Lawrence Blonde

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.

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

OBJECTIVE To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m2. RESULTS Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus.

Acknowledgments We would like to recognize Elliot Sternthal, MD, FACE, and Joseph Vassalotti, MD, for their review of these guidelines and thoughtful comments.

CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2016 EXECUTIVE SUMMARY.

Abbreviations: A1C = hemoglobin A1C AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ACEI = angiotensinconverting enzyme inhibitor AGI = alpha-glucosidase inhibitor apo B = apolipoprotein B ARB = angiotensin II receptor blocker ASCVD = atherosclerotic cardiovascular disease BAS = bile acid sequestrant BMI = body mass index BP = blood pressure CHD = coronary heart disease CKD = chronic kidney disease CVD = cardiovascular disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 EPA = eicosapentaenoic acid FDA = Food and Drug Administration GLP-1 = glucagon-like peptide 1 HDL-C = high-density-lipoprotein cholesterol LDL-C = low-densitylipoprotein cholesterol LDL-P = low-density-lipoprotein particle Look AHEAD = Look Action for Health in Diabetes NPH = neutral protamine Hagedorn OSA = obstructive sleep apnea SFU = sulfonylurea SGLT-2 = sodium glucose cotrans...

American Association of Clinical Endocrinologists' Comprehensive Diabetes Management Algorithm 2013 Consensus Statement - Executive Summary

Alan J. Garber, MD, PhD, FACE; Martin J. Abrahamson, MD; Joshua I. Barzilay, MD, FACE; Lawrence Blonde, MD, FACP, FACE; Zachary T. Bloomgarden, MD, MACE; Michael A. Bush, MD; Samuel Dagogo-Jack, MD, FACE; Michael B. Davidson, DO, FACE; Daniel Einhorn, MD, FACP, FACE; W. Timothy Garvey, MD; George Grunberger, MD, FACP, FACE; Yehuda Handelsman, MD, FACP, FACE, FNLA; Irl B. Hirsch, MD; Paul S. Jellinger, MD, MACE; Janet B. McGill, MD, FACE; Jeffrey I. Mechanick, MD, FACE, ECNU, FACN, FACP; Paul D. Rosenblit, MD, PhD, FACE, FNLA; Guillermo E. Umpierrez, MD, FACE; Michael H. Davidson, MD, FACC, FACP, FNLA

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY - CLINICAL PRACTICE GUIDELINES FOR DEVELOPING A DIABETES MELLITUS COMPREHENSIVE CARE PLAN - 2015

The American Association of Clinical Endocrinologists/American College of Endocrinology Medical Guidelines for Clinical Practice are systematically developed statements to assist healthcare professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances. Abbreviations: A1C = hemoglobin A1c AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascu...

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.

The Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Compared With Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily: A 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes

OBJECTIVE The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA1c = 7–11%) or previously on basal insulin ± OAD(s) (HbA1c = 7–10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8–40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA1c reduction after 26 weeks. RESULTS After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA1c by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex − IGlar OD]: 0.04% points [–0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS The use of extreme dosing intervals of 8–40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety.

American association of clinical endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement

Alan J. Garber, MD, PhD, FACE; Martin J. Abrahamson, MD; Joshua I. Barzilay, MD, FACE; Lawrence Blonde, MD, FACP, FACE; Zachary T. Bloomgarden, MD, MACE; Michael A. Bush, MD; Samuel Dagogo-Jack, MD, FACE; Michael B. Davidson, DO, FACE; Daniel Einhorn, MD, FACP, FACE; W. Timothy Garvey, MD; George Grunberger, MD, FACP, FACE; Yehuda Handelsman, MD, FACP, FACE, FNLA; Irl B. Hirsch, MD; Paul S. Jellinger, MD, MACE; Janet B. McGill, MD, FACE; Jeffrey I. Mechanick, MD, FACE, ECNU, FACN, FACP; Paul D. Rosenblit, MD, PhD, FACE, FNLA; Guillermo E. Umpierrez, MD, FACE; Michael H. Davidson, MD, FACC, FACP, FNLA

The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1–5 studies

Liraglutide is a new glucagon‐like peptide‐1 (GLP‐1) receptor agonist and a true GLP‐1 analogue. After successful phase 2 studies, liraglutide was assessed in a series of phase 3 trials [(Liraglutide Effect and Action in Diabetes (LEAD)] designed to demonstrate efficacy and safety across the continuum of type 2 diabetes antihyperglycaemic care, both as monotherapy and in combination with commonly used oral antidiabetic drugs (OADs). The LEAD programme also compared liraglutide with other OADs. As a monotherapy, liraglutide demonstrated significant improvements in glycaemic control in comparison with glimepiride. When combined with one or two OADs, reductions in haemoglobin A1c, fasting plasma glucose and postprandial glucose were generally greater with liraglutide than with comparators. Throughout the trials, liraglutide was associated with weight reduction; in most instances, the reduction from baseline was significantly greater than that seen with comparators. Improvements in assessments of beta‐cell function were consistently shown with liraglutide treatment across all trials. Furthermore, reductions in systolic blood pressure were reported. Liraglutide was associated with a low risk of hypoglycaemia and was generally well tolerated. The majority of adverse effects were gastrointestinal, the most frequent of which was nausea.