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  • 1.
    Alfredsson, Joakim
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US. Duke Univ, NC USA.
    Green, Jennifer B.
    Duke Univ, NC USA.
    Stevens, Susanna R.
    Duke Univ, NC USA.
    Reed, Shelby D.
    Duke Univ, NC USA.
    Armstrong, Paul W.
    Univ Alberta, Canada.
    Bethel, M. Angelyn
    Univ Oxford, England.
    Engel, Samuel S.
    Merck and Co Inc, NJ USA.
    McGuire, Darren K.
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Van de Werf, Frans
    Univ Leuven, Belgium.
    Hramiak, Irene
    Univ Western Ontario, Canada.
    White, Harvey D.
    Auckland City Hosp, New Zealand.
    Peterson, Eric D.
    Duke Univ, NC USA.
    Holman, Rury R.
    Univ Oxford, England.
    Sex differences in management and outcomes of patients with type 2 diabetes and cardiovascular disease: A report from TECOS2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 10, s. 2379-2388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Materials and methods: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo-controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Results: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant-years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71-0.89, adjusted HR 0.64, 95% CI 0.55-0.74; P amp;lt; .0001). Women also had a significantly lower risk of secondary CV outcomes and all-cause death. Conclusions: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes.

  • 2.
    Barker, A.
    et al.
    Cambridge Institute Public Heatlh, England .
    Lauria, A.
    University of Campus Biomed, Italy .
    Schloot, N.
    University of Dusseldorf, Germany University of Dusseldorf, Germany .
    Hosszufalusi, N.
    Semmelweis University, Hungary .
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Mathieu, C.
    Katholieke University of Leuven, Belgium .
    Mauricio, D.
    Hospital Arnau Vilanova, Spain .
    Nordwall, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Norrköping.
    Van der Schueren, B.
    Katholieke University of Leuven, Belgium .
    Mandrup-Poulsen, T.
    University of Copenhagen, Denmark .
    Scherbaum, W .A.
    University of Dusseldorf, Germany .
    Weets, I.
    Vrije University of Brussel, Belgium Vrije University of Brussel, Belgium Belgian Diabet Registry BDR, Belgium .
    Gorus, F. K.
    Vrije University of Brussel, Belgium Vrije University of Brussel, Belgium Belgian Diabet Registry BDR, Belgium .
    Wareham, N.
    Cambridge Institute Public Heatlh, England .
    Leslie, R. D.
    Queen Mary University of London, England .
    Pozzilli, P.
    University of Campus Biomed, Italy Queen Mary University of London, England .
    Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study2014Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, nr 3, s. 262-267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AimsC-peptide secretion is currently the only available clinical biomarker to measure residual -cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. MethodsWe analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on -cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. ResultsFasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (less than5years, n=344; greater than5yearsless than10years, n=668; greater than10yearsless than18years, n=991; greater than18years, n=1655). FCP levels were positively correlated with age (pless than0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (pless than0.0001). ConclusionsThis study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of -cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.

  • 3.
    Bergsten, P
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Islet protein profiling2009Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 11, s. 97-117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Islet protein profiling is defined as generation of extended protein expression data sets from islets or islet cells. Islets from rodent control and animal models of type 1 and type 2 diabetes mellitus and healthy humans and insulin- and glucagon-producing cell lines have been used. Protein profiling entails separation, differential expression determination, identification and expression analysis. Protein/peptide separation is either gel-based or by chromatography. Differential expression is based on comparison of visualized spots/proteins between gels or by sample labelling in gel-free systems. Identification of proteins is made by tryptic fragmentation of proteins, fragment mass determination and mass comparison with protein databases. Analysis of expression data sets interprets the complex protein changes into cellular mechanisms to generate hypotheses. The importance of such protein expression sets to elucidate islet cellular events is evidenced by the observation that only about 50% of the differentially expressed proteins and transcripts showed concordance when measured in parallel. Using protein profiling, different areas related to islet dysfunction in type 1 and type 2 diabetes mellitus have been addressed, including dysfunction induced by elevated levels of glucose and fatty acids and cytokines. Because islets from individuals with type 1 or type 2 diabetes mellitus have not yet been protein profiled, islets from rat (BB-DP) and mouse (NOD, ob/ob, MKR) models of the disease have been used, and mechanisms responsible for islet dysfunction delineated offering avenues of intervention.

  • 4. Bolinder, J.
    et al.
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Johansson, L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wilding, J.
    Langkilde, A. M.
    Sjöstrom, C. D.
    Sugg, J.
    Parikh, S.
    Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin2014Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, nr 2, s. 159-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims

    Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment.

    Methods

    This randomized, double-blind, placebo-controlled study (NCT00855166) enrolled patients with T2DM [mean: age 60.7 years; HbA1c 7.2%; body mass index (BMI) 31.9 kg/m(2); body weight 91.5 kg] inadequately controlled on metformin. Patients (N=182) were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by dual-energy X-ray absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated.

    Results

    A total of 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of urinary tract infection (UTI) and genital infection was similar in both treatment groups.

    Conclusions

    Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.

  • 5. Denison, H
    et al.
    Nilsson, C
    Kujacic, M
    Löfgren, L
    Karlsson, C
    Knutsson, M
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism. Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study2013Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 15, nr 2, s. 136-143Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687.

    METHODS: Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity.

    RESULTS: AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687.

    CONCLUSIONS: The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.

  • 6. Denison, H
    et al.
    Nilsson, C
    Löfgren, L
    Himmelmann, A
    Mårtensson, G
    Knutsson, M
    Al-Shurbaji, A
    Tornqvist, H
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial2014Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, nr 4, s. 334-343Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM:

    Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.

    METHODS:

    Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.

    RESULTS:

    Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.

    CONCLUSIONS:

    Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

  • 7. deSchoolmeester, J.
    et al.
    Palming, J.
    Persson, T.
    Pereira, M. J.
    Wallerstedt, E.
    Brown, H.
    Gill, D.
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lundgren, M.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Svensson, M. K.
    Rees, A.
    Eriksson, J. W.
    Differences between men and women in the regulation of adipose 11 beta-HSD1 and in its association with adiposity and insulin resistance2013Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 15, nr 11, s. 1056-1060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study explored sex differences in 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 +/- 15.3years, body mass index (BMI) 27.2 +/- 3.9kg/m(2)]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11-HSD1 mRNA expression. This study suggests that there are sex differences in 11-HSD1 regulation and in its associations with markers of obesity and IR.

  • 8. deSchoolmeester, J
    et al.
    Palming, J
    Persson, T
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Wallerstedt, E
    Brown, H
    Gill, D
    Renström, F
    Lundgren, M
    Svensson, M K
    Rees, A
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Differences between men and women in the regulation of adipose 11β-HSD1 and in its association with adiposity and insulin resistance2013Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 15, nr 11, s. 1056-1560Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study explored sex differences in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m2]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11β-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11β-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11β-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11β-HSD1 mRNA expression. This study suggests that there are sex differences in 11β-HSD1 regulation and in its associations with markers of obesity and IR.

  • 9. Ekström, N.
    et al.
    Miftaraj, M.
    Svensson, A. -M
    Sundell, K. Andersson
    Cederholm, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gudbjörnsdottir, S.
    Eliasson, B.
    Glucose-lowering treatment and clinical results in 163 121 patients with type 2 diabetes: an observational study from the Swedish national diabetes register2012Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, nr 8, s. 717-726Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To analyse clinical characteristics and treatment results in unselected type 2 diabetes mellitus (T2DM) patients, with non-pharmacological treatment as well as the most commonly used pharmacological glucose-lowering treatment regimens, in everyday clinical practice. Methods: In this population-based cross-sectional study, information was linked from the Swedish National Diabetes Register, Prescribed Drug Register and Patient Register. T2DM patients with non-pharmacological treatment and T2DM patients continuously using the 12 most common pharmacological treatment regimens were included in the study (n = 163121). Results: There were statistically significant differences in clinical characteristics between the groups. Patients with insulin-based treatment regimens had the longest duration of diabetes and more cardiovascular risk factors than the T2DM-population in general. The proportion of patients reaching HbA1c =7% varied between 70.1% (metformin) and 25.0% [premixed insulin (PMI) + SU) in patients with pharmacological treatment. 84.8% of the patients with non-pharmacological treatment reached target. Compared to patients on metformin, patients on other pharmacological treatments had a lower likelihood, with hazard ratios ranging from 0.58; 95% confidence interval (CI), 0.540.63 to 0.97;0.940.99, of having HbA1c =7% (adjusted for covariates). Patients on insulin-based treatments had the lowest likelihood, while non-pharmacological treatment was associated with an increased likelihood of having HbA1c =7%. Conclusion: This nation-wide study shows insufficiently reached treatment goals for haemoglobin A1c (HbA1c) in all treatment groups. Patients on insulin-based treatment regimens had the longest duration of diabetes, more cardiovascular risk factors and the highest proportions of patients not reaching HbA1c target.

  • 10.
    Ekström, Nils
    et al.
    Univ Gothenburg, Dept Med, Gothenburg, Sweden.;Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Svensson, Ann-Marie
    Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Miftaraj, Mervete
    Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Franzen, Stefan
    Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik. Med Prod Agcy, Uppsala, Sweden..
    Eliasson, Bjorn
    Univ Gothenburg, Dept Med, Gothenburg, Sweden..
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Dept Med, Gothenburg, Sweden.;Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Cardiovascular safety of glucose-lowering agents as add-on medication to metformin treatment in type 2 diabetes: report from the Swedish National Diabetes Register2016Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 18, nr 10, s. 990-998Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To investigate the relative safety of various glucose-lowering agents as add-on medication to metformin in type 2 diabetes in an observational study linking five national health registers. Research design and methods: Patients with type 2 diabetes who had been on metformin monotherapy and started another agent in addition to metformin were eligible for inclusion. The study period was 2005-2012. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, cardiovascular disease (CVD), coronary heart disease (CHD), stroke and congestive heart failure (CHF) were estimated using Cox proportional hazards models, weighted for a propensity score. Results: Of the 20 422 patients included in the study, 43% started on second-line treatment with sulphonylurea (SU), 21% basal insulin, 12% thiazolidinedione (TZD), 11% meglitinide, 10% dipeptidyl peptidase-4 (DPP-4) inhibitor, 1% glucagon-like peptide-1 (GLP-1) receptor agonist and 1% acarbose. At the index date, the mean patient age was similar to 60 years for all groups except the GLP-1 receptor agonist (56.0 years) and SU (62.9 years) groups. Diabetes duration and glycated haemoglobin levels were similar in all groups. When compared with SU, basal insulin was associated with an 18% higher risk and TZD with a 24% lower risk of mortality [HR 1.18 (95% CI 1.03-1.36) and 0.76 (95% CI 0.62-0.94)], respectively. DPP-4 inhibitor treatment was associated with significantly lower risks of CVD, fatal CVD, CHD, fatal CHD and CHF. Conclusions: This nationwide observational study showed that second-line treatment with TZD and DPP-4 inhibitor as add-on medication to metformin were associated with significantly lower risks of mortality and cardiovascular events compared with SU, whereas basal insulin was associated with a higher risk of mortality.

  • 11. Eriksson, A
    et al.
    Attvall, S
    Bonnier, M
    Eriksson, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rosander, B
    Karlsson, F A
    Short-term effects of metformin in type 2 diabetes2007Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 9, nr 4, s. 483-489Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined the early effects on glucose and lipid metabolism and on certain adipose tissue and inflammatory markers during treatment for 28 days. METHODS: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in the first week, 500 mg twice daily during week 2 and 1000 mg twice daily during weeks 3 and 4. RESULTS: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared to baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total cholesterol and low-density lipoprotein cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin. CONCLUSIONS: The data demonstrate that in type 2 diabetes, metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.

  • 12. Eriksson, A
    et al.
    Attvall, S
    Bonnier, M
    Eriksson, Jan W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rosander, B
    Karlsson, F A
    Short-term effects of metformin in type 2 diabetes2007Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 9, nr 3, s. 330-336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined early effects on glucose and lipid metabolism, and on certain adipose tissue and inflammatory markers during treatment for 28 days. METHODS: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in week 1, 500 mg twice daily in week 2 and 1000 mg twice daily in week 3 and 4. RESULTS: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared with baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total and LDL-cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin. CONCLUSIONS: The data demonstrate that in type 2 diabetes metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.

  • 13. Eriksson, A.
    et al.
    Attvall, S.
    Bonnier, M.
    Eriksson, Jan W.
    Rosander, B.
    Karlsson, F. Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Short-term effects of metformin in type 2 diabetes2007Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 9, nr 3, s. 330-336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined early effects on glucose and lipid metabolism, and on certain adipose tissue and inflammatory markers during treatment for 28 days.

    Methods: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in week 1, 500 mg twice daily in week 2 and 1000 mg twice daily in week 3 and 4.

    Results: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared with baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total and LDL-cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin.

    Conclusions: The data demonstrate that in type 2 diabetes metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.

  • 14.
    Fioretto, Paola
    et al.
    Department of Medicine, University of Padova, Padova, Italy.
    Del Prato, Stefano
    Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.
    Buse, John B.
    Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
    Goldenberg, Ronald
    LMC Diabetes & Endocrinology, Thornhill, Canada.
    Giorgino, Francesco
    Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.
    Reyner, Daniel
    AstraZeneca, Gaithersburg, Maryland, USA.
    Langkilde, Anna Maria
    AstraZeneca, Gothenburg, Sweden.
    Sjöstrom, C. David
    AstraZeneca, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca, Gothenburg, Sweden.
    Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 11, s. 2532-2540Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Dapagliflozin is a selective inhibitor of sodium glucose co-transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg vs placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR], 45-59 mL/min/1.73 m(2); chronic kidney disease [CKD] stage 3A). Materials and methods: In this double-blind, parallel group, Phase 3 study (NCT02413398, ) patients with inadequately controlled T2D (HbA1c 7.0%-11.0%) were randomized (1:1) to dapagliflozin 10 mg once daily (N = 160) or matching placebo (N = 161) for 24 weeks. Randomization was stratified by pre-enrolment glucose-lowering therapy. The primary endpoint was change from baseline in HbA1c at Week 24. Results: At Week 24, compared with placebo, dapagliflozin significantly decreased HbA1c (difference [95% CI], -0.34% [-0.53, -0.15]; P < 0.001), body weight (difference [95% CI], -1.25 kg [-1.90, -0.59]; P < 0.001), fasting plasma glucose (difference [95% CI], -0.9 mmol/L [-1.5, -0.4]; P = 0.001) and systolic blood pressure (difference [95% CI], -3.1 mmHg [-6.3, 0.0]; P < 0.05). Decreases from baseline in eGFR were greater with dapagliflozin than placebo at Week 24 (-2.49 mL/min/1.73 m(2) [-4.96, -0.02]), however, eGFR returned to baseline levels at Week 27 (3 weeks post-treatment) (0.61 mL/min/1.73 m(2) [-1.59, 2.81]). No increase in adverse events (AEs; 41.9% vs 47.8%) or serious AEs (5.6% vs 8.7%) were reported with dapagliflozin versus placebo. No AEs of bone fractures, amputations or DKA were reported. Conclusions: The findings of this study (NCT02413398, ) support the positive benefit/risk profile of dapagliflozin for the treatment of patients with T2D and CKD 3A.

  • 15.
    Gylfe, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Neurotransmitter control of islet hormone pulsatility2014Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, nr S1, s. 102-110Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Pulsatile secretion is an inherent property of hormone-releasing pancreatic islet cells. This secretory pattern is physiologically important and compromised in diabetes. Neurotransmitters released from islet cells may shape the pulses in auto/paracrine feedback loops. Within islets, glucose-stimulated -cells couple via gap junctions to generate synchronized insulin pulses. In contrast, - and -cells lack gap junctions, and glucagon release from islets stimulated by lack of glucose is non-pulsatile. Increasing glucose concentrations gradually inhibit glucagon secretion by -cell-intrinsic mechanism/s. Further glucose elevation will stimulate pulsatile insulin release and co-secretion of neurotransmitters. Excitatory ATP may synchronize -cells with -cells to generate coinciding pulses of insulin and somatostatin. Inhibitory neurotransmitters from - and -cells can then generate antiphase pulses of glucagon release. Neurotransmitters released from intrapancreatic ganglia are required to synchronize -cells between islets to coordinate insulin pulsatility from the entire pancreas, whereas paracrine intra-islet effects still suffice to explain coordinated pulsatile release of glucagon and somatostatin. The present review discusses how neurotransmitters contribute to the pulsatility at different levels of integration.

  • 16.
    Heerspink, Hiddo J. L.
    et al.
    Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center, Groningen, Netherlands.
    Sjöström, C. David
    AstraZeneca, Gothenburg, Sweden.
    Inzucchi, Silvio E.
    Section of Endocrinology, Yale University School of Medicine, New Haven, CT, United States.
    Hallow, Melissa K.
    Department of Epidemiology and Biostatistics, University of Georgia School of Public Health, Athens, GA, United States.
    Cain, Valerie A.
    Bogier Clinical and IT Solutions, Inc., Raleigh, NC, United States.
    Rossing, Peter
    Steno Diabetes Center Copenhagen, Gentofte, Denmark / Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
    Stefansson, Bergur V.
    AstraZeneca, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca, Gothenburg, Sweden.
    Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers2019Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 21, nr 3, s. 720-725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was −71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined. 

  • 17. Hellgren, M
    et al.
    Melander, A
    Östgren, Carl-Johan
    Malmö University Hospital.
    Rastam, L
    Lindblad, U
    Inverse association between plasma homocysteine, sulphonylurea exposure and physical activity: a community-based sample of type 2 diabetes patients in the Skaraborg hypertension and diabetes project.2005Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 7, nr 4, s. 421-Artikkel i tidsskrift (Fagfellevurdert)
  • 18.
    Jendle, Johan
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Birkenfeld, A. L.
    Department of Medicine III, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden, Helmholtz Center Munich at Technische Universität Dresden, Dresden, Germany.
    Polonsky, W. H.
    Behavioral Diabetes Institute, University of California San Diego, San Diego, CA, USA.
    Silver, R.
    Southern New Hampshire Diabetes and Endocrinology, Nashua, NH, USA.
    Uusinarkaus, K.
    DaVita Medical Group, University of Colorado School of Medicine, Colorado Springs, CO, USA.
    Hansen, T.
    Novo Nordisk A/S, Søborg, Denmark.
    Håkan-Bloch, J.
    Novo Nordisk A/S, Søborg, Denmark.
    Tadayon, S.
    Novo Nordisk A/S, Søborg, Denmark.
    Davies, M. J.
    University of Leicester, Diabetes Research Centre, Leicester, UK.
    Improved treatment satisfaction in patients with type 2 diabetes treated with once-weekly semaglutide in the SUSTAIN trials2019Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 21, nr 10, s. 2315-2326Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To investigate treatment satisfaction with semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, versus placebo/active comparators in theSUSTAIN clinical trial programme.

    METHODS: In SUSTAIN 2-5 and 7, the Diabetes Treatment Satisfaction Questionnaire was used to evaluate patient-perceived treatment satisfaction, hyperglycaemia and hypoglycaemia. Post hoc subgroup analyses were conducted to explore the effects of gastrointestinal adverse events (GI AEs), weight loss (>= 5%) or achieving glycaemic (HbA1c < 7%) targets on treatment satisfaction.

    RESULTS: Overall treatment satisfaction increased from baseline to end of treatment with all treatments across trials. Improvements were significantly greater with semaglutide versus comparators/placebo in SUSTAIN 2-5 (all P < 0.05), and generally greater in patients who achieved versus did not achieve weight loss and glycaemic targets, often with greater improvements with semaglutide 1.0 mg versus comparator/placebo in both weight loss groups. In SUSTAIN 7, improvements in overall treatment satisfaction were generally similar between semaglutide and dulaglutide, irrespective of weight loss or glycaemic control. In SUSTAIN 7, changes in overall treatment satisfaction score were generally lower in patients with versus without GI AEs at week 16 (except dulaglutide 0.75 mg), but similar by week 40. Perceived hyperglycaemia was significantly reduced from baseline to end of treatment with semaglutide versus all comparators/placebo (all P < 0.05). No differences between treatments were observed for perceived hypoglycaemia.

    CONCLUSIONS: Semaglutide was associated with significantly greater (SUSTAIN 2-5) or similar (SUSTAIN 7) improvements in overall treatment satisfaction versus comparators/placebo. Improvements in overall treatment satisfaction were generally greater in patients achieving versus not achieving treatment targets. Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4), NCT02305381 (SUSTAIN 5) and NCT02648204 (SUSTAIN 7). EudraCT: 2012-004827-19 (SUSTAIN 2), 2012-004826-92 (SUSTAIN 3), 2013-004392-12 (SUSTAIN 4), 2013-004502-26 (SUSTAIN 5) and 2014-005375-91 (SUSTAIN 7).

  • 19.
    Jendle, Johan
    et al.
    Örebro universitet, Hälsoakademin.
    Nauck, M. A.
    Matthews, D. R.
    Frid, A.
    Hermansen, K.
    During, M.
    Zdravkovic, M.
    Strauss, B. J.
    Garber, A. J.
    Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue2009Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 11, nr 12, s. 1163-1172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim The effect on body composition of liraglutide, a once-daily human glucagon-like peptide-1 analogue, as monotherapy or added to metformin was examined in patients with type 2 diabetes (T2D). Methods These were randomized, double-blind, parallel-group trials of 26 [Liraglutide Effect and Action in Diabetes-2 (LEAD-2)] and 52 weeks (LEAD-3). Patients with T2D, aged 18-80 years, body mass index (BMI) < 40 kg/m2 (LEAD-2), < 45 kg/m2 (LEAD-3) and HbA1c 7.0-11.0% were included. Patients were randomized to liraglutide 1.8, 1.2 or 0.6 mg/day, placebo or glimepiride 4 mg/day, all combined with metformin 1.5-2 g/day in LEAD-2 and to liraglutide 1.8, 1.2 or glimepiride 8 mg/day in LEAD-3. LEAD-2/3: total lean body tissue, fat tissue and fat percentage were measured. LEAD-2: adipose tissue area and hepatic steatosis were assessed. Results LEAD-2: fat percentage with liraglutide 1.2 and 1.8 mg/metformin was significantly reduced vs. glimepiride/metformin (p < 0.05) but not vs. placebo. Visceral and subcutaneous adipose tissue areas were reduced from baseline in all liraglutide/metformin arms. Except with liraglutide 0.6 mg/metformin, reductions were significantly different vs. changes seen with glimepiride (p < 0.05) but not with placebo. Liver-to-spleen attenuation ratio increased with liraglutide 1.8 mg/metformin possibly indicating reduced hepatic steatosis. LEAD-3: reductions in fat mass and fat percentage with liraglutide monotherapy were significantly different vs. increases with glimepiride (p < 0.01). Conclusion Liraglutide (monotherapy or added to metformin) significantly reduced fat mass and fat percentage vs. glimepiride in patients with T2D.

  • 20.
    Jendle, Johan
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Testa, Marcia A.
    Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston MA, USA.
    Martin, Sherry
    Eli Lilly and Company, Indianapolis, USA.
    Jiang, Honghua
    Eli Lilly and Company, Indianapolis, USA.
    Milicevic, Zvonko
    Eli Lilly and Company Regional Operations, Vienna, Austria.
    Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy2016Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 18, nr 10, s. 999-1005Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Insulin use with GLP-1 receptor agonists is of interest because of the potential for glucose lowering with reduced insulin dosing versus an insulin-only regimen. The AWARD-4 trial, designed to compare these regimens, included a sub-study using 24-hour continuous glucose monitoring (CGM).

    Methods: The AWARD-4 trial randomised 884 conventional insulin regimens-treated patients to dulaglutide 1.5 mg, 0.75 mg and glargine, all in combination with prandial insulin lispro. The CGM sub-study included 144 patients inserted with Medtronic CGMS® iPro™ CGM device to enable 3-day glucose monitoring. CGM sessions were completed at weeks 0, 13, 26, and 52. CGM measures included mean 24-hour glucose, percentage time in target glucose ranges, hyper- and hypoglycaemia, and glucose variability. The primary objective was treatment comparison for percentage time CGM glucose in the 3.9-7.8 mmol/L range after 26 weeks.

    Results: At week 26, mean CGM glucose decreased in all treatment groups (change from baseline -2.8 ± 0.3, -2.4 ± 0.3, and -2.5 ± 0.3 mmol/L for dulaglutide 1.5 mg, 0.75 mg, and glargine, respectively); between-group differences were not statistically significant. Treatment groups were similar for percentage time in 3.9-7.8 mmol/L range. Percentage time in 3.9-10.0 mmol/L range was greater for dulaglutide 1.5 mg than glargine (p < 0.05). Dulaglutide and glargine were associated with decreased glucose variability for all CGM variability indices. Overall within-patient SD was significantly reduced with dulaglutide 1.5 mg versus glargine (p < 0.05). At week 52, there were no significant differences between groups for measures of normoglycaemia or near-normoglycaemia and for the overall within-patient SD. Treatment with glargine was associated with greater increases in percentage time glucose was ≤3.9 mmol/L with statistically significant differences between the groups at 52 weeks (p < 0.05).

    Conclusions: In combination with prandial lispro, treatment with dulaglutide and glargine resulted in similar proportions of glucose values in the normoglycaemic range, but dulaglutide provided an improved balance between the proportion of values within the near-normoglycaemia range and values within the hypoglycaemic range.

  • 21.
    Kullberg, Joel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för radiologi.
    Ortiz-Nieto, Francisco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för radiologi.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för radiologi.
    Reproducibility of hepatic triglyceride content assessment in normals using localized magnetic resonance spectroscopy2009Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 11, nr 5, s. 516-518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To investigate the reproducibility of measurements of hepatic triglyceride content (HTGC) in subjects with normal HTGC using localized (1)H-magnetic resonance spectroscopy ((1)H-MRS) and a clinical 1.5T scanner. METHODS: The (1)H-MRS acquisition was performed with a common protocol using the whole-body coil and no respiratory triggering. An upper limit of normal HTGC of 5.56% was used. Duplicate measurements, including subject repositioning, were acquired from 23 subjects, 19 of whom had a normal HTGC. RESULTS: The mean coefficient of variation (CV) from the duplicate measurements was 14.8% (20.5% before exclusion of a subject who was considered to be an outlier). Mean CVs of subgroups below and above the 1% HTGC limit were 19.8 and 7.0 respectively. CONCLUSIONS: The mean CV calculated in subjects with HTGC in the normal range was found to be higher than CVs of wide range HTGC groups reported in the literature. It is concluded that the reproducibility of HTGC measurements using (1)H-MRS depends on the HTGC range. These findings are of importance in reproducibility studies and in estimations of required study group sizes.

  • 22.
    Leohr, Jennifer
    et al.
    Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
    Heathman, Michael
    Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
    Kjellsson, Maria C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Semi-physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high-fat meal2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 3, s. 660-666Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling approach.

    METHODS: ) were enrolled in a clinical study to assess the TG response after a high-fat meal, containing 60% fat. Non-linear mixed-effect modelling was used to analyse the TG concentrations of chylomicrons and large VLDL-V6 particles.

    RESULTS: The TGs in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response; only the VLDL-V6 showed a difference across the populations. A turn-over model successfully described the TG concentration-time profiles of both chylomicrons and large VLDL-V6 particles after the high-fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of TGs in the blood, and one compartment each for the chylomicrons and large VLDL-V6 particles. The rate constants for the production of chylomicrons and elimination of large VLDL-V6 particles, along with the conversion rate of chylomicrons to large VLDL-V6 particles were well defined.

    CONCLUSIONS: This is the first lipokinetic model to describe the absorption of TGs from dietary fats into the blood stream and compares the dynamics of TGs in chylomicrons and large VLDL-V6 particles among lean, obese and very obese people. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.

  • 23.
    Lindblad, U.
    et al.
    Department of Public Health and Community Medicine/Primary Health Care, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Enheten för allmämedicin, Göteborgs universitet, Göteborg, Sverige; Skaraborg Institute, Skövde, Sweden.
    Lindberg, G.
    Department of Clinical Sciences, Clinical Research Centre, Malmö University Hospital, Lund University, Malmö, Sweden; The NEPI Foundation, Malmö, Sweden.
    Månsson, N.-O.
    Department of Clinical Sciences, Clinical Research Centre, Malmö University Hospital, Lund University, Malmö, Sweden.
    Ranstam, J.
    The NEPI Foundation, Malmö, Sweden; Swedish National Competence Centre for Musculoskeletal Disorders, Department of Orthopædics, Lund University Hospital, Lund, Sweden.
    Tyrberg, M.
    Department of Ophtalmology, Helsingborg Hospital, Helsingborg, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Jansson, Stefan
    Family Medicine Research Centre, Örebro University Hospital, Örebro, Sweden.
    Lindwall, K.
    The NEPI Foundation, Malmö, Sweden; The NEPI Foundation, Linköping, Sweden.
    Svärdh, M.
    Department of Clinical Sciences, Clinical Research Centre, Malmö University Hospital, Lund University, Malmö, Sweden; The NEPI Foundation, Malmö, Sweden.
    Kindmalm, L
    Skaraborg Institute, Skövde, Sweden; Skaraborg Primary Care, Skövde, Sweden.
    Melander, A.
    Department of Clinical Sciences, Clinical Research Centre, Malmö University Hospital, Lund University, Malmö, Sweden; The NEPI Foundation, Malmö, Sweden; Community Medicine, Clinical Sciences, Malmö, Sweden.
    Can sulphonylurea addition to lifestyle changes help to delay diabetes development in subjects with impaired fasting glucose? The Nepi ANtidiabetes StudY (NANSY)2011Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 13, nr 2, s. 185-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Nepi ANtidiabetes StudY (NANSY) is a 5-year randomized, double-blind, placebo-controlled trial in Swedish primary care, examining whether the development of type 2 diabetes (T2D) and retinopathy (separately reported) would be delayed in 40- to 70-year-old subjects with impaired fasting glucose (IFG) who, in addition to lifestyle changes, were treated with either placebo or low-dosage sulphonylurea (SU) (1-mg glimepiride; Amaryl). Of 274 subjects (163 men, 111 women), 138 were allocated to placebo (46.0% men, 56.8% women) and 136 to glimepiride (54.0% men, 43.2% women). The primary endpoint was conversion to diabetes. Average follow-up time was 3.71 years; 96 subjects converted to diabetes, 55 allocated to placebo and 41 to glimepiride (absolute difference 9.8%; p = 0.072). In conclusion, the study failed to support the notion that low-dose SU added to lifestyle changes in IFG subjects would help to delay the conversion to diabetes.

  • 24.
    Ljunggren, Östen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Metabola bensjukdomar.
    Bolinder, J.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Wilding, J.
    Langkilde, A. M.
    Sjostrom, C. D.
    Sugg, J.
    Parikh, S.
    Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin2012Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, nr 11, s. 990-999Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycaemia in patients with type 2 diabetes (T2DM) by increasing urinary glucose excretion. Owing to its mechanism of action, dapagliflozin could potentially affect the renal tubular transportation of bone minerals. Therefore, markers of bone formation and resorption and bone mineral density (BMD) were evaluated in patients with T2DM after 50?weeks of dapagliflozin treatment. Methods This international, multi-centre, randomized, parallel-group, double-blind, placebo-controlled study (ClinicalTrials.gov NCT00855166) enrolled patients with T2DM (women 5575?years and men 3075?years; HbA1c 6.58.5%; BMI?=?25?kg/m2; body weight?=?120?kg) whose T2DM was inadequately controlled on metformin. One hundred and eighty-two patients were randomly assigned 1:1 to receive dapagliflozin 10?mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 50, serum markers of bone formation (procollagen type 1 N-terminal propeptide; P1NP) and resorption (C-terminal cross-linking telopeptides of type I collagen; CTX), bone mineral density (BMD) as assessed by standardized Dual-Energy X-ray Absorptiometry (DXA) measurements and adverse events of fracture were evaluated as safety objectives. Results One hundred and sixty-five patients (90.7%) completed the first 50 weeks. Compared with placebo, no significant changes from baseline in P1NP, CTX or BMD were identified over 50 weeks of dapagliflozin treatment, with no significant treatment-by-gender interactions. No fractures were reported. Conclusions Dapagliflozin had no effect on markers of bone formation and resorption or BMD after 50 weeks of treatment in both male and post-menopausal female patients whose T2DM was inadequately controlled on metformin.

  • 25.
    Lundkvist, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Katsogiannos, Petros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Sjöström, C. David
    AstraZeneca, Gothenburg.
    Johnsson, Eva
    AstraZeneca, Gothenburg.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year2017Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, nr 9, s. 1276-1288Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 26.
    Lundkvist, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Sjöström, C. David
    AstraZeneca, Gothenburg, Sweden..
    Amini, Sam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Pereira, Maria J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Johnsson, Eva
    AstraZeneca, Gothenburg, Sweden..
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    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 diabetes2017Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, nr 1, s. 49-60Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 27. Mogensen, M
    et al.
    Vind, B F
    Højlund, K
    Beck-Nielsen, H
    Sahlin, Kent
    Gymnastik- och idrottshögskolan, GIH, Institutionen för idrotts- och hälsovetenskap, Forskningsgruppen Mitokondriell funktion och metabolisk kontroll.
    Maximal lipid oxidation in patients with type 2 diabetes is normal and shows an adequate increase in response to aerobic training.2009Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 11, nr 9, s. 874-83Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: Insulin resistance in subjects with type 2 diabetes (T2D) and obesity is associated with an imbalance between the availability and the oxidation of lipids. We hypothesized that maximal whole-body lipid oxidation during exercise (FATmax) is reduced and that training-induced metabolic adaptation is attenuated in T2D. METHODS: Obese T2D (n = 12) and control (n = 11) subjects matched for age, sex, physical activity and body mass index completed 10 weeks of aerobic training. Subjects were investigated before and after training with maximal and submaximal exercise tests and euglycaemic-hyperinsulinaemic clamps combined with muscle biopsies. RESULTS: Training increased maximal oxygen consumption (VO(2max)) and muscle citrate synthase activity and decreased blood lactate concentrations during submaximal exercise in both groups (all p < 0.01). FATmax increased markedly (40-50%) in both T2D and control subjects after training (all p < 0.001). There were no significant differences in these variables and lactate threshold (%VO(2max)) between groups before or after training. Insulin-stimulated glucose disappearance rate (Rd) was lower in T2D vs. control subjects both before and after training. Rd increased in response to training in both groups (all p < 0.01). There was no correlation between Rd and measures of oxidative capacity or lipid oxidation during exercise or the training-induced changes in these parameters. CONCLUSIONS: FATmax was not reduced in T2D, and muscle oxidative capacity increased adequately in response to aerobic training in obese subjects with and without T2D. These metabolic adaptations to training seem to be unrelated to changes in insulin sensitivity and indicate that an impaired capacity for lipid oxidation is not a major cause of insulin resistance in T2D.

  • 28.
    Norhammar, Anna
    et al.
    Karolinska Inst, Dept Med, Cardiol Unit, Stockholm, Sweden;Capio St Gorans Hosp, Stockholm, Sweden.
    Bodegard, Johan
    AstraZeneca Europe & Canada, Oslo, Norway.
    Nystrom, Thomas
    Soder Sjukhuset, Dept Clin Sci & Educ, Div Internal Med, Unit Diabet Res, Stockholm, Sweden.
    Thuresson, Marcus
    Statisticon AB, Uppsala, Sweden.
    Rikner, Klas
    AstraZeneca Nordic Baltic, Sodertalje, Sweden.
    Nathanson, David
    Karolinska Univ Hosp, Div Internal Med, Unit Diabet Res, Stockholm, Sweden.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    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 study2019Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 21, nr 12, s. 2651-2659Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 29.
    Norhammar, Anna
    et al.
    Karolinska Inst, Dept Med, Cardiol Unit, Solna, Sweden;Capio St Gorans Hosp, Stockholm, Sweden.
    Bodegård, Johan
    AstraZeneca Nord Balt, Fredrik Selmersvei 6, N-0601 Oslo, Norway.
    Nyström, Thomas
    Dept Clin Sci & Educ, Div Internal Med, Unit Diabet Res, Sodersjukhuset, Sweden.
    Thuresson, Marcus
    Statisticon AB, Uppsala, Sweden.
    Nathanson, David
    Karolinska Inst, Dept Med Huddinge, Huddinge, Sweden.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    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 study2019Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 21, nr 5, s. 1136-1145Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 30.
    Nyström, Thomas
    et al.
    Karolinska Inst, Dept Clin Sci & Educ, Unit Diabet Res, Div Internal Med,Sodersjukhuset, Stockholm, Sweden..
    Bodegard, Johan
    AstraZeneca Nordic Balt, Sodertalje, Sweden..
    Nathanson, David
    Karolinska Inst, Dept Clin Sci & Educ, Unit Diabet Res, Div Internal Med,Sodersjukhuset, Stockholm, Sweden..
    Thuresson, Marcus
    Karolinska Inst, Dept Med, Cardiol Unit, Stockholm, Sweden.;Capio St Gorans Hosp, Stockholm, Sweden..
    Norhammar, Anna
    Statisticon AB, Uppsala, Sweden..
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Novel oral glucose-lowering drugs are associated with lower risk of all-cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes2017Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, nr 6, s. 831-841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To investigate the association of novel oral glucose-lowering drugs (GLDs), compared with that of insulin, with risk of all-cause mortality, cardiovascular disease (CVD) and severe hypoglycaemia.

    Methods: During 2013 to 2014 all patients with type 2 diabetes in Sweden identified as new users of novel oral GLDs, either dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT2) inhibitors (only dapagliflozin available in Sweden during the study period), with those initiating insulin as a comparison group, in the Prescribed Drug Register were included and followed in the Patient and Cause of Death Registers. The novel GLD group and insulin group were matched 1: 1 using propensity score. Cox regression models were used to estimate risks.

    Results: Of 37 603 patients, 21 758 were matched 1: 1 to novel GLD vs insulin groups, with median follow-up times of 1.51 years (16 304 patient-years) and 1.53 years (16 306 patientyears), respectively. Treatment with novel GLDs was associated with a 44% (hazard ratio [HR] 0.56 [95% confidence interval {CI} 0.49-0.64]), 15% (HR 0.85 [95% CI 0.73-0.99]) and 74% (0.26 [95% CI 0.12-0.57]) lower risk of all-cause mortality, CVD and hypoglycaemia, respectively, compared with insulin treatment. In separate analyses for the two novel GLDs, dapagliflozin was associated with lower risks of all-cause mortality and CVD (56% [HR 0.44, 95% CI 0.28-0.70] and 49% [HR 0.51, 95% CI 0.30-0.86], respectively), while DPP-4 inhibitor treatment was associated with lower risk of all-cause mortality (41% [HR 0.59, 95% CI 0.51-0.67]), but not with CVD (HR 0.87, 95% CI 0.75-1.01).

    Conclusions: Novel oral GLD treatment was associated with lower risk of all-cause mortality, CVD and severe hypoglycaemia compared with insulin treatment. Dapagliflozin was associated with a lower risk of both all-cause mortality and CVD, whereas DPP-4 inhibitor treatment was only associated with lower risk of all-cause mortality.

  • 31. Otonkoski, Timo
    et al.
    Banerjee, M.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för klinisk immunologi.
    Thornell, L-E.
    Virtanen, I.
    Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation2008Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 10 Suppl 4, s. 119-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Basement membranes (BMs) are an important part of the physiological microenvironment of pancreatic islet cells. In mouse islets, beta-cells interact directly with BMs of capillary endothelial cells. We have shown that in the human islets, the capillaries are surrounded by a double BM both in foetal and adult tissues. The endocrine islet cells are facing a BM that is separate from the endothelia. Laminins are the functionally most important component of BMs. The only laminin isoform present in the human endocrine islet BM is laminin-511 (previously known as laminin 10). The islet cells facing this BM have a strong and polarized expression of Lutheran glycoprotein, which is a well-known receptor for the laminin alpha 5 chain. Dispersed human islet cells adhere to purified human laminin-511 and the binding is equally effectively blocked by a soluble form of Lutheran as by antibody against integrin beta1. Our results reveal unique features of the BM structure of human islets, different from rodents. This information has potentially important implications for the generation of an optimal microenvironment for beta-cell function, proliferation and differentiation.

  • 32. Ott, V.
    et al.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schultes, B.
    Born, J.
    Hallschmid, M.
    Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism2012Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, nr 3, s. 214-221Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In recent years, the central nervous system (CNS) has emerged as a principle site of insulin action. This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and by experiments in humans that make use of the intranasal pathway of insulin administration to the brain. Employing neurobehavioural and metabolic measurements as well as functional imaging techniques, these studies have provided insight into a broad range of central and peripheral effects of brain insulin. The present review focusses on CNS effects of insulin administered via the intranasal route on cognition, in particular memory function, and whole-body energy homeostasis including glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer's disease where CNS insulin resistance might contribute to cognitive dysfunction.

  • 33.
    Persson, Frederik
    et al.
    Steno Diabet Ctr, Copenhagen, Denmark..
    Nystrom, Thomas
    Soder Sjukhuset, Karolinska Inst, Stockholm, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Copenhagen, Denmark..
    Carstensen, Bendix
    Steno Diabet Ctr, Copenhagen, Denmark..
    Gulseth, Hanne L.
    Oslo Univ Hosp, Oslo, Norway..
    Thuresson, Marcus
    Statisticon AB, Uppsala, Sweden..
    Fenici, Peter
    AstraZeneca, Cambridge, England..
    Nathanson, David
    Soder Sjukhuset, Karolinska Inst, Stockholm, Sweden..
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Norhammar, Anna
    Karolinska Inst, Stockholm, Sweden.;Capio St Gorans Hosp, Stockholm, Sweden..
    Bodegard, Johan
    AstraZeneca Nord Balt, N-0601 Oslo, Norway..
    Birkeland, Kare I.
    Oslo Univ Hosp, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 2, s. 344-351Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims

    To compare the sodium-glucose-cotransporter-2 (SGLT-2) inhibitor dapagliflozin with dipeptidyl peptidase-4 (DPP-4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non-fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting.

    Methods

    All patients with T2D prescribed glucose-lowering drugs (GLDs) during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors, matched 1:3 by propensity score, calculated by patient characteristics, comorbidities and drug treatment. Cox survival models were used to estimate hazard ratio (HR) per country separately, and a weighted average was calculated.

    Results

    After matching, a total of 40908 patients with T2D were identified as new users of dapagliflozin (n=10227) or a DPP-4 inhibitor (n=30681). The groups were well balanced at baseline; their mean age was 61years and 23% had CV disease. The mean follow-up time was 0.95years, with a total of 38760 patient-years. Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95% confidence interval [CI] 0.67-0.94), 0.62 (95% CI 0.50-0.77), and 0.59 (95% CI 0.49-0.72), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [95% CI 0.72-1.16]), stroke (0.79 [95% CI 0.61-1.03]) and CV mortality (0.76 [95% CI 0.53-1.08]) Neutral associations with atrial fibrillation and severe hypoglycaemia were observed.

    Conclusions

    Dapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population.

  • 34.
    Pettersson, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandberg, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Two-week treatment with the β3-adrenoceptor antagonist SR59230A normalizes the increased pancreatic islet blood flow in type 2 diabetic GK rats2012Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, nr 10, s. 960-962Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Goto-Kakizaki (GK) rat, a type 2 diabetes model, has increased pancreatic islet and white adipose tissue (WAT) blood flow, and this can be normalized by acute administration of SR59230A, a beta(3)-adrenoceptor antagonist. We now implanted osmotic pumps which allowed a constant release of saline or SR59230A (0.6 mg/kg x day) for 2 weeks. A decrease in islet blood flow was seen also after 2 weeks of continuous SR59230A treatment in the GK rat. However, no improvement in glucose tolerance was seen in the GK rats. Neither did SR59230A affect insulin secretion from isolated islets in vitro. WAT blood flow was not affected by the 2-week SR59230A treatment. Thus, the increased islet blood flow seen in the GK rat can be normalized for up to 2 weeks, which opens the possibilities for further studies on the long-term functional role on the islet blood flow increase in this type 2 diabetes model.

  • 35.
    Reed, Shelby D.
    et al.
    Duke Univ, NC USA.
    Li, Yanhong
    Duke Univ, NC USA.
    Leal, Jose
    Univ Oxford, England.
    Radican, Larry
    Merck and Co Inc, NJ USA.
    Adler, Amanda I.
    Addenbrookes Hosp, England.
    Alfredsson, Joakim
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Buse, John B.
    Univ N Carolina, NC USA.
    Green, Jennifer B.
    Duke Univ, NC USA.
    Kaufman, Keith D.
    Merck and Co Inc, NJ USA.
    Riefflin, Axel
    GMP, Germany.
    Van de Werf, Frans
    Univ Hosp, Belgium.
    Peterson, Eric D.
    Duke Univ, NC USA.
    Gray, Alastair M.
    Univ Oxford, England.
    Holman, Rury R.
    Univ Oxford, England.
    Longitudinal medical resources and costs among type 2 diabetes patients participating in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 7, s. 1732-1739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: TECOS, a cardiovascular safety trial (identifier: NCT00790205) involving 14 671 patients with type 2 diabetes and cardiovascular disease, demonstrated that sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome when added to best usual care. This study tested hypotheses that medical resource use and costs differed between these 2 treatment strategies. Materials and methods: Information concerning medical resource use was collected on case report forms throughout the trial and was valued using US costs for: Medicare payments for hospitalizations, medical procedures and outpatient visits, and wholesale acquisition costs (WAC) for diabetes-related medications. Hierarchical generalized linear models were used to compare resource use and US costs, accounting for variable intercountry practice patterns. Sensitivity analyses included resource valuation using English costs for a UK perspective. Results: There were no significant differences in hospitalizations, inpatient days, medical procedures, or outpatient visits during follow-up (mean and median 3.0 years in both groups). Hospitalization rates appeared to diverge after 2 years, with lower rates among sitagliptin-treated vs placebo patients after 2.5 years (relative rate, 0.90 [95% CI, 0.83-0.97]; P = .01). Mean medical costs, exclusive of study medication, were 11 937 USD in the sitagliptin arm and 12 409 USD in the placebo arm (P = .06). Mean sitagliptin costs based on undiscounted WAC were 9978 USD per patient. Differential UK total costs including study drug costs were smaller (911 GBP), primarily because of lower mean costs for sitagliptin (1072 GBP). Conclusions: Lower hospitalization rates across time with sitagliptin slightly offset sitagliptin treatment costs over 3 years in type 2 diabetes patients at high risk for cardiovascular events.

  • 36.
    Rådholm, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Primärvårdscentrum, Vårdcentralen Ödeshög. Univ New South Wales, Australia.
    Chalmers, John
    Univ New South Wales, Australia.
    Ohkuma, Toshiaki
    Univ New South Wales, Australia; Kyushu Univ, Japan.
    Peters, Sanne
    Univ Oxford, England.
    Poulter, Neil
    Imperial Coll, England.
    Hamet, Pavel
    Univ Montreal, Canada.
    Harrap, Stephen
    Univ Melbourne, Australia; Royal Melbourne Hosp, Australia.
    Woodward, Mark
    Univ New South Wales, Australia; Univ Oxford, England; Johns Hopkins Univ, MD USA.
    Use of the waist-to-height ratio to predict cardiovascular risk in patients with diabetes: Results from the ADVANCE-ON study2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 8, s. 1903-1910Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. Methods WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11125 participants with type 2 diabetes in the ADVANCE and ADVANCE-ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. Results Median follow-up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11-1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut-points, the equivalent WHtR cut-points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. Conclusions In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups.

  • 37.
    Rådholm, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Primärvårdscentrum, Vårdcentralen Ödeshög. Univ New South Wales, Australia.
    Zhou, Zien
    Univ New South Wales, Australia; Shanghai Jiao Tong Univ, Peoples R China.
    Clemens, Kristin
    Western Univ, Canada; Western Univ, Canada; Lawson Hlth Res Inst, Canada.
    Neal, Bruce
    Univ New South Wales, Australia; Univ New South Wales, Australia; Imperial Coll London, England.
    Woodward, Mark
    Univ New South Wales, Australia; Univ Oxford, England; Johns Hopkins Univ, MD USA.
    Effects of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes in women versus men2019Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sodium-glucose co-transporter-2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA-REG OUTCOME, CANVAS Program, DECLARE TIMI-58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction amp;gt;=.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction amp;gt;=.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men.

  • 38.
    Schernthaner, G.
    et al.
    Rudolfstiftung Hospital Vienna, Austria.
    Duran-Garcia, S.
    Hospital University of Valme, Spain.
    Hanefeld, M.
    GWT TUD GmbH, Germany.
    Langslet, G.
    Oslo University Hospital, Norway.
    Niskanen, L.
    University of Helsinki, Finland.
    Östgren, Carl Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i västra Östergötland, Primärvården i västra länsdelen.
    Malvolti, E.
    AstraZeneca, Turkey.
    Hardy, E.
    AstraZeneca LP, DE USA.
    Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION)2015Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 17, nr 7, s. 630-638Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. Methods: In this multinational, randomized, double-blind, phase IIIb/IV study (GENERATION; NCT01006603), patients aged greater than= 65 years were randomized (1:1) to receive saxagliptin 5 mg/day or glimepiride less than= 6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of glycated haemoglobin (HbA1c) less than7.0% at week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. Results: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9 vs 38.2%; odds ratio 0.99, 95% confidence interval 0.73, 1.34; p=0.9415); however, a significant treatment-by-age interaction effect was detected (p=0.0389): saxagliptin was numerically (but not significantly) superior to glimepiride for patients aged less than75 years (39.2 vs 33.3%) and numerically inferior for patients aged greater than= 75 years (35.9 vs 45.5%). The incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1 vs 15.3%; nominal pless than0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events compared with glimepiride. Conclusion: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged greater than= 65 years.

  • 39.
    Scholtes, Rosalie A.
    et al.
    Diabetes Centre, Department of Internal Medicine, Amsterdam University Medical Centres, location VUmc, Amsterdam, Netherlands.
    van Raalte, Daniël H.
    Diabetes Centre, Department of Internal Medicine, Amsterdam University Medical Centres, location VUmc, Amsterdam, Netherlands.
    Correa-Rotter, Ricardo
    Nephrology and Mineral Metabolism, National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.
    Toto, Robert D.
    University of Texas Southwestern Medical Center, Dallas, TX, United States.
    Heerspink, Hiddo J. L.
    Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Netherlands.
    Cain, Valerie
    Bogier Clinical and IT Solutions Inc., Raleigh, NC, United States.
    Sjöström, C. David
    AstraZeneca, Gothenburg, Sweden.
    Sartipy, Peter
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. AstraZeneca, Gothenburg, Sweden.
    Stefánsson, Bergur V.
    AstraZeneca, Gothenburg, Sweden.
    The effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes with or without renin-angiotensin system inhibitor treatment: a post hoc analysis2019Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Renin-angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium-glucose co-transporter-2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. Materials and methods: We evaluated the effects of dapagliflozin 10 mg/day over 12–24 weeks across 13 placebo-controlled studies in patients with T2D with a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. Results: Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo-adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. Conclusions: Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline. © 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  • 40. Sjöstrand, M
    et al.
    Ericsson, H
    Hartford, M
    Norjavaara, E
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pharmacodynamic effects of the oral glucokinase activator AZD6370 after single doses in healthy volunteers assessed with euglycaemic clamp2013Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 15, nr 1, s. 35-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamic effects of the glucokinase activator (GKA) AZD6370 in non-diabetic subjects, using the euglycaemic clamp to avoid the risk of hypoglycaemia.

    METHODS: Oral single ascending doses of AZD6370 10-650 mg or subcutaneous short-acting insulin 4 or 12 U were given to healthy fasting subjects. AZD6370 safety, tolerability and pharmacokinetics were assessed. Pharmacodynamic effects on serum (S)-insulin and glucose infusion rate (GIR) were investigated with euglycaemic clamp. AZD6370 10-20 mg was also assessed when taken with food without euglycaemic clamp.

    RESULTS: AZD6370 was well tolerated and no safety concerns were raised. AZD6370 was rapidly absorbed and eliminated, and plasma concentration was proportional to dose. Both S-insulin and GIR increased following AZD6370 administration. The observed increase in GIR correlated with increasing AZD6370 area under the plasma concentration vs. time curve, demonstrating a dose-concentration-dependent pharmacodynamic effect. AZD6370 at doses of 50 and 80 mg had similar effects to short-acting insulin 4 U on peripheral S-insulin levels but greater effects on GIR, suggesting an effect beyond the increase of peripheral S-insulin levels at lower doses. In the food interaction part of the study, performed without euglycaemic clamp, dose escalation was stopped at a low dose (20 mg) because of hypoglycaemia.

    CONCLUSION: The euglycaemic clamp was successfully used to avoid hypoglycaemia and to demonstrate pharmacodynamic effects, that is, markedly increased insulin secretion and glucose utilisation, following administration of AZD6370 in healthy fasting subjects. In addition to the effect on pancreatic insulin secretion, the data support an extra-pancreatic (hepatic) component of GKA action.

  • 41.
    Skog, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. University of Gothenburg, Institute of Biomedicine, Gothenburg, Sweden.
    Aetiology of type 1 diabetes: Physiological growth in children affects disease progression2018Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, nr 4, s. 775-785Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β-cell mass resulting from T-cell-mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C-peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β-cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent-onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30-fold increase in β-cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20-fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β-cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.

  • 42.
    Tengholm, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gylfe, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    cAMP signalling in insulin and glucagon secretion2017Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 19, s. 42-53Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The second messenger archetype cAMP is one of the most important cellular signalling molecules with central functions including the regulation of insulin and glucagon secretion from the pancreatic - and -cells, respectively. cAMP is generally considered as an amplifier of insulin secretion triggered by Ca2+ elevation in the -cells. Both messengers are also positive modulators of glucagon release from -cells, but in this case cAMP may be the important regulator and Ca2+ have a more permissive role. The actions of cAMP are mediated by protein kinase A (PKA) and the guanine nucleotide exchange factor Epac. The present review focuses on how cAMP is regulated by nutrients, hormones and neural factors in - and -cells via adenylyl cyclase-catalysed generation and phosphodiesterase-mediated degradation. We will also discuss how PKA and Epac affect ion fluxes and the secretory machinery to transduce the stimulatory effects on insulin and glucagon secretion. Finally, we will briefly describe disturbances of the cAMP system associated with diabetes and how cAMP signalling can be targeted to normalize hypo- and hypersecretion of insulin and glucagon, respectively, in diabetic patients.

  • 43.
    Wentzel, Parri
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Can we prevent diabetic birth defects with micronutrients?2009Inngår i: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 11, nr 8, s. 770-778Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Congenital malformations are more common in infants of diabetic women than in children of non-diabetic women. The mechanisms behind diabetes-induced congenital anomalies are not known. Disturbed micronutrient metabolism, in concert with oxidative stress, has been suggested as a cause of diabetes-induced malformations by several studies. In experimental work, administration of inositol, arachidonic acid and several antioxidative compounds, as well as folic acid, to the embryo, has proven to attenuate the teratogenic effects of a diabetic environment. Future therapeutic efforts may include supplementation with antioxidants or micronutrients, such as folic acid, to the pregnant diabetic woman, although exact compounds and doses need to be determined.

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