- Email: [email protected]
Cardiovascular risk factors are reduced with a low dose of acarbose in obese patients with polycystic ovary syndrome
Cardiovascular risk factors are reduced with a low dose of acarbose in obese patients with polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is defined by menstrual irregularity, hyperandrogenism, chronic anovulation, and enlarged ovaries with multiple follicles. Polycystic ovary syndrome is highly prevalent in women, affecting up to 10% of all women of reproductive age and reducing the possibility of spontaneous conception. In addition to altering reproductive function, PCOS has systemic implications, especially in the cardiovascular system. Cardiovascular risk (CVR) in PCOS patient increases because of insulin resistance, elevated androgen levels, and association with obesity. Those alterations promote cardiovascular risk factors, such as endothelial dysfunction, elevated homocysteine levels, left ventricular hypertrophy, and reduced high-density lipoprotein (HDL) cholesterol (1). (Fertil Steril威 2007;88:519 –22. ©2007 by American Society for Reproductive Medicine.)
Selectin is a family of cell adhesion molecules with leukocytechemotactic properties which contribute to atherogenesis. P-Selectin is part of this family and is expressed in the endothelium overlying atherosclerotic plaques, leading to endothelial dysfunction and increased CVR (2). In recent years, many drugs that improve insulin sensitivity have been used to treat PCOS patients. Metformin has been extensively studied but has some adverse effects which limit its use; therefore, studies on other agents that act on insulin sensitivity are necessary. Acarbose is an ␣-glucosidase inhibitor which acts by reducing and slowing down the intestinal absorption of glucose, with a reduction of the postprandial wave and a consequent reduction of insulin secretion (3). Acarbose administered to obese patients with PCOS promotes a decrease in free androgen index and body mass index (BMI) and an increase in SHBG, with improvement of hirsutism and menstrual pattern (4). The objective of the present study was to assess markers of CVR, such as lipid profile, arterial pressure, and adhesion molecules, after use of acarbose in obese patients with PCOS.
congenital adrenal hyperplasia, diabetes, and the use of hormonal medications or medications that might interfere with carbohydrate metabolism over the preceding 6 months. The project was approved by the Research Ethics Committee of the Gynecology Institute of the Federal University of Rio de Janeiro, and all patients signed an informed consent form. The patients were assigned by computer randomization (StatMate; GraphPad, San Diego, CA) into two groups of 15 patients each, taking either 50 mg acarbose or 50 mg placebo 3 times a day for 6 months. The patients underwent clinical (number of menstrual cycles, Ferriman–Gallwey hirsutism index) and anthropometric (weight, height, BMI, and blood pressure) evaluation before and after treatment.
A prospective randomized double-blind study was conducted on 30 obese patients with PCOS and insulin resistance who were treated with 150 mg/day acarbose or placebo for 6 months. The inclusion criteria were: menstrual disorders (less than 6 menstruations in 12 months), clinical or laboratory hyperandrogenism, BMI 30 – 40 kg/m2, and insulin resistance. The exclusion criteria were alterations of hepatic, thyroid and renal function, hyperprolactinemia,
We analyzed the following laboratory tests before and after treatment: total cholesterol, very low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (Roche Unimat 5 kit; Roche Diagnostics, Basel, Switzerland) and P-selectin (Duo-set ELISA, R&D Systems, MN). A glucose tolerance test (GTT) was performed 3 days after a diet containing 300 mg carbohydrates, with ingestion of glucose (75 g Dextrosol; Vita, Rio de Janeiro, Brazil) and venipuncture at 0, 30, 60, 90, and 120 minutes and analysis of the areas under the insulin and glucose curves. Glycemia was determined by the enzymatic colorimetric glucose oxidase test (MerckBiotrol, São Paulo, Brazil). Insulinemia was determined by RIA (Coat-a-Count; DPC, Los Angeles, CA).
Received September 8, 2006; revised November 16, 2006; accepted November 20, 2006. Reprint requests: Rui Alberto Ferriani, M.D., Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeirão Preto—USP, Av. Bandeirantes, n°3900- 8° andar, Ribeirão Preto—SP, Brasil, CEP 14049-900 (FAX: (16) 3633-1028; E-mail: [email protected]).
Using Bayesian methodology, we adjusted the pretreatment value of VLDL cholesterol and triglycerides for the equation. To determine simultaneously the within- and between-group variations, considering the borderline size of the sample and high variability of the data, we used Bayesian methodology with noninformative prioris and the
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.073
Fertility and Sterility姞 Vol. 88, No. 2, August 2007 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
519
Winburg software, version 1.3 (MRC Biostatistics Unit, Cambridge, UK, for statistical analysis). Among the 30 patients selected, we excluded two from the acarbose group (one abandon and one pregnancy) and one from the placebo group (abandon), with no cases of treatment intolerance. Four patients in the placebo groups and eleven in the acarbose group presented mild abdominal distention and flatulence, and all reported a reduction in side effects after the first 3 months. Before treatment, excluding VLDL cholesterol and triglycerides, the groups did not show any differences regarding any of the clinical or laboratory parameters. Compared with pretreatment values, the acarbose group presented a reduction in P-selectin levels, diastolic and systolic blood pressure, BMI, VLDL cholesterol, and tryglyceride levels and an increase in HDL cholesterol, whereas the placebo group did not show any difference between the pre-treatment and post-treatment values for any parameter analyzed. No changes occurred in the area under the insulin and glucose curves after the GTT (Table 1). We recorded a significant reduction of P-selectin in obese hyperinsulinemic PCOS patients with a low dose of acarbose treatment for 6 months. There are no data in the literature about the concentration of P-selectin in PCOS patients, nor are there any studies about the reduction of P-selectin in PCOS patients with any type of treatment.
P-Selectin is an adhesion molecule associated with endothelial dysfunction. Ridker et al. (2) reported a high correlation between P-selectin and coronary events. Acarbose is an ␣-glucosidase inhibitor that forms a reversible and dosedependent bond with the oligosaccharide site of ␣-glucosidase in the small intestine, thereby reducing the postprandial peak of glycemia by 20% and preventing glucidic toxicity (5). The reduced glucose absorption leads indirectly to an increase in glucagon-like peptide 1, which acts on the satiety center of the brain, reducing appetite and facilitating weight reduction (6). The lowest dose of acarbose with clinical effects is 150 mg/day; doses greater than 300 mg/day exceed the saturation of the ␣-glucosidase receptor and do not increase drug effectiveness (7, 8). Dosage is an important aspect of treatment, because side effects, such as flatulence, meteorism, and abdominal distention, are dose-dependent. Although there are no data relating PCOS and P-selectin, there are some studies about the use of acarbose and endothelial function. An experimental study by Schäfer et al. (9) showed reductions in P-selectin concentration and endothelial dysfunction with the use of acarbose in Zucker rats with impaired glucose tolerance. Delorme and Chiasson (10) provide a meta-analysis of seven major studies on the use of acarbose in the treatment of diabetes. Those studies showed that acarbose treatment was associated with
TABLE 1 Clinical and metabolic characteristics of the patients with polycystic ovarian syndrome before and after treatment with acarbose for 6 months. Placebo
Age (yrs) BMI (kg/m2) Total cholesterol (mg/dL) VLDL cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) P-Selectin (ng/mL) Area under the glucose curve after the GTT (mg/dL) Area under the insulin glucose curve after the GTT (IU/mL)
Acarbose
Before (n ⴝ 15)
After (n ⴝ 14)
Before (n ⴝ 15)
After (n ⴝ 13)
25.93 ⫾ 1.83 35.04 ⫾ 2.84 186.86 ⫾ 33.96 21.07 ⫾ 8.23 133.43 ⫾ 33.37 38.07 ⫾ 7.78 108.00 ⫾ 41.60 126 ⫾ 9.3 84.3 ⫾ 11.1 97.6 ⫾ 8.8 16,057 ⫾ 3,472
34.77 ⫾ 3.33 185.80 ⫾ 39.20 22.86 ⫾ 8.14 127.93 ⫾ 34.95 36.71 ⫾ 7.21 116.00 ⫾ 40.70 127 ⫾ 8.0 85.5 ⫾ 9.3 99.4 ⫾ 8.4 15,377 ⫾ 3,045
26.69 ⫾ 1.46 35.87 ⫾ 2.60 198.80 ⫾ 53.40 31.31 ⫾ 15.56 133.70 ⫾ 48.00 35.15 ⫾ 6.69 155.10 ⫾ 81.70 121 ⫾ 11.4 86.2 ⫾ 8.0 99.3 ⫾ 10.0 15,173 ⫾ 3,804
33.10 ⫾ 2.94* 200.50 ⫾ 48.70 26.85 ⫾ 16.55* 135.00 ⫾ 40.70 38.00 ⫾ 8.49* 136.20 ⫾ 83.40* 113 ⫾ 8.5* 78.2 ⫾ 11.1* 91.3 ⫾ 9.6* 15,194 ⫾ 3,116
16,909 ⫾ 8,167
15,692 ⫾ 5,252
17,090 ⫾ 6,469
13,845 ⫾ 5,976
Note: Variables are given as mean ⫾ SD. BMI ⫽ body mass index; GTT ⫽ glucose tolerance test; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein; VLDL ⫽ very low-density lipoprotein. * P⬍.05, before and after treatment in acarbose group. Penna. Cardiovascular risk with polycystic ovary syndrome. Fertil Steril 2007.
520
Penna et al.
Correspondence
Vol. 88, No. 2, August 2007
a 35% reduction in CVR, the mechanism for which was related to decreased oxidative stress induced by postprandial glycemic peak. Increased plasma osmolarity during the glucose peak may be associated with endothelial disfunction (11), and a 49% reduction in CVR and 91% reduction in myocardium infarction has been reported in impaired glucose tolerance and type 2 diabetes patients after using acarbose (12). Additionally, weight loss is probably more important than glycemic control in regulating circulating levels of inflammatory biomarkers such as P-selectin in morbidly obese subjects (13, 14). The reduction in BMI was a determinant of the results of the present study and may explain in part the decrease in P-selectin, because no improvement in insulin resistance or in the area under the insulin curve was observed. However, the present study is the only one conducted exclusively on obese patients, and the results agree with those reported on the effects of metformin on very obese women, suggesting a synergism of physiopathologic conditions (i.e., obesity and insulin resistance) (15). The relationship between blood pressure and cardiovascular events is well known. Hypertension is one of the most common causes of stroke and myocardium infarction. We recorded in the present study a significant reduction in both diastolic and systolic pressure with a low dose of acarbose. Obesity is a cause of hypertension. However, although only a few patients in the present study had hypertension, the majority were obese with normal blood pressure. The reduction of blood pressure with a low dose of acarbose may be related to reduced BMI. Zeymer (12) reported a 34% reduction in hypertension in impaired glucose intolerance and type 2 diabetes patients with acarbose. The present study showed a reduction in triglycerides and VLDL cholesterol levels in the acarbose group. There is a well known relationship between bad lipid profile and cardiovascular disease. Triglyceride levels were higher in obese PCOS patients than in normal-weight women without PCOS. There are two possible causes for this phenomenon: insulin resistance and glucose toxicity (16). The present data demonstrated a decrease in triglycerides with a low dose of acarbose, and these results are similar to what other studies of diabetes mellitus patients have reported (17). The reduction in triglycerides with the use of acarbose is related to the decreased glucose peak and glucose toxicity, with a consequent reduction of hepatic lipogenesis (3). Two other changes in the lipid profile were reported in the present study—VLDL cholesterol and HDL cholesterol— but neither was clinically significant after treatment. The increase of HDL cholesterol was not clinically significant, and this result is similar to that in existing literature about use of acarbose in diabetes mellitus patients. Fertility and Sterility姞
Finally, the present study suggests that the effects of acarbose in obese patients with PCOS could be useful not only for the treatment of clinical hormonal alterations associated with the syndrome but also as an important tool in the prevention of cardiovascular disease in these patients. Acknowledgments: The authors thank Edson Z Martinez, Ph.D., Marcia S Baggio, and Maria Albina Verceze Bortolieiro for their technical assistance.
Ivan Araujo Penna, M.D.a,b Paulo Roberto Bastos Canella, M.D.b Carolina Sales Vieira, M.D.a Marcos Felipe Silva de Sá, M.D.a Rosana Maria dos Reis, M.D.a Rui Alberto Ferriani, M.D.a a Department of Obstetrics and Gynecology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; and b Gynecology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil REFERENCES 1. Orio F, Palomba S, Spinelli L, Cascella T, Tauchmanova L, Zullo F, et al. The cardiovascular risk of young women with polycystic ovary syndrome. An observational, analytical, prospect case-control study. J Clin End Metab 2004;3696 –701. 2. Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001;103:491–5. 3. Laube H. Acarbose. Clin Drug Invest 2002;22:141–56. 4. Penna IA, Canella PR, Reis RM, Silva de Sa MF, Ferriani RA. Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study. Hum Reprod 2005;20:2396 – 401. 5. Hanefeld M, Fischer S and Schulze J. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732–7. 6. Gutzwiller JP. Glucagon like peptide-1 is a physiologic regulator of food intake in humans. Gastroenterology 1997;112:a1153. 7. Rodier M, Richard JL, Monnier L and Mirauze J. Effect of long term acarbose (Bay g 5421) therapy on metabolic control on noninsulindependent (type II) diabetes mellitus. Diabet Med 1988;14:12– 4. 8. Santeusanio F, Ventura MM, Contadinbi S. Efficacy and safety of two different dosages of acarbose in noninsulin dependent diabetic patients treated by diet alone. Diabet Nutr Metab 1993;6:147–54. 9. Schäfer A, Widder J, Eigenthaler M, Bischoff H, Ertl G, Bauersachs J. Increased platelet activation in young Zucker rats with impaired glucose tolerance is improved by acarbose. Thromb Haemost 2004; 92:97–103. 10. Delorme S, Chiasson JL. Acarbose in the prevention of cardiovascular disease in subjects with impaired glucose tolerance and type 2 diabetes mellitus. Curr Opin Pharmacol 2005;5:184 –9. 11. Keating FK, Sobel BE, Schneider DJ. Effects of increased concentration of glucose on platelet reactivity in healthy subjects and in patients with and without diabetes mellitus. Am J Cardiol 2003;92: 1362–5. 12. Zeymer U. Cardiovascular benefits of acarbose in impaired glucose tolerance and type 2 diabetes. Int J Cardiol 2006;1007:11–20. 13. Pontiroli AE, Pizzocri P, Koprivec D, Vedani P, Marchi M, Arcelloni C, et al. Body weight and glucose metabolism have a different effect on circulating levels of ICAM-1, E-selectin, and endothelin-1 in humans. Eur J Endocrinol 2004;150:195–200.
521
14. Sharman MJ, Volek JS. Weight loss leads to reductions in inflammatory biomarkers after a very-low-carbohydrate diet and a low-fat diet in overweight men. Clin Sci 2004;107:365–9. 15. Maciel GAR, Junior JMS, Motta ELA, Abi Haidas M, de Lima GR, Baracat EC. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril 2004;81:355– 60.
522
Penna et al.
Correspondence
16. Meyer C, McGrath BP, Teede HJ. Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. J Clin Endocrin Metab 2005;90:5711– 6. 17. Rachmani R, Bar-Dyan Y, Ronen Z, Levi Z, Slavachevsky I, Ravid M. The effect of acarbose on insulin resistance in obese hypertensive subjects with normal glucose tolerance: a randomized controlled study. Diabet Obes Metab 2004;6:63– 8.
Vol. 88, No. 2, August 2007
Selectin is a family of cell adhesion molecules with leukocytechemotactic properties which contribute to atherogenesis. P-Selectin is part of this family and is expressed in the endothelium overlying atherosclerotic plaques, leading to endothelial dysfunction and increased CVR (2). In recent years, many drugs that improve insulin sensitivity have been used to treat PCOS patients. Metformin has been extensively studied but has some adverse effects which limit its use; therefore, studies on other agents that act on insulin sensitivity are necessary. Acarbose is an ␣-glucosidase inhibitor which acts by reducing and slowing down the intestinal absorption of glucose, with a reduction of the postprandial wave and a consequent reduction of insulin secretion (3). Acarbose administered to obese patients with PCOS promotes a decrease in free androgen index and body mass index (BMI) and an increase in SHBG, with improvement of hirsutism and menstrual pattern (4). The objective of the present study was to assess markers of CVR, such as lipid profile, arterial pressure, and adhesion molecules, after use of acarbose in obese patients with PCOS.
congenital adrenal hyperplasia, diabetes, and the use of hormonal medications or medications that might interfere with carbohydrate metabolism over the preceding 6 months. The project was approved by the Research Ethics Committee of the Gynecology Institute of the Federal University of Rio de Janeiro, and all patients signed an informed consent form. The patients were assigned by computer randomization (StatMate; GraphPad, San Diego, CA) into two groups of 15 patients each, taking either 50 mg acarbose or 50 mg placebo 3 times a day for 6 months. The patients underwent clinical (number of menstrual cycles, Ferriman–Gallwey hirsutism index) and anthropometric (weight, height, BMI, and blood pressure) evaluation before and after treatment.
A prospective randomized double-blind study was conducted on 30 obese patients with PCOS and insulin resistance who were treated with 150 mg/day acarbose or placebo for 6 months. The inclusion criteria were: menstrual disorders (less than 6 menstruations in 12 months), clinical or laboratory hyperandrogenism, BMI 30 – 40 kg/m2, and insulin resistance. The exclusion criteria were alterations of hepatic, thyroid and renal function, hyperprolactinemia,
We analyzed the following laboratory tests before and after treatment: total cholesterol, very low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (Roche Unimat 5 kit; Roche Diagnostics, Basel, Switzerland) and P-selectin (Duo-set ELISA, R&D Systems, MN). A glucose tolerance test (GTT) was performed 3 days after a diet containing 300 mg carbohydrates, with ingestion of glucose (75 g Dextrosol; Vita, Rio de Janeiro, Brazil) and venipuncture at 0, 30, 60, 90, and 120 minutes and analysis of the areas under the insulin and glucose curves. Glycemia was determined by the enzymatic colorimetric glucose oxidase test (MerckBiotrol, São Paulo, Brazil). Insulinemia was determined by RIA (Coat-a-Count; DPC, Los Angeles, CA).
Received September 8, 2006; revised November 16, 2006; accepted November 20, 2006. Reprint requests: Rui Alberto Ferriani, M.D., Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeirão Preto—USP, Av. Bandeirantes, n°3900- 8° andar, Ribeirão Preto—SP, Brasil, CEP 14049-900 (FAX: (16) 3633-1028; E-mail: [email protected]).
Using Bayesian methodology, we adjusted the pretreatment value of VLDL cholesterol and triglycerides for the equation. To determine simultaneously the within- and between-group variations, considering the borderline size of the sample and high variability of the data, we used Bayesian methodology with noninformative prioris and the
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.073
Fertility and Sterility姞 Vol. 88, No. 2, August 2007 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
519
Winburg software, version 1.3 (MRC Biostatistics Unit, Cambridge, UK, for statistical analysis). Among the 30 patients selected, we excluded two from the acarbose group (one abandon and one pregnancy) and one from the placebo group (abandon), with no cases of treatment intolerance. Four patients in the placebo groups and eleven in the acarbose group presented mild abdominal distention and flatulence, and all reported a reduction in side effects after the first 3 months. Before treatment, excluding VLDL cholesterol and triglycerides, the groups did not show any differences regarding any of the clinical or laboratory parameters. Compared with pretreatment values, the acarbose group presented a reduction in P-selectin levels, diastolic and systolic blood pressure, BMI, VLDL cholesterol, and tryglyceride levels and an increase in HDL cholesterol, whereas the placebo group did not show any difference between the pre-treatment and post-treatment values for any parameter analyzed. No changes occurred in the area under the insulin and glucose curves after the GTT (Table 1). We recorded a significant reduction of P-selectin in obese hyperinsulinemic PCOS patients with a low dose of acarbose treatment for 6 months. There are no data in the literature about the concentration of P-selectin in PCOS patients, nor are there any studies about the reduction of P-selectin in PCOS patients with any type of treatment.
P-Selectin is an adhesion molecule associated with endothelial dysfunction. Ridker et al. (2) reported a high correlation between P-selectin and coronary events. Acarbose is an ␣-glucosidase inhibitor that forms a reversible and dosedependent bond with the oligosaccharide site of ␣-glucosidase in the small intestine, thereby reducing the postprandial peak of glycemia by 20% and preventing glucidic toxicity (5). The reduced glucose absorption leads indirectly to an increase in glucagon-like peptide 1, which acts on the satiety center of the brain, reducing appetite and facilitating weight reduction (6). The lowest dose of acarbose with clinical effects is 150 mg/day; doses greater than 300 mg/day exceed the saturation of the ␣-glucosidase receptor and do not increase drug effectiveness (7, 8). Dosage is an important aspect of treatment, because side effects, such as flatulence, meteorism, and abdominal distention, are dose-dependent. Although there are no data relating PCOS and P-selectin, there are some studies about the use of acarbose and endothelial function. An experimental study by Schäfer et al. (9) showed reductions in P-selectin concentration and endothelial dysfunction with the use of acarbose in Zucker rats with impaired glucose tolerance. Delorme and Chiasson (10) provide a meta-analysis of seven major studies on the use of acarbose in the treatment of diabetes. Those studies showed that acarbose treatment was associated with
TABLE 1 Clinical and metabolic characteristics of the patients with polycystic ovarian syndrome before and after treatment with acarbose for 6 months. Placebo
Age (yrs) BMI (kg/m2) Total cholesterol (mg/dL) VLDL cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) P-Selectin (ng/mL) Area under the glucose curve after the GTT (mg/dL) Area under the insulin glucose curve after the GTT (IU/mL)
Acarbose
Before (n ⴝ 15)
After (n ⴝ 14)
Before (n ⴝ 15)
After (n ⴝ 13)
25.93 ⫾ 1.83 35.04 ⫾ 2.84 186.86 ⫾ 33.96 21.07 ⫾ 8.23 133.43 ⫾ 33.37 38.07 ⫾ 7.78 108.00 ⫾ 41.60 126 ⫾ 9.3 84.3 ⫾ 11.1 97.6 ⫾ 8.8 16,057 ⫾ 3,472
34.77 ⫾ 3.33 185.80 ⫾ 39.20 22.86 ⫾ 8.14 127.93 ⫾ 34.95 36.71 ⫾ 7.21 116.00 ⫾ 40.70 127 ⫾ 8.0 85.5 ⫾ 9.3 99.4 ⫾ 8.4 15,377 ⫾ 3,045
26.69 ⫾ 1.46 35.87 ⫾ 2.60 198.80 ⫾ 53.40 31.31 ⫾ 15.56 133.70 ⫾ 48.00 35.15 ⫾ 6.69 155.10 ⫾ 81.70 121 ⫾ 11.4 86.2 ⫾ 8.0 99.3 ⫾ 10.0 15,173 ⫾ 3,804
33.10 ⫾ 2.94* 200.50 ⫾ 48.70 26.85 ⫾ 16.55* 135.00 ⫾ 40.70 38.00 ⫾ 8.49* 136.20 ⫾ 83.40* 113 ⫾ 8.5* 78.2 ⫾ 11.1* 91.3 ⫾ 9.6* 15,194 ⫾ 3,116
16,909 ⫾ 8,167
15,692 ⫾ 5,252
17,090 ⫾ 6,469
13,845 ⫾ 5,976
Note: Variables are given as mean ⫾ SD. BMI ⫽ body mass index; GTT ⫽ glucose tolerance test; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein; VLDL ⫽ very low-density lipoprotein. * P⬍.05, before and after treatment in acarbose group. Penna. Cardiovascular risk with polycystic ovary syndrome. Fertil Steril 2007.
520
Penna et al.
Correspondence
Vol. 88, No. 2, August 2007
a 35% reduction in CVR, the mechanism for which was related to decreased oxidative stress induced by postprandial glycemic peak. Increased plasma osmolarity during the glucose peak may be associated with endothelial disfunction (11), and a 49% reduction in CVR and 91% reduction in myocardium infarction has been reported in impaired glucose tolerance and type 2 diabetes patients after using acarbose (12). Additionally, weight loss is probably more important than glycemic control in regulating circulating levels of inflammatory biomarkers such as P-selectin in morbidly obese subjects (13, 14). The reduction in BMI was a determinant of the results of the present study and may explain in part the decrease in P-selectin, because no improvement in insulin resistance or in the area under the insulin curve was observed. However, the present study is the only one conducted exclusively on obese patients, and the results agree with those reported on the effects of metformin on very obese women, suggesting a synergism of physiopathologic conditions (i.e., obesity and insulin resistance) (15). The relationship between blood pressure and cardiovascular events is well known. Hypertension is one of the most common causes of stroke and myocardium infarction. We recorded in the present study a significant reduction in both diastolic and systolic pressure with a low dose of acarbose. Obesity is a cause of hypertension. However, although only a few patients in the present study had hypertension, the majority were obese with normal blood pressure. The reduction of blood pressure with a low dose of acarbose may be related to reduced BMI. Zeymer (12) reported a 34% reduction in hypertension in impaired glucose intolerance and type 2 diabetes patients with acarbose. The present study showed a reduction in triglycerides and VLDL cholesterol levels in the acarbose group. There is a well known relationship between bad lipid profile and cardiovascular disease. Triglyceride levels were higher in obese PCOS patients than in normal-weight women without PCOS. There are two possible causes for this phenomenon: insulin resistance and glucose toxicity (16). The present data demonstrated a decrease in triglycerides with a low dose of acarbose, and these results are similar to what other studies of diabetes mellitus patients have reported (17). The reduction in triglycerides with the use of acarbose is related to the decreased glucose peak and glucose toxicity, with a consequent reduction of hepatic lipogenesis (3). Two other changes in the lipid profile were reported in the present study—VLDL cholesterol and HDL cholesterol— but neither was clinically significant after treatment. The increase of HDL cholesterol was not clinically significant, and this result is similar to that in existing literature about use of acarbose in diabetes mellitus patients. Fertility and Sterility姞
Finally, the present study suggests that the effects of acarbose in obese patients with PCOS could be useful not only for the treatment of clinical hormonal alterations associated with the syndrome but also as an important tool in the prevention of cardiovascular disease in these patients. Acknowledgments: The authors thank Edson Z Martinez, Ph.D., Marcia S Baggio, and Maria Albina Verceze Bortolieiro for their technical assistance.
Ivan Araujo Penna, M.D.a,b Paulo Roberto Bastos Canella, M.D.b Carolina Sales Vieira, M.D.a Marcos Felipe Silva de Sá, M.D.a Rosana Maria dos Reis, M.D.a Rui Alberto Ferriani, M.D.a a Department of Obstetrics and Gynecology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; and b Gynecology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil REFERENCES 1. Orio F, Palomba S, Spinelli L, Cascella T, Tauchmanova L, Zullo F, et al. The cardiovascular risk of young women with polycystic ovary syndrome. An observational, analytical, prospect case-control study. J Clin End Metab 2004;3696 –701. 2. Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001;103:491–5. 3. Laube H. Acarbose. Clin Drug Invest 2002;22:141–56. 4. Penna IA, Canella PR, Reis RM, Silva de Sa MF, Ferriani RA. Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study. Hum Reprod 2005;20:2396 – 401. 5. Hanefeld M, Fischer S and Schulze J. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732–7. 6. Gutzwiller JP. Glucagon like peptide-1 is a physiologic regulator of food intake in humans. Gastroenterology 1997;112:a1153. 7. Rodier M, Richard JL, Monnier L and Mirauze J. Effect of long term acarbose (Bay g 5421) therapy on metabolic control on noninsulindependent (type II) diabetes mellitus. Diabet Med 1988;14:12– 4. 8. Santeusanio F, Ventura MM, Contadinbi S. Efficacy and safety of two different dosages of acarbose in noninsulin dependent diabetic patients treated by diet alone. Diabet Nutr Metab 1993;6:147–54. 9. Schäfer A, Widder J, Eigenthaler M, Bischoff H, Ertl G, Bauersachs J. Increased platelet activation in young Zucker rats with impaired glucose tolerance is improved by acarbose. Thromb Haemost 2004; 92:97–103. 10. Delorme S, Chiasson JL. Acarbose in the prevention of cardiovascular disease in subjects with impaired glucose tolerance and type 2 diabetes mellitus. Curr Opin Pharmacol 2005;5:184 –9. 11. Keating FK, Sobel BE, Schneider DJ. Effects of increased concentration of glucose on platelet reactivity in healthy subjects and in patients with and without diabetes mellitus. Am J Cardiol 2003;92: 1362–5. 12. Zeymer U. Cardiovascular benefits of acarbose in impaired glucose tolerance and type 2 diabetes. Int J Cardiol 2006;1007:11–20. 13. Pontiroli AE, Pizzocri P, Koprivec D, Vedani P, Marchi M, Arcelloni C, et al. Body weight and glucose metabolism have a different effect on circulating levels of ICAM-1, E-selectin, and endothelin-1 in humans. Eur J Endocrinol 2004;150:195–200.
521
14. Sharman MJ, Volek JS. Weight loss leads to reductions in inflammatory biomarkers after a very-low-carbohydrate diet and a low-fat diet in overweight men. Clin Sci 2004;107:365–9. 15. Maciel GAR, Junior JMS, Motta ELA, Abi Haidas M, de Lima GR, Baracat EC. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril 2004;81:355– 60.
522
Penna et al.
Correspondence
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