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The Effect of Hormone Replacement Therapy on Cardiovascular Risk Factors in Type 2 Diabetes
A Randomized Controlled Trial
Patrick J. Manning, MBChB, MMedSc, FRACP;
Anne Allum, EN;
Shirley Jones, RN;
Wayne H. F. Sutherland, PhD;
Sheila M. Williams, BSc(Hons)
Arch Intern Med. 2001;161:1772-1776.
ABSTRACT
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Background Postmenopausal women with diabetes are at high risk for cardiovascular
disease, compared with their nondiabetic counterparts. Combined continuous
hormone replacement therapy (HRT) is associated with improvements in serum
lipoprotein levels in nondiabetic women; however, the effect in women with
diabetes has not been determined. We evaluated the effect of combined continuous
HRT on lipoprotein and coagulation factor concentrations and glycemic control
in postmenopausal women with type 2 diabetes mellitus.
Methods In a randomized controlled crossover study, 61 subjects received combined
continuous HRT or placebo. Each treatment phase was of 6 months' duration,
with an 8-week washout phase between treatment phases.
Results Total cholesterol concentration decreased by 7% (95% confidence interval
[CI], 4%-11%) during HRT. For low-density lipoprotein concentration, the mean
decrease with HRT was 12% (95% CI, 6%-17%). Apolipoprotein B levels decreased
in keeping with the reduction in low-density lipoprotein cholesterol concentrations.
There were no significant changes in concentrations of high-density lipoprotein,
its subfractions, or triglycerides. Lipoprotein(a) and fibrinogen concentrations
were reduced by 21% (95% CI, 10%-31%) and 8% (95% CI, 2%-13%), respectively,
with HRT. Fructosamine concentrations declined by 5% (95% CI, 2%-9%) during
HRT.
Conclusions In postmenopausal women with type 2 diabetes mellitus, combined continuous
HRT has beneficial effects on lipoprotein concentrations and improves some
markers of coagulation and glycemic control.
INTRODUCTION
CARDIOVASCULAR disease accounts for more than 60% of the deaths among
diabetic patients.1 In population studies,
female patients with diabetes have 3 times the coronary heart disease mortality
rate of age- and sex-matched control subjects.2
Nonfatal cardiovascular events follow a similar pattern. This excess in coronary
artery disease is partly explained by abnormalities in lipoprotein metabolism.
Typically the diabetic lipid profile consists of hypertriglyceridemia, raised
levels of very low-density lipoprotein (VLDL), and reduced levels of high-density
lipoprotein (HDL).3 In nondiabetic women, menopause
has been shown to alter lipoprotein levels significantly, most frequently
in the form of an increase in low-density lipoprotein (LDL) cholesterol concentrations4; however, these changes may simply reflect the effect
of aging.5
Extensive and consistent observational evidence exists that estrogen
use reduces the risk for coronary heart disease in nondiabetic postmenopausal
women by at least 35%.6 However, a recent randomized
controlled trial has suggested that this beneficial effect may not be afforded
to women with established coronary artery disease.7
Unopposed estrogen decreases LDL levels by approximately 15% and increases
HDL levels by a similar amount; however, the effect on HDL may be less pronounced
with combined hormone replacement therapy (HRT), depending on the androgenicity
of the progestin used.8 The presumed beneficial
effect of HRT on the cardiovascular system may also be mediated by nonlipid
mechanisms. In addition, estrogen has been shown to improve vessel wall function,9 and oral, but not transdermal, estrogen reduces plasminogen
activator inhibitor type 1 (PAI-1) concentrations in nondiabetic postmenopausal
women.10
Although there are numerous studies examining the effect of HRT on the
concentrations of lipoproteins in nondiabetic postmenopausal women, there
have been few studies on their diabetic counterparts. The studies to date
have been of short duration and have used estrogen-only treatment regimens.11-12 The aim of this study was to examine
the effect of a 6-month combined, continuous regimen of HRT on lipoprotein
variables and markers of fibrinolysis and glycemic control in postmenopausal
women with type 2 diabetes.
PATIENTS AND METHODS
Female patients with a diagnosis of type 2 diabetes mellitus presenting
to the diabetes clinic of the Department of Medicine, Dunedin Hospital, Dunedin,
New Zealand, were eligible for entry into the study if they were postmenopausal
(defined as absence of menstrual periods for >2 years) and had no contraindication
to HRT (a history of estrogen-dependent cancer, undiagnosed vaginal bleeding,
uncontrolled hypertension, or severe liver dysfunction). Subjects were excluded
if they had poorly controlled diabetes (glycosylated hemoglobin [HbA1c] level, >10%), a concomitant significant medical disorder, or a myocardial
infarction or unstable angina within the past 3 months, or if they met the
New Zealand criteria for the use of statin therapy at the time of recruitment
(with no previous coronary artery disease, total cholesterol level of >347
mg/dL [>9 mmol/L]; with established coronary artery disease, total cholesterol
level of >270 mg/dL [>7 mmol/L]).
One investigator (P.J.M.) obtained a detailed medical history and performed
an examination of each subject. Weight was measured using electronic scales
with the subject in light clothing. Blood pressure was measured in the right
arm in the seated position. Blood samples were drawn after an overnight fast
on 2 successive days for measurement of concentrations of total cholesterol,
HDL cholesterol (including subfraction analysis), LDL cholesterol, total triglycerides,
lipoprotein(a) (Lp[a]), and apolipoproteins A-I (apoA-I) and B (apoB). The
mean of the results for the 2 successive days was used as the value for that
time in the study. Blood samples were also drawn for measures of glycemic
control (levels of fasting glucose, HbA1c, and fructosamine) and
concentrations of PAI-1 and fibrinogen.
Subjects who met the criteria for entry into the study entered an 8-week
run-in phase, during which time there was no alteration to their usual diabetes
management. Subjects were requested to continue with the dietary instructions
they had previously received as part of their care from the diabetes service.
At 8 weeks, subjects were randomized in a double-blind fashion to receive
HRT or placebo by means of a random number-generating process, and were allocated
the appropriate treatment by 1 investigator (S.J.) who did not interact with
the subjects at any other time during the study. The HRT preparation consisted
of conjugated equine estrogen, 0.625 mg (Premarin; Wyeth-Ayerst, Philadelphia,
Pa), and medroxyprogesterone acetate, 2.5 mg (Provera; Upjohn, Kalamazoo,
Mich). The estrogen and progestin medications were combined in a single capsule
that was identical in appearance to the placebo capsule. To minimize acute
adverse effects of HRT, study medication therapy was titrated upward for 4
weeks. At the end of this time, subjects were receiving 1 capsule per day
of placebo or HRT.
Subjects were seen every 3 months for measurement of weight and blood
pressure, inquiry of adverse events, blood sampling, and analysis of compliance
by capsule counting. After 6 months, the study medication was withdrawn, and
subjects entered an 8-week washout phase before changing to the other treatment
arm. Subjects were then followed up for an additional 6 months until the completion
of the study. Patients were withdrawn from the study if an adverse reaction
to study medication developed or if they experienced a serious concurrent
illness contraindicating HRT or met the current national criteria for commencing
therapy to lower lipid levels during the study. The study was approved by
our local ethics committee.
Sample size was calculated from the expected baseline lipoprotein concentrations
of the study group and the expected change in LDL cholesterol levels seen
with HRT in nondiabetic postmenopausal women.8
Because we used a crossover design, a sample of 48 subjects had a 90% power
to detect a significant difference at the level of P
= .05. To allow for a 20% dropout rate, we increased the sample size to 60.
LABORATORY ASSAYS
Venous blood was collected into EDTA-treated or plain tubes. Plasma
and serum were immediately separated by means of low-speed centrifugation
at 4°C. Plasma VLDL was separated by ultracentrifuging EDTA-treated plasma
according to the protocol of the Lipid Research Clinics Program.13
Concentration of HDL cholesterol was measured in the supernatant after precipitating
apoB-containing lipoproteins with dextran sulfate sodium and magnesium chloride.14 Concentration of HDL3 cholesterol was
measured in the supernatant after precipitation of lipoproteins using polyethylene
glycol.15 Cholesterol and triglyceride levels
were measured in plasma fractions by using commercial enzymatic kits (Boehringer
Mannheim, Mannheim, Germany). Plasma LDL cholesterol concentration was calculated
by subtracting HDL cholesterol concentration from the cholesterol concentration
in the density (d) >1.006 g/mL plasma fraction. Serum apoA-I and apoB levels
were measured by means of immunoturbidimetry.16
Plasma Lp(a) level was measured using a 2-site radioimmunoassay kit (Pharmacia,
Uppsala, Sweden).
Fibrinogen level was measured using a derived fibrinogen method using
a commercially available reagent (Thomborel S; Behring Diagnostics, Kanata,
Ontario).17
The PAI-1 antigen assay was performed using a commercially available
kit (Thrombonostika PAI-1; Organon Teknika, Boxtel, the Netherlands). Blood
glucose level was determined using a commercial glucose oxidase method (Boehringer
Mannheim) and HbA1c level was determined using a method based on
the turbidimetric inhibition immunoassay for hemolyzed whole blood (Tinaquant;
Boehringer Mannheim). Fructosamine level was measured according to the method
of Johnson et al.18
STATISTICAL ANALYSIS
The laboratory measurements were logarithm transformed before the data
were analyzed. Geometric means and ranges are presented for each subject at
the time of randomization. The data collected at the end of each treatment
period were used to compare HRT with placebo. They were analyzed as a crossover
trial using methods described by Senn19 with
a factor for period included in the model. The results are presented as ratios
of geometric means with 95% confidence intervals (CIs). There was no evidence
of a carryover effect.
RESULTS
Of the 70 patients undergoing screening for the study, 61 (87%) met
the entry criteria and agreed to participate; 9 (13%) had preexisting cardiovascular
disease. Subjects were randomized to active treatment (n = 29) or placebo
(n = 32) for the first 6 months of the study. Nine subjects withdrew while
receiving HRT (intolerant to HRT [n = 4], cardiovascular event [n = 1], personal
reasons [n = 2], and commenced therapy to lower lipid levels [n = 2]), and
2 withdrew while receiving placebo (cancer of the bowel [n = 1] and cerebrovascular
event [n = 1]). Two subjects were withdrawn during the 8-week washout phase
(cardiovascular event [n = 1] and peripheral vascular event [n = 1]), both
of whom had received placebo during the first 6-month treatment phase. Forty-eight
subjects completed the entire study. All subjects who continued in the study
were compliant with study medication (defined as a tablet count of >80%).
The medians and interquartile ranges for baseline data for the study
sample are presented in Table 1.
The baseline characteristics of those who did not complete the study were
compared with those of subjects who did using the Student t test. No statistically significant differences were found.
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Table 1. Characteristics of Study Subjects at Baseline*
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LIPOPROTEIN LEVELS
After 6 months, a significant decrease in total cholesterol level was
found during treatment with HRT compared with placebo (Table 2). This reduction in total cholesterol level (ratio of geometric
means, 7%) was due to a significant reduction in LDL cholesterol concentrations
(12%) with HRT treatment (Figure 1). In keeping with the reduction in LDL cholesterol level, apoB concentrations
decreased with HRT treatment. Serum apoA-I concentrations increased significantly,
and there was a nonsignificant trend toward an increase in levels of HDL cholesterol
and HDL subfractions during treatment with HRT. Total triglyceride, VLDL triglyceride,
and total VLDL levels did not change significantly during HRT treatment compared
with placebo. Lipoprotein(a) concentrations decreased significantly during
treatment with HRT.
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Table 2. Results at End of Each Treatment Phase*
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Ratio of geometric means and 95% confidence intervals (CIs). LDL
indicates low-density lipoprotein; HDL, high-density lipoprotein; Lp(a), lipoprotein(a);
apoA-I, apolipoprotein A-I; apoB, apolipoprotein B; PAI-1, plasminogen activator
inhibitor type 1; and HbA1c, glycosylated hemoglobin.
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FIBRINOGEN AND PAI-1
Significant reductions were noted in plasma fibrinogen levels with HRT
treatment. Although a trend toward a reduction in plasma PAI-1 concentrations
was noted, this was not significant.
OTHER MEASURES
Fasting plasma glucose and HbA1c levels were not significantly
different between treatment periods; however, fructosamine concentrations
were lower during treatment with HRT. There were no significant changes in
weight or body mass index (calculated as the weight in kilograms divided by
square of height in meters) throughout the study. With HRT, there was a nonsignificant
reduction of 2.84 mm Hg in systolic blood pressure (95% CI, -3.60 to
9.28 mm Hg) and an increase in diastolic blood pressure of 0.74 mm Hg (95%
CI, -3.50 to 2.02 mm Hg). Of the 62 women, 20 had undergone hysterectomies.
The effect of treatment was not significantly different for those with and
without hysterectomies for all the variables in Table 2.
COMMENT
To our knowledge, this is the first study to describe the effect of
combined continuous HRT on lipid and hemostatic risk factors for cardiovascular
disease in postmenopausal women with type 2 diabetes mellitus. In addition,
to our knowledge, it is the only trial that reports the effect of HRT for
a duration of greater than 3 months on cardiovascular risk factors and glycemic
control. Our study shows that the daily administration of 0.625 mg of conjugated
estrogens in combination with 2.5 mg of medroxyprogesterone acetate reduces
levels of total and LDL cholesterol, Lp(a), fibrinogen, and fructosamine and
increases plasma apoA-I levels in postmenopausal diabetic women.
Estrogen has been shown to directly increase hepatic LDL uptake via
up-regulation of LDL receptors.20 The 12% reduction
in LDL cholesterol levels in the present study is comparable to that seen
in other studies in women with diabetes using estrogen-only regimens, indicating
that medroxyprogesterone does not attenuate the ability of estrogen to lower
LDL levels in postmenopausal diabetic women.11-12
This degree of reduction in LDL cholesterol level is also similar to that
seen in nondiabetic women using the same preparation of HRT.8
The reduction in concentration of apoB, a structural protein for LDL, simply
reflects the reduction in circulating LDL concentration with HRT.
Unlike studies using estrogen-only regimens, our study did not show
an increase in levels of HDL cholesterol or its subfractions, although an
increasing trend was evident. This finding probably reflects the addition
of medroxyprogesterone to the estrogen therapy. In the Postmenopausal Estrogen/Progestin
Interventions Trial, in which HRT was given to nondiabetic women, the addition
of medroxyprogesterone diminished the increase in HDL levels seen with estrogen.8 Progestins increase the activity of hepatic lipases,
increasing the metabolism of HDL cholesterol, and the extent of this effect
is related to the androgenic properties of the progestin used.20
Cross-sectional studies in nondiabetic women, however, have shown no effect
from the addition of a progestin on HDL concentrations.21
The present study was primarily powered to detect a change in LDL cholesterol
levels in diabetic women using HRT, and the lack of an increase in HDL levels
may simply reflect an inadequate sample size. The increase in apoA-I levels
seen in our study supports the belief that HRT has a favorable effect on HDL
concentrations. Apolipoprotein A-I is located on the surface of HDL and plays
a central role in the transfer of free cholesterol from tissues and other
lipoproteins.20 Apolipoprotein A-I also appears
to protect lipoproteins from potentially atherogenic oxidative damage.
In nondiabetic women, oral HRT increases plasma triglyceride levels
primarily by increasing the production of large VLDL. In diabetic women, however,
combined HRT in the present study and estrogen-only therapy in 2 previous
studies11-12 did not alter plasma
triglyceride concentrations. The mechanism for this lack of effect on triglyceride
levels is unclear; however, it may be related to an improvement in insulin
sensitivity. This would lead to a reduction in the flux of VLDL to the liver,
which is the predominant cause of raised triglyceride levels in diabetic patients.
In a cross-sectional study of 694 women with diabetes, of whom 10% were current
users of HRT, a trend toward increasing triglyceride concentrations in those
women currently receiving estrogen was noted, although this effect was less
marked in those using combined estrogen and progestin therapy.22
However, there have been case reports of significant hypertriglyceridemia
developing in diabetic patients when HRT was commenced.23
It is therefore reassuring that no significant alteration in plasma triglyceride
levels was noted in the present study.
Hemostatic factors have an important role in determining cardiovascular
risk. Our results show that combined HRT reduces fibrinogen and Lp(a) concentrations
in postmenopausal diabetic women. Fibrinogen, PAI-1, and Lp(a) concentrations
have all been shown to be independent risk factors for cardiovascular disease.
Plasminogen activator inhibitor type 1 and Lp(a) exert this effect by interfering
with the process of fibrinolysis. Lipoprotein(a) also binds to macrophages
in the vessel wall, promoting the formation of foam cells. The level of Lp(a)
is increased in patients with type 2 diabetes, adding to their increased cardiovascular
risk. Hormone replacement therapy decreases Lp(a) levels by 17% to 23% in
nondiabetic women, and this effect is not altered by the addition of a progestin.8 Our study demonstrated a 21% lowering of Lp(a) levels
when women were receiving HRT. To our knowledge, this is the first report
of this effect of HRT on Lp(a) levels in women with type 2 diabetes. Our study
revealed a nonsignificant trend in reduction of PAI-1 levels. These levels
have been shown to be significantly reduced by estrogen-only or combined HRT
in nondiabetic women10 and with estrogen-only
HRT in women with diabetes.12 The addition
of a progestin may account for the failure to show a significant reduction
in PAI-1 levels in our study. The fibrinogen levels increase after menopause,
perhaps due to the effects of age, and decline with estrogen use in nondiabetic
women. Our results indicate that the same holds true for women with diabetes.
This effect in women with diabetes has not previously been described. The
changes in hemostatic factor concentrations measured in our study would appear
to be favorable and therefore would not explain an increase in cardiovascular
events described during the first year of combined HRT in the Heart and Estrogen/Progestin
Replacement Study (HERS) trial.
Our study showed a significant reduction in fructosamine levels and
a trend to a reduction in fasting glucose and HbA1c levels in those
women receiving HRT. These results suggest that HRT may have a beneficial
effect on glycemic control in postmenopausal women with type 2 diabetes. Improvements
in glucose homeostasis have been documented in women receiving short-term
estrogen-only HRT.11-12 Presumably,
this effect is mediated by an increase in insulin sensitivity, which has been
documented by euglycemic clamp methods.11
Of our original 61 subjects, 13 (21%) did not complete the study. Most
of these (n = 9) dropped out while receiving HRT, and the reasons were primarily
due to intolerance to medication, which was due to either breast tenderness
or nausea. This dropout rate is similar to that noted in other trials using
HRT for a prolonged period and was allowed for when estimating sample size
before recruitment. This trial was completed before the publication of the
HERS trial7 and was not powered to determine
the effect on cardiovascular events; however, no excess in cardiovascular
events was noted during the HRT phase. Although the analysis of this study
was not intention to treat, the baseline characteristics of those who dropped
out did not differ from those of the group as a whole. Compliance, as measured
by tablet counting, was greater than 80% in those subjects continuing in the
study, and blinding was not broken on any subject throughout the study.
CONCLUSIONS
Patients with diabetes are at high risk for cardiovascular disease.
There is compelling evidence that HRT exerts a beneficial effect on a number
of cardiovascular risk factors in nondiabetic women, and this study shows
that these beneficial changes also are observed in women with diabetes. However,
given the results of the HERS trial,7 there
is insufficient evidence at present to suggest that HRT should be used for
the prevention of coronary heart disease. This study demonstrates the need
for trials of HRT in diabetic women for primary prevention of coronary heart
disease using cardiovascular events as the end point.
AUTHOR INFORMATION
Accepted for publication January 18, 2001.
This study was supported by grants 96/331 (Dr Manning) and 99/500 (Ms
Williams) from the Health Research Council of New Zealand, Auckland.
The authors are very grateful to the patients who participated in this
study. We also thank J. I. Mann, DSc, for helpful comments in the preparation
of this manuscript.
Corresponding author and reprints: Patrick J. Manning, MBChB, MMedSc,
FRACP, Department of Medicine, Dunedin Hospital, 201 Great King St, Dunedin,
New Zealand (e-mail: PatrickManning{at}clear.net.nz).
From the Departments of Medicine (Drs Manning and Sutherland and Mss
Allum and Jones) and Preventive and Social Medicine (Ms Williams), School
of Medicine, University of Otago, Dunedin, New Zealand.
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