1. Diabetes mellitus & Cardiovascular Disease
Cardiology Grand Rounds
May 11, 2004
Dr. William Harper
Assistant Professor of Medicine, McMaster University.
Endocrinologist, Hamilton General Hospital

2. DM & Cardiovascular Disease
Understanding cardiovascular risk in patients with diabetes
Glycemic control & CVD: evidence
Glycemic control & CVD: best practice

3. Diabetes: Complications
Macrovascular
Microvascular
Stroke
Diabetic eye disease
(retinopathy and cataracts)
Heart disease and hypertension
2-4 X increased risk
Renal disease
Peripheral
vascular disease
Erectile Dysfunction
The risk of CAD and stroke is increased two to four times in patients with diabetes. Cardiovascular disease is a major cause of morbidity and mortality in diabetes. Morbidity and mortality rates are two to four times higher than in age- and sex-matched groups in the population without diabetes.
The eye and the kidney are common sites for microvascular complications of diabetes. Diabetic retinopathy is the leading cause of adult blindness in North America. Cataracts and glaucoma are also significantly more frequent in patients with diabetes, especially those over age 65. Diabetes is the leading cause of end-stage renal failure.
Foot problems, a frequent consequence of neuropathy and peripheral vascular disease, constitute a major complication. Diabetes is the leading cause of non-traumatic lower-extremity amputations in North America.
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

4. Fatal and Non-Fatal Myocardial Infarction
14% decrease per 1% decrement in HbA1c
p<0.0001 . 5 1 6 7 8 9
Updated mean HbA1c
Hazard ratio
UKPDS 35. BMJ 2000; 321:

5. Disease 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

6. How is CAD Different in Diabetes ?
> CAD extent
Multi-vessel disease
Distal disease – more difficult to revascularize
Silent ischemia/MI
Younger
Women
Worse outcomes despite revascularization
Increased re-stenosis after PCI even with stents
ACB: worse periop & long-term outcomes

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

8. 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!

9. 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

10. OASIS Study: Total Mortality
Diabetes/CVD (n = 1148)
RR=2.88 (2.37–3.49)
Diabetes/No CVD (n = 569)
No Diabetes/CVD (n = 3503)
No Diabetes/No CVD (n = 2796)
RR=1.99 (1.52–2.60)
Event Rate
RR=1.71 (1.44–2.04)
RR=1.00
OASIS study: total mortality
The OASIS study also supports the concept of diabetes as a CHD risk equivalent. This study is more generalizable than the Finnish East-West study since it was based in 6 different countries and has a larger population.
Reference:
Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102: 3 6 9 12 15 18 21 24
Months
Malmberg K et al. Circulation 2000;102:
©2000 Lippincott Williams & Wilkins.

11. Canadian Lipid Working Group: Target 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
The Canadian Lipid Working Group developed target levels for LDL, TC/HDL ratio and triglycerides, as listed in the chart.
Diabetes itself is a potent risk factor for CAD in both men and women over age 30.

12. Heart 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

13. T2DM & Atherosclerosis
How much risk !?!

14. T2DM & Atherosclerosis How much risk !?!
Epidemiological data: 2-4x increased

15. T2DM & Atherosclerosis How much ABSOLUTE risk !?!
It depends on the particular patient!
i.e. the patient in the study or the patient in your office!

16. T2DM & Atherosclerosis UKPDS
Cntrl group event rates
MI % 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

17. T2DM & Atherosclerosis What about the patient in your office?
UKPDS Risk Engine
Download at
Weigh the cardiovascular risk with the cost and side effects of preventative medications

18. DM & Cardiovascular Disease
Understanding cardiovascular risk in patients with diabetes
Glycemic control & CVD: evidence
Glycemic control & CVD: best practice

19. Glycemic 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)

20. Glycemic Control & atherosclerosis
UKPDS 33: Main study
Any DM related end point: 12% RRR
Microvascular 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 = NS)
No mortality benefit

21. Glycemic 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?

22. T2DM & 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)

23. UKPDS 33, Lancet 352:837-53, 1998.
DCCT, NEJM 329:977-86, 1993.

24. Natural History of Type 2 Diabetes
Insulin
resistance
Glucose
level
Insulin
Natural History of Type 2 Diabetes
Prior to type 2 diabetes insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to an increases in circulating insulin. So as insulin resistance increases, so does the production of insulin needed to keep blood sugars normal. As time progresses, the insulin resistance reach a peak and stabilize while the insulin producing cells begin to wear out. We call it pooped out pancreas.
First,
Impaired Glucose Tolerance (IGT): This is the point that the Beta cell begins to fail and blood sugars begin to elevate, especially after a large CHO load..
Type 2 Diabetes: Following the onset of Beta-cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time.
production b
-cell
dysfunction
Time
Normal
Impaired glucose
Type 2 diabetes
tolerance

25. ACS: 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?

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

27. ACS: DIGAMI Small study (N=620), single centre
Primary outcome negative
What 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…

28. Multifactorial DM Rx: STENO-2
Jan 2003, NEJM 348:383-93
RCT mimicking real life clinic
160 T2DM patients with microalbuminuria
Randomized:
Conventional Rx as per National Guidelines
versus
Intensive Rx
Behaviour modification
Pharmacotherapy: targeting BS, BP, Lipids, proteinuria, ASA (initially 2 prevention only, 1 prevention after 1999)

29. Multifactorial DM Rx: STENO-2

30. Multifactorial DM Rx: STENO-2

31. STENO-2, NEJM, 348:383-93, 2003.
UKPDS 33, Lancet 352:837-53, 1998.
DCCT, NEJM 329:977-86, 1993.

32. Multifactorial DM Rx: STENO-2

34. 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

35. Insulin Glargine (Lantus)
Little to no peak effect  Less hypoglycemia

36. DM & Cardiovascular Disease
Understanding cardiovascular risk in patients with diabetes
Glycemic control & CVD: evidence
Glycemic control & CVD: best practice

37. Sites of Action of Currently Available Therapeutic Options
MUSCLE
ADIPOSE TISSUE
LIVER
PANCREAS
GLUCOSE PRODUCTION
Metformin
Thiazolidinediones
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
Metformin
INSULIN SECRETION
Sulfonylureas: Glyburide, Gliclazide, Glimepiride
Non-SU Secretagogues: Repaglinide, Nateglinide
INTESTINE
GLUCOSE ABSORPTION
Alpha-glucosidase inhibitors

38. Hypoglycemia Wt. Gain Edema GI Lactic Liver Use in
effects Acidosis Toxicity Renal Failure
Glyburide  
Gliclazide  
Glimepiride  
Repaglinide
Nateglinide ?
Metformin
Acarbose  
Rosiglitazone  *
Pioglitazone  *
* Liver enzyme monitoring recommended in product monographs
Adapted from Lebovitz H: Endocrinol & Metab Clinics of NA; 30 (4)

39. TZD adverse effects Edema Mild anemia (dilutional) Weight gain
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

40. Drug Trade Dose Cost ODB
Glyburide
Diabeta
Start 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 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
Repaglinide
Gluconorm
Start 0.5 mg tid-qid
Max 4 mg qid
$45/mos
Nateglinide
Starlix
Start mg tid
Max 180 mg tid
Metformin
Glucophage
Start 500 mg od-bid
Max 1000 mg bid
Pioglitazone
Actos
Start mg od
Max 45 mg od
$92/mos
Rosiglitazone
Avandia
Start 4 mg od
Max 4 mg bid
$ 60/mos
$ 120/mos

42. Targeting Insulin Resistance?
Does targeting insulin resistance > insulin secretion reduce CV risk?

43. Metabolic 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

45. TZDs: 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)

46. Effect of Pioglitazone on Carotid Arterial Wall Thickness
Intimal-medial thickness (mm) * †
* p<0.005 † p<0.001 vs baseline
Koshiyama H et al. JCEM 2001;86:3452-6

47. 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)
versus
Insulin providing regimen (sulfonylurea, insulin)
PPAR, RECORD, PROACTIVE
TZD’s, CV outcomes

48. Targeting insulin Secretion?
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

49. DM & Cardiovascular Disease Bottom Line…
Understanding cardiovascular risk in patients with diabetes
Glycemic control & CVD: evidence
Glycemic control & CVD: best practice

50. DM & Cardiovascular Disease Bottom Line…
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
Glycemic control & CVD: evidence
Glycemic control & CVD: best practice

51. DM & Cardiovascular Disease Bottom Line…
Understanding cardiovascular risk in patients with diabetes
Glycemic control & CVD: evidence
Glycemic cntrl alone may reduce CVD (UKPDS, DIGAMI)
Glycemic cntrl combined with other risk factor modification reduces CVD (STENO-2)
Glycemic control & CVD: best practice

52. DM & Cardiovascular Disease Bottom Line…
Understanding cardiovascular risk in patients with diabetes
Glycemic control & CVD: evidence
Glycemic control & CVD: best practice
Patients with CVD: Glycemic target?

53. Patients 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 hypoglycemia with sensitizers alone, metformin weight-sparing
ACS?
CDA 2003 Guidelines: DIGAMI protocol

54. END

56. Insulin IV gtt CPG q1h x 2, then q2h:
Adjust Insulin IV infusion rate as per scale below:
< Call MD
U/h (5cc/h)
U/h (10cc/h)
U/h (15cc/h)
U/h (20cc/h)
U/h (25cc/h)
U/h (30cc/h)
U/h (35cc/h)
> Call MD

58. TZD Safety: Hepatotoxicity
Troglitazone
Rosiglitazone
Pioglitazone
Toxic to hepatocytes
in vitro ?
Yes 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)