Slowing Atherosclerosis in Type 2 Diabetes

Summarized by Robert W. Griffith, MD
March 5, 2007

Summary

The oral anti-diabetic drug pioglitazone significantly slows thickening of the carotid artery wall (intima-media thickening), compared to a sulphonylurea, glimepiride; this suggests it may well slow the risk of heart attack or stroke in type 2 diabetics.

Introduction

In type 2 diabetes there is an increased risk of heart attack and other cardiovascular events, such as stroke, that's clearly related to underlying progression of atherosclerosis.¹ With treatment - optimal control of blood pressure and low-density lipoprotein cholesterol (LDL-C) - the risk can be reduced considerably, but it remains higher than in people without diabetes.

There are 4 major types of oral treatment for type 2 diabetes:

• sulfonylureas (increase insulin secretion, e.g. glyburide, glimepiride)
• biguanides (increase insulin sensitivity, e.g. metformin)
• alpha-glucosidase inhibitors (AGIs, delay glucose absorption from the intestines, e.g. acarbose, miglitol)
• thiazolidinediones or glitazones (increase insulin sensitivity, e.g. pioglitazone, rosiglitazone)

In preliminary studies, the glitazones have beneficial effects on some 'markers' for atherosclerosis, namely C-reactive protein, coagulation factors, LDL-C, and intima cell function. This has led Chicago researchers to evaluate the effect of one of them, pioglitazone, on changes in the pathological development of atherosclerosis in patients with type 2 diabetes. They compared the effects of pioglitazone with those of a sulfonylurea on the relative thicknesses of the inner layer of the artery (the intima) and the middle, muscular layer (the media).

What was done

A randomized double-blind study was done in 462 newly diagnosed type 2 diabetics between 45 and 85 years of age. They had to be free of symptoms of cardiovascular disease, and their HbA1c had to be greater than 6.5%. They were randomly assigned to take pioglitazone (15 to 45 mg daily) or glimepiride (1 to 4 mg daily) for 72 weeks. The study was done at 28 centers in the Chicago area.

Ultrasound was used to measure the thickness of the media and the intima in the carotid arteries, delivering the carotid artery intima-media thickness, or CIMT. This was done at baseline, and at weeks 24, 48, and 72. All the images were read and scored by the same expert. Blood levels of HbA1c, lipids, and blood pressure were measured at the same intervals.²

What was found

Of the patients enrolled, 158 (68%) of the pioglitazone group and 165 (72%) of the glimepiride group completed the 72 weeks. Their average age was 60, their average body mass index (BMI) was 32 (i.e. in the obese range), and their average HbA1c was 7.4%.

Approximately 80% of the patients (175 pioglitazone and 186 glimepiride) had a baseline and at least one CIMT analysis during the study. At baseline, the average CIMT in the pioglitazone group was comparable to that of the glimepiride group (0.771 mm and 0.779 mm, respectively). At week 72, however, the progression of CIMT was different with pioglitazone than with glimepiride - there was an average loss of 0.001 mm with pioglitazone, compared to an increase of 0.012 mm with glimepiride. The difference was statistically significant, i.e. it could not have occurred by chance alone.

The average maximum thickness of the CIMT during the study was significantly different in the two groups: 0.002 mm with pioglitazone, 0.026 mm with glimepiride. The beneficial effects of pioglitazone were similar regardless of age, gender, duration of diabetes, blood pressure, blood cholesterol, or blood glucose levels.

During the study, there were 4 adverse cardiovascular events in the pioglitazone group, including 3 patients who required revascularization procedures. With glimepiride, there were 10 patients with cardiovascular events, 8 of whom required revascularization. As expected, edema and weight gain were more common in the pioglitazone group.

What the findings mean

Compared with a third-generation sulphonylurea, pioglitazone reduced the progression of coronary artery intima-media thickness in this study. Other studies have shown the value of CIMT scoring in predicting cardiovascular disease risk in type 2 diabetics. It follows, therefore, that pioglitazone treatment should slow the risk for cardiovascular events like heart failure or stroke in diabetics. However, large scale trials will be required to demonstrate the clinical relevance of the differences between these two antidiabetic medications shown here.

In the meantime, all other things being equal (and only you and your physician can determine that), you may select a glitazone rather than a sulfonylurea as your oral antidiabetic - always remembering that good control of your blood sugar is the prime concern . . .

Source

• Effect of pioglitazone compared with glimepiride on carotid-intima-media thickness in type 2 diabetes. A randomized trial. T. Mazzone, PM. Meyer , SB. Feinstein,  et al. , JAMA, 2006, vol. 296, pp. 2572--2581

Footnotes
1. In atherosclerosis deposits of fatty substances, cholesterol, cellular waste products, and calcium build up in the inner lining (the intima) of an artery; this buildup is called plaque.
2. HbA1c is shorthand for a type of hemoglobin, the oxygen-carrying element in red blood cells. (Hb stands for hemoglobin, and A1c is the designation of the subtype.) It's important because glucose binds to HbA1c and is only released very slowly, so that the HbA1c represents the average blood glucose level over the previous 4 weeks.

Related Links
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