Context: Few studies have assessed factors associated with severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D). Objective: Our objective was to determine frequency of and factors associated with the occurrence of SH and DKA in adults with T1D. Design and Setting: We conducted a cross-sectional analysis from the T1D Exchange clinic registry at 70 U.S. endocrinology centers. Patients: Analysis included 7012 participants in the T1D Exchange clinic registry aged 26 to 93 years old with T1D for ≥2 years. Results: Higher frequencies of SH and DKA were associated with lower socioeconomic status (P < .001). SH was strongly associated with diabetes duration (P < .001), with 18.6% of those with diabetes ≥40 years having an event in the past 12 months. SH frequency was lowest in those with hemoglobin A1c (HbA1c) levels of 7.0% (53 mmol/mol) to 7.5% (58 mmol/mol), being higher in those with HbA1c levels <7.0% (7.5% (>58 mmol/mol). DKA frequency increased with higher HbA1c levels (P < .001), with 21.0% of those with HbA1c ≥10.0% (≥86 mmol/mol) having an event in the past 12 months. Conclusions: SH and DKA are more common in those with lower socioeconomic status. DKA, most common in those with HbA1c ≥10.0% (≥86 mmol/mol), should be largely preventable. In contrast, SH, most frequent with diabetes ≥40 years duration, cannot be abolished given the limitation of current therapies. To reduce SH in adults with longstanding diabetes, consideration should be given to modifying HbA1c goals, particularly in patients with very low HbA1c levels.

Aim: To conduct a systematic review and meta‐analysis to understand the timing and factors associated with anti‐programmed cell death protein‐1 (PD‐1)/anti‐programmed cell death protein‐1 ligand (PD‐L1) inhibitor‐induced Type 1 diabetes.Methods: We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000–2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t‐tests.Results: The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5–448) days with ketoacidosis in 76% of cases. The average ± sd HbA_1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes‐associated antibodies at presentation, and those with antibodies had a more rapid onset (P=0.005) and higher incidence of diabetic ketoacidosis (P=0.02) compared to people without antibodies.Conclusions: Many people developed Type 1 diabetes within 3 months of initial PD‐1/PD‐L1 inhibitor exposure. People presenting with Type 1 diabetes‐associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state‐of‐the‐art therapies need to be aware of this potential severe adverse event.

BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001–0.552, P = 0.050). A1c was lower in ATG/G-CSF–treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. FUNDING. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.