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
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 ABSOLUTE risk !?! It depends on the particular patient! i.e. the patient in the study or the patient in your office!
T2DM & AtherosclerosisT2DM & Atherosclerosis
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
T2DM & AtherosclerosisT2DM & Atherosclerosis
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
DM & Cardiovascular DiseaseDM & Cardiovascular Disease
1. Understanding cardiovascular risk in patients with diabetes
2. Glycemic control & CVD: evidence
3. Glycemic control & CVD: best practice
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
Glycemic Control & atherosclerosisGlycemic Control & atherosclerosis
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?
Glycemic Control & atherosclerosisGlycemic Control & atherosclerosis
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)
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)
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
DM & Cardiovascular DiseaseDM & Cardiovascular Disease
1. Understanding cardiovascular risk in patients with diabetes
2. Glycemic control & CVD: evidence
3. Glycemic control & CVD: best practice
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…
1. Understanding cardiovascular risk in patients with diabetes
2. Glycemic control & CVD: evidence
3. Glycemic control & CVD: best practice
DM & Cardiovascular DiseaseDM & Cardiovascular DiseaseBottom Line…Bottom Line…
1. Understanding cardiovascular risk in patients with diabetes
• 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
3. Glycemic control & CVD: best practice
DM & Cardiovascular DiseaseDM & Cardiovascular DiseaseBottom Line…Bottom Line…
1. Understanding cardiovascular risk in patients with diabetes
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
DM & Cardiovascular DiseaseDM & Cardiovascular DiseaseBottom Line…Bottom Line…
1. Understanding cardiovascular risk in patients with diabetes
2. Glycemic control & CVD: evidence
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
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