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Endocrine Care |
University of Goteborg (B.A., G.J., G.H., B.-A.B.), S-413 45 Goteborg, Sweden; and Lilly Research Laboratories, Eli Lilly \|[amp ]\| Co. (A.S., I.P., T.M., P.W.A.), Indianapolis, Indiana 46285
Address all correspondence and requests for reprints to: Dr. Björn Andersson, Department of Medicine, Sahlgrenska University Hospital, Sahlgrenska, S-413 45 Goteborg, Sweden. E-mail: bjorn.andersson{at}medfak.gu.se
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Abstract |
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Introduction |
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Menopause is associated with an increased incidence of osteoporosis and type 2 diabetes. The association between type 2 diabetes and osteoporotic risk is uncertain; however, women who have had type 2 diabetes for at least 5 yr have an increased risk of hip fracture (5). Therefore, postmenopausal women with type 2 diabetes may represent a population who could benefit from RLX. To date, no studies have been specifically designed to investigate the effects of RLX on coronary heart disease (CHD) risk factors in postmenopausal women with type 2 diabetes or on insulin resistance in any population. Postmenopausal women with type 2 diabetes have an increased risk for developing CHD. The increased cardiovascular risk is due in part to the menopausal state; concomitant diabetes mellitus increases the risk by an additional 3- to 4-fold (6). Factors known to contribute to the increased risk of developing CHD in postmenopausal women with type 2 diabetes include dyslipidemia, poor glycemic control, abnormalities of coagulation, and members of the IGF system (7, 8, 9). A risk and benefit profile of any therapeutic intervention in these patients is influenced largely by the effect of the therapy on these risk factors.
Women with type 2 diabetes are often more hyperandrogenic than healthy women of similar age and body mass index (10). Hyperandrogenicity represents another independent risk factor for CHD in postmenopausal women and is associated with impaired glucose tolerance and type 2 diabetes (11, 12, 13). Short-term IGF-I therapy can improve insulin sensitivity and glucose homeostasis without evidence of influencing CHD risk (14). Reduction of IGF-I, however, may have long-term beneficial effects on the vascular endothelium, decreasing cardiovascular risk, because IGF-I is a potent mitogen for vascular smooth muscle cells (15).
Postmenopausal women with concomitant type 2 diabetes and hyperandrogenicity represent a population at particularly high risk for developing CHD. Therefore, we chose to investigate the effect of RLX on factors that are possible determinants of CHD risk in these women. Specifically, we examined the effect of RLX on objective measures of glycemic control, insulin sensitivity, and selected surrogate markers of cardiovascular risk, including coagulation factors, lipids, and members of the IGF system. We also determined whether RLX influences androgen status and body composition in this high risk population.
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Materials and Methods |
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This was a single center, randomized, double blind, placebo- controlled, cross-over study. Thirty subjects were enrolled and randomly assigned to one of two therapy sequences: RLX (60 mg/d) followed by placebo or placebo followed by RLX (60 mg/d).
Our study design is depicted in Fig. 1
. The study consisted of five phases: 1) screening to determine inclusion and exclusion criteria (visit 1), 2) 1-month lead-in period to stabilize subjects’ glycemic control (visit 2), 3) 12-wk treatment with placebo or RLX (visits 3–4), 4) 8-wk washout period, and ) 12-wk treatment with RLX or placebo (visits 5–6). Subjects who took placebo in phase 3 were given RLX in phase 5, and subjects who took RLX in phase 3 were given placebo in phase 5.
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All subjects were postmenopausal women, aged 45 to 75 yr, with a serum E2 level less than 70 pmol/liter and a serum SHBG level less than 60 nmol/liter at screening. Subjects had type 2 diabetes mellitus for more than 1 yr, defined as having a fasting plasma glucose of more than 6.1 mmol/liter or hemoglobin A1c (HbA1c) of 6.5% or more at screening. Diabetes could be treated with diet, exercise, or oral hypoglycemic agents. Eleven subjects changed their medication during the lead-in period (phase 2) and remained on their new medication through the rest of the study. Subjects were ambulatory and free of severe or chronically disabling conditions.
Subjects were excluded from the trial if they had known or past history of carcinoma of the breast or other estrogen-dependent neoplasia (e.g. endometrial carcinoma), had history of cancer within the previous 5 yr except for excised superficial basal cell carcinoma and squamous cell carcinoma of the skin, had a history of deep venous thrombosis, or had a body mass index greater than 45 kg/m2.
Subjects were also excluded from the trial if in the last 4 wk they had participated in a medical, surgical, or pharmaceutical investigation or if they had been treated with any of the following medications: anticonvulsants, thiazides, toremifene, tamoxifen, tibolone, androgens, E2, progestins, or systemic corticosteroids. Occasional treatment with insulin of no more than 10 d/therapy period was permitted. Occasional symptomatic use of topical steroids or vaginal estrogens (no more than three times per wk) was permitted.
Subjects experiencing clinically significant postmenopausal symptoms, abnormal uterine bleeding, acute or chronic liver disease, or impaired kidney function or who were not clinically euthyroid at screening were excluded from the study. Patients who consumed an excess of alcohol, abused drugs, were poor medical or psychiatric risks for therapy with an investigational drug, had previously participated in any study investigating RLX, or had a known or suspected allergy to RLX or any inactive ingredients in the study medications were also excluded.
All subjects were Swedish and Caucasian and were recruited by advertisement in a local newspaper. The protocol was approved by the ethical committee of University of Goteborg and by the Swedish Medical Product Agency, and all subjects signed informed consents.
RLX (provided as oral tablets containing 60 mg active ingredient) and the matching oral placebo tablets were supplied by Eli Lilly \|[amp ]\| Co. (Indianapolis, IN). The first two subjects randomized included one subject randomized to one of the therapy sequences and the other to the alternate sequence. All subsequent pairs of subjects were randomized in a similar fashion, thus ensuring that an equal number of subjects followed each of the two therapy sequences while the investigators remained blinded to the sequence assignment.
Sample size
The study was primarily designed to compare the effects of 12 wk of RLX vs. placebo on change in HbA1c. The selected sample size of 30 patients ensured approximately 80% power to detect a difference of 1.05 in pre- to posttherapy change in HbA1c between the 60 mg/d RLX and placebo therapy groups, assuming a reduction of 0.56 in HbA1c after RLX therapy for 12 wk and an increase of 0.49 in HbA1c after placebo therapy for 12 wk. An SD of 1.5 for the difference in changes in HbA1c between the two therapy groups was assumed. These assumptions are consistent with an identical study in which oral estrogen was used instead of RLX (16).
Statistical methods
The primary efficacy analysis of the 12-wk change in HbA1c was based only on subjects who completed the study. Only one subject discontinued the study before it was completed. We used the conventional two-period, two-sequence, cross-over ANOVA procedure (17) as the analysis tool. We were able to compare changes from beginning to end of treatment under RLX vs. placebo therapy using data from both therapy periods, because there was no carry-over effect in the model at a significance level of 0.10. The 8-wk wash-out period was deemed adequate by comparing the pretherapy values (for the two therapy periods) of all the efficacy variables. We calculated a 95% confidence interval for the difference in 12-wk changes brought about by RLX (60 mg/d) vs. placebo. All secondary efficacy analyses were carried out in a similar manner. No statistical adjustments were made for multiple comparisons; therefore, significant results should be interpreted with caution.
Laboratory methods
All laboratory parameters were measured at visits 3, 4, 5, and 6 (see Fig. 1
), and assays were performed in a central laboratory (Covance, Indianapolis, IN).
Assessment of glycemic control. Fasting plasma glucose was assayed as previously described (18). HbA1c was determined using the DIAMAT glycosylated hemoglobin analyzer system (Bio-Rad Laboratories, Inc., Hercules, CA) (19). Insulin was measured using RIA methods (Imx Insulin assay, Abbott Diagnostics; Santa Clara, CA).
Insulin sensitivity was determined based on glucose disappearance rate at randomization and at each visit thereafter under the conditions of a euglycemic hyperinsulinemic clamp as originally described by DeFronzo et al. (20). Briefly, after an overnight fast, each subject received a constant infusion of insulin (Actrapid MC, Novo, Copenhagen, Denmark) along with glucose solution (20%, wt/vol; 1.1 mol/liter) to an antecubital vein at a rate of 0.12 U/kg BW·min for 120 min. The rate of glucose infusion was adjusted to achieve a constant blood glucose level of 5.0 mmol/liter. The glucose disappearance rate was assumed to be equal to the rate of glucose infusion during the last 20 min of the euglycemic clamp, when steady state was achieved. For each euglycemic clamp that was performed, samples for plasma insulin were taken before insulin infusion and 80, 90, 100, 110, and 120 min after insulin infusion.
Measurement of selected surrogate markers of cardiovascular risk. Total cholesterol, high density lipoprotein cholesterol (HDL-C), triglycerides, low density lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp(a)), apolipoprotein A1 (apoA1), apoB, plasminogen activator inhibitor (PAI) and fibrinogen were measured at randomization and at each visit thereafter as previously described (18). LDL-C was calculated using the Friedwald equation and was also measured directly with the use of a commercial kit (21). Tissue plasminogen activator (t-PA) was measured at randomization and each visit thereafter using the Biopool Chromalize assay method (Covance, Indianapolis, IN).
Serum measurements of free T, total T, SHBG, IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels. T (free and total) and SHBG were measured at screening, at randomization, and each visit thereafter according to the methods described by Vermeulen et al. (22). IGF-I, IGFBP-1, and IGFBP-3 were measured by RIA at randomization and each visit thereafter as described by Blum et al. (23).
Assessment of body composition. Body composition was ascertained using the total body potassium method as previously described (10) and was measured at randomization and each visit thereafter. Waist and hip circumference were also measured at randomization and each visit thereafter as previously described (12). Sagittal abdominal diameter was determined as the distance between the examination table and the highest point of the abdomen in the recumbent position (24). Body weight was measured to the nearest 0.1 kg with participants in underwear and was measured at all visits.
Safety
The investigator recorded the occurrence of adverse events when reported by each subject. Other safety evaluations included vital signs (blood pressure, pulse) at all visits and routine fasting hematology and clinical chemistry measurements at screening, randomization, and all visits thereafter.
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Results |
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. Eighty percent of the subjects were on hypoglycemic medication at baseline.
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After treatment, RLX was not associated with a statistically significant change in HbA1c, fasting blood glucose, or insulin sensitivity (as assessed by euglycemic, hyperinsulinemic clamp) after 12 wk of treatment compared with placebo (Tables 2a and 2b). In particular, the mean difference between RLX and placebo in change from beginning to end of therapy for HbA1c was estimated to be 0.0, with a 95% confidence interval of (-0.004, 0.004).
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Changes in lipoproteins and coagulation factors are shown in Table 3. Treatment with RLX resulted in a significant decrease in fibrinogen levels. There was no significant difference between RLX and placebo in the changes in total cholesterol, HDL-C, LDL-C (calculated), LDL-C (direct measurement), triglycerides, Lp(a), apoA1, apoB, PAI-1, and t-PA.
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Changes in androgen hormone status and the IGF system are shown in Table 3. RLX reduced androgenicity by significantly increasing SHBG and lowering free T. Also, RLX significantly reduced total IGF-I and increased IGFBP-3 compared with placebo. There was no difference in the effect of placebo vs. RLX on changes in IGFBP-1 or total T levels.
Body composition
There were no significant effects on weight, waist circumference, waist to hip ratio, or sagittal abdominal diameter. However, lean body mass decreased slightly among women assigned to RLX after 12 wk (Table 4).
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There were no significant differences in the number of patients who reported at least one adverse event during RLX therapy vs. placebo therapy. No patients discontinued the study as a result of an adverse event. Several changes in safety laboratory values with RLX treatment observed in the current study were consistent with those observed in larger trials (increased alkaline phosphatase, decreased serum calcium, and decreased platelet count). Other effects of RLX that were statistically significant but not deemed clinically significant included decreased leukocyte count, decreased segmented neutrophils, and decreased alanine transaminase/serum glutamic pyruvic transaminase ratio. No significant changes in vital signs were seen between RLX and placebo treatments.
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Discussion |
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We decided to evaluate the effects of RLX on insulin sensitivity and glycemic control in women with type 2 diabetes in light of inconsistent results observed with other postmenopausal therapies, such as estrogen replacement therapy and hormone replacement therapy (HRT). Some studies indicate that HRT may have moderately beneficial effects on insulin sensitivity (16, 28), and glucose homeostasis (28), whereas others fail to show an effect on either parameter (29, 30, 31). The narrow confidence interval in our analysis of change in HbA1c levels excludes any clinically significant change in HbA1c, suggesting that a potential increase in HbA1c with RLX treatment is highly unlikely. Aside from the neutral effect of RLX presented here, to date there are no data showing whether other SERMs affect glycemic control or insulin sensitivity in women with diabetes.
In the current study the neutral or favorable effects of RLX on markers of cardiovascular risk were especially important for this high risk population. RLX was previously demonstrated to significantly lower LDL-C and have either a favorable or a neutral effect on a variety of surrogate markers of cardiovascular risk in postmenopausal women without diabetes (18). Similarly, tamoxifen has a favorable effect on LDL, with either neutral or favorable effects on other cardiovascular risk markers, in healthy postmenopausal women (32). In our study RLX did not significantly reduce LDL-C and apoB and tended to reduce Lp(a); however, the reduction was not significantly different from that with placebo. It is possible that we did not observe a statistically significant reduction in LDL-C or apoB because our sample size was too small. In a study that included a greater number of participants, RLX decreased LDL-C without changing triglycerides in postmenopausal women with evidence of preexisting diabetes who participated in the Multiple Outcomes of Raloxifene Evaluation trial (unpublished data). We did not observe any change in HDL-C levels in response to RLX, an effect consistent with our previous observations in women without DM (18). Many of the beneficial effects of HRT on lipoproteins are similar in postmenopausal women with and without diabetes (33, 34). Oral HRT, however, is associated with an exaggerated hypertriglyceridemic response in women with type 2 DM (34). The effects of tamoxifen and other SERMs on lipid levels in women with DM have not been evaluated.
In the current study RLX reduced plasma fibrinogen levels without affecting the levels of PAI and t-PA, main factors that control fibrinolysis. The fact that RLX has a fibrinogen- lowering effect in a diabetic population is especially important, because DM is usually accompanied by elevated fibrinogen levels (9). Furthermore, fibrinogen is a strong independent risk factor for cardiovascular events in epidemiological studies (35). Unlike RLX, HRT does not alter fibrinogen levels in healthy postmenopausal women and decreases the level of the fibrinolytic agent PAI-1 (36).
In the present study RLX significantly increased SHBG without increasing the levels of total T, thus lowering unbound T and improving baseline hyperandrogenicity. It is possible that a relationship exists among hyperandrogenicity, decreased glucose tolerance, and hyperinsulinemia; however, this relationship is not completely understood. Increased hyperandrogenicity may induce insulin resistance and decrease glucose tolerance (12), suggesting that hyperandrogenicity contributes to hyperinsulinemia (13). Furthermore, in a previous trial in which HRT decreased hyperandrogenicity, insulin sensitivity was also improved (16). On the other hand, hyperinsulinemia increases androgen output from the ovary (37, 38) and may suppress SHBG production in the liver (39, 40), suggesting that hyperinsulinemia causes hyperandrogenicity (41).
In the present trial, improvements in hyperandrogenicity induced by RLX were not accompanied by improvements in insulin sensitivity after 12 wk. Our data support the observations of several previous studies, which showed that reducing androgens does not improve insulin resistance (42, 43). Like RLX, other SERMs, such as clomiphene citrate (16, 44), tamoxifen (45, 46, 47), and droloxifene (48), have been observed to increase SHBG. Thus, SERMs in general may have estrogen agonist effects on SHBG and, therefore may reduce hyperandrogenicity.
Raloxifene treatment also decreased IGF-I and increased IGFBP-3, resulting in a reduction in unbound IGF-I. Similar observations have been noted in patients receiving oral estrogen (49), tamoxifen (45, 50), and clomiphene ( 44), indicating that reductions in IGF-I are at least partially mediated by the ER. As the majority of circulating IGF-I is produced in the liver (51), the reduction in serum IGF-I is probably an effect of RLX mediated by ER in hepatocytes (49, 52).
IGF-I may influence the risk of developing CHD in the diabetic state. On the one hand, IGF-I can improve insulin sensitivity and glucose homeostasis, mainly by inhibiting GH and glucagon secretion (14). On the other hand, reducing IGF-I may have beneficial effects on the vascular endothelium, thereby decreasing cardiovascular risk, as IGF-I is a potent mitogen for vascular smooth muscle cells (15). The clinical significance of IGF-I reduction by RLX, estrogen, or any other SERM therapies on CHD risk should be further evaluated.
In this trial RLX significantly decreased lean body mass and tended to decrease fat mass and body weight, although the last two observations were not statistically significant. These effects are different from those observed in a similar population taking oral estrogen, where fat mass and body weight were significantly increased (16, 53). This is consistent with the results of a larger study in which RLX had no effect on body weight or body mass index in postmenopausal women with osteoporosis (1). Lean body mass was measured using the total potassium method rather than the slightly superior, but more expensive, dual x-ray absorptiometry method. It is unknown whether the apparent lack of effect of RLX on fat mass in this cohort will be a consistent effect observed in women with diabetes, whether it is due to the method of measurement used, or whether it is due to the small sample size in this trial. Trials with a larger sample size that use x-ray absorptiometry to measure fat mass may help clarify this issue.
In summary, administration of RLX to postmenopausal women with type 2 diabetes had a neutral effect on insulin sensitivity, glucose homeostasis, and surrogate markers of cardiovascular risk while reducing hyperandrogenicity. These findings suggest that RLX may be used in postmenopausal diabetic women without deteriorating the diabetic state per se.
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Acknowledgments |
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Footnotes |
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Received April 18, 2001.
Accepted October 2, 2001.
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