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Original Studies |
Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo Prefectural Amagasaki Hospital, Hyogo 660-0828, Japan
Address all correspondence and requests for reprints to: Dr. H. Koshiyama, Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Hyogo 660-0828, Japan.
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Abstract |
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Introduction |
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It has recently been indicated that the measurement of carotid arterial intima-media thickness (IMT) using B-mode ultrasonography is a noninvasive and powerful tool to evaluate early atherosclerotic lesions (10, 11, 12, 13, 14). In the present study we investigated the effect of cyclic etidronate treatment on carotid arterial IMT in subjects with type 2 diabetes.
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Subjects and Methods |
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The study was designed as an open prospective study. All of the
subjects gave informed consent, and the study was approved by the
ethical committee of the hospital. A total of 114 Japanese subjects
with type 2 diabetes (30 men and 84 women; mean ± SE
age, 61.8 ± 1.1 yr) were included in the study, which consisted
of etidronate and control groups (Table 1
). The etidronate group (n = 57)
was consecutively selected from the randomly assigned subjects with
type 2 diabetes for a different study investigating the effects of
various combination treatments on osteopenia (15). Osteopenia was
defined as a bone mineral density (BMD) more than 1 SD
below the young adult average value (16). The BMD of L2–L4 was
measured as previously reported (17, 18, 19). Etidronate was
administered in a dose of 200 mg/day (taken in the middle of a 4-h fast
at night) for 14 days, followed by no medication for 12 weeks. The
control group consisted of 57 randomly selected subjects with type 2
diabetes who were not receiving etidronate, involving subjects both
with and without osteopenia.
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Blood hemoglobin A1c (HbA1c), serum total cholesterol, high density lipoprotein (HDL) cholesterol, and postprandial triglyceride levels were measured with standard procedures. Postprandial triglyceride levels were examined exactly 2 h after the conventional breakfast, as previously described (20, 21).
IMT measurements
IMT of the common carotid artery was measured with high resolution B-mode ultrasonography (LOGIQ 500, GE Yokogawa Medical Systems Co., Tokyo, Japan) with an electrical linear transducer (midfrequnecy, 7.5 MHz), as previously reported (12, 14, 20, 21, 22, 23, 24). Briefly, for each subject, measurements of IMT on both sides were performed on the far wall, which was defined as the distance from the leading edge of the first echogenic line to the second echogenic line. All segments of the common carotid arteries were scanned, and localized thickness more than 2.0 mm was excluded as plaque lesion from the measurement (12, 14). Three determinations of IMT were conducted, i.e. at the site of greatest thickness and at two other points. IMT values were averaged on three determinations for right and left common carotid arteries, and the greater value of averaged IMT was adopted as the representative data for each measurement. IMT was measured before and 12 months after the administration of etidronate by a single expert examiner, who was blinded to treatment group. IMT changes in the etidronate group were compared to those in the control group. The intraoperator coefficient of variation of repeated IMT measurements was 1.0%.
Statistical analysis
The results are expressed as the mean ± SE.
The difference in basal values and changes in IMT,
HbA1c, total cholesterol, HDL cholesterol, and
postprandial triglycerides between etidronate and control groups were
examined by Student’s t test and ANOVA. The difference in
prevalence of smoking habitus or hypertension was evaluated using the
2 test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As shown in Table 1
, there was no difference between the
etidronate and control groups in baseline characteristics, except for
BMD, which was reasonably lower in the etidronate group; there was no
difference between the two groups in age, duration of diabetes
mellitus, modalities of treatment for diabetes, use of lipid-lowering
drugs, frequency of complications (i.e. retinopathy,
nephropathy, or neuropathy), glycemic control
(HbA1c), total serum cholesterol, HDL
cholesterol, triglyceride levels, prevalence of coronary
artery/cerebrovascular/peripheral vascular/diseases or hypertension,
frequency of smoking habitus, or body mass index. Although there
appeared to be some differences in some parameters other than BMD
between the two groups, such as triglyceride level or prevalence of
nephropathy, the differences did not reach statistical significance
(for example, the P value for the difference in prevalence
of nephropathy was 0.1969).
Effect of etidronate treatment on parameters of cardiovascular risk
None of the cardiovascular parameters showed a significant change
during the study in the two groups, as shown in Table 2. BMD after 1 yr was not examined in the
control group. Etidronate failed to increase BMD significantly in
subjects with type 2 diabetes after 12 months, although it
significantly increased BMD after 18 and 24 months, as we previously
reported in a preliminary form (15).
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In the control group, IMT was decreased in 12, increased in
31, and unchanged in 15 subjects after a 1-yr period. In contrast, IMT
was decreased in 37, increased in 18, and unchanged in 2 of the
subjects receiving etidronate. Although there was a considerable
variation in the IMT changes, the etidronate group as a whole showed a
statistically significant decrease in IMT compared to the control group
(IMT changes, -0.038 ± 0.011 mm vs. 0.023 ±
0.015 mm; P < 0.005; Fig. 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The decrease in IMT after etidronate treatment shown in the present study was relatively small (-0.038 mm), but was significantly different from that in the control group. In addition, the annual change in the diabetic control group (0.023 ± 0.015 mm) was compatible with the value of 0.03 ± 0.01 mm in diabetic subjects reported by other investigators (24). We recently reported that troglitazone, an insulin sensitizer (20, 21), and amlodipine, a calcium channel blocker (22), have an inhibitory effect on IMT in type 2 diabetes. Other investigators recently reported that IMT was decreased after GH treatment in adults with GH deficiency (23, 24). The magnitude of the decrease in IMT after etidronate treatment was comparable, although slightly smaller, to those after troglitazone (-0.080 mm after 3 months) (21), amlodipine (-0.052 mm after 6 months) (22), and GH [-0.14 mm after 1 yr (23) or -0.08 mm after 1 yr (24)], and much greater than those after lipid-lowering agents [0.010 mm/yr; control, 0.029 mm/yr (27) or -0.0043 mm/yr (28)]. The IMT changes in the two studies with lipid-lowering drugs (27, 28) were below the differences in their replicate IMT measurements, which makes necessary the larger number of subjects than in the present study, as described above.
It is noteworthy that we excluded the plaque lesion, defined as a local thickness more than 2.0 mm, from the analysis of IMT measurement (14), as other investigators do (12, 23), although some reports appeared not to differentiate the plaque lesion and the diffuse intima-media thickening (29, 30). The reason for exclusion of plaque is that plague lesion is difficult to evaluate quantitatively, because the thickness of plaque shows a considerable variation depending on the direction of ultrasonographic probe because of its irregular shape. In addition, it is considered that the diffuse intima-media thickening and the plaque formation represent an early and an advanced atherosclerotic lesion, respectively (12, 14), although there is no evidence that the former lesion will evolve into the latter (11). Therefore, it is possible that IMT is decreased, whereas the plaque lesion remains unchanged, after administration of some antiatherogenic agent. Taken together, we consider that the IMT measurement excluding a plaque lesion is a sensitive method to detect the subtle inhibitory effect of a drug on early atherosclerotic lesions (12, 14, 20, 21, 22).
The mechanisms by which bisphosphonate may inhibit atherosclerosis remain to be elucidated. First, it is unlikely that etidronate acts though changes in the conventional risk factors, considering that the parameters for cardiovascular risk remained unchanged after etidronate. Second, bisphosphonates are indicated to be accumulated in arteries (25, 26). Therefore, the antiatherogenic actions of bisphosphonates may be attributable to their effects on calcium deposits in the arterial wall (6, 7, 26). It was reported that bisphosphonates may exert an additive inhibitory effect on human artery contractions with calcium channel blocker (26). In this context, it is intriguing that amlodipine has a potent inhibitory effect on IMT in diabetic subjects, although other effects of amlodipine than those as a calcium channel blocker have been suggested to be involved in its antiatherogenic action (22). Third, a very recent report has suggested that an inhibition of osteopontin release through an increase in PTH-related peptide secretion may be involved in the antiatherogenic action of bisphosphonates (31). Finally, it is possible that bisphosphonates may prevent macrophages from processing atherogenic LDL cholesterol, and they may also inhibit the formation of foam cells in the atherosclerotic process (25, 26).
In summary, the present study indicated that IMT was decreased after 1 yr of therapy with etidronate for osteopenia in type 2 diabetes, suggesting that etidronate in clinical dosage may have an inhibitory effect on early atherogenic process, at least in subjects with type 2 diabetes. The exact mechanisms by which etidronate exerts an antiatherogenic effect remain to be elucidated.
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Acknowledgments |
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Footnotes |
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Received November 10, 1999.
Revised February 2, 2000.
Accepted May 8, 2000.
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References |
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