Microvascular

Residual Risk

What risk remains after LDL-C management and intensive therapy?

Defining Residual Vascular Risk

The risk of macrovascular events and microvascular complications which persists in most patients despite current standards of achievement of low-density lipoprotein (LDL-C) goal and intensive control of blood pressure and blood glucose

Fruchart JC, et al. Am J Cardiol 2008;102:: 1K-34K.

Intensive Blood Pressure Control Fails to Address the Full Extent of Microvascular Complication in Diabetes"

UKPDS

BP lowering (<150/85 mmHg resulted in a 47% reduction in loss of visual acuity (P=0.0004), with no difference in the risk of neuropathy or renal disease1

ADVANCE

Aggressive BP reduction (systolic: 5.60.2 mmHg, diastolic 2.20.1 mmHg) had no significant effect on the risk of microvascular events2 Blockade of the renin-angiotensin system (RAS) with candesartan did nit significantly reduce the progression of diabetic retinopathy in patients with type 2 diabetes (T2D)3

DIRECT-Protect 2

1. UKPDS 39, BMJ 1998;317:713-20. 2. Patel A, et al. Lancet 2007;370:829-40. 3. Sjolie AK, et al. Lancet 2008;372:1385-93.

Intensive Glycemic Control and Microvascular Events in Patients " with Type 2 Diabetes

UKPDS:1
For each 1% reduction in HbA1c , there was a 37% reduction in the microvascular combined endpoint
Photocoagulationrequiring retinopathy Vitreous hemorrhage Fatal or non-fatal renal failure

ADVANCE:2
21% reduction in nephropathy, but no significant effect on retinopathy in the intensive glycemic control arm (HbA1c <6.5%)

1. Gerstein HC, et al. N Engl J Med 2008;358:2545-59. 2. Ninomiya JK, et al. Circula4on 2004;109:42-6.

Intensive vs Conventional Glucose " and Blood Pressure Control " on Microvascular Disease
Study
VADT (2009) (A1c 6.9%)

Eye
No benet

Neuropathy Nephropathy
(peripheral)
No benet Benet
(any increase in albuminuria)

ADVANCE (2008) (A1c 6.5%) ACCORD (2010) ACCORD (2010)

No benet Benet No benet No benet Benet

N/A N/A N/A No benet No benet

Benet N/A N/A Benet Benet

(intensive glucose therapy (intensive blood pressure)

ADVANCE BP (2007) (136/73 mmHg) STENO 2 (2008)

A1c 7.7% BP 140/74 LDL 71 mg/dl (1.8 mmol/L)

Residual Vascular Risk is Particularly Important in " Diabetes Management

Leading cause of blindness in adults 24,000 new cases Each year in US Leading cause of end-stage renal Disease in adults 44% new cases/yr Leading cause of non traumatic limb amputation 60% new cases/yr
2 to 4-fold increase In cerebrovascular disease and stroke

Diabetic retinopathy Stroke

8 out of 10 diabetic patients die from cardiovascular events 5-10 years reduction in life expectancy

Diabetic nephropathy Cardiovascular disease Diabetic neuropathy

NIDKK, National Diabetes Statistics facts sheet. HHS, NIH, 2006

Development or Progression of Diabetic Microvascular Complications

STENO 2 Study -13.3 yrs Follow-up
NEPHROPATHY RETINOPATHY

NEUROPATHY PERIPHERAL

Gaede P et al. N Engl J Med 2008 (Feb 7);358:580-91 Gaede P et al. N Engl J Med 2008 (Feb 7);358:580-91 Fioretto, P. et al. Nat. Rev. Endocrinol. 2010, 6, 1925