Potential kidney protective effects of glucagon-like peptide-1 receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes (T2DM) with chronic kidney disease (CKD). This class of medication has demonstrated promising results in reducing albuminuria, preserving estimated glomerular filtration rate (eGFR), and mitigating cardiovascular (CV) risk, making them potential therapeutic options for individuals with CKD. The kidney protective effects of GLP-1RAs extend beyond glycaemic control, and are thought to be attributed to their anti-inflammatory, antioxidant, and natriuretic properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure, or reduce CV and kidney related death in people with T2DM and CKD. The Research Study to See How Semaglutide (a once weekly subcutaneous administered GLP-1RA) Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) was recently stopped because of efficacy. The primary end point for the FLOW trial consists of a composite endpoint of (i) onset of chronic kidney failure; (ii) death from kidney failure; (iii) cardiovascular death; and (iv) onset of a persistent ≥50% reduction in eGFR from baseline. It has also been reported by the sponsors of the trial that the primary end point of the trial was reduced by 24% with both CKD and CV outcomes contributing to risk reduction. In anticipation of the results of the FLOW trial being published, we review the current evidence surrounding kidney outcomes and proposed kidney protective pathways associated with GLP-1RA use.

Utility of Repeat Sampling in Bilateral Aldosterone Suppression During Adrenal Vein Sampling for Primary Aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension. Accurate subtyping of PA is essential to identify unilateral disease, as adrenalectomy improves outcomes. Subtyping PA requires adrenal vein sampling (AVS), which is technically challenging and results from AVS may not always be conclusive. We present a case of a 37-year-old man with PA whose AVS studies were inconclusive due to apparent bilateral aldosterone suppression (ABAS). As a result, our patient was misdiagnosed as having bilateral PA and medically managed until a repeat AVS showed lateralization to the right adrenal gland. ABAS is an underrecognized phenomenon that may confound the subtyping of PA. We recommend repeating AVS in such cases and discuss strategies to minimize ABAS.

Hybrid Closed Loop in Adults With Type 1 Diabetes and Severely Impaired Hypoglycemia Awareness.

BACKGROUND: Benefits of hybrid closed-loop (HCL) systems in a high-risk group with type 1 diabetes and impaired awareness of hypoglycemia (IAH) have not been well-explored. METHODS: Adults with Edmonton HYPO scores ≥1047 were randomized to 26-weeks HCL (MiniMed™ 670G) vs standard therapy (multiple daily injections or insulin pump) without continuous glucose monitoring (CGM) (control). Primary outcome was percentage CGM time-in-range (TIR; 70-180 mg/dL) at 23 to 26 weeks post-randomization. Major secondary endpoints included magnitude of change in counter-regulatory hormones and autonomic symptom responses to hypoglycemia at 26-weeks post-randomization. A post hoc analysis evaluated glycemia risk index (GRI) comparing HCL with control groups at 26 weeks post-randomization. RESULTS: Nine participants (median [interquartile range (IQR)] age 51 [41, 59] years; 44% male; enrolment HYPO score 1183 [1058, 1308]; Clarke score 6 [6, 6]; n = 5 [HCL]; n = 4 [control]) completed the study. Time-in-range was higher using HCL vs control (70% [68, 74%] vs 48% [44, 50%], P = .014). Time <70 mg/dL did not differ (HCL 3.8% [2.7, 3.9] vs control 6.5% [4.3, 8.6], P = .14) although hypoglycemia episode duration was shorter (30 vs 50 minutes, P < .001) with HCL. Glycemia risk index was lower with HCL vs control (38.1 [30.0, 39.2] vs 70.8 [58.5, 72.4], P = .014). Following 6 months of HCL use, greater dopamine (24.0 [12.3, 27.6] vs -18.5 [-36.5, -4.8], P = .014), and growth hormone (6.3 [4.6, 16.8] vs 0.5 [-0.8, 3.0], P = .050) responses to hypoglycemia were observed. CONCLUSIONS: Six months of HCL use in high-risk adults with severe IAH increased glucose TIR and improved GRI without increased hypoglycemia, and partially restored counter-regulatory responses. CLINICAL TRIAL REGISTRATION: ACTRN12617000520336.

Outcomes associated with a variable rate insulin infusion diabetic ketoacidosis protocol.

AIMS: To relate adverse events with glucose correction rates in diabetic ketoacidosis (DKA) using variable rate intravenous insulin-infusions (VRIII). METHODS: Retrospective, observational study in adults with DKA who received insulin infusions between 2012 and 2017 at St Vincent's Hospital, Melbourne. Early correction of hyperglycaemia (<10 mmol/L) was evaluated for association with hypoglycaemia (<4.0 mmol/L), hypokalaemia (potassium <3.3 mmol/L) and clinical outcomes via regression analysis. RESULTS: The study involved 97 patients, with 93 % having type 1 diabetes. The mean age was 38 years, 47 % were women and 35 % were admitted to intensive care. Hypoglycaemia rates during 12 and 24 h of treatment were 6.2 % and 8.2 %, respectively with 58 % of patients recording their first BGL <10 mmol/L within 12 h and 88 % within 24 h. Ketone clearance time averaged at 15.6 h. Hyperglycaemia correction rates to <10 mmol/L were not different in those with/without hypoglycaemia at 12/24 h, in multivariate analysis including admission BGL. Hypokalaemia occurred in 40.2 % of patients and was associated with lower pH but not BGL correction rates. CONCLUSION: The VRIII protocol achieved early hyperglycaemia correction and ketoacidosis reversal with low hypoglycaemia risk. However, high hypokalaemia rates suggest the need for aggressive potassium replacement, especially in markedly acidotic patients.

Driving-Related Glucose Patterns Among Older Adults with Type 1 Diabetes.

Older adults with type 1 diabetes may face challenges driving safely. Glucose "above-5-to-drive" is often recommended for insulin-treated diabetes to minimize hypoglycemia while driving. However, the effectiveness of this recommendation among older adults has not been evaluated. Older drivers with type 1 diabetes were assessed while using sensor-augmented insulin pumps during a 2-week clinical trial run-in. Twenty-three drivers (median age 69 years [interquartile range; IQR 65-72]; diabetes duration 37 years [20-45]) undertook 618 trips (duration 10 min [5-21]). Most trips (n = 535; 87%) were <30 min duration; 9 trips (1.5%) exceeded 90 min and 3 trips (0.5%) exceeded 120 min. Pre-trip continuous glucose monitoring (CGM) was >5.0 mmol/L for 577 trips (93%) and none of these had CGM <3.9 mmol/L during driving (including 8 trips >90 min and 3 trips >120 min). During 41 trips with pre-trip CGM ≤5.0 mmol/L, 11 trips had CGM <3.9 mmol/L. Seventy-one CGM alerts occurred during 60 trips (10%), of which 54 of 71 alerts (76%) were unrelated to hypoglycemia. Our findings support a glucose "above-5-to-drive" recommendation to avoid CGM-detected hypoglycemia among older drivers, including for prolonged drives, and highlight the importance of active CGM low-glucose alerts to prevent hypoglycemia during driving. Driving-related CGM usability and alert functionality warrant investigation. Clinical trial ACTRN1261900515190.

Automated insulin delivery among adults with type 1 diabetes for up to 2 years: a real-world, multicentre study.

BACKGROUND AND AIMS: Automated insulin delivery (AID) improves glycaemia among people with type 1 diabetes in clinical trials and overseas real-world studies. Whether improvements are sustained beyond 12 months in the real world, and whether they occur in the Australian context, has not yet been established. We aimed to observe, up to 2 years, the effectiveness of initiating first-generation AID for type 1 diabetes management. METHODS: Retrospective, real-world, observational study using medical records, conducted across five sites in Australia. Adults with type 1 diabetes, who had AID initiated between February 2019 and December 2021, were observed for 6-24 months after initiation (until June 2022). Outcomes examined included glucose metrics assessed by glycated haemoglobin (HbA1c ) and continuous glucose monitoring (CGM), safety and therapy continuation. RESULTS: Ninety-four adults were studied (median age 39 years (interquartile range, IQR: 31-51); pre-initiation HbA1c 7.8% (7.2-8.6)). After AID initiation, HbA1c decreased by mean 0.5 percentage points (95% confidence interval (CI): -0.7 to -0.2) at 3 months (P < 0.001); CGM time in range 3.9-10.0 mmol/L increased by 11 percentage points (9-14) at 1 month (P < 0.001); these improvements were maintained up to 24 months (all P < 0.02). Median CGM time below 3.9 mmol/L was <1.5% pre- and post-AID initiation. The subgroup with pre-initiation HbA1c above 8.5% had the greatest HbA1c improvement (-1.4 percentage points (-1.8 to -1.1) at 3 months). Twelve individuals (13%) discontinued AID, predominantly citing difficulties with CGM. During the 150 person-years observed, four diabetes-related emergencies were documented: three severe hypoglycaemic events and one hyperglycaemic event without ketoacidosis. CONCLUSIONS: Early glucose improvements were observed after real-world AID initiation, sustained up to 2 years, without excess adverse events. The greatest benefits were observed among individuals with highest glycaemia before initiation. Future-generation systems with increased user-friendliness may enhance therapy continuation.

Baricitinib and ß-Cell Function in Patients with New-Onset Type 1 Diabetes.

BACKGROUND: Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves ß-cell function in type 1 diabetes is unclear. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration-time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring. RESULTS: A total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal-stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo. CONCLUSIONS: In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve ß-cell function as estimated by the mixed-meal-stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.).

Challenging Clinical Perspectives in Type 2 Diabetes with Tirzepatide, a First-in-Class Twincretin.

Tirzepatide is a first-in-class GIP/GLP-1 receptor agonist ('twincretin')-a single molecule that acts as an agonist at both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. In the SURPASS clinical trial program in type 2 diabetes mellitus (T2D), tirzepatide was associated with unprecedented reductions in HbA1c, clinically significant weight loss and other metabolic benefits, combined with low rates of hypoglycaemia across a wide range of patient characteristics. The safety and adverse event rate for tirzepatide appears comparable to that of GLP-1 receptor agonists. Although results from dedicated cardiovascular (CV) and kidney trials are currently not available, information to date suggests that tirzepatide may have CV and kidney benefits in people with T2D. Tirzepatide has been approved for the treatment of T2D in the USA, United Arab Emirates, European Union, Japan and Australia. Here, we review how tirzepatide will fit into the T2D treatment continuum. We also consider future directions with tirzepatide in T2D, including its potential for targeting cardio-renal-metabolic disease in T2D, and discuss how tirzepatide-and other co-agonists in development-may challenge current approaches for management of T2D.

Detection, management, and prevention of diabetes-related foot disease in the Australian context.

Diabetes-related foot disease (DFD) is a widely feared complication among people who live with diabetes. In Australia and globally, rates of disability, cardio-vascular disease, lower extremity amputation, and mortality are significantly increased in patients with DFD. In order to understand and prevent these outcomes, we analyse the common pathogenetic processes of neuropathy, arterial disease, and infection. The review then summarises important management considerations through the interdisciplinary lens. Using Australian and international guidelines, we offer a stepwise, evidence-based practical approach to the care of patients with DFD.

Stimulation parameters for directional vagus nerve stimulation.

BACKGROUND: Autonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic. METHODS: Male rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude. RESULTS: During application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range). CONCLUSIONS: This study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

Challenges of Glycemic Control in People With Diabetes and Advanced Kidney Disease and the Potential of Automated Insulin Delivery.

Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease in the world. It is known that maintaining optimal glycemic control can slow the progression of CKD. However, the failing kidney impacts glucose and insulin metabolism and contributes to increased glucose variability. Conventional methods of insulin delivery are not well equipped to adapt to this increased glycemic lability. Automated insulin delivery (AID) has been established as an effective treatment in patients with type 1 diabetes mellitus, and there is emerging evidence for their use in type 2 diabetes mellitus. However, few studies have examined their role in diabetes with concurrent advanced CKD. We discuss the potential benefits and challenges of AID use in patients with diabetes and advanced CKD, including those on dialysis.

Continuous Glucose Monitoring-Based Composite Metrics: A Review and Assessment of Performance in Recent-Onset and Long-Duration Type 1 Diabetes.

This study examined correlations between continuous glucose monitoring (CGM)-based composite metrics and standard glucose metrics within CGM data sets from individuals with recent-onset and long-duration type 1 diabetes. First, a literature review and critique of published CGM-based composite metrics was undertaken. Second, composite metric results were calculated for the two CGM data sets and correlations with six standard glucose metrics were examined. Fourteen composite metrics met selection criteria; these metrics focused on overall glycemia (n = 8), glycemic variability (n = 4), and hypoglycemia (n = 2), respectively. Results for the two diabetes cohorts were similar. All eight metrics focusing on overall glycemia strongly correlated with glucose time in range; none strongly correlated with time below range. The eight overall glycemia-focused and two hypoglycemia-focused composite metrics were all sensitive to automated insulin delivery therapeutic intervention. Until a composite metric can adequately capture both achieved target glycemia and hypoglycemia burden, the current two-dimensional CGM assessment approach may offer greatest clinical utility.

Lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery in a randomised trial.

AIM: To explore the lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery, an area previously receiving minimal attention. METHODS: Semi-structured interviews were conducted with adults aged 60 years or older with long-duration type 1 diabetes who participated in a randomised, open-label, two-stage crossover trial comparing first-generation closed-loop therapy (MiniMed 670G) versus sensor-augmented pump therapy. Interview recordings were transcribed, thematically analysed and assessed. RESULTS: Twenty-one older adults participated in interviews after using closed-loop therapy. Twenty were functionally independent, without frailty or major cognitive impairment; one was dependent on caregiver assistance, including for diabetes management. Quality of life benefits were identified, including improved sleep and reduced diabetes-related psychological burden, in the context of experiencing improved glucose levels. Gaps between expectations and reality of closed-loop therapy were also experienced, encountering disappointment amongst some participants. The cost was perceived as a barrier to continued closed-loop access post-trial. Usability issues were identified, such as disruptive overnight alarms and sensor inaccuracy. CONCLUSIONS: The lived experience of older adults without frailty or major cognitive impairment using first-generation closed-loop therapy was mainly positive and concordant with glycaemic benefits found in the trial. Older adults' lived experience using automated insulin delivery beyond trial environments requires exploration; moreover, the usability needs of older adults should be considered during future device development.

Diabetes IN hospital - Glucose and Outcomes in the COVID-19 pandemic (DINGO COVID-19): the 2020 Melbourne hospital experience prior to novel variants and vaccinations.

BACKGROUND AND AIMS: A relationship between diabetes, glucose and COVID-19 outcomes has been reported in international cohorts. This study aimed to assess the relationship between diabetes, hyperglycaemia and patient outcomes in those hospitalised with COVID-19 during the first year of the Victorian pandemic prior to novel variants and vaccinations. DESIGN, SETTING: Retrospective cohort study from March to November 2020 across five public health services in Melbourne, Australia. PARTICIPANTS: All consecutive adult patients admitted to acute wards of participating institutions during the study period with a diagnosis of COVID-19, comprising a large proportion of patients from residential care facilities and following dexamethasone becoming standard-of-care. Admissions in patients without known diabetes and without inpatient glucose testing were excluded. RESULTS: The DINGO COVID-19 cohort comprised 840 admissions. In 438 admissions (52%), there was no known diabetes or in-hospital hyperglycaemia, in 298 (35%) patients had known diabetes, and in 104 (12%) patients had hyperglycaemia without known diabetes. ICU admission was more common in those with diabetes (20%) and hyperglycaemia without diabetes (49%) than those with neither (11%, P < 0.001 for all comparisons). Mortality was higher in those with diabetes (24%) than those without diabetes or hyperglycaemia (16%, P = 0.02) but no difference between those with in-hospital hyperglycaemia and either of the other groups. On multivariable analysis, hyperglycaemia was associated with increased ICU admission (adjusted odds ratio (aOR) 6.7, 95% confidence interval (95% CI) 4.0-12, P < 0.001) and longer length of stay (aOR 173, 95% CI 11-2793, P < 0.001), while diabetes was associated with reduced ICU admission (aOR 0.55, 95% CI 0.33-0.94, P = 0.03). Neither diabetes nor hyperglycaemia was independently associated with in-hospital mortality. CONCLUSIONS: During the first year of the COVID-19 pandemic, in-hospital hyperglycaemia and known diabetes were not associated with in-hospital mortality, contrasting with published international experiences. This likely mainly relates to hyperglycaemia indicating receipt of mortality-reducing dexamethasone therapy. These differences in published experiences underscore the importance of understanding population and clinical treatment factors affecting glycaemia and COVID-19 morbidity within both local and global contexts.

Glucose profiles of older adults with type 1 diabetes using sensor-augmented pump therapy in Australia: pre-randomisation results from the ORACL study.

BACKGROUND: Older adults with type 1 diabetes are recommended modified glucose targets. However, data on the effects of diabetes technology in older age are scarce. We assessed older adults established on sensor-augmented insulin pump therapy during clinical trial run-in and compared their continuous glucose monitoring (CGM) profiles with consensus recommendations. We aimed to provide insight into the applicability of currently recommended CGM-based targets while accounting for current Diabetes UK guidelines. METHODS: In this analysis, adults aged 60 years or older with type 1 diabetes with a duration of at least 10 years and entering the Older Adult Closed Loop (ORACL) trial were studied. The trial was done at two tertiary hospitals in Australia. Individuals who were independent with diabetes self-management, as well as those receiving caregiver assistance for their diabetes management, were eligible for inclusion. Participants underwent baseline clinical assessment, which included medical history and examination, testing for frailty, functional ability, cognitive functioning, psychosocial wellbeing, and subjective sleep quality; fasting venous blood samples were collected for C-peptide, glucose, and glycated haemoglobin A1c measurement. Sensor-augmented pumps, carbohydrate-counting education, and diabetes education were provided to participants by diabetes nurse educators, dietitians, and endocrinologists experienced in type 1 diabetes clinical care. CGM data were subsequently collected for 2 weeks during sensor-augmented pump therapy. The ORACL trial is registered with the Australian New Zealand Clinical Trial Registry, ACTRN12619000515190. FINDINGS: Our analysis included all 30 participants who completed the ORACL trial run-in-19 (63%) women and 11 (37%) men (mean age 67 years [SD 5], median diabetes duration 38 years [IQR 20-47], and insulin total daily dose 0·55 units [0·41-0·66] per kg bodyweight). Ten (33%) of 30 participants had impaired hypoglycaemia awareness and six (20%) were pre-frail; none were frail. The median CGM time in range 3·9-10·0 mmol/L was 71% (IQR 64-79). The time spent with glucose above 10·0 mmol/L was 27% (18-35) and above 13·9 mmol/L was 3·9% (2·4-10·2). The time with glucose below 3·9 mmol/L was 2·0% (1·2-3·1) and the time below 3·0 mmol/L was 0·2% (0·1-0·4). Only two (7%) of 30 participants met all CGM-based consensus recommendations modified for older adults. Time in hypoglycaemia was lower among the 16 participants with predictive low-glucose alerts enabled than among the 14 participants not using predictive low-glucose alerts (median difference -1·1 percentage points [95% CI -2·0 to -0·1]; p=0·038). This difference was even greater overnight (-2·3 percentage points [-3·2 to -1·0]; p=0·0018). One serious adverse event occurred (elective cardiac stent). INTERPRETATION: Using sensor-augmented pumps after multidisciplinary education, this group of older adults without frailty achieved a time in range far exceeding minimum consensus recommendations. However, the current stringent hypoglycaemia recommendations for all older adults were not met. Predictive low alerts could reduce hypoglycaemia, particularly overnight. Investigation into the effectiveness of CGM-based targets that consider frailty, functional status, and diabetes therapies for older adults is warranted. FUNDING: JDRF and Diabetes Australia.

Late Afternoon Vigorous Exercise Increases Postmeal but Not Overnight Hypoglycemia in Adults with Type 1 Diabetes Managed with Automated Insulin Delivery.

Aim: To compare evening and overnight hypoglycemia risk after late afternoon exercise with a nonexercise control day in adults with type 1 diabetes using automated insulin delivery (AID). Methods: Thirty adults with type 1 diabetes using AID (Minimed 670G) performed in random order 40 min high intensity interval aerobic exercise (HIE), resistance (RE), and moderate intensity aerobic exercise (MIE) exercise each separated by >1 week. The closed-loop set-point was temporarily increased 2 h pre-exercise and a snack eaten if plasma glucose was ≤126 mg/dL pre-exercise. Exercise commenced at ∼16:00. A standardized meal was eaten at ∼20:40. Hypoglycemic events were defined as a continuous glucose monitor (CGM) reading <70 mg/dL for ≥15 min. Four-hour postevening meal and overnight (00:00-06:00) CGM metrics for exercise were compared with the prior nonexercise day. Results: There was no severe hypoglycemia. Between 00:00 and 06:00, the proportion of nights with hypoglycemia did not differ postexercise versus control for HIE (18% vs. 11%; P = 0.688), RE (4% vs. 14%; P = 0.375), and MIE (7% vs. 14%; P = 0.625). Time in range (TIR) (70-180 mg/dL), >75% for all nights, did not differ between exercise conditions and control. Hypoglycemia episodes postmeal after exercise versus control did not differ for HIE (22% vs. 7%; P = 0.219) and MIE (10% vs. 14%; P > 0.999), but were greater post-RE (39% vs. 10%; P = 0.012). Conclusions: Overnight TIR was excellent with AID without increased hypoglycemia postexercise between 00:00 and 06:00 compared with nonexercise days. In contrast, hypoglycemia risk was increased after the first meal post-RE, suggesting the importance of greater vigilance and specific guidelines for meal-time dosing, particularly with vigorous RE. ACTRN12618000905268.