Results from PERISCOPE: pioglitazone slows atherosclerosis

Data from the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) trial reported at Scientific Sessions of the American College of Cardiology 2008 Meeting suggest that pioglitazone can prevent atherosclerosis progression and produce clinically meaningful changes in cardiovascular risk factors including high-density lipoprotein (HDL) cholesterol in patients with type 2 diabetes. The results were reported by Dr Steve Nissen, Cleveland Clinic, Ohio and lead author of the paper.

Nissen SE, Nicholls SJ, Wolski K et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes. JAMA 2008;299:1561-73.

In PERISCOPE, 543 patients with coronary disease and typ e 2 diabetes were randomized and treated with glimepiride (1 to 4 mg) (n=273) or pioglitazone (15 to 45 mg) (n=270) for 18 months. At study entry, most patients in each treatment arm had hypertension, but were being treated with optimal antihypertensive treatment (Table 1).

Table 1. Patient characteristics at baseline


 Glimepiride
(N= 273)		Pioglitazone
(N= 270)
Mean age (years)59.760.0
Male65.9%68.9%
White80.6%83.3%
Mean duration of diabetes (years)5.95.8
Body mass index (kg/m2)32.032.1
Smokers19.4%11.5%
Hypertension91.6%83.3%
Prior MI25.6%33.0%

Patients underwent intravascular ultrasonography at baseline and at the end of the 18-month treatment period. In total, 360 patients had follow-up assessment. The primary endpoint was the change in percent atheroma volume (PAV) from baseline to study completion.

Mean PAV increased by 0.73% with glimepiride but decreased by 0.16% with pioglitazone (p=0.002). When the analysis was repeated imputing values for noncompleters based on baseline characteristics, there was an increase in mean PAV of 0.64% with glimepiride and a decrease of 0.06% (p=0.02). According to Dr Nissen, the data demonstrate that after 18 months treatment, patients assigned to glimepiride had unequivocal progression of coronary atherosclerosis whereas those treated with pioglitazone had no progression. ‘To our knowledge, this is the first study in which a diabetes therapy has been shown to slow or prevent progression of coronary atherosclerosis,’ he commented.

While there was some comment regarding the absolute changes in atherosclerosis reported, Dr Nissen commented that the differences observed in PERISCOPE were statistically robust and would translate to clinical benefits. Additionally, in an accompanying editorial by Drs P Steg, Centre Hospitalier Bichat-Claude Bernard, Paris, France and Michel Marre, Universite Paris VII, France, it was noted that the apparent effect of pioglitazone was well within the range of what is achieved with some treatments shown to improve cardiovascular outcomes, such as high-dose statins.1

Treatment with pioglitazone also produced meaningful changes in HDL cholesterol (increase by 16% compared with 4.1% on glimepiride, p<0.001), and triglycerides (decrease by 15.3% vs. increase of 0.6%, p<0.001) (Figure 1). Average fasting insulin, triglycerides, C-reactive protein and blood pressure were lower and HDL cholesterol higher on pioglitazone than glimepiride (Table 2).

Table 2. Average values over treatment for laboratory variables


 Glimepiride
(N= 273)		Pioglitazone
(N= 270)
Fasting insulin (μU/mL)26.516.0*
HDL cholesterol (mg/dL)43.746.8a
LDL cholesterol (mg/dL)96.195.6
Triglycerides (mg/dL)152119*
C-RP (mg/dL)2.21.2*
Blood pressure (mmHg)  
Systolic130.5128.1
Diastolic75.974.5
a p<0.05, *p<0.001  

As well, the data showed that the glucose-lowering effect of pioglitazone was more durable. Although glycated haemoglobin (HbA1c) was initially reduced more with glimepiride treatment, the average difference between the two groups over time was minimal (0.19%).

The adverse event profile of the two treatments differed. Hypoglycaemia occurred more frequently in the glimepiride group (37.0% vs. 15.2% with pioglitazone, p<0.001). In contrast, bone fractures occurred in 3.0% of patients in the pioglitazone group but none of the glimepiride group (p=0.004).

Although the mechanism by which pioglitazone alters atherosclerosis progression is not yet known, effects on lipids, C-reactive and blood pressure offer interesting possibilities for further investigation.

References

1. Steg PG, Marre M. Does PERISCOPE provide a new perspective on diabetic treatment? JAMA 2008;299:1603-4.

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