Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin.

AIMS: To assess the long-term glycaemic durability, safety and tolerability of dapagliflozin versus glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled by metformin alone. METHODS: This was a 52-week, randomised, double-blind study of dapagliflozin (n = 406) versus glipizide (n = 408), uptitrated over 18 weeks according to tolerability and glycaemic response to a maximum of 10 and 20 mg/day, respectively, as add-on therapies to metformin (≥ 1500 mg/day) with a 156-week double-blind extension period. Data over 104 weeks are reported here. RESULTS: In total, 53.1% of patients completed 104 weeks of treatment. After the greater initial decrease (0-18 weeks) in glycated haemoglobin (HbA1c) with glipizide, the 18-104-week HbA1c coefficient of failure (CoF) was lower with dapagliflozin (0.13%/year) than with glipizide (0.59%/year), resulting in significant dapagliflozin versus glipizide differences of -0.46%/year (95% CI -0.60,-0.33; p = 0.0001) for CoF and -0.18%(-2.0 mmol/mol) [95% CI -0.33(-3.6),-0.03(-0.3); p = 0.021] for 104-week HbA1c. Dapagliflozin produced sustained reductions in weight and systolic blood pressure, whereas glipizide increased weight and systolic blood pressure, giving 104-week dapagliflozin versus glipizide differences of -5.1 kg (95% CI: -5.7,-4.4) and -3.9 mmHg (95% CI: -6.1,-1.7), respectively. Over 104 weeks, the hypoglycaemia rate was 10-fold lower with dapagliflozin than with glipizide (4.2 vs. 45.8%), whereas patient proportions with events suggestive of genital infection and of urinary tract infection (UTI) were greater with dapagliflozin (14.8 and 13.5%, respectively) than with glipizide (2.9 and 9.1%, respectively). CONCLUSIONS: Over 2 years, compared with glipizide, dapagliflozin demonstrated greater glycaemic durability, sustained reductions in weight and systolic blood pressure and a low hypoglycaemia rate; however, genital infections and UTIs occurred more frequently.

[Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin]. / Vergleich von Dapagliflozin und Glipizid als Add-on-Therapie bei Typ-2-Diabetikern mit unzureichender Blutzuckerkontrolle unter Metformin.

OBJECTIVE: Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS: This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA1c, 7.7 %), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤ 10 or ≤ 20 mg/day, respectively. RESULTS: The primary end point, adjusted mean HbA1c reduction with dapagliflozin (-0.52 %) compared with glipizide (-0.52 %), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (-3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥ 5 % body weight reduction (33.3 %) versus glipizide (2.5 %; p < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5 %) versus glipizide (40.8 %; p < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation. CONCLUSIONS: Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.

An ATR-FTIR spectroscopic approach for measuring rapid kinetics at the mineral/water interface.

This study presents a methodology for studying rapid kinetic reactions for IR active compounds. In soils, sediments, and groundwater systems a rapid initial chemical reaction can comprise a substantial portion of the total reaction process at the mineral/water interface. Rapid-scan attenuated total reflectance (ATR) Fourier transform infrared (FTIR) spectroscopy is presented here as a new method for collecting rapid in situ kinetic data. As an example of its application, the initial oxidation of arsenite (As III) via Mn-oxides is examined. Using a rapid-scan technique, IR spectra were collected with a time resolution of up to 2.55 s (24 scans, 8 cm(-1) resolution). Through observation and analysis of IR bands corresponding to arsenate (AsV), rapid chemically-controlled As III oxidation is observed (initial pH 6-9) with 50% of the reaction occurring within the first one min. The oxidation of As III is followed by rapid binding of AsV to HMO, at least in part, through surface bound Mn II. The experimental data indicate that rapid-scan FTIR is an effective technique for acquisition of kinetic data, providing molecular scale information for rapid reactions at the solid/liquid interface.

Comparison of insulin sensitivity, clearance, and secretion estimates using euglycemic and hyperglycemic clamps in children.

The euglycemic clamp is the gold standard for estimating insulin sensitivity. The hyperglycemic clamp is easier to perform and is the gold standard for estimating beta-cell secretion. Reports in adults suggest that hyperglycemic clamps can estimate insulin sensitivity with results equivalent to euglycemic clamps. We investigated whether insulin sensitivity measures from both clamps are equivalent in children. Thirty-one lean and obese children (mean body mass index, 25.1 +/- 4.9 kg/m(2); mean age, 8.7 +/- 1.4 yr; 15 girls and 16 boys; 12 black and 19 white) were studied. All subjects underwent hyperglycemic clamps, then euglycemic clamps 2-6 wk later. Body composition was estimated by dual energy x-ray absorptiometry. Visceral and sc abdominal fat was estimated by abdominal magnetic resonance imaging. Whole-body glucose disposal and insulin sensitivity (SI clamp) derived from both clamps and normalized for total or visceral fat and lean mass were significantly correlated (r, 0.45-0.65; P < 0.05). However, absolute SI clamp values were not equivalent. Bland-Altman comparisons found that SI clamp estimates from hyperglycemic clamps became less precise as SI clamp increased. There were significant correlations between indices of beta-cell secretion from the hyperglycemic clamp and mean C-peptide values from the euglycemic clamp (P < 0.05). However, no correlation was found between measures of total insulin clearance (derived from the euglycemic clamp) and surrogates of hepatic insulin clearance (derived from the hyperglycemic clamp). In this cohort of diverse children, SI clamp values from euglycemic and hyperglycemic clamps were significantly correlated but were not equivalent, whereas the insulin clearance measures were not correlated. It cannot be assumed that the hyperglycemic clamp obviates the need for euglycemic clamp studies to accurately estimate insulin sensitivity in children.

Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts.

Controversy continues about whether, and to what levels of abundance, thyroid-stimulating hormone receptors (TSHR) are found in human tissues other than the thyroid gland. Restricted expression to the thyroid and orbit would suggest that TSHR represents the target autoantigen in thyroid-associated ophthalmopathy. A more generalized pattern of tissue expression would be inconsistent with TSHR acting as the autoantigen that is solely responsible for selectively targeting the immune system to the orbit. We have detected TSHR mRNA in human abdominal adipose tissue by Northern blot analysis. TSHR protein was also detected, by immunoblotting with two different antibodies, in preadipocytes isolated from human abdominal subcutaneous and omental adipose tissue and in derivative adipocytes differentiated in primary culture. Preadipocytes treated with thyroid-stimulating hormone (TSH) exhibited a sevenfold increase in the activity of p70 S6 kinase, a serine/threonine kinase recently recognized as a downstream target of TSHR in thyroid cells. Activation of p70 S6 kinase by TSH was also observed in orbital fibroblasts. Thus TSHR protein expression is found in fibroblasts from several anatomic locations, suggesting that factors other than site-limited TSHR expression must be involved in restricting the distribution of Graves' disease manifestations. Furthermore, the presence of functional TSHR in preadipocytes raises the possibility of a novel role for TSHR signaling in adipose tissue development.

HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis.

The purpose of this study was to determine the effects of mast cell coculture on human orbital fibroblasts. Thyroid-associated ophthalmopathy is characterized by infiltration of lymphocytes and mast cells and connective tissue activation in the orbit, leading to a disordered accumulation of hyaluronan and intense inflammation. Here, we report that HMC-1, an established human mast cell line, can activate human orbital fibroblasts to produce increased levels of prostaglandin E2 (PGE2) and hyaluronan when cocultured. HMC-1 cells up-regulate, in these fibroblasts, the expression of PG endoperoxide H synthase-2 (EC 1.14.99.1, PGHS-2), the inflammatory cyclooxygenase. This induction, at a pretranslational level, underlies the increase in PGE2 synthesis. The up-regulation can be attenuated with dexamethasone (10 nM), and the increase in PGE2 production can be inhibited by SC 58125, a specific PGHS-2 inhibitor. Moreover, anti-interleukin-4 receptor antibodies can block prostanoid production in the fibroblasts elicited by HMC-1 cells, suggesting that this cytokine might represent a molecular conduit for mast cell/fibroblast cross-talk. HMC-1 cells also increased hyaluronan synthesis, as was evidenced by a 2-fold increase in [3H]glucosamine incorporation into the macromolecule. To our knowledge, these findings are the first demonstrating the ability of mast cells to activate orbital fibroblasts, and the findings suggest a potential role for these cell-cell interactions in the pathogenesis of thyroid-associated ophthalmopathy.

Tricuspid valve replacement for gross tricuspid insufficiency due to dysplastic valve--a case report.

A case report is presented of a child in whom there was gross tricuspid insufficiency due to marked dysplasia of the tricuspid valve. This patient received prosthetic valve replacement in tricuspid position with excellent post-operative improvement. To the best of our knowledge, this is the first case report of a tricuspid valve replacement for a severely dysplastic tricuspid valve.

The anomalous left renal vein: CT appearance and clinical implications.

Persistence of portions or all of the fetal venous drainage of the left kidney may lead to a preaortic, circumaortic, or retroaortic type of left renal vein. The preaortic left renal vein, found in 85% of all cases, is almost always seen on abdominal CT scans. Its absence should alert the radiologist to look for a possible anomalous course. Awareness of associated anomalies such as duplication or transposition of the inferior vena cava makes the CT appearance of the anomalous left renal vein distinguishable from lymphadenopathy or dilated gonadal veins (14). The increased frequency of surgical procedures of the kidneys and the perirenal area has shown the need to recognize and document abnormal renal vasculature on CT scans of the abdomen.