Kudva, Yogish C.

Background: Standard insulin infusion sets (IISs) are to be replaced every 2 to 3 days to avoid complications and diabetic ketosis due to set failure. This pivotal trial evaluated the safety and performance of a new extended-wear infusion set (EIS) when used for 7 days by adults with type 1 diabetes (T1D). Methods: This single-arm, nonrandomized trial enrolled adults (18–80 years of age) with T1D, who used their own MiniMed™ 670G system with insulin lispro or insulin aspart and the EIS for up to 7 days, across 12 consecutive wears. Safety endpoints included incidence of serious adverse events (SAEs), serious adverse device effects (SADEs), unanticipated adverse device effects (UADEs), severe hypoglycemia (SevHypo), severe hyperglycemia (SevHyper), diabetic ketoacidosis (DKA), and skin infection. The EIS failure rate due to unexplained hyperglycemia (i.e., suspected occlusion), the overall EIS survival rate, glycemic control outcomes (i.e., A1C, mean sensor glucose and time spent in established glucose ranges), total daily insulin delivered, and satisfaction with the EIS were determined. Results: The intention to treat population ( n = 259, 48% men, 45.0 ± 14.1 years) wore a total of 3041 EIS devices. No SADE, UADE, or DKA events was reported. Overall rates of SAEs, SevHypo, SevHyper, and skin infection were 3.8, 2.5, 104.1, and 20.1 events per 100 participant-years. The rate of EIS failure due to unexplained hyperglycemia at the end of day 7 was 0.1% (95% confidence interval [CI]: 0.03–0.51) and 0.4% (95% CI: 0.16–1.00) for insulin lispro and aspart use, respectively. Overall EIS survival rate at the end of day 7 was 77.8% (95% CI: 76.2–79.3), glycemic control did not change, and participants reported greater satisfaction with the EIS compared with standard IISs worn before the study ( P < 0.001). Conclusions: This investigation demonstrates that the EIS, when worn for up to 7 days, was safe and rated with high satisfaction, without adversely affecting glycemic control in adults with T1D. Clinical Trial Registration number: NCT04113694 ( https://clinicaltrials.gov/ct2/show/NCT04113694 ).

Objective: Evaluating the feasibility of closed-loop insulin delivery with a zone model predictive control (zone-MPC) algorithm designed for pregnancy complicated by type 1 diabetes (T1D). Research Design and Methods: Pregnant women with T1D from 14 to 32 weeks gestation already using continuous glucose monitor (CGM) augmented pump therapy were enrolled in a 2-day multicenter supervised outpatient study evaluating pregnancy-specific zone-MPC based closed-loop control (CLC) with the interoperable artificial pancreas system (iAPS) running on an unlocked smartphone. Meals and activities were unrestricted. The primary outcome was the CGM percentage of time between 63 and 140 mg/dL compared with participants' 1-week run-in period. Early (2-h) postprandial glucose control was also evaluated. Results: Eleven participants completed the study (age: 30.6 ± 4.1 years; gestational age: 20.7 ± 3.5 weeks; weight: 76.5 ± 15.3 kg; hemoglobin A1c: 5.6% ± 0.5% at enrollment). No serious adverse events occurred. Compared with the 1-week run-in, there was an increased percentage of time in 63–140 mg/dL during supervised CLC (CLC: 81.5%, run-in: 64%, P = 0.007) with less time >140 mg/dL (CLC: 16.5%, run-in: 30.8%, P = 0.029) and time <63 mg/dL (CLC: 2.0%, run-in:5.2%, P = 0.039). There was also less time <54 mg/dL (CLC: 0.7%, run-in:1.6%, P = 0.030) and >180 mg/dL (CLC: 4.9%, run-in: 13.1%, P = 0.032). Overnight glucose control was comparable, except for less time >250 mg/dL (CLC: 0%, run-in:3.9%, P = 0.030) and lower glucose standard deviation (CLC: 23.8 mg/dL, run-in:42.8 mg/dL, P = 0.007) during CLC. Conclusion: In this pilot study, use of the pregnancy-specific zone-MPC was feasible in pregnant women with T1D. Although the duration of our study was short and the number of participants was small, our findings add to the limited data available on the use of CLC systems during pregnancy (NCT04492566).

Objective: To analyze insulin delivery and glycemic metrics throughout the menstrual cycle for women with type 1 diabetes using closed loop control (CLC) insulin delivery. Methods: Menstruating women using a CLC system in a clinical trial were invited to record their menstrual cycles through a cycle-tracking application. Sixteen participants provided data for this secondary analysis over three or more complete cycles. Insulin delivery and continuous glucose monitoring (CGM) data were analyzed in relation to reported cycle phases. Results: Insulin delivery and CGM metrics remained consistent during cycle phases. Intraparticipant variability of CGM metrics and weight-based insulin delivery did not change through cycle phases. Conclusions: For this sample of menstruating women with type 1 diabetes using a CLC system, insulin delivery and glycemic metrics remained stable throughout menstrual cycle phases. Additional studies in this population are needed, particularly among women who report variable glycemic control during their cycles. Trial Registration: NCT03591354.

Background: Automated insulin delivery (AID) systems have not been evaluated in the context of psychological and pharmacological stress in type 1 diabetes. Our objective was to determine glycemic control and insulin use with Zone Model Predictive Control (zone-MPC) AID system enhanced for states of persistent hyperglycemia versus sensor-augmented pump (SAP) during outpatient use, including in-clinic induced stress. Materials and Methods: Randomized, crossover, 2-week trial of zone-MPC AID versus SAP in 14 adults with type 1 diabetes. In each arm, each participant was studied in-clinic with psychological stress induction (Trier Social Stress Test [TSST] and Socially Evaluated Cold Pressor Test [SECPT]), followed by pharmacological stress induction with oral hydrocortisone (total four sessions per participant). The main outcomes were 2-week continuous glucose monitor percent time in range (TIR) 70–180 mg/dL, and glucose and insulin outcomes during and overnight following stress induction. Results: During psychological stress, AID decreased glycemic variability percentage by 13.4% ( P = 0.009). During pharmacological stress, including the following overnight, there were no differences in glucose outcomes and total insulin between AID and physician-assisted SAP. However, with AID total user-requested insulin was lower by 6.9 U ( P = 0.01) for pharmacological stress. Stress induction was validated by changes in heart rate and salivary cortisol levels. During the 2-week AID use, TIR was 74.4% (vs. SAP 63.1%, P = 0.001) and overnight TIR was 78.3% (vs. SAP 63.1%, P = 0.004). There were no adverse events. Conclusions: Zone-MPC AID can reduce glycemic variability and the need for user-requested insulin during pharmacological stress and can improve overall glycemic outcomes. Clinical Trial Identifier NCT04142229.

Background: Suboptimal glycemic control is associated with maternal and neonatal morbidity and mortality in pregnancy complicated by type 1 diabetes (T1D). Prospective analysis of continuous glucose monitoring (CGM) metrics, insulin pump settings, and insulin delivery can better characterize the changes in glycemic levels and insulin use throughout pregnancy with T1D. Materials and Methods: Prescribed parameters, insulin delivery, carbohydrate intake, and CGM data for 25 pregnant women with T1D from three U.S. sites were collected. Participants enrolled before 17 weeks gestation and used personal insulin pumps and study CGM. Mean daily total, basal, and bolus insulin doses (units/kg), CGM time in range (TIR: 63–140 mg/dL), and pump-entered carbohydrates were analyzed for every 2-week gestational interval. Linear mixed-effects regression models were used to evaluate changes across gestational ages compared to 12–14 weeks. Results: Basal insulin was higher during weeks 6–12 and 24–40. Daily bolus and total insulin were higher during weeks 20–40. Pump parameters were adjusted to intensify insulin therapy from 22 weeks onward. Average TIR across pregnancy was 59% ± 14%. Between 18 and 30 weeks, TIR was significantly lower, and time above range was significantly higher compared to the reference biweek. Time below target was lower between 22 and 34 weeks. Seven participants achieved >70% recommended TIR for pregnancy. Participants with maternal complications or infant neonatal intensive care unit admissions had lower TIR. Conclusion: While insulin dosing changed significantly with advancing gestation, most participants did not achieve >70% TIR. Customized anticipatory pump setting adjustments and automated systems aimed toward the designated TIR are needed to improve outcomes for this population. NCT03761615

AbstractDeath with a functioning graft and death‐censored renal allograft failure remain major problems for which effective preventative protocols are lacking. The retrospective cohort study aimed to determine whether histologic changes on a 5‐year surveillance kidney biopsy predict adverse outcomes after transplantation in recipients who had: both Type 2 diabetes (T2DM) and obesity (BMI ≥ 30 kg/m2) at the time of transplantation (T2DM/Obesity, n = 75); neither (No T2DM/No obesity, n = 78); No T2DM/Obesity (n = 41), and T2DM/No obesity (n = 47). On 5‐year biopsies, moderate‐to‐severe mesangial expansion was more common in the T2DM/Obesity group (Banff mm score ≥2 = 49.3%; Tervaert classification MS ≥ 2b = 26.7%) compared to the other groups (p < .001 for both scores). Risk factors included older age, higher BMI, HbA1C, and triglycerides at 1‐year post‐transplant. Moderate‐to‐severe mesangial expansion correlated with death with function (HR 1.74 (1.01, 2.98), p = .045 Banff and 1.89 (1.01, 3.51) p = .045 Tervaert) and with death‐censored graft loss (HR 3.2 (1.2, 8.8), p = .02 Banff and HR 3.8 (1.3, 11.5), p = .01 Tervaert) over a mean of 11.6 years of recipient follow‐up post‐transplant. These data suggest that mesangial expansion in recipients with T2DM and obesity may reflect systemic vascular injury and might be a novel biomarker to predict adverse outcomes post renal transplant.

OBJECTIVE Limited information is available about glycemic outcomes with a closed-loop control (CLC) system compared with a predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS After 6 months of use of a CLC system in a randomized trial, 109 participants with type 1 diabetes (age range, 14–72 years; mean HbA1c, 7.1% [54 mmol/mol]) were randomly assigned to CLC (N = 54, Control-IQ) or PLGS (N = 55, Basal-IQ) groups for 3 months. The primary outcome was continuous glucose monitor (CGM)-measured time in range (TIR) for 70–180 mg/dL. Baseline CGM metrics were computed from the last 3 months of the preceding study. RESULTS All 109 participants completed the study. Mean ± SD TIR was 71.1 ± 11.2% at baseline and 67.6 ± 12.6% using intention-to-treat analysis (69.1 ± 12.2% using per-protocol analysis excluding periods of study-wide suspension of device use) over 13 weeks on CLC vs. 70.0 ± 13.6% and 60.4 ± 17.1% on PLGS (difference = 5.9%; 95% CI 3.6%, 8.3%; P &lt; 0.001). Time &gt;180 mg/dL was lower in the CLC group than PLGS group (difference = −6.0%; 95% CI −8.4%, −3.7%; P &lt; 0.001) while time &lt;54 mg/dL was similar (0.04%; 95% CI −0.05%, 0.13%; P = 0.41). HbA1c after 13 weeks was lower on CLC than PLGS (7.2% [55 mmol/mol] vs. 7.5% [56 mmol/mol], difference −0.34% [−3.7 mmol/mol]; 95% CI −0.57% [−6.2 mmol/mol], −0.11% [1.2 mmol/mol]; P = 0.0035). CONCLUSIONS Following 6 months of CLC, switching to PLGS reduced TIR and increased HbA1c toward their pre-CLC values, while hypoglycemia remained similarly reduced with both CLC and PLGS.

Abstract Context: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies against checkpoints namely CTLA-4, PD-1 and PD-L1. These can cause pituitary dysfunction due to hypophysitis in addition to other endocrinopathies. While the prevalence and course of hypophysitis have been described extensively, the relationship between hypophysitis and cancer prognosis has only been investigated in melanoma patients on ipilimumab. Additionally, the impact of high dose glucocorticoids for hypophysitis treatment on survival has been unclear. Objective: In order to address these important questions, we aimed to characterize the frequency and course of hypophysitis from various ICIs, and to investigate a possible impact on overall survival in cancer patients.Design and Methods: We conducted a single center retrospective cohort study of adult cancer patients that received an ICI from 1/1/2012 - 12/31/2016, followed for a median of 14.8 months. A total of 896 patients were identified that received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab followed or preceded by pembrolizumab (n=70), pembrolizumab alone (n=406), and nivolumab alone (n=250). Results: Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months (range 0.8 to 11.7). Their median age at initiation of ICI was 57.9 years (range 42.4 to 78.5), 54% were males, and the most common malignancy was melanoma (81%). All had hypopituitarism showing secondary adrenal insufficiency (100%), central hypothyroidism (38.5%) and central hypogonadism (28.5% in men, 25% in premenopausal women). Sixty-four percent demonstrated pituitary enlargement on imaging which resolved on follow-up. Mass effects occurred in 50% and were managed by initial high dose glucocorticoids. Thyroiditis occurred in 19.2% of those with hypophysitis. Occurrence of hypophysitis was associated with better overall survival (median 50.7 vs 16.5 months; p value 0.015) and reduced mortality (RR 0.52, 95% CI 0.28 to 0.99; p value 0.036) after adjusting for age, sex and malignancy type. Conclusions: Hypophysitis, usually but not always accompanied by classic MRI features, occurrs within a few weeks in cancer patients most frequently after ipilimumab alone or in combination with a PD-1 inhibitor, rarely after pembrolizumab and never after nivolumab alone. ICI-induced hypophysitis presents as mass effects in half and as hypopituitarism in all patients involving the corticotrophs more commonly than thyrotrophs and gonadotrophs. The improved survival with a 48% lower mortality rate in patients with hypophysitis suggests its possible role as a marker for better efficacy of ICIs against malignancy.

AbstractBackgroundCurrent therapy for Type 1 diabetes (T1D) is characterized by significant glucose variability (GV). Pancreas transplantation (PT) is performed in certain T1D patients with and without end‐stage renal disease. To date, GV has been examined to a limited extent after PT.MethodsWe investigated GV using continuous glucose monitoring (CGM) 3‐6 weeks after PT.ResultsEleven patients had simultaneous kidney pancreas transplantation (SPK), nine pancreas after kidney (PAK), and six pancreas transplantation alone (PTA). Mean CGM showed no difference between SPK, 126.5 ± 13.9, PAK 119.9 ± 12.8, and PTA 131.1 ± 29 mg/dL (P value .6). Percentage of time in range (TIR, 70‐180 mg/dL) was 92% for SPK, 93.4% in PAK, and 88.5% in PTA with only 0.3%, 1.5%, and 0.3% of time <70 mg/dL. Percentage >180 mg/dL was 7.9% for SPK, 4.9% PAK, and 11% in PTA. Other measures of GV were similar in the three cohorts. In six patients, CGM was performed before and after PT and improved significantly. GV was also better compared with a matched cohort of T1D patients.ConclusionsAll 3 types of PT resulted in excellent glucose control 3‐6 weeks post‐procedure. CGM outcomes represent an important objective outcome after PT.

Objective Insulin-dependent diabetes can occur with immune checkpoint inhibitor (ICI) therapy. We aimed to characterize the frequency, natural history and potential predictors of ICI-induced diabetes. Research design and methods We reviewed 1444 patients treated with ICIs over 6 years at our cancer center, and from the 1163 patients who received programmed cell death protein 1 (PD-1) inhibitors, we identified 21 such cases, 12 of which developed new-onset insulin-dependent diabetes and 9 experienced worsening of pre-existing type 2 diabetes. Results ICI-induced diabetes occurred most frequently with pembrolizumab (2.2%) compared with nivolumab (1%) and ipilimumab (0%). The median age was 61 years, and body mass index was 31 kg/m2, which are both higher than expected for spontaneous type 1 diabetes. Other immune-related adverse events occurred in 62%, the most common being immune mediated thyroid disease. New-onset insulin-dependent diabetes developed after a median of four cycles or 5 months; 67% presented with diabetic ketoacidosis and 83% with low or undetectable C-peptide. Autoantibodies were elevated in 5/7 (71%) at the time of new-onset diabetes. Diabetes did not resolve during a median follow-up of 1 year. Conclusions PD-1 inhibitors can lead to insulin deficiency presenting as new-onset diabetes or worsening of pre-existing type 2 diabetes, with a frequency of 1.8 %. The underlying mechanism appears similar to spontaneous type 1 diabetes but there is a faster progression to severe insulin deficiency. Better characterization of ICI-induced diabetes will improve patient care and enhance our understanding of immune-mediated diabetes.