diabetic management of the cardiac patient...diabetic management of the cardiac patient dr peter a...

Diabetic Management

of the Cardiac Patient

Dr Peter A Senior BMedSci MBBS PhD FRCP(E)

Associate Professor, Director

Division of Endocrinology, University of Alberta

Disclosures

• Grants/Research Support: Boehringer-Ingelheim,

BMS, GSK, ISIS, Lilly, Novo

• Speakers Bureau/Honoraria: Animas, Astra

Zeneca, Bayer, BMS, Lilly, Novo Nordisk, Sanofi-

Aventis, Servier

• Consulting Fees: Bayer, Janssen, Lilly, Medtronic,

Novo Nordisk, GSK

• Other: Endocrinologist

Objectives

• Set appropriate Glycemic Targets for cardiac

patients with diabetes

• Risks and benefits of glucose lowering therapies

• in the acute setting

• in the chronic setting

Financial Practice Guidelines

• Hypothesis: Investing in an RRSP is an effective

strategy to ensure a financially secure retirement

• Recommendation: People should start an RRSP

(grade A, level 1)

25 yr old Cardiology R1?

63 yr old Cardiologist?

Context

• Diabetes is bad for the cardiovascular system

• Hyperglycemia is bad for the CVS

• Good glycemic control is good for the CVS

• Hypoglycemia has CV risks

• Tight glycemic control by any means is good

for the CVS

✅

✅

✅

✅

✅

UKPDS+10 -

glycemia

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

Vascular Protection Checklist 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

A – ACEi or ARB │ S – Statin │ A – ASA if indicated

E • Exercise – regular physical activity, healthy diet,

achieve and maintain healthy body weight

S • Smoking cessation

Case #1

• 64 yr Female, BMI 37

• PMH MI 2004, angioplasty & stent LAD 2009

• newly diagnosed T2DM, Dec 2013

• HbA1c 8.2%

• metformin intolerant

Approach

• Glycemic target: <= 7.0%

• Diet & Lifestyle

• Metformin: try again at lower dose

• what next?

Case #2

• 56 year male, admitted with AMI

• T2DM x 8 years, HbA1c 10.4%

• EF 25%, Creatinine 263µmol/l post angiogram

• metformin 1g bid, glyburide 10mg od

Approach

• Diet & Lifestyle

• Metformin: hold until AKI resolves

• Glyburide: hold

• Start Insulin (MDI) while in-patient

• Glycemic target: 7.0 - 8.5%

• Discharge on Basal insulin + metformin + OHA

Sites of Action of Antidiabetic Agents

Adapted from Bailey CJ. Trends Pharmacol Sci. 2011 Feb; 32(2):63-71

Pancreas

Adipose

tissue Liver

Gut

Kidney

Insulin

Metformin TZD

SGLT2i * AGI

DPP-4i

GLP-1 receptor agonist

SU/glinide

Blood

glucose

Stimulatory or positive effect

Inhibitory effect * none licensed in Canada

Metformin

• Biguanide, related to phenformin

• excreted unchanged by kidney

• reduces hepatic glucose production

• enhances insulin stimulated glucose uptake

• no weight gain, no hypoglycemia

• better outcomes in heart failure

Lower Mortality in Heart

Failure Patients on Metformin

Dosing Metabolised Hypo Weight

Gain

Glyburide qd Liver→active +++ ++

Gliclazide bid Liver→inactive + ++

Glimepiride qd Liver→partly active ++ ++

Repaglinide ac

meals Liver→inactive + +

Secretagogues

$

$

$$

$$

SU Monotherapy in T2D on ACM

(Cochrane Database Review of 72 RCTS)

First generation SU vs placebo

2 trials; 553 participants; high risk of bias (HRB)

First generation SU vs insulin

2 trials; 1944 participants; HRB

Second-generation sulphonylureas (SGS) vs metformin


SGS vs TZDs


SGS vs Insulin


SGS vs meglitinides


SGS vs incretin-based therapies


0.1 1.0 10

RR (95% CI)

1.46 0.87-2.45 P=0.15

1.18 0.88-1.59 P=0.26

0.98 0.61-1.58 P=0.68

0.92 0.60-1.41 P=0.70

0.96 0.79-1.18 P=0.72

1.44 0.47-4.42 P=0.52

1.39 0.52-3.68 P=0.51

RR CI P value

Hemmingsen B et al. Cochrane Database of Systematic Reviews 2013 Apr 30;4

Acarbose

• Slows digestion of oligosaccharides to monosaccharides

• Slows delivery of glucose to circulation

• Prevents post-prandial hyperglycemia

• Reduced CV events

• Safe

• Modest reduction in A1c

• Poorly tolerated (gas++)

STOP NIDDM

Acarbose and Development of CVD

Adapted from Chiasson JL et al. JAMA 2003; 290:486-94

0.06

0 200 400 600 800 1000 1200 1400

0.05

0.04

0.03

0.02

0.01

0.00

Placebo

Acarbose

P=0.04 (Log-rank test)

P=0.03 (Cox proportional model)

Pro

babili

ty o

f any C

V e

vent

0

667

635

643

608

633

596

615

577

604

558

424

376

232

203

686

682

N at risk

Placebo

Acarbose

Days after randomization

Effect of Acarbose on the probability of

remaining free of CV disease

Effect of Acarbose on the development

of CV disease

1.0 0.5 0.0 1.5 2.0

Hazard ratio

Favors

Acarbose

Favors

Placebo

P value

Coronary heart disease

Myocardial infarction 0.02

Angina 0.13

Revascularization 0.18

CV death 0.63

Cerebrovasc. event or stroke 0.51

Peripheral vasc. Disease 0.93

Any cardiovascular event 0.03

The STOP NIDDM trial’s primary endpoint was development of diabetes

and therefore not powered for CVD, which was an a priori secondary objective

Meta-analyses of Rosiglitazone or Pioglitazone vs

Comparators on Risk of MI, Ischemic Heart Disease or a

Composite of Major Macrovascular Events

Schernthaner G et al. Diabetes Obes Metab 2010;12:1023-35

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

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

Home PD et al. Lancet 2009; 373: 2125-35

RECORD: Components of the Primary Endpoint

0

2

4

6

8

10

All-cause death

Rosiglitazone

Active control

HR 0.86 (95% CI 0.68-1.08)

Cum

ula

tive (

%)

CV death

Rosiglitazone

Active control HR 0.84 (95% CI 0.59-1.18)

0

2

4

6

8

10

Myocardial infarction

Rosiglitazone

Active control

HR 1.14 (95% CI 0.80-1.63)

Cum

ula

tive (

%)

Stroke

Rosiglitazone

Active control

HR 0.72 (95% CI 0.49-1.06)

0

2

4

6

8

10

CV death, MI, and stroke

Rosiglitazone

Active control HR 0.93 (95% CI 0.74-1.15)

Cum

ula

tive (

%)

Heart failure

HR 2.10 (95% CI 1.35-3.27)

0 1 2 3 4 5 6

Time (years)

0 1 2 3 4 5 6

Time (years)

Rosiglitazone

Incretin Therapies

Inhibit GLP-1 breakdown

• alogliptin

• linagliptin (Trajenta)

• saxagliptin (Onglyza)

• sitagliptin (Januvia)

• vildagliptin

GLP-1 mimetics that are

resistant to breakdown

• albiglutide

• exenatide (Byetta)

• exenatide ER (Bydureon)

• liraglutide (Victoza)

• lixisenatide

italicized agents are not licensed for use in Canada

Incretin Therapies

DPP-IV inhibitors GLP-1

analogues

administration tablets injection

↓ glucagon secretion ++ ++

↑ insulin secretion + +++

inhibit gastric emptying N Y

nausea & vomiting N Y

weight loss N Y

EXAMINE: Primary Efficacy Endpoint*

*Primary endpoint: composite of CV death, non-fatal MI or non-fatal ischemic stroke.

White WB, et al. N Engl J Med 2013; [epub ahead of print].

EXAMINE: n = 5,380 patients (median age 61 years) with type 2 diabetes

(median duration 7.1 to 7.3 years) and acute coronary syndrome within

15-90 days of randomization. Median duration of follow-up: 18 months.

0

24

0

18

12

6

6 12 24 30

Months

Cu

mu

lative

in

cid

en

ce

of pri

ma

ry e

nd

-po

int

even

ts (

%)

HR 0.96

(upper boundary of the

one-sided repeated CI: 1.16)

18

Placebo

Alogliptin

Events, No. (%)

Placebo: 316 (11.8)

Alogliptin: 305 (11.3)

SAVOR TIMI-53: Primary

Efficacy*

*Primary endpoint: composite of CV death, non-fatal MI or non-fatal ischemic stroke.

Scirica BM, et al. N Engl J Med 2013; [epub ahead of print].

SAVOR TIMI-53: n = 16,492 patients (mean age 65 years) with

type 2 diabetes (mean duration 10.3 years) and established CVD (78-79%)

or multiple risk factors (21-22%). Median duration of follow-up: 2.1 years.

0

14

0

12

10

8

6

4

2

6 12 18 24

Months

% o

f pa

tie

nts

HR 1.00

95% CI 0.89-1.12

p (non-inferiority) < 0.001

p (superiority) = 0.99

Saxagliptin

Placebo

7.3%

3.7/100 person-yrs

7.2%

3.7/100 person-yrs

Older Drugs

lower

glucose CV benefit Weight Hypo

acarbose + Y1 ↓ 0

glitinides + neutral2 ↑ +

metformin + Y3 ↓ 0

sulphonylureas + ?Y 4 ↑ +

insulin + ?Y 4 ↑ +

1 STOP-NIDDM, 2 NAVIGATOR, 3 UKPDS, 4 UKPDS

extension

Newer Drugs

lower

glucose CV benefit Weight Hypo

DPP4i + ⟷1 ⟷ 0

GLP1-RA + ↓ 0

SGLT2i * + ↓ 0

TZD + ?↑ / ↓ 2 ↑ 0

1 SAVOR, EXAMINE. 2 FDA / RECORD / PROACTIVE. * none licensed in

Canada

Conclusions

• Diabetes Management is challenging

• Good glycemic control is important

• Glycemic targets must be individualized

• Clinical judgement required to safely use the

tools available

diabetic management of the cardiac patient...diabetic management of the cardiac patient dr peter a...

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