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Pereira, M. J., Thombare, K., Sarsenbayeva, A., Kamble, P. G., Almby, K., Lundqvist, M. & Eriksson, J. W. (2020). Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes. Molecular and Cellular Endocrinology, 503, Article ID 110696.
Open this publication in new window or tab >>Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes
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2020 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 503, article id 110696Article in journal (Refereed) Published
Abstract [en]

We aim to investigate the expression of the glucagon receptor (GCGR) in human adipose tissue, and the impact of glucagon in glucose uptake and lipolysis in human adipocytes. GCGR gene expression in human subcutaneous and visceral adipose tissue was demonstrated, albeit at low levels and with an inter-individual variation. Furthermore, GCGR expression was not significantly different between subjects with T2D and matched controls, and we found no significant association with BMI. Glucagon only at a supra-physiological concentration (10-100 nM) significantly increased basal and insulin-stimulated glucose uptake by up to 1.5-fold. Also, glucagon (0.01 and 1 nM) dose-dependently increased basal and isoproterenol-stimulated lipolysis up to 3.7- and 1.7-fold, respectively, compared to control. In addition, glucagon did not change insulin sensitivity to stimulate glucose uptake or inhibit lipolysis. In conclusion, we show that the GCGR gene is expressed at low levels in human adipose tissue, and glucagon at high concentrations can increase both glucose uptake and lipolysis in human adipocytes. Taken together, our data suggest that glucagon at physiological levels has minor direct effects on the regulation of adipocyte metabolism, but does not antagonize the insulin effect to stimulate glucose uptake and inhibit lipolysis in human adipocytes.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2020
Keywords
Glucagon, Adipose tissue, Metabolism, Glucose uptake, Lipolysis, Glucagon receptor
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-406177 (URN)10.1016/j.mce.2019.110696 (DOI)000508636400010 ()31891768 (PubMedID)
Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06Bibliographically approved
Katsogiannos, P., Kamble, P. G., Wiklund, U., Sundbom, M., Espes, D., Hammar, U., . . . Eriksson, J. (2020). Rapid changes in neuroendocrine regulation may contribute to reversal of type 2 diabetes after gastric bypass surgery. Endocrine (Basingstoke), 67(2), 344-353
Open this publication in new window or tab >>Rapid changes in neuroendocrine regulation may contribute to reversal of type 2 diabetes after gastric bypass surgery
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2020 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 67, no 2, p. 344-353Article in journal (Refereed) Published
Abstract [en]

Objective: To explore the role of hormones and the autonomic nervous system in the rapid remission of diabetes after Roux-en-Y Gastric Bypass (RYGB).

Research design and methods: Nineteen obese patients with type 2 diabetes, 7 M/12 F, were randomized (2:1) to RYGB or standard-of-care medical treatment (control). At baseline and 4 and 24 weeks post surgery, fasting blood sampling, OGTT, intravenous arginine challenge, and heart-rate variability (HRV) assessments were performed.

Results: At both 4 and 24 weeks post-RYGB the following effects were found: arginine-stimulated insulin secretion was reduced. GLP-1, GIP, and glucagon rise during OGTT was enhanced. IGF-1 and GH levels increased. In addition, total HRV and spectral components P-LF (power of low frequency) and P-HF (power of high frequency) increased. At 4 weeks, morning cortisol was lower than baseline and 24 weeks. At 24 weeks, NEFA levels during OGTT, and the P-LF/P-HF ratio decreased. None of these changes were seen in the control group.

Conclusions: There were rapid changes within 4 weeks after RYGB: signs of enhanced parasympathetic nerve activity, reduced morning cortisol, and enhanced incretin and glucagon responses to glucose. The findings suggest that neurohormonal mechanisms can contribute to the rapid improvement of insulin resistance and glycemia following RYGB in type 2 diabetes.

Place, publisher, year, edition, pages
SPRINGER, 2020
Keywords
Roux-en-Y gastric bypass, Type 2 diabetes, Incretins, Adipokines, Heart rate variability
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-407498 (URN)10.1007/s12020-020-02203-w (DOI)000514540100009 ()31983031 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved
Lind, L., Salihovic, S., Risérus, U., Kullberg, J., Johansson, L., Ahlström, H., . . . Oscarsson, J. (2020). THE PLASMA METABOLOMIC PROFILE IS DIFFERENTLY ASSOCIATED WITH LIVER FAT, VISCERAL ADIPOSE TISSUE AND PANCREATIC FAT: Supplementary Table 1..
Open this publication in new window or tab >>THE PLASMA METABOLOMIC PROFILE IS DIFFERENTLY ASSOCIATED WITH LIVER FAT, VISCERAL ADIPOSE TISSUE AND PANCREATIC FAT: Supplementary Table 1.
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2020 (English)Data set
Keywords
Ectopic fat, MRI, liver fat, pancreatic fat, metabolomics, obesity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-407950 (URN)
Available from: 2020-04-01 Created: 2020-04-01 Last updated: 2020-04-02Bibliographically approved
Edén, D., Panagiotou, G., Mokhtari, D., Eriksson, J., Åberg, M. & Siegbahn, A. (2019). Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner. Upsala Journal of Medical Sciences, 124(3), 158-167
Open this publication in new window or tab >>Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner
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2019 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 3, p. 158-167Article in journal (Refereed) Published
Abstract [en]

Background: Tissue factor (TF) combined with its ligand FVII initiates blood coagulation and intracellular signaling. Obese and type 2 diabetic subjects have increased TF expression in their adipose tissue and an increased risk for thrombotic complications. Here we address the role of TF/FVII on adipocyte functions.

Materials and methods: Subcutaneous fat was obtained by means of needle aspiration from healthy volunteers, and adipocytes were isolated after collagenase digestion. 3T3-L1 fibroblasts kept in culture were differentiated into adipocytes by addition of IBMX, dexamethasone, rosiglitazone, and insulin to the media. Proteins and mRNA were analyzed by western blot and RT-PCR. Coagulation activity was determined by a colorimetric FX-assay. Lipolysis was measured as free glycerol using a colorimetric method. Glucose uptake was evaluated by scintillation counting of D-[U-C-14] glucose.

Results: In isolated human primary adipocytes we found expression of TF and FVII. TF expression was confirmed in 3T3-L1 adipocytes, and both cell types were found to be procoagulant in a TF/FVIIa-dependent manner. FXa was generated without FVIIa added to the coagulation assay, and active site-inhibited FVIIa blocked FXa formation, supporting our finding of FVII production by human primary adipocytes. There was no evidence for a role of TF in either lipolysis or glucose uptake in our experimental settings.

Conclusion: Human primary adipocytes express active TF and FVII, and the TF/FVIIa complex formed on the adipocyte surface can activate substrate FX. Whether the TF/FVIIa complex conveys signaling pathways leading to biological functions and has any biological activity in adipocytes beyond coagulation remains to be elucidated.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
Keywords
Adipocytes, coagulation, FVII, lipolysis, tissue factor
National Category
Cardiac and Cardiovascular Systems Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-396115 (URN)10.1080/03009734.2019.1645248 (DOI)000481057900001 ()31407948 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationErik, Karin och Gösta Selanders Foundation
Available from: 2019-10-31 Created: 2019-10-31 Last updated: 2019-12-19Bibliographically approved
Norhammar, A., Bodegård, J., Nyström, T., Thuresson, M., Nathanson, D. & Eriksson, J. (2019). Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: A nationwide observational study. Diabetes, obesity and metabolism, 21(5), 1136-1145
Open this publication in new window or tab >>Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: A nationwide observational study
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2019 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 21, no 5, p. 1136-1145Article in journal (Refereed) Published
Abstract [en]

Aims: To investigate cardiovascular (CV) safety and event rates for dapagliflozin versus other glucose-lowering drugs (GLDs) in a real-world type 2 diabetes population after applying the main inclusion criteria and outcomes from the DECLARE-TIMI 58 study.

Methods: Patients with new initiation of dapagliflozin and/or other GLDs were identified in Swedish nationwide healthcare registries for the period 2013 to 2016. Patients were included if they met the main DECLARE-TIMI 58 inclusion criteria: age 40years and established CV disease or presence of multiple-risk factors, e.g. men aged 55years and women aged 60years with hypertension or dyslipidaemia. Propensity scores for the likelihood of dapagliflozin initiation were calculated, then 1:3 matching was carried out. DECLARE-TIMI 58 outcomes were hospitalization for heart failure (HHF) or CV-specific mortality, and major adverse CV events (MACE; CV-specific mortality, myocardial infarction, or stroke). Cox survival models were used to estimate hazard ratios (HRs).

Results: After matching, a total of 28408 new-users of dapagliflozin and/or other GLDs were identified, forming the population for the present study (henceforth referred to as the DECLARE-like cohort. The mean age of this cohort was 66years, and 34% had established CV disease. Dapagliflozin was associated with 21% lower risk of HHF or CV mortality versus other GLDs (HR 0.79, 95% confidence interval [CI] 0.69-0.92) and had no significant association with MACE (HR 0.90, 95% CI 0.79-1.03). HHF and CV mortality risks, separately, were lower at HR 0.79 (95% CI 0.67-0.93) and HR 0.75 (95% CI 0.57-0.97), respectively. Non-significant associations were seen for myocardial infarction and stroke: HR 0.91 (95% CI 0.74-1.11) and HR 1.06 (95% CI 0.87-1.30), respectively.

Conclusion: In a real-world population similar to those included in the DECLARE-TIMI 58 study, dapagliflozin was safe with regard to CV outcomes and resulted in lower event rates of HHF and CV mortality versus other GLDs.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
cardiovascular disease, cohort study, dapagliflozin, pharmaco-epidemiology, type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-383151 (URN)10.1111/dom.13627 (DOI)000465395000009 ()30609272 (PubMedID)
Funder
AstraZeneca
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved
Norhammar, A., Bodegard, J., Nystrom, T., Thuresson, M., Rikner, K., Nathanson, D. & Eriksson, J. (2019). Dapagliflozin vs non-SGLT-2i treatment is associated with lower healthcare costs in type 2 diabetes patients similar to participants in the DECLARE-TIMI 58 trial: A nationwide observational study. Diabetes, obesity and metabolism, 21(12), 2651-2659
Open this publication in new window or tab >>Dapagliflozin vs non-SGLT-2i treatment is associated with lower healthcare costs in type 2 diabetes patients similar to participants in the DECLARE-TIMI 58 trial: A nationwide observational study
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2019 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 21, no 12, p. 2651-2659Article in journal (Refereed) Published
Abstract [en]

Aims To investigate how the cardiovascular (CV) risk benefits of dapagliflozin translate into healthcare costs compared with other non-sodium-glucose cotransporter-2 inhibitor glucose-lowering drugs (oGLDs) in a real-world population with type 2 diabetes (T2D) that is similar to the population of the DECLARE-TIMI 58 trial. Methods Patients initiating dapagliflozin or oGLDs between 2013 and 2016 in Swedish nationwide healthcare registries were included if they fulfilled inclusion and exclusion criteria of the DECLARE-TIMI 58 trial (DECLARE-like population). Propensity scores for the likelihood of dapagliflozin initiation were calculated, followed by 1:3 matching with initiators of oGLDs. Per-patient cumulative costs for hospital healthcare (in- and outpatient) and for drugs were calculated from new initiation until end of follow-up. Results A total of 24 828 patients initiated a new GLD; 6207 initiated dapagliflozin and 18 621 initiated an oGLD. After matching based on 96 clinical and healthcare cost variables, groups were balanced at baseline. Mean cumulative 30-month healthcare cost per patient was similar in the dapagliflozin and oGLD groups ($11 807 and $11 906, respectively; difference, -$99; 95% CI, -$629, $483; P = 0.644). Initiation of dapagliflozin rather than an oGLD was associated with significantly lower hospital costs (-$658; 95% CI, -$1169, -$108; P = 0.024) and significantly higher drug costs ($559; 95% CI, $471, $648; P < 0.001). Hospital cost difference was related mainly to fewer CV- and T2D-associated complications with use of dapagliflozin compared with use of an oGLD (-$363; 95% CI, -$665, -$61; P = 0.008). Conclusion In a nationwide, real-world, DECLARE-like population, dapagliflozin was associated with lower hospital costs compared with an oGLD, mainly as a result of reduced rates of CV- and T2D-associated complications.

Place, publisher, year, edition, pages
WILEY, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-398852 (URN)10.1111/dom.13852 (DOI)000482664900001 ()31379124 (PubMedID)
Funder
AstraZeneca
Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-18Bibliographically approved
Katsogiannos, P., Kamble, P. G., Boersma, G. J., Karlsson, F. A., Lundkvist, P., Sundbom, M., . . . Eriksson, J. (2019). Early Changes in Adipose Tissue Morphology, Gene Expression, and Metabolism After RYGB in Patients With Obesity and T2D. Journal of Clinical Endocrinology and Metabolism, 104(7), 2601-2613
Open this publication in new window or tab >>Early Changes in Adipose Tissue Morphology, Gene Expression, and Metabolism After RYGB in Patients With Obesity and T2D
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2019 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 7, p. 2601-2613Article in journal (Refereed) Published
Abstract [en]

Context: Roux-en-Y gastric bypass (RYGB) surgery effectively prevents or treats type 2 diabetes (T2D). Adipose tissue (AT) mechanisms may be of importance.

Objective: To assess the relationship between early changes in whole-body and AT metabolism in surgically treated patients with T2D.

Design and Setting: A randomized single-center study.

Patients: Nineteen patients with T2D with body mass index 30 to 45 kg/m(2).

Interventions: Thirteen patients were assessed at baseline and 4 and 24 weeks after RYGB (preceded by a 4-week low-calorie diet) and compared with 6 control patients continuing standard medical treatment: oral glucose tolerance test, subcutaneous AT biopsies for gene expression, adipocyte size, glucose uptake, lipolysis, and insulin action.

Results: At 4 and 24 weeks post-RYGB, all patients but one had stopped diabetes medication. Fasting glucose, HbA(1c), and insulin levels decreased and the Matsuda index increased compared with baseline (P < 0.01 for all), indicating improved whole-body insulin sensitivity. Mean adipocyte size significantly reduced, more at 4 than at 24 weeks; at 4 weeks, glucose uptake per adipocyte was lowered, and isoproterenol-stimulated lipolysis tended to increase, whereas the fold insulin effects on glucose uptake and lipolysis were unchanged. Expression of genes involved in fatty acid oxidation, CPT1b and adiponectin, was increased at 4 weeks, whereas leptin and E2F1 (involved in cell proliferation) were reduced (P < 0.05 for all).

Conclusion: Glycemic control and in vivo insulin sensitivity improved 4 weeks after RYGB, but adipocyte insulin sensitivity did not change despite a marked reduction in adipocyte size. Thus, mechanisms for a rapid improvement of T2D after RYGB may occur mainly in other tissues than adipose.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-390982 (URN)10.1210/jc.2018-02165 (DOI)000474806300015 ()30689903 (PubMedID)
Funder
EXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Almby, K. E., Abrahamsson, N., Lundqvist, M. H., Hammar, U., Thombare, K., Panagiotou, A., . . . Eriksson, J. (2019). Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery. European Journal of Endocrinology, 181(2), 161-171
Open this publication in new window or tab >>Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
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2019 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 2, p. 161-171Article in journal (Refereed) Published
Abstract [en]

Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

Design: Experimental hyperinsulinemic-hypoglycemic clamp study.

Methods: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

Conclusions/interpretation: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-390513 (URN)10.1530/EJE-19-0171 (DOI)000472835100013 ()31176298 (PubMedID)
Funder
Swedish Diabetes AssociationErnfors FoundationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Sarsenbayeva, A., Marques-Santos, C. M., Thombare, K., Di Nunzio, G., Almby, K. E., Lundqvist, M. H., . . . Pereira, M. J. (2019). Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism. Psychoneuroendocrinology, 110, Article ID 104445.
Open this publication in new window or tab >>Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism
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2019 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 110, article id 104445Article in journal (Refereed) Published
Abstract [en]

Objective: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism.

Methods: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m(2)). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 mu M - 20 mu M) and aripiprazole (0.002 mu M - 100 mu M). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis.

Results: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term preincubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondria] functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG.

Conclusion: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2019
Keywords
Second-generation antipsychotics, Adipose tissue, Glucose metabolism, Lipid metabolism, Mitochondrial dysfunction, Inflammation
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-400415 (URN)10.1016/j.psyneuen.2019.104445 (DOI)000500388600024 ()31563732 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Mosenzon, O., Blicher, T. M., Rosenlund, S., Eriksson, J., Heller, S., Hels, O. H., . . . Desouza, C. (2019). Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. The Lancet Diabetes and Endocrinology, 7(7), 515-527
Open this publication in new window or tab >>Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial
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2019 (English)In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 7, no 7, p. 515-527Article in journal (Refereed) Published
Abstract [en]

Background: Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment.

Methods: This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1.73 m(2), and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without inetformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA k (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug.The trial is registered on ClinicalTrials. gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete.

Findings: Between Sept 20,2016, and Sept 29,2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA(1c) (estimated mean change of -1.0 percentage point (SE 0.1; -11 mmol/mol [SE 0.8]) vs-0.2 percentage points (SE 0.1; -2 mmol/mol [SE 0.8]); estimated treatment difference [ETD]: -0.8 percentage points, 95% CI -1.0 to -0.6; p<0.0001) and bodyweight (estimated mean change of -3.4 kg [SE 0.3] vs -0.9 kg [SE 0.3]; ETD, -2.5, 95% CI -3.2 to -1.8; p<0.0001) by the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in HbA(1c) -1.1 percentage points (SE 0.1; -12 mmol/mol [SE 0.8] versus -0.1 percentage points (SE 0.1; -1 mmol/mol [SE 0.8]; ETD -1.0 percentage points, 95% CI -1.2 to -0.8; p<0.0001); mean change in bodyweight -3.7 kg (SE 0.3) versus -1.1 kg (SE 0.3; ETD -2.7 kg, 95% CI -3.5 to -1.9; p<0-0001). More patients taking oral semaglutide than placebo had adverse events (120 [74%] of 163 vs 105 [65%] of 161), and discontinued treatment as a result (24 [15%] vs eight [5%]). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with placebo. Three deaths occurred during the treatment period that were not condsidered to be treatment related, one in the semaglutide group and two in the placebo group.

Interpretation: Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class. 

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-390086 (URN)10.1016/S2213-8587(19)30192-5 (DOI)000471906500012 ()31189517 (PubMedID)
Funder
Novo Nordisk
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Organisations
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ORCID iD: ORCID iD iconorcid.org/0000-0002-2639-9481

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