type 2 diabetes

Diabetes mellitus &Diabetes mellitus & Cardiovascular DiseaseCardiovascular Disease

Cardiology Grand Rounds

May 11, 2004

Dr. William HarperAssistant Professor of Medicine, McMaster University.

Endocrinologist, Hamilton General Hospital

www.drharper.ca

DM & Cardiovascular DiseaseDM & Cardiovascular Disease

1. Understanding cardiovascular risk in patients with diabetes

2. Glycemic control & CVD: evidence

3. Glycemic control & CVD: best practice

Macrovascular Microvascular

Stroke

Heart disease and hypertension

2-4 X increased risk

Foot problems

Diabetic eye disease(retinopathy and cataracts)

Renal disease

Peripheral Neuropathy

Peripheral vascular disease

Diabetes: ComplicationsDiabetes: Complications

Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

Complications

Erectile Dysfunction

Fatal and Non-Fatal Myocardial InfarctionFatal and Non-Fatal Myocardial Infarction

14% decrease per 1% decrement in HbA1c

p<0.0001

0.5

1

5

0 5 6 7 8 9 10 11Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Disease Burden of Diabetes MellitusDisease Burden of Diabetes Mellitus

• Leading cause of blindness (12.5% of cases)• Leading cause of ESRD (42% of cases)• 50% of all non-traumatic amputations• 2.5x increase risk of stroke• 2-4x increase in cardiovascular mortality• DM responsible for 25% of cardiac surgeries• Mortality in DM: 70% due to Cardiovascular

disease

How is CAD Different in Diabetes ?How is CAD Different in Diabetes ?

> CAD extent Multi-vessel disease Distal disease – more difficult to revascularize

Silent ischemia/MIYoungerWomenWorse outcomes despite revascularization

Increased re-stenosis after PCI even with stents ACB: worse periop & long-term outcomes

Haffner et al, NEJM, 339(4):229-34, 1998.Haffner et al, NEJM, 339(4):229-34, 1998.

Was Haffner right?Was Haffner right?

Conclusions based on no difference found between 2 groups:

No DM, prior MI N= 69 DM, no prior MI N = 890

Underpowered!

Evans et al.Evans et al.

BMJ 324: 939-942 April 2002 Cross-sectional study

DM 1155 patients MI 1347 patients

Cohort study DM 3477 patients MI 7414 patients

0.00

0.05

0.10

0.15

0.20

0.25

OASIS Study: Total MortalityOASIS Study: Total MortalityEven

t R

ate

Months

6 9 153 18 2112

RR=2.88 (2.37–3.49)RR=2.88 (2.37–3.49)

Malmberg K et al. Circulation 2000;102:1014-1019.©2000 Lippincott Williams & Wilkins.

24

RR=1.99 (1.52–2.60)RR=1.99 (1.52–2.60)

RR=1.71 (1.44–2.04)RR=1.71 (1.44–2.04)

RR=1.00RR=1.00

Diabetes/CVD (n = 1148)Diabetes/CVD (n = 1148)

No Diabetes/CVD (n = 3503)No Diabetes/CVD (n = 3503)

Diabetes/No CVD (n = 569)Diabetes/No CVD (n = 569)

No Diabetes/No CVD (n = 2796)No Diabetes/No CVD (n = 2796)

Canadian Lipid Working Group:Canadian Lipid Working Group:Target Levels in Diabetes = established CVDTarget Levels in Diabetes = established CVD Canadian recommendations place patients with diabetes in “very high”

risk group for CAD (1999):

LDL TC/HDL ratio TG

< 2.5 mmol/L < 4

< 2.0 mmol/L

Heart Protection Study & DMHeart Protection Study & DM n = 20,530 (3982 with Diabetes Mellitus) hi-risk patients

age 40-80, prior CAD or PVD, DM, HTN (males age > 65) Non-fasting TC > 3.5 mM

5.5 year RCT: Simvastatin 40 mg od vs placebo Mortality ARR 1.8% (NNT 56) Vascular Event ARR 5.4% (NNT 19)

– Coronary event, Stroke, Revascularisation

Benefit obtained even in low cholesterol patients: LDL baseline 2.5 mM 1.7 mM with Rx Prior LDL targets for hi-risk patients too high?

– Canadian Lipid Work Group 2.5 mM– NCEP 2.6 mM– CARE 3.2 mM

T2DM & AtherosclerosisT2DM & Atherosclerosis

How much risk !?!


How much risk !?! Epidemiological data: 2-4x increased


How much ABSOLUTE risk !?! It depends on the particular patient! i.e. the patient in the study or the patient in your office!


UKPDS Cntrl group event rates MI 1.74% per year Fatal MI 0.8% per year CVA 0.5% per year Amputation for PVD 0.16% per year

HOPE (> 55 y.o., DM + 1 CV risk factor) MI, CVA, or death from CVD Cntrl group event rate (i.e. no ramipril): 4% per year


What about the patient in your office? UKPDS Risk Engine Download at www.dtu.ox.uk Weigh the cardiovascular risk with the cost and

side effects of preventative medications

Glycemic Control & atherosclerosisGlycemic Control & atherosclerosis

UKPDS 33, Lancet 352:837-53, 1998.RCT of a policy of intensive BS control

FPG < 6 mM v.s. FPG < 15 mM Achieved a number of ways:

– Sulfonylurea (chlorpropamide or glibenclamide/glyburide)

– Metformin (overweight subgroup, add-on)

– Insulin (bedtime basal +/- basal/bolus regimens)

UKPDS 33: Main studyAny DM related end point: 12% RRRMicrovascular complications: 25% RRR

Reduced eye disease: retinal laser Sx (19%), cataract Sx (24%), DM retinopathy (21%)

33% RRR microalbuminuria, 74% RRR in doubling of creatinine

MI: 16% RRR (P = 0.052 NS)No mortality benefit


UKPDS 34: overweight metformin substudy Unlike sulfonylurea & insulin: no weight gain Any DM related end point: 32% RRR DM related death: 42% RRR All cause mortality: 36% RRR MI: 39% RRR Metformin + SU: increased mortality?


T2DM & Macrovascular diseaseT2DM & Macrovascular disease

Why no clear benefit in UKPDS to glycemic cntrl? Low CV risk patients:

UKPDS cntrl death rate: 1.2 % per year HOPE cntrl death rate: per year 2.5% per year

Unable to maintain glycemic cntrl due to limited interventions: Available: glyburide, chlorpropamide, metformin, regular insulin No newer sulfonylureas: glimepiride (Amaryl), gliclazide (diamicron) No meglitinides: repaglinide (Gluconorm), nateglinide (Starlix) No TZD’s: rosiglitazone (Avandia), pioglitazone (Actos) No insulin analogues: (Humalog, Novorapid, Lantus)

DCCT, NEJM 329:977-86, 1993.

UKPDS 33, Lancet 352:837-53, 1998.

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulinresistance

Insulinproduction

Glucoselevel

-celldysfunction

ACS: Glycemic ControlACS: Glycemic Control

2/3 of ACS patients may have dysglycemia: 1/3 overt DM (FBS > 7.0 mM, 2hPG > 11.1 mM) 1/3 IGT (2hPG > 7.8 mM) At time of discharge & 3 months later

Higher BS predicts worse outcomes: Increased mortality Increased CHF, cardiogenic shock (non-DM)

Stress hyperglycemia? Epiphenomenon?

DIGAMI 620 patients AMI, prior dx DM or BS > 11 mM IV insulin gtt started @ 5 U/h Titrated to keep BS 7-10.9 mM Insulin IV > 24h MDI > 3 months No in-hospital mortality benefit. Rx Increased hospitalization by 1.8d 0.5% reduction HbA1c @ 3 months @ 1 year % on Insulin: 72% Rx Group 49% Cntrl Group 1 year mort: ARR 7 % (26 - 19 %), NNT 14 3.4 y mort: ARR 11% (44 – 33 %), NNT 9

ACS: Glycemic ControlACS: Glycemic Control

ACS: DIGAMIACS: DIGAMI

Small study (N=620), single centrePrimary outcome negativeWhat part of intervention beneficial?

Few days of IV insulin? 3 months of SC insulin M.D.I. ?

• Benefit only seen at 1 year

DIGAMI 2…

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2Jan 2003, NEJM 348:383-93RCT mimicking real life clinic160 T2DM patients with microalbuminuriaRandomized:

Conventional Rx as per National Guidelinesversus

Intensive Rx• Behaviour modification• Pharmacotherapy: targeting BS, BP, Lipids,

proteinuria, ASA (initially 2 prevention only, 1 prevention after 1999)

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2

UKPDS 33, Lancet 352:837-53, 1998.

STENO-2, NEJM, 348:383-93, 2003.

DCCT, NEJM 329:977-86, 1993.

Multifactorial DM Rx: STENO-2Multifactorial DM Rx: STENO-2

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

Substitution of glycine and arginine residues gives name “glargine” 2 arginine residues make glargine more soluble in acidic pH of injection medium

but less soluble in physilogic pH of subQ tissues Once injected, glargine precipitates leading to slower absorption Glycine substitution prevents degradation in subQ tissues

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

Little to no peak effect Less hypoglycemia

GLUCOSE ABSORPTION

GLUCOSE PRODUCTION

Metformin Thiazolidinediones

MUSCLE

PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin

PANCREAS

INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide

ADIPOSE TISSUELIVER

Alpha-glucosidase inhibitors

INTESTINE

Sites of Action of Currently Sites of Action of Currently Available Therapeutic OptionsAvailable Therapeutic Options

Gliclazide 2+ + 0 0 +

Glimepiride 2+ + 0 0 +

Repaglinide 1+ + 0 0 0 0 +

Nateglinide 1+ ? 0 0 0 0 +

Metformin 0 0 0 2+ + 0 -

Acarbose 0 0 0 3+ 0

Rosiglitazone 0 + + 0 0 * +

Pioglitazone 0 + + 0 0 * +

Hypoglycemia Wt. Gain Edema GI Lactic Liver Use in effects Acidosis Toxicity Renal Failure

Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)909-933

* Liver enzyme monitoring recommended in product monographs

Glyburide 4+ + 0 0 -

TZD adverse effectsTZD adverse effects Edema

4-5% of patients get mild-moderate edema 15% if TZD used in combo with insulin

Mild anemia (dilutional) Weight gain

Increase in subcutaneous not visceral fat

Myalgia (pioglitazone only) Myalgia 5.4% pioglitaz. versus 2.7% placebo Few patients with unexplained CK > 10x ULN

Contraindicated in class II, III and IV CHF

Contraindicated if ALT > 2.5x ULN or active liver disease

Drug Trade Dose Cost ODB

Glyburide Diabeta Start 1.25-5 mg od

Spit dose bid > 10mg/d

Max 10 mg bid

$14/mos Yes

Gliclazide Diamicron Start 80 mg bid

Max 160 mg bid$90/mos No

Gliclazide

MRDiamicron

MR

Start 30 mg od

Max 120 mg od$30/mos Exp Sect 8

Glimepiride Amaryl Start 1-2 mg od

Max 8 mg od$30-40/mos No

Repaglinide Gluconorm Start 0.5 mg tid-qid

Max 4 mg qid$45/mos Exp Sect 8

Nateglinide Starlix Start 60-120 mg tid

Max 180 mg tid$45/mos No

Metformin Glucophage Start 500 mg od-bid

Max 1000 mg bid$14/mos Yes

Pioglitazone Actos Start 15-30 mg od

Max 45 mg od$92/mos Exp Sect 8

Rosiglitazone Avandia Start 4 mg od

Max 4 mg bid$ 60/mos

$ 120/mos

Exp Sect 8

Targeting Insulin Resistance?Targeting Insulin Resistance?

Does targeting insulin resistance > insulin secretion reduce CV risk?

Metabolic Syndrome: Clinical DiagnosisMetabolic Syndrome: Clinical Diagnosis

Presence of any 3 of the following: Abdominal obesity (M > 102 cm, F > 88 cm) TG > 1.7 mM Low HDL (M < 1.0 mM, F < 1.3 mM) BP > 130/85 FPG > 6.1 mM

TZDs: effect on Metabolic SyndromeTZDs: effect on Metabolic Syndrome

Reduce insulin resistance/blood sugar Mild decrease in diastolic BP (2-4 mmHg) Decrease PAI-1 (reduces procoagulant state) Lipids:

– ↓TG ↑HDL (pioglitazone > rosiglitazone?)– ↓LDL (pioglitazone)– ↑LDL (rosiglitazone)

No change in ApoB so ↑ due to larger less atherogenic particle size

Decrease in carotid artery intimal-media thickness (IMT)

Effect of Pioglitazone on Carotid Arterial Effect of Pioglitazone on Carotid Arterial Wall ThicknessWall Thickness

-0.1

-0.08

-0.06

-0.04

-0.02

0

0.02

0.04

3 months 6 months

pioglitazone

control

Inti

ma

l-m

edia

l th

ickn

ess

(mm

)

*

†

* p<0.005 † p<0.001 vs baseline Koshiyama H et al. JCEM 2001;86:3452-6

Targeting Insulin Resistance?Targeting Insulin Resistance?

Does targeting insulin resistance > insulin secretion reduce CV risk?

We don’t know yet! BARI-2D:

CV outomes Insulin sparing regimen (avandia, metformin)

versusInsulin providing regimen (sulfonylurea, insulin)

PPAR, RECORD, PROACTIVE TZD’s, CV outcomes

Targeting insulin Targeting insulin SecretionSecretion??

Improve glycemic control in hi-risk patients to reduce CV risk Using novel agents to get there! ACCORD – glycemic cntrl arm HbA1c < 6 %

glimepiride, insulin glargine, (and metformin, rosiglitazone)

NAVIGATOR – nateglinide ORIGIN, STREAM – insulin glargine DIGAMI II - insulin

DM & Cardiovascular DiseaseDM & Cardiovascular DiseaseBottom Line…Bottom Line…






• DM increased risk (< than established CAD?)• Risk extends into BS levels below diagnostic

threshold for DM• ACS: higher BS worse prognosis





2. Glycemic control & CVD: evidence• Glycemic cntrl alone may reduce CVD (UKPDS,

DIGAMI)• Glycemic cntrl combined with other risk factor

modification reduces CVD (STENO-2)





3. Glycemic control & CVD: best practice• Patients with CVD: Glycemic target?

Patients with CVD: glycemic targetPatients with CVD: glycemic target

Prevent microvascular complications (HbA1c < 7.0%) Prevent macrovascular complications?

CDA 2003 Guidelines: HbA1c < 6.0% (if can be safely done) No definitive evidence yet

Choice of DM therapy? Sensitizers > Secretagogues/Insulin No definitive evidence yet No hypoglycemia with sensitizers alone, metformin weight-sparing

ACS? CDA 2003 Guidelines: DIGAMI protocol No definitive evidence yet

ENDEND

Insulin IV gttInsulin IV gtt

CPG q1h x 2, then q2h:

Adjust Insulin IV infusion rate as per scale below:

< 4.0 Call MD

4.1-6.0 0.5 U/h (5cc/h)

6.1-8.0 1.0 U/h (10cc/h)

8.1-10.0 1.5 U/h (15cc/h)

10.1-12.0 2.0 U/h (20cc/h)

12.1-15.0 2.5 U/h (25cc/h)

15.1-18.1 3.0 U/h (30cc/h)

18.1-22.0 3.5 U/h (35cc/h)

> 22.1 Call MD

TZD Safety: HepatotoxicityTZD Safety: Hepatotoxicity

Troglitazone Rosiglitazone Pioglitazone

Toxic to hepatocytes

in vitro ?Yes No No

# of patients

pre-marketing

2510 4500 1526

ALT > 3x ULN 1.9% troglitaz.

0.6% placebo

0.17% rosiglitaz.

0.18% placebo

0.26% pioglitaz.

0.25% placebo

Post-marketing 45 liver failure

28 death

15 liver Tx

2 liver dysfn(1 case likely shock liver)

2 liver dysfn

type 2 diabetes

Documents

patients mi

diabetes glycemic control

cardiovascular risk

risk patients age

glycemic cntrl

evidence glycemic control

acs patients

low cv risk patients