Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes

OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process

Comparative Cost-Effectiveness of Hypertension Treatment in Non-Hispanic Blacks and Whites According to 2014 Guidelines: A Modeling Study

BackgroundWe compared the cost-effectiveness of hypertension treatment in non-Hispanic blacks and non-Hispanic whites according to 2014 US hypertension treatment guidelines.MethodsThe cardiovascular disease (CVD) policy model simulated CVD events, quality-adjusted life years (QALYs), and treatment costs in 35- to 74-year-old adults with untreated hypertension. CVD incidence, mortality, and risk factor levels were obtained from cohort studies, hospital registries, vital statistics, and national surveys. Stage 1 hypertension was defined as blood pressure 140-149/90-99mm Hg; stage 2 hypertension as ≥150/100mm Hg. Probabilistic input distribution sampling informed 95% uncertainty intervals (UIs). Incremental cost-effectiveness ratios (ICERs) < $50,000/QALY gained were considered cost-effective.ResultsTreating 0.7 million hypertensive non-Hispanic black adults would prevent about 8,000 CVD events annually; treating 3.4 million non-Hispanic whites would prevent about 35,000 events. Overall 2014 guideline implementation would be cost saving in both groups compared with no treatment. For stage 1 hypertension but without diabetes or chronic kidney disease, cost savings extended to non-Hispanic black males ages 35-44 but not same-aged non-Hispanic white males (ICER$57,000/QALY; 95% UI $15,000-$100,000) and cost-effectiveness extended to non-Hispanic black females ages 35-44 (ICER $46,000/QALY;$17,000-$76,000) but not same-aged non-Hispanic white females (ICER$181,000/QALY; $111,000-$235,000).ConclusionsCompared with non-Hispanic whites, cost-effectiveness of implementing hypertension guidelines would extend to a larger proportion of non-Hispanic black hypertensive patients

Projected Impact of Mexico’s Sugar-Sweetened Beverage Tax Policy on Diabetes and Cardiovascular Disease: A Modeling Study

Background: Rates of diabetes in Mexico are among the highest worldwide. In 2014, Mexico instituted a nationwide tax on sugar-sweetened beverages (SSBs) in order to reduce the high level of SSB consumption, a preventable cause of diabetes and cardiovascular disease (CVD). We used an established computer simulation model of CVD and country-specific data on demographics, epidemiology, SSB consumption, and short-term changes in consumption following the SSB tax in order to project potential long-range health and economic impacts of SSB taxation in Mexico. Methods and Findings: We used the Cardiovascular Disease Policy Model–Mexico, a state transition model of Mexican adults aged 35–94 y, to project the potential future effects of reduced SSB intake on diabetes incidence, CVD events, direct diabetes healthcare costs, and mortality over 10 y. Model inputs included short-term changes in SSB consumption in response to taxation (price elasticity) and data from government and market research surveys and public healthcare institutions. Two main scenarios were modeled: a 10% reduction in SSB consumption (corresponding to the reduction observed after tax implementation) and a 20% reduction in SSB consumption (possible with increases in taxation levels and/or additional measures to curb consumption). Given uncertainty about the degree to which Mexicans will replace calories from SSBs with calories from other sources, we evaluated a range of values for calorie compensation. We projected that a 10% reduction in SSB consumption with 39% calorie compensation among Mexican adults would result in about 189,300 (95% uncertainty interval [UI] 155,400–218,100) fewer incident type 2 diabetes cases, 20,400 fewer incident strokes and myocardial infarctions, and 18,900 fewer deaths occurring from 2013 to 2022. This scenario predicts that the SSB tax could save Mexico 983 million international dollars (95% UI $769 million–$1,173 million). The largest relative and absolute reductions in diabetes and CVD events occurred in the youngest age group modeled (35–44 y). This study’s strengths include the use of an established mathematical model of CVD and use of contemporary Mexican vital statistics, data from health surveys, healthcare costs, and SSB price elasticity estimates as well as probabilistic and deterministic sensitivity analyses to account for uncertainty. The limitations of the study include reliance on US-based studies for certain inputs where Mexico-specific data were lacking (specifically the associations between risk factors and CVD outcomes [from the Framingham Heart Study] and SSB calorie compensation assumptions), limited data on healthcare costs other than those related to diabetes, and lack of information on long-term SSB price elasticity that is specific to geographic and economic subgroups. Conclusions: Mexico’s high diabetes prevalence represents a public health crisis. While the long-term impact of Mexico’s SSB tax is not yet known, these projections, based on observed consumption reductions, suggest that Mexico’s SSB tax may substantially decrease morbidity and mortality from diabetes and CVD while reducing healthcare costs

Investigating associations between the built environment and physical activity among older people in 20 UK towns.

BACKGROUND: Policy initiatives such as WHO Age Friendly Cities recognise the importance of the urban environment for improving health of older people, who have both low physical activity (PA) levels and greater dependence on local neighbourhoods. Previous research in this age group is limited and rarely uses objective measures of either PA or the environment. METHODS: We investigated the association between objectively measured PA (Actigraph GT3x accelerometers) and multiple dimensions of the built environment, using a cross-sectional multilevel linear regression analysis. Exposures were captured by a novel foot-based audit tool that recorded fine-detail neighbourhood features relevant to PA in older adults, and routine data. RESULTS: 795 men and 638 women aged 69-92 years from two national cohorts, covering 20 British towns, were included in the analysis. Median time in moderate to vigorous PA (MVPA) was 27.9 (lower quartile: 13.8, upper quartile: 50.4) minutes per day. There was little evidence of associations between any of the physical environmental domains (eg, road and path quality defined by latent class analysis; number of bus stops; area aesthetics; density of shops and services; amount of green space) and MVPA. However, analysis of area-level income deprivation suggests that the social environment may be associated with PA in this age group. CONCLUSIONS: Although small effect sizes cannot be discounted, this study suggests that older individuals are less affected by their local physical environment and more by social environmental factors, reflecting both the functional heterogeneity of this age group and the varying nature of their activity spaces

Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials

OBJECTIVE: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. RESEARCH DESIGN AND METHODS: Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 <1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia. RESULTS: The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- (P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- (P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- (P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive (P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P < 0.01 for all]). CONCLUSIONS: The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points

Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.

BackgroundType 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.MethodsWe conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.ResultsA total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.ConclusionsTeplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.)

Targeting effector memory T cells with alefacept in new onset type 1 diabetes: 12 month results from the T1DAL study

Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D. Methods The T1DAL study is a phase II, double-blind, placebo-controlled trial that randomised T1D patients 12-35 years old within 100 days of diagnosis, 33 to alefacept (two 12-week courses of 15 mg IM per week, separated by a 12-week pause) and 16 to placebo, at 14 US sites. The primary endpoint was the change from baseline in mean 2-hour C-peptide area under the curve (AUC) at 12 months. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings The mean 2-hour C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110 nmol/L) in the alefacept group and decreased by 0.115 nmol/L (95% CI -0.278 to 0.047) in the placebo group, which was not significant (p=0.065). However, key secondary endpoints were met: the mean 4-hour C-peptide AUC was significantly higher (p=0.019), and daily insulin use and the rate of hypoglycemic events were significantly lower (p=0.02 and p<0.001, respectively) at 12 months in the alefacept vs. placebo groups. Safety and tolerability were comparable between groups. There was targeted depletion of Tems and Tcms, with sparing of naïve and regulatory T cells (Tregs). Interpretation At 12 months, alefacept preserved the 4-hour C-peptide AUC, lowered insulin use, and reduced hypoglycemic events, suggesting a signal of efficacy. Depletion of memory T cells with sparing of Tregs may be a useful strategy to preserve beta cell function in new-onset T1D