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Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients

With Elevated High Sensitivity C-Reactive Protein

Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients

With Elevated High Sensitivity C-Reactive Protein

The PIOSTAT StudyThe PIOSTAT Study

Markolf Hanefeld, MD, PhD; Nikolaus Marx, MD; Markolf Hanefeld, MD, PhD; Nikolaus Marx, MD; Andreas PfAndreas Pfüützner, MD, PhD; Werner Baurecht, MSc; tzner, MD, PhD; Werner Baurecht, MSc; Georg LGeorg Lüübben, MD; Efstrathios Karagiannis, MD; bben, MD; Efstrathios Karagiannis, MD;

Ulf Stier, MD; Thomas Forst, MDUlf Stier, MD; Thomas Forst, MD

Published in JACCPublished in JACC

January 23, 2007January 23, 2007


The PIOSTAT Study: Background The PIOSTAT Study: Background

• Markers of inflammation include high Markers of inflammation include high sensitivity C-reactive protein (hsCRP), matrix sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-9, and plasminogen metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1.activator inhibitor (PAI)-1.

• Elevations of these markers have been Elevations of these markers have been associated with higher rates of future CV associated with higher rates of future CV events.events.

Hanefeld et al. JACC. 2007 Jan 23; 49(3):290-7.


The PIOSTAT Study: Background (cont.)The PIOSTAT Study: Background (cont.)

• Statins are associated with a reduction in these Statins are associated with a reduction in these inflammatory markers.inflammatory markers.

• A new class of drugs, the thiazolidinediones (TZDs) A new class of drugs, the thiazolidinediones (TZDs) (PPAR-(PPAR-γγ agonists), have also been shown to have agonists), have also been shown to have anti-inflammatory properties, reducing CRP, MMP-9, anti-inflammatory properties, reducing CRP, MMP-9, (MCP)-1, and soluble CD40L.(MCP)-1, and soluble CD40L.

• The TZD Pioglitazone has recently been associated The TZD Pioglitazone has recently been associated with a reduction in cardiovascular endpoints in with a reduction in cardiovascular endpoints in patients with type 2 diabetes mellitus.patients with type 2 diabetes mellitus.



The PIOSTAT Study: Background (cont.)The PIOSTAT Study: Background (cont.)

• However, there is only scarce information on the However, there is only scarce information on the benefits of treatment with TZDs, alone or in benefits of treatment with TZDs, alone or in combination with statins, in patients with CVD and combination with statins, in patients with CVD and increased hs-CRP levels.increased hs-CRP levels.

• This study aimed to investigate the safety and This study aimed to investigate the safety and efficacy of pioglitazone and simvastatin in efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-combination versus each drug individually in non-diabetic subjects with CVD and elevated hs-CRP diabetic subjects with CVD and elevated hs-CRP levels.levels.



The PIOSTAT Study: Study DesignThe PIOSTAT Study: Study Design

125 patients, ages 30-70 years, with CVD and/or HTN and hs-CRP level >1.0mg/l 125 patients, ages 30-70 years, with CVD and/or HTN and hs-CRP level >1.0mg/l and <10 mg/l prior to randomization and <10 mg/l prior to randomization

Prospective. Double-Blind. Randomized. Prospective. Double-Blind. Randomized. Exclusion Criteria: Diabetes mellitus or chronic inflammatory diseases, statin therapy within 4 weeks, Exclusion Criteria: Diabetes mellitus or chronic inflammatory diseases, statin therapy within 4 weeks,

significant hepatic or renal disease, or CHFsignificant hepatic or renal disease, or CHF

125 patients, ages 30-70 years, with CVD and/or HTN and hs-CRP level >1.0mg/l 125 patients, ages 30-70 years, with CVD and/or HTN and hs-CRP level >1.0mg/l and <10 mg/l prior to randomization and <10 mg/l prior to randomization

Prospective. Double-Blind. Randomized. Prospective. Double-Blind. Randomized. Exclusion Criteria: Diabetes mellitus or chronic inflammatory diseases, statin therapy within 4 weeks, Exclusion Criteria: Diabetes mellitus or chronic inflammatory diseases, statin therapy within 4 weeks,

significant hepatic or renal disease, or CHFsignificant hepatic or renal disease, or CHF

RR

Pioglitazone Pioglitazone

MonotherapyMonotherapy

30 mg30 mg

n=39n=39

Simvastatin Simvastatin

MonotherapyMonotherapy

20 mg20 mg

n=43n=43

Simvastatin Plus Simvastatin Plus

PioglitazonePioglitazone

30 mg + 20 mg30 mg + 20 mg

n=43n=43

45 mg45 mg 40 mg40 mg 45 + 40 mg45 + 40 mg after 2 wks after 2 wks after 2 wks after 2 wks

6 week follow-up6 week follow-up6 week follow-up6 week follow-up Primary Endpoint: Changes in hs-CRPPrimary Endpoint: Changes in hs-CRP Secondary Endpoint: MMP-9, MCP-1, PAI-1, cholesterol, triglycerides, Secondary Endpoint: MMP-9, MCP-1, PAI-1, cholesterol, triglycerides,

glucose, HbAglucose, HbA1c1c, Homeostasis Model Assessment (HOMA), Weight, BMI, Homeostasis Model Assessment (HOMA), Weight, BMI

Primary Endpoint: Changes in hs-CRPPrimary Endpoint: Changes in hs-CRP Secondary Endpoint: MMP-9, MCP-1, PAI-1, cholesterol, triglycerides, Secondary Endpoint: MMP-9, MCP-1, PAI-1, cholesterol, triglycerides,

glucose, HbAglucose, HbA1c1c, Homeostasis Model Assessment (HOMA), Weight, BMI, Homeostasis Model Assessment (HOMA), Weight, BMI

after 2 wks after 2 wks



The PIOSTAT Study: Baseline CharacteristicsThe PIOSTAT Study: Baseline Characteristics

CharacteristicCharacteristic PioglitazonePioglitazone(n=39)(n=39)

SimvastatinSimvastatin(n=43)(n=43)

Pioglitazone + Pioglitazone + SimvastatinSimvastatin

(n=43)(n=43)

Age (yrs), meanAge (yrs), meanSDSD 59.559.5±7.8±7.8 57.357.3±8.4±8.4 59.059.0±8.6±8.6

BMI (kg/mBMI (kg/m22) mean) meanSDSD 30.830.8±4.8±4.8 30.530.5±3.7±3.7 31.231.2±4.1±4.1

Men/Women, n Men/Women, n 13/2613/26 16/2716/27 18/2518/25

CVD, n (%)CVD, n (%) 38 (97.4)38 (97.4) 41 (95.3)41 (95.3) 43 (100.0)43 (100.0)

Hypertension, n (%)Hypertension, n (%) 36 (92.3)36 (92.3) 39 (90.7)39 (90.7) 39 (90.7)39 (90.7)

RAS inhibition RAS inhibition therapy, n (%)therapy, n (%) 23 (59.0)23 (59.0) 21 (48.8)21 (48.8) 27 (62.8)27 (62.8)

Antithrombotic Antithrombotic therapy, n (%)therapy, n (%) 6 (15.4)6 (15.4) 10 (23.3)10 (23.3) 8 (18.6)8 (18.6)

Calcium channel Calcium channel blockers, n (%)blockers, n (%) 7 (17.9)7 (17.9) 10 (23.3)10 (23.3) 7 (16.3)7 (16.3)

Metabolic Syndrome, Metabolic Syndrome, n (%)n (%) 19 (48.7)19 (48.7) 24 (55.8)24 (55.8) 23 (53.5)23 (53.5)



The PIOSTAT Study: Primary EndpointThe PIOSTAT Study: Primary Endpoint

• There were no There were no significant significant differences in the differences in the baseline levels of baseline levels of hs-CRP between the hs-CRP between the three groups.three groups.

• At 12 weeks, At 12 weeks, pioglitazone and the pioglitazone and the combination combination regimen had an regimen had an additive effect in additive effect in reducing hs-CRPreducing hs-CRP

3.5+2.03.3+2.0

3.6+2.4

2.1+1.4

2.8+2.12.5+1.8

0

1

2

3

4

5

Piog. Simv. Piog. + Simv.

Baseline 12 weeks

3.5+2.03.3+2.0

3.6+2.4

2.1+1.4

2.8+2.12.5+1.8

0

1

2

3

4

5

Piog. Simv. Piog. + Simv.

Baseline 12 weeks

Reduction in hs-CRP Levels at 12 weeksReduction in hs-CRP Levels at 12 weeks

n = 39n = 39

p<0.001p<0.001

Red

uct

ion

in

hs-

CR

P (

mg

/l)

n = 43n = 43 n = 43n = 43



The PIOSTAT Study: Primary EndpointThe PIOSTAT Study: Primary Endpoint

• The combination of pioglitazone plus The combination of pioglitazone plus simvastatin had additive effects on hs-CRP, with simvastatin had additive effects on hs-CRP, with a 40% reduction from simvastatin monotherapy a 40% reduction from simvastatin monotherapy (p=0.01).(p=0.01).

• A subgroup analysis was performed in patients A subgroup analysis was performed in patients with and without metabolic syndrome (MetS), with and without metabolic syndrome (MetS), and the difference between monotherapy and and the difference between monotherapy and combination therapy was only significant for combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone simvastatin versus simvastatin plus pioglitazone in patients without metabolic syndrome.in patients without metabolic syndrome.



The PIOSTAT Study: Secondary EndpointThe PIOSTAT Study: Secondary Endpoint




(n=43)(n=43)

MMP-9 (ng/ml)MMP-9 (ng/ml) BaselineBaseline 12 weeks12 weeks

375.2 375.2 ± 173.0± 173.0297.5 297.5 ± 140.3*± 140.3*

383.0 383.0 ± 223.7± 223.7477.5 477.5 ± 250.9*± 250.9*

385.8 385.8 ± 201.5± 201.5307.4 307.4 ± 152.4*± 152.4*

MCP-1 (pg/ml)MCP-1 (pg/ml) BaselineBaseline 12 weeks12 weeks

399.8 ± 118.8399.8 ± 118.8372.5 ± 120.3372.5 ± 120.3

377.5 377.5 ± 99.1± 99.1388.3 ± 105.1388.3 ± 105.1

378.6 378.6 ± 121.8± 121.8360.2 ± 116.8360.2 ± 116.8

PAI-1 (ng/ml)PAI-1 (ng/ml) BaselineBaseline 12 weeks 12 weeks

30.5 ± 23.530.5 ± 23.518.8 ± 16.9*18.8 ± 16.9*

35.2 ± 43.535.2 ± 43.529.1 ± 32.229.1 ± 32.2

30.3 ± 26.530.3 ± 26.518.6 ± 17.4*18.6 ± 17.4*

Total CholesterolTotal Cholesterol BaselineBaseline 12 weeks12 weeks

5.60 ± 0.995.60 ± 0.995.67 ± 1.175.67 ± 1.17

5.73 ± 1.105.73 ± 1.104.44 ± 0.96*4.44 ± 0.96*

5.67 ± 1.265.67 ± 1.264.43 ± 0.95*4.43 ± 0.95*



The PIOSTAT Study: Secondary Endpoint (Cont.)The PIOSTAT Study: Secondary Endpoint (Cont.)




(n=43)(n=43)

LDL-cholesterol (mmol/l)LDL-cholesterol (mmol/l) BaselineBaseline 12 weeks12 weeks

3.50 ± 0.943.50 ± 0.943.56 ± 1.043.56 ± 1.04

3.60 ± 1.013.60 ± 1.012.32 ± 0.88*2.32 ± 0.88*

3.68 ± 1.103.68 ± 1.102.40 ± 0.91*2.40 ± 0.91*

HDL-cholesterol (mmol/)HDL-cholesterol (mmol/) BaselineBaseline 12 weeks12 weeks

1.41 ± 0.411.41 ± 0.411.44 ± 0.421.44 ± 0.42

1.43 ± 0.411.43 ± 0.411.52 ± 0.42*1.52 ± 0.42*

1.44 ± 0.451.44 ± 0.451.53 ± 0.45*1.53 ± 0.45*

Triglycerides (mmol/l)Triglycerides (mmol/l) BaselineBaseline 12 weeks12 weeks

1.50 ± 0.731.50 ± 0.731.46 ± 0.641.46 ± 0.64

1.63 ± 1.641.63 ± 1.641.36 ± 1.161.36 ± 1.16

1.45 ± 0.591.45 ± 0.591.13 ± 0.39*1.13 ± 0.39*

Glucose (mmol/l)Glucose (mmol/l) BaselineBaseline 12 weeks 12 weeks

5.63 ± 0.545.63 ± 0.545.23 ± 0.51*5.23 ± 0.51*

5.60 ± 0.625.60 ± 0.625.56 ± 0.555.56 ± 0.55

5.70 ± 0.665.70 ± 0.665.50 ± 0.685.50 ± 0.68



The PIOSTAT Study: Secondary Endpoint (Cont.)The PIOSTAT Study: Secondary Endpoint (Cont.)




(n=43)(n=43)

HbAHbA1c1c

BaselineBaseline 12 weeks12 weeks

5.47 ± 0.465.47 ± 0.465.37 ± 0.45*5.37 ± 0.45*

5.43 ± 0.405.43 ± 0.405.42 ± 0.415.42 ± 0.41

5.58 ± 0.405.58 ± 0.405.53 ± 0.355.53 ± 0.35

HOMAHOMA BaselineBaseline 12 weeks12 weeks

3.27 ± 2.213.27 ± 2.212.40 ± 0.97*2.40 ± 0.97*

3.52 ± 2.073.52 ± 2.073.63 ± 1.603.63 ± 1.60

3.70 ± 1.983.70 ± 1.982.81 ± 1.15*2.81 ± 1.15*

Body Weight (kg)Body Weight (kg) BaselineBaseline 12 weeks12 weeks

85.9 ± 15.285.9 ± 15.287.7 ± 15.4*87.7 ± 15.4*

87.4 ± 14.287.4 ± 14.287.4 ± 14.787.4 ± 14.7

87.4 ± 13.387.4 ± 13.388.6 ± 12.8*88.6 ± 12.8*

BMIBMI BaselineBaseline 12 weeks12 weeks

30.6 ± 4.730.6 ± 4.731.3 ± 5.2*31.3 ± 5.2*

30.5 ± 3.630.5 ± 3.630.5 ± 3.730.5 ± 3.7

31.1 ± 4.131.1 ± 4.131.6 ± 4.0*31.6 ± 4.0*



The PIOSTAT Study: Secondary Endpoints (Cont.)The PIOSTAT Study: Secondary Endpoints (Cont.)

• Homeostasis Model Assessment (HOMA) Homeostasis Model Assessment (HOMA) decreased in those receiving pioglitazone decreased in those receiving pioglitazone monotherapy (p=0.003) and pioglitazone plus monotherapy (p=0.003) and pioglitazone plus simvastatin (p<0.001).simvastatin (p<0.001).

• The correlation between changes in HOMA and hs-The correlation between changes in HOMA and hs-CRP was significant in the piolgitazone monotherapy CRP was significant in the piolgitazone monotherapy group (r=0.43; p=0.006).group (r=0.43; p=0.006).

• The PAI-1 and MMP-9 also significantly decreased The PAI-1 and MMP-9 also significantly decreased in the pioglitazone (monotherapy and combination in the pioglitazone (monotherapy and combination with simvastatin) groups.with simvastatin) groups.



The PIOSTAT Study: SummaryThe PIOSTAT Study: Summary

• Pioglitazone and simvastatin exerted anti-Pioglitazone and simvastatin exerted anti-inflammatory effects in non-diabetic patients with inflammatory effects in non-diabetic patients with CVD and elevated hs-CRP.CVD and elevated hs-CRP.

• Combining the two drugs resulted in an additive Combining the two drugs resulted in an additive effect on low-grade inflammation, without a effect on low-grade inflammation, without a significant increase in serious adverse events.significant increase in serious adverse events.

• For subgroups, the additive effect was only For subgroups, the additive effect was only significant for patients without MetS.significant for patients without MetS.


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