Effects of Liraglutide 3.0 Mg on Weight and Risk Factors in Hispanic Versus Non-Hipanic Populations: Subgroup Analysis from Scale Randomized Trials

Objective: Scarce data exist on pharmacotherapy for obesity in Hispanic individuals. This post hoc analysis of pooled data from 4 phase 3a trials compared the efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to a reduced-calorie diet and physical activity, in Hispanic versus non-Hispanic subgroups.Methods: We conducted the double-blind randomized, placebo-controlled trials in adults with a minimum body mass index (BMI) of 27 kg/m² with at least 1 comorbidity, or a minimum BMI of 30 kg/m², at clinical research sites worldwide. In this analysis, we investigated possible differences in treatment effects between 534 Hispanics (10.4% of the population) and 4,597 non-Hispanics (89.6%) through statistical tests of interaction between subgroups and treatment. Variables examined included mean and categorical weight change, cardiovascular risk markers, and safety data.Results: Both subgroups achieved clinically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: Hispanics 7.0% versus 1.5%, treatment difference -5.1% (95% CI, -6.2 to -4.0); non-Hispanics 7.5% versus 2.3%, -5.2% (95% CI, -5.5 to -4.8). More individuals in both subgroups lost ≥5%, >10%, and >15% of their baseline weight with liraglutide 3.0 mg than with placebo. Efficacy endpoints generally did not vary with ethnicity (P>.05). Adverse events were comparable between ethnic subgroups, with more gastrointestinal disorders reported with liraglutide 3.0 mg than placebo.Conclusion: Efficacy and safety were largely similar between Hispanic and non-Hispanic subgroups. Results support that liraglutide 3.0 mg, used with a reduced-calorie diet and physical activity, can facilitate weight loss in Hispanic individuals.Abbreviations:A1c = glycated hemoglobinBMI = body mass indexCI = confidence intervalFPG = fasting plasma glucoseGLP-1 = glucagon-like peptide-1hsCRP = high-sensitivity C-reactive proteinSCALE = Satiety and Clinical Adiposity – Liraglutide Evidence in individuals with and without diabetesT2DM = type 2 diabetes mellitus     

Long-Term,Sustained, Lifestyle-Induced Weight Loss in Severe Obesity: the Get-Real Program

Objective: To study the long-term effectiveness of a patient-centered, multidisciplinary lifestyle intervention treatment in patients medically eligible for bariatric surgery.Methods: Using a case-control study design, we compared treatment results for 98 adults (mean body mass index [BMI], 44.2 kg/m²) with the outcomes of 148 controls (mean BMI, 43.0 kg/m²) receiving standard care. The approach included a phased triage for inclusion, followed by 12 lifestyle intervention group sessions alternating with individual visits for behavior, diet, and exercise instructions.Results: At 2 years, weight loss averaged 15.3 ± 1.4 kg (P<.0010) (12 ± 1% of initial body weight [IBW], P<.001; 21 ± 2% of excess body weight [EBW], P<.001) in an intention-to-treat (ITT) analysis; in completers, weight loss was 18.8 ± 1.5 kg (P<.001) (15 ± 1% IBW, P<.001; 26 ± 3% EBW, P<.001). A total of 42 patients lost ≥10% IBW. Controls remained weight stable (P =.35); 3% lost ≥10% IBW. Patients achieving weight loss that would be considered satisfactory for bariatric surgery included 20% who achieved ≥35% EBW loss, 29% who achieved a BMI <35 kg/m² (if starting BMI <50 kg/m²) or BMI <40 kg/m² (if starting BMI ≥50 kg/m²), and 37% who achieved EBW loss ≤50%. These values for completers were 31, 39, and 48%, respectively. In the 55 patients starting the program ≥4 years ago, weight loss maintenance of 12 ± 1% IBW (ITT, 16 ± 1% in completers) was observed.Conclusion: Substantial nonsurgical weight loss, maintained at 2 to 4 years, is achievable in severely obese patients using comprehensive lifestyle approaches; the efficacy/safety trade-off in obesity treatment is an important consideration in interpreting these results.Abbreviations: BMI = body mass index EBW = excess body weight HbA_1c = glycated hemoglobin IBW = initial body weight LOCFA = last observation carried forward analysis     

SGLT-2 Inhibitor Therapy Added to GLP-1 Agonist Therapy in the Management of T2DM

Objective: To assess the real-world efficacy and safety of canagliflozin therapy added to type 2 diabetes mellitus (T2DM) patients who have received a minimum 1 year of glucagon-like peptide-1 (GLP-1) agonist therapy.Methods: This pre-post observational study assessed the efficacy and safety of canagliflozin in a group of T2DM patients from a community endocrinology practice who received GLP-1 agonist therapy for a minimum of 12 months. The primary study outcome was change in mean glycated hemoglobin (HbA1c) level from baseline. Secondary endpoints included changes in average weight, and comparison of the percentage of patients obtaining an HbA1c <7%.Results: A total of 75 patients met all the study criteria. Baseline patient characteristics were as follows: average age, 58 ± 9 years; mean duration of T2DM, 14 ± 6 years; 56% male; 92% Caucasian; baseline body mass index (BMI), 39.4 ± 9.4 kg/m²; and mean baseline HbA1c, 7.94 ± 0.69%. HbA1c and weight were significantly reduced by 0.39% and 4.6 kg, respectively. Adverse effects were reported by 13 (17.3%) patients, including 4 (5.3%) who discontinued canagliflozin because of adverse reactions.Conclusion: Canagliflozin was generally well tolerated and significantly further reduced mean HbA1c levels and body weight in patients with T2DM when added to GLP-1 regimen.Abbreviations:BP = blood pressureBUN = blood urea nitrogenCANTATA = Canagliflozin Treatment and Trial AnalysisDBP = diastolic blood pressureDKA = diabetic ketoacidosisDPP-4 = dipeptidyl peptidase-4EMR = electronic medical recordFDA = Food and Drug AdministrationGFR = glomerular filtration rateGLP-1 = glucagon-like peptide-1HbA1c = glycated hemoglobinHDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterolSCr = serum creatinineSGLT-2 = sodium glucose cotransporter 2T2DM = type 2 diabetes mellitusTZD = thiazolidinedioneUTI = urinary tract infection     

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

ObjectiveTo compare Iiraglutide versus common antihyperglycemic treatments in reducing hemoglobin A_1c (A1C) values across multiple levels of baseline glycemic control and in reaching glycemic targets.MethodsPooled 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 > 9.0%. 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, rosiglitazone, exenatide, and insulin glargine across all baseline A1C categories.ResultsIrrespective 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).ConclusionAcross a wide spectrum of baseline A1C categories, liraglutide is an efficacious treatment option for patients with type 2 diabetes. (Endocr Pract. 2011;17: 906-913)     

Comparison Of The Long-Term Effects Of Liraglutide And Glimepiride Monotherapy On Bone Mineral Density In Patients With Type 2 Diabetes

Objective: Patients with type 2 diabetes have an increased risk of fragility fractures; the cause is unclear but is likely multifactorial. Some diabetes treatments induce bone loss, accentuating underlying skeletal fragility and increasing fracture risk. This subgroup analysis aimed to compare long-term effects of liraglutide and glimepiride on bone mineral density (BMD) in patients with type 2 diabetes.Methods: LEAD-3, a 52-week, double-blind, activecontrol, phase III, multicenter trial, investigated the efficacy of liraglutide (1.2 and 1.8 mg/day) versus glimepiride monotherapy in type 2 diabetes. A 52-week, open-label extension followed, in which participants remained on randomized therapy. A subgroup of participants underwent BMD measurement by dual-energy X-ray absorptiometry at baseline, 52, and 104 weeks. The main outcome measure was change from baseline in total body BMD at 52 and 104 weeks, assessed by analysis of covariance.Results: A total of 746 patients with type 2 diabetes aged 19 to 79 years were randomized into the main trial. Of these, 61 patients (20 assigned to liraglutide 1.8 mg/day, 23 to liraglutide 1.2 mg/day, 18 to glimepiride 8 mg/day) had BMD measurements. Baseline age, body mass index, diabetes duration, glycated hemoglobin, and total BMD were similar across treatment groups. There was no apparent difference in mean total BMD change from baseline in patients receiving liraglutide 1.8 or 1.2 mg/day or glimepiride 8 mg/day at 52 or 104 weeks.Conclusion: In this small subgroup analysis, liraglutide monotherapy did not negatively affect total BMD in a 2-year prospective study, suggesting it may not exacerbate the consequences of bone fragility.Abbreviations:BMD = bone mineral densityBMI = body mass indexDPP-4 = dipeptidyl peptidase-4DXA = dual-energy X-ray absorptiometryGLP-1RA = glucagon-like peptide 1 receptor agonistLEAD = Liraglutide Effect and Action in DiabetesTZD = thiazolidinedione     

Mild Renal Impairment and the Efficacy and Safety of Liraglutide

ObjectiveTo determine the effect of mild renal impairment (RI) on the efficacy and safety of liraglutide in patients with type 2 diabetes mellitus.MethodsIn this meta-analysis, we examined the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies. Data from patients with type 2 diabetes who had normal renal function, mild RI, or moderate or severe RI were pooled for analysis. Renal function was measured by creatinine clearance as determined by the Cockcroft-Gault equation: normal renal function = creatinine clearance > 89 mL/min; mild RI = 60 mL/min ≤ creatinine clearance ≤ 89 mL/min; and moderate or severe RI = creatinine clearance < 60 mL/min. The meta-analysis included patients administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 weeks. In addition, a pooled analysis of all phase 2 and 3 liraglutide trials was done to examine rates of altered renal function.ResultsMild RI did not affect the estimated treatment differences in hemoglobin A_1c. Patients with normal renal function demonstrated decreases in body weight and systolic blood pressure with either dosage of liraglutide, whereas patients in either RI group also demonstrated a decrease in body weight and systolic blood pressure, but these differences were not significant compared with differences observed in the placebo group. Liraglutide treatment vs placebo was safe and well tolerated in patients with mild RI, as there were no significant differences in rates of renal injury, minor hypoglycemia, or nausea. A trend towards increased nausea was observed in patients with moderate or severe RI receiving liraglutide, although the number of patients in this treatment group was too low to determine significance.ConclusionMild RI, as determined by the CockcroftGault equation, had no effect on the efficacy and safety of liraglutide in this meta-analysis. (Endocr Pract. 2011; 17:345-355)     

The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway

Glucagon-like peptide-1 (GLP-1), an effective therapeutic agent for the treatment of diabetes, has been proven to protect pancreatic beta cells through many pathways. Recent evidence demonstrates that AMP-activated protein kinase (AMPK), as a metabolic regulator, coordinates beta-cell protein synthesis through regulation of the mammalian target of rapamycin (mTOR) signaling pathway. The purpose of the present study was to explore whether liraglutide, a human GLP-1 analogue, protects beta cells via AMPK/mTOR signaling. We evaluated INS-1 beta-cell line proliferation using the Cell Counting Kit-8, and examined the effect of GLP-1 on cellular ATP levels using an ATP assay kit. mTOR pathway protein expression levels were tested by Western blotting and glucolipotoxicity-induced cell apoptosis was evaluated by flow cytometry. Liraglutide increased beta-cell viability at an optimum concentration of 100 nmol/L in the presence of 11.1 or 30 mmol/L glucose. Liraglutide (100 nmol/L) activated mTOR and its downstream effectors, 70-kDa ribosomal protein S6 kinase and eIF4E-binding protein-1, in INS-1 cells. This effect was abated by pathway blockers: the AMPK activator AICAR and the mTOR inhibitor rapamycin. Furthermore, the effect of liraglutide on beta-cell proliferation was inhibited by AICAR and rapamycin. Liraglutide increased cellular ATP levels. In addition, liraglutide protected beta cells from glucolipotoxicity-induced apoptosis. This response was also prevented by rapamycin treatment. These results suggest that the enhancement of beta-cell proliferation by that GLP-1 receptor agonist liraglutide is mediated, at least in part, by AMPK/mTOR signaling. Liraglutide also prevents beta-cell glucolipotoxicity by activating mTOR.     

Lack of effect of prolonged treatment with liraglutide on cardiac remodeling in rats after acute myocardial infarction

Following the acute phase of a myocardial infarction, a set of structural and functional changes evolves in the myocardium, collectively referred to as cardiac remodeling. This complex set of processes, including interstitial fibrosis, inflammation, myocyte hypertrophy and apoptosis may progress to heart failure. Analogs of the incretin hormone glucagon-like peptide 1 (GLP-1) have shown some promise as cardioprotective agents. We hypothesized that a long-acting GLP-1 analog liraglutide would ameliorate cardiac remodeling over the course of 4 weeks in a rat model of non-reperfused myocardial infarction. In 134 male Sprague Dawley rats myocardial infarctions were induced by ligation of the left anterior descending coronary artery. Rats were randomized to either subcutaneous injection of placebo or 0.3 mg liraglutide once daily. Cardiac magnetic resonance imaging was performed after 4 weeks. Histology of the infarcted and remote non-infarcted myocardium, selected molecular remodeling markers and mitochondrial respiration in fibers of remote non-infarcted myocardium were analyzed. Left ventricular end diastolic volume increased in the infarcted hearts by 62% (from 0.58 ± 0.03 mL to 0.95 ± 0.07 mL, P < 0.05) compared to sham operated hearts and left ventricle ejection fraction decreased by 37% (63 ± 1%–40 ± 3%, P < 0.05). Increased interstitial fibrosis and phosphorylation of p38 Mitogen Activated Protein Kinase were observed in the non-infarct regions. Mitochondrial fatty acid oxidation was impaired. Liraglutide did not affect any of these alterations. Four-week treatment with liraglutide did not affect cardiac remodeling following a non-reperfused myocardial infarction, as assessed by cardiac magnetic resonance imaging, histological and molecular analysis and measurements of mitochondrial respiration.     

Partial Hospitalization: An Intervention for Youth with Poorly Controlled Diabetes Mellitus

Objective: To examine the efficacy of an integrated medical/psychiatric partial hospitalization program (PHP) to improve glycemic control in youth with both diabetes mellitus and mental health disorders.Methods: This retrospective chart review is of patients admitted to a PHP between 2005–2015 with concerns about diabetes mellitus care. Clinical characteristics, laboratory data, diabetic ketoacidosis hospitalizations, and outpatient clinic visit frequency were collected from the year prior to the year after PHP admission.Results: A total of 43 individuals met inclusion criteria: 22 (51%) were female, 40 (93%) had type 1 diabetes, the mean age was 15.2 ± 2.3 years, and the mean diabetes mellitus duration was 4.6 ± 3.6 years. Of those individuals, 35 of these patients had hemoglobin A1c (HbA1c) data available at baseline, 6 months, and 1 year after PHP. The average HbA1c before PHP admission was 11.3 ± 2.3% (100.5 ± 25 mmol/mol), and decreased to 9.2 ± 1.3% (76.7 ± 14.8 mmol/mol) within 6 months of PHP admission (P<.001). The average HbA1c 1 year after PHP was 10.7 ± 1.7 % (93.3 ± 19.1 mmol/mol). Overall, 24 patients (68%) had lower HbA1c, and 75% of those with improvement maintained an HbA1c reduction of ≥1% (≥10 mmol/mol) at 1 year compared to before PHP.Conclusion: Most patients demonstrated improved glycemic control within 6 months of PHP admission, and many of those maintained a ≥1% (≥10 mmol/mol) reduction in HbA1c at 1 year following PHP admission. This program may represent a promising intervention that could serve as a model for intensive outpatient management of youth with poorly controlled diabetes mellitus.Abbreviations: ADA = American Diabetes Association; DKA = diabetic ketoacidosis; EMR = electronic medical record; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases, 9^th revision; PHP = partial hospitalization program     

Metformin-Sustained Weight Loss and Reduced Android Fat Tissue At 12 Months In Empowir (Enhance The Metabolic Profile Of Women With Insulin Resistance): A Double Blind,Placebo-Controlled,Randomized Trial of Normoglycemic Women with Midlife Weight Gain

Objective: To assess 12-month body weight (BW) and body composition changes in normoglycemic women with midlife weight gain, after dietary and pharmacologic interventions targeting hyperinsulinemia.Methods: EMPOWIR (Enhance the Metabolic Profile of Women With Insulin Resistance; NCT00618072) was a double-blind, placebo-controlled, 12-month trial of women with >20-pound weight gain, normal glucose tolerance test, and increased area-under-the-curve insulin. Subjects (mean ± SD, 46.7 ± 6.5 years of age; body mass index, 30.8 ± 2.8 kg/m²; 50% white) attended 4 nutrition workshops to introduce a novel carbohydrate-modified diet (CMD) and were then randomized to one of three arms for 6 months (phase 1): CMD alone (D), or in combination with metformin (M), or metformin + rosiglitazone (MR), with rerandomization of the D group to one of the active treatment arms (phase 2, months 7 through 12). Repeated measure analysis of variance was used to assess BW at baseline, 6 months, and 12 months in 32 subjects with 12-month data; paired t tests compared baseline and 12-month dual-energy X-ray absorptiometry–derived body composition.Results: Mean (±SD) BW decreased significantly at 12 months in the M arm: 85.1 ± 8.5 kg to 79.8 ± 9.0 kg (P = .0003), with 54% of variance in weight over time explained by M treatment. Mean (±SD) percent android fat decreased significantly in the M and D arms: 53.5 ± 4.8% to 49.3 ± 7.6% (P = .010) and 52.9 ± 6.2% to 48.1 ± 8.7% (P = .021).Conclusion: In combination with a novel carbohydrate modified diet, metformin enhanced 12-month weight loss and improved body composition in ethnically diverse normoglycemic, hyperinsulinemic women with midlife weight gain. These findings suggest that EMPOWIR's easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.Abbreviations:ANOVA = analysis of varianceBC = body compositionBW = body weightCMD = carbohydrate-modified dietD = diet alone groupDXA = dual-energy X-ray absorptiometryEMPOWIR = Enhance the Metabolic Profile of Women With Insulin ResistanceM = metformin groupMR = metformin + rosiglitazone group     

Is Liraglutide A Useful Addition to Diabetes Therapy?

ObjectiveTo evaluate liraglutide as an antidiabetic agent.MethodsThe pertinent English-language medical literature was reviewed for the period from 1985 to April 2010 with use of data from MEDLINE.ResultsLiraglutide is a glucagonlike peptide-1 receptor analogue that stimulates insulin secretion, reduces postprandial glucagon release, causes a mild delay in gastric emptying, and may slightly decrease appetite. Mean reductions in hemoglobin A1c levels with liraglutide therapy range from 1.0% to 1.5% in comparison with baseline and are 1.0% and 1.3% in comparison with placebo. Head-to-head trials suggest that liraglutide may be more effective than glimepiride, rosiglitazone, insulin glargine, and exenatide. Some of the previous trials, however, are limited by use of submaximal doses of comparator drugs and an open-label design. The use of liraglutide is associated with a mean weight loss of 0.2 to 3.2 kg relative to baseline and 0.1 to 2.6 kg relative to placebo. Liraglutiderelated hypoglycemia is generally mild, but its incidence and severity substantially increase in conjunction with sulfonylureas. Gastrointestinal adverse effects such as nausea, diarrhea, or vomiting occurred in 44% to 56% of patients who received liraglutide versus 17% to 19% with placebo. Premature withdrawal from trials occurred in 4% to 15% of liraglutide-treated patients (mainly attributable to gastrointestinal adverse effects), in comparison with 3% to 5% of those receiving placebo.ConclusionThe 2 main advantages of liraglutide are mild degrees of weight loss and hypoglycemia. Important limitations, however, are the frequent occurrence of gastrointestinal adverse effects, the requirement of subcutaneous injection once daily, and the lack of long-term efficacy and safety data. Liraglutide may be a useful add-on therapy in patients with type 2 diabetes uncontrolled with metformin, when hypoglycemia, weight gain, or both are major concerns. (Endocr Pract. 2010;16:1028-1037)     

Design and synthesis of pyrrolo[3,2-d]pyrimidine HER2/EGFR dual inhibitors: Improvement of the physicochemical and pharmacokinetic profiles for potent in vivo anti-tumor efficacy

During the course of our studies on a novel HER2/EGFR dual inhibitor (TAK-285), we found an alternative potent pyrrolo[3,2-d]pyrimidine compound (1a). To enhance the pharmacokinetic (PK) profile of this compound, we conducted chemical modifications into its N-5 side chain and conversion of the chemically modified compounds into their salts. Among them, 2cb, the tosylate salt of compound 2c, showed potent HER2/EGFR kinase inhibitory activity (IC₅₀: 11/11 nM) and cellular growth inhibitory activity (BT-474 cell GI₅₀: 56 nM) with a good drug metabolism and PK (DMPK) profile. Furthermore, 2cb exhibited significant in vivo antitumor efficacy in both mouse and rat xenograft models with transplanted 4-1ST gastric cancer cell lines (mouse, T/C = 0%, 2cb po bid at 100 mg/kg; rat, T/C: -1%, 2cb po bid at 25 mg/kg).     

Durability of Effects of Exenatide Treatment on Glycemic Control,Body Weight,Systolic Blood Pressure,C-Reactive Protein,and Triglyceride Concentrations

ObjectiveTo determine (1) whether long-term treatment with exenatide is associated with reductions in C-reactive protein (CRP), systolic blood pressure (BP), and triglyceride concentrations in addition to reductions in body weight and hemoglobin A1c (A1C) levels and (2) whether these beneficial results persist without any loss of effect while exenatide is being used, and whether they reverse after its cessation.MethodsWe conducted a retrospective review of 141 patients with type 2 diabetes mellitus treated with exenatide at a tertiary clinic.ResultsExenatide (mean duration of treatment, 1.4 years) decreased A1C (0.7%), weight (5 kg), systolic BP (8 mm Hg), and triglyceride concentrations (46 mg/dL) (P < .05 for all). Sixty-one patients continued exenatide therapy throughout the study (mean duration of use, 2.4 years). Exenatide treatment reduced their mean weight by 7 kg, systolic BP by 8 mm Hg, triglycerides by 52 mg/dL, A1C by 1.3%, and CRP by 2.4 mg/L (P < .05 for all). Reductions in systolic BP and CRP were not related to weight loss. The reduction in CRP concentration was significantly related to the baseline CRP concentration (r = 0.78; P < .001) and to change in A1C (r = 0.68; P = .02). Patients who stopped taking exenatide had a reversal of the benefits within 6 months after cessation of treatment.Conclusion:Exenatide treatment in patients with type 2 diabetes has durable and persistent beneficial effects on A1C, weight, CRP, systolic BP, and triglyceride concentrations. Cessation of treatment reverses all these beneficial effects within 6 months. There was no evidence of loss of its effects while exenatide treatment was continued. (Endocr Pract. 2011;17:192-200)     

Evaluation of Treatment of Central Hypothyroidism Versus Primary Hypothyroidism in Relation to Levothyroxine Replacement Dose

Objective: The aim of this study was to evaluate levothyroxine (LT4) replacement daily doses in patients with central hypothyroidism (CeH) and compare them with those adequate for patients with primary hypothyroidism (P-HYPO).Methods: We included 53 patients with CeH and 57 with P-HYPO, matched by sex, age, weight, and body mass index, in the period of 1 year. At the time of inclusion, all presented a stable and adequate dose of LT4 for at least 3 months, considering as adequate the dose associated with normal thyroid-stimulating hormone (TSH) levels and free thyroxine (T4) in P-HYPO patients, and free T4 levels in CeH patients.Results: The absolute daily dose of LT4 differed significantly between the two groups, 103.0 ± 27.1 μg (CeH) and 89.3 ± 32.0 μg (P-HYPO) (P = .017), even after adjustment for age, gender, and free T4 (P = .04). The LT4 dose adjusted to weight was also higher after adjustment for age, gender and free T4 (P = .04), with an average of 1.3 ± 0.4 μg/kg (CeH) and 1.2 ± 0.4 μg/kg (P-HYPO). Sheehan syndrome patients had a lower absolute daily dose of LT4 (P = .001), and patients who underwent pituitary radiotherapy required higher doses (P = .008). There was no difference in the daily dose of LT4 according to other pituitary hormone deficiencies.Conclusion: The results reinforce the relevance of a careful individualization of LT4 replacement in CeH management and the need for new markers for proper LT4 replacement therapy in such cases.Abbreviations: BMI = body mass index; CeH = central hypothyroidism; GH = growth hormone; LT4 = levothyroxine; P-HYPO = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Clinical Use of Liraglutide in Type 2 Diabetes and its Effects on Cardiovascular Risk Factors

ObjectiveTo assess whether liraglutide, a glucagonlike peptide-1 receptor agonist, has cardioprotective properties in addition to its glycemic effects.MethodsWe performed a retrospective analysis of medical records of 110 obese patients with type 2 diabetes mellitus treated with liraglutide for at least 6 months between March 2010 and April 2011 at our tertiary care referral center. The variables analyzed were body mass index, hemoglobin A_1c (A1C), systolic blood pressure (SBP), plasma C-reactive protein (CRP) concentrations, and serum lipids.ResultsIn our overall study cohort, we noted a reduction in mean weight from 120 ± 5 kg to 115 ± 3 kg and a decrease in mean A1C from 7.8% ± 0.6% to 7.2% ± 0.2%. The mean triglyceride concentration decreased from 173 ± 19 mg/dL to 151 ± 15 mg/dL, the mean SBP was reduced from 132 ± 6 mm Hg to 125 ± 4 mm Hg, and the mean CRP concentration declined from 4.7 ± 0.8 mg/L to 3.2 ± 0.4 mg/L after treatment with liraglutide for a minimal duration of 6 months and a mean duration of 7.5 months (for all the foregoing changes, P < .05).These variables decreased whether these patients were previously treated with orally administered hypoglycemic agents alone or in combination with insulin or exenatide.ConclusionOur findings in a clinical practice show that liraglutide is a potent antidiabetes drug, whether given in combination with orally administered agents or insulin or as a substitution for exenatide. It lowers body weight, A1C levels, SBP, and CRP and triglyceride concentrations. (Endocr Pract. 2012;18:140-145)     

Visceral and Subcutaneous Fat Increased after Treatment of Graves Disease

Objective: Patients with Graves disease (GD) tend to gain weight after treatment, but it remains unknown if weight gain is associated with an increase in the visceral and/or subcutaneous fat areas (VFA, SFA).Methods: We enrolled 25 newly diagnosed GD patients (22 females, median age 33.0 years) and studied their clinical parameters, and VFA and SFA measured by a dual bioelectric impedance analysis. We divided them into 2 groups based on the rates of change in the VFA and SFA, and we compared clinical parameters at the baseline between the groups to evaluate factors that influence increases in the VFA and/or SFA with treatment.Results: The patients' body weight (BW), VFA, and SFA were significantly increased after a 6-month treatment (BW: from 54.3 ± 10.3 kg to 58.0 ± 11.2 kg; P<.001; VFA: from 47.1 ± 21.3 cm² to 54.7 ± 23.4 cm²; P = .004; SFA: from 159.8 ± 85.9 cm² to 182.2 ± 82.9 cm²; P = .008). The percent changes of BW correlated with the SFA (ρ = .591, P = .002), but not with the VFA. The patients with larger VFA increases had significantly less VFA at the baseline compared to those with smaller increases, expressed as median and interquartile range (33.9 cm² [22.7 to 47.5 cm²] versus 54.5 cm² [45.2 to 64.0], respectively; P = .011). A larger increase in the SFA was negatively associated with serum alkaline phosphatase. An increase in the SFA was associated with free triiodothyronine (T3) in a multivariate logistic analysis (odds ratio: 0.80 [0.59 to 0.97]; P = .013).Conclusion: The patients' BW, VFA, and SFA were increased after GD treatment. The increase in SFA seemed to contribute to weight gain and was associated with a low baseline level of free T3.Abbreviations: ALP = alkaline phosphatase; BMI = body mass index; BW = body weight; GD = Graves disease; SFA = subcutaneous fat area; T3 = triiodothyronine; T4 = thyroxine; TG = triglycerides; VFA = visceral fat areas     

Levothyroxine Replacement In Obese Hypothyroid Females After Total Thyroidectomy

Objective: Levothyroxine (LT4) replacement in hypothyroid obese patients is poorly understood. We assessed whether the LT4 regimen required to achieve euthyroidism differs between nonobese and obese hypothyroid females.Methods: We retrospectively identified nonobese and obese females who received LT4 starting with a standard dose of 1.6 μg/kg after total thyroidectomy for preoperative diagnosis of benign goiter. We examined the association between LT4 dosage required to achieve euthyroid state (thyroid-stimulating hormone [TSH] 0.4–2.5 mIU/L) and patient characteristics using linear regression models with and without adjustment for age, ethnicity, medication use, and postoperative hypoparathyroidism.Results: We identified 32 females (15 nonobese/17 obese) who achieved euthyroid state. Obese patients weighed more (104.1 ± 22.5 vs. 64.9 ± 10.0 kg, P<.0001) and required a higher final LT4 than nonobese (146 ± 38 vs. 102 ± 12 μg, P = .0002) but LT4 requirements per kg total body weight (TBW) were similar (1.60 ± 0.29 vs. 1.42 ± 0.38 μg/kg, P = .15). LT4 dose per kg ideal body weight (IBW) was higher in obese than in nonobese females (2.62 ± 0.67 vs. 1.88 ± 0.28 μg/kg, P = .0004) and this difference persisted after adjustments (P<.05). During LT4 titration, 47% and 20% of obese and nonobese patients had subnormal TSH episodes, respectively (P = .11). After taking LT4 compliance, malabsorption, and competing medication use into consideration, we found marked LT4 dose variability in obese patients. Patients who needed a mean daily LT4 dose ≤150 mg (124 ± 16 μg/day) compared with >150 μg (198 ± 4 μg/day) demonstrated lower LT4 per TBW (1.25 ± 0.18 vs. 1.84 ± 0.43 μg/kg, P = .03) and IBW (2.28 ± 0.47 vs. 3.44 ± 0.18 μg/kg, P<.0001), respectively.Conclusion: The standard approach to LT4 replacement in obese and nonobese females after thyroidectomy is imprecise. Mean daily LT4 doses in obese and nonobese patients were similar if expressed per kg TBW, though there was variability in the final LT4 among obese patients. We suggest initiating LT4 at a dose lower than that routinely recommended in obese females.Abbreviations:AACE = American Association of Clinical EndocrinologistsATA = American Thyroid AssociationBMI = body mass indexIBW = ideal body weightLT4 = levothyroxineTBW = total body weightTSH = thyroid-stimulating hormone     

Eating and Glycemic Control Among Critically Ill Patients Receiving Continuous Intravenous Insulin

Objective: Consensus guidelines recommend that intensive care unit (ICU) patients with blood glucose (BG) levels >180 mg/dL receive continuous intravenous insulin (CII). The effectiveness of CII at controlling BG levels among patients who are eating relative to those who are eating nothing by mouth (nil per os; NPO) has not been described.Methods: We conducted a retrospective cohort study of 260 adult patients (156 eating, 104 NPO) admitted to an ICU between January 1, 2014, and December 31, 2014, who received CII. Patients were excluded for a diagnosis of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic syndrome, admission to an obstetrics service, or receiving continuous enteral or parenteral nutrition.Results: Among 22 baseline characteristics, the proportion of patients receiving glucocorticoid treatment (GCTx) (17.3% eating, 37.5% NPO; P<.001) and APACHE II score (15.0 ± 7.5 eating, 17.9 ± 7.9 NPO; P = .004) were significantly different between eating and NPO patients. There was no significant difference in the primary outcome of patient-day weighted mean BG overall (153 ± 8 mg/dL eating, 156 ± 7 mg/dL NPO; P = .73), or day-by-day BG (P = .37) adjusted for GCTx and APACHE score. Surprisingly, there was a significant difference in the distribution of BG values, with eating patients having a higher percentage of BG readings in the recommended range of 140 to 180 mg/dL. However, eating patients showed greater glucose variability (coefficient of variation 23.1 ± 1.0 eating, 21.2 ± 1.0 NPO; P = .034).Conclusion: Eating may not adversely affect BG levels of ICU patients receiving CII. Whether or not prandial insulin improves glycemic control in this setting should be studied.Abbreviations: BG = blood glucose; CII = continuous insulin infusion; CV = coefficient of variation; HbA1c = hemoglobin A1c; ICU = intensive care unit; NPO = nil per os; PDWMBG = patient day weighted mean blood glucose     

High-Dose Glucocorticoid Treatment Does Not Induce Severe Hyperglycemia in Young Patients with Autoimmune Diseases by Cgms

Objective: High-dose glucocorticoids (HDG) are used in the treatment of autoimmune diseases. Glucocorticoids-induced hyperglycemia (GIH) is often described in elderly patients. In young patients with autoimmune diseases, however, the risk for GIH has not been well characterized.Methods: We recruited 24 inpatients (median age, 32 years; interquartile range, 25–42) with exacerbations of autoimmune diseases, receiving 1 to 2 mg/kg/day prednisone or equivalent methylprednisone. Fourteen subjects were naïve to glucocorticoids (group 1) and 10 subjects were on glucocorticoid maintenance (≤15 mg/day prednisone at least 3 months) (group 2) prior to HDG. All subjects were monitored by continuous glucose monitoring system (CGMS) for 3 days.Results: GIH developed in 21 (91%) subjects, 11/13 in group 1 and 10/10 in group 2. The main peak of glucose excursion (128.7 ± 6.4 mg/dL, group 1; 143.9 ± 10.0 mg/dL, group 2) occurred at 2 to 3 pm. Another peak occurred before sleep. Two-hour mean postprandial glucose levels were normal in both groups: breakfast, 105.0 ± 28.4 versus 125.6 ± 24.4 mg/dL, P = .065; lunch, 115.7 ± 21.1 versus 135.9 ± 29.0 mg/dL, P = .082; dinner, 122.8 ± 18.5 versus 137.8 ± 26.4 mg/dL, P = .144 in groups 1 and 2, respectively. There was a positive association between pretreatment hemoglobin A1C and peak glucose levels (P<.0001). Notably, 35% of our subjects experienced early morning hypoglycemia (65.2 ± 2.8 mg/dL).Conclusion: In hospitalized young patients with auto-immune diseases, CGMS data revealed that short-term consistent HDG treatment induced mild hyperglycemia, peaking in the early afternoon and before sleep. Early morning hypoglycemia was found in 35%.Abbreviations: A1C = hemoglobin A1C; AUC = the area under the curve; BG = blood glucose; BMI = body mass index; CGMS = continuous glucose monitoring system; DM = diabetes mellitus; FBG = fasting blood glucose; GA = glycated albumin; GCs = glucocorticoids; GIH = glucocorticoids-induced hyperglycemia; HDG = high-dose glucocorticoids; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; IG = interstitial glucose; IQR = interquartile range; PUMCH = Peking Union Medical College Hospital; SLE = systemic lupus erythematosus     

High-Precision Conformal Fractionated Radiotherapy Is Effective In Achieving Remission In Patients With Acromegaly After Failed Transsphenoidal Surgery

Objective: Variable efficacy of pituitary radiotherapy in acromegaly is reported. Here we sought to assess the efficacy of high-precision conformal fractionated radiotherapy (CRT) in patients with acromegaly after failed TSS.Methods: A retrospective analysis was conducted a in tertiary care referral center between 1999 to 2013 on 36 acromegaly patients (M: 16, F: 20; median age: 36.0 years) with macroadenoma and mean growth hormone (GH) and insulin-like growth factor-1 (IGF1) upper limits of normal (ULN) of 15.9 ± 14.3 ng/mL and 1.74 ± 0.43, respectively. The cohort was divided into 2 groups: 30 patients (M: 13, F: 17) who were medical treatment naïve, and 6 patients (M: 3, F: 3) who received medical treatment after CRT.Results: Normalization of GH (fasting GH <1 ng/mL), normalization of IGF1 (ULN <1), and remission (normalization of GH and IGF1) were achieved in 20 (55%), 23 (63%) and 20 (55%) patients, respectively. The mean time required to achieve remission was 63 ± 33.4 months. Follow-up duration was the only predictor of achieving remission. GH level declined exponentially by 65% and 89% at 2 and 5 years, respectively. New onset hypopituitarism was noted in 33% of patients. Tumor control was achieved in 100% of patients. In groups 1 and 2, 18 (60%) and 2 (33.3%) achieved remission post-CRT, and the mean times required to achieve remission were 58.6 ± 30.7 months and 102 ± 42.4 months, respectively.Conclusion: High-precision CRT is an effective modality to achieve remission in patients with acromegaly after failed TSS.Abbreviations:CRT = conformal fractionated radiotherapyCT = computed tomographyCTV = clinical target volumeDA = dopamine agonistsGH = growth hormoneGTV = gross tumor volumeIGF1 = insulin-like growth factor 1MRI = magnetic resonance imagingRT = radiotherapyPTV = planning target volumeSA = somatostatin analogueSRS = stereotactic radiosurgeryTSS = transsphenoidal surgeryULN = multiple of upper limit of normalWHO = World Health Organization