| 1. |
- Cariou, Bertrand, et al.
(författare)
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Effect of tirzepatide on body fat distribution pattern in people with type 2 diabetes
- 2024
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326.
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Tidskriftsartikel (refereegranskat)abstract
- AimsTo describe the overall fat distribution patterns independent of body mass index (BMI) in participants with type 2 diabetes (T2D) in the SURPASS-3 MRI substudy by comparison with sex- and BMI-matched virtual control groups (VCGs) derived from the UK Biobank imaging study at baseline and Week 52. MethodsFor each study participant at baseline and Week 52 (N = 296), a VCG of >= 150 participants with the same sex and similar BMI was identified from the UK Biobank imaging study (N = 40 172). Average visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT) and liver fat (LF) levels and the observed standard deviations (SDs; standardized normal z-scores: z-VAT, z-aSAT and z-LF) were calculated based on the matched VCGs. Differences in z-scores between baseline and Week 52 were calculated to describe potential shifts in fat distribution pattern independent of weight change. ResultsBaseline fat distribution patterns were similar across pooled tirzepatide (5, 10 and 15 mg) and insulin degludec (IDeg) arms. Compared with matched VCGs, SURPASS-3 participants had higher baseline VAT (mean [SD] z-VAT +0.42 [1.23]; p < 0.001) and LF (z-LF +1.24 [0.92]; p < 0.001) but similar aSAT (z-aSAT -0.13 [1.11]; p = 0.083). Tirzepatide-treated participants had significant decreases in z-VAT (-0.18 [0.58]; p < 0.001) and z-LF (-0.54 [0.84]; p < 0.001) but increased z-aSAT (+0.11 [0.50]; p = 0.012). Participants treated with IDeg had a significant change in z-LF only (-0.46 [0.90]; p = 0.001), while no significant changes were observed for z-VAT (+0.13 [0.52]; p = 0.096) and z-aSAT (+0.09 [0.61]; p = 0.303). ConclusionIn this exploratory analysis, treatment with tirzepatide in people with T2D resulted in a significant reduction of z-VAT and z-LF, while z-aSAT was increased from an initially negative value, suggesting a possible treatment-related shift towards a more balanced fat distribution pattern with prominent VAT and LF loss.
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| 2. |
- Linge, Jennifer, et al.
(författare)
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Skewness in Body fat Distribution Pattern Links to Specific Cardiometabolic Disease Risk Profiles
- 2024
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 09:3, s. 783-791
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Fat distribution pattern could help determine cardiometabolic risk profile. This study aimed to evaluate the association of balance/imbalance between visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT), and liver fat (LF) with incident type 2 diabetes (T2D) and cardiovascular disease (CVD) in the UK Biobank prospective cohort study.Methods: Magnetic resonance images of 40 174 participants were analyzed for VAT, aSAT, and LF using AMRA (R) Researcher. To assess fat distribution patterns independent of body mass index (BMI), fat z-scores (z-VAT, z-aSAT, z-LF) were calculated. Participants without prevalent T2D/CVD (N = 35 138) were partitioned based on balance between (1) z-VAT and z-LF (z-scores = 0 as cut-points for high/low), (2) z-VAT and z-aSAT, and (3) z-LF and z-aSAT. Associations with T2D/CVD were investigated using Cox regression (crude and adjusted for sex, age, BMI, lifestyle, arterial hypertension, statin treatment).Results: T2D was significantly associated with z-LF (hazard ratio, [95% CI] 1.74 [1.52-1.98], P < .001) and z-VAT (1.70 [1.49-1.95], P < .001). Both remained significant after full adjustment. For z-scores balance, strongest associations with T2D were z-VAT > 0 and z-LF > 0 (4.61 [2.98-7.12]), z-VAT > 0 and z-aSAT < 0 (4.48 [2.85-7.06]), and z-LF > 0 and z-aSAT < 0 (2.69 [1.76-4.12]), all P < .001. CVD was most strongly associated with z-VAT (1.22 [1.16-1.28], P < .001) which remained significant after adjustment for sex, age, BMI, and lifestyle. For z-scores balance, strongest associations with CVD were z-VAT > 0 and z-LF < 0 (1.53 [1.34-1.76], P < .001) and z-VAT > 0 and z-aSAT < 0 (1.54 [1.34-1.76], P < .001). When adjusted for sex, age, and BMI, only z-VAT > 0 and z-LF < 0 remained significant.Conclusion: High VAT in relation to BMI (z-VAT > 0) was consistently linked to both T2D and CVD; z-LF > 0 was linked to T2D only. Skewed fat distribution patterns showed elevated risk for CVD (z-VAT > 0 and z-LF < 0 and z-VAT > 0 and z-aSAT < 0) and T2D (z-VAT > 0 and z-aSAT < 0).
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| 3. |
- Prawitt, Janne, et al.
(författare)
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Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 60:7, s. 1861-1871
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.RESEARCH DESIGN AND METHODS: Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.RESULTS: FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.CONCLUSIONS: Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.
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| 4. |
- Raal, Frederick J., et al.
(författare)
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PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial
- 2015
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Ingår i: The Lancet. - : Elsevier: Lancet. - 0140-6736 .- 1474-547X. ; 385:9965, s. 331-340
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Tidskriftsartikel (refereegranskat)abstract
- Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19,2013.331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2.6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4.1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. Findings Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59.2% reduction [95% CI 53.4-65.1], monthly dose: 61.3% reduction [53.6-69.0]; both pless than0.0001) and at the mean of weeks 10 and 12 (60.2% reduction [95% CI 54.5-65.8] and 65.6% reduction [59.8-71.3]; both pless than0.0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). Interpretation In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo.
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| 5. |
- Schmidt, Amand F., et al.
(författare)
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:2, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
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| 6. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 7. |
- Yabe, Daisuke, et al.
(författare)
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Efficacy of lixisenatide in patients with type 2 diabetes : A post hoc analysis of patients with diverse β-cell function in the GetGoal-M and GetGoal-S trials
- 2016
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1056-8727. ; 30:7, s. 1385-1392
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To evaluate the impact of β-cell function on the efficacy of lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes (T2D). Materials and methods: In this post hoc analysis, patients from the Phase 3 GetGoal-M and GetGoal-S clinical trials randomized to lixisenatide 20. μg once daily were stratified into quartiles by baseline β-cell function, as measured by the secretory units of islet in transplantation (SUIT) index. Results: Patients (N = 437) were distributed evenly among SUIT index quartiles 1 to 4 (lowest to highest β-cell function). Clinical outcomes improved from baseline across all SUIT quartiles; mean changes at week 24 were: glycated hemoglobin (HbA1c; % [mmol/mol]), -0.99 (-10.8), -0.87 (-9.5), -0.86 (-9.4), -0.83 (-9.1); and postprandial plasma glucose (PPG; mmol/L), -7.9, -5.6, -5.5, -4.3 (overall effect . P .
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