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Riddle M.C.,Oregon Health And Science University | Aronson R.,LMC Diabetes & Endocrinology | Home P.,Northumbria University | Marre M.,University Paris Diderot | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS-We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA 1c reduction frombaseline was the primary end point. RESULTS-Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebocorrected change of HbA1c from baseline was -0.4% (95%CI -0.6 to -0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, -3.8 mmol/L; P < 0.0001); sevenpoint glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, -1.3 kg; P < 0.0001) and insulin dosage (-3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo. CONCLUSIONS-By improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options. © 2013 by the American Diabetes Association.

Aronson R.,LMC Diabetes & Endocrinology
Expert Review of Clinical Pharmacology | Year: 2013

Despite availability of new treatments for patients with Type 2 diabetes mellitus (T2DM), optimal management of glycemic control remains challenging. Treatment with basal insulin can improve HbA1c, but may not be sufficient to control postprandial plasma glucose (PPG) levels. Both fasting plasma glucose (FPG) and PPG levels contribute to overall glycemic control. In patients with moderate hyperglycemia, PPG excursions have a greater contribution to overall hyperglycemia, with this contribution being greatest when HbA1c is approximately 7-8% [1]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been designed to restore and maintain GLP-1 levels and attenuate PPG excursions. GLP-1RAs that predominantly affect PPG may complement the FPG lowering provided by basal insulin, possibly improving overall glycemic control without additional weight gain and with limited incidence of hypoglycemia. Lixisenatide as an add-on to basal insulin lowers PPG levels, improves HbA1c control and has a beneficial effect on weight in T2DM patients. © 2013 Informa UK Ltd.

Aronson R.,LMC Diabetes & Endocrinology
Diabetes Technology and Therapeutics | Year: 2012

Despite the recognized importance of optimal insulin therapy, patient adherence to insulin therapy is an ongoing clinical care challenge. Insulin omission continues to be frequent and underestimated and has been correlated with poorer glycemic control and increased rates of diabetes-related complications. Insulin users consistently indentify multiple factors that contribute to insulin injection-related anxiety and to non-adherence. Injection-related discomfort continues to bear a significant contribution. Over the last decade, with advances in needle manufacturing technology, shorter and narrower needles have been associated with progressively improving patient self-rating of injection discomfort. Consequently, patient surveys of insulin users show discomfort to rank in the bottom third of significant contributors by prevalence. However, healthcare providers (HCP) and family member care providers continue to demonstrate a high level of anticipated and perceived pain for the patient. HCP anxiety and pain anticipation are each associated with patient anxiety and may therefore play a significant contributing role in patient non-adherence. © Copyright 2012, Mary Ann Liebert, Inc.

Aronson R.,LMC Diabetes & Endocrinology
Current Medical Research and Opinion | Year: 2015

Background: Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action. Scope: Publications with titles containing the keywords 'linagliptin' or 'empagliflozin' were identified from a non-systematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012-2014. ClinicalTrials.gov was searched for entries containing these two keywords. Additional references known to the author were included. Findings: The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents. Conclusions: The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus. © 2015 All rights reserved: reproduction in whole or part not permitted.

Riddle M.C.,Oregon Health And Science University | Forst T.,Institute for Clinical Research and Development | Aronson R.,LMC Diabetes & Endocrinology | Sauque-Reyna L.,Institute Diabetes Obesidad y Nutricion Sociedad Civil | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial.We examined the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine. RESEARCH DESIGN AND METHODS-This double-blind, parallel-group trial enrolled patients with HbA1c 7-10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤7.8 mmol/L and HbA 1c 7-9% were randomized to lixisenatide 20 μg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA 1c change after randomization. RESULTS-The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m2, and daily glargine dosage of 44 units. HbA1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA1c by 0.71 vs. 0.40% with placebo (least squares mean difference, -0.32%; 95% CI, -0.46 to -0.17; P < 0.0001). More participants attained HbA1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo -3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo -0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide. CONCLUSIONS-Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin. © 2013 by the American Diabetes Association.

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