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Endocrine Connections Publish Ahead of Print, published on October 10, 2017 as doi:10.1530/EC-17-0217
The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome Running title: Atorvastatin on β cell requirement in PCOS 1
Thozhukat Sathyapalan,
2
Anne-Marie Coady
3
Eric S Kilpatrick
4
Stephen L Atkin
1
Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical
School, University of Hull, UK 2
Department of Obstetric Ultrasound, Hull & East Yorkshire Women's & Children's
Hospital, Hull, UK 3
Department of Clinical Biochemistry, Sidra Medical and Research Center, Doha, Qatar.
4
Department of Medicine, Weill Cornell Medical College, Doha, Qatar.
Corresponding Author Thozhukat Sathyapalan Michael White Diabetes Centre 220-236 Analby Road Hull Royal Infirmary Hull, HU3 2JZ, United Kingdom. Telephone - +44-1482675312 Fax - +44-1482675385 Email: [email protected]
ISRCTN number: ISRCTN24474824
Abstract word count 243
Manuscript word count - 1479
Copyright 2017 by Society for Endocrinology and European Society of Endocrinology.
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Abstract Background There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS) and there is evidence that statins improve metabolic parameters in these patients. However, there is some data to show that statins increase the risk of incipient diabetes. Material and Methods We have previously shown that 12-weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc-analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double blind placebo controlled study, 40 medication naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. Results There was a significant reduction in HOMA-β (240±3.2vs.177±2.3; pvalue8; free androgen index >8 respectively), oligomenorrhoea or amenorrhea and polycystic ovaries on transvaginal ultrasound 25. Subjects had no concurrent illness, were not on any medication for the preceding 6 months and were not planning to conceive. All patients gave written informed consent. The study was approved by the Hull and East Riding Local Research Ethics committee. Study bloods and measurement were done after an overnight fast. Compliance was monitored by counting returned medication. Fasting venous blood was collected into serum gel and fluoride oxalate tubes. Samples were separated by centrifugation at 2000 g for 15 min at 4oC, and the aliquots stored at –20oC. Analytical methods have been described previously11. The insulin resistance was calculated using the homeostasis
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model assessment (HOMA) method (HOMA-IR= (insulin x glucose)/22.5). Pancreatic beta cell function (HOMA-β) was calculated using (HOMA-β = (20 x insulin)/glucose3.5). Data are reported as mean ± SEM. Statistical analysis The sample size calculation for the original study was based on the known effects of atorvastatin on CRP in patients with impaired fasting glucose with the assumption that a
similar effect occurs in those with PCOS 11, 26. For 90% power, significance level of 5%
and adjusting for a possible 20% dropout rate, 20 subjects were enrolled in each group.
Comparisons between both the groups from baseline were carried out using the paired t test for biochemical data and clinical observations. The Wilcoxon signed rank test was applied to biochemical data that violated the assumptions of normality when tested using the Kolmogorov-Smirnov test. Between-group comparison of percent changes was performed using independent samples t test. Intention to treat analysis was done. For all analysis, a two-tailed P ≤0.05 was considered to indicate statistical significance. Statistical analysis was performed using SPSS for Windows NT, version 14.0 (SPSS Inc., Chicago, IL). Results: Thirty seven patients completed the study. Two patients from the placebo group and one patient from atorvastatin group dropped out of the study due to non-compliance. The mean age group of patients was 27.7 ± 1.4 years (atorvastatin 26.6 ± 1.2 vs. placebo 28.8 ± 1.8). The BMI were comparable in both atorvastatin and placebo group (33.20 ± 1.4 vs. 33.92 ± 1.4 kg/m2).
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There was a significant reduction in serum insulin levels and HOMA-IR in patients taking atorvastatin whilst there was significant increase in both these parameters in patients randomised to placebo. In the extension phase there were significant reduction in insulin and the HOMA-IR with metformin in the atorvastatin pre-treated group whereas, no significant changes in any of these parameters with metformin in the placebo pre-treatment group. However, there was a significant reduction in HOMA-β (240. ± 3.2 vs. 177 ± 2.3; p value
Endocrine Connections Publish Ahead of Print, published on October 10, 2017 as doi:10.1530/EC-17-0217
The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome Running title: Atorvastatin on β cell requirement in PCOS 1
Thozhukat Sathyapalan,
2
Anne-Marie Coady
3
Eric S Kilpatrick
4
Stephen L Atkin
1
Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical
School, University of Hull, UK 2
Department of Obstetric Ultrasound, Hull & East Yorkshire Women's & Children's
Hospital, Hull, UK 3
Department of Clinical Biochemistry, Sidra Medical and Research Center, Doha, Qatar.
4
Department of Medicine, Weill Cornell Medical College, Doha, Qatar.
Corresponding Author Thozhukat Sathyapalan Michael White Diabetes Centre 220-236 Analby Road Hull Royal Infirmary Hull, HU3 2JZ, United Kingdom. Telephone - +44-1482675312 Fax - +44-1482675385 Email: [email protected]
ISRCTN number: ISRCTN24474824
Abstract word count 243
Manuscript word count - 1479
Copyright 2017 by Society for Endocrinology and European Society of Endocrinology.
Page 2 of 14
Abstract Background There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS) and there is evidence that statins improve metabolic parameters in these patients. However, there is some data to show that statins increase the risk of incipient diabetes. Material and Methods We have previously shown that 12-weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc-analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double blind placebo controlled study, 40 medication naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. Results There was a significant reduction in HOMA-β (240±3.2vs.177±2.3; pvalue8; free androgen index >8 respectively), oligomenorrhoea or amenorrhea and polycystic ovaries on transvaginal ultrasound 25. Subjects had no concurrent illness, were not on any medication for the preceding 6 months and were not planning to conceive. All patients gave written informed consent. The study was approved by the Hull and East Riding Local Research Ethics committee. Study bloods and measurement were done after an overnight fast. Compliance was monitored by counting returned medication. Fasting venous blood was collected into serum gel and fluoride oxalate tubes. Samples were separated by centrifugation at 2000 g for 15 min at 4oC, and the aliquots stored at –20oC. Analytical methods have been described previously11. The insulin resistance was calculated using the homeostasis
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model assessment (HOMA) method (HOMA-IR= (insulin x glucose)/22.5). Pancreatic beta cell function (HOMA-β) was calculated using (HOMA-β = (20 x insulin)/glucose3.5). Data are reported as mean ± SEM. Statistical analysis The sample size calculation for the original study was based on the known effects of atorvastatin on CRP in patients with impaired fasting glucose with the assumption that a
similar effect occurs in those with PCOS 11, 26. For 90% power, significance level of 5%
and adjusting for a possible 20% dropout rate, 20 subjects were enrolled in each group.
Comparisons between both the groups from baseline were carried out using the paired t test for biochemical data and clinical observations. The Wilcoxon signed rank test was applied to biochemical data that violated the assumptions of normality when tested using the Kolmogorov-Smirnov test. Between-group comparison of percent changes was performed using independent samples t test. Intention to treat analysis was done. For all analysis, a two-tailed P ≤0.05 was considered to indicate statistical significance. Statistical analysis was performed using SPSS for Windows NT, version 14.0 (SPSS Inc., Chicago, IL). Results: Thirty seven patients completed the study. Two patients from the placebo group and one patient from atorvastatin group dropped out of the study due to non-compliance. The mean age group of patients was 27.7 ± 1.4 years (atorvastatin 26.6 ± 1.2 vs. placebo 28.8 ± 1.8). The BMI were comparable in both atorvastatin and placebo group (33.20 ± 1.4 vs. 33.92 ± 1.4 kg/m2).
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There was a significant reduction in serum insulin levels and HOMA-IR in patients taking atorvastatin whilst there was significant increase in both these parameters in patients randomised to placebo. In the extension phase there were significant reduction in insulin and the HOMA-IR with metformin in the atorvastatin pre-treated group whereas, no significant changes in any of these parameters with metformin in the placebo pre-treatment group. However, there was a significant reduction in HOMA-β (240. ± 3.2 vs. 177 ± 2.3; p value
