Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: a randomised trial

Leo Niskanen, Lawrence A Leiter, Edward Franek, Jianping Weng, Taner Damci, Manuel Muñoz-Torres, Jean-Paul Donnet, Lars Endahl, Trine Vang Skjøth, Allan Vaag, Leo Niskanen, Lawrence A Leiter, Edward Franek, Jianping Weng, Taner Damci, Manuel Muñoz-Torres, Jean-Paul Donnet, Lars Endahl, Trine Vang Skjøth, Allan Vaag

Abstract

Objective: Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of insulin degludec (70%) and insulin aspart (IAsp: 30%). Here, we compare the efficacy and safety of IDegAsp, an alternative IDegAsp formulation (AF: containing 45% IAsp), and biphasic IAsp 30 (BIAsp 30).

Design: Sixteen-week, open-label, randomised, treat-to-target trial.

Methods: Insulin-naive subjects with type 2 diabetes (18-75 years) and a HbA1c of 7-11% were randomised to twice-daily IDegAsp (n=61), AF (n=59) or BIAsp 30 (n=62), all in combination with metformin. Insulin was administered pre-breakfast and dinner (main evening meal) and titrated to pre-breakfast and pre-dinner plasma glucose (PG) targets of 4.0-6.0 mmol/l.

Results: Mean HbA1c after 16 weeks was comparable for IDegAsp, AF and BIAsp 30 (6.7, 6.6 and 6.7% respectively). With IDegAsp, 67% of subjects achieved HbA1c 7.0% Without confirmed hypoglycaemia in the last 4 weeks of treatment compared with 53% (AF) and 40% (BIAsp 30). Mean fasting PG was significantly lower for IDegAsp vs BIAsp 30 (treatment difference (TD): -0.99 mmol/l (95% confidence interval: -1.68; 0.29)) and AF vs BIAsp 30 (TD: -0.88 mmol/l (-1.58; -0.18)). A significant, 58% lower rate of confirmed hypoglycaemia was found for IDegAsp vs BIAsp 30 (rate ratio (RR): 0.42 (0.23; 0.75)); rates were similar for AF vs BIAsp 30 (RR: 0.92 (0.54; 1.57)). IDegAsp and AF had numerically lower rates of nocturnal confirmed hypoglycaemia vs BIAsp 30 (RR: 0.33 (0.09; 1.14) and 0.66 (0.22; 1.93) respectively).

Conclusions: IDegAsp provided comparable overall glycaemic control to BIAsp 30 with a significantly lower rate of hypoglycaemia.

Trial registration: ClinicalTrials.gov NCT00613951.

Figures

Figure 1
Figure 1
Trial flow diagram. *One participant randomised to IDegAsp was excluded from the trial before receiving insulin treatment because of a serious adverse event (respiratory insufficiency); †fatal serious adverse event (cardiac failure); ‡non-compliance with protocol-specified dosing of study drug.
Figure 2
Figure 2
Mean HbA1c (A) and mean FPG (B) over time. Error bars show s.e.m.
Figure 3
Figure 3
(A) Percentage of subjects achieving HbA1c targets of

Figure 4

Cumulative number of confirmed hypoglycaemic…

Figure 4

Cumulative number of confirmed hypoglycaemic episodes (A), cumulative number of confirmed nocturnal hypoglycaemic…

Figure 4
Cumulative number of confirmed hypoglycaemic episodes (A), cumulative number of confirmed nocturnal hypoglycaemic episodes (B) and scatter plot of the time of occurrence of confirmed hypoglycaemic episodes (C).
Figure 4
Figure 4
Cumulative number of confirmed hypoglycaemic episodes (A), cumulative number of confirmed nocturnal hypoglycaemic episodes (B) and scatter plot of the time of occurrence of confirmed hypoglycaemic episodes (C).

References

    1. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203. doi: 10.2337/dc08-9025.
    1. Vaag A, Lund S. Insulin initiation in patients with type 2 diabetes mellitus: treatment guidelines, clinical evidence and patterns of use of basal vs premixed insulin analogues. European Journal of Endocrinology. 2012;166:159–170. doi: 10.1530/EJE-11-0022.
    1. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, Levy JC. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. New England Journal of Medicine. 2007;357:1716–1730. doi: 10.1056/NEJMoa075392.
    1. Stehouwer MH, DeVries JH, Lumeij JA, Ader HJ, Engbers AM, Iperen AA, Snoek FJ, Heine RJ. Combined bedtime insulin – daytime sulphonylurea regimen compared with two different daily insulin regimens in type 2 diabetes: effects on HbA1c and hypoglycaemia rate – a randomised trial. Diabetes/Metabolism Research and Reviews. 2003;19:148–152. doi: 10.1002/dmrr.356.
    1. Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH. Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clinical Therapeutics. 2004;26:2034–2044. doi: 10.1016/j.clinthera.2004.12.015.
    1. Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA, Hu P, Bode B, Garber A. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260–265. doi: 10.2337/diacare.28.2.260.
    1. Kazda C, Hulstrunk H, Helsberg K, Langer F, Forst T, Hanefeld M. Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy. Journal of Diabetes and its Complications. 2006;20:145–152. doi: 10.1016/j.jdiacomp.2005.09.004.
    1. Wolffenbuttel BH, Klaff LJ, Bhushan R, Fahrbach JL, Jiang H, Martin S. Initiating insulin therapy in elderly patients with type 2 diabetes: efficacy and safety of lispro mix 25 vs. basal insulin combined with oral glucose-lowering agents. Diabetic Medicine. 2009;26:1147–1155. doi: 10.1111/j.1464-5491.2009.02824.x.
    1. Strojek K, Bebakar WM, Khutsoane DT, Pesic M, Smahelova A, Thomsen HF, Kalra S. Once-daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: an open-label, multinational RCT. Current Medical Research and Opinion. 2009;25:2887–2894. doi: 10.1185/03007990903354674.
    1. Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal T, Hemmingsen C, Wetterslev J. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ. 2011;343:d6898. doi: 10.1136/bmj.d6898.
    1. Kurtzhals P, Heise T, Strauss HM, Bøttcher SG, Granhall C, Haahr H, Jonassen I. Multi-hexamer formation is the underlying basis for the ultra-long glucose-lowering effect of insulin degludec. Diabetologia. 2011;54:S426. doi: 10.1007/s00125-011-2276-4.
    1. Heise T, Hermanski L, Nosek L, Feldmann A, Rasmussen S, Stryhn TK, Haahr H. Insulin degludec: less pharmacodynamic variability than insulin glargine under steady state conditions. Diabetologia. 2010;53:S387. doi: 10.1007/s00125-010-1872-z.
    1. Heise T, Hermanski L, Nosek L, Feldmann A, Rasmussen S, Haahr H. The pharmacodynamic variability of insulin degludec is consistently lower than insulin glargine over 24 hours at steady state. Diabetes. 2011;60:A263. doi: 10.2337/db11-868-1281.
    1. Nosek L, Heise T, Bøttcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect. Diabetologia. 2011;54:S429. doi: 10.1007/s00125-011-2276-4.
    1. Birkeland KI, Home PD, Wendisch U, Ratner RE, Johansen T, Endahl LA, Lyby K, Jendle JH, Roberts AP, DeVries JH, Meneghini LF. Insulin degludec in type 1 diabetes a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine. Diabetes Care. 2011;34:661–665. doi: 10.2337/dc10-1925.
    1. Garber A, King AB, Del Prato S, Sreenan S, Rosenstock J, Endahl LA, Francisco AMO, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1498–1507. doi: 10.1016/S0140-6736(12)60205-0.
    1. Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Francisco AMO, Pei H, Bode B. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1489–1497. doi: 10.1016/S0140-6736(12)60204-9.
    1. Jonassen I, Hoeg-Jensen T, Havelund S, Ribel U. Ultra-long acting insulin degludec can be combined with rapid-acting insulin aspart in a soluble co-formulation. Journal of Peptide Science. 2010;16:32. doi: 10.1002/psc.1301.
    1. Lindholm A, Jensen LB, Home PD, Raskin P, Boehm BO, Rastam J. Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care. 2002;25:876–882. doi: 10.2337/diacare.25.5.876.
    1. Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, Parish T, Scott G, Shankar G, Shores E, Swanson SJ, Taniguchi G, Wierda D, Zuckerman LA. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. Journal of Immunological Methods. 2004;289:1–16. doi: 10.1016/j.jim.2004.06.002.
    1. Bulsara MK, Holman CD, Davis EA, Jones TW. Evaluating risk factors associated with severe hypoglycaemia in epidemiology studies – what method should we use? Diabetic Medicine. 2004;21:914–919. doi: 10.1111/j.1464-5491.2004.01250.x.
    1. Kann PH, Wascher T, Zackova V, Moeller J, Medding J, Szocs A, Mokan M, Mrevlje F, Regulski M. Starting insulin therapy in type 2 diabetes: twice-daily biphasic insulin aspart 30 plus metformin versus once-daily insulin glargine plus glimepiride. Experimental and Clinical Endocrinology & Diabetes. 2006;114:527–532. doi: 10.1055/s-2006-949655.
    1. Khutsoane D, Sharma SK, Almustafa M, Jang HC, Azar ST, Danciulescu R, Shestakova M, Ayad NM, Guler S, Bech OM. Biphasic insulin aspart 30 treatment improves glycaemic control in patients with type 2 diabetes in a clinical practice setting: experience from the PRESENT study. Diabetes, Obesity & Metabolism. 2008;10:212–222. doi: 10.1111/j.1463-1326.2007.00826.x.
    1. Valensi P, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, Shah S, Shestakova M, Wenying Y. Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study. International Journal of Clinical Practice. 2009;63:522–531. doi: 10.1111/j.1742-1241.2009.02002.x.
    1. Heise T, Tack CJ, Cuddihy R, Davidson J, Gouet D, Liebl A, Romero E, Mersebach H, Dykiel P, Jorde R. A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes a randomized, controlled trial. Diabetes Care. 2011;34:669–674. doi: 10.2337/dc10-1905.
    1. Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010;375:481–489. doi: 10.1016/S0140-6736(09)61969-3.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe