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Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes
This study aimed to determine whether early administration of drugs that block the renin–angiotensin system slows the progression of change in glomerular mesangial fractional volume and retinopathy progression of two steps or more, according to the retinopathy severity scale. Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy.
Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy.
Diabetic nephropathy, responsible for more than 45% of cases of end-stage renal disease in the United States,
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may be structurally advanced once albuminuria becomes detectable.
2
,
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Blockers of the renin–angiotensin system are more effective than other antihypertensive agents in slowing nephropathy progression in patients who have proteinuria, diabetes mellitus, and a reduced glomerular filtration rate (GFR),
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–
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and such blockers can also decrease proteinuria in patients with diabetes.
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Although the reduction of proteinuria in patients with diabetes has been associated with a reduction in the rate of decline in GFR in small studies,
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this association has not been systematically tested; . . .
Journal Article
Stem Cell–Derived, Fully Differentiated Islets for Type 1 Diabetes
Zimislecel is an allogeneic stem cell–derived islet-cell therapy. This phase 1–2 study supports the hypothesis that zimislecel can restore physiologic islet function and thus treat persons with type 1 diabetes.
Journal Article
Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial
ObjectiveType 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota–immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).DesignPatients with recent-onset (<6 weeks) T1D (18–30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition.ResultsStimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.ConclusionFMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D.Trial registration numberNTR3697.
Journal Article
An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
In this trial, high-risk nondiabetic relatives of patients with type 1 diabetes were randomly assigned to receive teplizumab (an anti-CD3 monoclonal antibody) or placebo and were followed for type 1 diabetes. Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants.
Journal Article
Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes
In a double-blind trial, patients with type 1 diabetes and early-to-moderate diabetic kidney disease were randomly assigned to receive allopurinol, which may slow the decline in the glomerular filtration rate, or placebo. There were no clinically meaningful benefits of serum urate reduction on kidney outcomes with allopurinol therapy.
Journal Article
Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes
Aims/hypothesisThe aim of this study was to determine if retention of C-peptide following immunotherapy using recombinant GAD65 conjugated to aluminium hydroxide (GAD-alum) is influenced by HLA risk haplotypes DR3-DQ2 and DR4-DQ8.MethodsHLA-dependent treatment effect of GAD-alum therapy on C-peptide retention in individuals with recent-onset type 1 diabetes was evaluated using individual-level patient data from three placebo-controlled, randomised clinical trials using a mixed repeated measures model.ResultsA significant and dose-dependent effect was observed in individuals positive for the genotypes that include HLA-DR3-DQ2 but not HLA-DR4-DQ8 and in the broader subgroup of individuals positive for all genotypes that include HLA-DR3-DQ2 (i.e. including those also positive for HLA-DR4-DQ8). Higher doses (three or four injections) showed a treatment effect ratio of 1.596 (95% CI 1.132, 2.249; adjusted p = 0.0035) and 1.441 (95% CI 1.188, 1.749; adjusted p = 0.0007) vs placebo for the two respective HLA subgroups.Conclusions/interpretationGAD65-specific immunotherapy has a significant effect on C-peptide retention in individuals with recent-onset type 1 diabetes who have the DR3-DQ2 haplotype.
Journal Article
Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes
Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown.
In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events.
Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome.
Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).
Journal Article
Verapamil and beta cell function in adults with recent-onset type 1 diabetes
Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models
1
. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial (
NCT02372253
) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent-onset T1D.
A phase 2 placebo-controlled randomized trial reveals that verapamil promotes beta cell function in adult subjects with recent-onset type 1 diabetes.
Journal Article
Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes
This trial randomly assigned pregnant women with type 1 diabetes to standard insulin therapy with continuous glucose monitoring or to hybrid closed-loop therapy. The latter significantly improved maternal glycemic control.
Journal Article