Andrej Janez

Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin

Objective The effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory. In this study, we investigated the potential add-on effect of treatment with the glucagon-like peptide-1 receptor agonist liraglutide on weight loss in obese nondiabetic women with PCOS who had lost <5% body weight during pretreatment with metformin. Methods A total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months, participated in a 12-week open-label, prospective study. They were randomized to one of three treatment arms: metformin (MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QD s.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight. Results Thirty six patients (aged 31.3±7.1 years, BMI 37.1±4.6 kg/m2) completed the study: 14 on MET, 11 on LIRA, and 11 on combined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waist circumference. Subjects treated with COMBI lost on average 6.5±2.8 kg compared with a 3.8±3.7 kg loss in the LIRA group and a 1.2±1.4 kg loss in the MET group (P<0.001). The extent of weight loss was stratified: a total of 38% of subjects were high responders who lost ≥5% body weight, 22% of them in the COMBI arm compared with 16 and 0% in the LIRA and MET arm respectively. BMI decreased by 2.4±1.0 in the COMBI arm compared with 1.3±1.3 in LIRA and 0.5±0.5 in the MET arm (P<0.001). Waist circumference also decreased by 5.5±3.8 cm in the COMBI arm compared with 3.2±2.9 cm in LIRA and 1.6±2.9 cm in the MET arm (P=0.029). Subjects treated with liraglutide experienced more nausea than those treated with metformin, but severity of nausea decreased over time and did not correlate with weight loss. Conclusions Short-term combined treatment with liraglutide and metformin was associated with significant weight loss and decrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weight reduction on metformin monotherapy.

Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome

OBJECTIVE There is evidence of preclinical cardiovascular disease even in young women with polycystic ovary syndrome (PCOS). The aim of our study was to assess and compare the effects of metformin (MET) and rosiglitazone (ROSI) on endothelial function in PCOS patients. METHODS For 6 months, 26 women with PCOS received either MET or ROSI. Blood samples for assessment of androgens, lipids, and high-sensitive C-reactive protein were taken at baseline and at endpoint. Endothelium-dependent flow-mediated dilation (FMD) and glyceryl trinitrate-induced endothelium-independent dilation of brachial artery were studied before and after treatment. Homeostasis model assessment (HOMA(IR)) calculation was applied as a measure of insulin resistance (IR). RESULTS With treatment, FMD of brachial artery improved significantly from 4.2+/-6.6 to 10.2+/-5.9% in MET group (P=0.036) and from 2.9+/-3.2 to 7.6+/-4.9% in ROSI group (P=0.026), MET being as effective as ROSI (P=0.70). The endothelium-independent dilation did not change. Additionally, administration of MET was associated with a significant decrease in HOMA(IR) (P=0.003), serum total and serum-free testosterone (P=0.045 and P=0.008 respectively) and significantly higher frequencies of menstrual bleeding (P=0.006). CONCLUSIONS A 6-month therapy with insulin sensitizers, MET and ROSI, resulted in marked improvement of endothelial function in young PCOS patients without clinically evident atherosclerosis who were not severely insulin resistant. Neither drug was superior to the other. We conclude that therapeutic intervention with either insulin sensitizer may reverse the atherosclerotic process in PCOS patients at its early stage.

Assessment of insulin resistance in young women with polycystic ovary syndrome

Objectives: To determine whether serum levels of potential markers could detect insulin resistance (IR) in young women with polycystic ovary syndrome (PCOS). Methods: Serum levels of fasting glucose, insulin, intact proinsulin, resistin, and adiponectin were measured in 50 women with PCOS and known homeostatic model assessment (HOMA)‐IR values (≥ 2 indicating IR). The women were all younger than 25 years. Results: Of the 50 women, 49 had undetectable levels of resistin, 50 had intact proinsulin levels within the normal range, and 50 had adiponectin levels of 8.4 ± 3.3 mg/L, just below the normal range. When groups were compared, however, the 26 women (52%) with IR (HOMA‐IR values ≥ 2) had significantly higher intact proinsulin levels (3.2 ± 2.0 pmol/L vs 1.8 ± 1.0 pmol/L; P < 0.005) and significantly lower adiponectin levels (7.2 ± 2.9 mg/L vs 9.7 ± 3.3 mg/L; P < 0.01), than the 24 women (48%) without IR. Conclusion: Serum levels of intact proinsulin, resistin, or adiponectin were not detectors of IR in individual young women with PCOS.

Impact of metformin and rosiglitazone treatment on glucose transporter 4 mRNA expression in women with polycystic ovary syndrome

OBJECTIVE The insulin-resistant state of the polycystic ovary syndrome (PCOS) was found to be associated with a decreased glucose transporter GLUT4 expression in the insulin target tissues. This study was performed to explore whether the well-known clinical, hormonal and metabolic efficacy of metformin or rosiglitazone treatment is reflected in the modulation of adipocyte GLUT4 mRNA expression in patients with PCOS. METHODS We enrolled 35 women with PCOS. They received either metformin or rosiglitazone for 6 months. A history, blood samples for the measurement of androgens and s.c. adipose tissue samples were taken at baseline and end point. Quantification of GLUT4 mRNA expression in adipose tissue was performed using real-time quantitative PCR. Homeostasis model assessment (HOMA(IR)) score calculation was applied as a measure for insulin resistance (IR). RESULTS GLUT4 mRNA expression in adipose tissue increased significantly in both groups (P<0.001). The increase was more pronounced in the rosiglitazone group (P=0.040). There was a statistically significant improvement of HOMA(IR) in both groups (P=0.008). After treatment, frequencies of menstrual bleeding were significantly higher (P<0.001) and serum total testosterone levels significantly lower in both groups (P=0.001). CONCLUSIONS A 6-month therapy with insulin sensitizers resulted in marked improvement in adipose tissue GLUT4 mRNA expression in PCOS patients, rosiglitazone being more effective when compared with metformin. The augmentation of the insulin signal transduction was accompanied by a significant improvement of HOMA(IR), menstrual pattern and androgen profile.

Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome

Abstract Aim: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) stimulate satiety leading to reductions in food intake and body weight. The effects of long- acting GLP-1 RA liraglutide on eating behavior of women with PCOS have not been investigated yet. Methods: Thirty-six obese women with PCOS (mean ± SD, aged 31.2 ± 7.8 years, with BMI 38.7 ± 0.1 kg/m2), pretreated with metformin (1000 mg BID) were switched to liraglutide 1.2 mg QD sc for 12 weeks. Adiposity parameters and eating behavior as assessed by Three-Factor Eating Questionnaire (TFEQ-R18) were examined at baseline and after 12 weeks. Results: Subjects treated with liraglutide lost on average 3.8 ± 0.1 kg (p < 0.001). Significant reductions of waist circumference and visceral adipose tissue (VAT) mass, volume and area were demonstrated from liraglutide induction to the end of the study. TFEQ-R18 scores were significantly different pre- and post-liraglutide intervention. After treatment with liraglutide the uncontrolled eating (UE) score decreased from 36.8 ± 24.5 to 19.6 ± 18.4 (p < 0.001) and emotional eating (EE) score decreased from 49.9 ± 33.3 to 28.5 ± 26.9 (p < 0.001). Scores for cognitive restraint (CR) were not changed. Conclusions: Short-term liraglutide treatment was associated with weight loss and significantly improved eating behavior in obese women with PCOS.

A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.

OBJECTIVE The long-acting glucagon-like peptide 1 receptor agonist liraglutide is linked to progressive and sustained weight loss in obese people with diabetes. However, its efficacy and safety in women with polycystic ovary syndrome (PCOS) has not yet been addressed. DESIGN Thirty-two obese women (aged 27.6±7.2 years, BMI 39.5±6.2 kg/m2) with newly diagnosed PCOS were randomized to receive either liraglutide 1.2 mg QD sc (n=17) or metformin 1000 mg BID po (n=15) for 12 weeks; 28 patients completed the study (14 on liraglutide and 14 on metformin). The main outcome was change in body weight. RESULTS Intention-to-treat analysis showed significant BMI (−0.98 kg/m2; p<0.001), body weight (−2.52 kg; p<0.001), waist circumference (−3.38 cm; p<0.001) and whole-body fat mass (−1.26%; p<0.001) reduction in both treatment arms without significant differences between therapeutic groups. However, in a subgroup of patients (n=9) with insulin resistance (HOMAIR >2), severe obesity and higher odds ratio for the metabolic syndrome (OR=3.9), the patients fared much better with liraglutide than with metformin (mean BMI decreased 2.13 kg/m2 vs. 0.62 kg/m2, respectively). CONCLUSIONS Short-term liraglutide treatment was associated with significant weight loss in a subset of obese patients with newly diagnosed PCOS and a higher metabolic risk profile.

Phosphodiesterase 4 Inhibition as a Potential New Therapeutic Target in Obese Women With Polycystic Ovary Syndrome

CONTEXT Phosphodiesterase (PDE) enzymes, including members of PDE4, have been investigated in the regulation of endocrine and reproductive functions of ovaries. In addition, selective inhibition of PDE4 enzyme has recently been implicated in the regulation of metabolism with positive effects on glucose homeostasis and weight reduction. OBJECTIVE The aim of this study was to evaluate whether the PDE4 inhibitor roflumilast affects body weight and hormonal and metabolic status in obese women with polycystic ovary syndrome (PCOS). Design/Participants/Main Outcome Measures: A 12-week prospective randomized open-label study was conducted with 36 obese women with PCOS diagnosed by the National Eunice Kennedy Shriver Institute of Child Health and Human Development criteria that had been pretreated with metformin (MET). They were randomized to MET 1000 mg twice a day or combined treatment (COM) with MET 1000 mg twice a day and roflumilast 500 μg every day. The primary outcome was change in anthropometric measures of obesity. RESULTS Thirty-one patients (aged 33.8 ± 7.4 y, twice a day 36.4 ± 5.1 kg/m(2), mean ± SD) completed the study: 16 on MET and 15 on COM. Subjects treated with COM lost on average 4.2 ± 2.8 kg compared with a 0.9 ± 2.5 kg weight gain in the MET group (P = .025). Body mass index decreased for 1.6 ± 1.1 kg/m(2) in COM arm compared with increase for 0.9 ± 2.4 kg/m(2) in the MET arm (P = .046). Visceral adipose tissue area as assessed by dual-energy x-ray absorptiometry decreased from 136.7 ± 37.8 to 121.2 ± 36.2 cm(2) in the COM arm compared with an increase from 155.3 ± 61.9 to 166.7 ± 67.2 cm(2) in the MET arm (P = .02). From baseline to study end, both treatment interventions resulted in a significant reduction of androstenedione (P = .013), free T (P = .002), and homeostasis model assessment for insulin resistance score (P = .027) and a significant increase in SHBG (P = .024), although the between-treatment differences of the changes have not been statistically significant yet. CONCLUSION Roflumilast added to metformin reduced body weight in obese women with PCOS, primarily due to a loss of fat mass.

Impact of Treatment with Rosiglitazone or Metformin on Biomarkers for Insulin Resistance and Metabolic Syndrome in Patients with Polycystic Ovary Syndrome

Background: There is increasing evidence that insulin resistance (IR) has an important implication in the pathogenesis of polycystic ovary syndrome (PCOS), a common endocrinopathy in women. This study was performed to investigate the impact of different treatments for IR on five currently discussed markers for insulin resistance: Intact proinsulin, adiponectin, retinol-binding protein 4 (RBP4), resistin, and visfatin in patients with PCOS. Methods: Thirty-five women with clinically confirmed PCOS diagnosis were included in the study [age (mean±SD): 24.7±4.8 years; body mass index: 27.4+6.0 kg/m2]. They were randomized to receive either metformin (850 mg twice a day) or rosiglitazone (4 mg once a day). Blood samples for measurement of the HOMAIR score, visfatin, RBP4, intact proinsulin, resisitin, and adiponectin were taken at baseline and after 6 months of treatment. Results: Both drugs improved ovulation, and an increase in insulin sensitivity was observed, especially in the rosiglitazone arm. Adiponectin levels increased in both treatment arms (metformin: 8.6±3.3 to 16.7±7.2 mg/liter, p < 0.001; rosiglitazone: 8.2±3.5 to 26.2±9.5 mg/liter, p < 0.001), but the increase was more pronounced with rosiglitazone (p < 0.001). While no changes of visfatin concentrations were observed during rosiglitazone therapy (15.4±6.9 ng/ml vs 17.4±4.8 ng/ml, n.s.), there was an increase in the metformin treatment arm (11.9±4.0 to 21.8±8.3 ng/ml, p < 0.001). Significant increases demonstrated for RBP4 in both treatment arms were more pronounced in the metformin group (metformin: +66%, rosiglitazone: +33%). All patients were in stage I or II of ß-cell dysfunction and none of them showed increased intact proinsulin levels or changes in resisitin at baseline or end point. Conclusions: Both drugs slightly improved ovulation in our PCOS patient population during 6 months of therapy, which was accompanied by improved insulin sensitivity and an increase in adiponectin levels. Metformin increased visfatin concentrations. Despite improved insulin resistance, an increase in RBP4 concentration was seen for both drugs. Rosiglitazone seems to be the more favorable drug under these circumstances. However, our results regarding visfatin and RBP4 contradict other reports and further research is required to clarify their value as diagnostic markers for the metabolic syndrome. In this study, adiponectin appeared to be the most promising indicator of both metabolic status and therapeutic success.

Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study

Liraglutide (LIRA) treatment is associated with the dose-dependent reduction of weight. Higher doses are more effective than lower doses, although higher doses are also more poorly tolerated. Metformin may enhance the weight-lowering potential of LIRA via the stimulatory modulation of incretin in addition to its direct beneficial effects in PCOS. The aim of the present study was to evaluate whether metformin as an adjunct to low-dose LIRA affects body weight with increased efficacy compared with low-dose LIRA alone in obese patients with PCOS. In a 12-week study, 44 obese women with PCOS were randomly offered either combined treatment (COMBO) with 1,000 mg metformin twice a day and 1.2 mg LIRA once a day, or treatment with 1.2 mg LIRA alone. The primary outcome of treatment was an alteration in the levels of obesity. A total of 43 patients [aged 30.3±4.4 years; body mass index (BMI) 37.2±4.5 kg/m2; mean ± standard deviation] completed the study. The subjects treated with COMBO lost on average 6.2±2.4 kg compared with a 3.8±3.5 kg weight loss in the patients treated with LIRA alone (P=0.024). The BMI decreased by 2.2±0.8 kg/m2 in patients treated with COMBO and by 1.4±1.2 kg/m2 in patients treated with LIRA alone (P=0.024). A clinically significant ≥5% weight reduction was achieved in 59.1% of patients treated with COMBO and 42.9% of patients treated with LIRA alone. Reductions in glucose levels following oral glucose tolerance testing, as well as in androstenedione levels in the COMBO group were significantly greater compared with those in the LIRA group. The side effects were mild and transient in the two treatment groups. A combination of metformin and low-dose LIRA was more effective than low-dose LIRA alone in reducing body weight in obese patients with PCOS.

Efficacy of CD34+ Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Is Absent in Patients With Diabetes but Preserved in Patients With Insulin Resistance

We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). A total of 45 outpatients with DCM received granulocyte colony‐stimulating factor for 5 days. CD34+ cells were then collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no‐IR group). After stimulation, we found higher numbers of CD34+ cells in the IR group (94 ± 73 × 106 cells per liter) than in the no‐IR group (54 ± 35 × 106 cells per liter) or DM group (31 ± 20 × 106 cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34+ cells in the IR group (IR group, 216 ± 110 × 106 cells; no‐IR group, 127 ± 82 × 106 cells; DM group, 77 ± 83 × 106 cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6% ± 6.9%) and the no‐IR group (+4.4% ± 7.2%) but not in the DM group (−0.9% ± 5.4%; p = .035). The N‐terminal pro‐brain natriuretic peptide levels decreased in the IR and no‐IR groups, but not in the DM group (−606 ± 850 pg/ml; −698 ± 1,105 pg/ml; and +238 ± 963 pg/ml, respectively; p = .034). Transendocardial CD34+ cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34+ stem cell mobilization and a preserved clinical response to cell therapy.