CLIMACTERIC 2014;17:1–8
Metformin for overweight women at midlife: a double-blind, randomized, controlled trial R. Worsley, F. Jane, P. J. Robinson, R. J. Bell and S. R. Davis Women’s Health Research Program, School of Public Health and Preventive Medicine, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia Key words: INSULIN RESISTANCE, OBESITY, METFORMIN, WOMEN
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ABSTRACT Aim This study was undertaken to determine whether metformin would ameliorate insulin resistance, reduce weight and waist circumference and improve lipids in obese, but not morbidly obese, euglycemic women. Methods Obese women (body mass index (BMI) 30 and 40 kg/m2 and/or waist circumference 88 cm), aged 35–65 were randomized (1:1) to metformin 850 mg or identical placebo, twice daily for 26 weeks. The primary outcome was the change in insulin resistance determined by the homeostasis model of assessment (HOMA-IR). Secondary outcomes included fasting insulin, glucose, weight, waist circumference and BMI. Results Of the 125 women screened, 117 enrolled and 100 women, mean age 53 years, were included in the primary intention-to-treat analysis. Metformin resulted in statistically significant between-group difference in the change in HOMA-IR (change in median 0.04 vs. placebo 0.1, p 0.018) and BMI (mean change 1.00 kg/m2; 95% confidence interval (CI) 1.37 to 0.62 vs. placebo mean change 0.00; 95% CI 0.29 to 0.28, p 0.001). Statistically significant reductions in HbA1c (p 0.008) and fasting insulin (p 0.03) and a borderline decrease in high density lipoprotein cholesterol (p 0.07) were also observed for metformin, compared with placebo. No effects were seen for waist circumference, fasting glucose or other lipids. Conclusion Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg per day reduced insulin resistance and weight compared with placebo. Further studies are needed to determine whether the use of metformin will prevent the progression of insulin resistance to type 2 diabetes mellitus in obese women.
INTRODUCTION Globally more than 38% of women are overweight or obese, with obesity rates for women highest at ages 55–60 years1. Obesity induces insulin resistance (IR)2, a state of impaired insulin action. Both obesity and IR are associated with the development of many of the chronic diseases that affect midlife women, such as type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease and breast cancer3. IR is the core pathophysiological process of T2DM and prediabetes, an umbrella term for impaired fasting glucose and impaired glucose tolerance. T2DM and prediabetes are characterized by IR and elevated serum glucose levels. IR
with normal serum glucose levels precedes, and predicts progression to, prediabetes and T2DM4. Whilst considerable research efforts have been made to prevent the progression of prediabetes to T2DM, there has been little research targeting obese women who are euglycemic. Treatment of obesity and IR prior to the onset of hyperglycemia is an important therapeutic target as, by the time a person has developed prediabetes, they will already have appreciable β-cell dysfunction5. Body mass index (BMI) is one of the strongest predictors of progression of prediabetes to T2DM, with reductions in BMI resulting in reduced rates of progression4. Reducing BMI in obese women with euglycemia could therefore potentially mitigate the development of IR and prediabetes.
Correspondence: Professor S. R. Davis, Women’s Health Research Program, School of Public Health and Preventive Medicine, Monash University, 99 Commercial Rd, Melbourne, Victoria, Australia, 3004; E-mail: [email protected]
ORIGINAL ARTICLE © 2014 International Menopause Society DOI: 10.3109/13697137.2014.954997
Received 07-08-2014 Accepted 11-08-2014
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Metformin for obesity Metformin is an oral hypoglycemic agent of the biguanide class that has been used for over 50 years to treat T2DM6. The mechanism of action of metformin is not fully understood, though it is known to inhibit respiratory chain complex 1 within mitochondria, resulting in increases to AMP-activated protein kinase (AMPK), an enzyme which, amongst other actions, improves glucose uptake in muscle tissue. Metformin is thought to be an insulin sensitizer, reducing the apparent degree of IR in people both with and without T2DM4. Metformin has also been successfully used to prevent the progression of prediabetes to T2DM7. It has also been used to treat younger, obese women with polycystic ovarian syndrome (PCOS) and hyperinsulinemia8. Whilst metformin is an established therapy in T2DM and prediabetes, its use at an earlier clinical stage, that is in obese but euglycemic individuals, has not been well studied. Past studies have investigated the use of metformin for weight loss, but the findings are limited by use of open-label designs and a lack of placebo groups9. Obese midlife women are not dissimilar in their health profiles from younger women with PCOS in that they have relative androgen excess, abdominal obesity and an increased likelihood of IR10,11. Therefore, this study was undertaken to evaluate the efficacy of metformin in mitigating the development of IR in obese, but not morbidly obese, euglycemic women. We hypothesized that metformin would result in improved insulin sensitivity, estimated by the homeostasis model of assessment (HOMA-IR), weight loss, improved lipid parameters and reduced sex hormone binding globulin (SHBG).
METHODS Study participants Women were eligible if they were aged 35–65 years and had class I or II obesity (BMI 30 kg/m2 and 40 kg/m2 and/or a waist circumference 88 cm). Women were excluded if they had known diabetes or a hemoglobin A1c (HbA1c) 6.5%, were taking an oral hypoglycemic agent, had severe psychiatric or medical illness, consumed more than three standard drinks of alcohol per day, were pregnant or lactating, had acute or chronic renal or liver impairment, or had used testosterone or dehydroepiandrosterone in the previous 6 months. Use of menopausal hormone therapy or the oral contraceptive pill was permitted so long as the dose had been stable for at least 30 days prior to study entry. Women were recruited from the community via advertisements in electronic and print media and were screened for suitability via phone. The study was approved by the Monash University Human Research Ethics Committee (Clayton, Victoria, Australia) and all participants provided written, informed consent. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12610000836033.
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Study design and treatment The study was conducted according to CONSORT guidelines12. This was a single-center, double-blind, randomized, placebo-controlled, parallel-group trial. It consisted of a 2-week screening period plus a 26-week treatment phase, involving four study visits in all. Exit visits were undertaken for anyone completing at least 12 weeks of treatment. Participants attended the Monash University Women’s Health Research Program in Melbourne, Australia for their study visits. At the screening visit, all participants underwent a physical examination, including vital signs. Menopause status was determined by the menopause staging algorithm13. Women who met the eligibility criteria were invited to attend a baseline randomization visit. They were randomly assigned in a 1:1 ratio to receive metformin or an identical placebo, provided by Ascent Pty Ltd, The Rocks, NSW, Australia. The dose was titrated over 3 weeks from 425 mg at night to 850 mg twice a day. Women were asked to return all unused tablets. Treatment compliance was checked by counting returned tablets at 12 weeks and at the final visit. As obese women are at high risk for vitamin D deficiency, and as vitamin D deficiency may impact on IR14, vitamin D levels were measured at screening. Vitamin D supplementation was commenced in women with deficiency according to Endocrine Society Guidelines 201115.
Randomization The computer-generated 1:1 randomization schedule was held by R.J.B., who was not involved in the day-to-day conduct of the study. Allocation concealment was maintained until data analysis was complete. The study medication boxes were numbered and participants were sequentially assigned to the next unassigned treatment code at randomization. All study participants, study staff, including outcome assessors, remained blind to the intervention until the end of the analysis.
Outcomes measures Weight and BMI Women were weighed without shoes while wearing light clothing or underwear. Weight was measured to the nearest 0.1 kg using a digital scale and height was measured using a wall stadiometer. BMI was calculated as weight (kg)/height (m)2. Abdominal circumference was taken as the greatest measure between the lowest rib and the top of the pelvis.
Laboratory measures All biochemical analyses were performed by the Department of Biochemistry at the Alfred Hospital, Melbourne, Australia. The Abbott Architect ci16200 instrument (Abbott Diagnostics, Illinois, USA) was used to measure glucose, cholesterol,
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triglycerides, high density lipoprotein (HDL) cholesterol and insulin. Glucose was measured using a standard enzymatic (hexokinase) method. The coefficient of variability (CV) for the study period was 1.1% at low concentrations and 1.1% at high concentrations. Insulin was measured by chemiluminescent microparticle immunoassay with CVs of 4.3% at low concentration and 2.9% at high concentrations. HbA1c was measured using boronate affinity chromatography (HPLC) on the Primus CLC 385 instrument (Trinity Biotech, Bray, Ireland) with CVs of 2.5% and 2.7%. SHBG was measured by electro-chemiluminescence immunoassay on the Roche E170 instrument (Roche Diagnostics Australia Pty Ltd, Castle Hill, Australia) with CVs of 2.4% and 3.1%. HOMA-IR was calculated using the formula: fasting insulin (μU/ml) fasting glucose (mmol/l)/22.516. Low density lipoprotein (LDL) cholesterol was calculated according the Friedewald equation: LDL cholesterol (total cholesterol) (HDL cholesterol) (triglycerides/2.2), provided the triglyceride level is 4 mmol/l.
outcomes were change in fasting insulin, fasting glucose, HbA1c, BMI, waist circumference, lipid profile, and SHBG. Based on results of an earlier study, sample size was calculated assuming a mean difference in HOMA-IR between groups of 0.7 (standard deviation 1.1)17. Fifty-two participants per group were required to achieve a power of 90%. The analyses were performed as intention-to-treat. All participants who were randomized and provided any follow-up data were included in the analyses. Statistical analysis was performed using Stata Version 12.1 (Stata Corp, College Station, Texas, USA) and SPSS (version 20; SPSS Australasia Pty ltd, North Sydney, Australia). Log transformation was required for all biochemical results, including the primary outcome (HOMA-IR) as data were not normally distributed. Analysis was done using linear regression with change in lnHOMA-IR as the outcome variable and the independent variables including group allocation and baseline lnHOMA-IR. The principal investigator, S.R.D., designed the trial and supervised its conduct. The investigators collected the study data, which were analyzed by P.J.R. and R.J.B. The manuscript was prepared and submitted for publication by the authors, who vouch for the accuracy and completeness of the reported analyses. Ascent Pty Ltd had no role in the planning
Statistical analysis and sample size calculation The primary outcome was the change over 26 weeks in insulin resistance as estimated by HOMA-IR. Secondary
Attended WHRP for screening n = 125
Screen failure n=6
Early termination n=1 Randomized n = 118
Placebo n = 59
Early termination n=6
Metformin n = 59
Early termination n = 11
Attended 12 week visit n = 47
Attended 12 week visit n = 53
Early termination n=4
Early termination n=3
Attended final (26 week) visit n = 49 Figure 1
Withdrew prior to starting study drug n=1
Attended final (26 week) visit n = 44
Participant flow. WHRP, Women’s Health Research Program
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or conduct of the study or the data analyses, and the manuscript did not require Ascent’s approval prior to submission.
RESULTS
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Women were recruited between December 2011 and March 2013. A total of 125 women were screened for eligibility and 118 were randomized, 59 to each group (Figure 1). Of those, 100 completed 12 weeks of the study, with 93 of those completing the entire 26 weeks of the study. In all, 14 women left the active treatment group prior to study completion compared with ten in the placebo group. The two treatment groups were similar at baseline in terms of age, menopausal status, anthropometric characteristics and biochemistry (Table 1).
Efficacy outcomes The primary analysis included the 47 women in the metformin group and 53 women in the placebo group who provided any follow-up data and who therefore completed at least 12 weeks of therapy. Metformin treatment resulted in statistically sig-
Table 1 range)
nificant between-group difference in the change in HOMA-IR over the study period (median change 0.04 vs. placebo 0.1, p 0.018)) (Figure 2). Metformin was associated with statistically significant reductions in BMI (mean change 1.00 kg/m2 vs. placebo 0.1, p 0.001), HbA1c (median change - 0.1% vs. placebo 0.0%, p 0.008), and fasting insulin (median change 1.05 pmol/l vs. 0.4 pmol/l, p 0.029). A borderline significant decrease in HDL cholesterol (change of 0.1 mmol/l vs. placebo 0.0 mmol/l, p 0.074) was also seen in the metformin group (Table 2). No effects were seen for waist circumference, fasting glucose, total cholesterol, LDL cholesterol, triglycerides or SHBG.
Adverse events There was no significant difference in the frequency of adverse events between the two groups. Gastrointestinal symptoms (abdominal discomfort, diarrhea or vomiting) were experienced by six women in each group (10%). Adverse events lead to early termination in 12 participants, five in the placebo group and seven in the metformin group. One participant in the metformin group was diagnosed with invasive ductal
Baseline characteristics. Data are given as mean (standard deviation) or median (interquartile
Characteristics Patient characteristics Age (years) Premenopausal Postmenopausal* Years since menopause (median, range) (postmenopausal women only) Vital characteristics Height (cm) Weight (kg) Body mass index (kg/m2) Waist circumference (cm) Fasting biochemistry (normal range) HOMA-IR Insulin (3–16 pmol/l) Glucose (2.5–6 mmol/l) HbA1c ( 6%) Total cholesterol ( 5.5 mmol/l) HDL cholesterol ( 1.0 mmol/l) LDL cholesterol ( 3.5 mmol/l) Triglycerides ( 2.0 mmol/l) SHBG (age 50: 24.6–122 nmol/l; age 50: 17.3–125 nmol/l)
Placebo (n 59)
53.4 (7.1) 28.8% 71.2% 6.5 (1–30)
161.1 84.8 32.7 106.7
1.78 8.4 5.1 5.7 5.6 1.4 3.4 1.1 41.5
Metformin (n 58)
53.0 (7.4) 43.1% 56.9% 7 (1–23)
(5.2) (10) (6.3) (10.2)
163.0 (5.6) 87.6 (10.8) 33.0 (3.7) 107.6 (8.9)
(1.23–2.71) (5.5–11.4) (4.8–5.4) (5.5–5.9) (4.7–6.2) (1.2–1.7) (2.9–4.1) (0.8–1.7) (28.8–68.3)
1.95 8.65 5.2 5.7 5.8 1.4 3.7 1.4 44.3
(1.54–2.96) (6.7–12.8) (4.9–5.6) (5.5–5.9) (5.1–6.3) (1.2–1.6) (3.2–4.2) (1.1–1.7) (26.7–65.5)
*, p 0.107 for χ2 between-group and menopausal status HDL, high density lipoprotein; LDL, low density lipoprotein; SHBG, sex hormone binding protein
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carcinoma during the study on a routine mammogram. This was considered unrelated to the study. The participant informed researchers of the diagnosis at study completion.
In this study over 6 months, metformin therapy produced a statistically significant reduction in IR, estimated by HOMA-IR, and BMI in obese, middle-aged, euglycemic women. Metformin therapy also resulted in reductions in other measures that estimate IR, that is, fasting insulin and HbA1c. There was no significant change in waist circumference, lipids, fasting glucose, or SHBG. Our findings are consistent with previous research which has demonstrated the efficacy of metformin in reducing IR and BMI in adolescents with obesity and fasting hyperinsulinemia18 and in adults with prediabetes7, antipsychotic induced weight gain19 and PCOS20. The present study extends those findings by showing that metformin is effective in euglycemic obese women who are at an earlier stage of IR. The women in our study were significantly more insulinsensitive than participants in other studies as, unlike other studies, elevated fasting glucose, insulin or HOMA-IR were not inclusion criteria. Instead, women were recruited on the
(b) Change in insulin (pmol/l)
(a) 1.5 Change in HOMA
1 .5 0 –.5 –1 –1.5
Placebo
7 6 5 4 3 2 1 0 –1 –2 –3 –4 –5 –6 –7
Placebo
Metformin
excludes outside values
(c)
(d)
4
Change in weight (kg)
2 1 0 –1 –2 –3 –4
Placebo excludes outside values
Figure 2
Metformin
excludes outside values
3
Change in BMI (kg/m2)
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DISCUSSION
basis of BMI and/or waist circumference. Based on a study of over 2000 individuals without T2DM, a BMI above 28.7 kg/m2 predicts IR, as measured by the euglycemic insulin clamp test, with 78.7% sensitivity and 79.6% specificity21,22. Therefore we expected most of our participants to have an elevated HOMA-IR. The suggested cut-off values of HOMA-IR to define IR vary between studies from 1.6 to 3.823, suggesting that our group included both women with normal insulin sensitivity as well as some with relatively mild IR. Our participants were still at elevated risk of T2DM, however, with a median baseline HbA1c of 5.7% conferring a 5-year risk of T2DM between 9 and 25%22. In comparison, in the large Diabetes Prevention Program (DPP) that assessed the benefit of metformin for treating prediabetes, participants were required to have an elevated fasting glucose or impaired glucose tolerance7. In the DPP, the mean baseline fasting glucose was 5.9 mmol/l and the mean 7 baseline HbA1c was 5.91 0.5% . The DPP demonstrated weight loss associated with metformin of 2.0 kg that was maintained after 10 years of therapy24. In a study of metformin for antipsychotic induced weight gain, the baseline HOMA-IR was 6.2 (5.7–6.6), with baseline fasting insulin of 179.9 pmol/l25. Studies that have demonstrated the benefit of metformin for weight loss in adolescence have mostly included only adolescents
Metformin
6 5 4 3 2 1 0 –1 –2 –3 –4 –5 –6 –7 –8 –9 –10
Placebo
Metformin
excludes outside values
Significant reductions in (a) HOMA-IR, (b) fasting insulin, (c) body mass index (BMI), (d) weight
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with high degrees of IR18. For example, Love-Osborne required a HOMA-IR 3.5 and the presence of two other risk factors for IR such as acanthosis nigricans or family history of T2DM26, while most participants in another study had acanthosis nigricans27. Studies in women with PCOS have also included women with more significant degrees of IR28–30. That metformin was effective in our study population suggests that the weight loss induced by metformin may not be due entirely to improvements in insulin sensitivity. A recent study suggests that metformin does not improve insulin sensitivity but instead increases ‘glucose effectiveness’, that is the ability of serum glucose itself to regulate glucose homeostasis31. We did not demonstrate any improvement in fasting glucose, but did find a significant reduction in fasting insulin. This could represent either improved IR or improved glucose effectiveness or both. Metformin has multiple other actions beyond changes to insulin secretion and AMPK up-regulation of glucose and fatty acid metabolism. Metformin reduces appetite32, potentially through decreasing AMPK levels within the hypothalamus33, the area of the brain responsible for appetite control. Metformin may also increase leptin receptor expression in the hypothalamus34. The main strength of this study is its design as a randomized, double-blind, placebo-controlled trial. Previous studies have used less rigorous approaches, limiting the conclusions that could be drawn9. The inclusion of both premenopausal
and postmenopausal women across a broad age range also allows our findings to be generalized to a wider proportion of the population than previous studies. Limitations of our study include the reliance on HOMA-IR as a measure of IR. The gold standard for assessing IR is the euglycemic insulin clamp and the intravenous glucose tolerance test (IVGTT). However, these are highly invasive, time-consuming and costly tests. HOMA-IR has been extensively assessed in relation to the IVGTT and the euglycemic insulin clamp with relatively good correlation21,35. Assessment of compliance was also a limitation of the study. Compliance was assessed using pill-counting methods; however, due to the poor rate of return of pill bottles at the final visit, we were unable to compare compliance between groups. Ideally, an analysis of the effect of compliance on outcome in the metformin group would have been performed, with greater weight loss expected in participants who were more compliant with metformin treatment. The findings from this study broaden the potential clinical utility of metformin. By improving insulin sensitivity in women at midlife, the long-term sequelae of IR such as T2DM, cardiovascular disease, non-alcoholic fatty liver disease and dementia may be prevented. Further, larger-scale studies are required to ascertain whether this result can be replicated in other populations, and to identify any clinical factors which predict response to treatment. Studies of longer duration are
Table 2 Results. Data are given as mean (standard deviation) or median (interquartile range) Baseline
Variable
Placebo (n 53)
Fasting biochemistry HOMA-IR 1.78 (1.25–2.71) Insulin (pmol/l) 8.0 (5.5–11.4) HbA1c (%) 5.7 (5.5–5.8) Glucose (mmol/l) 5.1 (4.8–5.4) Total cholesterol 5.5 (4.7–6.1) (mmol/l) HDL cholesterol 1.5 (1.3–1.7) (mmol/l) LDL cholesterol 3.4 (2.9–4.1) (mmol/l) Triglycerides 1.1 (0.9–1.6) (mmol/l) SHBG (nmol/l) 41.8 (30.8–68.3) Clinical characteristics 32.6 (3.5) Body mass index (kg/m2) Weight (kg) 84.9 (9.9) Waist circum107.1 (10.5) ference (cm)
Week 26 Metformin (n 47)
1.87 8.8 5.7 5.2 5.8
(1.49–2.99) (6.6–12.9) (5.5–5.9) (5.0–5.6) (5.1–6.3)
Placebo (n 53)
1.88 8.4 5.7 5.2 5.6
(1.41–2.46) (6.0–10.3) (5.5–5.8) (4.8–5.5) (4.8–6.2)
Metformin (n 46)
1.83 7.75 5.6 5.1 5.5
Beta for treatment group* Log transformed variables (n 100)
(1.27–2.49) 0.152 (0.277 (6.1–10.8) 0.136 (0.258 (5.3–5.6) 0.0239 (0.041 (4.8–5.5) 0.014 (0.045 (4.8–6.0) 0.025 (0.067
to to to to to
0.027) p 0.018 0.014) p 0.029 0.006) p 0.008 0.017) p 0.367 0.018) p 0.258
1.4 (1.1–1.7)
1.5 (1.2–1.7)
1.3 (1.1–1.6)
0.042 (0.088 to 0.004) p 0.074
3.6 (3.1–3.9)
3.5 (2.8–3.9)
3.5 (2.9–3.8)
0.008 (0.071 to 0.055) p 0.800
1.4 (1.0–1.8)
1.1 (0.8–1.6)
1.6 (1.0–1.5)
0.029 (0.159 to 0.102) p 0.662
41.8 (26.5–65.5)
45.0 (34.5–68.3)
40.2 (29.7–64.7)
0.036 (0.174 to 0.102) p 0.608
32.8 (3.8)
32.5 (3.6)
31.8 (3.9)
Variables not transformed 0.99 (1.45 to 0.53) p 0.001
87.0 (10.8) 106.8 (8.9)
84.9 (9.9) 105.4 (9.2)
84.3 (10.8) 104.1 (8.2)
2.54 (3.76 to 0.38) p 0.001 1.03 (2.44 to 0.38) p 0.149
*, Placebo as reference (95% confidence interval) and p value in regression analysis of delta outcome adjusted for the baseline observation HDL, high density lipoprotein; LDL, low density lipoprotein; SHBG, sex hormone binding protein
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Worsley et al. Conflict of interest S.R.D. is a consultant and investigator for Trimel Pharmaceuticals and has research grant support from Lawley Pharmaceuticals and Besins Health Care. The authors alone are responsible for the content and writing of the paper.
CONCLUSION Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg/day resulted in improved insulin resistance and weight loss compared with placebo. Our findings support the use of metformin as an intervention to prevent progression of insulin resistance to type 2 diabetes mellitus in obese, but not morbidly obese, middle-aged women.
Source of funding This study was supported by the Bupa Health Foundation, Australia. Ascent Pty Ltd supplied the metformin and placebo but played no role in the study design, data collection, analyses or writing of this publication. R.W. has a NHMRC postgraduate scholarship. S.R.D. is an NHMRC principal research fellow (grant number 1041853).
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33. 34.
35.
women with polycystic ovary syndrome – a randomised, doubleblind, placebo-controlled trial. BJOG 2006;113:817–24 Pau CT, Keefe C, Duran J, Welt CK. Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an openlabel, interventional study. J Clin Endocrinol Metab 2014;99: 1870–8 Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II noninsulin-dependent diabetes. Obes Res 1998;6:47–53 Lim CT, Kola B, Korbonits M. AMPK as a mediator of hormonal signalling. J Mol Endocrinol 2010;44:87–97 Aubert G, Mansuy V, Voirol MJ, Pellerin L, Pralong FP. The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism 2011;60:327–34 Cersosimo E, Solis-Herrera C, Trautmann ME, Malloy J, Triplitt CL. Assessment of pancreatic beta-cell function: review of methods and clinical applications. Curr Diabetes Rev 2014; 10:2–42
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randomized, placebo-controlled study. Schizophrenia Res 2012;138:54–7 Love-Osborne K, Sheeder J, Zeitler P. Addition of metformin to a lifestyle modification program in adolescents with insulin resistance. J Pediatr 2008;152:817–22 Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006;91:2074–80 Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 1999;48:511–19 Gambineri A, Pelusi C, Genghini S, et al. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol 2004; 60:241–9 Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The effect of metformin on fat distribution and the metabolic syndrome in
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Metformin for overweight women at midlife: a double-blind, randomized, controlled trial R. Worsley, F. Jane, P. J. Robinson, R. J. Bell and S. R. Davis Women’s Health Research Program, School of Public Health and Preventive Medicine, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia Key words: INSULIN RESISTANCE, OBESITY, METFORMIN, WOMEN
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ABSTRACT Aim This study was undertaken to determine whether metformin would ameliorate insulin resistance, reduce weight and waist circumference and improve lipids in obese, but not morbidly obese, euglycemic women. Methods Obese women (body mass index (BMI) 30 and 40 kg/m2 and/or waist circumference 88 cm), aged 35–65 were randomized (1:1) to metformin 850 mg or identical placebo, twice daily for 26 weeks. The primary outcome was the change in insulin resistance determined by the homeostasis model of assessment (HOMA-IR). Secondary outcomes included fasting insulin, glucose, weight, waist circumference and BMI. Results Of the 125 women screened, 117 enrolled and 100 women, mean age 53 years, were included in the primary intention-to-treat analysis. Metformin resulted in statistically significant between-group difference in the change in HOMA-IR (change in median 0.04 vs. placebo 0.1, p 0.018) and BMI (mean change 1.00 kg/m2; 95% confidence interval (CI) 1.37 to 0.62 vs. placebo mean change 0.00; 95% CI 0.29 to 0.28, p 0.001). Statistically significant reductions in HbA1c (p 0.008) and fasting insulin (p 0.03) and a borderline decrease in high density lipoprotein cholesterol (p 0.07) were also observed for metformin, compared with placebo. No effects were seen for waist circumference, fasting glucose or other lipids. Conclusion Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg per day reduced insulin resistance and weight compared with placebo. Further studies are needed to determine whether the use of metformin will prevent the progression of insulin resistance to type 2 diabetes mellitus in obese women.
INTRODUCTION Globally more than 38% of women are overweight or obese, with obesity rates for women highest at ages 55–60 years1. Obesity induces insulin resistance (IR)2, a state of impaired insulin action. Both obesity and IR are associated with the development of many of the chronic diseases that affect midlife women, such as type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease and breast cancer3. IR is the core pathophysiological process of T2DM and prediabetes, an umbrella term for impaired fasting glucose and impaired glucose tolerance. T2DM and prediabetes are characterized by IR and elevated serum glucose levels. IR
with normal serum glucose levels precedes, and predicts progression to, prediabetes and T2DM4. Whilst considerable research efforts have been made to prevent the progression of prediabetes to T2DM, there has been little research targeting obese women who are euglycemic. Treatment of obesity and IR prior to the onset of hyperglycemia is an important therapeutic target as, by the time a person has developed prediabetes, they will already have appreciable β-cell dysfunction5. Body mass index (BMI) is one of the strongest predictors of progression of prediabetes to T2DM, with reductions in BMI resulting in reduced rates of progression4. Reducing BMI in obese women with euglycemia could therefore potentially mitigate the development of IR and prediabetes.
Correspondence: Professor S. R. Davis, Women’s Health Research Program, School of Public Health and Preventive Medicine, Monash University, 99 Commercial Rd, Melbourne, Victoria, Australia, 3004; E-mail: [email protected]
ORIGINAL ARTICLE © 2014 International Menopause Society DOI: 10.3109/13697137.2014.954997
Received 07-08-2014 Accepted 11-08-2014
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Metformin for obesity Metformin is an oral hypoglycemic agent of the biguanide class that has been used for over 50 years to treat T2DM6. The mechanism of action of metformin is not fully understood, though it is known to inhibit respiratory chain complex 1 within mitochondria, resulting in increases to AMP-activated protein kinase (AMPK), an enzyme which, amongst other actions, improves glucose uptake in muscle tissue. Metformin is thought to be an insulin sensitizer, reducing the apparent degree of IR in people both with and without T2DM4. Metformin has also been successfully used to prevent the progression of prediabetes to T2DM7. It has also been used to treat younger, obese women with polycystic ovarian syndrome (PCOS) and hyperinsulinemia8. Whilst metformin is an established therapy in T2DM and prediabetes, its use at an earlier clinical stage, that is in obese but euglycemic individuals, has not been well studied. Past studies have investigated the use of metformin for weight loss, but the findings are limited by use of open-label designs and a lack of placebo groups9. Obese midlife women are not dissimilar in their health profiles from younger women with PCOS in that they have relative androgen excess, abdominal obesity and an increased likelihood of IR10,11. Therefore, this study was undertaken to evaluate the efficacy of metformin in mitigating the development of IR in obese, but not morbidly obese, euglycemic women. We hypothesized that metformin would result in improved insulin sensitivity, estimated by the homeostasis model of assessment (HOMA-IR), weight loss, improved lipid parameters and reduced sex hormone binding globulin (SHBG).
METHODS Study participants Women were eligible if they were aged 35–65 years and had class I or II obesity (BMI 30 kg/m2 and 40 kg/m2 and/or a waist circumference 88 cm). Women were excluded if they had known diabetes or a hemoglobin A1c (HbA1c) 6.5%, were taking an oral hypoglycemic agent, had severe psychiatric or medical illness, consumed more than three standard drinks of alcohol per day, were pregnant or lactating, had acute or chronic renal or liver impairment, or had used testosterone or dehydroepiandrosterone in the previous 6 months. Use of menopausal hormone therapy or the oral contraceptive pill was permitted so long as the dose had been stable for at least 30 days prior to study entry. Women were recruited from the community via advertisements in electronic and print media and were screened for suitability via phone. The study was approved by the Monash University Human Research Ethics Committee (Clayton, Victoria, Australia) and all participants provided written, informed consent. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12610000836033.
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Study design and treatment The study was conducted according to CONSORT guidelines12. This was a single-center, double-blind, randomized, placebo-controlled, parallel-group trial. It consisted of a 2-week screening period plus a 26-week treatment phase, involving four study visits in all. Exit visits were undertaken for anyone completing at least 12 weeks of treatment. Participants attended the Monash University Women’s Health Research Program in Melbourne, Australia for their study visits. At the screening visit, all participants underwent a physical examination, including vital signs. Menopause status was determined by the menopause staging algorithm13. Women who met the eligibility criteria were invited to attend a baseline randomization visit. They were randomly assigned in a 1:1 ratio to receive metformin or an identical placebo, provided by Ascent Pty Ltd, The Rocks, NSW, Australia. The dose was titrated over 3 weeks from 425 mg at night to 850 mg twice a day. Women were asked to return all unused tablets. Treatment compliance was checked by counting returned tablets at 12 weeks and at the final visit. As obese women are at high risk for vitamin D deficiency, and as vitamin D deficiency may impact on IR14, vitamin D levels were measured at screening. Vitamin D supplementation was commenced in women with deficiency according to Endocrine Society Guidelines 201115.
Randomization The computer-generated 1:1 randomization schedule was held by R.J.B., who was not involved in the day-to-day conduct of the study. Allocation concealment was maintained until data analysis was complete. The study medication boxes were numbered and participants were sequentially assigned to the next unassigned treatment code at randomization. All study participants, study staff, including outcome assessors, remained blind to the intervention until the end of the analysis.
Outcomes measures Weight and BMI Women were weighed without shoes while wearing light clothing or underwear. Weight was measured to the nearest 0.1 kg using a digital scale and height was measured using a wall stadiometer. BMI was calculated as weight (kg)/height (m)2. Abdominal circumference was taken as the greatest measure between the lowest rib and the top of the pelvis.
Laboratory measures All biochemical analyses were performed by the Department of Biochemistry at the Alfred Hospital, Melbourne, Australia. The Abbott Architect ci16200 instrument (Abbott Diagnostics, Illinois, USA) was used to measure glucose, cholesterol,
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triglycerides, high density lipoprotein (HDL) cholesterol and insulin. Glucose was measured using a standard enzymatic (hexokinase) method. The coefficient of variability (CV) for the study period was 1.1% at low concentrations and 1.1% at high concentrations. Insulin was measured by chemiluminescent microparticle immunoassay with CVs of 4.3% at low concentration and 2.9% at high concentrations. HbA1c was measured using boronate affinity chromatography (HPLC) on the Primus CLC 385 instrument (Trinity Biotech, Bray, Ireland) with CVs of 2.5% and 2.7%. SHBG was measured by electro-chemiluminescence immunoassay on the Roche E170 instrument (Roche Diagnostics Australia Pty Ltd, Castle Hill, Australia) with CVs of 2.4% and 3.1%. HOMA-IR was calculated using the formula: fasting insulin (μU/ml) fasting glucose (mmol/l)/22.516. Low density lipoprotein (LDL) cholesterol was calculated according the Friedewald equation: LDL cholesterol (total cholesterol) (HDL cholesterol) (triglycerides/2.2), provided the triglyceride level is 4 mmol/l.
outcomes were change in fasting insulin, fasting glucose, HbA1c, BMI, waist circumference, lipid profile, and SHBG. Based on results of an earlier study, sample size was calculated assuming a mean difference in HOMA-IR between groups of 0.7 (standard deviation 1.1)17. Fifty-two participants per group were required to achieve a power of 90%. The analyses were performed as intention-to-treat. All participants who were randomized and provided any follow-up data were included in the analyses. Statistical analysis was performed using Stata Version 12.1 (Stata Corp, College Station, Texas, USA) and SPSS (version 20; SPSS Australasia Pty ltd, North Sydney, Australia). Log transformation was required for all biochemical results, including the primary outcome (HOMA-IR) as data were not normally distributed. Analysis was done using linear regression with change in lnHOMA-IR as the outcome variable and the independent variables including group allocation and baseline lnHOMA-IR. The principal investigator, S.R.D., designed the trial and supervised its conduct. The investigators collected the study data, which were analyzed by P.J.R. and R.J.B. The manuscript was prepared and submitted for publication by the authors, who vouch for the accuracy and completeness of the reported analyses. Ascent Pty Ltd had no role in the planning
Statistical analysis and sample size calculation The primary outcome was the change over 26 weeks in insulin resistance as estimated by HOMA-IR. Secondary
Attended WHRP for screening n = 125
Screen failure n=6
Early termination n=1 Randomized n = 118
Placebo n = 59
Early termination n=6
Metformin n = 59
Early termination n = 11
Attended 12 week visit n = 47
Attended 12 week visit n = 53
Early termination n=4
Early termination n=3
Attended final (26 week) visit n = 49 Figure 1
Withdrew prior to starting study drug n=1
Attended final (26 week) visit n = 44
Participant flow. WHRP, Women’s Health Research Program
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or conduct of the study or the data analyses, and the manuscript did not require Ascent’s approval prior to submission.
RESULTS
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Women were recruited between December 2011 and March 2013. A total of 125 women were screened for eligibility and 118 were randomized, 59 to each group (Figure 1). Of those, 100 completed 12 weeks of the study, with 93 of those completing the entire 26 weeks of the study. In all, 14 women left the active treatment group prior to study completion compared with ten in the placebo group. The two treatment groups were similar at baseline in terms of age, menopausal status, anthropometric characteristics and biochemistry (Table 1).
Efficacy outcomes The primary analysis included the 47 women in the metformin group and 53 women in the placebo group who provided any follow-up data and who therefore completed at least 12 weeks of therapy. Metformin treatment resulted in statistically sig-
Table 1 range)
nificant between-group difference in the change in HOMA-IR over the study period (median change 0.04 vs. placebo 0.1, p 0.018)) (Figure 2). Metformin was associated with statistically significant reductions in BMI (mean change 1.00 kg/m2 vs. placebo 0.1, p 0.001), HbA1c (median change - 0.1% vs. placebo 0.0%, p 0.008), and fasting insulin (median change 1.05 pmol/l vs. 0.4 pmol/l, p 0.029). A borderline significant decrease in HDL cholesterol (change of 0.1 mmol/l vs. placebo 0.0 mmol/l, p 0.074) was also seen in the metformin group (Table 2). No effects were seen for waist circumference, fasting glucose, total cholesterol, LDL cholesterol, triglycerides or SHBG.
Adverse events There was no significant difference in the frequency of adverse events between the two groups. Gastrointestinal symptoms (abdominal discomfort, diarrhea or vomiting) were experienced by six women in each group (10%). Adverse events lead to early termination in 12 participants, five in the placebo group and seven in the metformin group. One participant in the metformin group was diagnosed with invasive ductal
Baseline characteristics. Data are given as mean (standard deviation) or median (interquartile
Characteristics Patient characteristics Age (years) Premenopausal Postmenopausal* Years since menopause (median, range) (postmenopausal women only) Vital characteristics Height (cm) Weight (kg) Body mass index (kg/m2) Waist circumference (cm) Fasting biochemistry (normal range) HOMA-IR Insulin (3–16 pmol/l) Glucose (2.5–6 mmol/l) HbA1c ( 6%) Total cholesterol ( 5.5 mmol/l) HDL cholesterol ( 1.0 mmol/l) LDL cholesterol ( 3.5 mmol/l) Triglycerides ( 2.0 mmol/l) SHBG (age 50: 24.6–122 nmol/l; age 50: 17.3–125 nmol/l)
Placebo (n 59)
53.4 (7.1) 28.8% 71.2% 6.5 (1–30)
161.1 84.8 32.7 106.7
1.78 8.4 5.1 5.7 5.6 1.4 3.4 1.1 41.5
Metformin (n 58)
53.0 (7.4) 43.1% 56.9% 7 (1–23)
(5.2) (10) (6.3) (10.2)
163.0 (5.6) 87.6 (10.8) 33.0 (3.7) 107.6 (8.9)
(1.23–2.71) (5.5–11.4) (4.8–5.4) (5.5–5.9) (4.7–6.2) (1.2–1.7) (2.9–4.1) (0.8–1.7) (28.8–68.3)
1.95 8.65 5.2 5.7 5.8 1.4 3.7 1.4 44.3
(1.54–2.96) (6.7–12.8) (4.9–5.6) (5.5–5.9) (5.1–6.3) (1.2–1.6) (3.2–4.2) (1.1–1.7) (26.7–65.5)
*, p 0.107 for χ2 between-group and menopausal status HDL, high density lipoprotein; LDL, low density lipoprotein; SHBG, sex hormone binding protein
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carcinoma during the study on a routine mammogram. This was considered unrelated to the study. The participant informed researchers of the diagnosis at study completion.
In this study over 6 months, metformin therapy produced a statistically significant reduction in IR, estimated by HOMA-IR, and BMI in obese, middle-aged, euglycemic women. Metformin therapy also resulted in reductions in other measures that estimate IR, that is, fasting insulin and HbA1c. There was no significant change in waist circumference, lipids, fasting glucose, or SHBG. Our findings are consistent with previous research which has demonstrated the efficacy of metformin in reducing IR and BMI in adolescents with obesity and fasting hyperinsulinemia18 and in adults with prediabetes7, antipsychotic induced weight gain19 and PCOS20. The present study extends those findings by showing that metformin is effective in euglycemic obese women who are at an earlier stage of IR. The women in our study were significantly more insulinsensitive than participants in other studies as, unlike other studies, elevated fasting glucose, insulin or HOMA-IR were not inclusion criteria. Instead, women were recruited on the
(b) Change in insulin (pmol/l)
(a) 1.5 Change in HOMA
1 .5 0 –.5 –1 –1.5
Placebo
7 6 5 4 3 2 1 0 –1 –2 –3 –4 –5 –6 –7
Placebo
Metformin
excludes outside values
(c)
(d)
4
Change in weight (kg)
2 1 0 –1 –2 –3 –4
Placebo excludes outside values
Figure 2
Metformin
excludes outside values
3
Change in BMI (kg/m2)
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DISCUSSION
basis of BMI and/or waist circumference. Based on a study of over 2000 individuals without T2DM, a BMI above 28.7 kg/m2 predicts IR, as measured by the euglycemic insulin clamp test, with 78.7% sensitivity and 79.6% specificity21,22. Therefore we expected most of our participants to have an elevated HOMA-IR. The suggested cut-off values of HOMA-IR to define IR vary between studies from 1.6 to 3.823, suggesting that our group included both women with normal insulin sensitivity as well as some with relatively mild IR. Our participants were still at elevated risk of T2DM, however, with a median baseline HbA1c of 5.7% conferring a 5-year risk of T2DM between 9 and 25%22. In comparison, in the large Diabetes Prevention Program (DPP) that assessed the benefit of metformin for treating prediabetes, participants were required to have an elevated fasting glucose or impaired glucose tolerance7. In the DPP, the mean baseline fasting glucose was 5.9 mmol/l and the mean 7 baseline HbA1c was 5.91 0.5% . The DPP demonstrated weight loss associated with metformin of 2.0 kg that was maintained after 10 years of therapy24. In a study of metformin for antipsychotic induced weight gain, the baseline HOMA-IR was 6.2 (5.7–6.6), with baseline fasting insulin of 179.9 pmol/l25. Studies that have demonstrated the benefit of metformin for weight loss in adolescence have mostly included only adolescents
Metformin
6 5 4 3 2 1 0 –1 –2 –3 –4 –5 –6 –7 –8 –9 –10
Placebo
Metformin
excludes outside values
Significant reductions in (a) HOMA-IR, (b) fasting insulin, (c) body mass index (BMI), (d) weight
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with high degrees of IR18. For example, Love-Osborne required a HOMA-IR 3.5 and the presence of two other risk factors for IR such as acanthosis nigricans or family history of T2DM26, while most participants in another study had acanthosis nigricans27. Studies in women with PCOS have also included women with more significant degrees of IR28–30. That metformin was effective in our study population suggests that the weight loss induced by metformin may not be due entirely to improvements in insulin sensitivity. A recent study suggests that metformin does not improve insulin sensitivity but instead increases ‘glucose effectiveness’, that is the ability of serum glucose itself to regulate glucose homeostasis31. We did not demonstrate any improvement in fasting glucose, but did find a significant reduction in fasting insulin. This could represent either improved IR or improved glucose effectiveness or both. Metformin has multiple other actions beyond changes to insulin secretion and AMPK up-regulation of glucose and fatty acid metabolism. Metformin reduces appetite32, potentially through decreasing AMPK levels within the hypothalamus33, the area of the brain responsible for appetite control. Metformin may also increase leptin receptor expression in the hypothalamus34. The main strength of this study is its design as a randomized, double-blind, placebo-controlled trial. Previous studies have used less rigorous approaches, limiting the conclusions that could be drawn9. The inclusion of both premenopausal
and postmenopausal women across a broad age range also allows our findings to be generalized to a wider proportion of the population than previous studies. Limitations of our study include the reliance on HOMA-IR as a measure of IR. The gold standard for assessing IR is the euglycemic insulin clamp and the intravenous glucose tolerance test (IVGTT). However, these are highly invasive, time-consuming and costly tests. HOMA-IR has been extensively assessed in relation to the IVGTT and the euglycemic insulin clamp with relatively good correlation21,35. Assessment of compliance was also a limitation of the study. Compliance was assessed using pill-counting methods; however, due to the poor rate of return of pill bottles at the final visit, we were unable to compare compliance between groups. Ideally, an analysis of the effect of compliance on outcome in the metformin group would have been performed, with greater weight loss expected in participants who were more compliant with metformin treatment. The findings from this study broaden the potential clinical utility of metformin. By improving insulin sensitivity in women at midlife, the long-term sequelae of IR such as T2DM, cardiovascular disease, non-alcoholic fatty liver disease and dementia may be prevented. Further, larger-scale studies are required to ascertain whether this result can be replicated in other populations, and to identify any clinical factors which predict response to treatment. Studies of longer duration are
Table 2 Results. Data are given as mean (standard deviation) or median (interquartile range) Baseline
Variable
Placebo (n 53)
Fasting biochemistry HOMA-IR 1.78 (1.25–2.71) Insulin (pmol/l) 8.0 (5.5–11.4) HbA1c (%) 5.7 (5.5–5.8) Glucose (mmol/l) 5.1 (4.8–5.4) Total cholesterol 5.5 (4.7–6.1) (mmol/l) HDL cholesterol 1.5 (1.3–1.7) (mmol/l) LDL cholesterol 3.4 (2.9–4.1) (mmol/l) Triglycerides 1.1 (0.9–1.6) (mmol/l) SHBG (nmol/l) 41.8 (30.8–68.3) Clinical characteristics 32.6 (3.5) Body mass index (kg/m2) Weight (kg) 84.9 (9.9) Waist circum107.1 (10.5) ference (cm)
Week 26 Metformin (n 47)
1.87 8.8 5.7 5.2 5.8
(1.49–2.99) (6.6–12.9) (5.5–5.9) (5.0–5.6) (5.1–6.3)
Placebo (n 53)
1.88 8.4 5.7 5.2 5.6
(1.41–2.46) (6.0–10.3) (5.5–5.8) (4.8–5.5) (4.8–6.2)
Metformin (n 46)
1.83 7.75 5.6 5.1 5.5
Beta for treatment group* Log transformed variables (n 100)
(1.27–2.49) 0.152 (0.277 (6.1–10.8) 0.136 (0.258 (5.3–5.6) 0.0239 (0.041 (4.8–5.5) 0.014 (0.045 (4.8–6.0) 0.025 (0.067
to to to to to
0.027) p 0.018 0.014) p 0.029 0.006) p 0.008 0.017) p 0.367 0.018) p 0.258
1.4 (1.1–1.7)
1.5 (1.2–1.7)
1.3 (1.1–1.6)
0.042 (0.088 to 0.004) p 0.074
3.6 (3.1–3.9)
3.5 (2.8–3.9)
3.5 (2.9–3.8)
0.008 (0.071 to 0.055) p 0.800
1.4 (1.0–1.8)
1.1 (0.8–1.6)
1.6 (1.0–1.5)
0.029 (0.159 to 0.102) p 0.662
41.8 (26.5–65.5)
45.0 (34.5–68.3)
40.2 (29.7–64.7)
0.036 (0.174 to 0.102) p 0.608
32.8 (3.8)
32.5 (3.6)
31.8 (3.9)
Variables not transformed 0.99 (1.45 to 0.53) p 0.001
87.0 (10.8) 106.8 (8.9)
84.9 (9.9) 105.4 (9.2)
84.3 (10.8) 104.1 (8.2)
2.54 (3.76 to 0.38) p 0.001 1.03 (2.44 to 0.38) p 0.149
*, Placebo as reference (95% confidence interval) and p value in regression analysis of delta outcome adjusted for the baseline observation HDL, high density lipoprotein; LDL, low density lipoprotein; SHBG, sex hormone binding protein
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Metformin for obesity needed to determine whether the effect is sustainable beyond 6 months and whether metformin will prevent the progression of IR to glucose intolerance.
Worsley et al. Conflict of interest S.R.D. is a consultant and investigator for Trimel Pharmaceuticals and has research grant support from Lawley Pharmaceuticals and Besins Health Care. The authors alone are responsible for the content and writing of the paper.
CONCLUSION Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg/day resulted in improved insulin resistance and weight loss compared with placebo. Our findings support the use of metformin as an intervention to prevent progression of insulin resistance to type 2 diabetes mellitus in obese, but not morbidly obese, middle-aged women.
Source of funding This study was supported by the Bupa Health Foundation, Australia. Ascent Pty Ltd supplied the metformin and placebo but played no role in the study design, data collection, analyses or writing of this publication. R.W. has a NHMRC postgraduate scholarship. S.R.D. is an NHMRC principal research fellow (grant number 1041853).
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