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.

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.

Real-world effectiveness and safety of insulin glargine 100 U/mL plus lixisenatide in adults with type 2 diabetes: An international, multicentre, 12-month, prospective observational study.

AIM: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). MATERIALS AND METHODS: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6. RESULTS: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year]). CONCLUSIONS: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia.

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.

Saxagliptin/dapagliflozin is non-inferior to insulin glargine in terms of ß-cell function in subjects with latent autoimmune diabetes in adults: A 12-month, randomized, comparator-controlled pilot study.

AIM: To compare the efficacy and safety of saxagliptin/dapagliflozin and insulin glargine in people with latent autoimmune diabetes in adults (LADA). METHODS: In this phase 2b multicentre, open-label, comparator-controlled, parallel-group, non-inferiority study, we randomly assigned 33 people with LADA who had a fasting C-peptide concentration ≥0.2 nmol/L (0.6 ng/mL) to receive 1-year daily treatment with either the combination of saxagliptin (5 mg) plus dapagliflozin (10 mg) or insulin glargine (starting dose: 10 IU), both on top of metformin. The primary outcome was the 2-h mixed meal-stimulated C-peptide area under the curve (AUC), measured 12 months after randomization. Secondary outcomes were glycated haemoglobin (HbA1c) levels, change in body mass index (BMI), and hypoglycaemic events. RESULTS: In the modified intention-to-treat analysis, the primary outcome was similar in participants assigned to saxagliptin/dapagliflozin or to insulin glargine (median C-peptide AUC: 152.0 ng*min/mL [95% confidence interval {CI} 68.2; 357.4] vs. 122.2 ng*min/mL [95% CI 84.3; 255.8]; p for noninferiority = 0.0087). Participants randomized to saxagliptin/dapagliflozin lost more weight than those randomized to insulin glargine (median BMI change at the end of the study: -0.4 kg/m2 [95% CI -1.6; -0.3] vs. +0.4 kg/m2 [95% CI -0.3; +1.1]; p = 0.0076). No differences in HbA1c or in the number of participants experiencing hypoglycaemic events were found. CONCLUSIONS: Saxagliptin/dapagliflozin was non-inferior to glargine in terms of ß-cell function in this 12-month, small, phase 2b study, enrolling people with LADA with still viable endogenous insulin production. Weight loss was greater with saxagliptin/dapagliflozin, with no differences in glycaemic control or hypoglycaemic risk.

Bridging dose of U-100 glargine with first dose of insulin degludec improves glycaemia in the 48 h after transition in twice-daily glargine users.

AIMS: To study the effects of a bridging dose of U-100 glargine (U-100G) with the first dose of degludec in type 1 diabetes (T1D) patients transitioning from glargine to degludec, by comparing the glucose metrics 48 h before and after the transition. MATERIALS AND METHODS: Patients with T1D on a stable U-100G regimen and with glycated haemoglobin concentration <75 mmol/mol were randomized (double-blind) to one dose of placebo or U-100G with first dose of degludec, administered at 9:00 pm. Patients on once-daily U-100G at baseline received 50% of total U-100G dose (bridging dose), while patients on twice-daily U-100G received 50% of the evening U-100G dose. Participants wore a continuous glucose monitor during the study. RESULTS: Forty participants were randomized, of whom 37 completed the study. The cohort was 65% male, the mean age was 47 years, duration of T1D 22 years, BMI 26 kg/m2, HbA1c 51 mmol/mol and total daily insulin dose 0.7 units/kg body weight. The bridging group included 19 participants (once-daily U-100G: n = 12; twice-daily U-100G: n = 7) and the placebo group included 18 participants (once-daily U-100G: n = 12; twice-daily U-100G: n = 6). Change in time in range (TIR) was not significantly different between the two treatment groups. In secondary analyses, among twice-daily U-100G users, TIR (3.9-10 mmol/L) increased 8% in the bridging group in the 48 h after first dose of degludec compared to the preceding 48 h, while participants in the placebo group had a 9.5% decrease (p = 0.027). CONCLUSIONS: A subgroup of well-controlled twice-daily U-100G users transitioning to degludec benefited from a 50% bridging dose of evening U-100G with the first dose of degludec in a small pilot study.

Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes.

AIMS: To investigate the pharmacokinetic/pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes (T1D). MATERIALS AND METHODS: In this randomized, open-label, two-period crossover trial, 66 individuals with T1D (age 18-64 years; glycated haemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once-weekly icodec (8 weeks) and once-daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run-in with glargine U100 titrated to pre-breakfast plasma glucose (PG) of 4.4-7.2 mmol/L (80-130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16-52 h and 138-168 h after the last icodec dose and 0-24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic-pharmacodynamic modelling. Hypoglycaemia was recorded during the treatment periods based on self-measured PG. RESULTS: Icodec reached pharmacokinetic steady state on average within 2-3 weeks. At steady state, model-predicted daily proportions of glucose infusion rate during the 1-week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6% and 8.4%, respectively. Rates and duration of Level 2 hypoglycaemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant-year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100. CONCLUSIONS: The pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal-bolus insulin regimen in people with T1D.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

AIMS: To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). MATERIALS AND METHODS: Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. RESULTS: Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. CONCLUSIONS: In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

A prospective, multicentre, randomized, open-label comparison of a long-acting basal insulin analog glargine plus glulisine with premixed insulin in insulin naïve patients with Type 2 diabetes - A study from India.

AIMS: We aimed to compare the effectiveness of Glargine plus Glulisine to premixed insulin analogue, as measured by HbA1c ≤ 7.0% in insulin naive Type 2 Diabetes (T2D) patients with elevated fasting and/or postprandial plasma glucose. METHODS: Insulin-naive T2D patients (116 men, 84 women) on ≥ 2 oral hypoglycemic agents with inadequate glycemic control were randomized either to group 1 (insulin Glargine plus Glulisine, n = 101) or group 2 (Premixed Insulin analogue, n = 99). RESULTS: In the intention to treat analysis, at week 24, percentage of patients with good glycaemic control (HbA1c ≤ 7.0%) was similar between the two groups (16.8% in Group 1 vs. 13.1% in Group 2, χ2 - 0.535, p = 0.47). Significant reductions in fasting and postprandial levels were observed in groups 1 and 2 at both post-baseline time points (Week 12 and 24). In group 1, reduction in HbA1c from baseline to week 12 was 0.6 ± 0.1 and 0.7 ± 0.2 at week 24, p < 0.0001 for all. In group 2, no significant change in HbA1c was observed. In group 1, 83.2% required an additional dose of glulisine and in group 2, 88.9% required an additional dose of premixed insulin. Hypoglycemic events were similar in both groups (0.12 events per person-year in group 1 and 0.13 events per person-year in group 2). Weight gain was non-significant in both groups. CONCLUSIONS: Glargine plus Glulisine, though in higher dose was effective as premixed insulin in lowering HbA1c. Hypoglycemic events per person-year were similar in both groups.

Effect of basal insulin and omega 3 fatty acids on cognitive impairment in dysglycaemia: An exploratory analysis of the ORIGIN trial.

AIM: The outcomes reduction with an initial glargine intervention (ORIGIN) trial reported that, allocation to insulin glargine-mediated normoglycaemia versus standard care, and to omega 3 fatty acids versus placebo had a neutral effect on cognitive test scores when analysed as continuous variables. Analyses of these scores as standardized categorical variables using a previously validated strategy may yield different results. MATERIALS AND METHODS: The ORIGIN trial recruited participants with dysglycaemia and additional cardiovascular risk factors from 573 sites in 40 countries. They completed a mini mental state examination and a subset completed the digit symbol substitution test at baseline and up to three subsequent visits. The effect of the interventions on country-standardized substantive cognitive impairment, defined as the first occurrence of a baseline-adjusted follow-up mini mental state examination or digit symbol substitution test score ≥1.5 standard deviations below the baseline mean score in each participant's country was assessed using Cox proportional hazards models. RESULTS: During a median follow-up of 6.2 years, 2627 of 11 682 people (22.5%) developed country-standardized substantive cognitive impairment. The hazard of this outcome was reduced by 9% (hazard ratio 0.91, 95% confidence interval 0.85, 0.99; p = .023) in participants assigned to insulin glargine (21.6%) versus standard care (23.3%). Conversely, the hazard of this outcome was not affected by assignment to omega 3 fatty acid versus placebo (hazard ratio 0.93, 95% confidence interval 0.86, 1.01; p = .074). CONCLUSIONS: In this post hoc exploratory analysis, insulin glargine-mediated normoglycaemia but not omega 3 fatty acids reduced the hazard of substantive cognitive impairment in people with dysglycaemia and additional cardiovascular risk factors.

Insulin Glargine in Type 1 Diabetes Mellitus: A Review of Clinical Trials and Real-world Evidence Across Two Decades.

BACKGROUND: Over the past two decades, insulin glargine 100 U/mL (Gla-100) has emerged as the "standard of care" basal insulin for the management of type 1 diabetes mellitus (T1DM). Both formulations, insulin glargine 100 U/mL (Gla-100) and glargine 300 U/mL (Gla- 300) have been extensively studied against various comparator basal insulins across various clinical and real-world studies. In this comprehensive article, we reviewed the evidence on both insulin glargine formulations in T1DM across clinical trials and real-world studies. METHODS: Evidence in T1DM for Gla-100 and Gla-300 since their approvals in 2000 and 2015, respectively, were reviewed. RESULTS: Gla-100 when compared to the second-generation basal insulins, Gla-300 and IDeg-100, demonstrated a comparable risk of overall hypoglycemia, but the risk of nocturnal hypoglycemia was higher with Gla-100. Additional benefits of Gla-300 over Gla-100 include a prolonged (>24- hours) duration of action, a more stable glucose-lowering profile, improved treatment satisfaction, and greater flexibility in the dose administration timing. CONCLUSION: Both glargine formulations are largely comparable to other basal insulins in terms of glucose-lowering properties in T1DM. Further, risk of hypoglycemia is lower with Gla-100 than Neutral Protamine Hagedorn but comparable to insulin detemir.

Advancing type 2 diabetes therapy with iGlarLixi in older people: Pooled analysis of four randomized controlled trials.

AIM: To assess the efficacy and safety of iGlarLixi in older people (≥65 years) with type 2 diabetes (T2D) advancing or switching from oral agents, a glucagon-like peptide-1 receptor agonist (GLP-1RA), or basal insulin. MATERIALS AND METHODS: The data of participants aged <65 years and ≥65 years from four LixiLan trials (LixiLan-O, LixiLan-G, LixiLan-L, SoliMix) were evaluated over 26 or 30 weeks. RESULTS: Participants aged <65/≥65 years (n = 1039/n = 497) had a mean baseline body mass index of 31.4 and 30.7 kg/m2 and glycated haemoglobin (HbA1c) concentration of 66 mmol/mol (8.2%) and 65 mmol/mol (8.1%), respectively. Least squares mean HbA1c change from baseline to end of treatment (EOT) was -14.32 mmol/mol (-1.31%) (95% confidence interval [CI] -14.97, -13.77 [-1.37%, -1.26%]) for those aged <65 years and -13.66 mmol/mol (-1.25%) (95% CI -14.54, -12.79 [-1.33%, -1.17%]) for those aged ≥65 years. At EOT, achievement of HbA1c targets was similar between the group aged <65 years and the group aged ≥65 years: <53 mmol/mol (<7%) (59.0% and 56.5%, respectively), <59 mmol/mol (<7.5%) (75.5% and 73.0%, respectively) and <64 mmol/mol (<8%) (83.8% and 84.1%, respectively). The incidence and event rate of American Diabetes Association Level 1 hypoglycaemia during the studies were also comparable between the two groups: 26.7% and 28.2% and 1.7 and 2.1 events per patient-year for the group aged <65 years and the group aged ≥65 years, respectively. A clinically relevant reduction in HbA1c (>1% from baseline for HbA1c ≥64 mmol/mol [≥8%] or ≥0.5% from baseline for HbA1c <64 mmol/mol [<8%]) without hypoglycaemia was attained by 50.0% and 47.6% of participants aged <65 years and ≥65 years, respectively. Adverse events were similar between the two age groups. CONCLUSIONS: iGlarLixi is a simple, well-tolerated, once-daily alternative for treatment advancement in older people with T2D that provides significant improvements in glycaemic control without increasing hypoglycaemia risk, thus reducing the treatment burden.

5-Year simulation of diabetes-related complications in people treated with tirzepatide or semaglutide versus insulin glargine.

AIM: This study compared the 5-year incidence rate of macrovascular and microvascular complications for tirzepatide, semaglutide and insulin glargine in individuals with type 2 diabetes, using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model. RESEARCH DESIGN AND METHODS: This study was a 5-year SURPASS-2 trial extrapolation, with an insulin glargine arm added as an additional comparator. The 1-year treatment effects of tirzepatide (5, 10 or 15 mg), semaglutide (1 mg) and insulin glargine on glycated haemoglobin, systolic blood pressure, low-density lipoprotein and body weights were obtained from the SUSTAIN-4 and SURPASS-2 trials. We used the BRAVO model to predict 5-year complications for each study arm under two scenarios: the 1-year treatment effects persisted (optimistic) or diminished to none in 5 years (conservative). RESULTS: When compared with insulin glargine, we projected a 5-year risk reduction in cardiovascular adverse events [rate ratio (RR) 0.64, 95% confidence interval (CI) 0.61-0.67] and microvascular composite (RR 0.67, 95% CI 0.64-0.70) with 15 mg tirzepatide, and 5-year risk reduction in cardiovascular adverse events (RR 0.75, 95% CI 0.72-0.79) and microvascular composite (RR 0.79, 95% CI 0.76-0.82) with semaglutide (1 mg) under an optimistic scenario. Lower doses of tirzepatide also had similar, albeit smaller benefits. Treatment effects for tirzepatide and semaglutide were smaller but still significantly higher than insulin glargine under a conservative scenario. The 5-year risk reduction in diabetes-related complication events and mortality for the 15 mg tirzepatide compared with insulin glargine ranged from 49% to 10% under an optimistic scenario, which was reduced by 17%-33% when a conservative scenario was assumed. CONCLUSION: With the use of the BRAVO diabetes model, tirzepatide and semaglutide exhibited potential to reduce the risk of macrovascular and microvascular complications among individuals with type 2 diabetes, compared with insulin glargine in a 5-year window. Based on the current modelling assumptions, tirzepatide (15 mg) may potentially outperform semaglutide (1 mg). While the BRAVO model offered insights, the long-term cardiovascular benefit of tirzepatide should be further validated in a prospective clinical trial.

Treatment responses to basal insulin glargine 300 U/ml and glargine 100 U/ml in newly defined subphenotypes of type 2 diabetes: A post hoc analysis of the EDITION 3 randomized clinical trial.

INTRODUCTION: To compare responses to basal insulin glargine 300 U/ml (IGlar-300) and 100 U/ml (IGlar-100) in newly defined subphenotypes of type 2 diabetes. METHODS: Insulin-naive participants (n = 858) from the EDITION 3 trial were assigned to subphenotypes 'Mild Age-Related Diabetes (MARD)', 'Mild Obesity Diabetes (MOD)', 'Severe Insulin Resistant Diabetes (SIRD)' and 'Severe Insulin Deficient Diabetes (SIDD)'. Key variables were analysed at baseline and 26 weeks. RESULTS: Participants were comprised of MOD 56.1% (n = 481), SIDD 22.1% (n = 190), MARD 18.2% (n = 156) and SIRD 3.0% (n = 26). After 26 weeks a similar decrease in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) of 16-19 mmol/mol and 1.4-1.7 mmol/L, respectively, occurred in MARD and MOD with both insulins. SIDD had the most elevated HbA1c and FPG (80-83 mmol/mol/11.1-11.4 mmol/L) and reduction in both HbA1c and FPG was greater with IGlar-100 than with IGlar-300 (-18 vs. -15 mmol/mol and -1.6 vs. -1.3 mmol/L, respectively; each p = .03). In SIDD, despite receiving the highest basal insulin doses, HbA1c decline (57-60 mmol/mol/7.3-7.6%) was suboptimal at week 26. In MOD and SIDD lower incidences with IGlar-300 were found for level 1 nocturnal hypoglycaemia [odds ratio (OR) 0.59, 95% confidence intervals (CI) 0.36-0.97; OR 0.49, 95% CI 0.24-0.99]. In addition, fewer level 2 hypoglycaemia episodes occurred at any time with IGlar-300 in SIDD (OR 0.31, 95% CI 0.13-0.77). CONCLUSION: Both insulins produce comparable outcomes in type 2 diabetes subphenotypes, but in SIDD, add-on treatment to basal insulin is required to achieve glycaemic targets.

Unexpected evolution of a monster case of insulin-induced skin lipohypertrophy.

In this journal, in 2020, we published the case of a 74-year-old female outpatient with type-2 diabetes mellitus who self-injected insulin four times a day according to the basal-bolus regimen, with an high glycemic variability and an high rate of severe hypoglycemic episodes. Three years before, we had found two extraordinarily large skin lipohypertrophies, with large underlying fluid collections with high insulin concentration. A long educational and intensive training completely repaired the skin lesions with the disappearance of the subcutaneous insulin reservoirs. Glycemic variability has been reduced dramatically, severe hypoglycemia has almost completely disappeared and the daily dose of insulin has been reduced by 38%. However, this extraordinary, albeit unexpected, result was achieved in five years.

Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial.

Importance: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described. Objective: To assess the efficacy and safety of tirzepatide vs insulin lispro as an adjunctive therapy to insulin glargine. Design, Setting, and Participants: This open-label, phase 3b clinical trial was conducted at 135 sites in 15 countries (participants enrolled from October 19, 2020, to November 1, 2022) in 1428 adults with type 2 diabetes taking basal insulin. Interventions: Participants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708). Main Outcomes and Measures: Outcomes included noninferiority of tirzepatide (pooled cohort) vs insulin lispro, both in addition to insulin glargine, in HbA1c change from baseline at week 52 (noninferiority margin, 0.3%). Key secondary end points included change in body weight and percentage of participants achieving hemoglobin A1c (HbA1c) target of less than 7.0%. Results: Among 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was -2.1% vs -1.1% with insulin lispro, resulting in mean HbA1c levels of 6.7% vs 7.7% (estimated treatment difference, -0.98% [95% CI, -1.17% to -0.79%]; P < .001); results met noninferiority criteria and statistical superiority was achieved. Estimated mean change from baseline in body weight was -9.0 kg with tirzepatide and 3.2 kg with insulin lispro (estimated treatment difference, -12.2 kg [95% CI, -13.4 to -10.9]). The percentage of participants reaching HbA1c less than 7.0% was 68% (483 of 716) with tirzepatide and 36% (256 of 708) with insulin lispro (odds ratio, 4.2 [95% CI, 3.2-5.5]). The most common adverse events with tirzepatide were mild to moderate gastrointestinal symptoms (nausea: 14%-26%; diarrhea: 11%-15%; vomiting: 5%-13%). Hypoglycemia event rates (blood glucose level <54 mg/dL or severe hypoglycemia) were 0.4 events per patient-year with tirzepatide (pooled) and 4.4 events per patient-year with insulin lispro. Conclusions and Relevance: In people with inadequately controlled type 2 diabetes treated with basal insulin, weekly tirzepatide compared with prandial insulin as an additional treatment with insulin glargine demonstrated reductions in HbA1c and body weight with less hypoglycemia. Trial Registration: ClinicalTrials.gov Identifier: NCT04537923.

Pharmacokinetic and pharmacodynamic bioequivalence of Gan & Lee insulin analogues aspart (rapilin®), lispro (prandilin®) and glargine (basalin®) with EU- und US-sourced reference insulins.

AIM: For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States. METHODS: Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38) and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total ) and maximum insulin concentrations (Cins.max ). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total ) and maximum glucose infusion rate (GIRmax ). RESULTS: Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%-125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins. CONCLUSION: GL-Asp, GL-Lis and GL-Gla are bioequivalent to their EU- and US-reference products.