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Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.

ABSTRACT: Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 ?mol/L; n = 59), IDeg(B) (900 ?mol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments.In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.

SUBMITTER: Birkeland KI

PROVIDER: S-EPMC3041203 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.

Birkeland Kåre I KI Home Philip D PD Wendisch Ulrich U Ratner Robert E RE Johansen Thue T Endahl Lars A LA Lyby Karsten K Jendle Johan H JH Roberts Anthony P AP DeVries J Hans JH Meneghini Luigi F LF

Diabetes care 20110126 3

<h4>Objective</h4>Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.<h4>Research design and methods</h4>In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26. ...[more]

PMID: 21270174

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Project description:IntroductionThe purpose of this study was to compare insulin degludec with insulin glargine in terms of efficacy and safety in patients with type 2 diabetes.MethodsWe systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases for randomized controlled trials published prior to 13 August 2018 (no language restrictions) which compared insulin degludec with insulin glargine. Our main endpoints were glycemic control, hypoglycemic event, weight gain, and serious adverse events (SAEs). We assessed pooled data using random-effects models.ResultsA total of 15 studies that included 9619 patients in the insulin degludec arm of the studies and 7075 patients in the insulin glargine arm were identified and subsequently assessed. Our analysis showed that compared with insulin glargine, insulin degludec yielded an improved mean reduction in fasting plasma glucose (FPG) (weighted mean difference [WMD] - 5.20 mg/dL, 95% confidence interval [CI] - 7.34, - 3.07, P < 0.00001) and a lower ratio of participants experiencing ≥ 1 severe hypoglycemic event (relative risk [RR] 0.68, 95% CI 0.50, 0.93, P = 0.01) and nocturnal hypoglycemia (RR 0.81, 95% CI 0.75, 0.88, P < 0.0001); however, in the insulin degludec group there was a lower ratio of participants with glycated hemoglobin (HbA1c) of ≤ 7.0% (RR 0.92, 95% CI 0.86, 0.98, P = 0.01). There was no statistically significant difference between the two treatment groups for HbA1c reduction (WMD 0.03, 95% CI - 0.00, 0.07, P = 0.08), body weight gain (WMD 0.12, 95% CI - 0.19, 0.43, P = 0.46), and proportion of participants with SAEs (RR 0.97, 95% CI 0.92, 1.02, P = 0.20).ConclusionsInsulin degludec and insulin glargine provide similar glycemic control, but insulin degludec also lowers the risk of hypoglycemia. Consequently, insulin degludec may be an alternative treatment for the management of patients with type 2 diabetes who are prone to hypoglycemia with insulin glargine.

Project description:The effects of insulin on cardiomyocytes, such as positive inotropic action and glucose uptake are well described. However, in vitro studies comparing long-acting insulin analogues with regard to cardiomyocyte signalling and function have not been systematically conducted.Insulin receptor (IR) binding was assessed using membrane embedded and solubilised IR preparations. Insulin signalling was analysed in adult rat ventricular myocytes (ARVM) and HL-1 cardiac cells. Inotropic effects were examined in ARVM and the contribution of Akt to this effect was assessed by specific inhibition with triciribine. Furthermore, beating-rate in Cor.4U(®) human cardiomyocytes, glucose uptake in HL-1 cells, and prevention from H2O2 induced caspase 3/7 activation in cardiac cells overexpressing the human insulin receptor (H9c2-E2) were analysed. One-way ANOVA was performed to determine significance between conditions.Insulin degludec showed significant lower IR affinity in membrane embedded IR preparations. In HL-1 cardiomyocytes, stimulation with insulin degludec resulted in a lower Akt(Ser(473)) and Akt(Thr(308)) phosphorylation compared to insulin, insulin glargine and its active metabolite M1 after 5- and 10-min incubation. After 60-min treatment, phosphorylation of Akt was comparable for all insulin analogues. Stimulation of glucose uptake in HL-1 cells was increased by 40-60 %, with a similar result for all analogues. Incubation of electrically paced ARVM resulted for all insulins in a significantly increased sarcomere shortening, contractility- and relaxation-velocity. This positive inotropic effect of all insulins was Akt dependent. Additionally, in Cor.4U(®) cardiomyocytes a 10-20 % increased beating-rate was detected for all insulins, with slower onset of action in cells treated with insulin degludec. H9c2-E2 cells challenged with H2O2 showed a fivefold increase in caspase 3/7 activation, which could be abrogated by all insulins used.In conclusion, we compared for the first time the signalling and functional impact of the long-acting insulin analogues insulin glargine and insulin degludec in cardiomyocyte cell models. We demonstrated similar efficacy under steady-state conditions relative to regular insulin in functional endpoint experiments. However, it remains to be shown how these results translate to the in vivo situation.

Dataset Information

Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.

Publications

Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.

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