Timothy S. Bailey

Importance: Hypercortisolism is an underdiagnosed contributor to metabolic dysfunction in people with Type 2 diabetes (T2D). Although overt Cushing syndrome is rare, milder forms of cortisol excess, commonly termed mild autonomous cortisol secretion (MACS), appear substantially more common in selected high‐risk populations. Observations: Chronic cortisol excess contributes directly to insulin resistance, hepatic gluconeogenesis, visceral adiposity, hypertension, dyslipidaemia and cardiovascular disease. Many patients with hypercortisolism lack classic cushingoid features and instead present with resistant diabetes, resistant hypertension, obesity or progressive cardiometabolic disease. Emerging evidence suggests that abnormal cortisol suppression following a 1‐mg overnight dexamethasone suppression test (DST) occurs more frequently in patients with difficult‐to‐control T2D and resistant hypertension than previously appreciated. Current evidence supports a targeted case‐finding approach rather than universal screening. Patients most likely to benefit from evaluation include those with persistent hyperglycaemia despite intensive therapy, severe insulin resistance, resistant hypertension, adrenal incidentalomas or physical findings suggestive of cortisol excess. The overnight 1‐mg DST remains the preferred initial screening test because it is practical, inexpensive and widely available. Interpretation is supported by a confirmatory dexamethasone level ≥ 140 ng/dL and requires careful consideration of medication interactions, obesity, psychiatric disease, alcohol use, sleep disorders and assay variability. Conclusions and Relevance: Hypercortisolism likely contributes to metabolic dysfunction in a subset of patients with T2D, particularly those with resistant cardiometabolic disease. Recognition of high‐risk phenotypes and appropriate use of the DST may improve identification of patients with potentially treatable cortisol excess. Additional prospective studies are needed to clarify optimal screening strategies and determine whether earlier diagnosis and treatment improve long‐term cardiometabolic outcomes.

Background: Continuous glucose monitors (CGM) are increasingly being used to manage diabetes. We evaluated the performance and safety of an investigational 15-day G7 integrated CGM (iCGM; Dexcom) in adults with diabetes. Methods: This prospective, multicenter study enrolled adults (age ≥18 years) with type 1 diabetes (T1D) or type 2 diabetes (T2D) at six clinical sites in the United States. Four in-clinic visits were conducted on days 1–3, 4–7, 9–12, and 13–15.5, with frequent arterialized venous blood draws for comparator measurements using a Yellow Springs Instrument (YSI) 2300 Stat Plus glucose analyzer. Participants with T1D or T2D using intensive insulin therapy participated in clinic sessions with deliberate, closely monitored glucose manipulations. Accuracy evaluations included the mean absolute relative difference (MARD), proportion of CGM values within 15 mg/dL of YSI values <70 mg/dL or within 15% of YSI values ≥70 mg/dL (%15/15), as well as %20/20, %30/30, and %40/40 agreement rates. Performance related to iCGM special controls, user experience, and device safety were also assessed. Results: The study enrolled 130 adults with diabetes (mean ± standard deviation age 43.0 ± 14.4 years, 53.1% female, 86.9% with T1D) and analyzed 20,310 CGM-YSI matched pairs from 130 15-day G7 CGM devices. The overall MARD was 8.0% and the %15/15, %20/20, %30/30, and %40/40 agreement rates were 87.7%, 94.2%, 98.9%, and 99.8%, respectively. The device exceeded iCGM performance goals, and user experiences were broadly positive. No serious adverse events were reported. Conclusions: The 15-day G7 iCGM was accurate and safe in adults with diabetes throughout the 15.5-day wear period. Clinicaltrials.gov: NCT05263258.

The implanted Eversense Continuous Glucose Monitoring (CGM) System transitioned from 90- to 180- to 365-day durations marketed today. This report summarizes the 365-day clinical study. ENHANCE was a prospective, multicenter study evaluating the accuracy and safety of the Eversense 365 CGM system through 1 year in adults with diabetes. Accuracy and adverse events (AEs) were assessed during 14 in-clinic visits comparing CGM and Yellow Springs Instrument reference glucose measurements, including during hyperglycemia and hypoglycemia challenges. In total, 110 participants were implanted with the Eversense 365 CGM System. The overall mean absolute relative difference was 8.8% with primarily one calibration per week. The confirmed alert detection rate at 70 mg/dL was 96.6%, and at 180 mg/dL, it was 97.9%. Ninety percent of the sensors survived 365 days. Interoperable CGM special controls were met. No related serious AEs were reported. The Eversense 365 CGM was shown to be safe and accurate through 1 year with primarily one calibration per week.

Introduction: An error grid compares measured versus reference glucose concentrations to assign clinical risk values to observed errors. Widely used error grids for blood glucose monitors (BGMs) have limited value because they do not also reflect clinical accuracy of continuous glucose monitors (CGMs). Methods: Diabetes Technology Society (DTS) convened 89 international experts in glucose monitoring to (1) smooth the borders of the Surveillance Error Grid (SEG) zones and create a user-friendly tool—the DTS Error Grid; (2) define five risk zones of clinical point accuracy (A-E) to be identical for BGMs and CGMs; (3) determine a relationship between DTS Error Grid percent in Zone A and mean absolute relative difference (MARD) from analyzing 22 BGM and nine CGM accuracy studies; and (4) create trend risk categories (1-5) for CGM trend accuracy. Results: The DTS Error Grid for point accuracy contains five risk zones (A-E) with straight-line borders that can be applied to both BGM and CGM accuracy data. In a data set combining point accuracy data from 18 BGMs, 2.6% of total data pairs equally moved from Zones A to B and vice versa (SEG compared with DTS Error Grid). For every 1% increase in percent data in Zone A, the MARD decreased by approximately 0.33%. We also created a DTS Trend Accuracy Matrix with five trend risk categories (1-5) for CGM-reported trend indicators compared with reference trends calculated from reference glucose. Conclusion: The DTS Error Grid combines contemporary clinician input regarding clinical point accuracy for BGMs and CGMs. The DTS Trend Accuracy Matrix assesses accuracy of CGM trend indicators.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are 300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

Use of innovative technologies such as continuous glucose monitoring (CGM) and insulin delivery systems have been shown to be safe and effective in helping patients with diabetes achieve significantly improved glycemic outcomes compared to their previous therapies. However, these technologies are underutilized in many primary care practices. This narrative review discusses some of the clinical and economic benefits of tubeless insulin delivery devices and discusses how this technology can overcome the main obstacles inherent to use of conventional insulin delivery devices.

Background: SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin. Methods: This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters. Results: Of the 210 patients randomized, 200 (95.5%) completed the trial. Patients assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square [LS] mean difference = 0.05% [95% confidence interval [CI] = −0.13, 0.22]; 0.50 mmol/mol [−1.40, 2.39]), fasting plasma glucose (LS mean difference = 0.23 mmol/L [95% CI = −1.08, 1.53]; 4.12 mg/dL [−19.38, 27.62]), and changes in insulin dosages. Conclusions: Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports interchangeability between SAR-Asp and NN-Asp in T1D management.

Aim: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR‐Asp) and the insulin aspart reference product (NovoLog; NN‐Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN‐Asp in adults with type 1 diabetes (T1D). Materials and Methods: This multicentre, open‐label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once‐daily insulin glargine U100 as basal insulin to four 4‐week periods of alternating multiple daily injections of SAR‐Asp and NN‐Asp (NN‐Asp for the first 4 weeks, SAR‐Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN‐Asp (non‐switching group). At week 16, a single dose (0.15 U/kg) of SAR‐Asp in the switching group ( n = 95) or NN‐Asp in the non‐switching group ( n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (C _max ) of SAR‐Asp versus NN‐Asp after the single dose at week 16. Results: The extent of PK exposure was similar between the two treatments (SAR‐Asp in the switching group and NN‐Asp in the non‐switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8‐1.25. For C _max in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8‐1.25. Conclusions: PK exposure of SAR‐Asp (switching group) and reference NN‐Asp (non‐switching group) were similar, supporting interchangeability between these two insulin aspart products.