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Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride.
Jendle, J, Hyötyläinen, T, Orešič, M, Nyström, T
Cardiovascular diabetology. 2021;(1):237
Abstract
BACKGROUND Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease. METHODS In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS). RESULTS In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism. CONCLUSIONS Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted. TRIAL REGISTRATION NCT01425580.
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A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia.
Winzeler, B, Sailer, CO, Coynel, D, Zanchi, D, Vogt, DR, Urwyler, SA, Refardt, J, Christ-Crain, M
The Journal of clinical investigation. 2021;(20)
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Abstract
BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.
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Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution.
Jalleh, R, Pham, H, Marathe, CS, Wu, T, Buttfield, MD, Hatzinikolas, S, Malbert, CH, Rigda, RS, Lange, K, Trahair, LG, et al
Nutrients. 2020;(7)
Abstract
Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p < 0.001) and distal (p < 0.001) stomach and decreased EI (p < 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = -0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.
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Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases.
Xie, Y, Bowe, B, Gibson, AK, McGill, JB, Maddukuri, G, Yan, Y, Al-Aly, Z
Diabetes care. 2020;(11):2859-2869
Abstract
OBJECTIVE To examine the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1), dipeptidyl peptidase 4 inhibitors (DPP-4), and sulfonylureas on risk of kidney outcomes among people with type 2 diabetes. RESEARCH DESIGN AND METHODS U.S. veterans initiated on SGLT2i (n = 18,544), GLP-1 (n = 23,711), DPP-4 (n = 39,399), or sulfonylureas (n = 134,904) were followed for up to 3 years to evaluate the risk of the composite outcome of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease (ESKD), or all-cause mortality. Risks were estimated using survival models adjusted for predefined covariates as well as covariates identified by a high-dimensional variable selection algorithm through application of generalized propensity scores. RESULTS Compared with those treated with sulfonylureas, treatment with SGLT2i, GLP-1, and DPP-4 was associated with a lower risk of the composite outcome (hazard ratio 0.68 [95% CI 0.63, 0.74], 0.72 [0.67, 0.77], and 0.90 [0.86, 0.95], respectively). While we did not observe a statistically significant difference in risk between the SGLT2i and GLP-1 arms (0.95 [0.87, 1.04]), both SGLT2i and GLP-1 had a lower risk of the composite outcome than DPP-4 (0.76 [0.70, 0.82] and 0.79 [0.74, 0.85], respectively). Analyses by eGFR category suggested that compared with the sulfonylurea arm, those in the SGLT2i and GLP-1 arms exhibited a lower risk of the composite outcome in all eGFR categories, including eGFR <45 mL/min/1.73 m2. Compared with DPP-4, both SGLT2i and GLP-1 exhibited a reduced risk of the composite outcome in eGFR <90 to ≥60, <60 to ≥45, and <45 mL/min/1.73 m2. CONCLUSIONS In type 2 diabetes, treatment with SGLT2i or GLP-1 compared with DPP-4 or sulfonylureas was associated with a lower risk of adverse kidney outcomes.
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No Acute Effects of Exogenous Glucose-Dependent Insulinotropic Polypeptide on Energy Intake, Appetite, or Energy Expenditure When Added to Treatment With a Long-Acting Glucagon-Like Peptide 1 Receptor Agonist in Men With Type 2 Diabetes.
Bergmann, NC, Gasbjerg, LS, Heimbürger, SM, Krogh, LSL, Dela, F, Hartmann, B, Holst, JJ, Jessen, L, Christensen, MB, Vilsbøll, T, et al
Diabetes care. 2020;(3):588-596
Abstract
OBJECTIVE Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. RESEARCH DESIGN AND METHODS In a randomized, double-blind design, men with type 2 diabetes (n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed, and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). RESULTS Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion (P = 0.026 and P = 0.017) as assessed by area under the curve. CONCLUSIONS In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.
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GIP and GLP-1 Receptor Antagonism During a Meal in Healthy Individuals.
Gasbjerg, LS, Helsted, MM, Hartmann, B, Sparre-Ulrich, AH, Veedfald, S, Stensen, S, Lanng, AR, Bergmann, NC, Christensen, MB, Vilsbøll, T, et al
The Journal of clinical endocrinology and metabolism. 2020;(3)
Abstract
CONTEXT The actions of both endogenous incretin hormones during a meal have not previously been characterized. OBJECTIVE Using specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility. DESIGN Randomized, double-blinded, placebo-controlled, crossover design. SETTING On four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min). PATIENTS OR OTHER PARTICIPANTS Twelve healthy male volunteers. INTERVENTIONS Infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (0-20 min: 1000 pmol/kg/min; 20-270 min: 450 pmol/kg/min), GIP(3-30)NH2+exendin(9-39)NH2, or placebo/saline. MAIN OUTCOME MEASURE Baseline-subtracted area under the curve (bsAUC) of C-peptide. RESULTS Infusion of GIP(3-30)NH2+exendin(9-39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3-30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9-39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3-30)NH2+exendin(9-39)NH2 infusion were significantly lower than during GIP(3-30)NH2 (P = 0.0057), exendin(9-39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3-30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9-39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3-30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar. CONCLUSIONS Endogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other's effects in the control of postprandial glycemia in healthy men.
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Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial.
Yamada, Y, Katagiri, H, Hamamoto, Y, Deenadayalan, S, Navarria, A, Nishijima, K, Seino, Y, ,
The lancet. Diabetes & endocrinology. 2020;(5):377-391
Abstract
BACKGROUND Given the unique phenotype of type 2 diabetes in Japanese patients, novel therapies such as oral semaglutide require evaluation in this population. PIONEER 9 aimed to assess the dose-response of oral semaglutide and to compare the efficacy and safety of oral semaglutide with placebo and a subcutaneous GLP-1 receptor agonist in a Japanese population. METHODS PIONEER 9 was a 52-week, phase 2/3a, randomised, controlled trial done at 16 sites (clinics and university hospitals) in Japan. Japanese patients aged 20 years or older with uncontrolled type 2 diabetes managed by diet or exercise or with oral glucose-lowering drug monotherapy (washed out) were randomly assigned (1:1:1:1:1) to receive double-blind once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or placebo, or open-label subcutaneous once-daily liraglutide 0·9 mg. The primary endpoint was change in HbA1c from baseline to week 26 with the trial product (primary) estimand (which assumes all patients remained on trial product without rescue medication use) in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, NCT03018028. FINDINGS Between Jan 10, and July 11, 2017, 243 patients were randomly assigned to oral semaglutide 3 mg (n=49), 7 mg (n=49), or 14 mg (n=48), or placebo (n=49), or to liraglutide 0·9 mg (n=48). Changes in HbA1c from baseline (mean 8·2%) to week 26 were dose-dependent with oral semaglutide (mean change -1·1% [SE 0·1] for oral semaglutide 3 mg, -1·5% [0·1] for 7 mg, and -1·7% [0·1] for 14 mg), -0·1% (0·1) with placebo, and -1·4% (0·1) with liraglutide 0·9 mg. Estimated treatment differences for change in HbA1c compared with placebo were -1·1 percentage points (95% CI -1·4 to -0·8; p<0·0001) for oral semaglutide 3 mg, -1·5 percentage points (-1·7 to -1·2; p<0·0001) for oral semaglutide 7 mg, and -1·7 percentage points (-2·0 to -1·4; p<0·0001) for oral semaglutide 14 mg. Estimated treatment differences for change in HbA1c compared with liraglutide 0·9 mg were 0·3 percentage points (95% CI -0·0 to 0·6; p=0·0799) for oral semaglutide 3 mg, -0·1 percentage points (-0·4 to 0·2; p=0·3942) for oral semaglutide 7 mg, and -0·3 percentage points (-0·6 to -0·0; p=0·0272) for oral semaglutide 14 mg. Gastrointestinal events, predominantly of mild or moderate severity, were the most frequently reported class of adverse event with oral semaglutide: constipation was most common, occurring in five to six (10-13%) patients with oral semaglutide, three (6%) with placebo, and nine (19%) with liraglutide 0·9 mg. INTERPRETATION This study showed that oral semaglutide provides significant reductions in HbA1c compared with placebo in a dose-dependent manner in Japanese patients with type 2 diabetes, and has a safety profile consistent with that of GLP-1 receptor agonists. FUNDING Novo Nordisk.
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Switching to iGlarLixi Versus Continuing Daily or Weekly GLP-1 RA in Type 2 Diabetes Inadequately Controlled by GLP-1 RA and Oral Antihyperglycemic Therapy: The LixiLan-G Randomized Clinical Trial.
Blonde, L, Rosenstock, J, Del Prato, S, Henry, R, Shehadeh, N, Frias, J, Niemoeller, E, Souhami, E, Ji, C, Aroda, VR
Diabetes care. 2019;(11):2108-2116
Abstract
OBJECTIVE Fixed-ratio combinations of basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1 RA) allow concomitant administration of two proven complementary injectable therapies for type 2 diabetes. This study investigated switching to a titratable fixed-ratio combination of insulin glargine plus lixisenatide (iGlarLixi) in patients with type 2 diabetes receiving daily or weekly GLP-1 RA therapy. RESEARCH DESIGN AND METHODS LixiLan-G, a randomized, open-label, 26-week trial, compared switching to iGlarLixi versus continuing prior GLP-1 RA in patients with type 2 diabetes and HbA1c 7-9% (53-75 mmol/mol) taking maximum tolerated doses of a GLP-1 RA daily (60% on liraglutide once daily or exenatide twice daily) or weekly (40% on dulaglutide, exenatide extended release, or albiglutide) with metformin with or without pioglitazone and with or without sodium-glucose cotransporter 2 inhibitors. Adherence to randomized treatment was closely monitored throughout the study. RESULTS iGlarLixi (n = 257) reduced HbA1c more than continued GLP-1 RA therapy (n = 257) from a baseline 7.8% (62 mmol/mol) in both to 6.7% (50 mmol/mol) and 7.4% (57 mmol/mol), respectively, at 26 weeks (least squares mean difference -0.6%; P < 0.0001). More iGlarLixi patients achieved HbA1c <7% (53 mmol/mol) (62% vs. 26%; P < 0.0001) and the composite of HbA1c <7% without documented symptomatic hypoglycemia (<54 mg/dL). Nausea and vomiting rates as well as numbers of documented symptomatic hypoglycemia events per patient-year were generally low but greater with iGlarLixi versus continued GLP-1 RA therapy. CONCLUSIONS Switching to iGlarLixi improves glucose control for patients with type 2 diabetes insufficiently controlled on a maximum tolerated dose of a GLP-1 RA plus oral antihyperglycemic agents.
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Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide.
Rosenstock, J, Sorli, CH, Trautmann, ME, Morales, C, Wendisch, U, Dailey, G, Hompesch, M, Choi, IY, Kang, J, Stewart, J, et al
Diabetes care. 2019;(9):1733-1741
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Abstract
OBJECTIVE To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). RESEARCH DESIGN AND METHODS EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo (n = 37), or liraglutide (≤1.8 mg daily; n = 36). The primary efficacy end point was change in HbA1c from baseline to week 13. RESULTS From a baseline HbA1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ≥1 mg significantly reduced HbA1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ≥1 mg than placebo achieved HbA1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placebo-adjusted LS mean differences -1.4 and -2.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. CONCLUSIONS Efpeglenatide once weekly led to significant reductions in HbA1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.
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Role of adipose tissue GLP-1R expression in metabolic improvement after bariatric surgery in patients with type 2 diabetes.
Ejarque, M, Guerrero-Pérez, F, de la Morena, N, Casajoana, A, Virgili, N, López-Urdiales, R, Maymó-Masip, E, Pujol Gebelli, J, Garcia Ruiz de Gordejuela, A, Perez-Maraver, M, et al
Scientific reports. 2019;(1):6274
Abstract
We aimed to explore the relationship between GLP-1 receptor (GLP-1R) expression in adipose tissue (AT) and incretin secretion, glucose homeostasis and weight loss, in patients with morbid obesity and type 2 diabetes undergoing bariatric surgery. RNA was extracted from subcutaneous (SAT) and visceral (VAT) AT biopsies from 40 patients randomized to metabolic gastric bypass, sleeve gastrectomy or greater curvature plication. Biochemical parameters, fasting plasma insulin, glucagon and area under the curve (AUC) of GLP-1 following a standard meal test were determined before and 1 year after bariatric surgery. GLP-1R expression was higher in VAT than in SAT. GLP-1R expression in VAT correlated with weight (r = -0.453, p = 0.008), waist circumference (r = -0.494, p = 0.004), plasma insulin (r = -0.466, p = 0.007), and systolic blood pressure (BP) (r = -0.410, p = 0.018). At 1 year, GLP-1R expression in VAT was negatively associated with diastolic BP (r = -0.361, p = 0.039) and, following metabolic gastric bypass, with the increase of GLP-1 AUC, (R2 = 0.46, p = 0.038). Finally, GLP-1R in AT was similar independently of diabetes outcomes and was not associated with weight loss after surgery. Thus, GLP-1R expression in AT is of limited value to predict incretin response and does not play a role in metabolic outcomes after bariatric surgery.