State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

IL-21 and other serum proinflammatory cytokine levels in patients with multiple myeloma at diagnosis

Background: IL-6, IL1-β, TNF-α and IL-21 have been identified in the growth, progression and dissemination of multiple myeloma. To dte, there is no published data about serum levels of IL-21 in patients with multiple myeloma. In the present study we have investigated circulating levels of cytokines, such as IL-6, IL-1β, TNF-α, IL-21 and the association of these levels with the disease stage in newly diagnosed multiple myeloma patients. Materials and Methods: Twenty healthy controls and 44 newly diagnosed multiple myeloma patients were evaluated. Patients were classified according to Durie-Salmon criteria, international staging system (ISS) and bone disease. Quantification of cytokine levels in serum were performed by using ELISA. Results: The levels of cytokines in patients′ serum are found elevated than healthy controls. However, only the serum levels of IL-1β and TNF-α were found statistically significant. TNF-α levels of patients with ISS stage 3 were significantly higher than patients with ISS stage 1 and 2 (P 0.000). IL-1β was significantly elevated in advanced stage patients (stage II-III) (P 0.040). There was no correlation between IL-1β, TNF-α, IL-21 levels and bone lesions. IL-6 levels were significantly elevated who have at least three visible lytic bone lesions and/or bone fracture in comparison to patients who have one or two visible or no visible lytic bone lesions (P 0.048). Conclusion: It appears that there is no association of serum IL-21 level with multiple myeloma in contrast to the other cytokines such as IL-6, IL-1β, TNF-α

IL-21 and other serum proinflammatory cytokine levels in patients with multiple myeloma at diagnosis

Background: IL-6, IL1-β, TNF-α and IL-21 have been identified in the growth, progression and dissemination of multiple myeloma. To dte, there is no published data about serum levels of IL-21 in patients with multiple myeloma. In the present study we have investigated circulating levels of cytokines, such as IL-6, IL-1β, TNF-α, IL-21 and the association of these levels with the disease stage in newly diagnosed multiple myeloma patients. Materials and Methods: Twenty healthy controls and 44 newly diagnosed multiple myeloma patients were evaluated. Patients were classified according to Durie-Salmon criteria, international staging system (ISS) and bone disease. Quantification of cytokine levels in serum were performed by using ELISA. Results: The levels of cytokines in patients′ serum are found elevated than healthy controls. However, only the serum levels of IL-1β and TNF-α were found statistically significant. TNF-α levels of patients with ISS stage 3 were significantly higher than patients with ISS stage 1 and 2 (P 0.000). IL-1β was significantly elevated in advanced stage patients (stage II-III) (P 0.040). There was no correlation between IL-1β, TNF-α, IL-21 levels and bone lesions. IL-6 levels were significantly elevated who have at least three visible lytic bone lesions and/or bone fracture in comparison to patients who have one or two visible or no visible lytic bone lesions (P 0.048). Conclusion: It appears that there is no association of serum IL-21 level with multiple myeloma in contrast to the other cytokines such as IL-6, IL-1β, TNF-α