| 1. |
- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 2. |
- Barnett, A.H., et al.
(författare)
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Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy
- 2004
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 351:19, s. 1952-1961
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure, the rates of end-stage renal disease and cardiovascular events, and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.9 ml per minute per 1.73 m2 of body-surface area, where the minus sign denotes a decrement, with telmisartan (in 103 subjects), as compared with -14.9 ml per minute per 1.73 m2 with enalapril (in 113 subjects), for a treatment difference of -3.0 ml per minute per 1.73 m2 (95 percent confidence interval, -7.6 to 1.6 ml per minute per 1.73 m2). The lower boundary of the confidence interval, in favor of enalapril, was greater than the pre-defined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events. Copyright © 2004 Massachusetts Medical Society.
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| 3. |
- Ejskjaer, N, et al.
(författare)
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Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis
- 2009
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 29:11, s. 1179-1187
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.
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| 4. |
- Haugaard, S B, et al.
(författare)
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Sex and muscle structural lipids in obese subjects - an impact on insulin action?
- 2008
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38:7, s. 494-501
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Tidskriftsartikel (refereegranskat)abstract
- Background Long-chain polyunsaturated fatty acid (LCPUFA) especially the n-3-FA of skeletal muscle phospholipids may facilitate insulin action, whereas saturated and trans-FA act oppositely. Community studies show that non-diabetic weight matched obese men and women display similar insulin resistance, despite the fact that an android fat distribution is detrimental to insulin action. The increased extramyocellular fat mass of obese women may act in a paracrine manner such that its release of free FA and cytokines may hamper in situ desaturation and elongation of FA in skeletal muscle phospholipids. Material and methods To test the hypothesis that obese women may display an inferior FA composition compared to obese men, the FA composition of skeletal muscle phospholipids was determined in vastus lateralis biopsies obtained from 12 non-diabetic obese women with a typical gynoid fat distribution, nine non-diabetic obese men with a typical android fat distribution and 12 (seven females) lean age matched healthy controls (body mass index 34.6 +/- 1.0 kg m(-2), 36.5 +/- 1.2 and 22.5 +/- 0.5; age 47 +/- 2 years, 51 +/- 3 and 49 +/- 2). Results Obese women displayed decreased LCPUFA n-3 and ratio of n-3/n-6 PUFA, whereas trans-FA and palmitic-FA (C16 : 0) were increased compared to obese men and controls (all Ps < 0.05). Plasma high-density lipoprotein cholesterol (HDL-C), triglycerides and a marker of insulin sensitivity were similar between obese women and men but impaired compared to controls (Ps < 0.05). Conclusions The data support the hypothesis that insulin resistant non-diabetic obese men display a more optimal skeletal muscle phospholipid FA composition than their female counterparts, which may be a mechanism to compensate the detrimental effect on insulin action of an android fat distribution.
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| 6. |
- Andersson, Kerstin, et al.
(författare)
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Patients with insulin-dependent diabetes but not those with non-insulin-dependent diabetes have anti-sulfatide antibodies as determined with a new ELISA assay
- 2002
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 35:7, s. 463-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In sera from newly diagnosed insulin-dependent diabetes mellitus patients (IDDM type 1) autoantibodies occur against different antigen determinants often shared with neural tissues. The role of these autoantibodies in the disease process is not yet clarified but they can be used as a diagnostic tool in the detection of IDDM patients. METHODS: We have analysed the occurrence of sulfatide autoantibodies in serum from patients with type 1 diabetes (n = 20), individuals with pre-type 1 diabetes (n = 6), patients with type 2 diabetes (n = 32) and controls (n = 43). The method used for the determination of the autoantibodies was a newly developed microtitre-ELISA assay utilizing a complex of sulfatide-albumin as the ligand. RESULTS: The new assay procedure for serum sulfatide autoantibodies showed good reproducibility. The total (day-to-day) imprecision based on analyses of three different serum samples with positive titres varied between 11 and 14% during an assay period of 6 months. None of the controls (0/43) had positive titres of sulfatide antibodies. Of the patients with type 1 diabetes, 85% displayed positive titres of anti-sulfatide antibodies while none of the type 2 patients did so. All individuals with pre-type 1 diabetes had positive titres of sulfatide antibodies. CONCLUSIONS: We conclude that sulfatide autoantibodies in serum can be reproducibly assayed by the newly developed microtitre-ELISA procedure. Elevated titres of sulfatide autoantibodies are a constant finding in newly diagnosed type 1 patients.
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| 7. |
- Bouzakri, K, et al.
(författare)
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IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:3, s. 785-791
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1–associated phosphatidylinositol 3-kinase activity, and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal IRS-1 Ser (312) and Ser (616) phosphorylation was also increased in nondiabetic kidney transplant recipients. Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia.
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