Improving Patient Outcomes:Insights From Recent Clinical Trials in Diabetes

Improving Patient Outcomes:Insights From Recent Clinical Trials in Diabetes

Diabetes and CVD: Time To Act!Diabetes and CVD: Time To Act!Diabetes and CVD: Time To Act!Diabetes and CVD: Time To Act!

““With the rising tide of diabetes around the globe, With the rising tide of diabetes around the globe, the double jeopardy of diabetes and the double jeopardy of diabetes and

cardiovascular disease is set to result in an cardiovascular disease is set to result in an explosion of these and other complicationsexplosion of these and other complications——

unless preventive action is taken.”unless preventive action is taken.”

Prof Sir George Alberti, IDF PresidentProf Sir George Alberti, IDF President International Diabetes Federation 2001International Diabetes Federation 2001

http://www.idf.org/webdata/docs/CVD_ExecSum.pdf. Accessed May 25, 2004.

Impact of Type 2 Diabetes on Macrovascular DiseaseImpact 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 post–MI, post–CABG, and particularly post–PTCA

• Risk of stroke and peripheral vascular disease substantially increased

Betteridge DJ. Acta Diabetol. 1999;36:S25-S29. Nesto R. Acta Diabetol. 2001;38:S3-S8.

Atherosclerosis in Type 2 DiabetesAtherosclerosis 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.1992;12:647-656.

Type 2 Diabetes Is a Vascular DiseaseType 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. 2003;24:1601-1610. Holman R. Acta Diabetol. 2001;38:S9-S14.

UKPDS: Benefits of Tight BP Control inType 2 DiabetesUKPDS: 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 < 150/85)vs less tight (aim < 180/105);captopril vs atenolol regimen;mean BP during follow-up144/82 vs 154/87mm Hg (P < 0.0001)

RRR:24% diabetes-related end points32% diabetes-related deaths37% microvascular end points

Stroke

P = 0.013

Years from randomization

Pat

ien

ts w

ith

eve

nts

(%

)

0 91 2 4 75

0

10

20

863

Less tight controlTight control

RRR = 44% (95% CI,11-65%)

Adapted from UKPDS Group. BMJ. 1998;317:703-713.

UKPDS: Strong Association Between SBP and Microvascular End Points and MIUKPDS: 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

MIMicrovascular end points

Updated mean SBP (mm Hg)

Ad

jus

ted

in

cid

ence

per

10

00

pat

ien

t-ye

ars

(%)

110 170120 130 150 1601400

50

40

30

20

10

Adapted from Adler AI, et al. BMJ. 2000;321:412-419.

Diabetic DyslipidemiaDiabetic 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. 2004;27:S68-S71.

UKPDS: Risk Factors for CAD in Type 2 DiabetesUKPDS: 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. 1998;316:823-828.

CHD Prevention Trials With Statins in Patients With Diabetes: Subgroup Analyses 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. 2002;360:7-22.2. Goldberg RB, Mellies MJ, Sacks FM, et al. Circulation. 1998;98:2513-2519.3. Pyörälä K, Pedersen TR, Kjekshus J, et al. Diabetes Care. 1997;20:614-620.4. Haffner SM, Alexander CM, Cook TJ, et al. Arch Intern Med. 1999;159:2661-2667.

Greek Atorvastatin and CHD Evaluation (GREACE) StudyGreek Atorvastatin and CHD Evaluation (GREACE) Study

Population:1600 CHD patients (344 women)

Design:Randomized, open, 3-year study, atorvastatin (10-80 mg) vs usualcare

Atorvastatin titrated to achieve NCEP goal of LDL <2.6 mmol/L(< 100 mg/dL); mean dose, 24 mg/d

Usual care group 14% lipid-lowering drugs

Lipid changes:LDL-C 46%; non–HDL-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. 2002;18:220-228.

GREACE: Risk Reduction With Atorvastatin in Diabetic CohortGREACE: Risk Reduction With Atorvastatin in Diabetic Cohort

Risk reduction in composite primary end point:

Atorvastatin Usual care

All patients

Diabetes 0.42

0.49

n = 313 (20%)

n = 1297

P < 0.0001

P < 0.0001

0

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

19/04/23 11:17

Min 4 yMin 4 yMin 4 yMin 4 y

Atorvastatin 10 mgAtorvastatin 10 mg

28382838PatientsPatients

28382838PatientsPatients

d/b PBOd/b PBO

CARDS:Collaborative AtoRvastatin Diabetes StudyCARDS:Collaborative AtoRvastatin Diabetes Study

Patient PopulationPatient Population Type 2 diabetics Type 2 diabetics

(40-75 y)(40-75 y) No prior MI or CVDNo prior MI or CVD Other risk factors + Other risk factors + Lipid profile: Lipid profile:

LDL-C LDL-C 4.14 mmol/L 4.14 mmol/L (160 mg/dL)(160 mg/dL)

TGs TGs 6.78 mmol/L 6.78 mmol/L (600 mg/dL)(600 mg/dL)

Collaboration in the UK Collaboration in the UK with Diabetes UK, NHS with Diabetes UK, NHS R&D, and PfizerR&D, and Pfizer

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

Colhoun HM, et al. Diabet Med. 2002;19:201-211.

CARDSInclusion CriteriaCARDSInclusion 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. 2002;19:201-211.

CARDS Patient Baseline Characteristics CARDS Patient Baseline Characteristics

1350 (94.5%)1326 (94.0%)White ethnicity

28.7 (3.6)28.8 (3.5)BMI kg/m2 (SD)

515 (36.1%)537 (38.1%)Obese (BMI > 30 kg/m2)

456 (31.9%)453 (32.1%)Women

167 (11.7%)173 (12.3%) > 70

703 (49.2%)708 (50.2%) 60-70

558 (39.1%)529 (37.5%) < 60

Mean age (years)

Atorvastatinn (%)

Placebon (%)

61.8 61.5

http://www.cardstrial.org/healthcare/slideresources.asp. Accessed June 8, 2004.

CARDS Patient Baseline CharacteristicsCARDS Patient Baseline Characteristics

Smoking

498 (34.9%)485 (34.4%)

Current

622 (43.6%)601 (42.7%) Ex-smoker

308 (21.6%)323 (22.9%)

Never

956 (67)940 (67)On BP drug

BP

83 (8.5)83 (8.4) DBP (mm Hg)

144 (15.9)144 (16.1) SBP (mm Hg)

AtorvastatinMean (SD)

or n (%)

PlaceboMean (SD)

or n (%)

http://www.cardstrial.org/healthcare/slideresources.asp. Accessed June 8, 2004.

CARDS Patient Baseline Lipids* CARDS Patient Baseline Lipids*

1.3 (1.2-1.6)52 (45-60)

1.4 (1.2-1.6)53 (46-61)

HDL-C (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)

5.4 (4.8-5.9)207 (186-228)

5.4 (4.8-5.9)207 (185-229)

Total cholesterol (mmol/L)(mg/dL)

AtorvastatinMedian (IQR)

PlaceboMedian (IQR)

*Subject to final verification.

http://www.cardstrial.org/healthcare/slideresources.asp. Accessed June 8, 2004.

CARDS: Stopped Early Due to Significant Benefit of Atorvastatin TreatmentCARDS: 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)

AHA Prevention Conference VI Diabetes and Vascular Disease Goals of TherapyAHA Prevention Conference VI Diabetes and Vascular Disease Goals of Therapy

Glycemia HbA1c < 7% (ADA)

BP < 130/85 (JNC VI)

< 130/80 (ADA)

LDL-C < 2.6 mmol/L (100 mg/dL) (NCEP)

HDL-C < 1 mmol/L (< 40 mg/dL) Raise HDL (no goal)

TGs 2.2-5.6 mmol/L (200-499 mg/dL) Non–HDL-C < 3.4 mmol/L (130 mg/dL)

BMI > 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. 2002;105:2231-2239.

Trends in Risk Factor ControlTrends in Risk Factor Control

NHANES NHANES(1988-1994) (1999-2000)

HbA1c < 7% 44% 37%

BP < 130/80 mm Hg 29% 35.8%

TC < 2.3 mmol/L (200 mg/dL) 33.9% 48.2%

HbA1c < 7% and BP < 130/80 mm Hg andTC < 2.3 mmol/L (200 mg/dL) 5.2% 7.3%

Saydah SH, et al. JAMA. 2004;291:335-342.

• 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.

0 

 

פתח תקוה 7063, ת.ד. 8 בית ניאופרם, רח' השילוח ניאופרם בע"מ49170,

-E, 03 9373716, פקס.03 9373737 טל-mail:Neopharm@Neopharmisrael.com

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