ResearchPad - impacts-of-metabolism-on-clinical-challenges https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR26-08 Efficacy and Safety of Higher Dulaglutide Doses (3.0 MG and 4.5 MG) When Added to Metformin in Patients With Type 2 Diabetes: A Phase 3, Randomized, Double-Blind, Parallel ARM Study (Award-11)]]> https://www.researchpad.co/article/elastic_article_8592 Dulaglutide (DU) approved at doses of 0.75 and 1.5 mg once-weekly is an effective glucose lowering agent for treatment of type 2 diabetes (T2D). We hypothesized that higher investigational DU doses may provide further improvements in glucose control and body weight (BW) with an acceptable safety profile. The primary objective was to demonstrate superiority of once-weekly DU 3 mg and/or 4.5 mg to DU 1.5 mg for A1C change from baseline (BL) at 36 weeks (wks) in patients (pts) with inadequately controlled T2D on metformin therapy. Secondary objectives (controlled for multiplicity) included change in BW and % of pts achieving A1C <7% at 36 wks. Patients were randomized (1:1:1) to once-weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All pts initiated once-weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Two estimands were defined for efficacy analyses: an efficacy estimand (data on-treatment without rescue medication) and a treatment-regimen estimand (all data regardless of adherence or initiation of rescue). At BL, patients had a mean of: age 57.1 yrs, T2D duration 7.6 yrs, and A1C 8.6%, BW 95.7 kg, and BMI 34.2 kg/m2. Using the efficacy estimand, the DU 3 mg and 4.5 mg doses were superior to the DU 1.5 mg dose for A1C change from BL (1.5 mg, 1.53%; 3 mg, 1.71% [p=0.003]; 4.5 mg, 1.87% [p<0.001]), % of patients achieving HbA1c <7% (1.5 mg, 57%; 3.0 mg, 65% [p=0.006]; 4.5 mg, 71% [p<0.001]) and BW change from BL (1.5 mg, 3.1 kg; 3 mg, 4.0 kg [p=0.001]; 4.5 mg, 4.7 kg [p<0.001]). Using the treatment-regimen estimand, DU 4.5 mg was superior to DU 1.5 mg for A1C change, while the DU 3 mg dose did not achieve statistical significance (1.5 mg, 1.54%; 3.0 mg, 1.64% [p=0.096]; 4.5 mg, 1.77% [p<0.001]). Using the treatment-regimen estimand, more patients achieved A1C <7% with higher DU doses (1.5 mg, 50%; 3 mg, 56%; 4.5 mg, 62%) and results for BW change were similar to the efficacy estimand (1.5 mg, 3.0 kg; 3 mg, 3.8 kg; 4.5 mg, 4.6 kg), but the approach for type I error control did not permit formal statistical comparisons of these secondary objectives using this estimand. The safety profile for the higher DU doses was consistent with that known for 1.5 mg. The most commonly reported adverse events were nausea (DU 1.5 mg, 13.4%; DU 3 mg, 15.6%; DU 4.5 mg, 16.4%), vomiting (DU 1.5 mg, 5.6%; DU 3 mg, 8.3%; DU 4.5 mg, 9.3%), and diarrhea (DU 1.5 mg, 7.0%; DU 3 mg, 11.4%; DU 4.5 mg, 10.7%). Treatment discontinuation due to adverse events through 36 wks was low and similar across dose groups (DU 1.5 mg, 4.2%; DU 3 mg, 5.5%; DU 4.5 mg, 5.0%). In pts with T2D and inadequate glycemic control on metformin, escalation from DU 1.5 mg to DU 3 mg or DU 4.5 mg once-weekly provided clinically relevant, dose-related improvements in glycemic control and BW with an acceptable safety profile.

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<![CDATA[OR26-05 The Correction Factor for A1C in Anemic Patients]]> https://www.researchpad.co/article/Nb7b506aa-5e9f-4266-80c7-95e136b5d2cb <![CDATA[OR26-07 Mild Physiologic Hyperglycemia Does Not Affect Glucose Mediated but Impairs Insulin-Mediated Suppression of Plasma Glucagon in Healthy Normal Glucose Tolerant Subjects]]> https://www.researchpad.co/article/N3f44824d-6ceb-4dd1-a9e3-4950b5420626

Abstract

Plasma glucagon levels are regulated by plasma glucose concentrations as well as intra-islet and circulating insulin concentrations. Hyperglycemia adversely affects skeletal muscle and hepatic insulin sensitivity (glucotoxicity). However, the effect of physiologic hyperglycemia on glucose-mediated and insulin-mediated suppression of glucagon is not known. The aim of the present study was to evaluate effect of chronic (48 or 72 hours) physiologic increase (+45 mg/dl) in plasma glucose concentration on the suppression of plasma glucagon concentration in healthy NGT individuals: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 yrs, BMI = 27 ± 1 kg/m

) and 8 with FH of T2DM (FH+) (4M/4F, age = 48±2, BMI = 26±1 kg/m

). Subjects received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes)

and

72 hour glucose infusion. On another occasion subjects participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m

·min) euglycemic clamp

and

a 48 hour glucose infusion. Plasma insulin and C-peptide concentrations were obtained every 2-5 minutes during each hyperglycemic clamp step and plasma glucagon concentrations were measured every 10 minutes. The ratio of insulin/glucagon was measured and used as an index of insulin-medicated suppression of plasma glucagon. FPG concentration increased from 97±4 to 140±4 mg/dl during the 72 hour glucose infusion. Following chronic glucose infusion, plasma insulin levels were significantly higher during the basal state and during each hyperglycemic clamp step (by 59% and 78%). There was no difference in plasma glucagon levels following chronic glucose infusion and the degree of suppression of glucagon during 2-step hyperglycemic (+125 and +300 mg/dl) were similar. However, the plasma insulin/glucagon ratio was significantly higher during the fasting state (by 76%) and during the first (by 128%) and second (by 178%) hyperglycemic clamp steps. Similarly during the three step euglycemic clamp (10, 20, 40 mU/m

·min) studies following 48 hr glucose infusion, despite similar plasma glucose concentrations during each clamp step, plasma insulin and glucagon concentrations were higher following chronic glucose infusion. These results demonstrate that sustained physiologic hyperglycemia for 48 hrs or 72 hours (i.e. glucotoxicity) does not affect the glucose mediated suppression of glucagon, but impairs insulin-mediated suppression of glucagon, and could contribute to fasting and post-prandial hyperglycemia in T2DM patients.

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<![CDATA[OR26-01 Epinephrine Is Essential for Normal Renal Glucose Reabsorption via the Glucose Transporter GLUT2]]> https://www.researchpad.co/article/N69450e36-ff6e-4629-aed1-da7a984310a8 <![CDATA[OR26-02 The Effect on Ketogenesis of Withholding Early Parenteral Nutrition in Critically Ill Children, as a Potential Mediator of the Improved Acute Outcome]]> https://www.researchpad.co/article/N037759b6-de5e-4067-abac-4f052abc56a8 <![CDATA[OR26-04 Immediate Post-Operative Insulin Requirements May Predict Metabolic Outcome After Total Pancreatectomy and Islet Autologous Cell Transplant (TPIAT)]]> https://www.researchpad.co/article/Nc77af17e-1498-40ee-a4b0-d4b1a954f5ea <![CDATA[OR26-03 Lower Serum Myostatin Levels Are Associated with Higher Insulin Sensitivity in Adults with Overweight/Obesity]]> https://www.researchpad.co/article/Ne791b4c8-73d6-4d88-a7fc-db6515f7d6b6 <![CDATA[OR26-06 Fecal Microbiota Transplantation Trial for the Improvement of Metabolism (FMT-TRIM): A Randomized Double-Blind Placebo-Controlled Pilot Trial]]> https://www.researchpad.co/article/N21a35dad-9826-4fcf-8083-29efbf9bda31