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1.
A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the glucagon receptor antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus.
Bergman, A, Tan, B, Somayaji, VR, Calle, RA, Kazierad, DJ
Diabetes research and clinical practice. 2017;:95-104
Abstract
AIMS: The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM. METHODS After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28. RESULTS Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia. CONCLUSIONS PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM.
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Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.
Kazda, CM, Frias, J, Foga, I, Cui, X, Guzman, CB, Garhyan, P, Heilmann, C, Yang, JA, Hardy, TA
Diabetes, obesity & metabolism. 2017;(8):1071-1077
Abstract
AIMS: To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes. MATERIALS AND METHODS This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers. RESULTS At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of -0.49% (-5.4 mmol/mol) (95% CI: -0.56%, -0.42% [-6.1, -4.6 mmol/mol]; P < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P < .05 vs placebo). CONCLUSIONS Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.
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Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.
Kazierad, DJ, Bergman, A, Tan, B, Erion, DM, Somayaji, V, Lee, DS, Rolph, T
Diabetes, obesity & metabolism. 2016;(8):795-802
Abstract
AIMS: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). METHODS Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. RESULTS PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. CONCLUSION PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.
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[Possibilities of therapy GLP1 RA for diabetics with nephropathy].
Adamíková, A
Vnitrni lekarstvi. 2015;(4):312-5
Abstract
The incretin hormone GLP1 (glucagon-like peptide 1) has also systemic effects besides its effects on the pancreas. The renal expression for the receptors GLP1 and DPP4 has been described in a whole line of experimental stu-dies. Activation of the receptors for GLP1 in the kidneys has diuretic and natriuretic effects apparently through the renal tubular cells and sodium transporters. Pre-clinical incretin therapy decreased albuminuria, affected glomerulosclerosis, oxidative stress and fibrosis in the kidneys. Diabetic nephropathy is the major cause of kidney failure. In the course of renal insufficiency the functional possibilities and simultaneous safe compensation of diabetes are limited. The treatment GLP1 RA of patients with type 2 diabetes and nephropathy appear to be effective from the aspect of effectiveness and safety.
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GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women.
Iepsen, EW, Lundgren, JR, Hartmann, B, Pedersen, O, Hansen, T, Jørgensen, NR, Jensen, JE, Holst, JJ, Madsbad, S, Torekov, SS
The Journal of clinical endocrinology and metabolism. 2015;(8):2909-17
Abstract
CONTEXT Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. OBJECTIVE To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. DESIGN Randomized control study. SETTING Outpatient research hospital clinic. PARTICIPANTS Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. INTERVENTION After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. MAIN OUTCOME MEASURES Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. RESULTS Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 μg/L) vs a 2% (-1 ± 4 μg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. CONCLUSIONS Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.
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Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs.
Reubi, JC, Waser, B
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2015;(4):613-5
Abstract
UNLABELLED A high proportion of gut and bronchial neuroendocrine tumors (NETs) overexpresses somatostatin receptors, especially the sst2 subtype. It has also recently been observed that incretin receptors, namely glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors, can be overexpressed in gut and bronchial NETs. However, because not all tumors can express these receptors in sufficient amounts, in vivo imaging with a single radioligand may not always be successful. We therefore evaluated with in vitro methods whether a cocktail of radioligands targeting these 3 receptors would improve tumor labeling. METHODS In vitro receptor autoradiography was performed on 55 NETs, comparing in each successive section of tumor the binding with a single radioligand, either (125)I-Tyr(3)-octreotide, (125)I-GLP-1(7-36)amide, or (125)I-GIP(1-30), with the binding using a cocktail of all 3 radioligands, given concomitantly under identical experimental conditions. RESULTS Using the cocktail of radioligands, all tumors without exception showed moderate to very high binding, with a receptor density corresponding to 1,000-10,000 dpm/mg of tissue; conversely, single-ligand binding, although identifying most tumors as receptor-positive, failed to detect receptors or measured only a low density of receptors below 1,000 dpm/mg in a significant number of tumors. In addition, the cocktail of radioligands always provided a homogeneous labeling of the whole tumor, whereas single radioligands occasionally showed heterogeneous labeling. CONCLUSION The study suggests that the use of a cocktail of 3 radioligands binding to somatostatin receptors, GLP-1 receptors, and GIP receptors would allow detecting virtually all NETs and labeling them homogeneously in vivo, representing a significant improvement for imaging and therapy in NETs.
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[GLP-1 receptor agonists versus SGLT-2 inhibitors in obese type 2 diabetes patients].
Marques, AR, Jaafar, J, de Kalbermatten, B, Philippe, J
Revue medicale suisse. 2015;(477):1227-8, 1230-3
Abstract
Who never had a type 2 obese diabetic patient, treated by several oral antidiabetic drugs and insulin, with consequent weight gain associated with the therapeutic escalation and uncontrolled diabetes? The arrival of GLP-1 agonists and SGLT-2 inhibitors allows to reevaluate the management of these patients, with their favorable effects on glycemic control, weight and the risk of hypoglycemia and their complementary mechanisms to conventional treatments. The vicious cycle of weight gain and increased need of insulin is limited. The choice between these two molecules must be based on several factors (glycemic target, weight, comorbidities, route of administration, side effects, etc.), and the balanced enthusiasm of these new treatments with the insufficient data regarding their long-term safety and their impact on micro- and macrovascular complications.
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Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5).
Skrivanek, Z, Gaydos, BL, Chien, JY, Geiger, MJ, Heathman, MA, Berry, S, Anderson, JH, Forst, T, Milicevic, Z, Berry, D
Diabetes, obesity & metabolism. 2014;(8):748-56
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Abstract
AIMS: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose-finding portion whose results are presented here. METHODS Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected. RESULTS Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg showed the greatest placebo-adjusted mean change in weight [-1.99 (-2.88 to -1.20) kg] and in PR [0.78 (-2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30) mmHg]. CONCLUSIONS The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial.
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Evidence-based practice use of incretin-based therapy in the natural history of diabetes.
Schwartz, S
Postgraduate medicine. 2014;(3):66-84
Abstract
The incretin class of anti-hyperglycemic agents, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-inhibitors, is an important addition to the therapeutic armamentarium for the management of appropriate patients with type 2 diabetes mellitus as an adjunct to diet and exercise and/or with the agents metformin, sulfonylureas, thiazolidinediones, or any combination thereof. More recently, US Food and Drug Administration (FDA)-approved indications for incretins were expanded to include use with basal insulin. This review article takes an evidence-based practice approach in discussing the importance of aggressive treatment for diabetes, the principles of incretin physiology and pathophysiology, use of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, and patient types and contexts where incretin therapy has been found beneficial, from metabolic syndrome to overt diabetes.
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A randomized controlled trial comparing the GLP-1 receptor agonist liraglutide to a sulphonylurea as add on to metformin in patients with established type 2 diabetes during Ramadan: the Treat 4 Ramadan Trial.
Brady, EM, Davies, MJ, Gray, LJ, Saeed, MA, Smith, D, Hanif, W, Khunti, K
Diabetes, obesity & metabolism. 2014;(6):527-36
Abstract
AIMS: To compare a sulphonylurea with the glucagon like peptide-1 (GLP-1) receptor agonist liraglutide in combination with metformin in patients on mono/dual oral therapy with established type 2 diabetes fasting during Ramadan. METHODS Ninety-nine adults intending to fast during Ramadan [50% male, mean age 52 years, body mass index (BMI) 32 kg/m(2)] were randomized from two UK sites. Baseline data were collected ≥14 days prior to Ramadan and at 3 and 12 weeks after Ramadan. RESULTS At 12 weeks, more patients in the liraglutide compared with the sulphonylurea group achieved a composite endpoint of haemoglobin A1c (HbA1c) < 7%, no weight gain and no severe hypoglycaemia but this did not reach statistical significance [odds ratio (OR) 4.08, 95% confidence interval (CI) 0.97, 17.22, p = 0.06]. From a baseline of 7.7% there was no change in HbA1c at 12 weeks in the sulphonylurea (+0.02%) compared with a 0.3% reduction in the liraglutide group (adjusted coefficient -0.41, 95% CI -0.83, 0.01, p = 0.05). Significant reductions were also observed in weight and diastolic blood pressure (BP) in the liraglutide compared with the sulphonylurea group. Treatment satisfaction was comparable across the treatment groups. There were no episodes of severe hypoglycaemia in either group, however, self-recorded episodes of blood glucose ≤3.9 mmol/l were significantly lower with liraglutide (incidence rate ratio 0.29, 95% CI 0.19, 0.41, p < 0.0001). CONCLUSIONS Liraglutide compared with sulphonylurea is well tolerated and maybe an effective therapy in combination with metformin during Ramadan with more patients able to achieve target HbA1c, lose or maintain weight with no severe hypoglycaemia. This was achieved with a high level of treatment satisfaction.