Predicting Factors Associated with Hypoglycemia Reduction with Automated Predictive Insulin Suspension in Patients at High Risk of Severe Hypoglycemia: An Analysis from the SMILE Randomized Trial

Background: This analysis from the SMILE randomized study was performed to identify predictive factors associated with the greatest reductions in hypoglycemia with the Medtronic MiniMed™ 640G Suspend before low feature in adults with type 1 diabetes at high risk of severe hypoglycemia. Methods: Clinical and treatment-related factors associated with decreased sensor hypoglycemia (SH) were identified in participants from the intervention arm by univariate and multivariate analyses. Results: The reduction in SH events <54 mg/dL (<3.0 mmol/L) in the intervention group was significantly (P < 0.0001) associated with the baseline mean number of sensor hypoglycemic events (MNSHE) <54 mg/dL. When excluding continuous glucose monitoring (CGM) factors not readily available (MNSHE, duration of SH events, area under the curve, mean amplitude of glycemic excursions), only the baseline mean time spent <54 mg/dL was found to be a significant independent predictor factor (P < 0.0001). Baseline HbA1c, mean self-monitoring of blood glucose (SMBG), and coefficient of variation of SMBG were significant, although weak, predictors in the absence of any CGM data. Conclusions: The greatest reductions in SH events achieved with the MiniMed 640G system with the Suspend before low feature were seen in participants with higher baseline MNSHE. Measuring these (usually uncollected) events can be a useful tool to predict hypoglycemia reduction. ClinicalTrials.gov Registration Identifier NCT02733991

Advanced hybrid closed loop therapy versus conventional treatment in adults with type 1 diabetes (ADAPT): a randomised controlled study

Background: Adults with type 1 diabetes who are treated with multiple daily injections of insulin plus intermittently scanned continuous glucose monitoring (isCGM) can have suboptimal glucose control. We aimed to assess the efficacy of an advanced hybrid closed loop (AHCL) system compared with such therapy in this population. Methods: The Advanced Hybrid Closed Loop Study in Adult Population with Type 1 Diabetes (ADAPT) trial is a prospective, multicentre, open-label, randomised controlled trial that involved 14 centres in three European countries (France, Germany, and the UK). We enrolled patients who were at least 18 years of age, had a type 1 diabetes duration of at least 2 years, HbA1c of at least 8% (64 mmol/mol), and were using multiple daily injections of insulin plus isCGM (cohort A) or real time continuous glucose monitoring (cohort B) for at least 3 months. Here, only results for cohort A are reported. Participants were randomly allocated 1:1 to AHCL therapy or continuation of multiple daily injections of insulin plus continuous glucose monitoring for 6 months with an investigator-blinded block randomisation procedure. Participants and treating clinicians could not be masked to the arm assignment. The primary endpoint was the between-group difference in mean HbA1c change from baseline to 6 months in the intention-to-treat population using AHCL therapy and those using multiple daily injections of insulin plus isCGM. The primary endpoint was analysed using a repeated measures random-effects model with the study arm and period as factors. Safety endpoints included the number of device deficiencies, severe hypoglycaemic events, diabetic ketoacidosis, and serious adverse events. This study is registered with ClinicalTrials.gov, NCT04235504. Findings: Between July 13, 2020, and March 12, 2021, 105 people were screened and 82 randomly assigned to treatment (41 in each arm). At 6 months, mean HbA1c had decreased by 1·54% (SD 0·73), from 9·00% to 7·32% in the AHCL group and 0·20% (0·80) in the multiple daily injections of insulin plus isCGM from 9·07% to 8·91% (model-based difference −1·42%, 95% CI −1·74 to −1·10; p<0·0001). No diabetic ketoacidosis, severe hypoglycaemia, or serious adverse events related to study devices occurred in either group; two severe hypoglycaemic events occurred in the run-in phase. 15 device-related non-serious adverse events occurred in the AHCL group, compared with three in the multiple daily injections of insulin plus isCGM group. Two serious adverse events occurred (one in each group), these were breast cancer (in one patient in the AHCL group) and intravitreous haemorrhage (in one patient in the multiple daily injections of insulin plus isCGM group). Interpretation: In people with type 1 diabetes using multiple daily injections of insulin plus isCGM and with HbA1c of at least 8%, the use of AHCL confers benefits in terms of glycaemic control beyond those that can be achieved with multiple daily injections of insulin plus isCGM. These data support wider access to AHCL in people with type 1 diabetes not at target glucose levels. Funding: Medtronic International Trading Sàrl

Twelve-month results of the ADAPT randomized controlled trial: Reproducibility and sustainability of advanced hybrid closed-loop therapy outcomes versus conventional therapy in adults with type 1 diabetes

Aims To reassess the 6-month efficacy and to assess the 12-month sustained efficacy of the MiniMed™ 780G advanced hybrid closed-loop automated insulin delivery (AID) system compared to multiple daily injections plus intermittently scanned glucose monitoring (MDI+isCGM) in people with type 1 diabetes not meeting glucose targets. Methods The ADAPT study was a prospective, multicentre, open-label, randomized control trial in people with type 1 diabetes, with a glycated haemoglobin (HbA1c) concentration of at least 8.0% (64 mmol/mol), on MDI+isCGM therapy. After a 6-month study phase, participants randomized at baseline to MDI+isCGM switched to AID (SWITCH) while the others continued AID therapy (SUSTAIN) for an additional 6 months. The primary endpoint of this continuation phase was the within-group change in mean HbA1c between 6 and 12 months, with superiority in the SWITCH group and noninferiority in the SUSTAIN group (ClinicalTrials.gov: NCT04235504). Results A total of 39 SWITCH and 36 SUSTAIN participants entered the continuation phase. In the SWITCH group, HbA1c was significantly decreased by −1.4% (95% confidence interval [CI] −1.7% to −1.1%; P  Conclusion ADAPT study phase glycaemic improvements were reproduced and sustained in the continuation phase, supporting the early adoption of AID therapy in people with type 1 diabetes not meeting glucose targets on MDI therapy.</p

Correction: The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel-like factor 5 (KLF5)-dependent manner (Journal of Biological Chemistry)

Correction: The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel-like factor 5 (KLF5)-dependent manner (Journal of Biological Chemistry

The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel-like Factor 5 (KLF5)-defendent manner

The histone deacetylase inhibitor (HDACi) sodium butyrate promotes differentiation of colon cancer cells as evidenced by induced expression and enzyme activity of the differentiation marker intestinal alkaline phosphatase (ALPi). Screening of a panel of 33 colon cancer cell lines identified cell lines sensitive (42%) and resistant (58%) to butyrate induction of ALP activity. This differential sensitivity was similarly evident following treatment with the structurally distinct HDACi, MS-275. Resistant cell lines were significantly enriched for those harboring the CpG island methylator phenotype (p = 0.036, Chi square test), and resistant cell lines harbored methylation of the ALPi promoter, particularly of a CpG site within a critical KLF/Sp regulatory element required for butyrate induction of ALPi promoter activity. However, butyrate induction of an exogenous ALPi promoter-reporter paralleled up-regulation of endogenous ALPi expression across the cell lines, suggesting the presence or absence of a key transcriptional regulator is the major determinant of ALPi induction. Through microarray profiling of sensitive and resistant cell lines, we identified KLF5 to be both basally more highly expressed as well as preferentially induced by butyrate in sensitive cell lines. KLF5 overexpression induced ALPi promoter-reporter activity in resistant cell lines, KLF5 knockdown attenuated butyrate induction of ALPi expression in sensitive lines, and butyrate selectively enhanced KLF5 binding to the ALPi promoter in sensitive cells. These findings demonstrate that butyrate induction of the cell differentiation marker ALPi is mediated through KLF5 and identifies subsets of colon cancer cell lines responsive and refractory to this effect