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Diabetes and Cardiovascular Disease
Facing the Venerable Threat with New Opportunites
Paul W. Armstrong MD
March 13
ACC Rockies
Research Grants Boehringer Ingelheim sanofi aventis Merck Astra Zeneca CSL
Consultant / Speaker Merck Bayer
Data & Safety Monitoring Boards Bayer Eli Lilly Mast Theraputics
2016
Disclosure Statement
Paul W. Armstrong MD
Detailed financial disclosure at http://www.vigour.ualberta.ca
Marriage between Diabetes and CV Disease
♦ Raging Global Epidemic
♦ The Major Risk Factor for CV Disease
♦ Some Rx for Diabetes may Worsen
Outcomes
♦ New Rx Choices
Why is this a Marriage of Necessity?
Age-Adjusted Prevalence of Obesity and
Diagnosed Diabetes Among U.S. Adults
2010Obesity (BMI≥30 kg/m2) Diabetes
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System
Available at http://www.cdc.gov/diabetes/statistics
Diabetes: the growing global burden
1Adapted from IDF. E-Atlas. Available at: www.eatlas.idf.org (accessed 05.03.07).2Diabetes Atlas, third edition © International Diabetes Federation, 2006.
IDF:2
• Diabetes currently affects 246 million people worldwide
• It is expected to affect 380 million by 2025
1
12.3M patient years follow-up; Mean Age 55; 48% women
Diabetes* is Associated with Significant Loss of Life Years
*Type 1 or 2 diabetes mellitus
Emerging Risk Factors Collaboration. N Engl J Med. 2011;3;364:829-41.
7
6
5
4
3
2
1
0
0 40 50 60 70 80 90
Ye
ars
of
Lif
e L
os
t
Age (year)
7
6
5
4
3
2
1
0
0 40 50 60 70 80 90
Age (year)
Non-vascular deaths
Vascular deaths
Men Women
On average, a 50-year-old person with diabetes and
no history of vascular disease will die 6 years earlier
relative to a counterpart without diabetes
Diabetic
RetinopathyLeading cause
of blindness
in adults1,2
Diabetic
NephropathyLeading cause of
end-stage renal
disease3,4
Cardiovascular
Disease
Stroke
2- to 4-fold increase in cardiovascular mortality and stroke5
Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity amputations
8/10 individuals with
diabetes die from CV
events6
Complications of Diabetes
Top: Adapted Pepine CJ et al. Am J Cardiol 1998)Bottom: Adapted Ramlo-Halsted BA, Edelman SV. Primary Care 1999
Development and Progression of
Type 2 Diabetes and Related Complications
Insulin level
Insulin resistance
Hepatic glucose production
Beta cell function
Foam
cellsFatty
streak
Intermediate
lesion
Atheroma Fibrous
plaque
Complicated
lesion/rupture
Impaired glucose tolerance
Diabetes diagnosis
Frank diabetes
4-7 years
Development of macrovascular complications
Development of microvascular complications
Type 2 diabetes & incidence CV diseases: 1·9 M (1.8% diabetics)
Distribution of initial presentation without prior CV history
Shah et al; Lancet Diabetes & Endocrinology 2015Median f/up 5.5y : CV Death 1.53 (1.45-1.62)
Event Rates 5.7% 17.9%*
n=1,887,062 n= 34,198
Our results will help to inform drug development and the
design of trials in type 2 diabetes. Trials have often
included acute myocardial infarction and acute stroke as
their primary event endpoints, because of a previous
perception that these outcomes were the main disease
burdens in type 2 diabetes, or that they are easier to
ascertain and validate than chronic disease endpoints. We
propose that chronic disease endpoints such as heart
failure, peripheral arterial disease, and stable angina are
important to consider in the choice of primary endpoint
because they are common, have a high morbidity burden,
and might have different treatment effects from myocardial
infarction or stroke.
Shah et al The Lancet Diabetes & Endocrinology 2015
Slide Source
Lipids Online Slide Librarywww.lipidsonline.org
Vascular Protection Checklist: CDA 2013
A • A1C – optimal glycemic control (usually ≤7%)
B • BP – optimal blood pressure control (<130/80)
C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat
D • Drugs to protect the heart (regardless of baseline BP or LDL)
A – ACEi or ARB │ S – Statin │ A – ASA if indicated
E • Exercise / Eating healthily – regular physical
activity, achieve and maintain healthy body weight
S • Smoking cessation
Slide Source
Lipids Online Slide Librarywww.lipidsonline.org
Diagnostic Criteria for Diabetes, IFG & IGT
American Diabetes Association. Diabetes Care 2003.
Fasting G
lucose (
mm
ol/
L)
(mg/dL)
Normalglucose
IGT
2-h Postload Glucose (mmol/L)
(mg/dL)
140 200
126
100
Diabetes
7.0 11.1
8.5
7.5
6.5
5.5
4.5
3.5
IFG + IGTIFG
2.5 4.5 6.5 8.5 10.5 12.5 14.5
IFG = Impaired fasting glucose
IGT = Impaired glucose tolerance
‘Glucose triad’ of diabetes management
HbA1c = glycated haemoglobin
Post-meal
glucoseFasting
glucose
HbA1c ≥ 6,5%Average long-term
glucose level
HbA 1c: the Key Player
Glycated Hb derived from nonenzymatic
addition glucose to amino gps of Hb
Concentration depends on both blood
glucose & RBC life span
Because RBC’s in circulation ~ 120 days it
represents integrated glucose conc’n over
preceding 8-12 weeks
Free of large daily blood glucose fluctuations
Well aligned with risk retinopathy, CKD, CV
disease & mortality
Marriage between Diabetes and CV Disease
♦ Raging Global Epidemic
♦ The Major Risk Factor for CV Disease
♦ Some Rx of Diabetes may Worsen Outcomes
♦ New Rx Choices
Why is this a Marriage of Necessity?
Diabetes awareness, Rx & Control
NHANES survey: 21M DM
AHA Stats 2016 update
Would attaining normal A1C reduce CV risk
in patients with type 2 DM?
• ACCORD: Action to Control
Cardiovascular Risk in Diabetes
• ADVANCE: Action in Diabetes and
Vascular Disease: PRETRAX AND
DIAMICRON MR CONTROLLED
EVALUATION
• VADT: Veterans Affairs Diabetes Trial
Would attaining normal A1C reduce CV risk
in patients with type 2 DM?
• ACCORD: Action to Control
Cardiovascular Risk in Diabetes
• ADVANCE: Action in Diabetes and
Vascular Disease: PRETRAX AND
DIAMICRON MR CONTROLLED
EVALUATION
• VADT: Veterans Affairs Diabetes Trial
Survival: HbA1C and Diabetes
All Cause Mortality(3.9 yrs)
Oral Combo Oral / Insulin
Lancet 2010
Acute Complications and Effects
of Severe Hypoglycemia
Plasma glucose level
1
2
3
4
5
6
mmol/L
• Cognitive impairment
• Unusual behaviour
• Seizure
• Coma
• Brain death
Progressive
Neuroglycopenia2
• Abnormal prolonged
cardiac repolarization -
↑ QTc and QTd
• Sudden death
Increased Risk of
Cardiac Arrhythmia1
1. Landstedt-Hallin L et al. J Intern Med. 1999; 246:299-307
2. Cryer PE. J Clin Invest. 2007; 117(4):868-70
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
Older Patients have Less Perception of Hypoglycemia
Bremer JP et al. Diabetes Care. 2009; 32 (8):1513-17
12
14
10
8
6
4
2
0
Auto
nom
ic
sym
pto
ms
Baseline Hypo Recovery
**
12
10
8
6
4
2
0
Ne
uro
gly
copenic
sym
pto
ms
Baseline Hypo Recovery
*
Middle-aged
(39-64 years)
Older
(≥65 years)
Meta-analyses of Rosiglitazone or Pioglitazone vs
Comparators on Risk of MI, Ischaemic Heart Disease
or a Composite of Major Macrovascular Events
Schernthaner G et al. Diabetes Obes Metab 2010;12:1023-35
3.53.02.52.01.51.00.50.0
Friedrich et al. (MI)
Selvin et al. (CV morbidity)
GSK-ICT (MI)
Friedrich et al. (IHD)
Shuster et al. (MI)
FDA (Serious IHD)
Nissen & Wolski (MI)
Singh et al. (MI)
FDA (IHD)
Paaty & Furberg (MI)
Diamond et al. (MI, highest estimate)
Dahabreh & Economopoulos (MI, highest estimate)
GSK-ICT (IHD)
Bracken (MI, excl. RECORD)
Diamond et al. (MI, lowest estimate)
Bracken (MI, incl. RECORD)
Dahabreh & Economopoulos (MI, lowest estimate)
Monami et al. (MI)
FDA (CV death/MI/stroke)
GSK-ICT (CV death/MI/stroke)
Mannucci et al. (non-fatal coronary events)
Mannucci et al. (non-fatal MI)
Selvin et al. (CV morbidity, incl. PROactive)
Selvin et al. (CV morbidity, excl. PROactive)
Nagajothi et al. (MI)
Lincoff et al. (death/MI)
Perez et al. (death/MI/stroke, incl. PROactive)
Lincoff et al. (death/MI/stroke, incl. PROactive)
Mannucci et al. (non-fatal coronary events)Lincoff et al. (MI)
Lincoff et al. (death/MI/stroke, excl. PROactive)
Perez et al. (death/MI/stroke, excl. PROactive)
Hazard or Odds or Risk Ratio
Rosiglitazone
meta-analyses
Pioglitazone
meta-analyses
FDA Guidance for Industry to Evaluate CV Risk in New Antihyperglycemic Medications1
July 2008: In order to establish the safety of a new antihyperglycemic medication to treat T2DM, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee provided guidance on risk assessment
Effects on CV risk to be more thoroughly addressed during antihyperglycemic medication development
Recommendation to demonstrate that therapy will not result in unacceptable increase in CV risk
Key areas to be addressed by study sponsors (inclusion of patients with a higher risk of CV events [eg, patients with advanced CV disease, elderly patients, and patients with impaired renal function], study duration ≥2 years)
1- Center for Drug Evaluation and Research. Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008. http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed September 12, 2014.
T2DM = type 2 diabetes mellitus; CV = cardiovascular.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
4. Choice of pharmacological agents should be
individualized taking into consideration [Grade D,
consensus]
Patient Characteristics
• Degree of hyperglycemia
• Presence of co-morbidities
• Patient preference
• Ability to access treatments
Properties of the Treatment
• Effectiveness and durability of
lowering BG
• Risk of hypoglycemia
• Effectiveness in reducing
complications
• Effect on body weight
• Side effects
• Contraindications
Recommendation 4
Sites of Action of Antidiabetic Agents
Adapted from Bailey CJ. Trends Pharmacol Sci. 2011 courtesy M Hussain
Pancreas
Adipose
tissueLiver
Gut
Kidney
Insulin
Metformin TZD
SGLT2iAGI
DPP-4i
GLP-1 receptor agonist
SU/Biguanide
Blood
glucose
Stimulatory or positive effect
Inhibitory effect
AGI= α-glycosidase(acarbose)
New Hypoglycemic Agents
Incretin effect = augmentation glucose/stimulated
insulin secretion by intestinally derived peptides
Incretins released in presence of glucose and
nutrients in the gut
Oral glucose load more effective than same
glucose given IV in releasing insulin
Incretins rapidly inactivated by dipeptidyl
peptidase-4 (DPP4) = very short half-life
Incretin pathway attenuated in type 2 diabetes
27
Pancreas β-cells:
Glucose-dependent
insulin secretion
GLP-1 secreted by intestinal
endocrine cells in response
to food intake
Brain:
Promotes satiety
Appetite
Liver:
Hepatic glucose
Stomach:
Slows gastric emptying
• GLP-1 accounts for ~60% of total insulin release after a meal.3
• GLP-1 effects are reduced in patients with type 2 diabetes.3
Pancreas α-cells:
Postprandial glucagon
Flint A, et al. J Clin Invest. 1998; Larsson H, et al. Acta Physiol Scand.1997; Nauck MA, et al. Diabetologia. 1996;. Drucker DJ. Diabetes.1998
Glucagon-Like Peptide (GLP-1) Hormone: Effects in Humans
GLP-1 & GIP Degraded by the DPP-4 Enzyme
Meal
Intestinal
GLP-1 and
GIP
release
GLP-1 and GIP
Actions
DPP-4
Enzyme
GLP-1 and GIP
Intact
GLP-1, GIP
MetabolitesRapid Inactivation
Half-life*
incretins ~ 2 minutes
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
DPP-4 inhibitors:sitagliptin,
saxagliptin, alogliptin
X
GIP=glucose-dependent insulinotropic polypeptide
GLP= glucagon-like peptide
Exenatide:
Incretin Modulators in Clinical Use
Generic Trade Names
GLP1-Receptor Agonists exenatide Byetta
liraglutide Victoza
albiglutide Tanzeum*
dulaglutide Trulicity
(exenatide ER) (Bydureon)
DPP4 inhibitors sitagliptin Januvia
saxagliptin Onglyza
alogliptin Nesina*
linagliptin Trajenta
*approved but not launched in Canada
• Diabetes associated with increased risk of heart failure(HF) similar to MI & stroke
• Incidence increases with age
• In CAD pts, type 2 DM is known to increase the risk of hospitalization for heart failure by ~30%
• Mortality diabetic HF is ~ double that of non-diabetics
• Diabetes in HF is “frequent, forgotten & often fatal” (Bell)
• Anti-diabetic Rx ( insulin, thiazolidinediones: pioglitazone & rosiglitazone, some DPPP-4 have been associated with an increased incidence of HF
30
Background: Diabetes & Heart Failure
LLGLancet 2015 Gilbert & Krum
Glucose Lowering Therapies and Heart Failure
Bhatt DL, Cavender MA. JACC Heart Fail. 2014;2:583-5.
Non-Therapy Related EffectsDifferences in Concomitant
Medications Confounding Medical Co-
Morbidities Play of Chance
Heart
Failure
Diagnosis
Volume RelatedDecreased Fluid
Clearance Increased Fluid
Peripheral Edema
Anti-Hyperglycemic
Therapies
Direct Myocardial Effects Adverse Remodeling Myocardial
Depression Advanced Glycation
End Products
SAVOR-TIMI 53: Temporal Rates forHospitalization for Heart Failure
HR, hazard ratio; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus –Thrombolysis
in Myocardial Infarction 53 .
Scirica BM et al. Circulation. 2014 ;130:1579-88.
Placebo 8212 8036 7856 7389 4959
Saxagliptin 8280 8064 7867 7375 4978
0
1
2
3
4
0 180 360 540 720
HR 1.80
(1.29-2.55)
P=0.001
0.6%
1.3%
2.8%
1.1%
1.9%
3.5%
HR 1.46
(1.15-1.88)
P=0.002
HR 1.27
(1.07-1.51)
P=0.007
Ho
sp
ita
liza
tio
n f
or
He
art
Fa
ilu
re (
%)
Days from Randomization
Saxagliptin
Placebo
Despite comparable primary endpoint rates,
saxagliptin, compared with placebo, was associated
with higher rates of hospitalization for heart failure
Primary:To demonstrate that the risk of cardiovascular events (CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina) in patients treated with sitagliptin in addition to usual care was non-inferior to that in patients treated without sitagliptin in addition to usual care
Prespecified secondary:To analyze effects on hospitalization for heart failure and related outcomes
Objectives of TECOS
• Type 2 diabetes (A1c ≥6.5% and ≤8.0%)
– Stable monotherapy OR dual combination therapy with metformin,
pioglitazone, or sulfonylurea or *stable dose of insulin with or without
metformin
• ≥50 years old
• Preexisting vascular disease defined as having:
– History of myocardial infarction
– Prior coronary revascularization
– Coronary angiography with at least one ≥50% stenosis
– History of ischemic stroke
– Carotid arterial disease with ≥50% carotid stenosis
– Peripheral arterial disease with objective evidence
• Able to see usual care provider at least twice yearly
Major Inclusion Criteria
*Amended 13Sept201034
Primary Composite CV Outcome* Per Protocol Analysis for Noninferiority
* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina
Time to First Hospitalization for Heart Failure*
* ITT population
HR (95% CI): 1.00 (0.84–1.20)
P = 0.95
Trial HR (95% CI) P-Value
SAVOR-TIMI1.27
(1.07–1.51) 0.007
EXAMINE1.19
(0.89–1.59)0.235
TECOS1.00
(0.84–1.20)1.000
SAVOR-TIMI +
EXAMINE + TECOS1.14
(0.97–1.34)0.102
SAVOR-TIMI 53, EXAMINE, and TECOS*:Hospitalization for Heart Failure
* Unadjusted
Test for heterogeneity for 3 trials:
p=0.16, I2=44.9
ELIXA: Lixisenatide vs. Placebo
Effects on CV Outcomes
Pfeffer MA et al. ADA Scientific Sessions 2015
Sites of Action of Antidiabetic Agents
Adapted from Bailey CJ. Trends Pharmacol Sci. 2011 courtesy M Hussain
Pancreas
Adipose
tissueLiver
Gut
Kidney
Insulin
Metformin TZD
SGLT2inbitorsAGI
DPP-4i
GLP-1 receptor agonist
SU/glinide
Blood
glucose
Stimulatory or positive effect
Inhibitory effect
Empagliflozin
• Empagliflozin is a highly selective inhibitor of the sodium
glucose cotransporter 2 (SGLT2) in the kidney
• Glucose reduction occurs by reducing renal glucose
reabsorption and thus increasing urinary glucose
excretion
• In patients with type 2 diabetes, empagliflozin leads to1:
– Significant reductions in HbA1c
– Weight loss
– Reductions in blood pressure without increases in heart rate
40
Empagliflozin modulates several factors related
to CV risk
41
BPArterial stiffness
GlucoseInsulin
Albuminuria
Uric acid
Other
↑LDL-C↑HDL-C
Triglycerides
Oxidative stress
Sympathetic
nervous system activity
WeightVisceral adiposity
Number needed to treat (NNT) to prevent one death
across landmark trials in patients with high CV risk
46
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
LEADER: Liraglutide(GLP-1 agonist)
Updated 3/7/16 with commentary) New top-line trial data
released today show that liraglutide (Victoza, Novo
Nordisk) significantly reduces the risk of major adverse
cardiovascular events.
The results come from the multicenter, international
Liraglutide Effect and Action in Diabetes: Evaluation of
Cardiovascular Outcome Results—A Long Term
Evaluation (LEADER) trial. The study began in 2010 and
followed 9340 high-risk adults with type 2 diabetes for 5
years, comparing those randomly assigned to liraglutide
or placebo, along with standard treatment.
The primary end point was defined as the composite
outcome of the first occurrence of cardiovascular death,
nonfatal myocardial infarction, or nonfatal stroke. The trial
met criteria for both noninferiority and superiority for all
three of the end-point components.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
4. Choice of pharmacological agents should be
individualized taking into consideration [Grade D,
consensus]
Patient Characteristics
• Degree of hyperglycemia
• Presence of co-morbidities
• CV comorbidities
• Patient preference
• Ability to access treatments
Properties of the Treatment
• Effectiveness and durability of
lowering BG
• Risk of hypoglycemia
• Risk Heart Failure
• Effectiveness in reducing
complications
• Mortality/CV Risk Reduction
• Effect on body weight
• Side effects
• Contraindications
Recommendation 4 [Adapted for 2016 pwa]
Diabetes & CV Disease: Take Home
Huge/growing health care problem
Key multifactorial aggressive approach
to primary secondary prevention
Revascularization choice / issues
Real potential for Rx harm
Novel Pharmacologic Rx choices that
avoid CV harm & enhance outcomes
“For medicine, the greatest
surprises lie still ahead of us, but
they are there waiting to be
discovered or stumbled over
sooner or later”
Lewis Thomas