Glargine U100 Research Articles

Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial

Insulin icodec (icodec) is a basal insulin analogue suitable for once-weekly dosing. ONWARDS 4 aimed to assess the efficacy and safety of once-weekly icodec compared with once-daily insulin glargine U100 (glargine U100) in individuals with long-standing type 2 diabetes on a basal-bolus regimen. In this 26-week, phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial, adults from 80 sites (outpatient clinics and hospital departments) across nine countries (Belgium, India, Italy, Japan, Mexico, the Netherlands, Romania, Russia, and the USA) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0%) were randomly assigned (1:1) to receive once-weekly icodec or once-daily glargine U100 combined with 2-4 daily bolus insulin aspart injections. The primary outcome was change in HbA1c from baseline to week 26 (non-inferiority margin of 0·3 percentage points). The primary outcome was evaluated in the full analysis set (ie, all randomly assigned participants). Safety outcomes were evaluated in the safety analysis set (ie, all participants randomly assigned who received at least one dose of trial product). This trial is registered with ClinicalTrials.gov, NCT04880850. Between May 14 and Oct 29, 2021, 746 participants were screened for eligibility, of whom 582 (78%) were randomly assigned (291 [50%] to icodec treatment and 291 [50%] to glargine U100 treatment). Participants had a mean duration of type 2 diabetes of 17·1 years (SD 8·4). At week 26, estimated mean change in HbA1c was -1·16 percentage points in the icodec group (baseline 8·29%) and -1·18 percentage points in the glargine U100 group (baseline 8·31%), showing non-inferiority for icodec versus glargine U100 (estimated treatment difference 0·02 percentage points [95% CI -0·11 to 0·15], p<0·0001). Overall, 171 (59%) of 291 participants in the icodec group and 167 (57%) of 291 participants in the glargine U100 group had an adverse event. 35 serious adverse events were reported in 22 (8%) of 291 participants in the icodec group and 33 serious adverse events were reported in 25 (9%) of 291 participants receiving glargine U100. Overall, combined level 2 and level 3 hypoglycaemia rates were similar between treatment groups. No new safety concerns were identified for icodec. In people with long-standing type 2 diabetes on a basal-bolus regimen, once-weekly icodec showed similar improvements in glycaemic control, with fewer basal insulin injections, lower bolus insulin dose, and with no increase in hypoglycaemic rates compared with once-daily glargine U100. Key strengths of this trial include the use of masked continous glucose monitoring; the high trial completion rate; and the inclusion of a large, diverse, and multinational population. Limitations include the relatively short trial duration and the open-label design. Novo Nordisk.

ONWARDS and upwards for basal insulin

In this issue of The Lancet, Chantal Mathieu and colleagues present the findings of ONWARDS 4, a phase 3 randomised, open-label, treat-to-target, non-inferiority trial comparing the novel once-weekly insulin icodec (n=291) versus once-daily insulin glargine U100 (n=291) in people with long-standing type 2 diabetes on basal-bolus insulin therapy. 1 Mathieu C Ásbjörnsdóttir B Bajaj HS et al. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. Lancet. 2023; (published online May 5.)https://doi.org/10.1016/S0140-6736(23)00520-2 Summary Full Text Full Text PDF Google Scholar The trial was conducted in Belgium, India, Italy, Japan, Mexico, the Netherlands, Romania, Russia, and the USA. The participants had a mean duration of type 2 diabetes of 17·1 years (SD 8·4), a mean age at baseline of 59·8 years (SD 10·0), and 304 of the 582 participants were men and 278 were women. The primary outcome in ONWARDS 4 was met, with both icodec and glargine U100 shown to be equally effective at reducing HbA1c from baseline by week 26 (estimated mean change in HbA1c −1·16 percentage points in the icodec group [baseline 8·29%] and −1·18 percentage points in the glargine U100 group [baseline 8·31%]; estimated treatment difference 0·02 percentage points [95% CI −0·11 to 0·15], p<0·0001). Given the age, duration of diabetes, and number of comorbidities of participants, the percentage of time spent with glucose concentrations within the target range of 70–180 mg/dL (3·9–10·0 mmol/L) by week 26 (ie, trial end) was impressive; 66·9% in the icodec group and 66·4% in the glargine group. In addition, the percentage of time spent with glucose concentrations less than 54 mg/dL (<3·0 mmol/L) was low, not differing significantly between the groups (0·7% for the icodec group and 0·6% for the glargine U100 group). Overall, combined level 2 and 3 hypoglycaemia rates were similar between treatment groups, there were no significant differences in weight gain, and no new safety signals emerged. These findings would suggest that once-weekly icodec is a viable therapeutic option for people with type 2 diabetes on a basal-bolus insulin regimen, and, perhaps more importantly, heralds the introduction of once-weekly insulins into clinical practice, an exciting and welcome addition to the insulin family. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trialIn people with long-standing type 2 diabetes on a basal-bolus regimen, once-weekly icodec showed similar improvements in glycaemic control, with fewer basal insulin injections, lower bolus insulin dose, and with no increase in hypoglycaemic rates compared with once-daily glargine U100. Key strengths of this trial include the use of masked continous glucose monitoring; the high trial completion rate; and the inclusion of a large, diverse, and multinational population. Limitations include the relatively short trial duration and the open-label design. Full-Text PDF

Efficacy and Safety of Insulin Icodec Versus Glargine U100- A meta-analysis of randomized controlled trials

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Assessment of circulating insulin using liquid chromatography-mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β-cell function.

To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes. Using liquid chromatography-mass spectrometry (LC-MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC-MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

Effectiveness, safety, initial optimal dose, and optimal maintenance dose range of basal insulin regimens for type 2 diabetes: A systematic review with meta-analysis.

To investigate the effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins in insulin-naïve patients with type 2 diabetes mellitus. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched from January 2000 to February 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was adopted. The registration ID is CRD42022319078 in PROSPERO. Among 11 163 citations retrieved, 35 publications met the planned criteria. From meta-analyses and network meta-analyses, we found that when injecting basal insulin regimens at bedtime, the optimal choice in order of most to least effective might be glargine U-300 or degludec U-100, glargine U-100 or detemir, followed by neutral protamine hagedorn (NPH). Injecting glargine U-100 in the morning may be more effective (ie, more patients archiving glycated hemoglobin < 7.0%) and lead to fewer hypoglycemic events than injecting it at bedtime. The optimal starting dose for the initiation of any basal insulins can be 0.10-0.20 U/kg/day. There is no eligible evidence to investigate the optimal maintenance dose for basal insulins. The five basal insulins are effective for the target population. Glargine U-300, degludec U-100, glargine U-100, and detemir lead to fewer hypoglycemic events than NPH without compromising glycemic control.

Increased Time in Range with Ultra Rapid Lispro Treatment in Participants with Type 2 Diabetes: PRONTO-Time in Range.

To evaluate time in range metrics and HbA1c in people with type 2 diabetes (T2D) treated with ultra rapid lispro (URLi) using continuous glucose monitoring (CGM) for the first time in this population. This was a Phase 3b, 12-week, single-treatment study in adults with T2D on basal-bolus multiple daily injection (MDI) therapy using basal insulin glargine U-100 along with a rapid-acting insulin analog. Following a 4-week baseline period, 176 participants were newly treated with prandial URLi. Participants used unblinded CGM (Freestyle Libre). Primary endpoint was time in range (TIR) (70-180mg/dl) during the daytime period at Week 12 compared to baseline with gated secondary endpoints of HbA1c change from baseline and 24-h TIR (70-180mg/dl). Improved glycemic control was observed at Week 12 versus baseline including mean daytime TIR (change from baseline [Δ] 3.8%; P = 0.007), HbA1c (Δ - 0.44%; P < 0.001), and 24-h TIR (Δ 3.3%; P = 0.016) with no significant difference in time below range (TBR). After 12weeks, there was a statistically significant decrease in postprandial glucose incremental area under curve, overall, across all meals, within 1h (P = 0.005) or 2h (P < 0.001) after the start of a meal. Basal, bolus, and total insulin dose were intensified with increased bolus/total dose ratio at Week 12 (50.7%) versus baseline (44.5%; P < 0.001). There were no severe hypoglycemia events during the treatment period. In people with T2D, URLi in an MDI regimen was efficacious with improved glycemic control including TIR, HbA1c, and postprandial glucose without increased hypoglycemia/TBR. CLINICALTRIAL REGISTRATION NUMBER: NCT04605991.

Correlation Between Time in Range and HbA1c in People with Type 2 Diabetes on Basal Insulin: Post Hoc Analysis of the SWITCH PRO Study.

Use of continuous glucose monitoring (CGM) in people with diabetes may provide a more complete picture of glycemic control than glycated hemoglobin (HbA1c) measurements, which do not capture day-to-day fluctuations in blood glucose levels. The randomized, crossover, phase IV SWITCH PRO study assessed time in range (TIR), derived from CGM, following treatment with insulin degludec or insulin glargine U100 in patients with type 2 diabetes at risk for hypoglycemia. This post hoc analysis evaluated the relationship between TIR and HbA1c, following treatment intensification during the SWITCH PRO study. Correlation between absolute values for TIR (assessed over 2-week intervals) and HbA1c, at baseline and at the end of maintenance period 1 (M1; week 18) or maintenance period 2 (M2; week 36), were assessed by linear regression and using the Spearman correlation coefficient (rs). These methods were also used to assess correlation between change in TIR and change in HbA1c from baseline to the end of M1, both in the full cohort and in subgroups stratified by baseline median HbA1c (≥ 7.5% [≥ 58.5mmol/mol] or < 7.5% [< 58.5mmol/mol]). A total of 419 participants were included in the analysis. A moderate inverse linear correlation was observed between TIR and HbA1c at baseline (rs -0.54), becoming stronger following treatment intensification during maintenance periods M1 (weeks 17-18: rs -0.59) and M2 (weeks35-36: rs -0.60). Changes in TIR and HbA1c from baseline to end of M1 were also linearly inversely correlated in the full cohort (rs -0.40) and the subgroup with baseline HbA1c ≥ 7.5% (rs -0.43). This was less apparent in the subgroup with baseline HbA1c < 7.5% (rs -0.17) (p-interaction = 0.07). Results from this post hoc analysis of data from SWITCH PRO, one of the first large interventional clinical studies to use TIR as the primary outcome, further support TIR as a valid clinical indicator of glycemic control. ClinicalTrials.gov identifier, NCT03687827.

IDF2022-1166 Response to glargine U-100 initiation in new subgroups of type 2 diabetes replicated in randomised controlled trials

IDF2022-1166 Response to glargine U-100 initiation in new subgroups of type 2 diabetes replicated in randomised controlled trials

Commentary on glucose reduction in type 2 diabetes (GRADE).

Commentary on glucose reduction in type 2 diabetes (GRADE).

Higher Derived Time in Range With IDegLira Versus Insulin Glargine U100 in People With Type 2 Diabetes.

Derived time in range (dTIR), calculated from self-monitored blood glucose (SMBG-dTIR) profiles, has demonstrated correlation with risk of cardiovascular and microvascular complications. This post hoc analysis of the DUAL V and DUAL VIII trials aimed to compare dTIR with an insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus insulin glargine 100 units/mL (glargine U100) in people with type 2 diabetes (T2D). Nine-point SMBG profiles were taken more than 24 hours at baseline and end of trial (EOT: 26 weeks [DUAL V] and 104 weeks [DUAL VIII]) and used to derive the percentage of readings within target range (70-180 mg/dL). Estimated treatment differences (ETDs, IDegLira-glargine U100) were analyzed using analysis of covariance, with treatment as fixed effects and baseline response as a covariate. ETDs for change from baseline to EOT in dTIR were significantly greater with IDegLira versus glargine U100 in DUAL V (4.18%, P = .027) and DUAL VIII (5.17%, P = .001). The proportions of people achieving ≥70% dTIR at EOT with IDegLira and glargine U100, respectively, were 62% and 60% in DUAL V (P = .7541), and 50% and 26% in DUAL VIII (P < .0001). The proportion achieving a ≥5% increase in dTIR from baseline to EOT with IDegLira and glargine U100 was 63% in both groups in DUAL V (P = .9043), and 44% and 25%, respectively, in DUAL VIII (P < .0001). IDegLira was associated with significantly greater increases in dTIR versus basal insulin alone in people with T2D. ClinicalTrials.gov, NCT01952145 (DUAL V); ClinicalTrials.gov, NCT02501161 (DUAL VIII).

Endocrinological evaluation of dawn phenomenon in patients with diabetes and comparison of insulin glargine U-100 biosimilar (Insulin Glargine BS Injection "Lilly") and glargine U-300 (Lantus XR): a randomized controlled study.

We investigated the pathophysiology of the dawn phenomenon by examining the effects of changes in blood glucose levels from late night to early morning on various hormones in a group taking glargine BS and a group taking Lantus XR, with the goal of achieving better glycemic control. Patients with types 1 and 2 diabetes scheduled for inpatient education were divided into BS and XR groups. Blood glucose levels were tracked from 0:00 to 7:00, while blood samples were extracted at 3:00 and 7:00 to measure glucose levels and hormones related to the dawn phenomenon. Overall, we analyzed blood sample and intermittently scanned Continuous Glucose Monitoring data of 43 and 40 patients, respectively. From 0:00 to 7:00, the mean blood glucose was significantly lower in the BS group, although the fluctuation was similar (p < 0.0001). The BS group also exhibited significantly higher ∆ACTH (p = 0.0215) and ∆ cortisol (p = 0.0430) than the XR group. In the BS group, ∆Glu exhibited a significant negative correlation with ∆ACTH and ∆cortisol (p = 0.0491). Similar findings were not observed in the XR group. These results suggest that XR may be a better choice for long-acting insulin since it is less likely to induce cortisol secretion. Further, analysis of the dawn phenomenon and non-dawn phenomenon groups showed the mean CPR levels at 3:00 and 7:00 were significantly higher in the latter (p = 0.0135). This supports the conventional belief that appropriate basal insulin replacement therapy is a beneficial treatment for the dawn phenomenon.

Real-world Clinical Effectiveness on Glycaemic Parameters, Safety and Additional Benefits of Glargine U300 (Toujeo®) Initiation after Oral Antidiabetic Drug Failure in Insulin-naïve Patients with type 2 Diabetes Mellitus.

Several studies have proved the advantages of second-generation insulin analogs in lowering intra-individual variability in plasma insulin levels, flexibility in dosing, a sustained glucose-lowering effect, and decreasing the risk of hypoglycemia. Glargine 300 is one of the newer second-generation basal insulin analogs to have been approved for both type 1 and 2 diabetes. The present study aims to assess the real-world clinical effectiveness and safety of Glargine U300 (Toujeo®) initiation after oral antidiabetic drug failure in insulin-naïve patients with T2DM. A prospective, observational study was conducted where participants were interviewed regarding their basic demographics, body weight, and treatment details. Glycemic parameters (HbA1C%, Fasting Plasma Glucose, and Post Prandial Blood Glucose) were observed in the initial 6 months, and changes were noted and compared. Any hypoglycemic events or other complications were also noted. Data collected were statistically analyzed. The study included a total of 188 patients. Treatment with glargine 300 significantly reduced the mean HbA1C level from 9.78% at baseline to 7.90% at the end of 6 months of treatment (p < 0.001). 10.60% of patients achieved the glycemic target of ≤7.0% by the end of 6 months, while only 6.90% were within the target range at baseline. Similarly, significant reduction in FPG was observed at the end of 6 months treatment period with Glargine U300. A significant increase in dose requirement was observed throughout the study phase (p < 0.001). Incidence of hypoglycemia was noted in 2.12% of subjects. The lower incidence statistics of hypoglycemia coupled with sustained positive glycemic effects, stands out to be a prominent advantage of Glargine U300 over its other congeners.

A case of type 1 Diabetes mellitus unresponsive to insulin glulisine

A 29-year-old man applied to the internal medicine outpatient clinic with fatigue and high plasma glucose levels. He had type 1 Diabetes Mellitus for 10 years and was using insulin glargine U300 and insulin glulisine for treatment. His glycosylated hemoglobin level was 16.7%, and he was hospitalized. Insulin doses were calculated as 1 unite/kg /day; glulisine 3x8 unit/day and glargine U300 1x18 unit/day were ordered. Although we increased the total insulin dosage to 1,5 units/kg/day, the plasma glucose measurements did not improve. The short-acting insulin analog was switched to insulin aspart based on the fact that insulin autoantibodies might cause this situation. On aspart treatment, the patient suffered from hypoglycemia with the same doses of glulisine. The occurrence of insulin autoantibodies against glulisine was confirmed clinically. Basal insulin dose was reduced to 20 units, and aspart 3x6 units/day was enough for plasma glucose control. &#x0D; Hyperglycemia due to autoantibodies against analog insulins is very rare. Here we report a type 1 Diabetes Mellitus patient who was on glulisine treatment for 10 years, and whose blood glucose measurements deteriorated recently. Hyperglycemia was regulated after the insulin switch from glulisine to aspart. This rare case report must be kept in mind in hyperglycemic patients with a history of long-time analog insulin treatment.

Changes of HbA1c variability after the switch to a longer-acting insulin analog in people with type 1 diabetes.

This study investigated whether longer-acting basal analogs (insulin degludec and insulin glargine U300) could reduce visit-to-visit hemoglobin A1c (HbA1c) variability in patients with type 1 diabetes. Ninety adults with type 1 diabetes for whom the basal insulin was switched to a longer-acting insulin analog were analyzed retrospectively. The coefficient of variation of HbA1c levels (CV-HbA1c) during the year before and after the switch was compared. The CV-HbA1c after the switch was not significantly different from that before the switch (4.39 ± 2.24% vs 4.25 ± 2.07%; P=0.506). The linear regression model revealed that CV-HbA1c before the switch was independently associated with the change of CV-HbA1c (regression coefficient per standard deviation=-0.568, P < 0.001), whereas the other variables were not (all P > 0.05). In conclusion, CV-HbA1c remained unchanged after the switch on average, but CV-HbA1c before the switch was associated with the decrease of CV-HbA1c in individuals with type 1 diabetes.

PSUN227 A retrospective comparison of Basal Bolus using Glargine U-300 and Glulisine with Premix Insulin

Abstract Objectives The objective of this retrospective analysis was to compare the occurrence of Level 1 hypoglycaemia, Level 2 hypoglycaemia, nocturnal hypoglycaemia and mean HBA1C reduction in patients treated with premixed insulin 30/70 (Insulin Isophane/NPH 70% + Human Insulin/Soluble Insulin 30%) and after initiating a basal bolus regime using Glargine U-300 and Glulisine. Level 1 hypoglycaemia is blood glucose less than 70 mg/dL but above 54 mg/dL. Level 2 hypoglycaemia is blood glucose less than 54 mg/dL. Methodology and Data Analysis Data was collected retrospectively over 6 months on adult outpatients who were on pre mix insulin 30/70 for at least 2 years and who frequently experienced hypoglycaemic episodes and after transitioning these patients to a basal bolus regime Glargine U-300 and Glulisine. Those were having an underlying etiology which would predispose them to hypoglycaemia were excluded. The exclusion criteria included malignancy, drug induced causes except premix insulin, Chronic Kidney disease stage 4 or 5 and acute or chronic hepatic failure. Blood glucose monitoring was done by a 7 point Self Monitoring of Blood Glucose. A total of 30 cases were randomly chosen and data were sought from patients’ home glucose logs, case notes and Electronic health care records. Data were analysed by Microsoft Excel and was compared with paired-T test. Results The average number of Level 1 hypoglycaemic episodes per week on premix insulin dropped from 6.517 to 0.9655 (t = -10.807456, p&amp;lt;0.00001) after initiating the basal bolus regime. The average number of level 2 hypoglycaemic episodes per week dropped from 2.034 to 0.379 (t = -8.733497, p&amp;lt;0.00001) after changing to basal bolus regime. There was also a reduction in the occurrence of average nocturnal hypoglycaemic episodes from 2.655 on pre mix insulin to 0.2068 on the basal bolus regimen (t = -8.635475, p&amp;lt;0.00001).The mean HbA1C reduction was 3.16% in three months after commencing the basal bolus regime (t = -27.554737, p&amp;lt;0.00001). Conclusions Outpatient treatment with the basal bolus regime consisting of Glargine U -300 and Glulisine as compared to the premix insulin use showed a marked reduction in Level 1 and Level 2 hypoglycaemic episodes and nocturnal hypoglycaemic episodes per week. The decreased hypoglycaemic event rates in hypoglycaemia resulted in better compliance and adherence which was reflected as a significant reduction in HbA1C. In the future more retrospective and prospective studies will be helpful with Glargine U-300 and Glulisine. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

LBSUN210 Efficacy And Safety Profile Of Insulin Icodec Versus Insulin Glargine U100 In Type 2 Diabetes Mellitus: A Meta-Analysis Of Randomized Controlled Trials

Abstract In the context of diabetes, clinical inertia is defined as the failure to initiate insulin therapy or its intensification when treatment goals have not been met. Patient-related factors that contribute to this phenomenon include inability to follow complex regimens, cost of treatment and drug side effects. Icodec is a novel, investigational, ultra-long acting, once-weekly insulin analog with a potential for better treatment adherence. However, early evidence from phase 2 trials on icodec in type 2 diabetes mellitus (T2D) is conflicting. To study the efficacy and safety of insulin icodec, we conducted a meta-analysis of published randomized controlled trials (RCTs) on weekly icodec vs. daily glargine U100 in patients with uncontrolled T2D (HbA1c &amp;gt; 7%). A systematic search in major online databases was done to identify and review relevant RCTs. Two authors independently performed the study selection and extracted study data. Data on glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), time-in-range of 70-180 mg/dL (TIR), adverse events and hypoglycemia events were noted. Significance level of 95% was used to provide pooled estimates. Random effects model was used for analysis with significant heterogeneity (I2&amp;gt;50%). Three trials with 606 patients were included. Pooled analysis of available data showed that icodec resulted in a significantly greater mean reduction of HbA1c (mean difference (MD)=0.18%[0.13,0.22], p&amp;lt;0. 00001, I2=84% in 2 studies), mean reduction of FPG (MD=3.87mg/dl [3.18, 4.57],p&amp;lt;0. 00001, I2=0%), longer TIR (MD=4.39% [3.94, 4.85], p&amp;lt;0. 00001, I2=0%), but had significantly greater propensity to lead to level 1 hypoglycemia (Odds Ratio (OR)=1.59 [1.11,2.28], p=0. 01, I2=29%) when compared to glargine U100. Funnel plot analysis on the propensity for icodec to lead to any hypoglycemia event decreased the I2 statistic from 78% to 0% and showed significantly greater hypoglycemia events with icodec (OR=2.59 [1.67,4. 01], p&amp;lt;0. 001). There was no significant difference in the number of patients with end-of-trial HbA1c &amp;lt;7%, and any adverse event, or hypoglycemia level 2 or 3. Of note, only one hypoglycemia level 3 event was noted (patient on icodec). Once-weekly icodec had significantly better glycemic control compared to daily glargine U100, but had significantly greater hypoglycemia events. Data from ongoing trials on this novel drug can be added to the analysis as they become available. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

LBSUN207 Efficacy And Safety Of Degludec U100 Versus Glargine U300 For The Hospital Management Of Patients With Type 2 Diabetes: A Prospective, Open-label, Non-inferiority Randomized Controlled Trial

Abstract Aims No head-to-head comparisons of two ultra-long acting insulins, degludec-100 and glargine-300, have been reported in the inpatient setting. We compared the efficacy and safety of these two insulins for the hospital management of patients with type 2 diabetes (T2D). Methods This target-to-treat, randomized controlled trial enrolled patients with T2D admitted for coronary artery bypass graft surgery (CABG). On the day of transition (day 2 of surgery) from intravenous insulin infusion to multiple subcutaneous insulin injections, patients were randomly assigned (1: 1) to receive a basal-bolus regimen using either degludec-100 or glargine-300 as basal and glulisine as bolus before meals. Insulin was adjusted daily to maintain a fasting blood glucose (BG) &amp;lt;140 mg/dL and pre-meal BG &amp;lt;180, while avoiding hypoglycemia &amp;lt;70 mg/dL. The primary endpoint was non-inferiority in mean differences between groups in their daily BG concentrations measured during the duration of the hospital stay and a week post-discharge, up to 12 days (point-of-care measurements, pre-breakfast, pre-lunch, pre-dinner and nighttime [0300 hours]: non-inferiority was deemed a difference &amp;lt;18 mg/dL). The major safety outcome was the occurrence of hypoglycemia. Secondary outcome measures included mean differences between groups in their daily BG concentrations, time in range (TIR, %), time below range (TBR, %), and time above range(TAR, %), as assessed by continuous glucose monitoring system (CGMS, n = 142). Results Between October 12, 2021, and February 10, 2022, 324 consecutive patients with T2D undergoing CABG were screened, 239 patients were randomly assigned to treatment; 122 to degludec-100 group and 117 to glargine-300 group. The mean daily BG concentration in the degludec-100 group (157 mg/dL [SD 25]) was not inferior to that in the glargine-300 group (162 mg/dL [SD 24]), with a mean BG difference of -5 mg/dL (95% CI, -11 to 2, p = 0.18). There were no differences between degludec-100 group and glargine-300 group in mean percentage of readings within target BG of 70-180 mg/dL (74% ± 29% vs. 73% ± 30%, p = 0.19), daily basal insulin dose (19 ± 8 vs. 21 ± 9 units/day, p = 0.13), length of stay in hospital (median [IQR]: 9 [8-11] vs. 9 [8-11] days, p = 0.51), or hospital complications (21.3% vs. 21.4%, p = 0.99). There were no differences in the proportion of patients with BG &amp;lt;70 mg/dL (15.6% vs. 23.1%, p = 0.14) or &amp;lt;54 mg/dL (1.6% vs. 4.3%, p = 0.226) between degludec-100 and glargine-300 groups. There was no difference between groups in mean daily BG concentrations (141 ± 26 vs. 142 ± 28 mg/dL, p = 0.88), TIR (72. 0% vs. 72.9%, p = 0.71), TBR (5.9% vs. 5.2%, p = 0.50) and TAR (22. 0% vs. 21.8%, 0.93) as assessed by CGMS. Conclusions Treatment with degludec-100 as a basal insulin is as effective and safe as glargine-300 for the hospital management of patients with T2D admitted to cardiac surgery service in the non-intensive care unit setting. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes

BackgroundData are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes.MethodsWe assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons.ResultsDuring a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group.ConclusionsIn participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.)

Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes

BackgroundThe comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.MethodsIn this trial involving participants with type 2 diabetes of less than 10 years’ duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.ResultsA total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.ConclusionsAll four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.)

Comparison of the Impact of Insulin Degludec U100 and Insulin Glargine U300 on Glycemic Variability and Oxidative Stress in Insulin-Naive Patients With Type 2 Diabetes Mellitus: Pilot Study for a Randomized Trial

BackgroundThere is an ongoing discussion about possible differences between insulin degludec (IDeg-100) and glargine U300 (IGlar-300). There is little data and head-to-head comparison of IDeg-100 and IGlar-300 regarding their simultaneous impact on glycemic variability and oxidative stress in patients with type 2 diabetes mellitus (T2DM).ObjectiveIn our randomized, open-label, crossover study, we compared the impact of IDeg-100 and IGlar-300 on glycemic variability and oxidative stress in insulin-naive patients with T2DM.MethodsWe recruited a total of 25 adult patients with T2DM (7 females) whose diabetes was uncontrolled (HbA1c ≥7.5%) on two or more oral glucose-lowering drugs; a total of 22 completed the study. Mean age was 57.3 (SD 6.99) years and duration of diabetes was 9.94 (SD 5.01) years. After the washout period, they were randomized alternately to first receive either IDeg-100 or IGlar-300 along with metformin. Each insulin was administered for 12 weeks and then switched. At the beginning and end of each phase, biochemical and oxidative stress parameters were analyzed. On 3 consecutive days prior to each control point, patients performed a 7-point self-monitoring of blood glucose profile. Oxidative stress was assessed by measuring thiol groups and hydroperoxides (determination of reactive oxygen metabolites test) in serum.ResultsIGlar-300 reduced mean glucose by 0.02-0.13 mmol/L, and IDeg-100 reduced glucose by 0.10-0.16 mmol/L, with no significant difference. The reduction of the coefficient of glucose variation also did not show a statistically significant difference. IGlar-300 increased thiols by 0.08 µmol/L and IDeg-100 increased thiols by 0.15 µmol/L, with no significant difference (P=.07) between them. IGlar-300 reduced hydroperoxides by 0.040 CARR U and IDeg-100 increased hydroperoxides by 0.034 CARR U, but the difference was not significant (P=.12).ConclusionsThe results of our study do not show a significant difference regarding glycemic variability between patients receiving either insulin IDeg-100 or IGlar-300, although IGlar-300 showed greater dispersion of data. No significant difference in oxidative stress was observed. In a larger study, doses of insulins should be higher to achieve significant impact on glycemic parameters and consequently on glycemic variability and oxidative stress.Trial RegistrationClinicalTrials.gov, NCT04692415; https://clinicaltrials.gov/ct2/show/NCT04692415