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Efficacy and safety of lixisenatide in patients with type 2 diabetes and renal impairment.
Hanefeld, M, Arteaga, JM, Leiter, LA, Marchesini, G, Nikonova, E, Shestakova, M, Stager, W, Gómez-Huelgas, R
Diabetes, obesity & metabolism. 2017;(11):1594-1601
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Abstract
AIMS: This post hoc assessment evaluated the efficacy and safety of once-daily, prandial glucagon-like peptide-1 receptor agonist lixisenatide in patients with type 2 diabetes (T2D) and normal renal function (estimated glomerular filtration rate ≥90 mL/min), or mild (60-89 mL/min) or moderate (30-59 mL/min) renal impairment. METHODS Patients from 9 lixisenatide trials in the GetGoal clinical trial programme were categorized by baseline creatinine clearance: normal renal function (lixisenatide n = 2094, placebo n = 1150); renal impairment (mild: lixisenatide n = 637, placebo n = 414; moderate: lixisenatide n = 122, placebo n = 68). Meta-analyses of placebo-adjusted mean differences between baseline renal categories were performed for efficacy and safety outcomes. RESULTS HbA1c, 2-hour postprandial plasma glucose and fasting plasma glucose were comparably reduced in lixisenatide-treated patients with normal renal function, and mild and moderate renal impairment. The most common adverse events (AEs) in all renal function categories were gastrointestinal (GI), predominantly nausea and vomiting. A 14% higher incidence of GI AEs and a 10% higher incidence of nausea and vomiting were seen with mild impairment vs normal function (P = .003 for both), but no significant differences were observed between the mild and moderate impairment categories (P = .99 and P = .57, respectively), or between the moderate impairment and normal categories (P = .16 and P = .65, respectively). Additionally, the incidence of hypoglycaemia was similar in all categories. CONCLUSIONS This study demonstrates that baseline renal status does not affect efficacy outcomes in lixisenatide- vs placebo-treated patients, and that no lixisenatide dose adjustment is required for patients with T2D with mild or moderate renal impairment.
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A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients.
Abd El Aziz, MS, Kahle, M, Meier, JJ, Nauck, MA
Diabetes, obesity & metabolism. 2017;(2):216-227
Abstract
AIMS: To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM). METHODS Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared. RESULTS Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight. CONCLUSIONS Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.
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Inverse association between carbohydrate consumption and plasma adropin concentrations in humans.
Stevens, JR, Kearney, ML, St-Onge, MP, Stanhope, KL, Havel, PJ, Kanaley, JA, Thyfault, JP, Weiss, EP, Butler, AA
Obesity (Silver Spring, Md.). 2016;(8):1731-40
Abstract
OBJECTIVE The role of metabolic condition and diet in regulating circulating levels of adropin, a peptide hormone linked to cardiometabolic control, is not well understood. In this study, weight loss and diet effects on plasma adropin concentrations were examined. METHODS This report includes data from (1) a weight loss trial, (2) an evaluation of acute exercise effects on mixed-meal (60% kcal from carbohydrates) tolerance test responses, and (3) a meta-analysis to determine normal fasting adropin concentrations. RESULTS Distribution of plasma adropin concentrations exhibited positive skew and kurtosis. The effect of weight loss on plasma adropin concentrations was dependent on baseline plasma adropin concentrations, with an inverse association between baseline and a decline in concentrations after weight loss (Spearman's ρ = -0.575; P < 0.001). When ranked by baseline plasma adropin concentrations, only values in the upper quartile declined with weight loss. Plasma adropin concentrations under the main area of the bell curve correlated negatively with habitual carbohydrate intake and plasma lipids. There was a negative correlation between baseline values and a transient decline in plasma adropin during the mixed-meal tolerance test. CONCLUSIONS Plasma adropin concentrations in humans are sensitive to dietary macronutrients, perhaps due to habitual consumption of carbohydrate-rich diets suppressing circulating levels. Very high adropin levels may indicate cardiometabolic conditions sensitive to weight loss.
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Early Pharmacodynamic Effects of Exenatide Once Weekly in Type 2 Diabetes Are Independent of Weight Loss: A Pooled Analysis of Patient-level Data.
Trautmann, ME, Han, J, Ruggles, J
Clinical therapeutics. 2016;(6):1464-1473
Abstract
PURPOSE Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective (~50 pg/mL) and steady-state (~300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses. METHODS This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed. FINDINGS Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA1c, FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not. IMPLICATIONS Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.
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Casein-derived lactotripeptides reduce systolic and diastolic blood pressure in a meta-analysis of randomised clinical trials.
Fekete, ÁA, Givens, DI, Lovegrove, JA
Nutrients. 2015;(1):659-81
Abstract
There is an urgent need to treat individuals with high blood pressure (BP) with effective dietary strategies. Previous studies suggest a small, but significant decrease in BP after lactotripeptides (LTP) ingestion, although the data are inconsistent. The study aim was to perform a comprehensive meta-analysis of data from all relevant randomised controlled trials (RCT). Medline, Cochrane library, EMBASE and Web of Science were searched until May 2014. Eligibility criteria were RCT that examined the effects of LTP on BP in adults, with systolic BP (SBP) and diastolic BP (DBP) as outcome measures. Thirty RCT met the inclusion criteria, which resulted in 33 sets of data. The pooled treatment effect for SBP was -2.95 mmHg (95% CI: -4.17, -1.73; p < 0.001), and for DBP was -1.51 mmHg (95% CI: -2.21, -0.80; p < 0.001). Sub-group analyses revealed that reduction of BP in Japanese studies was significantly greater, compared with European studies (p = 0.002 for SBP and p < 0.001 for DBP). The 24-h ambulatory BP (AMBP) response to LTP supplementation was statistically non-significant (p = 0.101 for SBP and p = 0.166 for DBP). Both publication bias and "small-study effect" were identified, which shifted the treatment effect towards less significant SBP and non-significant DBP reduction after LTP consumption. LTP may be effective in BP reduction, especially in Japanese individuals; however sub-group, meta-regression analyses and statistically significant publication biases suggest inconsistencies.
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Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis.
Videlock, EJ, Cheng, V, Cremonini, F
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2013;(9):1084-1092.e3; quiz e68
Abstract
BACKGROUND & AIMS Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. METHODS MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). RESULTS The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 μg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3-2.9), and the NNT was 7 (95% CI, 5-11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 μg linaclotide vs placebo (95% CI, 2.80-6.47), and the NNT was 7 (95% CI, 5-8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. CONCLUSIONS On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo.
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Glatiramer acetate for multiple sclerosis.
La Mantia, L, Munari, LM, Lovati, R
The Cochrane database of systematic reviews. 2010;(5):CD004678
Abstract
BACKGROUND This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2004 , Issue 1 . Art. No.: CD004678. DOI: 10.1002/14651858.CD004678)Previous studies have shown that glatiramer acetate (Copaxone (R)), a synthetic amino acid polymer is effective in experimental allergic encephalomyelitis (EAE), and improve the outcome of patients with multiple sclerosis (MS). OBJECTIVES To verify the clinical efficacy of glatiramer acetate in the treatment of MS patients with relapsing remitting (RR) and progressive (P) course. SEARCH STRATEGY We searched the Cochrane MS Group Trials Register (26 March 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2009), MEDLINE (PubMed) (January 1966 to 26 March 2009), EMBASE (January 1988 to 26 March 2009) and hand searching of symposia reports (1990-2009). SELECTION CRITERIA All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review. DATA COLLECTION AND ANALYSIS Both patients with RR and P MS were analysed. Study protocols were comparable across trials. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against side effects, including injection-site reactions. MAIN RESULTS Among 409 retrieved references, we identified 16 RCTs; six of them, published between 1987 and 2007, met the selection criteria and were included in this review. Five hundred and forty RR patients and 1049 PMS contributed to the analysis. In RR MS, a decrease in the mean EDSS score (-0.33 and -0.45), was found respectively at 2 years and 35 months without any significant effect on sustained disease progression. The reduction of mean number of relapse was evident at 1 year (-0.35 ) 2 years (-0.51 ) and 35 months (-0.64), but significant studies ' heterogeneity was found. The number of hospitalisations and steroid courses were significantly reduced. No benefit was shown in P MS patients. No major toxicity was found. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety. Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. AUTHORS' CONCLUSIONS Glatiramer acetate did show a partial efficacy in RR MS in term of relapse -related clinical outcomes, without any significant effect on clinical progression of disease measured as sustained disability. The drug is not effective in progressive MS patients.
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A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis.
Pillai, G, Gieschke, R, Goggin, T, Jacqmin, P, Schimmer, RC, Steimer, JL
British journal of clinical pharmacology. 2004;(6):618-31
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Abstract
AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.