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Patients with type 2 diabetes and atherosclerotic cardiovascular disease are at high clinical risk. We assessed the effect of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on total cardiovascular events and admissions to hospital in the EMPA-REG OUTCOME trial.

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

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Neurokinin B (NKB) is obligate for human puberty, but its role in adult female gonadotropin secretion and ovarian follicle growth is unknown.

Context:Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women.Objective:To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion.Design:Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study.Setting:Clinical research facility.Patients or other participants:Healthy females with regular menses.Intervention(s):NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4–6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle.Main outcome measure(s):Plasma gonadotropin and estradiol secretion.Results:After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P< .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P< .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P< .05).Conclusions:These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.

Context:Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high secretion levels of LH and T. Currently, there is no treatment licensed specifically for PCOS.Objective:The objective of this study was to investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and T concentrations and thereby presenting a novel therapeutic approach to the management of PCOS.Design:This study is a double-blind, double-dummy, placebo-controlled, phase 2 trial.Settings:University hospitals and private clinical research centers were included.Participants:Women with PCOS aged 18–45 years participated.Intervention:Intervention included AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days.Main Outcome Measure:Change from baseline in the area under the LH serum concentration–time curve over 8 hours (area under the curve) on day 7 relative to placebo was measured.Results:Of a total 67 randomized patients, 65 were evaluable. On day 7, the following baseline-adjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: 1) a reduction of 52.0% (95% confidence interval [CI], 29.6–67.3%) in LH area under the curve; 2) a reduction of 28.7% (95% CI, 13.9–40.9%) in total T concentration; and 3) a reduction of 3.55 LH pulses/8 hours (95% CI, 2.0–5.1) (all nominal P< .05).Conclusions:The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and T concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.

Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.

Background:Patients with resistant hypertension (rHT) have increased risk of adverse outcomes and death. Type 2 diabetes (T2D) and rHT often coexist. Empagliflozin (EMPA) reduced systolic blood pressure (SBP) and improved CV outcomes and death in patients with T2D and CVD in the EMPA-REG OUTCOME trial. We aimed to explore the effects of EMPA in patients with and without rHT in a post-hoc analysis.Methods:In total, 7020 patients were treated with EMPA 10mg, 25mg, or placebo (PBO) with median follow-up of 3.1 years. We defined rHT at baseline (BL) as the use of ?3 classes of anti-hypertensive drugs (AHD) including a diuretic and uncontrolled BP (SBP?140 and/or DBP?90mmHg), or use of ?4 classes of AHD and controlled BP (SBP<140 and DBP<90mmHg). We explored the effect of EMPA within subgroups of rHT on CV death, hospitalisation for HF (HHF), 3p-MACE, all-cause death, and incident/worsening nephropathy by Cox regression and SBP over time by a mixed model repeated measures analysis.Results:Overall, 1579 (22.5%) patients had rHT; these were older (64.8 vs. 62.7 years), had more concomitant diseases, including coronary artery disease (78.7 vs. 74.7%) and HF (17.3 vs. 8.0%), and lower eGFR (68.1 vs. 75.8 ml/min/1.73 m2). BL SBP was 142?18 in rHT vs. 133?16 in no-rHT. Mean difference in change in SBP from BL to week 12 with EMPA vs PBO was -4.50 (95% CI: -6.00, -3.00) mmHg in rHT vs. -3.72 (-4.52, -2.92) mmHg in no-rHT and remained lower during treatment. Patients with rHT had 1.5 to 2-fold risk of HHF, incident/worsening nephropathy and CV death compared to non-rHT. EMPA consistently improved all outcomes in patients with and without rHT (Figure). The incidence of any AEs and serious AEs was higher in those with rHT, but balanced across treatments.Conclusions:EMPA induced a clinically relevant reduction in SBP and consistently improved all outcomes in patients with and without rHT. These results support the use of EMPA for lowering BP in patients with T2D and as a potential add-on treatment for rHT.

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Patients with loss-of-function mutation in neurokinin B (NKB) and its receptor show hypogonadotropic hypogonadism characterised by failure to progress through puberty, indicating the involvement of this newly described hypothalamic peptide in human reproduction. However the role of NKB in regulating ovarian function in adult women is unknown. We tested the hypothesis that a NKB antagonist would decrease gonadotropin secretion and inhibit folliculogenesis in healthy women.

Introduction Hyperthyroidism is a well established cause of atrial fibrillation (AF). Thyroid Stimulating Hormone-secreting pituitary tumours are rare causes of pituitary hyperthyroidism. Whilst pituitary causes of hyperthyroidism are much less common than primary thyroid pathology, establishing a clear aetiology is critical in minimising complications and providing appropriate treatment. Measuring Thyroid Stimulating Hormone (TSH) alone to screen for hyperthyroidism may be insufficient to appropriately evaluate the thyroid status in such cases.Case presentation A 63-year-old Caucasian man, previously fit and well, presented with a five-day history of shortness of breath associated with wheeze and dry cough. He denied symptoms of hyperthyroidism and his family, social and past history were unremarkable. Initial investigation was in keeping with a diagnosis of atrial fibrillation (AF) with fast ventricular response leading to cardiac decompensation.Conclusion This case reiterates the need to evaluate thyroid function in all patients presenting with atrial fibrillation. TSH-secreting pituitary adenomas must be considered when evaluating the cause of hyperthyroidism. Early diagnosis and treatment of such adenomas is critical in reducing neurological and endocrine complications.