Functional insulin therapy in type 1 diabetics: Short-term effects on weight and nutritional intake.

INTRODUCTION-AIM: Flexible insulin therapy is currently considered the gold standard therapy of type 1 diabetes. We aimed to study the evolution of glycemic control, weight and nutritional intake of a group of patients with type 1 diabetes, three months after the initiation of functional insulin therapy (FIT). METHODS: This was a prospective longitudinal study having included 30 type 1 diabetic patients hospitalized for education to FIT. Each patient underwent an assessment of glycemic control (glycated hemoglobin (A1C) and number of hypoglycemia), weight and nutritional intake before FIT and 3 months after the initiation of this educative approach. RESULTS: The mean age of patients was 21,8 ± 7,9 years and the sex ratio was 0,5. The mean duration of diabetes was 7,2 ± 6 years. Three months after initiation of FIT, we observed a significant lowering of A1C, which went from 9,2 ± 1,6% to 8,3 ± 1,4% (p<0,001) of the number of minor hypoglycemia (p=0,001) and that of severe hypoglycemia (p= 0,021). the average weight went from 64,6 ± 13,1 kg to 65,5 ± 13,5 kg (p = 0,040) with a significant increase in BMI (p = 0,041). Weight gain was observed in 67% of patients. This weight gain contrasted with a significant decrease in caloric (p = 0,040) and in carbohydrates intakes (p = 0,027). CONCLUSION: Weight gain, associated with better glycemic control, should encourage the healthcare team to strengthen therapeutic education of patients undergoing FIT in order to limit weight gain.

Clinical perspectives on the frequency of hypoglycemia in treat-to-target randomized controlled trials comparing basal insulin analogs in type 2 diabetes: a narrative review.

The objective of this review was to comprehensively present and summarize trends in reported rates of hypoglycemia with one or two times per day basal insulin analogs in individuals with type 2 diabetes to help address and contextualize the emerging theoretical concern of increased hypoglycemic risk with once-weekly basal insulins.Hypoglycemia data were extracted from treat-to-target randomized clinical trials conducted during 2000-2022. Published articles were identified on PubMed or within the US Food and Drug Administration submission documents. Overall, 57 articles were identified: 44 assessed hypoglycemic outcomes in participants receiving basal-only therapy (33 in insulin-naive participants; 11 in insulin-experienced participants), 4 in a mixed population (insulin-naive and insulin-experienced participants) and 9 in participants receiving basal-bolus therapy. For the analysis, emphasis was placed on level 2 (blood glucose <3.0 mmol/L (<54 mg/dL)) and level 3 (or severe) hypoglycemia.Overall, event rates for level 2 or level 3 hypoglycemia across most studies ranged from 0.06 to 7.10 events/person-year of exposure (PYE) for participants receiving a basal-only insulin regimen; the rate for basal-bolus regimens ranged from 2.4 to 13.6 events/PYE. Rates were generally lower with second-generation basal insulins (insulin degludec or insulin glargine U300) than with neutral protamine Hagedorn insulin or first-generation basal insulins (insulin detemir or insulin glargine U100). Subgroup categorization by sulfonylurea usage, end-of-treatment insulin dose or glycated hemoglobin reduction did not show consistent trends on overall hypoglycemia rates. Hypoglycemia rates reported so far for once-weekly basal insulins are consistent with or lower than those reported for daily-administered basal insulin analogs.

Is polyethylene glycol loxenatide 100 µg the preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus? A meta-analysis and trial sequential analysis.

OBJECTIVE: This study aimed to systematically evaluate the efficacy, safety and optimal dose of polyethylene glycol loxenatide (PEX168) for treating type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Clinical trials of PEX168 for T2DM were identified in 8 databases, with a build time limit of January 2023. Included studies were subjected to meta-analysis and trial sequential analysis (TSA). RESULTS: On the efficacy endpoint, the meta-analysis showed that PEX168 100 µg significantly reduced 0.86% glycated hemoglobin type A1c (HbA1c) (MD -0.86, 95% CI -1.02 - -0.70,  p<0.00001), 1.11 mmol/L fasting plasma glucose (FPG) (MD -1.11, 95% CI -1.49 - -0.74, p<0.00001) and 1.91 mmol/L 2h postprandial glucose (PPG) (MD -1.91, 95% CI -3.35 - -0.46, p=0.01) compared with placebo. The TSA showed that all these benefits were conclusive. On safety endpoints, total adverse events (AEs), gastrointestinal (GI) AEs, serious AEs, and hypoglycemia were comparable to placebo for PEX168 100 µg (p>0.05). In the dose comparison, the HbA1c, FPG, and 2h PPG of PEX168 200 µg were comparable to 100 µg (p>0.05), while GI AEs were significantly higher than 100 µg (RR=2.84, 95% CI 1.64-4.93,  p=0.0002). CONCLUSIONS: PEX168 100 µg can significantly lower blood glucose and does not increase the risk of total AEs, GI AEs, and hypoglycemia, which may be a preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus.

Effectiveness of hospital-based oral dextrose gel in prevention and treatment of asymptomatic newborns at risk of hypoglycemia.

OBJECTIVE: To evaluate the effectiveness of using hospital-based 40% dextrose gel (DG) in preventing and treating asymptomatic hypoglycemia in infants of diabetic mothers (IDM), large for gestational age (LGA), and macrosomic neonates. METHODS: A medical chart review was conducted to compare data between before (April 2018 to March 2019, epoch 1) and after (September 2020 to November 2021, epoch 2) 40% DG implementation. DG, prepared by the hospital pharmaceutical unit, was applied within 30-45 min after birth, and three additional doses could be repeated during the first 6 h of life in combination with early feeding. The primary outcome was the rate of intravenous dextrose administration. Secondary outcomes were the incidence of hypoglycemia, first capillary blood glucose concentrations, and the length of hospital stay. RESULTS: Six hundred forty-three at-risk newborns were included (320 before and 323 after implementation of DG). Maternal and neonatal baseline characteristics were not different between the two epochs. The incidence of hypoglycemia was not different (17.8% in before versus 14.6% in after implementation, p = 0.26). The rate of intravenous dextrose administration after DG implementation was significantly lower than that before DG implementation (3.4% versus 10.3%, p < 0.001, risk reduction ratio = 0.33, 95% CI = 0.17-0.64). The length of hospital stay was not different between the two epochs. CONCLUSIONS: Implementing a protocol for administration of hospital-based 40% DG can reduce the need of intravenous dextrose administration among IDM, LGA and macrosomic neonates.

Comparing Equil patch versus traditional catheter insulin pump in type 2 diabetes using continuous glucose monitoring metrics and profiles.

AIMS: It is not clear whether there are differences in glycemic control between the Equil patch and the MMT-712 insulin pump. Our objective was to compare two types of insulin pumps in the treatment of type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM) metrics and profiles. METHODS: This was a randomized case-crossover clinical trial. Participants were hospitalized and randomly allocated to two groups and underwent two types of insulin pump treatments (group A: Equil patch-Medtronic MMT-712 insulin pump; group B: Medtronic MMT-712-Equil patch insulin pump) separated by a 1-day washout period. Glycemic control was achieved after 7-8 days of insulin pump therapy. Each patient received CGM for 5 consecutive days (from day 1 to day 5). On day 3 of CGM performance, the Equil patch insulin pump treatment was switched to Medtronic MMT-712 insulin pump treatment at the same basal and bolus insulin doses or vice versa. CGM metrics and profiles including glycemic variability (GV), time in range (TIR, 3.9-10.0 mmol/L), time below range (TBR, <3.9 mmol/L), time above range (TAR, >10.0 mmol/L), and postprandial glucose excursions, as well as incidence of hypoglycemia. RESULTS: Forty-six T2DM patients completed the study. There was no significant difference in parameters of daily GV and postprandial glucose excursions between the Equil patch insulin pump treatment and the Medtronic insulin pump treatment. Similarly, there was no between-treatment difference in TIR, TBR, and TAR, as well as the incidence of hypoglycemia. CONCLUSION: The Equil patch insulin pump was similar to the traditional MMT-712 insulin pump in terms of glycemic control. Equil patch insulin pump is a reliable tool for glycemic management of diabetes mellitus.

Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians.

BACKGROUND: Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. PURPOSE: To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). DATA SOURCES: MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. STUDY SELECTION: RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. DATA EXTRACTION: Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. DATA SYNTHESIS: A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). LIMITATIONS: Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. CONCLUSION: In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42022322129).

Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

Aim: The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. Methods: A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Results: Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. Conclusion: The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Efficacy and safety of sitagliptin with basal-plus insulin regimen versus insulin alone in non-critically ill hospitalized patients with type 2 diabetes: SITA-PLUS hospital trial.

AIMS: To compare the efficacy and safety of basal-plus (BP) insulin regimen with or without sitagliptin in non-critically ill patients with type 2 diabetes (T2D). METHODS: This open-label, randomized clinical trial included inpatients with a previous diagnosis of T2D and blood glucose (BG) between 180 and 400 mg/dL. Participants received basal and correctional insulin doses (BP regimen) either with or without sitagliptin. The primary outcome was the difference in the mean daily BG among the groups. RESULTS: Seventy-six patients (mean age 60 years, 64 % men) were randomized. Compared with BP insulin therapy alone, the sitagliptin-BP combination led to a lower mean daily BG (158.8 vs 175.0 mg/dL, P = 0.014), a higher percentage of readings within a BG range of 70-180 mg/dL (75.9 % vs 64.7 %, P < 0.001), and a lower number of BG readings >180 mg/dL (P < 0.001). Sitagliptin-BP resulted in fewer basal and supplementary insulin doses (P = 0.024 and P = 0.017, respectively) and lower daily insulin injections (P = 0.023) than those with insulin alone. The proportion of patients with hypoglycemia was similar in the two groups. CONCLUSIONS: For inpatients with T2D and hyperglycemia, the sitagliptin and BP regimen combination is safe and more effective than insulin therapy alone. CLINICALTRIALS: gov identifier: NCT05579119.

Refractory Hypoglycemia Due to Sulfonylurea Contamination of Illicit Opioid Medications.

Illicit drug supply adulteration can heighten the risk for adverse health outcomes. Sulfonylurea medications are widely used in the treatment of diabetes mellitus (DM). Unintentional or intentional overdose of sulfonylureas can cause refractory hypoglycemia. This case report describes a 62-year-old male patient who presented to the emergency department (ED) after being found on the ground with signs of mild trauma. He was noted to be persistently hypoglycemic despite boluses of intravenous dextrose, a dextrose infusion, and oral nutrition. The patient did report purchase and oral ingestion of pills sold as oxycodone and that the pill shape and color were different from his usual supply. The patient was empirically treated with octreotide resulting in normalization of his serum glucose. Testing demonstrated a serum glipizide concentration six times the reporting range. This case represents unintentional sulfonylurea exposure in the setting of non-prescribed oxycodone use, resulting in hypoglycemia refractory to intravenous dextrose and oral nutrition. Octreotide is an additional potential treatment for this condition. As in this case, ingestion of street drugs may present a potential source of sulfonylurea exposure. Opioid contamination with sulfonylureas has not been widely reported in the literature and knowledge about this potential exposure is important for the prompt recognition and treatment of these patients by emergency physicians.

Effects of Switching from Degludec to Glargine U300 in Patients with Insulin-Dependent Type 1 Diabetes: A Retrospective Study.

Background and Objectives: Degludec (Deg) and glargine U300 (Gla-300) are insulin analogs with longer and smoother pharmacodynamic action than glargine U100 (Gla-100), a long-acting insulin that has been widely used for many years in type 1 and type 2 diabetes. Both improve glycemic variability (GV) and the frequency of hypoglycemia, unlike Gla-100. However, it is unclear which insulin analog affects GV and hypoglycemia better in patients with insulin-dependent type 1 diabetes. We evaluated the effects of switching from Deg to Gla-300 on the day-to-day GV and the frequency of hypoglycemia in patients with insulin-dependent type 1 diabetes treated with Deg-containing basal-bolus insulin therapy (BBT). Materials and Methods: We conducted a retrospective study on 24 patients with insulin-dependent type 1 diabetes whose treatment was switched from Deg-containing BBT to Gla-300-containing BBT. We evaluated the day-to-day GV measured as the standard deviation of fasting blood glucose levels (SD-FBG) calculated by the self-monitoring of blood glucose records, the frequency of hypoglycemia (total, severe, and nocturnal), and blood glucose levels measured as fasting plasma glucose (FPG) levels and hemoglobin A1c (HbA1c). Results: The characteristics of the patients included in the analysis with high SD-FBG had frequent hypoglycemic events, despite the use of Deg-containing BBT. For this population, SD-FBG and the frequency of nocturnal hypoglycemia decreased after the switch from Deg to Gla-300. Despite the decrease in the frequency of nocturnal hypoglycemia, the FPG and HbA1c did not worsen by the switch. The change in the SD-FBG had a negative correlation with the SD-FBG at baseline and a positive correlation with serum albumin levels. Conclusions: Switching from Deg to Gla-300 improved the SD-FBG and decreased the frequency of nocturnal hypoglycemia in insulin-dependent type 1 diabetes treated with Deg-containing BBT, especially in cases with low serum albumin levels and a high GV.

Management of Outpatients With Diabetes at High Risk of Hypoglycemia.

This JAMA Clinical Guidelines Synopsis summarizes the Endocrine Society's 2023 recommendations on management of outpatients with diabetes and high risk of hypoglycemia.

Association Between Intrapartum Nitrous Oxide for Labor Analgesia and Short-Term Neonatal Outcomes.

OBJECTIVE: To evaluate the association between intrapartum nitrous oxide use and adverse short-term neonatal outcomes. METHODS: This was a retrospective cohort study of individuals with singleton gestations at 35 or more weeks who attempted labor and delivered at an academic hospital between June 1, 2015, and February 28, 2020. Data were extracted from the electronic medical record using billing and diagnostic codes. Patients were classified based on whether they received no intrapartum analgesia or received nitrous oxide only. Those who received other analgesia types were excluded. The primary outcome was neonatal intensive care unit (NICU) admission. Secondary outcomes included Apgar score less than 7 at 1 minute and 5 minutes, respiratory composite outcome (including meconium aspiration syndrome, neonatal bronchopulmonary disorders, neonatal transient tachypnea, and other neonatal respiratory distress that required NICU admission), hypoglycemia, and hyperbilirubinemia. Univariable and multivariable analyses were used to estimate the association between nitrous oxide exposure intrapartum and the selected outcomes. RESULTS: Of 6,047 included, 4,153 (68.7%) received no analgesia, and 1,894 (31.3%) received nitrous oxide only. In comparison with individuals who received no analgesia, those who received nitrous oxide were more likely to be nulliparous, be of Black racial identity, have noncommercial insurance, and be less likely to deliver by intrapartum cesarean. The reception of nitrous oxide, compared with the reception of no analgesia, was associated with a lower likelihood of NICU admission (6.4% vs 8.1%; adjusted odds ratio [aOR] 0.77, 95% CI, 0.62-0.96) and an increased likelihood of neonatal hyperbilirubinemia (aOR 1.23, 95% CI, 1.08-1.41). Inhaled nitrous oxide exposure, in comparison with the reception of no analgesia, was not associated with the other secondary outcomes, including Apgar score less than 7 at 1 minute (odds ratio [OR] 0.74, 95% CI, 0.50-1.10) or 5 minutes (OR 0.91, 95% CI, 0.32-2.60), respiratory composite outcome (OR 0.91, 95% CI, 0.70-1.17), and hypoglycemia (OR 0.82, 95% CI, 0.64-1.05). CONCLUSION: In this single-center retrospective cohort of low-risk patients, intrapartum inhaled nitrous oxide, compared with the reception of no analgesia, was associated with a decreased risk for NICU admission but with an increased risk for hyperbilirubinemia; other outcomes did not differ. These findings may be used to counsel patients when considering nitrous oxide for labor analgesia.

Balancing efficacy and adverse reactions using everolimus in a patient with metastatic malignant insulinoma: Case report.

INTRODUCTION: Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of the abdomen can identify a pancreatic tumor corresponding to insulinoma. Loco-regional metastases define the metastatic cases. The first-line therapeutic approach is surgery, while other medical treatments like diazoxide and everolimus play also a role. These treatments have shown efficacy in regulating blood glucose and, to some extent, controlling tumor progression. CASE PRESENTATION: We present the case of a 48-year-old female who was admitted for severe hypoglycemia episodes. She presented neuroglycopenic symptoms without any other clinical features. High levels of C-peptide and insulin during severe hypoglycemia confirmed the presence of endogenous hyperinsulinism. The CT scan of the abdomen confirmed the existence of an insulinoma along with several hepatic metastases. Surgery was proposed as a first-line approach. However, due to the persistent occurrence of severe hypoglycemia episodes, other treatment options were necessary such as diazoxide and everolimus. Diazoxide caused a significant improvement in the patient's blood glucose levels. Nonetheless, glycemic control was unsustainable, obligating the switch to everolimus, which showed better control of blood glucose levels with challenging management due to the appearance of grade 3 stomatitis as a side effect. The patient died 1 year after the diagnosis due to tumor progression. CONCLUSION: Balancing the benefits of enhanced glycemic control with the difficulties posed by side effect management of everolimus underscores the need to carefully consider both efficacy and potential adverse events.

Novel Automated Self-adjusting Subcutaneous Insulin Algorithm Improves Glycemic Control and Physician Efficiency in Hospitalized Patients.

BACKGROUND: Hyperglycemia occurs in 22% to 46% of hospitalized patients, negatively affecting patient outcomes, including mortality, inpatient complications, length of stay, and hospital costs. Achieving inpatient glycemic control is challenging due to inconsistent caloric intake, changes from home medications, a catabolic state in the setting of acute illness, consequences of acute inflammation, intercurrent infection, and limitations in labor-intensive glucose monitoring and insulin administration. METHOD: We conducted a retrospective cross-sectional analysis at the University of California San Francisco hospitals between September 3, 2020 and September 2, 2021, comparing point-of-care glucose measurements in patients on nil per os (NPO), continuous total parenteral nutrition, or continuous tube feeding assigned to our novel automated self-adjusting subcutaneous insulin algorithm (SQIA) or conventional, physician-driven insulin dosing. We also evaluated physician efficiency by tracking the number of insulin orders placed or modified. RESULTS: The proportion of glucose in range (70-180 mg/dL) was higher in the SQIA group than in the conventional group (71.0% vs 69.0%, P = .153). The SQIA led to a lower proportion of severe hyperglycemia (>250 mg/dL; 5.8% vs 7.2%, P = .017), hypoglycemia (54-69 mg/dL; 0.8% vs 1.2%, P = .029), and severe hypoglycemia (<54 mg/dL; 0.3% vs 0.5%, P = .076) events. The number of orders a physician had to place while a patient was on the SQIA was reduced by a factor of more than 12, when compared with while a patient was on conventional insulin dosing. CONCLUSIONS: The SQIA reduced severe hyperglycemia, hypoglycemia, and severe hypoglycemia compared with conventional insulin dosing. It also improved physician efficiency by reducing the number of order modifications a physician had to place.

Canagliflozin or acarbose versus placebo to ameliorate post-bariatric hypoglycaemia - The HypoBar I randomized clinical trial protocol.

INTRODUCTION: Post-bariatric hypoglycaemia (PBH) is a rare yet disabling clinical condition, mostly reported after Roux-en-Y gastric bypass (RYGB) surgery. RYGB is one of the most widely used and effective bariatric procedures. The pathophysiology of PBH remains unclear, and treatment options are limited in effectiveness and/or carry significant side effects. Acarbose slows carbohydrates digestion and absorption and is generally considered first-line pharmacological treatment for PBH but its gastrointestinal side effects limit patient compliance. Canagliflozin inhibits intestinal and renal sodium-dependent glucose absorption and reduces postprandial excursions of glucose, insulin and incretins after RYGB - effects that could be beneficial in ameliorating PBH. AIMS: The trial aims to investigate how blood glucose levels are affected during daily living in subjects with PBH during treatment with canagliflozin or acarbose compared with placebo, and to study the meal-induced entero-endocrine mechanisms implied in the treatment responses. METHODS: In a double-blinded, randomized, crossover clinical trial, HypoBar I will investigate the effectiveness in reducing the risk of PBH, safety, ambulatory glucose profile and entero-endocrine responses when PBH is treated with canagliflozin 300 mg twice daily during a 4-week intervention period, compared with acarbose 50 mg thrice daily or placebo. ETHICS AND DISSEMINATION: HypoBar I is approved by the Local regulatory entities. Results will be published in peer-reviewed journals. CONCLUSION: If effective, well-tolerated and safe, canagliflozin could be a novel treatment for people with PBH. HypoBar I might also unravel new mechanisms underlying PBH, potentially identifying new treatment targets. TRIAL REGISTRATION: EudraCT number 2022-000157-87.

Impartial feature selection using multi-agent reinforcement learning for adverse glycemic event prediction.

We developed an attention model to predict future adverse glycemic events 30 min in advance based on the observation of past glycemic values over a 35 min period. The proposed model effectively encodes insulin administration and meal intake time using Time2Vec (T2V) for glucose prediction. The proposed impartial feature selection algorithm is designed to distribute rewards proportionally according to agent contributions. Agent contributions are calculated by a step-by-step negation of updated agents. Thus, the proposed feature selection algorithm optimizes features from electronic medical records to improve performance. For evaluation, we collected continuous glucose monitoring data from 102 patients with type 2 diabetes admitted to Cheonan Hospital, Soonchunhyang University. Using our proposed model, we achieved F1-scores of 89.0%, 60.6%, and 89.8% for normoglycemia, hypoglycemia, and hyperglycemia, respectively.

Impact of a Hyperkalemia Protocol Tailored to Glucose Concentration and Renal Function on Insulin-Induced Hypoglycemia in Patients with Low Pretreatment Glucose.

BACKGROUND: Hyperkalemia is a common electrolyte abnormality that requires urgent treatment. Insulin is an effective treatment for hyperkalemia, but risk factors for developing insulin-induced hypoglycemia exist (e.g., low pretreatment glucose or renal impairment). OBJECTIVE: This study evaluated the impact of a hyperkalemia protocol tailored to glucose concentration and renal function on insulin-induced hypoglycemia. METHODS: This was a retrospective cohort study of emergency department patients with glucose ≤ 100 mg/dL treated with insulin for hyperkalemia. The primary outcome was incidence of hypoglycemia in patients treated prior to (July 1, 2018-June 30, 2019) vs. after (January 1, 2020-December 31, 2020) the protocol update, which individualized insulin and dextrose doses by glucose concentration and renal function. Secondary outcomes included change in potassium and protocol safety. We assessed factors associated with hypoglycemia using multiple logistic regression. RESULTS: We included 202 total patients (preimplementation: 114, postimplementation: 88). Initial insulin dose was lower in the postimplementation group (p < 0.001). We found a nonsignificant reduction in hypoglycemia in the postimplementation group (42.1% vs. 30.7%, p = 0.10). Degree of potassium reduction was similar in patients who received insulin 5 units vs. 10 units (p = 0.72). Higher pretreatment glucose (log odds ratio [OR] -0.05, 95% confidence interval [CI] -0.08 to -0.02) and additional insulin administration (log OR -1.55, 95% CI -3.01 to -0.25) were associated with reduced risk of developing hypoglycemia. CONCLUSION: A hyperkalemia protocol update was not associated with a significant reduction in hypoglycemia, and the incidence of hypoglycemia remained higher than anticipated. Future studies attempting to optimize treatment in this high-risk population are warranted.

Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far.

Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of - 0.57% in the SEED trial and - 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters.