Increased Risk Of Hypoglycemia Research Articles

Impact of pre- and post-exercise strategies on hypoglycemic risk for two modalities of aerobic exercise among adults and adolescents living with type 1 diabetes using continuous subcutaneous insulin infusion: A randomized controlled trial.

We investigated strategies to mitigate hypoglycemic risk during and after different aerobic exercises in people with type 1 diabetes (pwT1D) using continuous subcutaneous insulin infusion. Thirty-seven pwT1D (21 adults, 16 adolescents; HbA1c = 7.5 ± 1.0 %) participated in two post-absorptive (4-h post-meal) exercise sessions (60-min continuous moderate intensity [CONT] vs. intermittent [INT]). Pre-exercise basal rate reduction (BRR) was either 40 % or 80 %, 90 min before exercise. Post-exercise, participants undertook either a 20 % BRR for 10 h with 20 % reduced dinner bolus (INS) or a 45 g post-exercise carbohydrate (CHO) snack with a 50 % insulin bolus, and a 30 g bedtime CHO snack without bolus (snack). While a similar number of hypoglycemic events (31 vs. 28) were observed between exercise modalities, CONT led to a greater decrease in blood glucose during exercise compared to INT (-3.1 ± 2.3, CONT vs. -2.7 ± 2.2 mmol/l, INT, P = 0.005). Changes in blood glucose during exercise (-3.0 ± 2.4, 40 %BRR vs. -2.8 ± 2.1 mmol/l, 80 %BRR, P = 0.076) and the number of hypoglycemic events (35 vs. 24) were similar between 40 % and 80 %BRR. Time in hyperglycemia was lower with INS compared to snack in the first 30 min after exercise, but no differences were observed for late recovery period or nighttime. Compared to INT, CONT led to greater blood glucose decline without increasing hypoglycemia risk. A larger pre-exercise BRR did not further reduce hypoglycemia risk during exercise. Post-exercise INS and snack strategies led to comparable glucose profiles in pwT1D.

Use of continuous glucose monitoring when initiating glucagon-like peptide-1 receptor agonist therapy in insulin-treated diabetes.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) medications have been shown to be effective in achieving optimal glucose control and reducing all-cause death, cardiovascular death, nonfatal myocardial infarction, hospitalization for heart failure, and end-stage kidney disease in individuals with type 1 (T1D) and type 2 diabetes (T2D). However, use of these medications has been associated with increased hypoglycaemia risk in patients treated with concomitant antihyperglycaemic medications. The risk is particularly high in patients with T1D due to their loss of glucagon counter-regulatory response. This article reviews the effect of GLP-1RA formulations on the development of hypoglycaemia in individuals with T1D and T2D treated with insulin therapy, discusses the benefits of continuous glucose monitoring with GLP-1RA treatment, and presents strategies for safely initiating GLP-1RA therapy in these individuals.

Consistent glycaemic efficacy and safety of concomitant use of iGlarLixi and sodium-glucose co-transporter-2 inhibitor therapy for type 2 diabetes: A patient-level pooled analysis of three randomised clinical trials

AimsSodium glucose co-transporter 2 inhibitors (SGLT2is) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardio- and reno-protective benefits are recommended in people with type 2 diabetes (T2D) at high risk of cardiovascular disease, chronic kidney disease, and/or heart failure. This pooled analysis compared efficacy and safety outcomes of iGlarLixi with or without SGLT2is in people with T2D. MethodsThis post hoc analysis evaluated outcomes in participants who were receiving an SGLT2i when initiating iGlarLixi (SGLT2i users) and those who were not (SGLT2i non-users) in a pooled dataset from three trials: LixiLan-G (advancing from a GLP-1 RA), SoliMix and LixiLan ONE CAN (advancing from basal insulin). ResultsBaseline characteristics were generally similar between 219 users and 746 non-users. Least squares mean changes in HbA1c from baseline to Week 26 were similar for users (−1.2 % [95 % confidence intervals: −1.4 %, −1.1 %]) and non-users (−1.2 % [−1.2 %, −1.1 %]). Changes in body weight, fasting glucose and post-prandial glucose were similar between groups, as were hypoglycaemic events. ConclusionsPooled results from three studies of adults with T2D demonstrated that iGlarLixi provided similar clinically meaningful improvements in glycaemic control without increased hypoglycaemia risk, regardless of concomitant use of SGLT2is.

Ambient Heat and Risk of Serious Hypoglycemia in Older Adults With Diabetes Using Insulin in the U.S. and Taiwan: A Cross-National Case-Crossover Study.

To measure the association between ambient heat and hypoglycemia-related emergency department visit or hospitalization in insulin users. We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the U.S. (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016-2019. We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design. Among ∼2 million insulin users in the U.S. (32,461 hypoglycemia case subjects), odds ratios of hypoglycemia for HI >99th, 95-98th, 85-94th, and 75-84th percentiles compared with the 25-74th percentile were 1.38 (95% CI, 1.28-1.48), 1.14 (1.08-1.20), 1.12 (1.08-1.17), and 1.09 (1.04-1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (∼283,000 insulin users, 10,162 hypoglycemia case subjects). In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk.

The effect of the modified fat-protein unit algorithm compared with that of carbohydrate counting on postprandial glucose in adults with type-1 diabetes when consuming meals with differing macronutrient compositions: a randomized crossover trial

BackgroundThe optimization of glucose control in type-1 diabetes is challenged by postprandial glycemic variability. This study aimed to compare the postprandial glycemic effects of carbohydrate counting and the modified fat-protein unit (FPU) algorithms following meals with different protein and fat emphases in adults with type-1 diabetes.MethodsThirty adults with type-1 diabetes aged 18 to 45 years participated in a randomized crossover trial. In a random order, participants consumed four test meals with equivalent energy and different macronutrient emphases on four separate mornings. The modified FPU algorithms and carbohydrate counting were used to determine the insulin dose for the test meals. A continuous glucose monitoring system was used to measured postprandial glycemia.ResultsCompared with carbohydrate counting, the modified FPU algorithm significantly decreased the late postprandial mean glucose levels (p = 0.026) in high protein-fat meals. The number of hypoglycemia episodes was similar between insulin dosing algorithms for the high protein-fat meals; hypoglycemic events were considerably higher for the modified FPU in the normal protein-fat meal (p = 0.042).ConclusionsThe modified FPU algorithm may improve postprandial glycemic control after consuming high protein-fat meals in adults with type-1 diabetes but may result in increased hypoglycemia risk when used with a normal protein-fat meal.

Achieving Normoglycemia With Tirzepatide: Analysis of SURPASS 1-4 Trials.

Tirzepatide is a novel single-molecule glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, which demonstrated unprecedented improvements in glycemic control and body weight reduction, in the SURPASS phase 3 program. In this exploratory analysis, we aimed to characterize tirzepatide-treated participants who achieved HbA1c <5.7% and evaluate changes in clinical markers associated with long-term cardiometabolic health. Baseline characteristics and change from baseline to week 40 for several efficacy and safety parameters were analyzed according to HbA1c attainment category (<5.7%, 5.7-6.5%, and >6.5%) using descriptive statistics in participants taking ≥75% of treatment doses, without rescue medication, in the SURPASS 1-4 trials (N = 3,229). Logistic regression models with tirzepatide doses adjusted as a covariate were used to obtain odds ratios and assess the impact of patient characteristics achieving an HbA1c <5.7%. Tirzepatide-treated participants who achieved HbA1c <5.7% were slightly younger, with a shorter duration of diabetes and lower HbA1c value at baseline compared with those who did not achieve HbA1c <5.7%. In addition, they showed greater improvements in HbA1c, body weight, waist circumference, blood pressure, liver enzymes, and lipid parameters without increasing hypoglycemia risk. Normoglycemia was unprecedently achieved in a significant proportion of participants in the SURPASS clinical program, without increasing hypoglycemia risk, and was associated with an overall improvement in metabolic health.

Safety of User-Initiated Intensification of Insulin Delivery Using Cambridge Hybrid Closed-Loop Algorithm.

Many hybrid closed-loop (HCL) systems struggle to manage unusually high glucose levels as experienced with intercurrent illness or pre-menstrually. Manual correction boluses may be needed, increasing hypoglycemia risk with overcorrection. The Cambridge HCL system includes a user-initiated algorithm intensification mode ("Boost"), activation of which increases automated insulin delivery by approximately 35%, while remaining glucose-responsive. In this analysis, we assessed the safety of "Boost" mode. We retrospectively analyzed data from closed-loop studies involving young children (1-7 years, n = 24), children and adolescents (10-17 years, n = 19), adults (≥24 years, n = 13), and older adults (≥60 years, n = 20) with type 1 diabetes. Outcomes were calculated per participant for days with ≥30 minutes of "Boost" use versus days with no "Boost" use. Participants with <10 "Boost" days were excluded. The main outcome was time spent in hypoglycemia <70 and <54 mg/dL. Eight weeks of data for 76 participants were analyzed. There was no difference in time spent <70 and <54 mg/dL between "Boost" days and "non-Boost" days; mean difference: -0.10% (95% confidence interval [CI] -0.28 to 0.07; P = .249) time <70 mg/dL, and 0.03 (-0.04 to 0.09; P = .416) time < 54 mg/dL. Time in significant hyperglycemia >300 mg/dL was 1.39 percentage points (1.01 to 1.77; P < .001) higher on "Boost" days, with higher mean glucose and lower time in target range (P < .001). Use of an algorithm intensification mode in HCL therapy is safe across all age groups with type 1 diabetes. The higher time in hyperglycemia observed on "Boost" days suggests that users are more likely to use algorithm intensification on days with extreme hyperglycemic excursions.

Glycemic Outcomes of Hospitalized Patients on Ambulatory Humulin-R U-500 Insulin

ObjectiveManaging hospitalized patients on ambulatory U-500 insulin is challenging because of limited guidance on how to safely adjust insulin doses during admission. We sought to evaluate glycemic outcomes in relation to inpatient insulin doses in patients receiving U-500 prior to hospitalization. MethodsRetrospective study of hospitalized patients on ambulatory U-500 seen consecutively from January 2015 to December 2019. Primary outcomes were inpatient hypoglycemia, hyperglycemia, and normoglycemia at different insulin dosages expressed as weight-based (unit/kg/d) inpatient total daily dose (TDD) and ratio of inpatient to outpatient TDD. ResultsWe identified 66 admissions of 46 unique patients. The median (interquartile range) body mass index was 41.0 kg/m2 (35.1, 46.8), home TDD 212 units (120, 300), and home insulin dose 1.6 units/kg/d (1.1, 2.2). The median (interquartile range) inpatient insulin dose was 0.7 unit/kg/d (0.3, 1.0) and the ratio of inpatient to outpatient TDD was 0.4 (0.2, 0.8). Hyperglycemia persisted throughout the hospitalization. For the outcomes of hyperglycemia and normoglycemia, we found no association between increased levels of insulin dosages. For the outcome of hypoglycemia, significantly higher odds were observed when non-fasting patients received an inpatient TDD that was either > 40% of their home TDD or > 0.6 unit/kg/d of insulin. ConclusionPatients on ambulatory U-500 have significant hyperglycemia during admission. Inpatient insulin doses of 40% of home TDD or ≤ 0.6 unit/kg were not associated with increased hypoglycemia risk. Further prospective studies are needed to determine effective doses in these high-risk patients.

Predictors of HbA1c reduction and hypoglycemia in type 2 diabetes mellitus individuals switching from premixed to basal insulin: an exploratory analysis of optimization study

Objective To identify population with type 2 diabetes mellitus (T2DM) who are more likely to benefit from switching to basal insulin (BI) treatment from premixed insulin. Methods This secondary analysis included data from a previously published study (Optimization: NCT00693771) which was a single-arm, multicenter, 16 weeks, phase IV study. The analysis included participants with T2DM inadequately controlled with premixed insulin plus oral hypoglycemic drugs (OADs) who switched to BI plus OADs. Results Among the 297 participants included for analysis, subjects with fasting C-peptide (FCP)>1.2 nmol/L group showed a trend for greater reduction in HbA1c [Least square mean difference (LSMD), −0.59; 95% confidence interval (CI), −0.98 to −0.21; p = 0.003] and FPG (LSMD, −1.36; 95% CI, −2.20 to −0.53; p = 0.002) than those with FCP ≤ 0.4 nmol/L. The baseline insulin glargine 100 U/mL (Gla-100) dose increased significantly in 0.4 to ≤ 1.2 nmol/L group with LS mean difference (SE) of 0.16 (0.01) U/kg/day (p = 0.008) compared to FCP ≤ 0.4 nmol/L group. When combined with Diabetes Treatment Satisfaction Questionnaire (DTSQ) score, participants with a C-peptide level of 0.4 to ≤1.2 nmol/L (OR, 4.05; 95% CI, 1.08 to 15.22; p = 0.039) had significantly higher odds of achieving HbA1c <7%. The number of participants experiencing documented symptomatic hypoglycaemia (≤3.9 mmol/L) was higher in the FCP ≤0.4 nmol/L group compared to those in 0.4 to ≤1.2 nmol/L FCP group at any time of the day (31.6 vs. 17.1%) and during night (00:00 ∼ 05:59) (17.1 vs. 7.5%). Conclusion The findings from this study proposed that FCP is an important biomarker to identify T2DM participants who experience improved glucose control without compromising on hypoglycemia levels during switch from premixed insulin to BI. Participants especially with FCP levels >1.2 nmol/L may respond better in terms of HbA1c reduction without increased hypoglycemia risk compared to those with lower FCP values.

Insulin settings and their association with time in range in patients with type 1 diabetes users of predictive low glucose suspend (PLGS) augmented insulin pumps in Santiago, Chile

AimsSensor augmented insulin pumps have become a powerful tool for managing type 1 diabetes (T1D). This study aimed to analyze the insulin pump configuration in users of predictive insulin suspension technology (PLGS). MethodsT1D patients on insulin pumps with PLGS (Medtronic 640G®) were enrolled. Data was obtained from medical records and pump data was downloaded for 30 days. Basal insulin, bolus calculator parameters, and PLGS operation parameters were analyzed and compared with Time in Range, Time Below Range, and Time Above Range. Results112 patients were included, with average TIR of 73,96 % and HbA1c 7,0 % and 25 months of follow-up. Basal insulin remained similar to initial doses, with an increase of 27 % for the Dawn phenomenon. The Carbohydrate ratio was slightly more aggressive. Insulin sensitivity was 17 % less stringent than initially programmed. No differences were observed in Time in Rage according to the number of basal, ratio, and sensitivity segments. Time of insulin suspension correlated directly with Time Bellow Range. ConclusionsPatients with good metabolic control have basal insulin programming similar to their initiation doses with less aggressive sensitivity factors. Excessive suspension time determined by PLGS could be an expression of excess insulin and increased hypoglycemia risk.

MO613: Acute Kidney Injury and Hypoglycaemia Risk in Hospitalized Diabetic Patients

Abstract BACKGROUND AND AIMS Acute kidney injury (AKI) remains one of the most common complications in hospitalized diabetic patients. The relationship between chronic kidney disease (CKD) and hypoglycaemia is well established: both renal neoglucogenesis and insulin clearance are diminished in this population, increasing the risk for hypoglycaemic episodes. A correlation between AKI and hypoglycaemia remains to be proven. A recent study stated that AKI increases hypoglycaemia risk in critically ill patients; other showed higher risk for hypoglycaemic episodes after hospital discharge. We focused on a correlation between AKI and hypoglycaemia risk in hospitalized diabetic patients. METHOD We performed an observational retrospective analysis of all hospitalized diabetic patients in Internal Medicine's ward between 2018 and 2019. Our sample was divided according to the presence/absence of AKI during hospitalization. We considered AKI as a rise of serum creatinine (SCr) &amp;gt;0.3 mg/dL in 48 h or &amp;gt;50% in a week. Baseline kidney function was calculated using CKD-EPI equation, according to the mean ambulatory SCr from the previous 6 months. All patients with CKD stage ≥4 were excluded. We collected 240 diabetic patients with AKI and, to obtain similar sample sizes, aleatory selected 240 diabetic patients without AKI. Hypoglycaemia was defined as peripheral blood sugar levels &amp;lt;70 mg/dL and stratified according to American Diabetes Association classification. IBM SPSS 23.0 was used to perform all statistical analysis. RESULTS We selected 480 diabetic patients with an average age of 81.2 ± 9.2 years; most were women (59.8%) and 36.0% were treated with insulin. Across both populations, hypoglycaemic episodes were more prevalent in insulin-treated patients, with lower baseline glomerular filtration rates (GFR) and higher age and were associated with longer hospitalizations (16.6 ± 12.4 days) and higher 30-day mortality rate {OR 3.7 [confidence interval (CI) 95% 1.6–8.7], P &amp;lt; 0.001}. Diabetic patients with AKI were older (82.7 versus 80.1 years, P = .001), had lower baseline GFR (59.1 versus 70 mL/min/1.73 m2 P &amp;lt; 0.001), longer hospital stays (13.8 ± 11.3 days, P = 0.007) and higher mortality rate (14.0% versus 7.3%, P = 0.05). Hypoglycaemic episodes were more prevalent in diabetic patients with AKI (40.8% versus 15.8%, P &amp;lt; 0.001); the occurrence of AKI during hospitalization increased hypoglycaemia risk by 4.2 times [OR 4.21 (CI 2.56–6.97), P &amp;lt; 0.001]. This relationship maintained after multivariate analysis, which accounted the differences between both groups. The first hypoglycaemic event occurred, on average, 6.7 ± 6.1 days after AKI; a longer time in AKI, irrespective of the severity, associated with higher hypoglycaemia risk and 30-day mortality rate, with a cut-off of 5.5 days resulting in higher frequency of this adverse event. CONCLUSION We found that AKI constitutes an important risk factor for hypoglycaemic episodes in hospitalized diabetic patients, mainly in elderly patients and those with lower baseline GFR. AKI's duration, irrespective of the severity, was the main contributor to higher hypoglycaemia risk. Our data support the need for individualized risk stratification for hypoglycaemic events—we should adapt our clinical practice to prevent or mitigate the impact of these adverse events during hospitalization and after discharge.

Continuous glucose monitoring demonstrates low risk of clinically significant hypoglycemia associated with sulphonylurea treatment in an African type 2 diabetes population: results from the OPTIMAL observational multicenter study

IntroductionPeople living with diabetes in low-resource settings may be at increased hypoglycemia risk due to food insecurity and limited access to glucose monitoring. We aimed to assess hypoglycemia risk associated...

Does optimal HbA1c in diabetes differ according to drug treatment? An evaluation of national electronic database in Malta

Background and aimsA J-shaped relationship between HbA1c and mortality has been reported in subjects with type 2 diabetes. The postulated mechanism linking low HbA1c with increased mortality is increased hypoglycaemia risk. We tested this hypothesis by comparing the relationship between low HbA1c to mortality in patients on therapies with different hypoglycaemia risk. MethodsWe selected patients on any type of treatment for diabetes from a national electronic database (n = 25,743) and linked to other databases, including laboratory database and the national mortality register. ResultsWe observed a J–shaped or U–shaped association between HbA1c and all–cause mortality in the whole type 2 diabetes patient cohort as well as in patients on metformin monotherapy and in those on metformin-sulphonylurea combination therapy, but not in subjects on sulphonylurea monotherapy or in those on insulin. ConclusionsOur data confirm the J-shaped relationship between HbA1c and mortality in type 2 diabetes, but suggest that a low HbA1c is deleterious even in absence of hypoglycaemia and that subjects with type 2 diabetes might require a slightly elevated blood glucose for optimal outcome. Our data also suggest that the increased mortality associated with sulphonylureas cannot be mediated solely through increased hypoglycaemia risk.

Impact of My Dose Coach App Frequency of Use on Clinical Outcomes in Type 2 Diabetes.

IntroductionMy Dose Coach (MDC) is a US Food and Drug Administration-approved digital smartphone application designed to help users with type 2 diabetes (T2D) titrate their basal insulin (BI) according to a clinician-prescribed individualized titration plan. The aim of this analysis was to assess the impact of the frequency of MDC use on clinical outcomes.MethodsThis retrospective observational analysis included people with T2D who were registered for MDC (August 1st, 2018–April 30th, 2020) and received BI. Users with an activated care plan and ≥2 fasting blood glucose (FBG) observations spanning ≥2 weeks were defined as active. Outcomes included percentage achieving their individual FBG target, time to FBG target, change in FBG, change in insulin dose and hypoglycemia. Users were stratified into high (>3 days per week), moderate (>1– ≤3 days per week), and low (≤1 day per week) MDC usage groups.ResultsThe analysis included 2517 active MDC users. Approximately 49% of users had high MDC usage. Overall, 44% of users across all usage frequencies achieved their individual FBG target. High MDC use was associated with significantly better FBG target achievement and less time to FBG target versus moderate- and low-usage groups (p≤0.01 for all). Insulin dose change was significantly greater in the high- versus moderate-usage group (p=0.01). There was no significant difference in hypoglycemia incidence among MDC usage groups (12%–16% of users in any usage group).ConclusionsMore frequent MDC usage was associated with better FBG outcomes without increased hypoglycemia risk.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01245-9.

Automated Insulin Delivery with SGLT2i Combination Therapy in Type 1 Diabetes

Background:Use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as adjunct therapy to insulin in type 1 diabetes (T1D) has been previously studied. In this study, we present data from the first free-living trial combining low-dose SGLT2i with commercial automated insulin delivery (AID) or predictive low glucose suspend (PLGS) systems.Methods:In an 8-week, randomized, controlled crossover trial, adults with T1D received 5 mg/day empagliflozin (EMPA) or no drug (NOEMPA) as adjunct to insulin therapy. Participants were also randomized to sequential orders of AID (Control-IQ) and PLGS (Basal-IQ) systems for 4 and 2 weeks, respectively. The primary endpoint was percent time-in-range (TIR) 70–180 mg/dL during daytime (7:00–23:00 h) while on AID (NCT04201496).Findings:A total of 39 subjects were enrolled, 35 were randomized, 34 (EMPA; n = 18 and NOEMPA n = 16) were analyzed according to the intention-to-treat principle, and 32 (EMPA; n = 16 and NOEMPA n = 16) completed the trial. On AID, EMPA versus NOEMPA had higher daytime TIR 81% versus 71% with a mean estimated difference of +9.9% (confidence interval [95% CI] 0.6–19.1); p = 0.04. On PLGS, the EMPA versus NOEMPA daytime TIR was 80% versus 63%, mean estimated difference of +16.5% (95% CI 7.3–25.7); p < 0.001. One subject on SGLT2i and AID had one episode of diabetic ketoacidosis with nonfunctioning insulin pump infusion site occlusion contributory.Interpretation:In an 8-week outpatient study, addition of 5 mg daily empagliflozin to commercially available AID or PLGS systems significantly improved daytime glucose control in individuals with T1D, without increased hypoglycemia risk. However, the risk of ketosis and ketoacidosis remains. Therefore, future studies with SGLT2i will need modifications to closed-loop control algorithms to enhance safety.

192-OR: Glycemic Control with Once-Weekly Basal Insulin Fc (BIF) in Persons with Type 2 Diabetes Mellitus (T2DM) Using Continuous Glucose Monitoring (CGM) in a Phase 2 Study

Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein assessed for the treatment of diabetes mellitus. A 32-week study evaluating the safety and efficacy of BIF vs. degludec in persons with T2DM previously treated with a basal insulin showed HbA1c non-inferiority of BIF vs. degludec with significantly fewer hypoglycemic events (≤70 mg/dL). Here we present CGM data derived by Dexcom G6, allowing a more detailed assessment of glycemic control of BIF vs. degludec. The study included 2 dosing algorithms for BIF with different fasting glucose (FG) targets: ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Degludec was titrated to FG ≤100 mg/dL. Subjects were randomized to 1 of the 3 arms. Subject (N=399) mean age was 60.2 yrs and baseline HbA1c was 8.1%. For the entire 32 weeks, the percent of 24 hrs in range, hyperglycemia and hypoglycemia was similar for the 3 arms (Figure). At Week 32, total duration of hypoglycemia was similar across 7 days post-injection for BIF-A1 and A2, showing that duration of hypoglycemia is independent of day post-injection. CGM data confirm that BIF showed similar glycemic control vs. degludec despite higher FG targets and numerically lower time in hypoglycemia. The flat pharmacokinetic profile enables near peakless insulin concentrations without an increase in hypoglycemia risk at highest exposure. Disclosure C. M. Kazda: Employee; Self; Eli Lilly and Company. J. Chien: Stock/Shareholder; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. E. Chigutsa: Employee; Self; Eli Lilly and Company. W. Landschulz: Employee; Self; Lilly Diabetes, Employee; Spouse/Partner; Covance Inc., Stock/Shareholder; Self; Lilly Diabetes. P. Wullenweber: None. A. Haupt: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. Funding Eli Lilly and Company

Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial

OBJECTIVEInsulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine 100 units/mL (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and one or more oral glucose-lowering medications.RESEARCH DESIGN AND METHODSThis multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal insulin–treated (total daily dose 10–50 units) people with type 2 diabetes (HbA1c 7.0–10.0% [53.0–85.8 mmol/mol]) to icodec with an initial 100% loading dose (in which only the first dose was doubled [icodec LD]), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. Primary end point was percent time in range (TIR; 3.9–10.0 mmol/L [70–180 mg/dL]) during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary end points included HbA1c, adverse events (AEs), and hypoglycemia.RESULTSEstimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; n = 54), 66.0% (icodec NLD; n = 50), and 65.0% (IGlar U100; n = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points [95% CI 1.8–13.9]). Mean HbA1c reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% (54.4 mmol/mol icodec LD) and 7.4% (57.6 mmol/mol icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.CONCLUSIONSSwitching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.

Monitoring and management of hyperglycemia in patients with advanced diabetic kidney disease.

Diabetes mellitus is the leading cause of end-stage renal disease, and uncontrolled hyperglycemia is directly related to the increased mortality in this setting. As kidney function decreases, it becomes more challenging to control blood glucose since the risk of hypoglycemia increases. Decreased appetite, changes in glycaemia homeostasis, along with reduced renal excretion of anti-hyperglycemic drugs tend to facilitate the occurrence of hypoglycemia, despite the paradoxical occurrence of insulin resistance in advanced kidney disease. Thus, in patients using insulin and/or oral anti-hyperglycemic agents, dynamic adjustments with drug dose reduction or drug switching are often necessary. Furthermore, in addition to consider these pharmacokinetics alterations, it is of utmost importance to choose drugs with proven cardio-renal benefits in this setting, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists. In this review, we summarize the indications and contraindications, titration of doses and side effects of the available anti-hyperglycemic agents in the presence of advanced diabetic kidney disease (DKD) and dialysis, highlighting the risks and benefits of the different agents. Additionally, basic renal function assessment and monitoring of glycemic control in DKD will be evaluated in order to guide the use of drugs and define the glycemic targets to be achieved.

Effect of dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes: post-hoc renal analysis of the DEPICT randomised controlled trials

The DEPICT-1 and DEPICT-2 studies showed that dapagliflozin as an adjunct to insulin in individuals with inadequately controlled type 1 diabetes improved glycaemic control and bodyweight, without increase in risk of hypoglycaemia. We aimed to determine the effect of dapagliflozin on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) using pooled data from the DEPICT studies. In this post-hoc analysis, we used data pooled from both DEPICT studies (DEPICT-1 ran from Nov 11, 2014, to Aug 25, 2017; DEPICT-2 ran from July 8, 2015, to April 18, 2018), in which participants were aged 18-75 years, with inadequately controlled type 1 diabetes and with a baseline UACR of at least 30 mg/g. In the DEPICT studies, participants were randomly assigned (1:1:1) to receive dapagliflozin (5 mg or 10 mg) or placebo all plus insulin, for 24 weeks, with a 28-week long-term extension (ie, 52 weeks in total). In this post-hoc analysis, we assessed the percentage change from baseline in UACR and in eGFR, up to 52 weeks. UACR, eGFR, and safety were assessed in all eligible participants who had received at least one dose of study drug. HbA1c, bodyweight, and systolic blood pressure were assessed in all participants who received at least one dose of study drug during the first 24-week period, and who had a baseline and any post-baseline assessment for that parameter. The DEPICT trials were registered with ClinicalTrials.gov, NCT02268214 (DEPICT-1), NCT02460978 (DEPICT-2), and are now complete. 251 participants with albuminuria at baseline were included in this post-hoc analysis; of whom 80 (32%) had been randomly assigned to dapagliflozin 5 mg, 84 (33%) to dapagliflozin 10 mg, and 87 (35%) to placebo. Compared with placebo, treatment with both dapagliflozin doses improved UACR over 52 weeks. At week 52, mean difference in change from baseline versus placebo in UACR was -13·3% (95% CI -37·2 to 19·8) for dapagliflozin 5 mg and -31·1% (-49·9 to -5·2) for dapagliflozin 10 mg. No notable change from baseline was seen in eGFR, with a mean difference in change from baseline versus placebo of 3·27 mL/min per 1·73 m2 (95% CI -0·92 to 7·45) for dapagliflozin 5 mg and 2·12 mL/min per 1·73 m2 (-2·03 to 6·27) for dapagliflozin 10 mg. Similar proportions of participants in each treatment group had adverse events and serious adverse events, including hypoglycaemia and diabetic ketoacidosis; no new safety signals were identified in this population. Treatment with dapagliflozin resulted in UACR reduction, which might provide renoprotective benefits in individuals with type 1 diabetes and albuminuria. Dedicated prospective studies are needed to confirm these findings as prespecified endpoints. AstraZeneca.

Neuro Developmental Consequences of Neonatal Hypoglycemia.

Neonatal hypoglycemia (HG) can cause neurologic damage, epilepsy, mental retardation, behavioral and personality disorders and death. The longest the HG lasts and the greatest the glucose nadir the consequences are more pronounced. Comorbidities are rather important in development of neurological damage. Hypoxemia and ischemia can cause permanent brain damage. Small for gestational age (SGA), large for gestational age (LGA), intrauterine growth restriction, gestational age bellow the 37th week, low Apgar score, sepsis, children whose mothers have toxemia, diabetes or chorioamnionitis are all newborns with increased HG risk. Comparing 34 patients with NH and 34 children without NH with similar GA, BW, BL, the Apgar score, we found statistically significant differences in motor and mental development using the Griffith scale. Children with neonatal HG fared significantly worse than those without neonatal HG. Therefore, CBG measurements and early recognition of neonatal HG is of significant importance in preventing motor and mental damage in children. A larger and well-balanced cohort of patients followed for a longer period is also necessary to clarify and discern in detail the importance of neonatal HG and other perinatal factors in neurodevelopmental damage.