Giorgio Sesti

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

BACKGROUND Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. FUNDING Novo Nordisk A/S.

Switching to Once-Daily Liraglutide From Twice-Daily Exenatide Further Improves Glycemic Control in Patients With Type 2 Diabetes Using Oral Agents

OBJECTIVE To evaluate efficacy and safety of switching from twice-daily exenatide to once-daily liraglutide or of 40 weeks of continuous liraglutide therapy. RESEARCH DESIGN AND METHODS When added to oral antidiabetes drugs in a 26-week randomized trial (Liraglutide Effect and Action in Diabetes [LEAD]-6), liraglutide more effectively improved A1C, fasting plasma glucose, and the homeostasis model of β-cell function (HOMA-B) than exenatide, with less persistent nausea and hypoglycemia. In this 14-week extension of LEAD-6, patients switched from 10 μg twice-daily exenatide to 1.8 mg once-daily liraglutide or continued liraglutide. RESULTS Switching from exenatide to liraglutide further and significantly reduced A1C (0.32%), fasting plasma glucose (0.9 mmol/l), body weight (0.9 kg), and systolic blood pressure (3.8 mmHg) with minimal minor hypoglycemia (1.30 episodes/patient-year) or nausea (3.2%). Among patients continuing liraglutide, further significant decreases in body weight (0.4 kg) and systolic blood pressure (2.2 mmHg) occurred with 0.74 episodes/patient-year of minor hypoglycemia and 1.5% experiencing nausea. CONCLUSIONS Conversion from exenatide to liraglutide is well tolerated and provides additional glycemic control and cardiometabolic benefits.

Elevated one-hour post-load plasma glucose levels identifies subjects with normal glucose tolerance but early carotid atherosclerosis

OBJECTIVE To examine whether individuals with normal glucose tolerance (NGT), whose 1-h post-load plasma glucose is >or=155 mg/dl, or with impaired glucose tolerance (IGT) have an increased carotid intima-media thickness (IMT), as compared with NGT individuals with 1-h post-load plasma <155 mg/dl. METHODS Atherosclerosis risk factors, oral glucose tolerance test (OGTT), and ultrasound manual measurement of IMT were analyzed in 400 non-diabetic Caucasians. RESULTS As compared with individuals with a 1-h post-load plasma glucose <155 mg/dl, NGT individuals with a 1-h post-load plasma glucose >or=155 mg/dl exhibited higher hsCRP (2.0+/-1.5 vs. 1.5+/-1.0, P=0.008), and IMT (0.82+/-0.20 vs. 0.71+/-0.16; P=0.006), and lower insulin sensitivity (71+/-39 vs. 105+/-57; P<0.0001), and IGF-1 levels (214+/-88 vs. 176+/-49; P<0.03). No significant differences were observed in metabolic and cardiovascular risk factors between IGT and NGT subjects with a 1-h post-load glucose >or=155 mg/dl. Of the three glycemic parameters, 1-h and 2-h post-load glucose, but not fasting glucose, were significantly correlated with IMT. In a stepwise multivariate regression analysis in a model including age, gender, and a variety of atherosclerosis risk factors, the three variables that remained significantly associated with IMT were age (P<0.0001), BMI (P<0.0001), and 1-h post-load glucose (P=0.02) accounting for 20.2% of its variation. CONCLUSIONS NGT subjects with a 1-h post-load glucose >or=155 mg/dl have an atherogenic profile similar to IGT individuals. These data suggest that a cutoff point of 155 mg/dl for the 1-h post-load glucose during OGTT may be helpful in the identification of NGT subjects at increased risk for cardiovascular disease.

G972R IRS-1 Variant Impairs Insulin Regulation of Endothelial Nitric Oxide Synthase in Cultured Human Endothelial Cells

Background—Impaired insulin-mediated vasodilation might contribute to vascular damage in insulin-resistant states. Little is known about insulin regulation of nitric oxide (NO) synthesis in insulin-resistant cells. The aim of this work was to investigate insulin regulation of NO synthesis in human umbilical vein endothelial cells (HUVECs) carrying the IRS-1 gene G972R variant, known to be associated with impaired insulin activation of the PI3-kinase (PI3-K) pathway in transfected cells. Methods and Results—HUVECs were screened for the presence of the G972R-IRS-1 (HUVEC-G972R) variant by restriction fragment length polymorphisms. After 24-hour exposure to 10−7 mol/L insulin, endothelial NO synthase (eNOS) mRNA (reverse transcription–polymerase chain reaction), eNOS protein levels (Western blotting), and NOS activity (conversion of [3H]arginine into [3H]citrulline) were increased in wild-type HUVECs (HUVEC-WT), whereas they did not change from baseline in HUVEC-G972R. Compared with HUVEC-WT, in HUVEC-G972R after 2 and 10 minutes of insulin stimulation, IRS-1–associated PI3-K activity was reduced by 47% and 32%, respectively; Akt phosphorylation was decreased by 40% at both time points; and eNOS-Ser1177 phosphorylation was reduced by 38% and 51%, respectively. In HUVEC-WT, eNOS-Thr495 phosphorylation decreased after insulin stimulation. In contrast, in HUVEC-G972R, eNOS-Thr495 phosphorylation increased after insulin stimulation and was 40% greater than in HUVEC-WT. Conclusions—Our data demonstrate that genetic impairment of the (IRS)-1/PI3-K/PDK-1/Akt insulin signaling cascade determines impaired insulin-stimulated NO release and suggest that the G972R-IRS-1 polymorphism, through a direct impairment of Akt/eNOS activation in endothelial cells, may contribute to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease.

A Review of Efficacy and Safety Data Regarding the Use of Liraglutide, a Once-Daily Human Glucagon-Like Peptide 1 Analogue, in the Treatment of Type 2 Diabetes Mellitus

BACKGROUND Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) that is administered as a once-daily subcutaneous injection. OBJECTIVE The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials. METHODS Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and vildagliptin. Original research papers about liraglutide that were published in peer-reviewed journals were considered. RESULTS The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA(1c)) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA(1c) goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved beta-cell function, as measured by homeostasis model assessment for beta-cell function analysis (20%-44%) and by ratios of pro-insulin to insulin (-0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient. CONCLUSION Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM.

Components of the Metabolic Syndrome and Carotid Atherosclerosis: Role of Elevated Blood Pressure

Elevated blood pressure is among the factors that contribute to the metabolic syndrome (MetS). It is not known whether subjects with MetS and elevated blood pressure are at the same cardiovascular risk as subjects with MetS but without elevated blood pressure. To clarify this point, we have evaluated the prevalence of carotid atherosclerosis in subjects with MetS with or without elevated blood pressure. A large population was examined (842 women and 1011 men). Blood pressure, lipids, glucose, and waist were measured by routine methods. Carotid atherosclerosis was evaluated by echo Doppler examination. The prevalence of MetS was 24.4% in women and 28.7% in men. The prevalence of carotid atherosclerosis was 35.1% in women and 37.3% in men (p=NS), and increased with increasing number of MetS components. Age, smoking, and systolic blood pressure (SBP) were associated with the presence of carotid atherosclerosis (logistic model), whereas age, high-density lipoprotein cholesterol, and SBP were associated with the extent of atherosclerosis (linear model). When comparing subjects with an equal number of MetS components, the prevalence of carotid atherosclerosis was significantly higher in subjects with elevated blood pressure than in those without. No difference in carotid atherosclerosis prevalence was found in subjects bearing or not bearing components of the syndrome other than elevated blood pressure. The present findings demonstrate that subjects with MetS and elevated blood pressure have increased carotid atherosclerosis compared with subjects with MetS but without elevated blood pressure. The diagnosis of MetS per se might not adequately identify subjects at elevated cardiovascular risk.

Efficacy of antihyperglycemic therapies and the influence of baseline hemoglobin A(1C): a meta-analysis of the liraglutide development program.

OBJECTIVE To compare liraglutide versus common antihyperglycemic treatments in reducing hemoglobin A1c (A1C) values across multiple levels of baseline glycemic control and in reaching glycemic targets. METHODS Pooled patient data from 7 phase 3, multinational, randomized controlled trials in patients with type 2 diabetes were stratified by baseline A1C values into 5 categories: ≤7.5%, >7.5% to 8.0%, >8.0% to 8.5%, >8.5% to 9.0%, and y9.0%. The changes in A1C from baseline to week 26 of treatment and patient proportions reaching A1C targets of <7.0% and ≤6.5% were compared between liraglutide (1.8 mg daily) and sitagliptin, glimepiride, rosiglit-azone, exenatide, and insulin glargine across all baseline A1C categories. RESULTS Irrespective of treatment, reductions in A1C levels were generally greater in groups with higher baseline A1C values. After 26 weeks of treatment, liraglutide produced the greatest reductions in A1C values across all baseline categories, ranging from 0.7% to 1.8% (baseline A1C categories ≤7.5% to >9.0%, respectively), followed by insulin glargine (0.3% to 1.5%) and then by glimepiride (0.4% to 1.3%). Generally, larger percentages of patients achieved the A1C target of ≤6.5% with liraglutide therapy across all baseline categories (from 62% of patients with A1C values ≤7.5% to 10% of patients with A1C values >9.0%) in comparison with other treatments (ranging from 49% to 0% of patients, respectively). Similarly, greater proportions of patients also reached the A1C target of <7.0% with liraglutide therapy across all baseline categories (from 83% of patients with A1C values ≤7.5% to 25% of patients with A1C values >9.0%) versus comparators (from 74% to 5% of patients, respectively). CONCLUSION Across a wide spectrum of baseline A1C categories, liraglutide is an efficacious treatment option for patients with type 2 diabetes.

Liraglutide achieves A1C targets more often than sitagliptin or exenatide when added to metformin in patients with type 2 diabetes and a baseline A1C <8.0%.

OBJECTIVE Compare the safety and efficacy of liraglutide to that of sitagliptin or exenatide as add-on to metformin in patients with type 2 diabetes (T2D) and glycated hemoglobin (A1C) <8.0%. METHODS Post hoc analysis of 26-week data from liraglutide 1.8 mg once daily (OD) versus exenatide 10 μg twice daily (LEAD-6) and liraglutide 1.8 mg OD versus sitagliptin 100 mg OD (LIRA-DPP-4); only patients treated as add-on to metformin with baseline A1C <8.0% were included. Efficacy analysis was performed on the intention-to-treat population with missing values imputed by last observation carried forward. RESULTS More patients achieved A1C targets (<7.0% and ≤6.5%) with liraglutide versus exenatide or sitagliptin; the difference was greatest for A1C ≤6.5% (LEAD-6: 65% versus 35%; odds ratio [OR]=3.37, 95% confidence interval [CI]: 1.31-8.63; P = .01 or LIRA-DPP-4: 53% versus 19%; OR = 4.78, 95% CI 2.10 to 10.87; P = .0002). Significantly more patients achieved a composite endpoint of A1C <7.0% with no weight gain or hypoglycemia with liraglutide compared with exenatide (78% versus 42%; OR = 4.99, 95% CI: 1.77 to 14.04; P = .0023) or sitagliptin (61% versus 21%; OR = 5.95, 95% CI: 2.66 to 13.29; P<.0001). All treatments were well tolerated, there was no major hypoglycemia and few patients (8 to 10%) experienced minor hypoglycemia. CONCLUSION When added to metformin in patients with an A1C <8.0%, more patients using liraglutide 1.8 mg reached A1C targets than with exenatide or sitagliptin. Sitagliptin had particularly low efficacy in this analysis. These data support the use of liraglutide 1.8 mg as a safe and effective alternative to sitagliptin or exenatide following metformin failure in patients with an A1C <8.0%.

Transgenic mice overexpressing human G972R IRS-1 show impaired insulin action and insulin secretion

Molecular scanning of human insulin receptor substrate (Irs) genes revealed a single lrs1 prevalent variant, a glycine to arginine change at codon 972 (G972R); previous in vitro studies had demonstrated that the presence of this variant results in an impaired activation of the insulin signalling pathway, while human studies gave controversial results regarding its role in the pathogenesis of insulin resistance and related diseases. To address in vivo impact of this IRS‐1 variant on whole body glucose homeostasis and insulin signalling, we have generated transgenic mice overexpressing it (Tg972) and evaluated insulin action in the liver, skeletal muscle and adipose tissue and assessed glucose homeostasis both under a normal diet and a high‐fat diet. We found that Tg972 mice developed age‐related glucose and insulin intolerance and hyperglycaemia, with insulin levels comparatively low. Glucose utilization and insulin signalling were impaired in all key insulin target tissues in Tg972 mice. There were no differences in pancreatic morphology between Tg972 and wild‐type mice, however when insulin secretion was evaluated in isolated islets, it was significantly reduced in Tg972 mice islets at any glucose concentration tested. Under a high‐fat diet, Tg972 mice had increased body and adipose tissue weight, and were more prone to develop diet‐induced glucose and insulin intolerance. So, we believe that Tg972 mice may represent a useful model to elucidate the interaction between genetic and environmental factors in insulin resistance pathogenesis. Furthermore, they may become an important tool to test novel tailored therapies.

Use and effectiveness of dapagliflozin in routine clinical practice. An Italian multicenter retrospective study

In randomized controlled trials (RCTs), sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have been shown to confer glycaemic and extra‐glycaemic benefits. The DARWIN‐T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase‐4 inhibitors, gliclazide, or glucagon‐like peptide‐1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose‐lowering medications (GLMs), 6751 of whom had a follow‐up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real‐world study shows an initial channelling of dapagliflozin to difficult‐to‐treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.