Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

OBJECTIVETo evaluate efficacy and safety of LixiLan (iGlarLixi), a novel titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide (Lixi), compared with both components, iGlar and Lixi, given separately in type 2 diabetes inadequately controlled on metformin with or without a second oral glucose-lowering drug. RESEARCH DESIGN AND METHODSAfter a 4-week run-in to optimize metformin and stop other oral antidiabetic drugs, participants (N = 1,170, mean diabetes duration ∼8.8 years, BMI ∼31.7 kg/m 2 ) were randomly assigned to open-label once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum insulin dose of 60 units/day, or to once-daily Lixi (20 mg/day) while continuing with metformin. The primary outcome was HbA 1c change at 30 weeks. RESULTSGreater reductions in HbA 1c from baseline (8.1% [65 mmol/mol]) were achieved with iGlarLixi compared with iGlar and Lixi (21.6%, 21.3%, 20.9%, respectively), reaching mean final HbA 1c levels of 6.5% (48 mmol/mol) for iGlarLixi versus 6.8% (51 mmol/mol) and 7.3% (56 mmol/mol) for iGlar and Lixi, respectively (both P < 0.0001). More subjects reached target HbA 1c <7% with iGlarLixi (74%) versus iGlar (59%) or Lixi (33%) (P < 0.0001 for all). Mean body weight decreased with iGlarLixi (20.3 kg) and Lixi (22.3 kg) and increased with iGlar (+1.1 kg, difference 1.4 kg, P < 0.0001). Documented symptomatic hypoglycemia (£70 mg/dL) was similar with iGlarLixi and iGlar (1.4 and 1.2 events/patient-year) and lower with Lixi (0.3 events/ patient-year). iGlarLixi improved postprandial glycemic control versus iGlar and demonstrated considerably fewer nausea (9.6%) and vomiting (3.2%) events than Lixi (24% and 6.4%, respectively). CONCLUSIONSiGlarLixi complemented iGlar and Lixi effects to achieve meaningful HbA 1c reductions, close to near normoglycemia without increases in either hypoglycemia or weight, compared with iGlar, and had low gastrointestinal adverse effects compared with Lixi.

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This study evaluated the long-term safety and efficacy of dapagliflozin as an adjunct to adjustable insulin in patients with type 1 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS DEPICT-1 (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) was a randomized (1:1:1), double-blind, placebo-controlled phase 3 study of dapagliflozin 5 mg and 10 mg in patients with type 1 diabetes (HbA 1c 7.5-10.5% [58-91 mmol/mol]) (NCT02268214). The results of the 52-week study, consisting of the 24-week short-term and 28-week extension period, are reported here. RESULTS Of the 833 patients randomized into the study, 708 (85%) completed the 52-week study. Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA 1c (difference vs. placebo [95% CI] 20.

Because chronic L-arginine supplementation improves insulin sensitivity and endothelial function in nonobese type 2 diabetic patients, the aim of this study was to evaluate the effects of a long-term oral L-arginine therapy on adipose fat mass (FM) and muscle free-fat mass (FFM) distribution, daily glucose levels, insulin sensitivity, endothelial function, oxidative stress, and adipokine release in obese type 2 diabetic patients with insulin resistance who were treated with a combined period of hypocaloric diet and exercise training. Thirty-three type 2 diabetic patients participated in a hypocaloric diet plus an exercise training program for 21 days. Furthermore, they were divided into two groups in randomized order: the first group was also treated with L-arginine (8.3 g/day), and the second group was treated with placebo. Although in the placebo group body weight, waist circumference, daily glucose profiles, fructosamine, insulin, and homeostasis model assessment index significantly decreased, L-arginine supplementation further decreased FM (P < 0.05) and waist circumference (P < 0.0001), preserving FFM (P < 0.03), and improved mean daily glucose profiles (P < 0.0001) and fructosamine (P < 0.03). Moreover, change in area under the curve of cGMP (second messenger of nitric oxide; P < 0.001), superoxide dismutase (index of antioxidant capacity; P < 0.01), and adiponectin levels (P < 0.02) increased, whereas basal endothelin-1 levels (P < 0.01) and leptin-to-adiponectin ratio (P < 0.05) decreased in the L-arginine group. Long-term oral L-arginine treatment resulted in an additive effect compared with a diet and exercise training program alone on glucose metabolism and insulin sensitivity. Furthermore, it improved endothelial function, oxidative stress, and adipokine release in obese type 2 diabetic patients with insulin resistance.

Endothelial nitric oxide synthase (eNOS) variants were previously demonstrated in cardiovascular disease. To evaluate whether eNOS gene variants are associated with insulin resistance and type 2 diabetes, we evaluated polymorphisms in Exon7 (E298D), intron 18 (IVS18 ؉ 27A3 C), and intron 23 (IVS23 ؉ 10G3 T) in 159 type 2 diabetic patients without macrovascular complications and in 207 healthy control subjects. Samples for all hormonal and metabolic variables were obtained after an overnight fast. The D298 and IVS18 ؉ 27C alleles, but not the IVS23 ؉ 10G3 T variant, were significantly more frequent in type 2 diabetic patients than in control subjects. The two-and three-loci haplotype analysis showed that there is a statistically significant association between the eNOS variants and type 2 diabetes. No significant differences were observed in the clinical characteristics of type 2 diabetic patients according to genotypes (except for visceral obesity [waist-to-hip ratio], which was significantly more present in D298 homozygotes). Healthy control subjects homozygous for both D298 and IVS18 ؉ 27C presented higher insulin, C-peptide, and nitric oxide levels, as well as higher HOMA (homeostasis model assessment) values than the double wild-type homozygotes, with values superimposable on those found in type 2 diabetic patients. In conclusion, we described a significant association between eNOS gene polymorphisms and type 2 diabetes, suggesting a new genetic susceptibility factor for hyperinsulinemia, insulin resistance, and type 2 diabetes. Diabetes 52:1270 -1275, 2003 T ype 2 diabetes is associated with a marked increase in coronary heart disease (CHD) (1), and increased risk factors for CHD before the onset of type 2 diabetes have been shown in several populations (2,3). In addition, type 2 diabetic patients with clinical cardiovascular disease sustain a worse prognosis for survival than cardiovascular disease patients without diabetes (4). This seems correlated to the high atherogenic state already present in a prediabetic state, which might be partly related to insulin resistance (5).Recently, endothelial dysfunction, such as nitric oxide (NO) impairment, is regarded as an early step in the development of insulin resistance, atherosclerosis, and type 2 diabetes (6 -8). Studies evaluating the relation between CHD and endothelial dysfunction have clearly demonstrated that reduced NO-dependent endothelial vasodilation is an early functional disturbance in the development of atherosclerotic lesions (6 -8). In addition, among the many activities of NO, it has demonstrated its ability to modulate peripheral and hepatic glucose metabolism and insulin secretion, according to Pieper (9), who suggested that NO alterations play an important role in the evolution of insulin resistance and type 2 diabetes. Moreover, our group has found high NO levels and endothelial dysfunction in type 2 diabetic patients and first-degree relatives of subjects with type 2 diabetes (10), as well as in subjects with the insulin resistance syndrome...

Inflammation, a risk factor for cardiovascular disease, is associated with low plasma levels of antioxidant vitamins. In addition to vitamins, other antioxidants modulate the synthesis of inflammatory markers in vitro and contribute to the total antioxidant capacity (TAC) of a diet. However, the relationship between dietary TAC and markers of inflammation has never been evaluated in vivo. We investigated the relationship between dietary TAC and markers of systemic (high-sensitivity C-reactive protein (hs-CRP), leucocytes) and vascular (soluble intercellular cell adhesion molecule-1) inflammation in 243 nondiabetic subjects. General Linear Model (GLM) analysis showed a significant (P¼0·005) inverse relationship between hs-CRP and quartiles of energyadjusted dietary TAC, even when recognized modulating factors of inflammation, namely alcohol, fibre, vitamin C, a-tocopherol, b-carotene, BMI, waist circumference, HDL-cholesterol, hypertension, insulin sensitivity and plasma b-carotene, were included in the model as covariates (P¼0·004). The relationship was stronger for subjects with hypertension (P¼0·013 v. P¼ 0·109 for normotensive individuals). Among dietary factors, TAC was significantly higher (5·3 (SD 3·0) v. 4·9 (SD 2·7) mmol Trolox/d; P¼0·026) in subjects with low plasma hs-CRP (range: 0·0-4·1 mg/l) than in subjects with high plasma hs-CRP (range: 4·2-27·8 mg/l). We conclude that dietary TAC is inversely and independently correlated with plasma concentrations of hs-CRP and this could be one of the mechanisms explaining the protective effects against CVD of antioxidant-rich foods such as fruits, whole cereals and red wine. This could be of particular significance for subjects with high blood pressure.

OBJECTIVE -The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine-3Ј,5Ј-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS-A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemichyperinsulinemic clamp combined with [6, H 2 ]glucose infusion. A total of 10 normal subjects underwent the same test as control subjects.RESULTS -In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal.CONCLUSIONS -L-Arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 24:875-880, 2001C ontradictory results have been found concerning the influence of insulin on nitric oxide (NO), a potent molecule with vasodilatory function. Baron et al. (1,2) showed that insulinmediated vasodilation is largely dependent on the action of insulin on NO release, whereas Petrie et al. (3) have shown that endothelial NO synthesis and insulin sensitivity are positively correlated in healthy individuals. In addition, in obese patients and patients with type 2 diabetes, the insulin-mediated vasodilatory response seems blunted (4). However, Yki-Jarvinen et al. (5) were unable to find any correlation between insulin action and increment in blood flow in normal and obese subjects, although all agree that methacoline-induced vasodilation is impaired in insulin-resistant subjects.L-Arginine is a precursor for NO, and both in vitro and in vivo studies have demonstrated that L-arginine can augment vascular dilation under certain conditions (6). Experimental studies in cholesterol-fed rabbits have shown that dietary supplementation with L-arginine causes attenuation of endothelial dysfunction with increased NO activity, resulting in reduced platelet activation (7), monocyte adhesion (8), and a marked reduction in aortic and coronary atherosclerosis (9). Moreover, in young hypercholesterolemic adults, the administr...