (%
)
- ----
HEART FAILURE HOSPITALIZATIONHR=0.62P<0.001
-
1.0
-
2.01.5
-
0.5
- Dapagliflozin
DPP4i
-
0
4 -
0 -
2 -
Cum
Inci
denc
e (%
)
Years
MACE
DECLARE-TIMI58 TRIAL: CURRENTLY THE LARGEST OUTCOME TRIAL ONGOING INVOLVING SGLT-2 INHIBITORS
Study is well powered to answer the question as to whether DAPAGLIFLOZIN COULD OFFER CV BENEFITS,
as well as addressing other safety related questions.1
Primary Outcome Measures: [ Time Frame: up to 6 years ].• Time to first event included in the composite endpoint of
CV death, MI or ischemic stroke
THE MUCH LARGER
DECLARE-TIMI58:
EXPECTED TO REPORT IN 2018.
Plans to include 17,150 individuals with T2DM and has indicated a target
of 1390 3-point MACE
Secondary Outcome Measures: [ Time Frame: up to 6 years ]. • Time to first event of Hospitalization for Congestive Heart Failure• Time to first event included in the composite endpoint of CV
death, MI, ischemic stroke, hospitalization for heart failure, hospitalization for unstable angina pectoris, or hospitalization for any revascularization
• Time to All cause mortality• Body weight change from baseline
SGLT2 Inhibitors and Potential CV Impact
Weight loss and reduced visceral fat
Uric acid
Na+H+
Inflammation & Oxidative stress
SNS activity
Arterial stiffnessGlucoseGlucose
Blood pressure &
Heart rate Plasma Volume
Ang 1-7AT2 receptor
Insulin Resistance
Insulin Resistance
Ketones
GLP-1 RAs SGLT2i
Glycemic control (A1c)
GLP-1 RA/SGLT2i
Insulin sensitivity
Beta cell function
Atherogenesis
Hemodynamic benefit
MACE
COMBINATION THERAPY WITH SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST
DeFronzo RA, Diab Obes Metab 19:1353-1362, 2017
Weight
CARDIOVASCULAR INTERVENTION TRIALS
● GLP-1 Receptor Agonists
● Pioglitazone
● SGLT-2 Inhibitor
LEADER, SUSTAIN-6EXSCEL (P=0.06)
PROactive, IRIS, FDAPeriscope, Chicago
EMPA-REG OUTCOMECANVASCV REAL
● Metformin
UKPDS (n=342)
THE FAB FOUR
GLP-1 RAs
PIOGLITAZONESGLT2i METFORMIN