Improving Patient Outcomes: Insights From Recent Clinical Trials in Diabetes

1
Improving Patient OutcomesInsights From Recent
Clinical Trials in Diabetes
2
Diabetes and CVD Time To Act!

• With the rising tide of diabetes around the
  globe, the double jeopardy of diabetes and
  cardiovascular disease is set to result in an
  explosion of these and other complicationsunless
  preventive action is taken.
• Prof Sir George Alberti, IDF President
• International Diabetes Federation 2001

http//www.idf.org/webdata/docs/CVD_ExecSum.pdf.
Accessed May 25, 2004.
3
Impact of Type 2 Diabetes on Macrovascular Disease

• Largest cause of morbidity and mortality
• Risk of CVD increased 2- to 4-fold
• Higher case fatality vs. non diabetic individuals
• Reduced survival postMI, postCABG, and
  particularly postPTCA
• Risk of stroke and peripheral vascular disease
  substantially increased

Betteridge DJ. Acta Diabetol. 199936S25-S29.
Nesto R. Acta Diabetol. 200138S3-S8.
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Atherosclerosis in Type 2 Diabetes

• The Black Box

• Diabetic dyslipidemia
• Procoagulant state
• Insulin resistance/ hyperinsulinemia
• Glycation and advanced glycation of proteins
• Glycoxidation and oxidation
• Hormone-, growth factor-, and cytokine-enhanced
  SMC proliferation and foam cell formation

Bierman E. Arterioscler Thromb.199212647-656.
5
Type 2 Diabetes Is a Vascular Disease

• Hyperglycemia is just 1 risk factor among many
  for CVD
• Intensive blood glucose control can reduce
  microvascular, but not macrovascular,
  complications of diabetes
• CVD risk reduction should involve appropriate
  management of all major modifiable risk factors

De Backer G, et al. Eur Heart J.
2003241601-1610. Holman R. Acta Diabetol.
200138S9-S14.
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UKPDS Benefits of Tight BP Control inType 2
Diabetes

• Population
• 1148 patients, mean age 56 y mean BP at
  entry, 160/94 mm Hg
• Treatment
• Tight control (aim lt 150/85) vs less tight (aim
  lt 180/105) captopril vs atenolol regimen mean
  BP during follow-up 144/82 vs 154/87 mm Hg (P lt
  0.0001)
• RRR
• 24 diabetes-related end points 32
  diabetes-related deaths 37 microvascular end
  points

Stroke
RRR 44 (95 CI,11-65)
Patients with events ()
P 0.013
0
9
1
2
4
7
5
8
6
3
Years from randomization
Adapted from UKPDS Group. BMJ. 1998317703-713.
7
UKPDS Strong Association Between SBP and
Microvascular End Points and MI

• Incidence of microvascular end points and MI by
  updated mean SBP
• Adjusted for age, sex, and ethnic group
• Expressed for white men,
• 50-54 y at baseline and with mean diabetes
  duration of10 y

50
MI Microvascular end points
40
30
Adjusted incidence per 1000 patient-years ()
20
10
0
110
170
120
130
150
160
140
Updated mean SBP (mm Hg)
Adapted from Adler AI, et al. BMJ.
2000321412-419.
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Diabetic Dyslipidemia

• Compared with nondiabetic individuals, patients
  with
• diabetic dyslipidemia may have
• Elevated plasma triglyceride levels
• Decreased plasma HDL-C levels
• Relatively normal plasma LDL-C levels
• Relatively high proportion of small, dense LDL-C

American Diabetes Association. Diabetes Care.
200427S68-S71.
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UKPDS Risk Factors for CAD in Type 2 Diabetes

• ?LDL-C
• ?HDL-C
• ?TGs
• ?HbA1c
• ?SBP
• ?Fasting plasma glucose
• Smoking status

Turner RC, et al. BMJ. 1998316823-828.
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CHD Prevention Trials With Statins in Patients
With Diabetes Subgroup Analyses
CHD risk reduction CHD risk reductionStudy Drug
Nondiabetics Diabetics Primary Prevention HPS1
Simvastatin 25 26 Secondary Prevention
CARE2 Pravastatin 23 25 4S3
Simvastatin 32 55 4S reanalysis4
Simvastatin 32 42 HPS1 Simvastatin
24 12 NS
CHD end points HPS first major vascular
event CARE absolute risk of coronary
events 4S major CHD events 4S reanalysis
major coronary events. Cohorts HPS risk
reduction for the entire cohort (nondiabetics and
patients with diabetes). Footnote NS results
not statistically significant. 1. HPS
Collaborative Group. Lancet. 20023607-22. 2.
Goldberg RB, Mellies MJ, Sacks FM, et al.
Circulation. 1998982513-2519. 3. Pyörälä K,
Pedersen TR, Kjekshus J, et al. Diabetes Care.
199720614-620. 4. Haffner SM, Alexander CM,
Cook TJ, et al. Arch Intern Med.
19991592661-2667.
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Greek Atorvastatin and CHD Evaluation (GREACE)
Study

• Population
• 1600 CHD patients (344 women)
• Design
• Randomized, open, 3-year study, atorvastatin
  (10-80 mg) vs usual care
• Atorvastatin titrated to achieve NCEP goal of
  LDL lt2.6 mmol/L (lt 100 mg/dL) mean dose, 24
  mg/d
• Usual care group 14 lipid-lowering drugs
• Lipid changes
• LDL-C ? 46 nonHDL-C ? 44 TGs ? 31
• HDL-C ? 7 (absolute LDL-C ? 2.1 mmol/L 81
  mg/dL)
• Primary end points
• Death, nonfatal MI, unstable angina, CHF,
  stroke, and revascularization

Athyros VG, et al. Curr Med Res Opin.
200218220-228.
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GREACE Risk Reduction With Atorvastatin in
Diabetic Cohort

• Risk reduction in composite primary end point

Diabetes
0.42
n 313 (20)
P lt 0.0001
All patients
0.49
n 1297
P lt 0.0001

0
Atorvastatin
Usual care
Athyros VG, et al. Curr Med Res Opin.
200218220-228.
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CARDSCollaborative AtoRvastatin Diabetes Study

• Patient Population
• Type 2 diabetics
• (40-75 y)
• No prior MI or CVD
• Other risk factors
• Lipid profile
• LDL-C ? 4.14 mmol/L (160 mg/dL)
• TGs ? 6.78 mmol/L (600 mg/dL)
• Collaboration in the UK with Diabetes UK, NHS
  RD, and Pfizer

d/b PBO
2838Patients
Atorvastatin 10 mg
Min 4 y

• Primary End Point
• Time to major CV event
• (CHD death, nonfatal MI,
• revascularization, CABG, stroke)

Colhoun HM, et al. Diabet Med. 200219201-211.
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CARDSInclusion Criteria

• Type 2 DM (WHO criteria) for at least 6 months
  prior to screening
• Age 40-75 y
• No history of CVD
• LDL-C ? 4.14 mmol/L (160 mg/dL)
• TGs ? 6.78 mmol/L (600 mg/dL)
• At least 1 other risk factor
• Hypertension (history of BP, or SBP ? 140 or DBP
  ? 90 mm Hg
• Retinopathy
• Micro-(albumin/creatinine ratio ? 2.5 mg/mmol/L)
  or macroalbuminuria
• (? 25 mg/mmol/L)
• Current smoker (all patients were counselled to
  quit)

Colhoun HM, et al. Diabet Med. 200219201-211.
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CARDS Patient Baseline Characteristics
61.8
61.5
http//www.cardstrial.org/healthcare/slideresource
s.asp. Accessed June 8, 2004.
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CARDS Patient Baseline Characteristics
AtorvastatinMean (SD)or n ()
PlaceboMean (SD)or n ()
BP
144 (15.9)
144 (16.1)
SBP (mm Hg)
83 (8.5)
83 (8.4)
DBP (mm Hg)
956 (67)
940 (67)
On BP drug
Smoking
308 (21.6)
323 (22.9)
Current
622 (43.6)
601 (42.7)
Ex-smoker
Never
498 (34.9)
485 (34.4)
http//www.cardstrial.org/healthcare/slideresource
s.asp. Accessed June 8, 2004.
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CARDS Patient Baseline Lipids
AtorvastatinMedian (IQR)
PlaceboMedian (IQR)
5.4 (4.8-5.9)207 (186-228)
5.4 (4.8-5.9)207 (185-229)
Total cholesterol (mmol/L) (mg/dL)
3.1 (2.6-3.6)119 (100-138)
3.1 (2.6-3.6)118 (100-137)
LDL-C (mmol/L) (mg/dL)
1.3 (1.2-1.6)52 (45-60)
1.4 (1.2-1.6)53 (46-61)
HDL-C (mmol/L) (mg/dL)
Subject to final verification.
http//www.cardstrial.org/healthcare/slideresource
s.asp. Accessed June 8, 2004.
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CARDS Stopped Early Due to Significant Benefit
of Atorvastatin Treatment

• In June 2003, the independent Steering Committee
  stopped the trial after only 2 years because the
  magnitude of benefit for the primary end point
  exceeded the prespecified stopping rule
• Preliminary results of the CARDS trial showed a
  significant reduction in MI, stroke, and other
  coronary events in patients treated with
  atorvastatin
• CARDS became the second atorvastatin trial to end
  early because of observed treatment benefit
  (ASCOT-LLA was the first)

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AHA Prevention Conference VI Diabetes and
Vascular Disease Goals of Therapy

• Glycemia HbA1c lt 7 (ADA)
• BP lt 130/85 (JNC VI) lt 130/80 (ADA)
• LDL-C lt 2.6 mmol/L (100 mg/dL) (NCEP)
• HDL-C lt 1 mmol/L (lt 40 mg/dL) Raise HDL (no goal)
• TGs 2.2-5.6 mmol/L (200-499 mg/dL) NonHDL-C lt
  3.4 mmol/L (130 mg/dL)
• BMI gt 25 kg/m2 Lose 10 body wt (OEI)
• Physical activity Exercise (ADA)
• Cigarettes Stop
• Prothrombotic state Low-dose aspirin (ADA)

Grundy SM, et al. Circulation. 20021052231-2239.
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Trends in Risk Factor Control

• NHANES NHANES (1988-1994) (1999-2000)
• HbA1c lt 7 44 37
• BP lt 130/80 mm Hg 29 35.8
• TC lt 2.3 mmol/L (200 mg/dL) 33.9 48.2
• HbA1c lt 7 and BP lt 130/80 mm Hg andTC lt 2.3
  mmol/L (200 mg/dL) 5.2 7.3

Saydah SH, et al. JAMA. 2004291335-342.
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• LIPITOR (atorvastatin calcium) is indicated as an
  adjunct to diet to reduce elevated total
  cholesterol, LDL-cholesterol, apo B, and TG
  levels and to increase HDL-cholesterol in
  patients with primary hypercholesterolemia
  (heterozygous familial) or combined
  hyperlipidemia.
• In clinical trials, the most common adverse
  events were constipation, flatulence, dyspepsia
  and abdominal pain, headache, nausea, myalgia,
  asthenia, diarrhea, insomnia.
• LIPITOR is contraindicated in patients with
  hypersensitivity to any component of this
  medication in patients with active liver disease
  or unexplained persistent elevation of serum
  transaminases myopathy in women during
  pregnancy, in nursing mothers, and in women of
  child-bearing potential not using appropriate
  contraceptive measures.
• Liver function tests should be performed before
  the initiation of treatment, at 6 and 12 weeks
  after initiation of therapy or elevation in dose,
  and periodically thereafter. LIPITOR should be
  used with caution in patients who consume
  substantial quantities of alcohol and/or have a
  history of liver disease. LIPITOR therapy should
  be discontinued if markedly elevated CPK levels
  occur or myopathy is diagnosed or suspected.

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0  

• LIPITOR is available in 10-mg, 20-mg, 40-mg, and
  80-mg film-coated tablets, administered once
  daily.
• For further information please see prescribing
  information.
• Lip06FE05

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