Aim
To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR‐Asp) and the insulin aspart reference product (NovoLog; NN‐Asp) leads to equivalent pharmacokinetic (PK) ...exposure compared with continuous use of NN‐Asp in adults with type 1 diabetes (T1D).
Materials and Methods
This multicentre, open‐label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once‐daily insulin glargine U100 as basal insulin to four 4‐week periods of alternating multiple daily injections of SAR‐Asp and NN‐Asp (NN‐Asp for the first 4 weeks, SAR‐Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN‐Asp (non‐switching group). At week 16, a single dose (0.15 U/kg) of SAR‐Asp in the switching group (n = 95) or NN‐Asp in the non‐switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax) of SAR‐Asp versus NN‐Asp after the single dose at week 16.
Results
The extent of PK exposure was similar between the two treatments (SAR‐Asp in the switching group and NN‐Asp in the non‐switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8‐1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8‐1.25.
Conclusions
PK exposure of SAR‐Asp (switching group) and reference NN‐Asp (non‐switching group) were similar, supporting interchangeability between these two insulin aspart products.
Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic ...polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes.
This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003.
Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years SD 10·6, 476 51% were female, 710 76% were White, and 561 60% were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol SD 9·7). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was –12·8% (SE 0·6) and –14·7% (0·5), respectively, and –3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of –9·6% percentage points (95% CI –11·1 to –8·1) with tirzepatide 10 mg and –11·6% percentage points (–13·0 to –10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79–83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator.
In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management.
Eli Lilly and Company.
Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 ...antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation.
This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test MMTT), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155.
Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA
(a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema).
The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme.
Novo Nordisk.
SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a ...randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin.
This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters.
Of the 210 patients randomized, 200 (95.5%) completed the trial. Patients assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square LS mean difference = 0.05% 95% confidence interval CI = -0.13, 0.22; 0.50 mmol/mol -1.40, 2.39), fasting plasma glucose (LS mean difference = 0.23 mmol/L 95% CI = -1.08, 1.53; 4.12 mg/dL -19.38, 27.62), and changes in insulin dosages.
Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports interchangeability between SAR-Asp and NN-Asp in T1D management.
With disease progression, the need to intensify therapy with insulin is often required in patients with T2D to improve glycemic control. Addressing the manner in which insulin is delivered may impact ...outcomes. The purpose of this study was to broadly evaluate the clinical benefits of switching from insulin delivery via insulin pen/syringe to a wearable insulin delivery device (V-Go) in patients with T2D across multidisciplinary investigators spanning 8 states. A retrospective analysis of electronic medical records evaluated change in A1C, insulin total daily dose (TDD) and weight in 283 patients. Baseline mean ± SD characteristics were A1C 9.2 ± 1.5%, BMI 34.8 kg/m2 ± 6.7, weight 221 ± 45 lbs and TDD 76 ± 47 u/day (range 14 to 300) with basal-bolus (n=192, 68%), basal (n=64, 23%) and premix (n=15, 5%) regimens being predominately prescribed. Concomitant anti-hyperglycemic agents were prescribed in 77% of patients with a mean of 1.7 ± 0.8 agents/patient prescribed. Effect of V-Go was evaluated following a mean duration of 2.9 ± 1.3 and 7.1 ± 3.0 months of use. Significant decreases in A1C and TDD were observed at both time points. Change in weight was significant (+2.3 lbs; P<0.0001) at the first time point, however, was not significant (+2.1 lbs; P=0.106) by the second time point. Switching to insulin delivery with V-Go proved clinically beneficial compared to prior therapy.
Disclosure
R.S. Hundal: Speaker's Bureau; Self; Valeritas, Inc., Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Amarin Corporation, Eli Lilly and Company, Merck & Co., Inc. S. Kowalyk: Speaker's Bureau; Self; Valeritas, Inc.. J. Cases: None. A. Al-Karadsheh: None. A.P. Wakim: Speaker's Bureau; Self; Versartis, Inc.. Research Support; Self; Valeritas, Inc.. M. Doyle: None. J.H. Sink: Other Relationship; Self; Janssen Pharmaceuticals, Inc., valeritas. Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Becton, Dickinson and Company. A. Spence: None. J.L. Brewer: Speaker's Bureau; Self; Valeritas, Inc., Janssen Pharmaceuticals, Inc. C.C. Nikkel: Employee; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
Achieving A1C targets is a fundamental component of quality measures such as HEDIS and Star ratings. A typical basal-bolus insulin regimen requires 4 insulin injections a day. Adherence decreases as ...the number of injections increases and non-adherence to therapy is a primary reason for failure to achieve glycemic control. Less invasive options for insulin delivery may improve patient adherence leading to positive clinical outcomes. This multi-state retrospective analysis evaluated the achievement of glycemic targets compared to prior therapy in 186 patients switched from a basal-bolus regimen to a 24-hour wearable insulin delivery device (V-Go). At baseline, mean A1C was 9.1%, weight 219 lbs and insulin total daily dose (TDD) was 84 u/day across a mean of 4.3 injections/day. Forty-five percent of patients were poorly controlled (A1C > 9%) and less than 30% had achieved an A1C < 8% despite basal-bolus therapy. After 7 months of V-Go use, changes from baseline in A1C and TDD were significant (P<0.0001). Mean change (95% CI) in A1C was -1.02% (-1.24, -0.78) and TDD was reduced by 32% or 25 u/day (31, 19). Weight did not significantly change. Switching to V-Go, resulted in significant improvement to achievement of glycemic targets (90% increase in A1C values < 8% and 50% decrease in A1C values > 9%) compared to prior basal-bolus regimen, having positive implications on quality metrics.
Disclosure
R.S. Hundal: Speaker's Bureau; Self; Valeritas, Inc., Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Amarin Corporation, Eli Lilly and Company, Merck & Co., Inc. S. Kowalyk: Speaker's Bureau; Self; Valeritas, Inc.. J. Cases: None. A. Al-Karadsheh: None. A.P. Wakim: Speaker's Bureau; Self; Versartis, Inc.. Research Support; Self; Valeritas, Inc.. M. Doyle: None. J.H. Sink: Other Relationship; Self; Janssen Pharmaceuticals, Inc., valeritas. Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Becton, Dickinson and Company. A. Spence: None. J.L. Brewer: Speaker's Bureau; Self; Valeritas, Inc., Janssen Pharmaceuticals, Inc. C.C. Nikkel: Employee; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
A retrospective analysis was conducted to determine if duration of diabetes impacted clinical outcomes when switching from insulin pens/syringes to a wearable insulin delivery device (V-Go) in ...patients inadequately controlled. Patients (N=186) with T2D were stratified based on known duration of diabetes. A1C and insulin total daily dose (TDD) were extracted at baseline and two follow-up visits for each stratum. Paired t-tests were used to compare changes in A1C and TDD and a one-factor repeated measures ANCOVA model was performed to test for differences between groups with duration of diabetes as the factor and the corresponding baseline measurement as the covariate. Seventy-two percent of patients switched to V-Go had been diagnosed with diabetes for ≥ 10 years and 58% were switched to V-Go from conventional basal-bolus therapy. Clinical outcomes on V-Go were evaluated after a mean of 3 and 7 months. Regardless of duration of diabetes strata, significant reductions in A1C from baseline were observed. Further, all strata benefited from reductions in TDD with the exception of the duration stratum with the lowest baseline TDD (15 to 20 years), which maintained similar dosing on V-Go compared to baseline. By 7 months, no between group differences were observed for changes in A1C or TDD when controlling for baseline measurements. Insulin delivery with V-Go proved clinically beneficial regardless of duration of diabetes.
Disclosure
J. Cases: None. S. Kowalyk: Speaker's Bureau; Self; Valeritas, Inc. R.S. Hundal: Speaker's Bureau; Self; Valeritas, Inc., Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Amarin Corporation, Eli Lilly and Company, Merck & Co., Inc.. A. Al-Karadsheh: None. A.P. Wakim: Speaker's Bureau; Self; Versartis, Inc.. Research Support; Self; Valeritas, Inc.. M. Doyle: None. J.H. Sink: Other Relationship; Self; Janssen Pharmaceuticals, Inc., valeritas. Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Becton, Dickinson and Company. A. Spence: None. J.L. Brewer: Speaker's Bureau; Self; Valeritas, Inc., Janssen Pharmaceuticals, Inc. C.C. Nikkel: Employee; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels.
To determine the phase 3 efficacy and safety of a naturally derived krill oil ...with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA CaPre), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia.
This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate.
Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks.
The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups.
A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men 65.2%), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% 95% CI, -20.4% to -1.5%; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% 95% CI, -23.1% to -2.4%; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% 95% CI, -8.0% to 1.6%; P = .18), VLDL-C (-3.8% 95% CI, -12.2% to 4.7%; P = .38), HDL-C (0.7% 95% CI, -3.7% to 5.1%; P = .77), or LDL-C (4.5% 95% CI, -5.9% to 14.8%; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% 95% CI, -34.5% to -4.6%; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% 95% CI, -33.8% to -5.3%; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo.
This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia.
ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.
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