New insulins and insulin therapy

While the pharmacokinetic properties of the long-acting insulin analogues, insulin glargine and insulin detemir, clearly demonstrate clinical benefits over NPH insulin in terms of reduced frequency of overall and nocturnal hypoglycaemic events and lowered glycaemic variability, several new insulin analogues with even longer and smoother time-action profiles are being developed and explored. Among these, insulin degludec is the first to enter the market. The ultra-long action profile of this insulin analogue is mainly the result of a slow and stable release of insulin degludec monomers from soluble multihexamers that form after subcutaneous administration. In the last year, the results of the first phase II trials with insulin degludec have been published, where the efficacy and safety of this basal insulin analogue have been compared with insulin glargine in patients with type 1 (T1D) and type 2 (T2D) diabetes. With regard to short-acting insulins for mealtime insulin supplementation, there is also a search for new insulins with a more rapid onset of action, and hence improved postprandial glucose control. LinjetaTM (formerly named VIAject) is a human insulin formulation with faster insulin absorption and action than insulin lispro and regular human insulin. A new drug application to market LinjetaTM as a treatment for diabetes was submitted to the US Food and Drug Administration (FDA) by the manufacturer at the beginning of 2010. However, the FDA’s review cycle, which was announced late in 2010, concluded that the application could not be approved in its present form. The FDA’s complete response letter included comments related to clinical trials, statistical analysis and chemistry, manufacturing and controls. The FDA requested that the company should conduct two new phase III clinical trials using the commercial formulation, one in patients with T1D and the other in patients with T2D, to establish efficacy and safety with regard to hypoglycaemia and toleration. Co-administration of hyaluronidase together with insulin is another novel concept which has been proven to accelerate the absorption of both insulin lispro and regular human insulin in healthy subjects. In this review, we comment on two recent publications in which the pharmacokinetic and pharmacodynamic characteristics of LinjetaTM and co-formulations of prandial insulins with recombinant human hyaluronidase were investigated in patients with T1D. Lastly, a recent review on the ongoing discussion regarding insulin treatment and cancer risk is included. Birkeland KI 1 , Home PD 2 , Wendisch U 3 , Ratner RE 4 , Johansen T 5 , Endahl LA 5 , Lyby K 5 , Jendle JH 6 , Roberts AP 7 , DeVries JH 8 , Meneghini LF 9 1 Oslo University Hospital and Faculty of Medicine, Oslo, Norway, 2 Newcastle University, Newcastle upon Tyne, UK, 3 Group Practice in Internal Medicine and Diabetology, Hamburg, Germany, 4 Medstar Research Institute, Washington, DC, USA, 5 NovoNordisk A/S, Soeborg, Denmark, 6 Örebro University Hospital, Örebro, Sweden, 7 Royal Adelaide Hospital, Adelaide, SA, Australia, 8 University of Amsterdam, The Netherlands, and 9 University of Miami Miller School of Medicine, Miami, FL, USA Diabetes Care 2011; 34 : 661–5 Background: To investigate the efficacy and safety of two formulations of insulin degludec (IDeg), administered once daily together with mealtime insulin aspart in patients with T1D. Comparison was made with a similar basal-bolus regimen consisting of insulin glargine (IGlar) and aspart. Methods: Adult patients with T1D (mean A1c 8.4%) were randomised (open-label) to be treated for 16 weeks with once-daily (evening) subcutaneous injections of either of two different insulin degludec formulations, IDeg(A) (600 μmol/l; n = 59), IDeg(B) (900 μmol/l; n = 60), or with IGlar (n = 59). All patients received insulin aspart at mealtimes. Results: At 16 weeks, mean A1c was comparable for all three basal insulin therapies: IDeg(A) 7.8 ± 0.8%, IDeg(B) 8.0 ± 1.0% and IGlar 7.6 ± 0.8%.. Similarly, there was no difference in mean fasting plasma glucose across treatment groups (8.3 ± 4.0, 8.3 ± 2.8 and 8.9 ± 3.5 mmol/l, respectively). In comparison with IGlar, the estimated mean rate of confirmed hypoglycaemia (<3.1 mmol/l) was 28% lower for IDeg(A) [rate ratio (RR) 0.72, 95% confidence interval (CI) 0.52–1.00] and 10% lower for IDeg(B) [RR 0.90 (0.65–1.24)], and rates of nocturnal hypoglycaemia were reduced by 58% with IDeg(A) [RR 0.42 (0.25–0.69)] and by 29% with IDeg(B) [RR 0.71 (0.44–1.16)]. Mean total daily insulin doses remained essentially unchanged from baseline values in all treatment arms. The overall rates and nature of adverse events were comparable between groups. Conclusions: IDeg is a safe and well tolerated basal insulin in patients with T1D, providing comparable glycaemic control to IGlar at similar doses but with lower frequency of hypoglycaemia. Zinman B 1 , Fulcher G 2 , Rao PV 3 , Thomas N 4 , Endahl LA 5 , Johansen T 5 , Lindh R 5 , Lewin A 6 , Rosenstock J 7 , Pinget M 8 , Mathieu C 9 1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada, 2 Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia, 3 Nizam’s Institute of Medical Sciences University, Hyderabad, India, 4 Christian Medical College, Vellore, India, 5 Novo Nordisk, Soeborg, Denmark, 6 National Research Institute, Los Angeles, CA, USA, 7 Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA, 8 University Hospital Strasbourg, France, and 9 UZ Gasthuisberg Katholieke Universiteit Leuven, Leuven, Belgium Lancet 2011; 377 : 924–31 Background: To assess the efficacy and safety of insulin degludec administered once daily or three times a week in patients with T2D. Comparison was made with insulin glargine injected once daily. Methods: Insulin-naive patients with T2D (age 18–75 years), inadequately controlled with oral antidiabetic drugs (A1c 7%–11%), were eligible in this 16-week, multicentre, open-label trial. Sixty-two patients were randomised to administer insulin degludec (900 μmol/l) three times a week (starting dose 20 U per injection; 1 U = 9 nmol), 60 patients to receive insulin degludec (600 μmol/l) once daily (starting dose 10 U; 1 U = 6 nmol), 61 patients to receive insulin degludec (900 μmol/l) once daily (starting dose 10 U; 1 U = 9 nmol) and 62 to administer insulin glargine once daily (starting dose 10 U; 1 U = 6 nmol). All patients were on combination therapy with metformin. The primary outcome was HbA1c following 16 weeks of treatment. Results: At 16 weeks, the mean HbA1c values were comparable in the four treatment groups: 7.3% (SD 1.1), 7.4% (1.0), 7.5% (1.1) and 7.2% (0.9), respectively. The estimated mean HbA1c difference in comparison with insulin glargine was 0.08% (95% CI –0.23 to 0.40) for insulin degludec administered three times a week, and 0.17% (–0.15 to 0.48) and 0.28% (–0.04 to 0.59), respectively, for the 600 μmol/l and 900 μmol/l insulin degludec formulations given once daily. The overall rate of hypoglycaemic events was low, and the frequency and pattern of adverse events were similar across the treatment groups. Conclusions: Insulin degludec provides comparable glycaemic control and safety profile to insulin glargine in patients with T2D, and – according to its ultra-long action profile – it might allow prolonged dosing intervals. Heise T 1 , Tack CJ 2 , Cuddihy R 3 , Davidson J 4 , Gouet D 5 , Liebl A 6 , Romero E 7 , Mersebach H 8 , Dykiel P 8 , Jorde R 9 1 Profil Institut für Stoffwechselforschnung, Neuss, Germany, 2 Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 3 International Diabetes Center, Park Nicollet, Minneapolis, MA, USA, 4 Department of Medicine, Division of Endocrinology, University of Texas, Southwestern Medical School, Dallas, TX, USA, 5 Hopital Saint Louis, Centre Hospitalier de La Rochelle, La Rochelle, France, 6 Center for Diabetes and Meabolism, Fachklinik, Bad Heilbrunn, Germany, 7 University of Valladolid, Instituto de Endocrinologia y Nutricion, Valladolid, Spain, 8 Novo Nordisk A/S, Soeborg, Denmark, and 9 Institute of Clinical Medicine, University of Tromsoe, Tromsoe, Norway Diabetes Care 2011; 34 : 669–74 Background: To compare the safety and efficacy of two formulations of a soluble co-formulation of insulin degludec and insulin aspart (70%/30% v/v and 55%/45% v/v, respectively) and insulin glargine in insulin-naive patients with T2D inadequately controlled with oral antidiabetic drugs. Methods: Patients with T2D (mean age 59.1 years, A1c 8.5%, body mass index 30.3 kg/m2) were randomly allocated (open-label) to 16 weeks of treatment with once-daily injection (before evening meal) of insulin degludec/aspart 70/30 (n = 59), insulin/aspart 55/45 (n = 59), or insulin glargine (n = 60). All patients received combination therapy with metformin. Insulin doses were titrated to a fasting plasma glucose target of 4–6 mmol/l. Results: At 16 weeks, mean A1c had decreased to comparable levels across the treatment groups: insulin degludec/aspart 70/30 7.0%, insulin degludec/aspart 55/45 7.2% and insulin glargine 7.1%. There was a similar relative proportion of patients who improved their A1c below 7.0% without experiencing confirmed hypoglycaemia (plasma glucose < 3.1 mmol/l) over the last 4-week period of the trial (51%, 47% and 50% in the three treatment groups, respectively). Mean 2-h post-dinner plasma glucose increase was less prominent for insulin degludec/aspart 70/30 (0.13 mmol/l) and insulin degludec/aspart 55/45 (0.24 mmol/l) than for insulin glargine (1.63 mmol/l), whereas fasting plasma glucose was similar (6.8 mmol/l, 7.4 mmol/l and 7.0 mmol/l, respectively). Estimated rates of confirmed hypoglycaemic events were lower for insulin degludec/aspart 70/30 (1.2 events per patient-year) and insulin glargine (0.7 events per patient-year) than for insulin degludec/aspart 55/45 (2.4 events per patient year). Likewise, nocturnal hypoglycaemia occurred more frequently with insulin degludec/aspart 55/45 (27 events) than with insulin degludec/aspart 70/30 (1 event) and insulin glargine (3 events). Conclusions: The 70%/30% (v/v) co-formulation of insulin degludec and insulin aspart administered once daily provided comparable overall glycaemic control and hypoglycaemia rates compared with insulin glargine but better postprandial glucose control after dinner. Comment: Insulin degludec is a soluble, basal insulin analogue with a smooth and stable pharmacokinetic profile, with a duration of action exceeding 24 h (1) and with low within-subject variability (2). In the referenced reports, the safety and efficacy of different formulations of insulin degludec were compared with insulin glargine in short-term, proof-of-concept trials. In patients with T1D, once-daily injection of insulin degludec together with insulin aspart at mealtimes resulted in essentially the same glycaemic control as that observed when insulin glargine was used for basal insulin supplementation. The rates of confirmed hypoglycaemic episodes were lower for insulin degludec; this was most readily observed during night-time, and in those patients who were allocated to use the 600 μmol/l formulation of insulin degludec [according to the authors, the higher strength insulin degludec formulation (900 μmol/l) has therefore been discontinued from further clinical development]. Similarly, in patients with T2D, insulin degludec administered once daily as add-on to metformin did not differ from insulin glargine in terms of glycaemic control or risk of hypoglycaemia or other adverse events. Interestingly, demonstrating its prolonged duration of action, insulin degludec (900 μmol/l) also provided comparable glycaemic outcomes when given only three times a week, although with a tendency to more frequent hypoglycaemic episodes. The latter finding may have been due to the fact that approximately twice as much insulin was administered per injection when insulin degludec was given three times a week in comparison with the once-daily insulin regimens. Another intriguing feature of insulin degludec is that it can be co-formulated with a rapid-acting insulin analogue (pre-mixed insulin). In the study by Heise et al., the two tested formulations of insulin degludec and insulin aspart (relative proportions 70/30 and 55/45, respectively) injected once daily provided comparable overall glycaemic control to insulin glargine. The postprandial glucose excursion after dinner was less pronounced with the two insulin degludec formulations than with glargine. This was perhaps an expected finding, given the prandial, rapid-acting component of insulin aspart in these formulations. Notably, the rate of hypoglycaemic events, and especially the frequency of nocturnal hypoglycaemia, was considerably higher with the 55/45 degludec/aspart formulation. Based on this finding, the clinical development of this co-formulation has been stopped. In summary, the results of these phase 2 trials are promising and indicate that insulin degludec may allow more flexible insulin regimens with less frequent insulin injections in patients with T2D. Moreover, the findings suggest that insulin degludec may have the potential to further reduce the risk of hypoglycaemia, in particular in patients with T1D as well as in patients with T2D necessitating more complex insulin regimens. Additional data from longer term studies are much awaited to clarify in more detail the efficacy and safety characteristics and the potential clinical benefits of this novel basal insulin analogue. Philotheou A 1 , Arslanian S 2 , Blatniczky L 3 , Peterkova V 4 , Souhami E 5 , Danne T 6 1 University of Cape Town Diabetes Clinical Trials Unit, New Groote Schuur Hospital, Cape Town, South Africa, 2 Divisions of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, and Weight Management and Wellness, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 3 Buda Children’s Hospital, Budapest, Hungary, 4 Endocrinological Scientific Centre, Russian Academy of Science, Moscow, Russia, 5 Sanofi-aventis, Antony, France, and 6 Children’s Hospital auf der Bult, Hannover, Germany Diabetes Technol Ther 2011; 13 : 327–34 Background: To evaluate the efficacy and safety of insulin glulisine compared with insulin lispro as part of a basal-bolus regimen in children and adolescents with T1D. Methods: Children and adolescents aged 4–17 years (n = 572) using insulin glargine or NPH insulin as basal insulin were enrolled in a 26-week, multicentre, open, centrally randomised, parallel-group study. Subjects were randomised to receive glulisine (n = 277) or lispro (n = 295) 0–15 min before a meal. Results: Both groups exhibited similar A1c levels at baseline. The adjusted mean change in A1c from baseline to endpoint was+0.10 ± 0.08% in the glulisine group and +0.16 ± 0.07% in the lispro group. The difference in the adjusted means for the change from baseline in A1c between the treatments was equal to −0.06% (95% CI −0.24 to 0.12), confirming non-inferiority of glulisine vs. lispro. Similar effects on A1c levels were reported in both groups after 12 and 26 weeks. For all age groups, the percentage of subjects achieving the American Diabetes Association recommended A1c target was significantly higher (p = 0.039) with glulisine (38.4%) than with lispro (32.0%). This difference was most pronounced in adolescents (13–17 years). At baseline, the mean blood glucose profiles were comparable for all three time points in both groups. At endpoint, only the mean pre-breakfast blood glucose was significantly lower in the glulisine group. Most subjects had three to four bolus insulin injections at baseline, which remained stable throughout the study. No significant differences between the two treatment arms were reported for the monthly events rate per patient of all, severe, nocturnal, or severe nocturnal symptomatic hypoglycaemia from month 4 to treatment to endpoint for glulisine and lispro, respectively. Frequency and type of adverse events, serious adverse events, or hypoglycaemia reported as serious adverse events were similar between the groups. Conclusions: In children and adolescents withT1D, glulisine is non-inferior to lispro in terms of A1c change, and is similarly well tolerated to lispro. Heinemann L 1,2 , Hompesch M 2 , Flacke F 3 , Simms P 3 , Pohl R 3 , Albus K 3 , Pfützner A 4 , Steiner S 3 1 Profil Institut für Stoffwechselforschung, Neuss, Germany, 2 Profil Institute for Clinical Research Inc., San Diego, CA, USA, 3 Biodel Inc., Danbury, CT, USA, and 4 IKFE, Institute for Clinical Research and Development, Mainz, Germany J Diabetes Sci Technol 2011; 5 : 681–6 Background: To compare postprandial glucose control in patients with T1D following administration of VIAjectTM (LinjetaTM), insulin lispro and regular human insulin. Methods: On three occasions, and with normalised preprandial glucose control, patients (n = 18) received an individually tailored dose of each insulin immediately before a meal. Results: Insulin absorption was faster following injection of VIAjectTM than after administration of insulin lispro and human regular the time to insulin being ± ± 7.6 min and ± vs. insulin lispro = VIAjectTM vs. regular human insulin < and insulin lispro vs. regular human insulin < postprandial blood glucose was lower with VIAjectTM ± = and insulin lispro ± = compared with regular human insulin ± The difference between and glucose levels was after administration of VIAjectTM ± than after injection of either insulin lispro ± = or regular human insulin ± = and the the blood glucose was with VIAjectTM than with regular human insulin (p < Conclusions: The more rapid absorption of VIAjectTM results in less pronounced postprandial glucose Hompesch M 1 , 2 , L 1 , 2 1 Profil Institute for Clinical CA, USA, and 2 San Diego, CA, USA Diabetes Care 2011; 34 : Background: To assess the of of recombinant human hyaluronidase on and of insulin lispro and human regular insulin in patients with T1D. Methods: Patients (n = were given individually titrated doses of insulin lispro or human regular insulin with or without of before a meal. Results: With of the insulin by (p = for insulin lispro and by (p < for human regular compared with administration of the insulin without Mean blood glucose decreased 26 for insulin lispro (p = and 24 for human regular and the total postprandial glycaemic the for blood glucose were reduced by (p = and (p = for insulin lispro and human regular respectively. Frequency of hypoglycaemia was similar for insulin lispro with or without of whereas it was reduced when human regular insulin was administered together with Conclusions: Co-administration of with insulin lispro and human regular insulin resulted in insulin absorption and improved postprandial blood glucose control. Comment: The T1D study with rapid-acting insulin analogues to comparable efficacy in a comparison between lispro and However, it the all insulin analogues are or patient may using one over the Notably, the of the insulin analogues, patients to control of postprandial glucose there is a clinical for insulin formulations that are even more from the subcutaneous injection and the insulin LinjetaTM is a formulation of human insulin which of insulin. studies in healthy subjects have that LinjetaTM has a faster onset of action compared with regular human insulin and insulin lispro The study by Heinemann et similar findings in patients with T1D, and also that the faster rate of absorption of LinjetaTM is by a less pronounced increase in postprandial glucose the FDA studies to as The by Hompesch and another to accelerate the absorption of by of prandial insulins with For more than hyaluronidase has been as an to the absorption and of other injected This the of in the subcutaneous to of In the of the of a that of insulin and hence the rate of insulin absorption In the insulin are over a which their In the study in patients with T1D, of the absorption of both regular human insulin and insulin lispro, to a faster and insulin and a of the postprandial glucose While the findings are trials are to clarify the potential clinical of this of 1 , C 2 , C 3 , M 4 , D 5 , 6 , E 7 , J 8 1 Centre for Diabetes and Metabolism and Research Centre, Hospital, UK, 2 University Hospital La Spain, 3 Department of Research Centre, University Hospital of UK, 4 Medical University Hospital Mainz, Mainz, Germany, 5 Royal Hospital and University of UK, 6 Diabetes Novo Nordisk A/S, Novo Nordisk Denmark, 7 Diabetes Department of Medicine and Hospital, and 8 Department of University of Ther 2011; Background: The of insulin treatments the potential to cancer development and was in following of several studies this with the that diabetes might be to an of and was in to on this those diabetes and and those diabetes Methods: A was with who are in the of and insulin analogue and The were to present on with after each Results: studies have over the potential properties of insulin analogues, although and a of cancer 1 insulin properties as for with insulin However, of the is by the of and and by studies frequently to Most insulin analogues not differ in their response profile to human and for those that there are to potential clinical it is that new are that can better the clinical of in response profile vs. human insulin. Conclusions: more data to increase of this with and between and insulin Comment: This review the most recent on the insulin treatment and cancer the have to be with as the was by a company it a the the that in not allow on to this with patients to an has received for or and received from several received as a of from Diabetes and and received for from Diabetes and

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