Impact of kidney function on the safety and efficacy of insulin degludec versus insulin glargine U300 in people with type 2 diabetes: A post hoc analysis of the CONCLUDE trial.
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SUBMITTER: Pieber TR
PROVIDER: S-EPMC9298323 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
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Impact of kidney function on the safety and efficacy of insulin degludec versus insulin glargine U300 in people with type 2 diabetes: A post hoc analysis of the CONCLUDE trial.
Pieber Thomas R TR Bajaj Harpreet S HS Heller Simon R SR Jia Ting T Khunti Kamlesh K Klonoff David C DC Ladelund Steen S Leiter Lawrence A LA Wagner Lily L Philis-Tsimikas Athena A
Diabetes, obesity & metabolism 20211017 2
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Project description:Aims/hypothesisA head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.MethodsThis randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0-5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.ResultsOf the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.Conclusions/interpretationThere was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.Trial registrationClinicalTrials.gov NCT03078478 FUNDING: This trial was funded by Novo Nordisk (Bagsvaerd, Denmark).
| S-EPMC7054369 | biostudies-literature
Project description:IntroductionThis study aimed to evaluate the short-term cost-effectiveness of insulin degludec 200 units/mL (degludec) versus insulin glargine 300 units/mL (glargine U300) from a Dutch societal perspective.MethodsA previously published model estimated costs [2018 euros (EUR)] and effectiveness [quality-adjusted life years (QALYs)] with degludec compared with glargine U300 over a 1-year time horizon. The model captured hypoglycaemia rates and insulin dosing. Clinical outcomes were informed by CONCLUDE (NCT03078478), a head-to-head randomised controlled trial in insulin-experienced patients with type 2 diabetes.ResultsTreatment with degludec was associated with mean annual cost savings (EUR 24.71 per patient) relative to glargine U300, driven by a lower basal insulin dose and lower severe hypoglycaemia rate with degludec compared with glargine U300. Lower rates of non-severe nocturnal and severe hypoglycaemia resulted in improved effectiveness (+ 0.0045 QALYs) with degludec relative to glargine U300. In sensitivity analyses, changes to the vast majority of model parameters did not materially affect model outcomes.ConclusionsThis short-term analysis, informed by the latest clinical trial evidence, demonstrated that degludec was a cost-effective treatment option relative to glargine U300. As such, our modelling analysis suggests that degludec would represent an efficient use of Dutch public healthcare resources in this patient population.
| S-EPMC7467476 | biostudies-literature
Project description:ObjectiveTirzepatide reduces HbA1c and body weight, and creatinine-based estimated glomerular filtration rate (eGFR) decline. Unlike creatine-derived eGFR (eGFR-creatinine), cystatin C-derived eGFR (eGFR-cystatin C) is unaffected by muscle mass changes. We assessed effects of tirzepatide on eGFR-creatinine and eGFR-cystatin C.Research design and methodsOur primary outcome was eGFR change from baseline at 52 weeks with pooled tirzepatide (5, 10, and 15 mg) and titrated insulin glargine in adults with type 2 diabetes and high cardiovascular risk (SURPASS-4).ResultsLeast squares mean (SE) eGFR-creatinine (mL/min/1.73 m2) changes from baseline with tirzepatide and insulin glargine were -2.5 (0.38) and -3.9 (0.38) (between-group difference, 1.4 [95% CI 0.3-2.4]) and -3.5 (0.37) and -5.3 (0.37) (between-group difference, 1.8 [95% CI 0.8-2.8]) for eGFR-cystatin C. Baseline, 1-year, and 1-year change from baseline values significantly correlated between eGFR-cystatin C and eGFR-creatinine. Measures of eGFR changes did not correlate with body weight changes.ConclusionsTirzepatide slows the eGFR decline rate, supporting a kidney-protective effect.
| S-EPMC10369133 | biostudies-literature
Project description:The impacts of insulin degludec U100 (Deg-100) and insulin glargine U300 (Gla-300) on glycemic variability (GV) in patients with type 1 diabetes, as well as the impact of major nutrient components on GV in these patients, remain unclear. This was an observational, cross-sectional, retrospective study. Type 1 diabetes mellitus patients treated with either Deg-100 or Gla-300 as basal insulin were enrolled. After the participants underwent continuous glucose monitoring, GV indices and major nutrient components were analyzed. Forty patients with type 1 diabetes were enrolled, and 20 participants used Deg-100, and 20 used Gla-300. There was no significant difference in major nutrient components between the two groups. Better GV indices of standard deviation, coefficient of variation, mean amplitude of glycemic excursion, AUCn, M-value, CONGA1, CONGA2, and CONGA4 were noted in the Gla-300 group versus Deg-100 group. Compared with patients who received once-daily injection in the morning (QD), Deg-100 administration once daily at bedtime (HS) yielded a higher low blood glucose index during both day and nocturnal periods, indicating a higher risk of hypoglycemic events. By contrast, there were significantly lower levels of CONGA1, CONGA2, and CONGA4 during insulin Gla-300 QD administration than during HS administration, indicating a lower GV of a short interval. In this real-world study involving type 1 diabetes patients, Gla-300 appears to offer more stable glucose variability than Deg-100. Administering once-daily injections could lower the risk of hypoglycemia in the Deg-100 group and minimize GV in the Gla-300 group compared to bedtime injections.
| S-EPMC11618557 | biostudies-literature
Project description:We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin (HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity (B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event (AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs.
| S-EPMC5067686 | biostudies-literature
Project description:IntroductionTo estimate the cost-effectiveness of insulin degludec (IDeg) versus insulin glargine U100 (IGlar U100) and new-to-market basal insulin analogues in patients with diabetes in order to aid decision-making in a complex basal insulin market.MethodsA simple, short-term model was used to evaluate the costs and effects of treatment with IDeg versus IGlar U100 over a 12-month period in patients with type 1 (T1DM) and type 2 diabetes (T2DM) from the perspective of the UK National Health Service. New-to-market basal insulin analogues were evaluated in scenario analyses.ResultsIDeg is dominant (more effective and less costly) versus IGlar U100 in patients with T1DM and patients with T2DM on a basal-only therapy regimen (T2DMBOT), and is cost-effective versus IGlar U100 in patients with T2DM on a basal-bolus regimen (T2DMB/B). In T1DM, lower costs are primarily driven by lower insulin costs, as a result of a lower daily dose of IDeg. In T2DMBOT, lower overall costs with IDeg are driven by lower costs of severe hypoglycaemic events due to the significant reduction in number of events with IDeg versus IGlar U100. Improvements in clinical outcomes in all three patient groups are a result of the reduced incidence of hypoglycaemic events. Sensitivity analyses demonstrate that the results are robust. Scenario analyses versus two new-to-market basal insulin analogues indicate that in patients with T1DM and T2DMBOT, IDeg is likely to be highly cost-effective versus IGlar biosimilar Abasaglar® and dominant versus IGlar U300 (Toujeo®). In T2DMB/B, IDeg is likely to be cost-effective versus both comparators, with incremental cost-effectiveness ratios (ICERs) below the accepted threshold.ConclusionIDeg is a cost-effective alternative to IGlar U100 for patients with diabetes in the UK, and it also likely to be cost-effective versus two new-to-market basal insulin analogues.
| S-EPMC5380498 | biostudies-literature
Project description:IntroductionThis post hoc analysis evaluated subgroup data from China (Chinese mainland, n = 100; Taiwan, n = 45) in ONWARDS 3, a 26-week, randomized, double-blind, double-dummy, treat-to-target, phase 3a trial comparing the efficacy and safety of once-weekly insulin icodec (icodec) versus once-daily insulin degludec (degludec) in insulin-naive participants with type 2 diabetes (T2D).MethodsAdults were randomized 1:1 to icodec and once-daily placebo (icodec; n = 72) or degludec and once-weekly placebo (degludec; n = 73). The primary endpoint was change in glycated hemoglobin (HbA1c) (baseline to week 26). Secondary assessments included change in fasting plasma glucose (FPG; baseline to week 26); total weekly insulin dose (weeks 24-26); body weight change (baseline to week 26); and clinically significant or severe hypoglycemia rates (baseline to week 31 [5-week follow-up included]).ResultsAt week 26, from baseline values of 8.22% (icodec) and 8.39% (degludec), estimated mean changes in HbA1c were - 1.38% points and - 1.10% points, respectively (estimated treatment difference [95% confidence interval], - 0.28%-points [- 0.50%-points, - 0.05%-points]; p = 0.0152). For icodec and degludec, estimated mean FPG change (- 2.3 mmol/L vs. - 2.3 mmol/L), estimated mean insulin doses (158 U/week vs. 142 U/week), and estimated body weight change (2.5 kg vs. 2.4 kg) were similar. Combined clinically significant or severe hypoglycemia rates were low (0.10 [icodec] vs. 0.07 [degludec] events per patient-year of exposure), with no statistically significant difference between groups.ConclusionIn insulin-naive Chinese individuals with T2D, once-weekly icodec treatment showed significantly greater HbA1c reductions after 26 weeks than once-daily degludec, with low combined clinically significant or severe hypoglycemia rates across groups.ClinicaltrialsGov identifierNCT04795531.
| S-EPMC11926311 | biostudies-literature
Project description:In the DEVOTE and SWITCH 2 trials, insulin degludec 100 units/mL (degludec) was superior to insulin glargine 100 units/mL (glargine U100) with respect to the rates of severe (DEVOTE; across trial) and overall symptomatic (SWITCH 2; during the maintenance period of the trial) hypoglycaemia in individuals with type 2 diabetes. In this post hoc analysis, data from 7635 individuals from DEVOTE and 720 individuals from SWITCH 2 were analysed by subgroups of diabetes duration at baseline (<10, ≥10-<15, ≥15-<20 and ≥20 years) using prespecified models from both trials. There was a trend towards lower rates of hypoglycaemia with degludec versus glargine U100 across all diabetes duration subgroups in both trials, with the difference being statistically significant in some subgroups in DEVOTE and SWITCH 2. Overall, however, no significant interaction was observed between diabetes duration and treatment (DEVOTE interaction, P = .496; SWITCH 2 interaction, P = .144). Therefore, in this post hoc analysis of DEVOTE and SWITCH 2, diabetes duration did not appear to affect the reduction in rates of hypoglycaemia observed with degludec compared with glargine U100.
| S-EPMC8286333 | biostudies-literature
Project description: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.
| S-EPMC9308081 | biostudies-literature
Project description:AimTreat-to-target, randomized controlled trials have confirmed lower rates of hypoglycaemia at equivalent glycaemic control with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 1 (T1D) or type 2 diabetes (T2D). Treat-to-target trials are designed to enable comparisons of safety and tolerability at a similar HbA1c level. In this post hoc analysis of the SWITCH 1 and 2 trials, we utilised a patient-level modelling approach to compare how glycaemic control might differ between basal insulins at a similar rate of hypoglycaemia.Materials and methodsData for HbA1c and symptomatic hypoglycaemia from the SWITCH 1 and SWITCH 2 trials were analyzed separately for patients with type 1 diabetes and type 2 diabetes, respectively. The association between the individual patient-level risk of hypoglycaemia and HbA1c was investigated using a Poisson regression model and used to estimate potential differences in glycaemic control with degludec versus glargine U100, at the same rate of hypoglycaemia.ResultsImprovements in glycaemic control increased the incidence of hypoglycaemia with both basal insulins across diabetes types. Our analysis suggests that patients could achieve a mean HbA1c reduction of 0.70 [0.05; 2.20]95% CI (for type 1 diabetes) or 0.96 [0.39; 1.99]95% CI (for type 2 diabetes) percentage points (8 [1; 24]95% CI or 10 [4; 22]95% CI mmol/mol, respectively) further with degludec than with glargine U100 before incurring an equivalent risk of hypoglycaemia.ConclusionOur findings suggest that patients in clinical practice may be able to achieve lower glycaemia targets with degludec versus glargine U100, before incurring an equivalent risk of hypoglycaemia.
| S-EPMC7186831 | biostudies-literature