Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial.

Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.

Recent advances in the treatment of erectile dysfunction in patients with diabetes mellitus.

OBJECTIVE: To present current information on the pathogenesis of and available therapeutic options for erectile dysfunction (ED) in patients with diabetes. METHODS: We provide a detailed review of the following topics: (1) peripheral and central neurotransmitter pathways involved in the penile erectile process (for example, nitric oxide, acetylcholine, vasoactive intestinal polypeptide, and prostaglandin E(1)), (2) pathogenesis of ED in patients with diabetes (vascular insufficiency, endothelial dysfunction, and autonomic neuropathy), (3) currently available treatment options for ED and their advantages and disadvantages, (4) potential new avenues for future research, and (5) the possibility of preventive treatment. RESULTS: Clearly a need exists for effective treatment options for ED in patients with diabetes. Because the development of ED in patients with diabetes is often caused by several interrelated mechanisms, including vascular disease, endothelial dysfunction, autonomic neuropathy, hormone imbalance, and certain medications, a thorough understanding of the various pathways involved in penile erection and their modulation in diabetes is essential for physicians to design an effective treatment plan. Interventions that modulate the erectile pathway at different points include therapies that enhance the erectile mechanism (amplification of the nitric oxide pathway), inhibit the detumescence mechanism, or affect the final common pathway by augmenting smooth muscle relaxation. Oral therapy, intracavernosal injections, transurethral pellets, combination therapy, and surgical procedures are available treatment strategies. CONCLUSION: Despite the availability of many treatment options for ED, early intervention and prevention (by such measures as improved glycemic control and general reduction of associated risk factors) should be emphasized because many of the diabetes-related complications leading to ED are irreversible.

A multinational population survey of intravaginal ejaculation latency time.

INTRODUCTION: Intravaginal ejaculation latency time (IELT), defined as the time between the start of vaginal intromission and the start of intravaginal ejaculation, is increasingly used in clinical trials to assess the amount of selective serotonin reuptake inhibitor-induced ejaculation delay in men with premature ejaculation. Prospectively, stopwatch assessment of IELTs has superior accuracy compared with retrospective questionnaire and spontaneous reported latency. However, the IELT distribution in the general male population has not been previously assessed. AIM: To determine the stopwatch assessed-IELT distribution in large random male cohorts of different countries. METHODS: A total of 500 couples were recruited from five countries: the Netherlands, United Kingdom, Spain, Turkey, and the United States. Enrolled men were aged 18 years or older, had a stable heterosexual relationship for at least 6 months, with regular sexual intercourse. The surveyed population were not included or excluded by their ejaculatory status and comorbidities. This survey was performed on a "normal" general population. Sexual events and stopwatch-timed IELTs during a 4-week period were recorded, as well as circumcision status and condom use. MAIN OUTCOME MEASURES: The IELT, circumcision status, and condom use. RESULTS: The distribution of the IELT in all the five countries was positively skewed, with a median IELT of 5.4 minutes (range, 0.55-44.1 minutes). The median IELT decreased significantly with age, from 6.5 minutes in the 18-30 years group, to 4.3 minutes in the group older than 51 years (P<0.0001). The median IELT varied between countries, with the median value for Turkey being the lowest, i.e., 3.7 minutes (0.9-30.4 minutes), which was significantly different from each of the other countries. Comparison of circumcised (N=98) and not-circumcised (N=261) men in countries excluding Turkey resulted in median IELT values of 6.7 minutes (0.7-44.1 minutes) in circumcised compared with 6.0 minutes (0.5-37.4 minutes) in not-circumcised men (not significant). The median IELT value was not affected by condom use. CONCLUSION: The IELT distribution is positively skewed. The overall median value was 5.4 minutes but with differences between countries. For all five countries, median IELT values were independent of condom usage. In countries excluding Turkey, the median IELT values were independent of circumcision status.

Onset and duration of action of sildenafil for the treatment of erectile dysfunction.

AIMS: To determine the onset and duration of action of sildenafil in patients with erectile dysfunction (ED). METHODS: Two randomised, double-blind, placebo-controlled, two-way crossover studies were conducted in men with ED of no known organic cause. Study I: The time to onset of erections after sildenafil (50 mg) or placebo dosing following visual sexual stimulation (VSS) was assessed in 17 patients. Patients not achieving >60% penile rigidity by 70 min postdose as measured by a RigiScan(R) monitoring device were assigned an onset time of 70 min. Study II: The duration of grade 3 (hard enough for penetration) and grade 4 (fully hard) erections, determined by self-assessment during 60 min of VSS starting 2 and 4 h after sildenafil (100 mg) or placebo dosing, was measured in 16 patients. RESULTS: Study I: The median time (range) to onset of erections was 27 min (in a range of 12--70) after receiving sildenafil 50 mg. In the sildenafil group, 71% of patients experienced onset of erections within 30 min of dosing, and 82% responded within 45 min. Of the patients who achieved >60% penile rigidity after sildenafil, 86% had done so by 30 min after dosing. Study II: When VSS began 2 h postdose, the median duration of grade 3 or 4 erections was 19.5 min (0--55) for sildenafil vs 0 min (0--23) for placebo. When VSS began 4 h postdose, the median duration was 5 min (0--45) for sildenafil compared with 0 min for placebo (0--27). CONCLUSIONS: Sildenafil is an effective oral treatment for ED that produces a penetrative erection as early as 12 min and for most patients, within 30 min after dosing, and a duration of action lasting at least 4 h.

The enhancement of vaginal vasocongestion by sildenafil in healthy premenopausal women.

OBJECTIVE: This study examined the effect of a single oral dose of sildenafil citrate (Viagra, Pfizer, Inc., New York, NY) on vaginal vasocongestion and subjective sexual arousal in healthy premenopausal women. METHODS: Twelve women without sexual dysfunction were randomly assigned to receive either a single oral 50 mg dose of sildenafil or matching placebo in a first session and the alternate medication in a second session. Subjective measures of sexual arousal were assessed after participants had been exposed to erotic stimulus conditions. Vaginal vasocongestion was recorded continuously during baseline, neutral, and erotic stimulus conditions. At the end of each session, subjects were also asked to specify which treatment they suspected they had received. RESULTS: Significant increases in vaginal vasocongestion were found with sildenafil treatment compared with placebo. There were no differences between treatments on subjective sexual arousal experience. Analyses by suspected treatment received found that significantly stronger sexual arousal and vaginal wetness were reported for the treatment that was believed to be sildenafil vs. the treatment that was believed to be placebo. The suspected treatment sequence was incorrect for half of the women. Sildenafil was well tolerated, with no evidence of significant adverse events. CONCLUSIONS: Sildenafil was found to be effective in enhancing vaginal engorgement during erotic stimulus conditions in healthy women without sexual dysfunction but was not associated with an effect on subjective sexual arousal.