Abstract
Introduction
I
In a new statement published online in May 2013, the European Medicines Agency (EMA) has concluded that insulin-glargine–containing medicines (Lantus, Optisulin, Sanofi) for diabetes do not show an increased risk of cancer, so the balance of the medicine's benefits and risks remains unchanged. In previous years, we have repeatedly commented on the issue of a potential link between insulin analogs and cancer. A series of four highly controversial epidemiological articles in Diabetologia had indicated this link as a possibility for glargine. In a response in 2011, the FDA updated the information about the safety of insulin glargine. In addition to the four published observational studies, the FDA had reviewed results from a five-year randomized trial comparing glargine to neutral protamine Hagedorn (NPH) insulin in individuals with type 2 diabetes. The results did not support an increased risk of cancer associated with Lantus in comparison to NPH insulin. In Europe, the Committee for Medicinal Products for Human Use (CHMP) requested that the Lantus-producer Sanofi provide further data; the company subsequently carried out further studies and submitted the results to the CHMP for review. The new data include results from two cohort studies. The first collected information from around 175,000 patients in Northern Europe treated with insulin glargine, human insulin, or combined insulin, while the other obtained data from approximately 140,000 patients in the United States. Both looked at the occurrence of breast, colorectal, and prostate cancer with various insulins. Also included in the review were results from a case–control study conducted in Canada, France, and the United Kingdom, comparing 775 patients with diabetes who had breast cancer with a control group of patients who had diabetes but did not have breast cancer, comparing insulin glargine with human insulin and other types of insulin. “Based on the assessment of the population-based studies, the CHMP concluded that overall the data did not indicate an increased risk of cancer with insulin glargine,” said the EMA. It notes also that “there is no known mechanism by which insulin glargine would cause cancer and that a cancer risk has not been seen in laboratory studies.” Particularly the last remark may raise some eyebrows as several cell culture models have indicated potential changes in the mitogenic properties of insulin analogs compared with human insulin, but the relevance of these observations for the human situation remains questionable. (1)
With regard to short-acting insulins for meal-time insulin supplementation, the patents will expire in the next few years for current “rapid-acting” insulins (humalog, aspart, glulisine), which means that those will also become more accessible for many more patients. At the same time, this serves as an incentive for the pharmaceutical industry to intensify efforts to create an ultra-rapid-acting insulin. A quicker insulin action would better match the rapid rise in blood sugar that follows meals (and better mimic the near immediate speed of the first-phase insulin response in nondiabetic people). A faster insulin would also be more convenient than current rapid-acting insulins, which in studies still deliver the best postprandial glucose control when taken before meals. Newer ultra-rapid-acting insulins could also be associated with less hypoglycemia (and thus potentially less weight gain). If these new insulins can drop blood glucose more quickly, patients would be less likely to stack insulin and have a lower risk for delayed hypoglycemia. Finally, development of an ultra-rapid-acting insulin may prove to be a critical step forward for the artificial pancreas, since closed-loop algorithms' ability to control glucose tightly is limited by the slow speed of available rapid-acting analogs.
All in all, this review demonstrates that also in 2013 significant advances in our understanding of new insulins have been made. As we comment on the recent trials, we are looking forward to the upcoming results of large clinical trials to identify patients that profit from these developments. However, even in the more affluent countries, the regulatory approval is no longer sufficient to secure reimbursement for these new insulins. In 2013, for the first time a newly developed insulin (Tresiba®) was not marketed in Germany in spite of approval by EMA. The overall German health policy development with new regulatory processes (called “AMNOG”) made it unlikely that reimbursement was achievable in the current situation, and thus Novo Nordisk refrained from market introduction.
Long-Acting Insulin Analogs: Insulin Degludec—Approved for Treatment of Type 1 and Type 2 Diabetes in Europe
Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): 2-year results of a randomized clinical trial
Bode BW1, Buse JB2, Fischer M3, Garg SK4, Marre M5, Merker L6, Renard E7, Russell Jones DL8, Hansen CT9, Rana A9, Heller SR10, on behalf of the BEGIN Basal-Bolus Type 1 Investigators
1Atlanta Diabetes Associates, Atlanta, GA; 2University of North Carolina School of Medicine, Chapel Hill, NC; 3Glasgow Royal Infirmary, Glasgow, United Kingdom; 4Barbara Davis Center of Childhood Diabetes, Aurora, CO; 5Bichat Claude Bernard Hospital, Paris, France; 6Diabetes and Nierenzentrum, Dormagen, Germany; 7Montpellier University Hospital, Montpellier, France; 8Royal Surrey County Hospital, Guilford, United Kingdom; 9Novo Nordisk A/S, Soeborg, Denmark; and 10University of Sheffield, United Kingdom
Diabet Med 2013 May 26: [Epub ahead of print]; DOI: 10/1111/dme.12243
Background
To compare the efficacy and safety of insulin degludec versus insulin glargine (both together with meal-time insulin aspart) in patients with type 1 diabetes over a 2-year period.
Methods
Open-label trial with a 1-year main study followed by a 1-year extension period. Patients were randomized to once-daily insulin degludec or insulin glargine and titrated to fasting plasma glucose levels of 3.9–4.9 mmol/L.
Results
The rate of nocturnal confirmed hypoglycemia (plasma glucose <3.1 mmol/L or severe episodes necessitating assistance) was 25% lower with insulin degludec than with insulin glargine (p=0.02), whereas rates of overall confirmed hypoglycemia, severe hypoglycemic episodes, and adverse events were similar between groups. Improvements in glycemic control (glycated hemoglobin and fasting plasma glucose) were comparable in the two groups. In the insulin degludec-treated patients this was achieved with 12% less basal and 9% less total daily insulin doses than in the insulin glargine-treated patients (p<0.01).
Conclusions
Long-term basal insulin supplementation with insulin degludec in patients with type 1 diabetes required lower insulin doses and reduced the risk for nocturnal hypoglycemia by 25% as compared with insulin glargine therapy.
Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension
Mathieu C1, Hollander P2, Miranda-Palma B3, Cooper J4, Franek E5, Russell-Jones D6, Larsen J7, Tamer SC7, Bain SC8
1UZ Gasthuisberg, KU Leuven, Leuven, Belgium; 2Baylor Endocrine Center, Dallas, TX; 3Miller School of Medicine, University of Miami, Miami, FL; 4Department of Medicine, Stavanger University Hospital, Stavanger, Norway; 5Central Clinical Hospital MSWiA and Medical Research Center, Polish Academy of Sciences, Warsaw, Poland; 6Royal Surrey County Hospital and University of Surrey, Guildford, United Kingdom; 7Novo Nordisk A/S, Soeborg, Denmark; and 8Institute of Life Sciences, Swansea University, Swansea, United Kingdom
J Clin Endocrinol Metab 2013;
Background
To evaluate the efficacy and safety of insulin degludec once daily with varying injection timing in patients with type 1 diabetes.
Methods
A 26-week, open-label, treat-to-target, noninferiority trial comparing forced flexible dosing of once-daily insulin degludec (injections given in fixed schedule with 8–40 hours between doses) with insulin degludec or insulin glargine given at a fixed time once daily. Thereafter, in a 26-week extension period, all patients randomized to insulin degludec were transferred to a free-flexible regimen (dosing of degludec allowed any time of the day) and compared with patients continuing on insulin glargine therapy.
Results
After the first 26-week period, reductions in mean glycated hemoglobin were similar in patients using forced flexible dosing of insulin degludec (−0.40%) or fixed dosing of insulin degludec (−0.41%) or glargine (−0.58%) (p=NS). The decrease in fasting plasma glucose was comparable with forced-flexible degludec and fixed insulin glargine dosing, whereas it was greater with fixed degludec (−2.54 mmol/L) than with forced-flexible degludec injections (−1.28 mmol/L) (p=0.021). At week 52, the free-flexible insulin degludec regimen resulted in similar mean glycated hemoglobin but with a more pronounced lowering of fasting plasma glucose (between-group difference −1.07 mmol/L, p=0.005) as compared with the insulin glargine therapy. Rates of overall confirmed hypoglycemia (plasma glucose <3.1 mmol/L or severe hypoglycemia) were comparable at week 26 and at week 52. At 26 weeks, nocturnal confirmed hypoglycemia with the forced-flexible degludec regimen was 37% lower than with fixed degludec (p=0.003) and 40% lower than with fixed glargine dosing (p=0.001). At 52 weeks, the rate of nocturnal confirmed hypoglycemia was 25% lower with free-flexible insulin degludec therapy than with insulin glargine.
Conclusions
Insulin degludec therapy in patients with type 1 diabetes allows variation of the daily administration timing without compromising glycemic control or safety, as compared with once-daily, fixed-time insulin degludec or glargine regimens. This may result in better adherence to basal insulin supplementation by permitting changes in injection time according to personal needs.
Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, open-label, treat-to-target trial
Hirsch IB1, Bode B2, Courreges J-P3, Dykiel P4, Franek E5, Hermansen K6, King A7, Mersebach H8, Davies M9
1University of Washington Medical Center–Roosevelt, Seattle, WA; 2Atlanta Diabetes Association, Atlanta, GA; 3Diabetology and Vascular Disease Unit, General Hospital, Narbonne, France; 4BioStat Degludec, Novo Nordisk A/S, Soeborg, Denmark; 5Department of Internal Diseases, Endocrinology and Diabetology, CSK MSWiA, and Medical Research Center, Polish Academy of Science, Warsaw, Poland; 6Department of Endocrinology and Metabolism MEA, Aarhus University Hospital, Aarhus, Denmark; 7Department of Endocrinology, Diabetes Care Center, Salinas, CA; 8Medical and Science Degludec, Novo Nordisk A/S, Soeborg, Denmark; and 9Department of Cardiovascular Sciences, University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
Diabetes Care 2012;
Background
To evaluate the efficacy and tolerability of a basal-bolus regimen consisting of a coformulation of insulin degludec and insulin aspart administered once daily at a main meal together with insulin aspart at the other meals (IDegAsp) in patients with type 1 diabetes. Comparison was made with a conventional basal-bolus therapy using insulin detemir and meal-time insulin aspart (IDet).
Methods
Multinational, parallel-group, open-label, treat-to-target trial, where 548 adult patients with type 1 diabetes (glycated hemoglobin 7.0–10.0%; body–mass index ≤35.0 kg/m2) were randomized 2:1 to IDegAsp or IDet regimens over a 26-week period. IDegAsp was administered with a meal, and IDet was given in the evening with the addition of a second, breakfast dose if required.
Results
Reductions in glycated hemoglobin were similar with IDegAsp (−0.75%) and IDet (−0.70%) regimens (estimated treatment difference IDegAsp minus IDet 0.05% [95% confidence interval (CI) −0.18 to 0.08]), confirming noninferiority for IDegAsp versus IDet. Rates of severe hypoglycemia (0.33 vs. 0.42 episodes/patient-year) and overall confirmed (plasma glucose <3.1 mmol/L) hypoglycemia (39.17 vs. 44.34 episodes/patient-year) were comparable between the IDegAsp and IDet groups. The rate of nocturnal confirmed hypoglycemia was 37% lower with IDegAsp than with IDet (3.71 and 5.72 episodes/patient-year, respectively; p<0.05). Weight gain was more pronounced with IDegAsp (2.3 kg) than with IDet (1.3 kg) (p<0.05). Despite achieving similar improvements in glycemic control, the total insulin dose was 13% lower in the IDegAsp group than in the IDet group (p<0.0001). No differences were observed between the two insulin regimens regarding health-related quality of life, safety parameters, or adverse events.
Conclusions
A basal-bolus insulin regimen comprised of a once-daily administration of an insulin degludec/insulin aspart coformulation at a main meal together with insulin aspart at the other meals improves glycemic control equally well and is noninferior to a conventional basal-bolus insulin therapy with once- or twice-daily injections of insulin detemir in combination with meal-time insulin aspart. In comparison with the IDet therapy, the IDegAsp regimen results in a reduced risk of nocturnal hypoglycemia and fewer daily insulin injections.
Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes. A 1-year randomized, treat-to-target trial (BEGIN Once Long)
Zinman B1, Philis-Tsimikas A2, Cariou B3, Handelsman Y4, Rodbard HW5, Johansen T6, Endahl L6, Mathieu C7, on behalf of the NN1250-3579 (BEGIN Once Long) trial investigators
1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; 2Scripps Whittier Diabetes Institute, La Jolla, CA; 3Clinique d'Endocrinologie, l'Institute du Thorax, CHU Nantes, France; 4Metabolic Institute of America, Tarzana, CA; 5Endocrine and Metabolic Consultants, Rockville, MD; 6Novo Nordisk A/S, Soeborg, Denmark; and 7UZ Leuven, University of Leuven, Belgium
Diabetes Care 2012;
Background
To compare the efficacy and safety of insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).
Methods
Parallel-group, randomized, open-label, treat-to-target trial. Adult patients with type 2 diabetes with inadequate glycemic control (A1C 7–10%) despite treatment with OADs were randomized 3:1 to once-daily basal insulin replacement with insulin degludec or insulin glargine in combination with metformin over 1 year. Insulin doses were titrated to attain prebreakfast plasma glucose of 3.9–4.9 mmol/L. Primary endpoint was validation of noninferiority of degludec versus glargine therapy in A1C reduction at study end (ITT-analysis).
Results
In total, 1,030 patients (mean age 59 years and baseline A1C 8.2%) were randomized to degludec (n=773) or glargine (n=257) therapy. The reduction in A1C was similar in the two groups (degludec −1.06%; glargine −1.19%) with an estimated treatment difference between degludec versus glargine of 0.09% (95% CI −0.04 to 0.22), confirming noninferiority. Total rates of confirmed hypoglycemic episodes (plasma glucose <3.1 mmol/L or severe hypoglycemia necessitating assistance) were comparable between the two groups (degludec 1.52 and glargine 1.85 episodes/patient-year of exposure, respectively). The rate of nocturnal confirmed hypoglycemia was generally low, but significantly lower with degludec than with glargine (0.25 and 0.39 episodes/patient-year of exposure, respectively; p=0.038). The relative proportion of patients achieving A1C below 7% without experiencing hypoglycemia was similar in the two groups. Mean total insulin doses at the end of the study period were comparable (degludec 0.59 and glargine 0.60 units/kg body weight, respectively). Relative proportion of adverse events was similar in both groups.
Conclusions
Insulin degludec and insulin glargine, both administered in a once-daily basal regimen together with metformin, provided comparable improvements in long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower frequency of nocturnal hypoglycemia with insulin degludec.
The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel group, treat-to-target trial in individuals with type 2 diabetes
Meneghini L1, Atkin SL2, Gough SCL3, Raz I4, Blonde L5, Shestakova M6, Bain S7, Johansen T8, Begtrup K8, Birkeland KI9, on behalf of the NN1250-3668 (BEGIN FLEX) trial investigators
1University of Miami Miller School of Medicine, Miami, FL; 2Michael White Diabetes Centre, Hull York Medical School, Hull, United Kingdom; 3Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom; 4Diabetes Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel; 5Ochsner Diabetes Research Unit, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA; 6Endocrinology Research Center, Moscow, Russian Federation; 7Abertawe Bro Morgannwg University Health Board, Singleton Hospital, Swansea, United Kingdom; 8Novo Nordisk A/S, Soeborg, Denmark; and 9Department of Endocrinology, Oslo University Hospital, and Faculty of Medicine, University of Oslo, Oslo, Norway
Diabetes Care 2013;
Background
To investigate the efficacy and safety of varying the time of administration of insulin degludec in patients with type 2 diabetes.
Methods
A 26-week, open-label, treat-to-target trial. Adult patients with type 2 diabetes either previously insulin-naïve and receiving treatment with OADs (A1C 7–11%) or patients with ongoing therapy with basal insulin±OADs (A1C 7–10%) were eligible and randomized to three parallel groups: (a) once-daily insulin degludec, administered in a varying way according to a prespecified dosing schedule with 8–40-hour intervals between each injection (n=229); (b) once-daily insulin degludec administered at the main evening meal (n=230); (c) once-daily insulin glargine given at the same time each day (n=230). The primary outcome was noninferiority of flexible degludec dosing to glargine therapy in terms of A1C reduction at study end.
Results
After 26 weeks, the reductions in A1C were comparable in all three study groups (flexible degludec −1.28%, standardized degludec −1.07%, and standardized glargine −1.26%, respectively). The estimated treatment difference of flexible degludec to glargine therapy was 0.04% (95% CI −0.12 to 0.20), demonstrating noninferiority. Rates of overall confirmed hypoglycemic events as well as rates of nocturnal confirmed hypoglycemia and adverse event profiles were comparable across the three study groups.
Conclusion
The timing of the once-daily injection of insulin degludec can be varied substantially from day to day without jeopardizing glycemic control or safety.
Low-volume insulin degludec 200 units/mL once daily improves glycemic control similar to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN LOW VOLUME trial
Gough SCL1, Bhargava A2, Jain R3, Mersebach H4, Rasmussen S4, Bergenstal RM5
1Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom; 2Iowa Diabetes and Endocrinology Center, Des Moines, IA; 3Aurora Advanced Healthcare, Milwaukee, WI; 4Novo Nordisk A/S, Soeborg, Denmark; and 5International Diabetes Center at Park Nicollet, Minneapolis, MN
Diabetes Care 2013 May 28: [Epub ahead of print]; DOI: 10.2337/dc12-2329
Background
A more concentrated formulation of insulin degludec (200 units/mL) has been developed that contains equal units of insulin in half the volume compared with the standard 100 units/mL formulation. In this study, the efficacy and safety of once-daily administration of the 200 units/mL formulation of degludec was compared with once-daily insulin glargine (100 units/mL) in insulin-naïve type 2 diabetes patients with insufficient glycemic control with oral antidiabetic drugs.
Methods
A 26-week, open-label, treat-to-target trial; 457 patients with type 2 diabetes (mean A1C 8.3%, fasting plasma glucose 9.6 mmol/L, and body mass index 32.4 kg/m2) were randomized to receive once-daily insulin degludec 200 units/mL or insulin glargine, both in combination with metformin with or without addition of a dipeptidyl peptidase-4 inhibitor. Insulin dose was initiated with 10 units/day, and titrated weekly to achieve self-measured fasting plasma glucose below 5 mmol/L.
Results
At the end of the study period, the reduction in A1C was almost identical in the two groups (−1.3%). The mean decrease in fasting plasma glucose was larger with insulin degludec 200 units/mL than with insulin glargine (−3.7 vs. −3.4 mmol/L, respectively; p<0.02). Rates of overall confirmed hypoglycemic episodes were similar with insulin degludec 200 units/mL and insulin glargine (1.22 vs. 1.42 episodes/patient-year, respectively); this was also the case with nocturnal confirmed hypoglycemia (0.18 vs. 0.28 events/patient-year, respectively). The mean daily insulin dose was 11% lower with degludec 200 units/mL than with glargine (p<0.05). Therapy with insulin degludec 200 units/mL was well tolerated, and the adverse event profile was comparable in the two groups.
Conclusion
In this treat-to-target trial, insulin therapy with degludec 200 units/mL resulted in comparable A1C reductions as glargine in insulin-naïve patients with type 2 diabetes, with a low rate of hypoglycemia.
In the molecular structure of degludec, the amino acid residue threonine in position B30 of the natural human insulin has been removed, and a 16-carbon fatty diacid has been coupled to lysine in position B29 via a glutamic acid spacer. By so doing, degludec forms soluble multihexamers after subcutaneous administration, which then slowly dissociate and results in a slow and stable release of degludec monomers into the circulation. Pharmacodynamic investigations in patients with type 1 and type 2 diabetes (2,3) have indeed shown that the glucose-lowering action of degludec is stable and flat, and that it extends for more than 40 hours with a terminal half-life at a steady state of approximately 25 hours. After once-daily administration, a steady state is achieved after about 3 days, and in patients with type 1 diabetes the day-to-day variability of the glucose-lowering effect of degludec at steady-state conditions is four times lower relative to that with insulin glargine.
In earlier chapters, we have reviewed the first series of published phase 2 and phase 3 trials, where the efficacy and safety of insulin degludec had been compared with insulin glargine in treat-to-target designed studies in adult patients with type 1 and type 2 diabetes. In short, the findings of those trials showed reduced rates of hypoglycemic events—and above all of nocturnal hypoglycemia—at comparable improvements in glycemic control (i.e., reductions in A1C). The study by Bode et al., which reports data from an extension period of a previously published phase 3 trial (4), suggests that the same apply after long-term (2-year) basal insulin replacement with degludec in type 1 diabetes. Perhaps not surprisingly, similar findings were observed in a meta-analysis of all phase 3 trials with once-daily degludec versus glargine and with durations of 26–52 weeks (5). In the type 1 diabetes population (two trials), the rate of self-reported, nocturnal confirmed episodes of hypoglycemia was 25% lower with degludec versus glargine, whereas the overall rate of hypoglycemia was comparable. In patients with type 2 diabetes (five trials), glargine therapy resulted in significant reductions in both total rates of hypoglycemia (17% lower) and nocturnal hypoglycemia (32% lower).
The ultra-long action profile of degludec should also allow less stringent timing of basal insulin administration from day to day. Accordingly, the study by Meneghini and co-workers, who tested this concept in a standardized way in patients with type 2 diabetes, showed that glycemic control or safety (i.e., risk of hypoglycemia) was not compromised despite very large dosing intervals between daily injections. Likewise, applying more flexible once-daily dosing of degludec in patients with type 1 diabetes resulted in similar improvement in glycemic control and less nocturnal hypoglycemia relative to insulin glargine administered at the same time every day, as showed in the study by Mathieu et al.
Another feature of degludec is that it can be mixed with short-acting insulins without the risk of forming hybrid hexamers and erratic pharmacokinetics/dynamics. Thus, a premixed insulin degludec/insulin aspart formulation has been developed (Ryzodeg®), consisting of 70% degludec and 30% aspart. The rationale was to create an action profile in which the prandial insulin profile of aspart is superimposed on the ultra-long-acting profile of degludec. This coformulation has previously been tested in a short-term, phase 2 trial in patients with type 2 diabetes and was proven to provide comparable glycemic control and lower risk of hypoglycemia, as compared with biphasic NPH/aspart-insulin (6). In the study by Hirsch and colleagues, similar findings were observed in patients with type 1 diabetes, where the premixed degludec/aspart formulation administered before the main meal together with prandial aspart at the other meals was compared with a basal-bolus regimen consisting of basal insulin replacement with insulin detemir given once or twice daily in combination with mealtime aspart. An obvious advantage with the use of the degludec/aspart coformulation is that fewer daily injections are needed. On the other hand, titration of the basal insulin replacement might prove more difficult, and fine-tuning of the prandial insulin dose according to variations in meal intake, physical activity, and so on, is not possible with a premixed insulin. Notably, in the trial by Hirsch et al., the proportion of patients achieving the preset targets of glycemic control was rather low (about ¼ with A1C below 7%).
Pegylated Insulin Lispro: Results of the First Phase 2 Clinical Trials
A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes
Bergenstal RM1, Rosenstock J2, Arakaki RF3, Prince MJ4, Qu Y4, Howey DC4, Jacober SJ4
1International Diabetes Center at Park Nicollet, Minneapolis, MN; 2Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX; 3University of Hawaii at Manoa, Honolulu, HI; and 4Eli Lilly and Company, Indianapolis, IN
Diabetes Care 2012;
Background
To compare the effect of LY2605541 versus insulin glargine on fasting blood glucose in patients with type 2 diabetes.
Methods
A 12-week, randomized, open-label, phase 2 trial. Patients with type 2 diabetes with A1C <10.5% and ongoing combination therapy with once-daily insulin (glargine or NPH) and metformin and/or sulphonylurea were eligible. During a lead-in period, all patients administered their basal insulin once daily in the morning. Thereafter, patients with glargine (n=248) or NPH (n=95) were randomized 2:1 to therapy with a daily morning dose of LY2605541 (n=195) or glargine (n=95). Insulin doses were titrated according to standardized algorithms, to achieve self-measured fasting blood glucose <5.6 mmol/L.
Results
At study end, laboratory-measured fasting plasma glucose was similar in the two groups (LY2605541 6.6±0.1 and glargine 6.5±0.2 mmol/L, respectively), and there was no difference in A1C (7.0±0.1% vs. 7.2±0.1%). Intraday blood glucose variability (standard deviation of self-measurements of blood glucose) was lower with LY2605541 (1.9±0.1 mmol/L) than with glargine (2.2±0.1 mmol/L)(p=0.031). LY2605541 therapy resulted in weight loss (−0.6±0.2 kg), whereas glargine was associated with weight gain (0.3±0.2 kg), the treatment difference being −0.8 kg (p=0.001). The rates of overall and nocturnal hypoglycemic events were similar in the two groups. However, when adjusting for baseline hypoglycemia, nocturnal hypoglycemia was reduced by 48% in LY2605541 patients (p=0.021). Adverse events were comparable across the groups. Alanine aminotransferase and aspartate aminotransferase levels were significantly higher with LY2605541 (p<0.001), albeit within the normal range.
Conclusions
Treatment with LY2605541 and glargine in patients with type 2 diabetes resulted in comparable glycemic control and overall hypoglycemia rates, but LY2605541 exhibited lower intraday glucose variability and reduced nocturnal hypoglycemia and weight loss relative to glargine.
Better glycemic control and weight loss with the novel long-acting basal insulin LY2605541 compared with insulin glargine in type 1 diabetes
Rosenstock J1, Bergenstal RM2, Blevins TC3, Morrow LA4, Prince MJ5, Qu Y5, Sinha VP5, Howey DC5, Jacober SJ5
1Dallas Diabetes and Endocrine Center at Medical City Dallas, Dallas, TX; 2International Diabetes Center at Park Nicollet, Minneapolis, MN; 3Texas Diabetes and Endocrinology, Austin, TX; 4Profil Institute for Clinical Research, Inc., Chula Vista, CA; and 5Eli Lilly and Company, Indianapolis, IN
Diabetes Care 2013;
Background
To compare effects of LY2605541 and insulin glargine as basal insulin replacement in a basal-bolus regimen on daily mean glucose control in patients with type 1 diabetes.
Methods
Randomized, phase 2, open-label, 2×2 crossover trial; 137 patients with type 1 diabetes were randomized to once-daily (pre-breakfast) LY2605541 or glargine plus meal-time insulin for 8 weeks, followed by crossover therapy for an additional 8-week period. Daily mean glucose was determined from 8-point profiles of self-monitored blood glucose. The noninferiority boundary was preset at 10.8 mg/dL.
Results
In comparison with insulin glargine, LY2605541 fulfilled noninferiority and superiority criteria in daily mean glucose (LY2605541 144.2 mg/dL and glargine 151.7 mg/dL, respectively); the least squares mean difference being −9.9 mg/dL ([90% CI −14.6 to −5.2 mg/dL], p<0.001). Reductions in fasting blood glucose variability and A1C were greater with LY2605541 than with glargine (p<0.001 for both parameters). Mealtime insulin dose was reduced with LY2605541 and increased with glargine. LY2605541 was associated with weight loss (on average −1.2 kg), and glargine with weight gain (0.7 kg) (p<0.001). The rate of overall hypoglycemia was higher with LY2605541 (p=0.04), whereas the rate of nocturnal hypoglycemia was lower (p=0.01) relative to glargine. Total adverse events (including severe hypoglycemic events) were comparable, but gastrointestinal-linked events were more frequently observed with LY2605541 (15% vs. 4%, p<0.001). Mean changes of liver enzymes (alanine aminotransferase and aspartate aminotransferase), triglycerides, and LDL-cholesterol were higher, and HDL cholesterol lower with LY2605541 than with glargine (p<0.02 for all parameters), although they were all within normal ranges.
Conclusions
Relative to glargine, replacement of basal insulin with LY2605541 in patients with type 1 diabetes resulted in better improvements in glycemic control, increased rate of overall hypoglycemia, but lower incidence of nocturnal hypoglycemia, weight loss, and reduced mealtime insulin doses.
LY2605541, developed by Lilly, is a novel long-acting insulin analog based on the polyethyleneglycol(PEG)-ylation principle. It consists of insulin lispro covalently modified with a 20 kDa PEG-unit attached to lysine at position B29. The large hydrodynamic size results in delayed insulin absorption from the subcutaneous depot and reduced renal clearance, and hence prolonged duration of action. It has also been speculated that the large functional size of the molecule might influence the tissue distribution, leading to a more hepatoselective mode of action. As reviewed (7), initial pharmacokinetic/dynamic studies with LY2605541 indicate a flat action profile with duration of more than 36 hours and with low variability.
From the first two published phase 2 trials in patients with type 1 and type 2 diabetes, it seems that basal insulin supplementation with LY2605541 results in similar or better glycemic control, lower glucose variability, and possibly a lower risk of nocturnal hypoglycemia, as compared with glargine. Moreover, weight loss was a consistent finding in both trials. With regard to safety, the underlying cause of the observed elevations in liver enzymes and triglycerides (albeit within normal levels) needs to be further explored; while these findings might be due to a more preferential hepatic action, potential hepatotoxic effects must be ruled out. Hopefully, additional data from longer-term trials will clarify in greater detail the benefits and safety aspects of this basal insulin analog.
Insulin Glargine Approved Down to 2 Years of Age
A randomized trial comparing the rate of hypoglycemia—assessed using continuous glucose monitoring—in 125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study)
Danne T1, Philotheou A2, Goldman D3, Guo X3, Ping L3, Cali A4, Johnston P3
1Kinder- und Jugendkrankenhaus “AUF DER BULT”, Hannover, Germany; 2Diabetes Clinical Trials Unit, UCT Private Academic Hospital, Cape Town, South Africa; 3Sanofi, Bridgewater, NJ; 4Sanofi, Paris, France
Pediatr Diabetes 2013 Jun 3: [Epub ahead of print]; DOI: 10.1111/pedi.12051
Background
Avoidance of hypoglycemia is a key consideration in treating young children with type 1 diabetes mellitus (T1DM). The objective of the study was to evaluate hypoglycemia with insulin glargine versus NPH insulin in young children, using continuous glucose monitoring (CGM).
Methods
Children aged 1 to <6 years treated with once-daily glargine versus once- or twice-daily NPH, with bolus insulin lispro/regular human insulin provided to all, were studied in a 24-week, multicenter, randomized, open-label study. Primary endpoint was event rate of composite hypoglycemia [symptomatic hypoglycemia, low CGM excursions (<3.9 mmol/L), or low fingerstick blood glucose (FSBG; <3.9 mmol/L)]. Noninferiority of glargine versus NPH was assessed for the primary endpoint.
Results
One hundred twenty-five patients (mean age, 4.2 years) were randomized to treatment (glargine, n=61; NPH, n=64). At baseline, mean HbA1c was 8.0% and 8.2% with glargine and NPH, respectively. Composite hypoglycemia episodes/100 patient-years were 1.93 for glargine and 1.69 for NPH; glargine noninferiority was not met. Events/100 patient-years of symptomatic hypoglycemia were 0.26 for glargine versus 0.33 for NPH; low CGM excursions 0.75 versus 0.72; and low FSBG 1.93 versus 1.68. There was a slight difference in between-group severe/nocturnal/severe nocturnal hypoglycemia and glycemic control. All glargine-treated patients received once-daily injections; on most study days, NPH-treated patients received twice-daily injections.
Conclusions
While glargine noninferiority was not achieved, in young children with T1DM there was a slight difference in hypoglycemia outcomes and glycemic control between glargine and NPH. Once-daily glargine may therefore be a feasible alternative to basal insulin in young populations for whom administering injections can be problematic.
PRESCHOOL is the largest prospective study to date investigating the occurrence of hypoglycemia in children with type 1 diabetes aged ≥1 to <6 years. The results appear confusing at first sight as a composite endpoint of various measures for hypoglycemia was used because of concerns regarding the statistical power in this difficult-to-recruit young population. It is common clinical knowledge that families introduced to a new insulin regimen test FSBG more frequently and are less likely to change the insulin dose. As more patients in the insulin glargine group had to switch to a new basal insulin regimen from their pretrial basal insulin, more FSBG was performed overall in this group. As a result, in the insulin glargine group, there were a greater number of low FSBG values, which were not recorded at times of low CGM excursions or symptomatic hypoglycemia signals, and thus glargine noninferiority was not achieved. In contrast, CGM monitoring is a more objective means of low blood glucose detection. It is thus independent of parental choice regarding when to check FSBG instinctively and may be influenced by other factors such as mealtimes, concern over new insulin regimens, or recent/upcoming periods of exercise. Investigation of hypoglycemia by CGM showed no significant difference between regimens in terms of confirmed low CGM. CGM therefore should be the preferred means to study hypoglycemia when CGM also permits an accurate assessment of daily blood glucose variability.
Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes
Bolli GB1, Hahn AD2, Schmidt R2, Eisenblaetter T2, Dahmen R2, Heise T3, Becker RH2
1Department of Internal Medicine, University of Perugia, Perugia, Italy; 2Sanofi-Aventis, Frankfurt/Main, Germany; 3Profil Institut für Stoffwechselforschung, Neuss, Germany
Diabetes Care 2012;
Objective
In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects.
Methods
Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units/kg glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng/mL (33 pmol/L) per analyte.
Results
Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve (AUC) between time of dosing and 30 hours after dosing [AUC (0–30 hours)] was 1,261 (66), 2,867 (35), and 4,693 (22) pmol/h/L at doses of 0.3, 0.6, and 1.2 units/kg, respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC (0–30 hours) of the glucose infusion rate after glargine administration (r=0.74; p<0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points.
Conclusions
After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine.
Since M2 levels were also below the level of detection, it was concluded that M1, and not glargine itself, mediated the glucodynamic effects. In vivo, insulin glargine is rapidly cleaved into its metabolites, both of which have lower metabolic and similar mitogenic potencies to human insulin. This may serve as additional evidence for the safety of glargine, as the absence of insulin glargine from the circulation after subcutaneous injection questions the relevance of the in vitro findings of enhanced IGF-1 binding and mitogenicity.
The Quest for Ultra-Fast Mealtime Insulin Action
A T3R3 hexamer of the human insulin variant B28Asp
Palmieri LC1, Fávero-Retto MP1,2,3, Lourenço D4, Lima LM1,4,5
1School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 2Brazilian National Cancer Institute (INCA), 20230-014, Rio de Janeiro, RJ, Brazil; 3Brazilian National Institute of Traumatology and Orthopedics (INTO), Rio de Janeiro, RJ, Brazil; 4Laboratory for Biotechnology (LaBio-DIPRO), Brazilian National Institute of Metrology, Quality and Technology–INMETRO, Rio de Janeiro, Brazil; 5National Institute of Science and Technology for Structural Biology and Bioimaging (INBEB-INCT), Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil
Biophys Chem 2013;
Abstract
Insulin shows a complex equilibrium between monomers and hexamers, involving varying conformers and association states. We sought to perform a structural characterization of the fast-acting human insulin variant B28Asp (“aspart”). Small-angle X-ray scattering measurements reveal similar globular behavior in both the aspart and regular human insulin, with an Rg of 19Å and a Dmax of approximately 50Å, indicating similar mean quaternary assembly distribution. Crystallographic assays revealed a T3R3 assembly of the aspart insulin formed by the TR dimer in the asymmetric unit, with all the first 8 residues of the B chain in the R-state monomer in helical conformation and the participation of its B3Asn in the stabilization of the hexamer. Our data provide access to novel structural information on aspart insulin such as an aspart insulin dimer in solution, the aspart insulin in T conformation and a pure R-state conformer establishing a T3R3 assembly, providing further insight on the stepwise conformational transition and assembly of this fast insulin.
A review of a family of ultra-rapid-acting insulins: formulation development
Krasner A1, Pohl R1, Simms P1, Pichotta P1, Hauser R1, De Souza E1
1Biodel Inc., Danbury, CT
J Diabetes Sci Technol 2012;
Abstract
This review summarizes the clinical development of a family of ultra-rapid-acting recombinant human insulin formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize insulin hexamers. In addition, insulin monomer surface charges are chemically masked with citrate to prevent reaggregation. The first phase 1 trials were performed using BIOD-090, an acidic 25 U/mL insulin formulation, which contained disodium-EDTA (NaEDTA). When compared with regular human insulin (RHI) and/or insulin lispro in multiple phase 1 studies, BIOD-090 consistently showed more rapid absorption and/or onset of action. A standard meal challenge study also demonstrated improved postprandial glucose profiles associated with BIOD-090. However, increased patient exposure in larger phase 3 trials showed that this formulation was associated with an increased incidence of local injection site reactions, most commonly pain. A next-generation formulation, BIOD-100, contained the same excipients as a standard insulin concentration of 100 U/mL. BIOD-100 maintained an ultra-rapid action profile and was associated with modest but significantly improved toleration when compared with BIOD-090. In order to further improve toleration, the hypothesis that NaEDTA contributed to discomfort by chelating endogenous calcium was tested by either substituting calcium-EDTA for NaEDTA or by adding calcium chloride to the NaEDTA formulation. These calcium formulations essentially eliminated the excess discomfort associated with BIOD-090 but were associated with less optimal pharmacokinetic profiles in humans. Recent efforts have succeeded in developing ultra-rapid-acting human insulin formulations with acceptable injection site toleration by optimizing concentrations of calcium (BIOD-125) and with the use of magnesium sulfate to mitigate discomfort (BIOD-123). Similar formulation technology has also been shown to accelerate absorption of insulin analogs in animal models.
Ultra-rapid absorption of recombinant human insulin induced by zinc chelation and surface charge masking
Pohl R1, Hauser R1, Li M1, De Souza E1, Feldstein R1, Seibert R1, Ozhan K2, Kashyap N3, Steiner S4
1Biodel Inc., Danbury, CT; 2Louisiana State University, Baton Rouge, Louisiana; 3Pii, Hunt Valley, Maryland; 4Steiner Ventures, Mt. Kisco, NY
J Diabetes Sci Technol 2012;
Background
In order to enhance the absorption of insulin following subcutaneous injection, excipients were selected to hasten the dissociation rate of insulin hexamers and reduce their tendency to reassociate postinjection. A novel formulation of recombinant human insulin containing citrate and disodium ethylenediaminetetraacetic acid (EDTA) has been tested in clinic and has a very rapid onset of action in patients with diabetes. In order to understand the basis for the rapid insulin absorption, in vitro experiments using analytical ultracentrifugation, protein charge assessment, and light scattering have been performed with this novel human insulin formulation and compared with a commercially available insulin formulation (RHI).
Method
Analytical ultracentrifugation and dynamic light scattering were used to infer the relative distributions of insulin monomers, dimers, and hexamers in the formulations. Electrical resistance of the insulin solutions characterized the overall net surface charge on the insulin complexes in solution.
Results
The results of these experiments demonstrate that the zinc chelating (disodium EDTA) and charge-masking (citrate) excipients used in the formulation changed the properties of RHI in solution, making it dissociate more rapidly into smaller, charge-masked monomer/dimer units, which are twice as rapidly absorbed following subcutaneous injection than RHI (Tmax 60±43 vs. 120±70 min).
Conclusions
The combination of rapid dissociation of insulin hexamers upon dilution due to the zinc chelating effects of disodium EDTA followed by the inhibition of insulin monomer/dimer reassociation due to the charge-masking effects of citrate provide the basis for the ultra-rapid absorption of this novel insulin formulation.
Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase
Morrow L1, Muchmore DB2, Hompesch M1, Ludington EA2, Vaughn DE2
1Profil Institute for Clinical Research, Chula Vista, CA; 2Halozyme Therapeutics, San Diego, CA
Diabetes Care 2013;
Objective
To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20).
Research Design and Methods
This double-blind, six-way, crossover, euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20.
Results
The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123–131 min and 50% total glucose infused at 183–186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71–79 min and 50% glucose infused at 127–140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 hours, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action.
Conclusions
Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action.
Just as last year the current progress on new basal insulins was already on the horizon, this year indicates imminent progress in speeding up the insulin action for prandial insulin. Although presently no full articles on clinical studies are available yet, the announcement of Novo in December 2012 that it will advance FIAsp, an ultra-rapid-acting version of Novolog (insulin aspart), directly into phase 3 trials in late 2013 is of particular interest. The protocols are announced on
In contrast, Halozyme is also attempting to produce faster-acting insulin by adding an enzyme (rHuPH20) that would temporarily degrade connective tissue in the skin, allowing insulin to be absorbed more quickly. Another approach to subcutaneous injection of rHuPH20 described in the article above will test an injection of rHuPH20 before inserting an insulin pump infusion set (“preadministration”). As mealtime insulin administration leaves a lot to be desired, all of these approaches may hold a great potential benefit to patients if long-term effectivity and safety can be established.
Author Disclosure Statement
T.D. has been a speaker on an advisory panel and has research support from AstraZeneca, Bayer, Bristol-Myers Squibb, DexCom, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Medtronic, NovoNordisk, Roche, Sanofi, Unomedical, Ypsomed and holds no stocks. J.B. has received consulting and/or lecture fees from Abbott Diabetes Care, AstraZeneca, Sanofi-Aventis and Merck Sharp & Dohme.