| 1. |
- Bolinder, Jan, et al.
(författare)
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Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin
- 2012
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 97:3, s. 1020-1031
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Tidskriftsartikel (refereegranskat)abstract
- Context:Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding.Objectives:Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components.Design and Setting:This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries.Patients:Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin.Intervention:Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk.Main Outcome Measures:Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated.Results:At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, −2.08 kg [95% confidence interval (CI) = −2.84 to −1.31; P < 0.0001]; waist circumference, −1.52 cm (95% CI = −2.74 to −0.31; P = 0.0143); FM, −1.48 kg (95% CI = −2.22 to −0.74; P = 0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI = 15.5 to 36.7; P < 0.0001); VAT, −258.4 cm3 (95% CI = −448.1 to −68.6; nominal P = 0.0084); SAT, −184.9 cm3 (95% CI = −359.7 to −10.1; nominal P = 0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%.Conclusions:Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.
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| 2. |
- Carlzon, Daniel, et al.
(författare)
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Both Low and High Serum IGF-1 Levels Associate With Increased Risk of Cardiovascular Events in Elderly Men
- 2014
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:11, s. 2308-2316
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Tidskriftsartikel (refereegranskat)abstract
- Context: Most previous prospective studies suggest that low serum IGF-1 associates with increased risk of cardiovascular disease (CVD) events whereas other studies suggest that high serum IGF-1 associates with increased risk of CVD events. Objective: We tested the hypothesis that not only low, but also high serum IGF-1 levels associate with increased risk of CVD events in elderly men. Setting and Design: Serum IGF-1 levels were measured in 2901 elderly men (age 69-81 years) included in the Swedish cohort of the prospective, population-based Osteoporotic Fractures in Men Study (MrOS), Sweden cohort. Data for CVD events were obtained from national Swedish registers with no loss of followup. Results: During followup (median, 5.1 y) 589 participants experienced a CVD event. The association between serum IGF-1 and risk of CVD events was nonlinear, and restricted cubic spline Cox regression analysis revealed a U-shaped association between serum IGF-1 levels and CVD events (P < .01 for nonlinearity). Low as well as high serum IGF-1 (quintile 1 or 5 vs quintiles 2-4) significantly associated with increased risk for CVD events (hazard ratio [HR] = 1.25, 95% confidence interval, [CI], 1.02-1.54; and HR = 1.35, 95% CI 1.10-1.66, respectively). These associations remained after adjustment for prevalent CVD and multiple risk factors. High serum IGF-1 associated with increased risk of coronary heart disease (CHD) events but not with risk of cerebrovascular events. Conclusions: Both low and high serum IGF-1 levels are risk markers for CVD events in elderly men. The association between high serum IGF-1 and CVD events is mainly driven by CHD events.
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| 3. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:3, s. 1033-41
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids. OBJECTIVE: The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men. DESIGN: Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 +/- 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 +/- 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 +/- 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry. RESULTS: The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 x 10(-6)). This association was confirmed both in the MrOS Sweden study (P = 9 x 10(-7)) and in the MrOS US study (P = 1 x 10(-4)). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 x 10(-14)) and E1 (P = 8 x 10(-19)) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05). CONCLUSIONS: rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.
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| 4. |
- Eriksson, Anna L, et al.
(författare)
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Serum Glycine Levels Are Associated With Cortical Bone Properties and Fracture Risk in Men.
- 2021
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 106:12, s. e5021-e5029
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Tidskriftsartikel (refereegranskat)abstract
- In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD).To investigate associations for serum and urinary glycine levels with BMD, bone microstructure, and fracture risk in men.In the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n = 965) and 5-year follow-up (n = 546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high-resolution peripheral quantitative computed tomography. Urinary (n = 2682) glycine was analyzed at baseline. X-ray-validated fractures (n = 594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures).Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n = 7543) combining MrOS Sweden data with data from 3 other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (P = 7.7 × 10-9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (P = 0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum: hazard ratio [HR] per SD increase = 1.22, 95% CI, 1.05-1.43; urine: HR = 1.13, 95% CI, 1.02-1.24). These fracture associations were only marginally reduced in models adjusted by FRAX with BMD.Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men.
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| 5. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 5029-37
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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| 6. |
- Grundberg, Elin, et al.
(författare)
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The impact of estradiol on bone mineral density is modulated by the specific estrogen receptor-alpha cofactor retinoblastoma-interacting zinc finger protein-1 insertion/deletion polymorphism.
- 2007
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:6, s. 2300-6
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Estrogens regulate bone mass by binding to the estrogen receptor (ER)-alpha as well as ER-beta. The specific ERalpha cofactor retinoblastoma-interacting zinc finger protein (RIZ)-1 enhances ERalpha function in the presence of estrogen. OBJECTIVE: The objective of the study was to determine whether a RIZ P704 insertion (+)/deletion (-) (indel) polymorphism modulates the impact of estradiol on bone mineral density (BMD) and study the association between the polymorphism and BMD in elderly subjects. DESIGN: This was a population-based, prospective, and cross-sectional study, the Swedish MrOS Study, and the Malmö OPRA Study, respectively. SETTING: The study was conducted at three academic medical centers: Sahlgrenska Academy in Gothenburg, Malmö University Hospital, and Uppsala University Hospital. PARTICIPANTS: In total, 4058 men and women, aged 69-81 yr, were randomly selected from population registries. MAIN OUTCOME MEASURES: BMD (grams per square centimeter) was measured at femoral neck, trochanter, lumbar spine, and total body. RESULTS: The RIZ P704(+/+) genotype was associated with low BMD in both women (femoral neck, P < 0.001; trochanter, P < 0.01; lumbar spine, P < 0.05; total body, P < 0.01) and men (lumbar spine, P < 0.05). However, the association between the polymorphism and BMD was dependent on estradiol status. The positive correlation between serum estradiol and BMD was significantly modulated by the genotype with a stronger correlation in the P704(+/+) group than the P704(-/-) group (r = 0.19 vs. r = 0.08, P < 0.05). CONCLUSIONS: These large-scale studies of elderly men and women indicate that the ERalpha cofactor RIZ gene has a prominent effect on BMD, and the P704 genotype modulates the impact of estradiol on BMD. Further studies are required to determine whether this polymorphism modulates the estrogenic response to estradiol treatment.
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| 7. |
- Langdahl, Bente L., et al.
(författare)
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A 24-Month Study Evaluating the Efficacy and Safety of Denosumab for the Treatment of Men With Low Bone Mineral Density : Results From the ADAMO Trial
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 100:4, s. 1335-1342
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Tidskriftsartikel (refereegranskat)abstract
- Context: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. Objective: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). Design: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. Setting: This was a multicenter study conducted in North America and Europe. Participants: A total of 228 men entered the open-label phase and 219 completed the study. Intervention: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. Main Outcome Measures: BMD, serum collagen type I C-telopeptide, and safety were measured. Results: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. Conclusions: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.
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| 8. |
- Movérare-Skrtic, Sofia, et al.
(författare)
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Serum insulin-like growth factor-I concentration is associated with leukocyte telomere length in a population-based cohort of elderly men.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:12, s. 5078-84
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Both leukocyte telomere length and IGF-I are associated with the aging process. A previous in vitro study suggested that IGF-I may modulate telomerase activity in white blood cells, but little is known whether these two systems interact in vivo. PATIENTS AND METHODS: Leukocyte telomere length was determined using a quantitative PCR assay in 2744 elderly men (mean age 75.5 yr, range 69-81 yr) included in the population-based Osteoporotic Fractures in Men-Sweden study. Serum IGF-I concentration was measured using RIA. RESULTS: Subjects with a leukocyte telomere length in the lowest tertile group had lower serum IGF-I concentration than subjects in the two tertile groups with longer telomere lengths (P = 0.005). Logistic regression analyses showed that a higher serum IGF-I concentration was associated with a significantly reduced risk of having a leukocyte telomere length in the lowest tertile group and also after adjustment for multiple covariates (P < 0.01). Multivariate linear regression analyses demonstrated that tertile of leukocyte telomere length was positively, whereas age was negatively, associated with serum IGF-I concentration in elderly men. CONCLUSIONS: In this large population-based, cross-sectional study, leukocyte telomere length was positively associated with serum IGF-I concentration in elderly men. The mechanisms underlying the association between serum IGF-I concentration and leukocyte telomere length remain to be determined.
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| 9. |
- Ohlsson, Claes, 1965, et al.
(författare)
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Comparisons of Immunoassay and Mass Spectrometry Measurements of Serum Estradiol Levels and Their Influence on Clinical Association Studies in Men
- 2013
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:6, s. E1097-E1102
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Tidskriftsartikel (refereegranskat)abstract
- Context: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known Objective: Our objective was to compare immunoassay and MS measurements of E2 levels in men and Design and Setting: Middle-aged and older male subjects participating in the population-based Main Outcome Measures: Immunoassay and MS measurements of serum E2 were compared and Results: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately Conclusions: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a
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| 10. |
- Ohlsson, Claes, 1965, et al.
(författare)
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Low Serum Levels of Dehydroepiandrosterone Sulfate Predict All-Cause and Cardiovascular Mortality in Elderly Swedish Men
- 2010
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 95:9, s. 4406-4414
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Tidskriftsartikel (refereegranskat)abstract
- Context: The age-related decline in dehydroepiandrosterone (DHEA) levels is thought to be of importance for general and vascular aging. However, data on the association between DHEA and mortality are conflicting. Objectives: We tested the hypothesis that low serum DHEA and DHEA sulfate (DHEA-S) levels predict all-cause and cardiovascular disease (CVD) death in elderly men. Design, Setting, and Participants: We used gas/liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based MrOS Sweden study (2644 men, aged 69-81 yr). Mortality data were obtained from central registers and analyzed using Cox proportional hazards regressions. Main Outcome Measures: All-cause and CVD mortality by serum DHEA(-S) levels. Results: During a mean 4.5-yr follow-up, 328 deaths occurred. Low levels of DHEA-S (quartile 1 vs. quartiles 2-4), predicted death from all causes [hazard ratio (HR) 1.54,95% confidence interval (CI) 1.21-1.96; adjusted for traditional cardiovascular risk factors], from CVD (n = 123 deaths; HR 1.61, 95% CI 1.10-2.37) and ischemic heart disease (n = 73; HR 1.67, 95% CI 1.02-2.74) but not cancer. Analyses with DHEA gave similar results. The association between low DHEA-S and CVD death remained after adjustment for C-reactive protein and circulating estradiol and testosterone levels. When stratified by the median age of 75.4 yr, the mortality prediction by low DHEA-S was more pronounced among younger (age adjusted HR for CVD death 2.64, 95% CI 1.37-5.09) than older men (HR 1.30, 95% CI 0.83-2.04). Conclusions: Low serum levels of DHEA(-S) predict death from all causes, CVD, and ischemic heart disease in older men.
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