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Abstract Context Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. Objective To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D. Design Phase 3a, double-blind, placebo-controlled, 30-week trial. Setting This study included 90 sites in five countries. Patients We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin. Interventions Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo. Main Outcome Measures Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30. Results At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, –1.35 (14.8 mmol/mol); 95% CI, –1.61 to –1.10 and ETD, –1.75% (19.2 mmol/mol); 95% CI, –2.01 to –1.50; both P < 0.0001]. Severe or blood glucose–confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, –2.31; 95% CI, –3.33 to –1.29 and ETD, –5.06; 95% CI, –6.08 to –4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders. Conclusions Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo. The randomized, double-blind SUSTAIN 5 trial demonstrated the superiority of once-weekly semaglutide vs placebo in patients with uncontrolled T2D on basal insulin therapy.

Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy A double-blind, randomized, pioglitazone-comparative study David M. Kendall , MD 1 , Cindy J. Rubin , MD 2 , Pharis Mohideen , MD 2 , Jean-Marie Ledeine , MSC 3 , Rene Belder , MD 2 , Jorge Gross , MD 4 , Paul Norwood , MD 5 , Michael O’Mahony , MD 6 , Kenneth Sall , MD 7 , Greg Sloan , MD 8 , Anthony Roberts , MBBS 9 , Fred T. Fiedorek , MD 2 and Ralph A. DeFronzo , MD 10 1 International Diabetes Center and the University of Minnesota, Minneapolis, Minnesota 2 Bristol-Myers Squibb, Princeton, New Jersey 3 Bristol-Myers Squibb, Braine-l’Alleud, Belgium 4 Centro De Pesquisa Em Diabetes, Rio Grande Do Sul, Brazil 5 Valley Research, Fresno, California 6 Corunna Medical Services, Ontario, Canada 7 Sall Research Medical Center, Bellflower, California 8 Emerald Coast Research Group, Chipley, Florida 9 South Australian Endocrine Clinical Research, Keswick Adelaide, Australia 10 University of Texas Health Sciences Center at San Antonio, San Antonio, Texas Address correspondence reprint requests to Ralph A. DeFronzo, MD, Department of Medicine, Division of Diabetes, University of Texas Health Sciences Center at San Antonio, Building HSC-DTL, Room 3.380S, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail: albarado{at}uthscsa.edu Abstract OBJECTIVE —We sought to evaluate the effects of muraglitazar, a dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities. RESEARCH DESIGN AND METHODS —A double-blind, randomized, controlled trial was performed in 1,159 patients with type 2 diabetes inadequately controlled with metformin. Patients received once-daily doses of either 5 mg muraglitazar or 30 mg pioglitazone for a total of 24 weeks in addition to open-label metformin. Patients were continued in a double-blind fashion for an additional 26 weeks. RESULTS —Analyses were conducted at week 24 for HbA 1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (−1.14% from baseline), and pioglitazone reduced mean A1C to 7.28% (−0.85% from baseline; P < 0.0001, muraglitazar vs. pioglitazone). At week 12, muraglitazar and pioglitazone reduced mean plasma triglyceride (−28 vs. −14%), apolipoprotein B (−12 vs. −6%), and non-HDL cholesterol (−6 vs. −1%) and increased HDL cholesterol (19 vs. 14%), respectively ( P < 0.0001 vs. pioglitazone for all comparisons). At week 24, weight gain (1.4 and 0.6 kg, respectively) and edema (9.2 and 7.2%, respectively) were observed in the muraglitazar and pioglitazone groups; at week 50, weight gain and edema were 2.5 and 1.5 kg, respectively, and 11.8 and 8.9%, respectively. At week 50, heart failure was reported in seven patients (five with muraglitazar and two with pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from perforated duodenal ulcer in the pioglitazone group. CONCLUSIONS —We found that 5 mg muraglitazar resulted in greater improvements in A1C and lipid parameters than a submaximal dose of 30 mg pioglitazone when added to metformin. Weight gain and edema were more common when muraglitazar was compared with a submaximal dose of pioglitazone. apo, apolipoprotein CHF, congestive heart failure CRP, C-reactive protein CVD, cardiovascular disease FFA, free fatty acid FPG, fasting plasma glucose HOMA-IR, homeostasis model assessment of insulin resistance LOCF, last observation carried forward NYHA, New York Heart Association PAI-1, plasminogen activator inhibitor type 1 PPAR, peroxisome proliferator–activated receptor Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 31, 2006. Received June 22, 2005. DIABETES CARE

Patients with type 2 diabetes mellitus are routinely treated with combinations of glucose-lowering agents. The adverse event (AE) profile and effects on glycemic control have not been assessed for the glucagon-like peptide-1 receptor agonist exenatide once weekly in combination with a thiazolidinedione (TZD) with or without metformin. This study was conducted to examine the long-term safety profile and changes in glycemic control and weight for exenatide once weekly with TZD with or without metformin in patients with type 2 diabetes mellitus over 2 years. In this single-arm, open-label trial with treatment up to 104 or 117 weeks, patients received 2 mg exenatide once weekly while continuing treatment with a TZD with or without metformin. Patients were either exenatide-naïve before this study or had previously received exenatide twice daily, which was discontinued on initiating exenatide once weekly. Patients were on a stable dosage of TZD (rosiglitazone or pioglitazone) and, if applicable, metformin. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. Descriptive statistics were used for absolute and change-from-baseline data, and a one-sample t test for within-group change in glycosylated hemoglobin (HbA1c). Of 134 patients in the intent-to-treat population (baseline mean [SD] HbA1c,7.2% [1.0%]), 44 were exenatide-naïve (baseline HbA1c, 7.8% [1.0%]) and 90 switched from exenatide twice daily (baseline HbA1c, 7.0% [0.8%]). Of intent-to-treat patients, 106 (79%) completed the final treatment visit (week 104 or week 117). The most common AEs were nausea (17% of patients) and injection-site nodule (12% of patients). Serious AEs were reported in 14% of patients and 5% withdrew because of a treatment-emergent AE. No identifiable pattern of serious AEs was observed. There were 4 reports of edema and no reports of heart failure. No major hypoglycemia was reported; minor hypoglycemia was reported in 4% of patients. Exenatide-naïve patients experienced mean (SE) HbA1c reductions of −0.7% (0.2%) and weight reductions of −2.7 (0.8) kg, whereas patients with prior exposure to exenatide twice daily experienced a reduction of −0.4% (0.1%) in HbA1c and no change in weight. Adverse events over 2 years were consistent with the reported safety profiles of exenatide once weekly and TZDs. Exenatide-naïve patients experienced improvements in HbA1c and weight, while patients with the benefit of prior exenatide therapy experienced an additional reduction from baseline in HbA1c and no additional change in weight after 2 years. ClinicalTrials.gov identifier: NCT00753896.

This essay proposes a conceptual framework combining elements of Clausewitz's On War with trend-forecasting techniques to describe future operational environments. This framework captures how the interaction of megatrends-the rate of technological change, the composition of the international system, and the strength of state governance-shapes the character of competition, confrontation, and conflict in each period. We argue this framework can help military officers build the future force.

Erectile dysfunction (impotence) affects approximately 10 million to 20 million men in the United States. 1 , 2 It becomes more frequent with age, 3 but is not an inevitable consequence of normal aging. 4 It is usually due to organic factors or diseases, such as pelvic vascular disease, diabetes mellitus, neurodegenerative disorders, side effects of medication, pelvic surgery, and trauma. 3 , 4 Erectile dysfunction impairs sexual performance, diminishes self-esteem, 2 , 3 and disrupts personal relationships. 1 Current treatments for erectile dysfunction include oral medications, vacuum pumps, vascular surgery, penile prostheses, and intracavernosal injections. Oral medications, such as yohimbine, have limited efficacy. 5 , 6 Vacuum pumps may be . . .

OBJECTIVE: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]). RESULTS: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C greater-than-or-equal0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group. CONCLUSIONS: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.

To determine if a human fibroblast-derived dermal substitute could promote the healing of diabetic foot ulcers. A randomized, controlled, multicenter study was undertaken at 35 centers throughout the U.S. and enrolled 314 patients to evaluate complete wound closure by 12 weeks. Patients were randomized to either the Dermagraft treatment group or control (conventional therapy). Except for the application of Dermagraft, treatment of study ulcers was identical for patients in both groups. All patients received pressure-reducing footwear and were allowed to be ambulatory during the study. The results demonstrated that patients with chronic diabetic foot ulcers of >6 weeks duration experienced a significant clinical benefit when treated with Dermagraft versus patients treated with conventional therapy alone. With regard to complete wound closure by week 12, 30.0% (39 of 130) of Dermagraft patients healed compared with 18.3% (21 of 115) of control patients (P = 0.023). The overall incidence of adverse events was similar for both the Dermagraft and control groups, but the Dermagraft group experienced significantly fewer ulcer-related adverse events. The data from this study show that Dermagraft is a safe and effective treatment for chronic diabetic foot ulcers.

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers Applicability of a novel insulin-independent treatment John P.H. Wilding , MD 1 , Paul Norwood , MD 2 , Caroline T'joen , MSC 3 , Arnaud Bastien , MD 4 , James F. List , MD, PHD 4 and Fred T. Fiedorek , MD 4 1 University of Liverpool, School of Clinical Sciences, Liverpool, England; 2 University of California at San Francisco, Valley Research, Fresno, California; 3 Global Biometric Sciences, Bristol-Myers Squibb, Braine-l'Alleud, Belgium; 4 Global Clinical Research, Bristol-Myers Squibb, Princeton, New Jersey. Corresponding author: John P.H. Wilding, j.p.h.wilding{at}liv.ac.uk . Abstract OBJECTIVE To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort ( n = 4), patients in the treatment cohort ( n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]). RESULTS At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group. CONCLUSIONS In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo. Footnotes Clinical trial reg. no. NCT00357370, clinicaltrials.gov . A complete list of investigators can be found in an online appendix, available at http://care.diabetesjournals.org/cgi/content/full/dc09-0517/DC1 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received March 16, 2009. Accepted June 3, 2009. © 2009 by the American Diabetes Association.

The Efficacy and Safety of Dermagraft in Improving the Healing of Chronic Diabetic Foot Ulcers Results of a prospective randomized trial William A. Marston , MD 1 , Jason Hanft , DPM 2 , Paul Norwood , MD 3 , Richard Pollak , DPM 4 and for the Dermagraft Diabetic Foot Ulcer Study Group 1 University of North Carolina School of Medicine, Chapel Hill, North Carolina 2 Foot & Ankle Institute of South Florida, South Miami, Florida 3 Valley Endocrine, Fresno, California 4 University of Texas Health Science Center, San Antonio, Texas; and the Dermagraft Joint Venture, La Jolla, California Abstract OBJECTIVE —To determine if a human fibroblast–derived dermal substitute could promote the healing of diabetic foot ulcers. RESEARCH DESIGN AND METHODS —A randomized, controlled, multicenter study was undertaken at 35 centers throughout the U.S. and enrolled 314 patients to evaluate complete wound closure by 12 weeks. Patients were randomized to either the Dermagraft treatment group or control (conventional therapy). Except for the application of Dermagraft, treatment of study ulcers was identical for patients in both groups. All patients received pressure-reducing footwear and were allowed to be ambulatory during the study. RESULTS —The results demonstrated that patients with chronic diabetic foot ulcers of >6 weeks duration experienced a significant clinical benefit when treated with Dermagraft versus patients treated with conventional therapy alone. With regard to complete wound closure by week 12, 30.0% (39 of 130) of Dermagraft patients healed compared with 18.3% (21 of 115) of control patients ( P = 0.023). The overall incidence of adverse events was similar for both the Dermagraft and control groups, but the Dermagraft group experienced significantly fewer ulcer-related adverse events. CONCLUSIONS —The data from this study show that Dermagraft is a safe and effective treatment for chronic diabetic foot ulcers. Footnotes Address correspondence and reprint requests to William Marston, Campus Box 7212, 210 Burnett-Womack, University of North Carolina, Chapel Hill, NC 27599-7212. E-mail: sky{at}med.unc.edu . Received for publication 23 December 2002 and accepted in revised form 10 March 2003. W.A.M. is on the speaker’s bureau for Smith and Nephew, Inc., and has received honoraria and travel support for lectures and travel programs from Smith and Nephew, Inc. J.H. has received consulting fees for lectures and program sponsorship from Advanced Tissue Sciences, holds stock in ATIS, and has been a paid speaker for Smith and Nephew, Inc. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE