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PharmD Student, College of Pharmacy, University of Southern Nevada, Henderson, NV
Director of Continuing Education; Associate Professor of Pharmacy Practice, College of Pharmacy, University of Southern Nevada
Reprints: Dr. Smith, College of Pharmacy, University of Southern Nevada, 11 Sunset Way, Henderson, NV 89014, fax 702/990-4435, ksmith{at}usn.edu
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DATA SOURCES: Relevant publications were identified through a systematic search of PubMed English-language literature (1950–February 2008) using the MeSH terms and key words acarbose and polycystic ovary syndrome.
STUDY SELECTION AND DATA EXTRACTION: The literature search retrieved 6 primary literature citations. Three randomized controlled clinical trials and one open-label study were evaluated. The other 2 citations were not evaluated due to only a peripheral mention of PCOS in relation to diabetes.
DATA SYNTHESIS: PCOS is a complex disorder presenting most commonly with oligomenorrhea or amenorrhea, infertility, hirsutism, acne, and obesity. Acarbose is a promising therapy for PCOS because of its effects on postprandial insulin levels. In multiple clinical studies, acarbose improved hirsutism, acne, and menstrual irregularities through reduction in androgen concentrations and through increased androgen binding. When compared with metformin in women with PCOS and clomiphene-resistant infertility, acarbose induced greater weight loss and improved menstrual regularity and signs of fertility to a similar degree. Markers of cardiovascular risk were also significantly improved following 6 months of acarbose therapy in obese women with PCOS. Adverse effects, specifically gastrointestinal, were documented. Despite promising results, the studies were limited by small sample sizes and, in some cases, methods that were not clearly defined.
CONCLUSIONS: Several trials have evaluated the use of acarbose in the management of PCOS with positive clinical evidence, but the results of these trials have not been corroborated by more rigorous studies.
Key Words: acarbose, polycystic ovary syndrome
Published Online, May 6, 2008. www.theannals.com, DOI 10.1345/aph.1K639
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The pathophysiology of insulin resistance in PCOS is not clearly understood.2,3 Insulin resistance, seen as impaired insulin-mediated glucose uptake, is frequently seen in PCOS.4 Glucose levels are often normal due to increased compensatory insulin secretion. However, hyperinsulinemia may increase androgen synthesis and/or decrease androgen catabolism. Insulin also enhances gonadotropin-releasing hormone action and inhibits hepatic synthesis of sex hormone binding globulin (SHBG). These factors contribute to irregular menstrual cycles, caused by altered luteinizing hormone (LH) patterns, decreased follicle-stimulating hormone (FSH) concentrations, and increased levels of unbound circulating testosterone. The result is seen in the clinical manifestations of PCOS. Antidiabetic agents, along with various individualized treatment strategies for infertility, menstrual irregularity, acne, and/or hirsutism, are important options in the management of PCOS.3
Acarbose is an oral tablet used in the management of type 2
diabetes.5,6
Acarbose reduces the postprandial rise in both serum glucose and insulin
levels by inhibiting 
-glucosidase, an enzyme responsible for the
intestinal absorption of carbohydrates. Dose-related adverse effects,
including flatulence, diarrhea, and abdominal distention, may be minimized by
titration. Unlike other antidiabetic drugs, acarbose does not cause
hypoglycemia because it does not stimulate insulin release. Acarbose exhibits
a low systemic absorption profile.
LITERATURE REVIEW
Studies were identified through a systematic search of PubMed
English-language literature (1950–February 2008) using the text words
and MeSH terms acarbose and PCOS. Six studies were identified; 3 randomized
controlled clinical trials and 1 open-label study were included in our review.
Table 1 provides a summary of
the major findings of those
studies.4,7-9
The remaining articles were not evaluated as they pertained to acarbose use in
patients with diabetes.
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A prospective, randomized, double-blind, placebo-controlled study evaluated
the usefulness of acarbose in patients with PCOS and
hyperinsulinemia.4
Effects of acarbose on clinical manifestations of hyperandrogenism, serum
hormone concentrations, and insulin response to an oral glucose tolerance test
were the main outcome measures. The study included 30 normal-weight patients
with PCOS and 15 women of normal weight who served as controls. The subjects
with PCOS were randomized to receive either acarbose 100 mg or placebo before
meals 3 times daily for 3 months. The patients in the PCOS group met typical
diagnostic criteria for PCOS and exhibited normal glucose tolerance but an
elevated insulin response to an oral glucose tolerance test. LH, FSH,
testosterone, androstenedione, dehydroepiandrosterone-sulfate (DHEA-S),
prolactin (PRL), 17-hydroxyprogesterone (17 -OHP), and SHBG were
measured at baseline during the follicular phase.
Patients treated with acarbose had a significant decrease in acne scores from pretreatment values (p < 0.05); no significant change was noted in the placebo group. Although the hirsutism scores did not change significantly, 6 (40%) women in the acarbose group experienced slightly diminished hair growth after the 3-month treatment period; no change was noted in the placebo group. Nine (60%) patients treated with acarbose versus none who received placebo experienced a return to regular menstrual cycles; however, specific criteria were not defined. Reports of gastrointestinal disturbances were noted in all participants who received acarbose, but in only 5 who received placebo.4
In addition to significant changes in clinical parameters, participants treated with acarbose had significant decreases in LH, testosterone, and androstenedione concentrations and an increase in SHBG concentrations versus pretreatment values (p < 0.05). Hormone and SHBG concentrations did not significantly change compared with pretreatment values in subjects receiving placebo. Although blood glucose concentrations after an oral glucose tolerance test did not change, women receiving acarbose did present with a significant decline in insulin response to an oral glucose tolerance test from pretreatment values (p < 0.05), which was not observed in the placebo group.4
This study demonstrated that acarbose produces positive clinical effects in hyperinsulinemic patients with PCOS. Unfortunately, the enrollment criteria excluded an important segment of the PCOS population—obese patients. In addition, neither infertility nor medication adherence was assessed.4
Metformin improves ovulation rates in women with clomiphene citrate–resistant PCOS, but acarbose was not studied in this capacity prior to a trial conducted by Sönmez et al.7 This prospective, randomized, open-label, comparison study evaluated the effects of metformin and acarbose on insulin resistance, hormone concentrations, and ovulation rates in patients with clomiphene-resistant PCOS.
Participants met the majority of diagnostic criteria for PCOS, but not all had every major manifestation. Resistance to clomiphene citrate was defined as failure to ovulate with a clomiphene citrate dose of 150 mg/day. Serum concentrations of insulin, glucose, LH, FSH, thyroid-stimulating hormone (TSH), thyroxine, estradiol, progesterone, PRL, and testosterone were measured during the follicular phase after an overnight fast. Evaluation of endometrial thickness, the uterus, the ovaries, and the number and diameter of the follicles was performed using transvaginal ultrasound. A mid-luteal serum progesterone concentration greater than 8 ng/mL was accepted as a sign of ovulation. The 30 patients in this study were randomized into 2 groups of 15, based on a power analysis. Women in group I were treated with acarbose 100 mg 3 times a day for 3 months, while women in group II received metformin 850 mg 2 times a day for 3 months. Both groups were also given clomiphene citrate 50 mg 2 times a day. Outcomes included weight changes, body mass index (BMI), regularity of menstrual cycles, follicular growth, and hormone concentrations.7
Participants in the acarbose group, but none in the metformin group, experienced statistically significant weight loss from the pretreatment values (p < 0.01). Nine of 13 (69.2%) women in the acarbose treatment group experienced a return to normal menstrual cycles at the conclusion of the study (p < 0.01). In the metformin group, 80% achieved normal menstrual rhythms (5 already had normal menstrual cycles prior to the onset of the study) (p < 0.01). At the conclusion of the study, the groups were similar in the number of women returning to normal menstrual rhythms (p > 0.05). Gastrointestinal adverse effects were similar between the acarbose group (n = 9 reports), and metformin group (7).7
Patients in both groups had significantly reduced LH, LH:FSH ratio, and testosterone and fasting insulin concentrations, and significantly increased FSH concentrations versus pretreatment values (p < 0.05), but no between-group differences were noted. Both groups experienced a significant increase in ovulation and monthly mid-luteal serum progesterone levels during the 3-month treatment period compared with pretreatment scores (p < 0.05). Ovulation rates and progesterone levels were similar between the acarbose and metformin groups during the first and third months of the trial (p > 0.05) but were higher in the metformin group in the second month of treatment (p < 0.05).7
Acarbose may be an alternative to metformin for women with PCOS and clomiphene citrate resistance. The trial was not conducted in a double-blind fashion and adherence was not assessed. The investigators reported a statistically significant decrease in weight,7 unlike the previous study4; however, the clinical significance is questionable.7 This was probably a result of the higher BMI (>25 kg/m2) in women in this study. A reduction in body weight may be especially important to the outcomes of this study, as a healthy weight may improve fertility. The researchers offered no hypothesis as to why the acarbose group did not experience a statistically significant increase in ovulation rates and progesterone levels during the second month of the trial versus pretrial values.
Obesity and insulin resistance have a synergistic relationship, thereby
perpetuating further hyperandrogenism in women with PCOS. Penna et
al.8
conducted a prospective, randomized, double-blind, placebo-controlled study
involving 30 obese women with PCOS and insulin resistance. The study sought to
determine the endocrine, metabolic, and clinical effects of low-dose acarbose
in women with PCOS and an increased BMI. Inclusion criteria were similar to
those of the previously described studies but included women with a BMI of
30–40 kg/m2. The following laboratory values were
measured at enrollment and at the conclusion of the study: LH, FSH, PRL,
testosterone, androstenedione, DHEA-S, 17 -OHP, SHBG, urinary cortisol,
unbound thyroxin, TSH, urea, creatinine, aspartate aminotransferase, and
alanine aminotransferase. An oral glucose tolerance test was also performed.
Patients were randomized into 2 groups of 15 each. For 6 months, one group was
administered acarbose 50 mg and the other received matched placebo 3 times a
day.
The acarbose group had a decreased BMI, experienced better menstrual patterns, and had higher SHBG concentrations and lower unbound androgen indexes compared with pretreatment values. The placebo group did not show a significant difference in any of these parameters versus pretreatment values. No patient in the acarbose group experienced significant intolerance to the gastrointestinal adverse effects often seen with that drug.8
This study noted several positive findings when a low dose of acarbose was administered to obese women with PCOS, including an improvement in gastrointestinal adverse effects over time; however, there was no mention of potential dose titration. Patients in this study experienced a significant but slight decrease in BMI,8 which, as with the Sönmez et al.7 study, was probably due to higher pre-enrollment BMI values.8 A slight, but not statistically significant, worsening of insulin resistance was noted in patients receiving acarbose, which the authors thought was due to higher BMI values; however, insulin resistance did not change in the placebo group.
Women with PCOS have an increased cardiovascular risk due to insulin resistance, high androgen levels, and the syndrome's association with increased BMI. A follow-up analysis of the study by Penna et al.8 sought to determine the effects of acarbose use on several markers of cardiovascular risk in 30 obese patients with PCOS.9 This prospective, randomized, double-blind, placebo-controlled study evaluated various indicators of cardiovascular risk: lipid profiles, arterial pressures, and adhesion molecules, specifically P-selectin, which is thought to contribute to atherogenesis. Inclusion criteria for this study were similar to those of the previous study, including BMI values of 30–40 kg/m2. The following laboratory analyses were measured at baseline and at the end of the study: total cholesterol, very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and P-selectin. In addition, an oral glucose tolerance test was conducted. The 30 patients were randomized into 2 groups of 15 and were assigned to take either acarbose 50 mg or placebo 3 times daily for 6 months.
At the end of the study, the acarbose group had a statistically significant decrease in P-selectin concentrations, blood pressure, BMI, VLDL-C, and triglycerides, as well as a statistically significant increase in HDL-C. These parameters did not change notably in the placebo group. The following limitations of this trial were noted. The investigators did not define the diagnostic criteria for PCOS as clearly as was done in the previous studies. There were significant baseline differences between the acarbose and placebo groups in pretreatment VLDL-C and triglyceride concentrations, which make it unclear whether the results were completely due to acarbose therapy. Lastly, no mention was made of efforts to titrate the acarbose dosage above 150 mg daily.9
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The importance of maintaining good glycemic control and normal insulin levels in women with PCOS makes acarbose a drug worthy of further investigation in large-scale, randomized, double-blind, placebo-controlled studies. Until such trials are conducted, it is too early to determine whether acarbose should be a routinely recommended treatment strategy for PCOS, either by itself or in combination with other medications.
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References |
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-glucosidase
inhibitor, in PCOS patients with increased insulin response and normal glucose
tolerance. Hum Reprod2001;16:2066-72.
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