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