Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism.

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

Risk of Cardiovascular Conditions in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study.

INTRODUCTION: In patients with chronic hypoparathyroidism disordered calcium homeostasis has been associated with risk of cardiovascular diseases, including cardiomyopathy, congestive heart failure, and arrhythmia; however, larger-scale studies are needed to examine these risks. This study evaluated the risk of cardiovascular conditions among patients with chronic hypoparathyroidism. METHODS: Adults with and without chronic hypoparathyroidism were selected from a medical insurance claims database in the USA from January 2007 to June 2017, and were followed for up to 5 years. Associations between chronic hypoparathyroidism and incident atrial fibrillation (AF), tachyarrhythmia, myocardial infarction (MI), coronary artery disease (CAD), heart failure (HF), stroke, cerebrovascular disease, peripheral vascular disease (PVD), and a combined cardiovascular endpoint of cerebrovascular disease, CAD, HF, and PVD were compared between cohorts using Kaplan-Meier analyses and unadjusted and adjusted Cox proportional hazards models. RESULTS: In 8097 patients with chronic hypoparathyroidism compared with 40,485 patients without, respectively, mean ± SD ages were 58.6 ± 16.3 and 47.3 ± 18.0 years, 76.2% and 54.4% were female, and 19.4% and 9.5% had the combination of cardiovascular findings at baseline. In adjusted analyses, patients with chronic hypoparathyroidism had significantly higher risk (adjusted hazard ratio and 95% confidence interval) of incident AF (1.72; 1.51-1.97), tachyarrhythmia (1.68; 1.32-2.14), MI (1.18; 1.01-1.38), CAD (1.39; 1.26-1.54), HF (1.64; 1.46-1.84), stroke (1.45; 1.31-1.62), cerebrovascular disease (1.48; 1.34-1.62), PVD (1.66; 1.51-1.81), and combined cardiovascular endpoint (1.63; 1.52-1.75), all P < 0.001 except P = 0.036 for MI, compared with patients without chronic hypoparathyroidism. CONCLUSIONS: This large retrospective cohort study showed that chronic hypoparathyroidism was associated with increased risk of incident cardiovascular conditions and arrhythmias. Results should be evaluated in light of limitations inherent to claims database analyses. Further studies are warranted to investigate reasons for these risks and to develop strategies for reducing cardiovascular conditions in patients with chronic hypoparathyroidism.

Risk of Chronic Kidney Disease and Estimated Glomerular Filtration Rate Decline in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study.

INTRODUCTION: Chronic hypoparathyroidism, treated with conventional therapy of oral calcium supplements and active vitamin D, may increase the risk of kidney complications. This study examined risks of development and progression of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) decline in patients with chronic hypoparathyroidism. METHODS: A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017 included patients with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism followed for up to 5 years. Main outcome measures were (1) development of CKD, defined as new diagnosis of CKD stage 3 and higher or ≥ 2 eGFR measurements < 60 ml/min/1.73 m2 ≥ 3 months apart, (2) progression of CKD, defined as increase in baseline CKD stage, (3) progression to end-stage kidney disease (ESKD), and (4) eGFR decline ≥ 30% from baseline. Time-to-event analyses included Kaplan-Meier analyses with log-rank tests, and both unadjusted and adjusted Cox proportional hazards models were used to compare outcomes between cohorts. RESULTS: The study included 8097 adults with and 40,485 without chronic hypoparathyroidism. In Kaplan-Meier analyses, patients with chronic hypoparathyroidism had higher risk of developing CKD and CKD progression and higher rates of eGFR decline (all P < 0.001). In multivariable Cox models adjusted for baseline characteristics, hazard ratios (95% confidence intervals [CIs]) were 2.91 (2.61-3.25) for developing CKD, 1.58 (1.23-2.01) for CKD stage progression, 2.14 (1.51-3.04) for progression to ESKD, and 2.56 (1.62-4.03) for eGFR decline (all P < 0.001) among patients with chronic hypoparathyroidism compared with those without hypoparathyroidism. CONCLUSION: Patients with chronic hypoparathyroidism have increased risk of development and progression of CKD and eGFR decline compared with those without hypoparathyroidism. Further studies are warranted to understand underlying mechanisms for the associations between chronic hypoparathyroidism and kidney disease.

Risk of Nephrolithiasis and Nephrocalcinosis in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study.

INTRODUCTION: Chronic hypoparathyroidism managed with conventional treatment, comprising oral administration of calcium and active vitamin D, has been associated with renal complications, including nephrolithiasis and nephrocalcinosis. Further larger-scale studies are needed to examine these risks. This study evaluated the risk of nephrolithiasis and nephrocalcinosis in patients with chronic hypoparathyroidism. METHODS: A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017. Included patients were those with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism over a maximum of 5-year follow-up. The main outcome measures were nephrolithiasis, identified by diagnosis codes or procedure codes for removing kidney stones, and nephrocalcinosis, identified by diagnosis codes. RESULTS: The nephrolithiasis analyses included 8097 adult patients with hypoparathyroidism and 40,485 adult patients without hypoparathyroidism. After excluding patients with a diagnosis of nephrocalcinosis at baseline, nephrocalcinosis analyses included 8051 patients with hypoparathyroidism and 40,466 patients without hypoparathyroidism. During 5 years of follow-up, patients with chronic hypoparathyroidism had significantly increased risk of nephrolithiasis and nephrocalcinosis in Kaplan-Meier analysis compared with patients without hypoparathyroidism (both P < 0.001). In the adjusted analyses, chronic hypoparathyroidism was associated with higher risks of nephrolithiasis (hazard ratio [HR], 1.81; 95% confidence interval [CI] 1.60-2.04) and nephrocalcinosis (HR, 6.94; 95% CI 4.41-10.92). A sensitivity analysis restricted to patients with at least one kidney imaging examination showed that 2.6% of patients (n = 59) with hypoparathyroidism and 0.5% of patients (n = 20) without hypoparathyroidism (ratio, 5.5; P < 0.001) developed nephrocalcinosis. CONCLUSIONS: This large retrospective cohort study showed a statistically significant and clinically meaningful increased risk of nephrolithiasis and nephrocalcinosis in patients who have chronic hypoparathyroidism compared with those who do not have chronic hypoparathyroidism.

Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84).

CONTEXT: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. OBJECTIVE: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. DESIGN/SETTING: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). PATIENTS: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. INTERVENTIONS: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). MAIN OUTCOME MEASURES: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. RESULTS: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). CONCLUSIONS: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).

Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism.

CONTEXT: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. OBJECTIVE: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. DESIGN: Open-label extension study; 5-year interim analysis. SETTING: 12 US centers. PATIENTS: Adults (N = 49) with chronic hypoparathyroidism. INTERVENTION(S): rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. MAIN OUTCOME MEASURE(S): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. RESULTS: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. CONCLUSION: Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study.

BACKGROUND: Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma. METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560. FINDINGS: We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90). INTERPRETATION: Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. FUNDING: US National Cancer Institute and Massachusetts General Hospital.

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients.

BACKGROUND: Type 1 diabetes (T1D) results from destruction of pancreatic ß cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining ß cells in patients with newly diagnosed T1D. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS: A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS: In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT00965458. FUNDING: NIH and Astellas.

Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial.

Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Type 1 diabetes results from autoimmune targeting of the pancreatic ß cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual ß cells in patients newly diagnosed with type 1 diabetes. METHODS: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve ß-cell function in patients with new-onset type 1 diabetes.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial.

BACKGROUND: Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve ß-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS: In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS: 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION: Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in ß-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING: MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Management of diabetic ketoacidosis in children and adolescents.

Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus. While it can occur in all types of diabetes mellitus, it is seen most often in patients with type 1 diabetes, either at presentation or as a result of non-compliance with medical therapy. DKA is characterized by hyperglycemia, acidosis, dehydration, and electrolyte abnormalities, which result from a deficiency of insulin and an excess of counter-regulatory hormones. Therapy is aimed at repleting fluids, and correcting acidosis and electrolyte disturbances by administration of intravenous fluid and intravenous insulin. Rapid correction should be avoided as it may result in untoward effects, including cerebral edema. Frequent monitoring of neurologic status and metabolic parameters aids in avoidance or early detection of complications. While much is still not understood about the most serious complication, cerebral edema, recent studies suggest that its development may be tied to a loss of cerebral autoregulation and a vasogenic mechanism of edema formation. Treatment of cerebral edema includes fluid restriction and administration of mannitol. Once DKA has resolved, subcutaneous insulin is initiated with careful consideration of its pharmacokinetics to avoid a period of insulin deficiency and metabolic decompensation.

Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells.

Immune modulators can arrest loss of insulin secretion in type 1 diabetes mellitus (T1DM), but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether exendin-4, a glucagon-like peptide-1 receptor agonist, would enhance remission of T1DM in NOD mice treated with anti-CD3 monoclonal antibody (mAb) and studied the effects of exendin-4 treatment on cellular and metabolic responses of beta-cells. Diabetic NOD mice treated with anti-CD3 mAb and exendin-4 had a higher rate of remission (44%) than mice treated with anti-CD3 mAb alone (37%) or exendin-4 (0%) or insulin or IgG alone (0%) (P < 0.01). The effect of exendin-4 on reversal of diabetes after anti-CD3 mAb was greatest in mice with a glucose level of less than 350 mg/dl at diagnosis (63 vs. 39%, P < 0.05). Exendin-4 did not affect beta-cell area, replication, or apoptosis or reduce the frequency of diabetogenic or regulatory T cells or modulate the antigenicity of islet cells. Reversal of T1DM with anti-CD3 mAb was associated with recovery of insulin in glucose transporter-2(+)/insulin(-) islet cells that were identified at diagnosis. Glucose tolerance and insulin responses improved in mice treated with combination therapy, and exendin-4 increased insulin content and insulin release from beta-cells. We conclude that treatment with glucagon-like peptide-1 receptor agonist enhances remission of T1DM in NOD mice treated with anti-CD3 mAb by enhancing the recovery of the residual islets. This combinatorial approach may be useful in treatment of patients with new-onset T1DM.

Autoimmunity and beta cell regeneration in mouse and human type 1 diabetes: the peace is not enough.

Accumulating data from animal models of type 1 diabetes and some findings from clinical studies suggest that autoimmune destruction of islet beta cells is associated with enhanced beta cell regeneration. Successful immune therapies, aimed at preservation of islet cell mass, result in a remarkable reduction of beta cell regeneration. Treated or not, as long as the task of treatment is limited by "making peace" with autoimmunity, the process of beta cell loss continues. Additional therapeutic modalities capable of stimulating beta cell regeneration in the absence of active autoimmune destruction are urgently needed.