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Lundkvist, Per
Publications (10 of 17) Show all publications
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
Lundkvist, P., Pereira, M. J., Kamble, P. G., Katsogiannos, P., Langkilde, A. M., Esterline, R., . . . Eriksson, J. W. (2019). Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes.. Journal of Clinical Endocrinology and Metabolism, 104(1), 193-201
Open this publication in new window or tab >>Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes.
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2019 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 1, p. 193-201Article in journal (Refereed) Published
Abstract [en]

Context: The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown.

Objective: To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed.

Design, Setting, and Patients: A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin.

Interventions: Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed.

Results: Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D.

Conclusion: The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-373521 (URN)10.1210/jc.2018-00969 (DOI)000461917800025 ()30137410 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-04-10Bibliographically approved
Lundkvist, P. (2019). Metabolic and endocrine effects of SGLT2 inhibition. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Metabolic and endocrine effects of SGLT2 inhibition
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity and type 2 diabetes (T2D) are two growing global health problems with similar comorbidity profiles. SGLT2 inhibitors (SGLT2i) improve blood glucose control and can relieve both T2D and obesity, as well as their associated health problems such as hypertension, kidney failure, and cardiovascular disease.

In paper I, 50 obese patients without diabetes were treated for 24 weeks with SGLT2i dapagliflozin + GLP-1 receptor agonist (GLP-1RA) exenatide or placebo. They were examined regarding body weight loss and body composition. The placebo-adjusted weight loss was 4.13 kg, mostly attributable to adipose tissue loss.

In paper II, 43 completers of the study in paper I entered a 28-week extension phase in which all participants received active treatment. We found major reductions in body weight, adipose tissue volume, blood pressure and prediabetes that were sustained at 52 weeks. 

In paper III, 84 patients with T2D and non-alcoholic fatty liver disease underwent a 12-week treatment with dapagliflozin, omega-3 (n-3) carboxylic acids (OM-3CA), the combination of both or placebo to assess effects on liver fat content. MRI showed significant reductions of liver fat versus baseline and, for the combination, versus placebo.

In paper IV: 15 metformin-treated patients with T2D were assessed for changes in plasma glucagon levels following a single dose of dapagliflozin during experiments with stable versus falling plasma glucose. Changes in glucagon levels could largely be explained by changes in glucose levels.

In conclusion, SGLT2 inhibition can lower body weight and cardiovascular risk factors in obese patients without diabetes when combined with GLP-1RA, and it can reduce liver fat in T2D patients, in particular when given together with OM-3CA. SGLT2i effects on glucagon secretion can largely be explained by lower glucose levels rather than direct α-cell effects.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1534
Keywords
SGLT2 inhibition, GLP-1 receptor agonism, DPP4 inhibition, NAFLD, prediabetes, type 2 diabetes, obesity, metabolic syndrome, glucagon.
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-373522 (URN)978-91-513-0561-5 (ISBN)
Public defence
2019-03-08, Enghoff lecture-hall, Entrance 50, Uppsala academic hospital, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
AstraZeneca
Note

Osäker på serie, ISSN ovan ISBN 

Available from: 2019-02-13 Created: 2019-01-20 Last updated: 2019-02-18
Pereira, M. J., Lundkvist, P., Kamble, P. G., Lau, J., Martins, J. G., Sjostrom, C. D., . . . Eriksson, J. W. (2018). A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss. Diabetes Therapy, 9(4), 1511-1532
Open this publication in new window or tab >>A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss
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2018 (English)In: Diabetes Therapy, ISSN 1869-6953, E-ISSN 1869-6961, Vol. 9, no 4, p. 1511-1532Article in journal (Refereed) Published
Abstract [en]

The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m(2)] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation. Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 mu mol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW. Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation. AstraZeneca.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
Keywords
Dapagliflozin, Exenatide, Lipid metabolism, Obesity, Single-nucleotide polymorphism, Weight loss
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-362039 (URN)10.1007/s13300-018-0449-6 (DOI)000440115700010 ()29949016 (PubMedID)
Funder
AstraZeneca
Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved
Pereira, M. J., Boersma, G. J., Kamble, P. G., Lundkvist, P., Almby, K. E. & Eriksson, J. (2018). Direct effects of glucagon on human adipose tissue metabolism. Paper presented at 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY. Diabetologia, 61, S245-S246
Open this publication in new window or tab >>Direct effects of glucagon on human adipose tissue metabolism
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S245-S246Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-367132 (URN)000443556003092 ()
Conference
54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), OCT 01-05, 2018, Berlin, GERMANY
Funder
Swedish Society for Medical Research (SSMF)Swedish Diabetes Association
Available from: 2018-11-30 Created: 2018-11-30 Last updated: 2018-11-30Bibliographically approved
Eriksson, J. W., Lundkvist, P., Jansson, P.-A., Johansson, L., Kvarnstrom, M., Moris, L., . . . Oscarsson, J. (2018). Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia, 61(9), 1923-1934
Open this publication in new window or tab >>Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 9, p. 1923-1934Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA). individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21). 4 g OM3-CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). Results Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m(2) (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%,p = 0.037) in comparison with placebo. There was an interaction between the PNPLA31148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transfcrase (gamma-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in gamma-GT correlated with changes in liver PDFF (rho = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. Conclusions/interpretation Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Dapagliflozin, Docosahexaenoic acid, Eicosapentaenoic acid, Liver steatosis, Non-alcoholic fatty liver disease, Omega-3 fatty acids, Proton density fat fraction, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-364901 (URN)10.1007/s00125-018-4675-2 (DOI)000440408500005 ()29971527 (PubMedID)
Funder
AstraZeneca
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2019-01-28Bibliographically approved
Sidibeh, C. O., Pereira, M. J., Abalo, X., Boersma, G. J., Skrtic, S., Lundkvist, P., . . . Eriksson, J. (2018). FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes. Endocrine (Basingstoke), 62(1), 116-128
Open this publication in new window or tab >>FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes
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2018 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 62, no 1, p. 116-128Article in journal (Refereed) Published
Abstract [en]

Purpose Here, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1. Methods Human SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 nondiabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes. Results FKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake. Conclusions FKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Type 2 diabetes, Glucocorticoids, Insulin resistance, Adipose tissue, FKBP51, SAFit1
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-363413 (URN)10.1007/s12020-018-1674-5 (DOI)000445383900014 ()30032404 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationSwedish Society for Medical Research (SSMF)AstraZeneca
Available from: 2018-10-19 Created: 2018-10-19 Last updated: 2018-10-19Bibliographically approved
Kamble, P. G., Pereira, M. J., Gustafsson, S., Lundkvist, P., Castillejo-Lopez, C., Fall, T., . . . Eriksson, J. W. (2018). Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover.. Adipocyte, 7(4), 285-296
Open this publication in new window or tab >>Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover.
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2018 (English)In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 7, no 4, p. 285-296Article in journal (Refereed) Published
Abstract [en]

Protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target genes expression were investigated and compared between the genotype groups. On fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p<0.05) also accompanied with a higher antilipolytic effect of insulin post-OGTT (p<0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.

Keywords
PPARG Pro12Ala, human adipose tissue, metabolism and adipogenesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-357116 (URN)10.1080/21623945.2018.1503030 (DOI)000450440700007 ()30064293 (PubMedID)
Available from: 2018-08-12 Created: 2018-08-12 Last updated: 2019-01-23Bibliographically approved
Lundkvist, P., Pereira, M. J., Katsogiannos, P., Sjöström, C. D., Johnsson, E. & Eriksson, J. W. (2017). Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes, obesity and metabolism, 19(9), 1276-1288
Open this publication in new window or tab >>Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year
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2017 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, no 9, p. 1276-1288Article in journal (Refereed) Published
Abstract [en]

Aims: Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24weeks. Here, we examined these effects over 1year in obese adults without diabetes.

Materials and methods: Obese adults without diabetes (N=50; aged 18-70years; body mass index, 30-45kg/m(2)) were initially randomized to double-blind oral dapagliflozin 10mg once daily plus subcutaneous long-acting exenatide 2mg once weekly or to placebo. They entered an open-label extension from 24 to 52weeks during which all participants received active treatment.

Results: Of the original 25 dapagliflozin+exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52weeks of treatment. At baseline, mean body weight was 104.6kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin+exenatide at 24weeks were sustained at 52weeks, respectively, for body weight (-4.5 and -5.7kg), total adipose tissue volume (-3.8 and -5.3L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0mm Hg). Effects on body weight, SBP and glycaemia at 52weeks with placebodapagliflozin+exenatide were similar to those observed with continuation of dapagliflozin+exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin+exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed.

Conclusions: Dapagliflozin+exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52weeks and was well tolerated in obese adults without diabetes.

Keywords
dapagliflozin, exenatide, obesity, prediabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-334932 (URN)10.1111/dom.12954 (DOI)000408241200010 ()28345814 (PubMedID)
Funder
AstraZeneca
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2019-01-20Bibliographically approved
Lundkvist, P., Sjöström, C. D., Amini, S., Pereira, M. J., Johnsson, E. & Eriksson, J. W. (2017). Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes, obesity and metabolism, 19(1), 49-60
Open this publication in new window or tab >>Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes
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2017 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, no 1, p. 49-60Article in journal (Refereed) Published
Abstract [en]

Aims: To explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes.

Materials and methods: In this single-centre, double-blind trial, we randomized 50 obese adults without diabetes (aged 18-70 years; body mass index 30-45 kg/m(2)) to oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or placebo. MRI was used to assess change in body composition. Participants were instructed to follow a balanced diet and exercise moderately.

Results: Of 25 dapagliflozin/exenatide-and 25 placebo-treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was -4.13 kg (95% confidence interval -6.44, -1.81; P <.001), which was mostly attributable to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% of participants achieved >= 5% body weight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P <.01). The difference in SBP change for dapagliflozin/ exenatide versus placebo was -6.7 mm Hg. As expected, nausea and injection-site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only two and three participants, respectively, discontinued because of adverse events.

Conclusions: Compared with placebo, dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes.

Keywords
dapagliflozin, exenatide, obesity, prediabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-314407 (URN)10.1111/dom.12779 (DOI)000390987800006 ()
Funder
AstraZeneca
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2019-01-20Bibliographically approved
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