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7/5/2019
1
Newer Diabetes Medications and CV
OutcomesPriya Vellanki MD
Division of Endocrinology, Metabolism and LipidsEmory University
Clinical Director, Endocrinology ClinicGrady Memorial Hospital
External Industry Relationships *
Company Name(s) Role
Equity, stock, or options in biomedical industry companies or publishers
None None
Industry funds to Emory University for research
Boehringer IngelheimSanofi Novo-Nordisk
Co-investigator (Investigator-Initiated Research Projects)
IndustryAdvisory/Consultant activities
Merck Boehringer Ingelheim
Consultant activities
Conflicts of interest
Objectives
• Review cardiovascular epidemiology in diabetes
• Discuss rationale and background for CV outcome trials in diabetes
• Review results of CV outcomes trials with diabetes medication
7/5/2019
2
Diabetes is associated with significant loss of life years
Seshasai et al. N Engl J Med 2011;364:829‐41
.
0
7
6
5
4
3
2
1
040 50 60 70 80 90
Age (years)
Yearsof life lost
Men7
6
5
4
3
2
1
040 50 60 70 80 900
Age (years)
Women
Non‐vascular deaths
Vascular deaths
Cumulative incidence of coronary events by prevalent CHD and diabetes status
Mondesir et al. Am Heart J 2016;181:43‐51
Diabetes and h/o CHD
CHD only Diabetes only (“SEVERE”)
Severe diabetes: Insulin use or microalbuminuria
Diabetes only No diabetes nor CHD
Question
• CV events and mortality is increasing in patients with diabetes.
A) True
B) False
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3
Global Mortality for CVD and Diabetes
Data from GBD Mortality and Causes of Death Collaborators. (1980–2015)
Pasquel FJ, Gregg EW & Ali MK Endocrinol Metab Clin North Am. 2018 Mar;47(1):1‐32
T2DM and CV Events Over Time
Rawshani A, et al. N Engl J Med. 2017;376:1407-1418.
Swedish National Diabetes Register from 1998 through 2012 and followed through 2014
Question
• Does treatment of diabetes lower cardiovascular events?
A) Yes
B) No
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4
A1C and Complications: UKPDS
UKPDS Group. Lancet. 1998;352:837-853.
All patients assigned to regimen
IntensiveConventional
Time from randomization (y)60 3 9 12 15
0
HbA1c
7
8
9
6
MedianHbA1c
(%)
UKPDS: Risk Reductions With Intensive Therapy (Median HbA1c = 7.0%)
% R
isk
Red
uct
ion
-50 -46
-12
-25
-29
-24
-33
-16
-45
-40
-35
-30
-25
-20
-15
-10
-5
0 Any Diabetes
Related Endpoint
Microvascular Endpoints Laser Rx Cataract Albuminuria Myocardial
Infarction Sudden Death
P = 0.029
P = 0.0031
P = 0.046
P = 0.000054
P = 0.052
P < 0.047
P = 0.0099
UKPDS Group. Lancet 1998;352:837-853.
Microvascular complications
Myocardial infarction
HbA1c
37%
14%
Lowering HbA1c reduces the risk of complications
Deaths related to diabetes21%
1%
Stratton IM, et al. BMJ 2000; 321:405–412.
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Severe Hypoglycemia in 3 Outcome Trials of Intensive Glucose Control in Type 2 Diabetes
0
5
10
15
20
25
VADT ACCORD ADVANCE
% P
atie
nts
with
at l
east
one
sev
ere
hypo
glyc
emic
eve
nt d
urin
g th
e tri
al
Intensive Control Standard Control
p < .001
p < .001
p < .001
Adapted from: 1. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545-2559. 2. The ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. 3. Duckworth W, et al.. N Engl J Med. 2009;360:129-139.
Question
• Does treatment of diabetes lower cardiovascular events?
A) Yes
B) No
Yes, treatment of diabetes does lower CV events BUT… intensive glucose control (HbA1c < 6.5%) does NOT lower CV events
EFFICACY
Lowering HgA1c
SAFETY
Hypoglycemia Prevention
Management of Type 2 Diabetes
Individualized Algorithm
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6
0
2
4
6
8
10
12
14
1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020
Soluble insulin
SGLT-2 inhibitor
Bromocriptine-QR
Bile acid sequestrant
DPP-4 inhibitor
AmylinGLP-1 RA
Basal insulin analogGlinideThiazolidinedione
MetforminHuman insulin
Sulphonylurea
Phenformin
Intermediate-acting insulin
α-glucosidase-I
Num
ber o
f Cla
sses
of
Antih
yper
glyc
emic
Agen
ts
YearUGDP, DCCT and UKPDS studies.
Anti-diabetic Agents Over Time
Rapid-acting insulin analog
Current Antihyperglycemic Medications
Sulfonylureas
Generalized insulin
secretagogue
12 Groups with Different Mechanisms of Action
-GlucosidaseInhibitors
Delay CHO absorption
Biguanide
Reduces hepaticinsulin
resistance
TZDs
Reduce peripheral insulin
resistance
Amylin Analog
Suppressesglucagon
GLP-1 Analogs
Stimulate cellsSuppress glucagon
Colesevelam
Bile acid sequestrant
Bromocriptine
Hypothalamicpituitary reset
InsulinReplacement
Therapy
SGLT-2 Inhibitors
Block renal glucose reabsorption
Glinides
Restore postprandial
insulin patterns
Glinides
Restore postprandial
insulin patterns
DPP-4 Inhibitors
RestoreGLP-1 Level
EFFICACY
Lowering HgA1c
SAFETY
Hypoglycemia Prevention
Management of Type 2 Diabetes: 2017
Cardiovascular Disease
Prevention
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7
FDA 2008: Evaluating CV Risk in Drugs Intended to Treat T2D
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116994.htm
FDA Recommendations
• Independent CV endpoints committee to adjudicate (blinded) CV events during all phase 2 and phase 3 trials
• Events: • 1) CV mortality, 2) MI, and 3) stroke,
and can include: hospitalization for ACS, urgent revascularization, other endpoints.
• Enough endpoints, high risk population
MACE
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FDA Criteria for Assessing CV Risk
Pre‐Approval
Post‐Approval
Noninferiority
Noninferiority
Superiority
HR 1.3 HR 1.8
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
Hirshberg B, et al. Diabetes Care. 2011;134(suppl 2):S101-S106.
HR, hazard ratio.
Hazard Ratio
Outcome: MACE = 1) CV mortality, 2) MI, and 3) stroke, and can include: hospitalization for ACS, urgent revascularization
MACE
CONFIDENTIAL
2008 2020
EXSCEL (exenatide)EXSCEL (exenatide)
LEADER (liraglutide)LEADER (liraglutide)
REWIND (dulaglutide)REWIND (dulaglutide)
ELIXA (lixisenatide)
2014
SUSTAIN-6 (semaglutide)
2010 2012 2016
CANVAS (canagliflozin)
DECLARE (dapagliflozin)
EMPA-Reg(empagliflozin)
2018
GLP1 Receptor Agonists
SGLT-2 Inhibitors
EXAMINE (alogliptin)
CARMELINA (linagliptin)
TECOS (sitagliptin)
SAVOR (saxagliptin)
DPP-4 Inhibitors
23
Reported
Not-Reported
Cardiovascular Safety Studies
Harmony (Albiglutide)
VERTIS (ertigliflozin)
Let’s talk about old drugs
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Metformin‐ initial drug to treat type 2 diabetes
METFORMIN: UKPDS 34 provided some evidence for beneficial CV effects of metformin in overweight patients
1. UKPDS 34. Lancet 1998;352:854–65. 2. http://www.medicines.org.uk/emc/medicine/23244/SPC.3. Holman et al. N Engl J Med 2008;359:1577–89.
Significant reduction in MI maintained over 10 years’ follow‐up3
1997 1999 2001 2003 2005 2007
No. of events:
Conventional therapy 73 83 92 106 118 126
Metformin 39 45 55 64 68 81
Myocardial infarction
Metformin vs conventionalp = 0.01
Time from randomisation (years)
0 3 6 9 12 15
0.0
10
20
30
Proportion of patients w
ith eve
nts
(%)
Intensive (n = 951; events = 139)
Conventional (n = 411; events = 73)
Metformin (n = 342; events = 89)
Risk of MI is 39% lower with metformin vs conventional therapy in obese patients1,2
1.4
1.2
1.0
0.8
0.6
0.4
HR
(95
% C
I)
RR 0.611
p = 0.01RR 0.67p = 0.005
Overall values at study end in 1997
Annual values during 10‐year post‐trial monitoring period
0.4
Total # patients* Total # events*
36 1452 3
283 9
672 55
3041 610
587 4
400 4
630 14
1250 15
1805 46
2222 312
1035 4
96 2
458 4
145 2
300 26
2097 61
4351 72
858 13
495 13
543 24
262 5
2789 34
374 11
1551 38502 11
272 4801 3
1172 4
29,783 1495
SulfonylureasMeta‐analysis of SU CV safety trials (115 trials, ≥ 6 months)
found no consistent association with MACE risk
*SU + comparator groups combined.Monami et al.Diabetes Obes Metab 2013;15:938–53.
First author (year)
Birkeland 1996Chou 2008
Perriello 2006Gerstein 2010
UKPDS 33 1998Hanefeld 2007
Seino 2010
Charbonnel 2005 Matthews 2005
Rubin 2008Home 2009
Arechavaleta 2011va der Laar 2004
Mazzone 2006
Riddle 1998
Giles 2010
Tolman 2009
Kahn 2006
Goke 2010
Garber 2009
Nissen 2008
Ristic 2007
Ferrannini 2009
Bakris 2006
Gallwitz 2012
Jain 2006
Johnston 1998
Nauck 2011
Seck 2010
Overall
0.01 0.1 1 10 100
Favours SUs Favours comparators
MH‐OR (95% CI)
Overall MACE risk estimate for SU vs comparators was not increased: MH‐OR 1.08 (95% CI: 0.86–1.36); p = 0.52
‘CV safety of SUs cannot be considered established unless evaluated in long‐term CVOTs’4
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CAROLINA Study Design
CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D)
CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D)
• Multi‐national, randomized, double‐blind, active‐controlled clinical trial
• 6,033 adults with T2D with increased cardiovascular risk or established cardiovascular disease, median duration of more than 6 years.
• Aim: cardiovascular safety of linagliptin (5 mg once daily) compared with the sulfonylurea glimepiride (both added to stable background glucose‐lowering medication).
ADA 2019: No difference in cardiovascular outcome!
https://clinicaltrials.gov/ct2/show/NCT01243424
Question
• What is the CV outcome safety for DPP‐4 inhibitors?
A) No difference in CV safety
B) Increased events (harm)
C) Decreased events (benefit)
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DPP4‐i: For the primary outcome, all completed CVOTs fall within the FDA mandated upper 95% CI limit of 1.3
.
†Total event rate, %.
1. Scirica et al. N Engl J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352.
4. Rossenstock JAMA 2018
1.0 2.00.80.6
HR (95% CI)
1.3
Number of events(event rate, % per 100 person‐years)
Placebo+ usual care
Comparator + usual care
DPP4 inhibitor trials
SAVOR‐TIMI 531 609 (3.7%) 613 (3.7%)
CARMELINA 434 (12.4†%) 420 (12.1†%)
EXAMINE2 316 (11.8%†) 305 (11.3%†)
TECOS3 851 (4.17%) 839 (4.06%)
Favours comparator Favours placebo
FDA Safety recommendation: Saxagliptin and Alogliptin
http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm
CONFIDENTIAL
Cardiovascular events in high risk patients with T2D
DPP4 inhibitors
• SAVOR (Saxagliptin) • EXAMINE (Alogliptin)
• TECOS (Sitagliptin) • CARMELINA (Linagliptin)
33
Neutral Effect
Cardiovascular Safety Studies
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Question
• Which 2 GLP1‐RA do not show an effect on CV outcomes ?
A) Exenatide and Lixisenatide
B) Albiglutide and Dulaglutide
C) Semaglutide and Liraglutide
Cardiovascular Trials: GLP1‐RAsCardiovascular Trials: GLP1‐RAs
Short-acting:• Exenatide• Lixisenatide
Long-acting:• Exenatide- weekly• Albiglutide• Liraglutide• Dulaglutide• Semaglutide
FDA Approved GLP1-RA
CV Death, Non-fatal MI or Non-fatal Stroke
Marso SP, et al. N Engl J Med. 2016;375:311-322.
CV Death, Non-fatal MI or Non-fatal Stroke
Marso SP, et al. N Engl J Med. 2016;375:1834-1844.
Harmony‐ Albiglutide
Hernandez et al. Lancet 2018; 392: 1519–29
Liraglutide‐ Leader
GLP1-RA Cardiovascular Outcome Trials
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GLP‐1RA Cardiovascular Outcomes
• Exscel Study (exenatide weekly) and ELIXA (lixisenatide)
• No difference in CV outcomes
• Some caveats• Semaglutide – worsening retinopathy, ? Had prior retinopathy
Question
• Which 2 GLP1‐RA do not show an effect on CV outcomes ?
A) Exenatide and Lixisenatide
B) Albiglutide and Dulaglutide
C) Semaglutide and Liraglutide
CONFIDENTIAL
Cardiovascular events in high risk patients with T2D
DPP4 inhibitors
• SAVOR (Saxagliptin) • EXAMINE (Alogliptin)
• TECOS (Sitagliptin) • CARMELINA (Linagliptin)
GLP‐1 RA
• ELIXA (Lixisenatide)
• EXSCEL (Exenatide weekly)
• LEADER (Liraglutide)
• SUSTAIN (Semaglutide)
• REWIND (Dulaglutide)
• HARMONY (Albiglutide)39
Reduced CV Events
Cardiovascular Safety Studies
Neutral Effect
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Cardiovascular Trials: SGLT2‐InhibitorsCardiovascular Trials: SGLT2‐Inhibitors
FDA Approved SGLT2-I
• Canagliflozin• Dapagliflozin• Empagliflozin• Ertugliflozin
Question
• Which SGLT2‐I show a benefit on CV outcomes ?
A) Empagliflozin
B) Canagliflozin
C) Dapagliflozin
D) All of them
SGLT‐2 Inhibitor – kidney is target organRenal glucose reabsorption
Glucose
Proximal tubuleS1 segment
SGLT2~90% glucose reabsorption
SGLT-1~10% glucose reabsorption
S3 segment
Collectingducts
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SGLT‐2 Inhibitor – Mechanism of Action
Glucose
SGLT-2Inhibitors
Glucosuria Loss of calories
EMPA‐REG (Empagliflozin) CANVAS (Canagliflozin) Dapagliflozin (DECLARE)
CANA: 26.9% vs. PBO: 31.5% event per 1000 patient-years (hazard ratio, 0.86; 95% CI, 0.75 to 0.97)
DAPA: 8.8% vs. PBO: 9.4% event per 1000 patient-years (hazard ratio, 0.93; 95% CI, 0.84 to 1.03)
EMPA: 10.5% vs. PBO: 12.1% event per 1000 patient-years (hazard ratio, 0.86; 95% CI, 0.74 to 0.99)
1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018
The SGLT2‐i CV Outcome TrialsPrimary outcome: 3‐point MACE (CV death, MI, stroke)
Hospitalization from Heart Failure, SGLT2‐I CVOTs
EMPA‐REG (Empagliflozin) CANVAS (Canagliflozin) Dapagliflozin (DECLARE)
HR: 0.65; 95% CI, 0.50 to 0.85)
HR: 0.67; 95% CI, 0.52 to 0.87)
HR: 0.73; 95% CI, 0.61 to 0.88)
1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018
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The SGLT‐2 Inhibitors and Renal Outcome
The EMPA‐REG, CANVAS and DECLARE trials showed empagliflozin, canagliflozin and dapagliflozin were associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care.1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018
Caveats for SGLT‐2i
• Genital mycotic infections
• UTI
• Orthostatic hypotension
• Euglycemic DKA (rare)
• Increased risk of amputations (canagloflozin)
Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk
48
1. 4S investigator. Lancet 1994; 344: 1383‐89, http://www.trialresultscenter.org/study2590‐4S.htm; 2. HOPE investigator N Engl J Med 2000;342:145‐53, http://www.trialresultscenter.org/study2606‐HOPE.htm
Simvastatin1
for 5.4 years
High CV risk 5% diabetes, 26% hypertension
1994 2000 2015
Pre‐statin era
High CV risk38% diabetes, 46% hypertension
Ramipril2
for 5 years
Pre‐ACEi/ARB era
<29% statin
Empagliflozin for 3 years
T2DM with high CV risk 92% hypertension
>80% ACEi/ARB
>75% statin
7/5/2019
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ADA Standards of Care, 2019; volume 42 issue Supplement 1
Das et al. J Am Coll Cardiol 2018;72: 3200
Diabetes Drugs for Patients with ASCVD
CONFIDENTIAL
Cardiovascular events in high risk patients with T2D
DPP4 inhibitors• SAVOR (Saxagliptin) • EXAMINE (Alogliptin) • TECOS (Sitagliptin) • CARMELINA (Linagliptin)GLP‐1 RA• ELIXA (Lixisenatide)• EXSCEL (Exenatide weekly)• LEADER (Liraglutide)• SUSTAIN (Semaglutide)• REWIND (Dulaglutide)• HARMONY (Albiglutide)SGLT2‐I• EMPA‐REG (Empagliflozin)• DECLARE‐TIMI (Dapagliflozin)• CANVAS (Canagliflozin)
51
Reduced CV Events
Cardiovascular Safety Studies
Neutral Effect
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Management of Diabetes in 2019
SU TZD DPP4‐i SGLT2‐i GLP1‐RA
Insulin
Efficacy ++ ++ + ++ +++ +++
Hypoglycemia XX ++ +++ ++ ++ XX
Heart Failure ? XX (X)/‐ ++++ ++ ?
ASCVD +/‐ ++ ‐ +++ ++++ ‐
Renal protection + ‐ ‐ ++++ ++ +
Additional Safety Concerns/ AE
CV risk with old SU,
weight gain
Bladder Cancer (?), fractures, weight gain
Pancreatitis
(+)
eDKA,amputations
(?cana) Yeast infections
Pancreatitis (?)
Weight gain
Take home points
• CV disease is common in patients with diabetes
• Intensive glucose control does not change CV outcomes
• Metformin is first line for treatment of diabetes
• If ASCVD, still start with metformin and add an SGLT2i or a GLP‐1RA with proven CV benefit
• DPP4‐I are neutral for CV outcomes
But remember
• None of these studies are for primary prevention
Questions?
AcknowledgementsSupported by K12-HD085850, K23 DK11324-01A1 (start 8/2019) from the
National Institutes of Health